Hoi Tim Mach

HOI NGH TIM M CH MIEN TRUNG M RONG LAN TH V
I. T NG QUAN
KHUY N CO M I C A AHA/ACCF/HRS V CH N ON I N TM
Hunh Vn Minh, Nguy n Vn i n Hong Anh Ti n Tr ng i h c Y D c Hu i n tm l m t phng ti n c n lm sng tng i n gi n nhng tnh hi u qu cao trong ch n on b nh l tim m ch. Vi c khai thc ti m l c ch n on c a i n tm l c n thi t trong th c t nhi u lc qu l m d ng i n tm trong ch n on b nh. Nhi u k t qu c i n tm khng ni ln c s bi n i b t th ng m ch l m t ch n on c a bnh nh suy tim, b nh ng m ch vnh, thi u nng vnhho c l nh ng m t theo ngh ring khng theo quy c nh t nh, ho c theo nh ng thu t ng qu c khng cn ph n nh c b n ch t c a s bi n i v b nh h c. Tr c nh ng th c ti n 3 t ch c tim m ch l n l Hi p H i Tim M ch Hoa K, Tr ng Mn Tim M ch Hoa K v H i Nh p H c (vi t t c l AHA/ACCF/HRS) ph i h p, xu t khuy n co m i v ch n on i n tm nm 2009, bao g m cc v n sau: 1. Quy nh v thu t ng ch n on i n tm 2. Quy nh v tiu chu n ch n on i n tm Nh m thay i quan i m, cch ti p c n, thu t ng , tiu chu n ch n on, c tnh nh t qun khi ti p c n ch n on i n tm . hi u r tnh i m i c a khuy n co chng ti ti p t c phn tch c th cc tiu i m trn. I. KHUY N CO NM 2009 C A AHA/ACCF/HRS V THU T NG CH N ON I N TM Thu t ng trong ch n on thnh 2 ph n bao g m 117 ch n on m t i n g m 14 m c (b ng 1) v thu t ng ch n on b nh l th pht lm bi n i tm i n tm . 1. Thu t ng ch n on m t i n tm - R i lo n nh p M t s thu t ng ch n on trong r i lo n nh p c thay i b sung hay b i do khng cn ph h p cho ch n on nh sau: + Khng nn ch n on bl c xoang nh III + Bl c d n truy n trong tim khng nn ch n on bl c ph i h p nh bl c 2 b, bl c 3 b v khng ph n nh ng b n ch t c a t n thng gi i ph u c a h th ng d n truy n. + Khuy n co cn tch bl c d n truy n 2:1 thnh m t nhm ring, khng ghp chung bl c t l 2:1 vo trong nhm bl c II Mobitz 2 nh tr c y. + M t thu t ng bl c m i c a vo l bl c do ti n kch thch, khng nn ch n on h i ch ng ti n kch thch trn i n tm . V H i ch ng ti n kch thch l ph i h p nhi u ki u r i lo n d n tuy n nh th t v thu t ng c tnh ch t b nh h c ch khng ph i l ch n on c a i n tm . + Khng phn bi t c nh p nhanh c QRS h p l trn th t hay th t th nn ch n on nh p nhanh c QRS h p.
+ Khng phn bi t c nh p nhanh c QRS r ng l trn th t hay th t th nn ch n on nh p nhanh c QRS r ng. - B nh l c tim Do s pht tri n c a m t s cng c thm d tim m ch nn m t s thu t ng khng ph n nh c b n ch t c a s bi n i, nn trong ch n on i n tm c a b nh l c tim c thay i: + Khng nn ch n on dy th t tri m ph i thay th b ng thu t ng ph i th t tri. Trong ch n on ph i th t trn i n tm khng nn ch n on ph i th t tri tm thu hay ph i th t tri tm trng, do s bi n i c a sng T do nhi u nguyn nhn khc nhau nn khng ph n nh ton di n c a ph i c tim. B ng 1:
2. Thu t ng ch n on b nh l - Bi n i i n tim do th pht c a m t s b nh l t o nn c th dng trong ch n on i n tm : B ng 2:
Thu t ng ny c chia thnh thnh 2 nhm: thu t ng khuyn dng (mi tn lin t c) v nhm c n ph i cn nh c khi dng (mi tn khng lin t c). 3. Thu t ng m t m c c a bi n i i n tm B ng 3:
4. Khuy n co v B ng 4:
nh gi so snh s bi n
i c a i n tm
hi n t i v tr c y.
5. Nguyn t c chung c a ch n on i n tm B ng 5:
6. Nguyn t c ch n on ghp i gi a m t v ch n on b nh nguyn B ng 6:
7. M t s cch ch n on theo thi quen c th ch p nh n B ng 7:
8. Nguyn t c ghp i gi a thu t ng ch n on m t v thu t ng ch m c B ng 8:
II. KHUY N CO NM 2009 C A AHA/ACCF/HRS V TIU CHU N CH N ON I N TM 1. Tiu chu n v r i lo n nh p tim - R i lo n d n truy n trong th t Tiu chu n c a bl c trong ti n kch thch th t khng nn p d ng cho ng d n truy n ph ki u Mahaim, v vi c ch n on ng ph Mahaim l khng xc nh r b m t trn i n tm Bl c ki u Brugada l s d n truy n khng hon ton V1 km ST bi n i khng nn a vo ch n on bl c khng hon ton v bi u hi n c a i n tm d ng Brugada l 3 type khc nhau nn kh xc nh. Khi ni m m i trong bl c l bl c trong nh i mu th ng tm m c xu t hi n sng Q chuy n o vng sau v bn (I, II, III, aVF, aVL) v bl c trong thi u mu th ng tm m c khi xu t hi n thong qua QRS gin r ng v ST chnh xu ng vng t n thng c p tnh. B ng 9: Tiu chu n Bl c d n truy n trong tim Lo i bl c Tiu chu n Bl c nhnh ph i khng hon ton c QRS t 110-120ms ng i l n, 90-100ms tr t 4-16 tu i v 86-90ms tr d i 8 tu i, cc tiu chu n khc gi ng v i tiu chu n bl c cnh ph i. nh ng ng i c b nh tim m ch th bl c nhnh ph i khng hon ton l V1
Bl c nhnh ph i khng hon ton
Bl c nhnh ph i hon ton
Bl c nhnh tri khng hon ton
Bl c nhnh tri hon ton
c r < 20ms. Tiu chu n ch n on rsr V1 khng c gi tr ch n on. + QRS > 120ms ng i l n, >100ms tr 416tu i, >90ms tr < 4 tu i + rsr, rsR ho c rSR V1, V2. Sng R ho c r th ng r ng hn R u tin. R c mc xu t hi n V1 hay V2. + Sng S di hn sng R 40ms trong I v V6 ng i l n. + Th i gian u QRS n nh sng R V5 v V6 l n hn V1 50ms. Trong 4 tiu chu n trn 3 tiu chu n u tin dng ch n on. Khi sng R khng c mc th nn dng tiu chu n 4. + Th i gian QRS l 110-119ms ng i l n, 90-100ms tr em 8-16 tu i v 80-90ms tr nh hn 8 tu i. + Xu t hi n ki u i n tim ph i th t tri V4, V5, V6 th i gian t u QRS n + nh sng R l 60ms + Khng th y sng q chuy n o I, V5, V6. + QRS ko di > 120ms ng i l n, > 100ms tr 4-16 tu i v 90ms tr d i 4 tu i. + sng R c mc chuy n o I, aVL, V5 v V5, V6 khng c QRS V6 v d ng RS chuy n ti p. + Khng th y q I, V5, V6 nhng c q h p aVL m khng ph i nh i mu. + nhnh n i i n >60ms chuy n o V5, V6 nhng V1, V2, V3 th bnh th ng. Sng r th y xu t hi n chuy n o vng d i tim. + ST v T o ng c so v i QRS + T dng trong chuy n o c QRS dng + ST chnh xu ng ho c T m nh ng chuy n o c QRS m l b t th ng + Bi n i tr c c a i n tim
Cc tiu chu n v r i lo n nh p tim khc khng thay i ch thay i danh php trong ch n on ( trnh by ph n I) 2. Tiu chu n v b nh l c tim - Dy nh Sng P ch dng ch n on xc nh cho s b t th ng c a nh ph i hay nh tri, hn l ch n on nh ph i l n, ph i nh, tng gnh nh. Khi ch n on c s b t th ng c a nh nn ph i h p nhi u tiu chu n ch n on.
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Tiu chu n ko di d n truy n trong nh c n c ch tr ng v tiu chu n ny ph n nh ng m c s b t th ng c a nh. - Ph i th t Th i gian QRS r t c gi tr ch n on ph i th t o n ST-T chnh khng c ngha trong ch n on ph i th t. B t th ng nh tri: m t s tr ng h p ph i th t tri c lin quan n bi n b t th ng nh tri, s lin quan ny c gi tr khi ph i th t c bl c nhnh. Tr c QRS dng h tr thm trong ch n on nhng khng c gi tr trong ch n on quy t nh QT ko di: khi ph i th t tng kh i l ng c th t th QT s ko di trn i n tm , nhng ng c l i QT ko di g p trn nhi u b nh l khc nhau, nn y ch l tiu chu n tin l ng. Hi n di n c a bl c d n truy n trong tim: Ph i th t ph i h p bl c nhnh tri c n ph i cn nh c khng nn c ch n on c n ph i lm thm m t s thm d khc nh siu m tim c k t qu ch n on t hn. B ng 10: Cc tiu chu n ph Ch s R cao V1 T l R:S V1 S su V5 S su V6 R cao aVR S nh V1 R nh V5,6 Gi m t l R:S V5 Gi m t l R:S V6 Gi m t l R:S V5 n V6 (R I + S III) (S I + R III) Rl n V1,2 + Snh I, aVL-SV1 RV1+ S V5,6 R nh n V1(QRS <0,12s) QR V1 Tiu chu n ph RSR V1(QRS<0,12s) S>R I, II, III S I v Q III R:S V1 > R:S V3,4 T m V1 n V1 P II bin i th t ph i theo cc tc gi (khuy n co (2009) c a AHA/ACCF/HRS) [1] Bin >6mm >1.0 >10mm >3mm >4mm <2mm <3mm <0,75mm <0,4mm <0,04mm >15mm >6mm >10,5mm >0,035s C C C C C C >2,5mm Tc gi nghin c u u tin Myers Myers Myers Myers Sokolow Myers Myers Myers Myers Sokolow Lewis Butler Sokolow Myer Myer Nm 1948 1948 1948 1948 1949 1948 1948 1948 1948 1949 1914 1986 1949 1948 1948
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1mm=0,1mV
12
B ng 11: Cc tiu chu n ph
i th t tri theo cc tc gi (khuy n co (2009) c a AHA/ACCF/HRS) [1] i n th Tc gi nghin c u u tin Lewis Gubner Gubner Sokolow Goldberger Schack Romhit Wilson Mazzoleni Sokolow Romhite Murphy Gant Gant Holt McPhie Wolff Wilson Wilson Manning Manning Casale Casale Siegel Nm
i n th chuy n R I + S III RI R aVL R aVF Q ho c S aVR
o chi >16mm > 25mm >15mm >11mm >20mm >19mm o chi b t k >19mm >23mm >25mm >35mm >45mm >35mm >40mm o ng c b t k o ng c b t k >35mm >1.0 >26mm >45mm >33mm >25mm >59mm >93mm >28mm >20mm o >175mm o tr c tim 1944 1964 1949 1969 1984 1957 1957 1962 1958 1956 1944 1944 1964 1964 1985 1985 1982 1914 1943 1943 1949 1949 1950 1968
(R I S I) + (S III R III)
R + S m t chuy n i n th chuy n S V1 S V2 S V1 + R V5 S V2 + R V5,6 S V1,2 + R V5,6 S V1,2 + R V5 S+R m t chuy n R V5 : R V6 R m t chuy n S V2 + R V4,5 R V5 R V6
K t h p i n th chi v tr c tim RS aVF +V2+V6 (> 30 tu i) RS aVF +V2+V6 (< 30 tu i) S V3 + R aVL (nam) S V3 + R aVL (n ) T ng i n th 12 chuy n K t h p i n th v khng i n th
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i n th -STT-nh tri-Tr c QRS (R aVL + S V2) x th i gian QRS (T ng i n th 12 C ) x QRS (s) Tiu chu n c bl c nhnh tri tr c S V1 + R V5 + S V5 S V1,2 + R V6 + S V5 S III+ max R/S chuy n (nam) S III+ max R/S chuy n Tiu chu n ph Max R/S chuy n tri) S V1 R V5,6 S III+maxR/S chuy n tri) RI o ng c(tr c o b t k
i m >2436mm/s >1742mm/s >25mm >25mm >30mm >28mm >29mm >2mm >15mm >40mm >11mm
Romhit Molly Molly Bozzi Bozzi Gertsch Gertsch Vandenberg Vandenberg Vandenberg Vandenberg Vandenberg
1968 1992 1992 1976 1976 1988 1988 1991 1991 1991 1991 1991
o b t k (n )
i c bl c nhnh ph i o tr c tim (tr c
1mm = 0,1mV C : chuy n o - Thi u mu v nh i mu c tim B ng 12: Tiu chu n bi n i ST trong thi u mu c tim Ch s V tr thm d chuy n o Tiu chu n 12 chuy n o - Nam >40 tu i ST chnh ln 0,2mV V2, V3 v 0,1mV cc chuy n o khc. - Nam<40 tu i ST chnh 0,25mV V2, V3 - N ST chnh 1,5mV V2, V3 v 0,1mV cc chuy n o khc - Chung cho c 2 gi i 30 tu i ST chnh V3R, V4R 0,05mV v 30 tu i ST chnh 0,1mV. V7 n V9 ST chnh ln 0,05mV. - Chung c 2 gi i ST chnh xu ng c ngha 0,05mV V2, V3 v 0,1mV cc chuy n o khc - Khi ST chnh xu ng >0,1mV trn 8 chuy n o, k t h p v i ST chnh ln aVR ho c V1, kh nng t n thng nhi u nhnh ng m ch vnh ho c t c thn chung c a ng m ch vnh tri c ngha.
Tiu chu n
chnh ST
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Cc chuy n thm Bi n
o c n thm d V3R, V4R khi ST chnh ln >0,1mV II, III, aVF Sng T o ng c v i QT ko di c n ch n on i sng T phn bi t v i sng T trong xu t huy t n i so g n y (CVA: Cerebrovascular Accident).
3. Tiu chu n hnh thi c a cc sng trn i n tm - o n ST-T: + S bi n i ST-T c n phn bi t b t th ng ti c c nguyn pht hay th pht. N u ko di ti c c m khng bi n i kh c c l b t th ng ti c c nguyn pht.Ng c l i b t th ng xu t hi n giai o n kh c c th t nh ko di th i gian QRS, thay i hnh d ng QRS, l nh ng bi n i ti c c th pht. + M t s tr ng h p k t h p c 2 s bi n i ti c c do nguyn pht v th pht. + Ch o n ST chnh ph thu c v tu i v gi i - Sng T: + Khi c i n tm m t sng T c n k t h p v i s m t o n ST + C n qua st s bi n i sng T cc chu k tim pht hi n s lun phin i n h c c a sng T - Sng U: + Ch khi sng U o ng c, sng U trng ln sng T ho c bin sng U l n hn sng T. 4. Khuy n co v m t s tiu chu n c n ti p t c nghin c u trong tng lai M t s tiu chu n c n nghin c u b sung trong m t s tr ng h p ch n on i n tm : (1) C n tri n khai nhi u nghin c u xc nh tiu chu n ch n on i n tm theo t ng tu i. (2) Ti p t c nghin c u s lin quan gi a bi n i ST-T trong ph i th t tri, tiu chu n c a ph i th t tri. trong m t s tr ng h p khng h i (3) Cc tiu chu n i n th , tr c, ko di QRS, b t th ng nh tri c n c nghin c u b sung trong ch n on ph i th t tri km bl c (4) tr em c n nghin c u thm m t s chuy n o thm d m i. (5) Nghin c u bi n i i n th QRS theo th i gian trong ph i th t tri. III. K T LU N 1. Ch n on i n tm nn theo danh php quy nh c 2. C th ph i h p cc danh php ch n on khai thc on c a i n tm (b ng 6, 8). 3. Nn theo th t 6 nguyn t c quy nh trong ch n on i 4. M t s thu t ng do thoi quen c a t ng trung tm c c n gi i h n ch s d ng khi c n thi t (b ng 7). th B ng 1 h t kh nng ch n n tm (b ng 5). i n tm nhng
TI LI U THAM KH O
1. Borys Surawicz, Rory Childers, Barbara J. Deal, and Leonard S. Gettes, AHA/ACCF/HRS Recommendations for the Standardization and Interpretation of the Electrocardiogram: Part III: Intraventricular Conduction Disturbances. A Scientific Statement From the American Heart Association Electrocardiography and Arrhythmias Committee, Council on Clinical the American College of Cardiology Foundation; and
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the Heart Rhythm Society Endorsed by the International Society for Computerized Electrocardiology 2009;53;976-981; originally published online Feb 19, 2009; J. Am. Coll. Cardiol. 2. E. William Hancock, Barbara J. Deal, David M. Mirvis, Peter Okin, Paul Kligfield, and Leonard S. GettesJ. AHA/ACCF/HRS Recommendations for the Standardization and Interpretation of the Electrocardiogram: Part V: Electrocardiogram Changes. Associated With Cardiac. Chamber Hypertrophy A Scientific Statement From the American Heart Association Electrocardiography and Arrhythmias. Committee, Council on Clinical Cardiology; the American College of. Cardiology Foundation; and the Heart Rhythm Society Endorsed by the. International Society for Computerized Electrocardiology. 2009, Am. Coll. Cardiol.;53;992-1002; originally published online Feb 19, 2009; 3. Galen S. Wagner, Peter Macfarlane, Hein Wellens, Mark Josephson, Anton Gorgels, David M. Mirvis, Olle Pahlm, Borys Surawicz, Paul Kligfield, Rory Childers, and Leonard S. Gettes, AHA/ACCF/HRS Recommendations for the Standardization and Interpretation of the Electrocardiogram: Part VI: Acute Ischemia/Infarction A Scientific Statement From the American Heart Association Electrocardiography and Arrhythmias Committee, Council on Clinical Cardiology; the American College of Cardiology Foundation; and the Heart Rhythm Society Endorsed by the International Society for Computerized. Electrocardiology , 2009;53;1003-1011; originally published online Feb 19, 2009; J. Am. Coll. Cardiol. 4. Pentti M. Rautaharju, Borys Surawicz, and Leonard S. Gettes AHA/ACCF/HRS Recommendations for the Standardization and Interpretation of the Electrocardiogram: Part IV: The ST Segment, T and U Waves, and the QT Interval A Scientific Statement From the American Heart Association Electrocardiography and Arrhythmias Committee, Council on Clinical Cardiology; the American College of Cardiology Foundation; and the. Heart Rhythm Society Endorsed by the International Society for. Computerized Electrocardiology. 2009;53;982-991; originally published online Feb 19, 2009; J. Am. Coll. Cardiol.
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M T S Y U T NGUY C LIN QUAN N NGUY C B NH L M CH VNH TRONG 10 NM T I T I C NG NG T NH TH A THIN HU

Hunh Vn Minh, on Ph c Thu c Hong Anh Ti n, Ph m Vn Lnh, Nguy n Dung V Vn Th ng, Nguy n Minh Tm Hong Th Thu Hng Tr ng i h c Y D c Hu TM T T t v n : D phng tin pht c xem l chi n l c chnh c a T ch c Y t th gi i v i mong mu n ch ng lm gi m cc y u t nguy c tai bi n m ch vnh trong th k XXI. ti n hnh cng tc d phng tin pht, c n ph i nghin c u vai tr c a t ng y u t nguy c v s lin k t gi a cc y u t nguy c v i nhau i t ng v phng php nghin c u: G m 1471 ng i dn tu i t 20 tr ln t i Th a Thin Hu t nm 2006-2007. Phng php nghin c u: Nghin c u m t c t ngang v phn tch. Khm v nguy c b nh l m ch vnh theo thang i m Framingham xt nghi m nh gi m c v i u tra cc y u t nguy c trong c ng ng. K t qu nghin c u: Nguy c b nh m ch vnh sau 10 nm t i lin quan v i cc y u t nguy c sau: Tu i, tu i cng cao, nguy c m c b nh cng tng (r = 0.704, p <0.001). Thu c l, s gi thu c/nm cao nguy c m c BMV cng cao (r = 0.397, p < 0.05), Huy t p: Tr s huy t p tm thu v huy t p tm trng cng cao nguy c m ch vnh cng cao (r =0.609 v r = 0.575, p <0.001). Ch s CT, LDL v TG cao v ch s HDL-C th p nguy c cng cao (r = 0.321; r= 0.325 v r= 0.238, l n l t, p< 0.001) (r= 104, p< 0.001). Ch s m n i t ng v t l m c th (r =0.361 v r = 0.222; p <0.001), t s VB/VM (r =0.314; p <0.001) cng cao nguy c BMV cng cao. M c tng ng mu lc i (r= 0.288 p<0.0001). K t lu n: Chng ta c th d phng hi u qu b nh l m ch vnh b ng cch ngn ng a v h n ch cc y u t nguy c b nh l tim m ch ABSTRACT Background: Primary prevention was the main strategy of WHO with the aim to decrease the risk of coronary heart disease. The best way to success in primary prevention was research each risk factor and the relationship between each risk factor. Methods: Base on 1471 people with age above 20 at Thua Thien Hue province from 2006-2007. Cross-sectional study, calculate the risk with the Framingham software. Results: There was the relationship between the 10-years risk of coronary heart disease with following risk factors: Age (r = 0.704, p <0.001). Tobacco consumption (r = 0.397, p < 0.05). Systolic blood pressure (r =0.609, p <0.001). Diastolic blood pressure (r = 0.575, p <0.001). Cholesterol, LDL-cholesterol,
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Triglyceride, HDL-cholesterol (r = 0.321, r= 0.325 and r= 0.238, r= 104, respectively, p< 0.001). Waist-hip ratio (r =0.314; p <0.001). Glucose level (r= 0.288 p<0.0001). Conclusion: We can effectively prevent coronary heart disease by decrease the risk factor of cardiovascular disease. TV N Trong th p nin v a qua c nhi u ti n b c ghi nh n trong cng tc d phng b nh tim do m ch vnh. Ti n b ng ghi nh n nh t l vi c m nh d n p d ng cc ti n b y h c trong i u tr nh m h n ch ti pht b nh nh ng b nh nhn x y ra b nh m ch vnh, chnh l d phng th pht. V n cn t n t i nhi u a phng v qu c gia l cha ch tr ng ng m c trong qu n l v i u tr lm gi m cc y u t nguy c nh ng b nh nhn cha t ng m c b nh m ch vnh, chnh l d phng tin pht. D phng tin pht c xem l chi n l c chnh c a T ch c Y t th gi i v i mong mu n ch ng lm gi m cc y u t nguy c tai bi n m ch vnh trong th k XXI. ti n hnh cng tc d phng tin pht, c n ph i nghin c u vai tr c a t ng y u t nguy c v s lin k t gi a cc y u t nguy c v i nhau. Nm 2006, m t nghin c u Trung Qu c cng b k t qu nh gi nguy c m c b nh m ch vnh v m ch no theo thang i m Framingham cho th y t l m c b nh m ch vnh v m ch no kho ng 3% - 4%. n c ta hi n nay, s l ng ti nghin c u nh gi cc y u t nguy c c a b nh m ch vnh t i c ng ng m t cch h th ng cn qu khim t n, do cha a ra c cc gi i php d phng cho c ng ng. Chnh v v y, chng ti ti n hnh nghin c u xc nh cc y u t nguy c b nh m ch vnh t i c ng ng t nh Th a Thin Hu trn c s xu t cc gi i php d phng cho cho c ng ng I. II. 2.1. I T NG V PHNG PHP NGHIN C U i t ng nghin c u G m 1471 ng i dn tu i t 20 tr ln t i Th a Thin Hu t nm 2006-2007 2.2. Phng php nghin c u 2.2.1. Thi t k nghin c u: Nghin c u m t c t ngang v phn tch 2.2.2. C m u : C m u trong m i x c tnh theo cng th c sau:
Z n =
2 1
p (1 p ) d
2
Trong : n: S i t ng c n nghin c u, : m c ngha th ng k, d = 0.05 ( chnh xc mong c), Z/2: gi tr Z thu c t b ng Z ng v i c ch n. y chng ti ch n = 5% nn Z/2 tng ng l 1.96 (kho ng tin c y = 95%), P = 3-4% (t l b nh trong c ng ng theo nghin c u t i Trung Qu c ) n= 1,962 x 0,04(1-0,04)/ 0,0025 = 59 C m u cho m i n v nghin c u (x, ph ng) l 59, c m u cho ton t nh 24 x, ph ng l 1400, thm 5% d phng cho nn c m u i u tra l 1470 2.2.3. Phng php ch n m u
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Ch n cc huy n, x/ ph ng theo phng php ng u nhin t l . Ch n h i u tra ng u nhin theo danh sch, nh ng ng i c i u tra trong m i h ph i t 20 tu i tr ln, i u tra h t h ny n h khc cho n khi m u 60 - 62 ng i / x. 2.3. Phng php thu th p thng tin Khm v xt nghi m nh gi m c nguy c b nh l m ch vnh theo thang i m Framingham v i u tra cc y u t nguy c trong c ng ng. 2.4. Phng php nh gi cc k t qu nghin c u 2.4.1. Ch n on tng huy t p: Phn theo WHO/ISH 2003 T i u Bnh th ng Bnh th ng - cao THA giai o n I THA giai o n II THA giai o n III HA tm thu (mmHg) < 120 120-129 130 - 139 140 - 159 160-180 > 180 HA tm trng (mmHg) < 80 80-84 85 - 89 90 - 99 100- 110 > 110
2.4.2. Ch n on r i lo n lipid: Theo tiu chu n c a H i Chu Thi Bnh Dng v x v a ng m ch v b nh l m ch mu (4.1998) Phn r i lo n cc thnh ph n lipid mu theo NCEP Ch s (mg/dl) Phn lo i < 200 (<5,2 mmol/L) T t 200 - 239 (5,2 - 6,2 mmol/L) Cao gi i h n TC Cao 240 ( 6,2 mmol/L) < 40 (<1 mmol/L) Th p HDL-C > 60 (>1,6 mmol/L) Cao < 100 (< 2,6 mmol/L) T i u 100 - 129 (2,6 - 3,4 mmol/L) G n t i u 130 - 159 (3,4 - 4,2 mmol/L) Cao gi i h n LDL-C 160 - 189 (4,2 - 5mmol/L) Cao R t cao 190 ( 5mmol/L) < 150 (< 1,7 mmol/L) Bnh th ng 150 - 199 (1,7 - 2,3 mmol/L) Cao gi i h n TG 200 - 499 (2,3 - 5,7 mmol/L) Cao R t cao 500 ( 5,7 mmol/L) 2.4.3. Ch n on b nh i ng: Theo tiu chu n c a T ch c y t Th gi i 1998: ng huy t lc i > 126 mg/dl (7 mmol/L) sau 2 l n th . 2.4.4. nh gi tnh tr ng bo ph +D a vo BMI: Theo tiu chu n ch n on bo ph c a t ch c Y t Th gi i dnh cho cc n c chu . Phn lo i BMI G y < 18,5 Bnh th ng 18,5 - 22,9 Bo ph C nguy c 23 - 24,9
19
Bo 1 25 - 29,9 Bo 2 30 + D a vo VB: nam > 102 cm, n > 88 cm c g i l bo ph. + D a vo t l VB/VM: nam > 0,9, n > 0,85 c g i l bo ph. + D a vo ch s m c th : > 15. + D a vo ch s m n i t ng: Nam > 25, n >35 2.4.5. nh gi m c nghi n thu c l: theo test Fagerstrom, 2.4.6. nh gi au th t ng c theo b cu h i Rose 2.4.7. D on nguy c m c b nh m ch vnh: theo thang i m Framingham hi u ch nh theo ng i Vi t Nam III. K T QU NGHIN C U 3.1. c i m m u nghin c u i t ng bao g m: TP Hu chi m 26.99%, huy n Hng Tr 30.05%, huy n A L i 29.64%, huy n Ph Vang 13.32%. trong 536 nam (37,45%) v 935 n (62,55%) , tu i nh nh t l 20, tu i l n nh t l 90. 3.2. T l nguy c b nh l m ch vnh 10 nm t i B ng 3.1. Phn b m c nguy c m c b nh m ch vnh 10 nm t i M c nguy c Th p Trung bnh Cao Chung p B nh ng m ch vnh 10 nm t i n 897 379 195 1471 <0.0001 i t ng nguy c trung % 60.98 25.76 13.26 100.00
C 60.98% i t ng c nguy c th p b nh , 25.76% bnh, v 13.26 % i t ng c nguy c cao. 3.3. Phn b cc y u t nguy c b nh l m ch vnh
33.51 23.7
20.9
7.79 4.35 2.34 R i loan Ht lipide t hu c l T HA Beo phi i t ho L i s ng ng t inh t ai
20
Hnh 3.1. Cc y u t nguy c c a m u nghin c u R i lo n lipid mu 35.51%, ht thu c l 23.70%, THA 20.91%, bo ph 7.79%, T 4.35%, l i s ng tnh t i 2.34% . S khc bi t t l gi a cc y u t nguy c l c ngha th ng k (p < 0.0001). 3.4. M i lin quan gi a cc y u t nguy c v i b nh l m ch vnh trong 10 nm t i 3.4.1. Ch s m n i t ng c th B ng 3.2: Nguy c m c b nh m ch vnh, sau 10 nm t i theo ch s m n i t ng M c nguy c B. th ng Cao nh Cao p Ch s m Th p n 868 29 0 % Trung bnh n % n Cao % T ng c ng n %
64.53 331 24.61 146 10.86 1345 91.43 <0.0001 24.78 46 39.32 42 35.90 117 7.95 0 2 22.22 7 77.78 9 0.62 <0.0001 <0.0001 <0.0001
<0.0001
Khi ch s m bnh th ng: M c nguy c BMV th p chi m t l cao (64.53% v 89.29%). Khi ch s m cao m c nguy c cao chi m t l cao (77.78%), nguy c trung bnh 22.22 %, khng c tr ng h p nguy c th p. 3.4.2.T l m c th B ng 3.3: Nguy c m c BMV sau 10 nm t i theo t l m c th Ch s m c th M c th (Nam) 1 2 3 4 TC M c th (N ) 1 2 3 4 TC Nguy c m ch vnh sau 10 nm t i Th p Trung bnh Cao T ng c ng n % n % n % n % 27 142 58 29 256 31 357 191 62 641 90.00 66.05 40.28 19.73 60.98 68.89 87.50 64.53 33.33 60.98 1 54 52 58 165 8 40 85 81 214 3.33 25.12 36.11 39.45 25.76 17.78 9.80 28.72 43.55 25.76 2 19 34 60 115 6 11 20 43 80 6.67 8.83 23.61 40.82 13.26 13.33 2.70 6.75 23.12 13.26 30 215 144 147 536 45 408 296 186 935 2.04 14.62 9.79 9.99 100.00 3.06 27.74 20.12 12.64 100.00
21
c 2 gi i, khi t l m c th khng cao, m c nguy c th p BMV chi m a s (90% v i nam, 69% v i n ), Nhng khi t l m cao, m c nguy c trung bnh v cao u tng ln r r t c 2 gi i (39.45% v 40.82% v i nam, 43.55 v 23.12% v i n ). S khc bi t gi a cc t l c ngha th ng k (p<0.05 v <0.001). 3.4.3.Tnh tr ng ht thu c l (gi/nm) v HA B ng 3.4: Tng quan gi a nguy c m c BMV sau 10 nm t i v i tu i, ht thu c l (gi/nm) v HA Tng quan r r p r p r p Nguy c b nh MV Nam Tu i 0.777 0.000 0.686 0.000 0.704 0.001 Thu c l (gi/nm) 0.236 0.048 0.078 0.185 0.397 0.032 HATT 0.535 0.000 0.659 0.000 0.609 0.001 HATTr 0.510 0.000 0.612 0.000 0.575 0.001
- Nguy c m c BMV sau 10 nm t i c m i tng quan thu n ch t ch v i tu i, tu i cng cao nguy c m c b nh cng tng (r = 0.704, p <0.001), tng quan thu n v c ngha v i tnh tr ng ht thu c l (r = 0.39, p<0.05), c m i tng quan thu n v c ngha v i HATT v HATTr (r = 0.609 v 0.575, p<0.05)
Tuong quan Frammingham MV va HATD
140 Tuong quan Frammingham MV va HATT y = 0.7892x + 68.91 R2 = 0.3231
HATD
H TD A
250 200 150 100 50 0 0
TC
y = 1.5084x + 111.81 R2 = 0.3709
120 100 80 60 40 20
20
40
60
80
0 0 20 40 % Frammingham 60 80
% Fram m ingham
Hnh 3.2. Tng quan gi a nguy c BMV sau 10 nm v i huy t p tm thu
Hnh 3.3. Tng quan gi a nguy c BMV sau 10 nm v i huy t p tm trng
3.4.4. Bo ph B ng 3.5: Tng quan gi a nguy c BMV sau 10 nm v i ch s bo ph Tng quan Nguy c b nh MV Nam r p r N p r TC p BMI 0.122 0.005 0.079 0.016 0.099 0.001 VB/VM 0.295 0.000 0.325 0.000 0.314 0.001 M t ng 0.321 0.000 0.325 0.000 0.361 0.001 %m 0.474 0.000 0.428 0.000 0.222 0.001
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Nguy c m c BMV sau 10 nm t i c m i tng quan thu n ch t ch v i v i t VB/VM (r = 0.314, p < 0.01), v i ch s m n i t ng v t l m c th (r =0.361 v r = 0.222; p <0.001). 3.4.5. R i lo n lipid mu B ng 3.6: Tng quan gi a nguy c BMV sau 10 nm t i v i m t s thng s v lipid mu Tng quan r p r p r p Nguy c b nh MV Nam CT 0.294 0.000 0.406 0.000 0.321 0.001 HDL -0.166 0.000 -0.062 0.060 -0.104 0.001 LDL 0.345 0.000 0.400 0.000 0.325 0.001 TG 0.096 0.026 0.323 0.000 0.238 0.001
C m i tng quan thu n m c gi a nguy c BMV v i CT, LDL v TG (r = 0.321; r = 0.325 v r = 0.238, l n l t, p< 0.001) v c m i tng quan ngh ch m c nh gi a nguy c BMV v i HDL (r = -0.104, p< 0.001) 3.4.6. Tng quan gi a b nh m ch vnh v i ng mu lc i
Tng quan gi a glucose mu i v NCMV
80 60 NCMV 40 20 0 0 100 200 300 400 500 600 Glucose m u i y = 0.0701x + 0.2522 R2 = 0.0617
r = 0.248 p<0.0001 Hnh 3.3: Tng quan gi a nguy c b nh m ch vnh 10 nm t i v i ng mu lc i C m i tng quan thu n gi a ng mu lc i v i nguy c BMV ( r= 0.248 p<0.0001) v TBMN v i (r= 0.288 p<0.0001) IV. BN LU N 4.1. Nguy c m c b nh m ch vnh trong 10 nm t i theo thang i m Framingham M c nguy c c phn theo 3 c p : nguy c th p khi c < 5 i m; m c nguy c trung bnh khi c 5 i m n < 15 i m, m c nguy c cao khi c 15 i m. Nh v y, nguy c th p chi m 60.98 %; nguy c trung bnh chi m 25.76%, nguy c cao 13.26 %. T y c th tnh c v i dn s t i t nh ta tnh n nm 2007 l 1.134.480 ng i th 691.805 ng i c nguy c th p; 292.242 ng i c nguy c trung bnh; 150.432 ng i c nguy c cao. N u ch tnh nh ng ng i c nguy c trung bnh
TC
23
v nguy c cao c n ph i qu n l v i u tr th c n 442.674 ng i chi m 39.02 % thu c di n ny. y qu l con s bo ng, m t v n l n c n ph i c s quan tm u t ti chnh, t p trung tr tu c a ngnh y t v nhi u ngnh ch c nng lin quan m i c th gi i quy t c. 4.2. M i tng quan m c nguy c b nh l m ch vnh v i m t s y u t nguy c 4.2.1. Tng quan gi a tu i, gi i v m c nguy c m ch vnh Trong nghin c u c a chng ti th y c m i tng quan ch t ch gi a m c nguy c chung c a b nh m ch vnh v i tu i c hai gi i, tu i cng cao, nguy c m c b nh cng tng (r = 0.620, p <0.0001; r = 0.613, p <0.0001 l n l t). Nghin c u c a Framingham cng cho th y k t qu tng t . 4.2.2. Tng quan gi a ht thu c l v m c nguy c m ch vnh M i tng quan gi a ht thu c l (s gi thu c l/nm) v m c nguy c m ch vnh, m ch no c nhi u tc gi kh ng nh. Nguy c cao hn nhi u n u i t ng b t u ht tr c tu i 16. Nghin c u c a chng ti cng th y c m i tng quan thu n gi a s gi thu c nguy c m ch vnh (r = 0.39, p < 0.001, r = 0.11; p< 0,05) l /nm v m c Nguy c m c b nh tim m ch c a m t ng i b thu c l sau 1 nm s tr v thuy t ph c gi ng nh ng i khng ht thu c l. y l m t y u t quan tr ng nh ng ng i ang ht thu c l b ht thu c. Khi b ht thu c s gi m nguy ti pht cc bi n c chnh kho ng 50%. 4.2.3. Tng quan gi a m c nguy c m ch vnh v cc ch s ch s bo ph -M c nguy c m ch vnh c m i tng quan thu n y u v i BMI (r = 0.122 v i p <0.005); Tng quan thu n m c v a c ngha v i t l VB/VM (r = 0.314, p <0.001). -M c nguy c m ch vnh c m i tng quan thu n c ngha v i ch s m n i t ng ( r= 0.195, p< 001) v t l m c th (r =0.222 v p <0.001). gi m nguy c tim m ch, c n ph i gi m cn n ng. Vi n NHLBI (the National Heart, Lung and Blood Institute) khuy n co s gia tng ho t ng th l c l m t ph n quan tr ng c a chng trnh ki m sot cn n ng: gi m l ng calo n vo, ho t ng th l c, t p th d c 4.2.4. M i tng quan gi a Cholesterol v m c nguy c m ch vnh Qua nghin c u chng ti nh n th y c m i tng quan thu n gi a CT v m c nguy c m ch vnh sau 10 nm (r = 0.294, p <0.0001) (b ng 3.38). i u ny ch ng t CT l y u t nguy c r t c gi tr cho d on b nh l tim m ch. K t qu ny cng ph h p v i nghin c u c a Framigham. 4.2.5. Tng quan gi a HDL v m c nguy c m ch vnh T nghin c u Framingham, ng i ta nh n th y c m i tng quan ngh ch gi a m c HDL-C v t n su t BMV (p<0,001) c nam l n n gi i. K t qu nghin c u c a chng ti cng tng t , HDL -C tng quan ngh ch ch t ch v i m c nguy c m ch vnh (r= -0.538, v i p< 0,0001) (hnh 3.22). Nh v y, khi can thi p b ng cc gi i php: ch n u ng, luy n t p ho c dng thu c lm tng HDL- C th s gi m c nguy c m c b nh tim m ch [7]. 4.2.6. Tng quan gi a tng huy t p v m c nguy c m ch vnh
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C m i tng quan thu n gi a HATT, HATTr v m c nguy c b nh MVMN (r= 0.571 v i p< 0,001 v r= 0.481 v i p< 0,001) (Hnh 3.35). ng i d i 50 tu i, c HA tm thu v tm trng u lin quan v i nguy c tim m ch; trn tu i ny, HA tm thu l YTD quan tr ng hn nhi u. Nghin c u Framingham cho th y c s lin quan ch t ch gi a tr s HA v nguy c b nh m ch vnh, nguy c cng tng khi HA cng cao, nguy c tng g p i n u HA tm trng tng m i 10 mmHg ho c HA tm thu tng m i 20 mmHg; v vi c i u tr lm gi m HA s lm gi m nguy c BMV, c bi t, i u tr THA tm thu n c lm gi m r r t nguy c b nh m ch vnh v m ch no [9], [16]. V. K T LU N Nguy c b nh m ch vnh sau 10 nm t i lin quan v i cc y u t nguy c sau: - Tu i, tu i cng cao, nguy c m c b nh cng tng (r = 0.704, p <0.001). - Thu c l, s gi thu c/nm cao nguy c m c BMV cng cao (r = 0.397, p < 0.05), - Huy t p: Tr s huy t p tm thu v huy t p tm trng cng cao nguy c m ch vnh cng cao (r =0.609 v r = 0.575, p <0.001). - Ch s CT, LDL v TG cao v ch s HDL-C th p nguy c cng cao (r = 0.321; r= 0.325 v r= 0.238, l n l t, p< 0.001) ( r= 104, p< 0.001). - Ch s m n i t ng v t l m c th (r =0.361 v r = 0.222; p <0.001), t s VB/VM (r =0.314; p <0.001) cng cao nguy c BMV cng cao. - M c tng ng mu lc i (r= 0.288 p<0.0001). VI. XU T GI I PHP D PHNG - Li u php thay i cch s ng: Khng ht thu c, tng c ng v n ng th l c, ch n u ng gi m th c n ng v t thch h p, gi m bia r u. - Pht hi n s m v i u tr s m khi m c b nh tng huy t p, i ng, RLLM - T p trung truy n thng gio d c s c kho cho nhn dn cc vng xa, thi u thng tin v d phng b nh l m ch vnh v m ch no trn nhi u knh.
TI LI U THAM KH O 1. H ng Gio ( 2001), "Gi tr c a t l cholesterol t trong th p v i cholesterol t trong cao ( LDL/HDL) trong nh gi i u tr r i lo n lipid mu" Th i s tim m ch h c , 39, pp. 16-22 2. Ph m Gia Kh i (2000), c i m d ch t h c b nh tng huy t p t i H N i, T p ch Tim m ch h c s 21/2000. 3. Nguy n C u L i (2002), Nghin c u s khng insulin, m t y u t nguy c c l p c a b nh ng m ch vnh, Lu n n ti n s Y h c. i h c Y khoa Hu 4. Tr n Lm (2006) Nghin c u tc d ng c a Atorvastatin trn n ng protein ph n ng C nh y cao b nh nhn suy ng m ch vnh m n, lu n n CKII. i h c Y khoa Hu .
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5. Th ch Nguy n, Hunh Vn Minh v c ng s (2007), D phng tin php ton di n b nh tim m ch, M t s v n c p nh t trong ch n on v i u tr b nh tim m ch, nh xu t b n y h c. 6. Nguy n Th Kim Thnh (2007), Nghin c u ch s d bo nguy c ti m ch theo thang i m Framigham cc i t ng b o hi m y t t i b nh vi n tr ng i h c y khoa Hu , T p ch tim m ch h c, s 47, 2007. 7. Antonio MG et al (2000), Blood lipids and coronary heart disease, The ILIB lipid handbook for clinical practice, 2nd edition, pp. 7-18. 8. Briel M et al (2005), Statin therapy for prevention and treatment of acute and chronic cardiovascular disease: update on recent trials and metaanalyses, Curr Opin Lipidol, 16 (6), pp. 601-05. 9. Dagenais GR et al (2005), Impact of cigarette smoking in high-risk patients participating in a clinical trial, Eur J Cardiovasc Prev Rehabil, 12(1), pp. 75-81. 10. David Waters et al (1996), Effects of cigarette smoking on the angiographic evolution of coronary atherosclerosis - A canadian coronary atherosclerosis intervention (CCAIT) substudy, Circulation, (94), pp. 614-21. 11. Henry Purcell, Caroline Daly (2006), Reducing the cardiovascular risk in diabetes, Medical Progress, pp. 57-61. 12. Judith Mackay, George A. Mensah (2004), Risk factors, Deaths from coronary heart disease, The atlas of heart disease and stroke, WHO, pp. 22-42, 48-49. 13. Michael R. Ehrenstein et al (2005), Statins for atherosclerosis - As good as it gets ?, NEJM, 352, pp. 73-75. 14. Michelle A. Albert et al (2001), Effect of statin therapy on CRP levels-The PRavastatin INflammation/CRP Evaluation (PRINCE) study, JAMA, (286), pp.64-70. 15. Peter Libby et al (2002), Inflammation and atherosclerosis, Circulation, 105, pp. 1135-45. 16. Sidney C. Smith, Richard V. Milani et al (2004), Atherosclerotic vascular disease conference, Circulation, 109, pp. 2613-16.
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NGNG TH
KHI NG
Tr ng L Vn Bng i h c Y D c Hu
1. Ngng th Ngng th c bi u hi n b i m t s ngng lu ng kh trong th i gian trn hay b ng 10 giy, h h p tr l i th ng ph i h p v i s th c d y r t ng n hay gi m gi c ng . Bn c nh s ngng th , ng i ta nh ngha m t hnh th c khng hon ton, gi m th l m t s gi m lu ng kh t nh t l 50%, ph i h p v i m t s m t bo ha oxy hemoglobine b ng hay trn 4%. V phng di n a k gi c ng , h i ch ng ngng th khi ng c nh ngha b ng m t ch s ngng th . Nhng qua s l n ngng th , m c tr m tr ng ch c l ng gi m t cch trung th c b i s theo di ng th i bo ha oxy mu ng m ch d n n m t b nh c nh lm sng r (tng li b, r i lo n tm th n kinh, tng huy t p, b nh m ch vnh). Ng i ta phn bi t 3 type ngng th : - Ngng th t c ngh n th ng g p nh t, - Ngng th trung ng t g p, - Ngng th h n h p ph i h p hai lo i trn. 2. Ngy Hi n t ng th ng g p (86% ng i nam ngy). H i b nh v n cn t tin c y. Nh ng y u t lm d l gi i nam, tu i (t i a l 60-70 tu i), tng cn, u ng r u, s d ng m t s thu c gy gin c. Ngy l m t than phi n ban u th ng g p trong s pht hi n h i ch ng ngng th khi ng t c ngh n. Ch s ngy (s l n ngy trong m t gi trong gi c ng ) c th tnh c. M t ng i ngy c ch s trn 30. M t tr ng h p n ng, ch s trn 300. 3. H i ch ng khng cao c a ng h h p trn l s ph i h p m t tnh tr ng li b qu m c, nh ng bi n c h h p ban m ngoi ngng th -gi m th (ngy, th c d y ng n, gi i h n cung l ng...) v tt i u tr b ng thng kh p l c dng lin t c.
NGNG TH
1.
KHI NG T C NGH N
nh ngha Ngng th khi ng c b n thnh ph n: X p ng kh. Ph i g ng s c th , nhng khng thnh cng. M c oxy trong mu t t xu ng. Khi s l ng oxy a ln no b gi m, no a ra tn hi u cho c th ph i t nh gi c v th . i u n y c ng i bn c nh nghe c m t kho ng im l ng theo sau l th h n h n. 2. D ch t h c Ngng th khi ng t c ngh n c c tnh nh h ng n kho ng 4% nam v 2% n . Trong m t nghin c u ng i trn 18 tu i, ngng th khi ng t c ngh n c
27
c on l 1,5% m i nm trn 5 nm nghin c u. T l n y c th cao hn v dn chng b bo ph nhi u hn v bo ph th lm x u i ngng th khi ng t c ngh n. ng kinh ng c l ch c 10% s ng i trn hi n nay c i u tr m thi. M t vi nhm ng i c th b ngng th khi ng t c ngh n hn: - Tr c 50 tu i, nam c th b ngng th khi ng t c ngh n nhi u hn n . - Sau 50 tu i, nguy c b b nh gi ng nhau gi a nam v n . - Trong s nh ng b nh nhn bo ph, 70% b ngng th khi ng t c ngh n. - Ngng th khi ng t c ngh n gia tng tr m tr ng v t l m c b nh theo s gia tng bo ph. - Trong s b nh nhn tim m ch, 30 50% b ngng th khi ng t c ngh n, v trong s b nh nhn b t qu c 60% b ngng th khi ng t c ngh n. - M t nghin c u g n y c tnh c 14% v n ng vin bng v 34% n ng g y b ngng th khi ng t c ngh n. - Ng i M g c Phi c nguy c b ngng th khi ng t c ngh n g p 2,5 l n so v i ng i Caucasian. n , 7,5% nam b ngng th khi ng t c ngh n. Ngng th khi ng t c ngh n nam gi i ng i Trung chi m t l 4% v n gi i ng i 2%. 3. Nguyn nhn ng sau vm h u, l i Khng kh trong m t l n th bnh th ng i qua mi, g v y l i, qua c h ng v gi a cc dy thanh m i vo trong ph i Lu ng khng kh c th gi m n u m t ng i b v o vch ngn mi. M t vch ngn mi c th b v o qua m t bn hay hai bn lm h p l i ng kh. Nh ng mng l c trong mi g i l cu ng mi c th b t c ngh n khi chng b sng ln. N u vm h u v l i g (v t treo trn lng c a h ng) di v l ch b ch, c th ri ra pha sau v bt l i ng th . Lng c a l i cng c th ri ra pha sau v bt ng th c bi t khi n m ng a. Cu i cng cc thnh bn c a h ng c th ri cng v i nhau lm h p v bt ng th . ch ng l i t c ngh n n y, x y ra thm n a: - Nh ng c th lm vi c lm gin l ng ng c ra v lm h th p c honh t b nh nhn ht c khng kh. - p l c m ht khng kh vo trong ph i - ng mi, vm h u, l i v m thanh qu n c th gp ph n lm h p ng kh. - N u su t th i gian c g ng th , ng kh b x p l i, nh ng m c a ng kh ht v i nhau b i p l c m. - L ng ng c c g ng y kh vo trong cng kh khn, th p l c m cng l n v nh ng m c a ng th cng b ng kn v i nhau. - Cu i cng, khi oxy trong mu gi m, b nh nhn th c y hay m c ng tr nn nng hn. Ng i b ngng th khi ng t c ngh n c ng kh h p hn ng i bnh th ng, th ng th ng y l i v vm h u. Khi n m ng a, vm h u trn ng kh. Khi c thanh qu n gin th vm h u c th ri ra sau. i u n y c th lm t c ngh n ng kh. C c m l i ng v tr, y l i dnh vo xng hm pha tr c. Ph n l n ng i ta c kho ng tr ng sau l i th m khng c n y l i ra pha tr c. Tuy nhin, khi b nh nhn b ngng th khi ng t c ngh n th c d y, c n y c n ho t
28
ng y y l i ra pha tr c m ng th . Su t trong gi c ng ph n l n cc c bao g m c c m l i gin ra. Trong m t giai o n c bi t c a gi c ng , giai o n c ng m t nhanh, cc c hon ton gin ra. S gin c c m l i trong lc ng cho php y l i ri ra pha sau v ng kh ng l i.
vm h u m m v l i g
l i l p m lt thnh sau h ng h nh nhn l i ami an
H u h ng l vng chnh c a t c ngh n ng kh trn, vm h u m m c th b l i ra v b ko di ra. L i g c th b sng ln. y l i c th nh ra sau v c n tr ng kh. L p m lt c a thnh sau h ng c th i vo trong nh ng ph n g p l i c a m th a. Nh ng c t tr c a h ng c th nh ra v ng l i ng gi a. Nh ng h nh nhn c th l n ra gy t c ngh n ng kh. B nh nhn b ngng th khi ng t c ngh n th ng khng th c d y trong m v i m i m t giai o n ngng th . Th ng th ng, trong khi ngng th , no ch nh th c t m t gi c ng su (giai o n 3,4, v c ng m t nhanh) n m c ng nng. R i th c c m l i co c ng v y l i ra sau v b nh nhn th c. B nh nhn c th duy tr gi c ng , nhng gi c ng su b gin o n. 4. C ch Ngng th khi ng t c ngh n do s ng l i ( x p) cc ng h h p trong lc ht vo, gy nn m t p l c m trong h ng (p l c b). S x p n y c th x y ra m t hay nhi u v tr c a h u h ng hay h h ng. C nhi u y u t c th gp ph n vo c ch sinh b nh v i nhi u m c khc nhau ty thu c vo b nh nhn: - Nh ng y u t c th h c: ph i h nh nhn , xng hm a ra sau, t c ngh n mi, bo ph v.v.....Nh ng y u t n y lm gi m kh u knh nh ng ng kh v lm gia tng khng; s gia tng khng n y tng ln trong m t s t th , nh g p c v n m nghing lng, v khi gia tng thng kh ph n x th x y ra ngng th . - Gia tng gin c a nh ng ng kh trn (s m m) - Nh ng y u t th n kinh-c ( c lm n ng b i u ng r u v s d ng thu c gy ng ); gi m qu nhi u trng l c c gin h ng (c dng gi t th l i, xng l i, mng h u) trong khi ng ( ng su hay ng ch p ch n), trong tr ng thi c b n hay p ng v i nh ng kch thch c h c ( b t th ng ph n x gy nn b i p l c m k ht vo kch thch nh ng th th h ng, hay b i th tch ph i) hay ha h c (gi m nh y c m c a nh ng trung tm h h p v i thi u oxy hay tng carbonic).
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- Khng ng b gi a ho t ng cc c gin v ho t ng c honh. - Ch m th c d y trong tr ng h p x p ng kh trn. Ngng th n y gy nn m t s b t th ng n ng kh oxy mu (gi m oxy mu) v m t s b t th ng kh carbonic mu (tng carbonic mu). S tng kh carbonic mu n y kch thch thng kh, gy th c d y ng n.
Bnh th ng trong lc ng , nh ng c ki m sot l i v mng h u m m gi cho ng th m ra N u nh ng c n y gin ra, ng kh b h p l i, gy ngy v kh th N u nh ng c n y gin ra qu nhi u, th ng th tr nn b t c ngh n v ngn c n th
5. Tri u ch ng Ngng th khi ng t c ngh n c nhi u h u qu c nghin c u k . Tr c tin, l lm gin o n gi c ng . B nh nhn v i gin o n gi c ng khng th t p trung, suy ngh, hay nh l i nh ng g x y ra trong ngy. i u n y gy nn nh ng tai n n t i ch lm vi c v khi li xe. Th t v y, ng i b ngng th khi ng t c ngh n c nguy c b tai n n xe g p ba l n ng i bnh th ng. 5.1. Tng huy t p Ngng th khi ng t c ngh n gy tng huy t p v b nh tim. Ngng th th ng x y ra ban m (m i 1-4 pht) c th gy nn gia tng stress trn tim. Khi b o ha oxy trong mu gi m v ngng th ti p di n, h th ng th n kinh giao c m ho t ng. H th ng n y truy n tn hi u th n kinh v tn hi u adrenaline n m ch mu gy co th t m ch mu v n tim gy tim lm vi c nhi u hn. Khi m ch mu co th t, mu n no v c nhi u hn. Tuy nhin, s gia tng huy t p yu c u tim ho t ng nhi u hn bm mu qua cc m ch mu nh . i u , k t h p v i tn hi u i v i tim lm tim lm vi c nhi u hn v n ng oxy mu th p hn s gy nn s gia tng stress trn tim trong su t m. Trong lc ng l th i gian tim th ng t lm vi c v c th l th i gian ngh ngi. Trong s nh ng b nh nhn b ngng th khi ng t c ngh n khng c tng huy t p, 45% s pht tri n tng huy t p trong vng 4 nm. Khi ngng th khi ng t c ngh n c i u tr , tng huy t p h xu ng. 5.2. Bi n ch ng tim Nguy c suy tim sung huy t gia tng 2-3 l n v nguy c t qu gia tng 1-5 l n b nh nhn b ngng th khi ng t c ngh n
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Ngng th khi ng t c ngh n c th c bi n ch ng rung nh. Sau khi i u tr , 50% b nh nhn rung nh ti pht, nhng b nh nhn b ngng th khi ng t c ngh n th 80% rung nh ti pht. Cu i cng, ngng th khi ng t c ngh n c th lm gia tng nguy c t t . 6. Ch n on v nh gi ngng th khi ng t c ngh n 6.1. B nh s v khm lm sng Ngng th khi ng t c ngh n c th c ch n on v nh gi b i nh ng phng php khch quan (nh n th c hay nh h ng n) v ch quan (cn c trn s th t, cn c trn nh ng d li u kinh nghi m). 6.1.1. Thang i m ng Epworth Khng bao Nguy c Nguy c Nguy c ng gi ng ng t ng v a nhi u (3) (0) (1) (2) Ng i v c Xem truy n hnh Ng i khng ho t ng m t ni cng c ng (r p chi u bng, hay h i h p) L hnh khch c a m t chi c xe trong m t gi N m ngh vo bu i chi u (khi c th ) Ng i v ni chuy n phi m v i m t ng i no Ng i yn l ng sau bu i tra (khng u ng r u) Trong m t chi c xe khi ng ng l i trong vi pht Sau khi s p x p m i lo i, i m s c tnh. Ph m vi l 0-24 K t qu : 0-9 : ng trung bnh trong ngy. Tuy nhin n u b n nh n th y c m t s thay i gi c ng th ng qui th b n c th n khm bc s 10-15: ng nhi u trong ngy, ph i n khm bc s xc nh nguyn nhn v c th i u tr . 16-24: ng tr m tr ng trong ngy. B t bu c ph i n khm bc s v ph i i u tr . 6.1.2. B nh s B nh s bao g m cc cu h i: - hon thnh cng vi c - ng trong ngy - b nh s li xe v tai n n - ng ch p m t lt - ng trong lc h i h p
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- gi m tr nh 6.1.3. Khm lm sng Khm lm sng c th c hi n kh o st nh ng vng c a ng kh c th b x p. Trong mi, bao g m vch ngn, polyp mi, ph i VA, v thanh qu n mi (lng c a mi). Trong mi ng, khm vm h u, ami an v thnh thanh qu n. Cu i cng, soi thanh qu n b ng ng soi m m th ng c th c hi n kh o st ng kh trong lc th ch ng v th thu t kch thch ngy. 6.2. a k gi c ng Tt khch quan u tin i v i ngng th khi ng t c ngh n l a k gi c ng , l tt o l ng nh ng thng s khc nhau v th c th v sinh l m t ng i ng . a k gi c ng bao g m: - M t i n no -M t i nm t - M t i n c - o lu ng kh mi ng v mi - oc ng l ng ng c v b ng - Ghi bng m thanh m c a ngy - M c oxy mu b ng oxy k - Theo di b ng video b nh nhn trong su t th i gian kh o st. i n no theo di nh ng sng c a no v c th dng xc nh m c ng hay t nh to. N gip xc nh n u c m t bi n c (c ng h h p hay chn tay) gi c ng . lm r i lo n m c i nm t kh o st nh ng c ng c a m t. Trong su t gi c ng c c ng ng m t cch c bi t t bn n y sang bn kia. m t nhanh (ng n m m), m t c Kh o st n y c th gip xc nh th i gian ng c c ng m t nhanh. i n c kh o st nh ng c ng c a c. Th ng th ng, km theo m t my kh o st gin c a c (trng l c). Trong giai o n 1-4 c a theo di t c m gi c ng c m t trng l c c c b n, tuy nhin, trong gi c ng c c ng m t nhanh t t c c u gin. i n c cng gip xc nh th i gian gi c ng c c ng m t nhanh. M t i n c c a chn c th c s d ng pht hi n h i ch ng chn yn ngh hay nh ng c ng chn t ng lc trong khi ng . Lu ng kh mi ng v mi c th c kh o st b i nhi u phng php khc nhau gip xc nh kch c v t n su t th trong khi ng . Nh ng c ng c a l ng ng c v b ng x y ra v i m i m t s c g ng th v c th dng phn bi t gi a ngng th khi ng trung ng v ngng th khi ng t c ngh n (trong khi ngng th khi ng trung ng, tn hi u gy th khng truy n i, lm cho nh ng c khng c g ng th c. Trong khi ngng th khi ng t c ngh n, nh ng c c g ng th , nhng kh khng di chuy n c). Kh o st m c n o c a ngy c th c s d ng nh l ng ngy. S kh o st n y c th cng c s d ng nh gi s thay i sau i u tr ngy. Oxy k c s d ng kh o st s gi m oxy trong mu trong th i gian b ngng th v gi m th . Theo di b ng video c n nh t pht hi n nh ng r i lo n c ng, tnh tr ng c n gi c ng hay ng kinh trong gi c ng . Th ng th ng b nh nhn khng nh c nh ng ho t ng x y ra khi ng nh i l i, ni chuy n hay nh ng tnh
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tr ng c n gi c ng ; v v y video gip chng ta xem l i nh ng bi n c x y ra trong gi c ng c a b nh nhn. D li u khi th c hi n a k gi c ng s c phn tch b i chuyn gia v gi c ng . S l ng l n ngng th , gi m th , c ng c a chn, gi m b o ha oxy v m c ngng th c ghi l i thnh m t bo co ng qui cch, v ch n on c thi t l p.
a k gi c ng trong ngng th khi ng t c ngh n. Cc ng c ghi l i (t trn d i c m, 2 ng i n m t d , 1 xu ng): 3 ng i n no , 1 ng i n c ng i n tm , 1 ng lu l ng mi, 1 ng vnh ai ng c, 1 ng vnh ai b ng, 1 ng oxy mu o u ngn tay (pulse oxymetry) 6.3. Tt pht hi n ti m tng nhi u c a gi c ng Gi c ng c th c kh o st b ng tt pht hi n ti m tng nhi u gi c ng . M t cch c b n, tt pht hi n ti m tng nhi u c a gi c ng kh o st m t ng i no ng nhanh trong ngy. Tt ny c th c hi n sau khi c k t qu kh o st gi c ng ban m ( a k gi c ng ). Tt n y bao g m 4 n 5 gi c ng ch p m t ko di 20 pht v cch nhau 2 gi . Ng i c h ng d n c g ng hon t t v ng . Th i gian trung bnh i ng c tnh cho t t c 4 hay 5 tt. Th i gian bnh th ng i ng l l n hn 10 pht. Ng qu m c l t hn 5 pht ng . 6.4. Tt duy tr t nh to Tt duy tr t nh to cng kh o st ng trong ngy. Ng i th c hi n tt c h ng d n c g ng th c t nh. Tt n y c l p l i 4 l n trong 40 pht, cch nhau 2 gi . Khng ng trong t t c 4 tt l cch kh o st khch quan nh t c a khng ng ngy. 7. Nh ng tiu chu n ch n on h i ch ng ngng th khi ng t c ngh n theo phn lo i th gi i v nh ng r i lo n gi c ng B nh nhn than phi n m t ng hay m mng nhi u vo ban ngy. B nh nhn i khi khng bi t nh ng d u ch ng lm sng n y tuy nhin c quan st b i nh ng ng i khc. Nhi u o n b t c ngh n h h p th ng x y ra trong lc ng . Nh ng d u ch ng ph i h p bao g m:
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- Ngy vang, - Nh c u bu i sng, - Mi ng kh lc th c d y, - T c ng c trong lc ng tr em. Theo di a k gi c ng cho th y: C hn 5 l n ngng th t c ngh n v i th i gian trn 10 giy trong 1 gi ng v m t trong nhi u d u ch ng sau: - Nh ng lc th c d y ng n th ng x y ra ph i h p v i nh ng l n ngng th , - nh p tim ch m hay nhanh - M t bo ha oxy mu ng m ch ph i h p hay khng v i nh ng o n ngng th . - Tt pht hi n ti m tng nhi u c a gi c ng v i m t s ti m tng c a gi c ng trung bnh d i 10 pht. - C th ph i h p v i nh ng b nh n i khoa khc nh ph ai ami an. - Nh ng r i lo n khc c a gi c ng c th xu t hi n nh nh ng c ng nh k c a c ng chn hay cn ng thong qua 8. i u tr 8.1. i u tr n i khoa 8.1.1. Thay i hnh vi Thay i hnh vi l i u tr n gi n nh t i v i ngng th khi ng t c ngh n nh . Thay i t th khi ng c th lm gi m ngng th . Gi m bo ph lm gi m ch s ngng th -gi m th xu ng 25%. 8.1.2. Thu c Thu c x t steroid, thu c lm gi m xung huy t mi nh oxymetalizone v neosynephrine n u b t c ngh n mi. Hormone gip n u do suy gip.... 8.1.3. Thi t b rng Thi t b rng gi hm v l i pha tr c v gi vm h u ln trn nh v y ngn c n s ng l i c a ng th , c s d ng cho ngng th nh . 8.1.4. p l c ng kh dng tnh lin t c y l phng php i u tr t t nh t cho t t c m c ngng th . My t o p l c ng kh dng tnh lin t c th i kh nng v c lm m qua m t ng ng n vo m t kh u trang.
8.1.5. p l c ng kh dng tnh hai m c Khng gi ng nh phng php p l c ng kh dng lin t c cung c p m t p l c u n, h ng nh cho ng kh trn khi b nh nhn th vo v th ra, phng php p l c ng kh dng tnh hai m c thi t l p m t p l c cao hn khi b nh nhn ht vo v gi m xu ng m t p l c th p hn khi th ra. M c tiu c a i u tr n y l nng ki u th y u c a ngng th trung ng. M t vi thi t b c a my t o p l c ng kh
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dng tnh hai m c c th i u ch nh m t cch t ng t kh i pht ho t ng th n u thi t b pht hi n b nh nhn khng th sau m t vi giy. 8.2. i u tr ngo i khoa 8.2.1. Ph u thu t ng kh mi Ph u thu t nh m vo cc nguyn nhn gy t c ngh n mi nh v o vch ngn, polype mi. 8.2.2. Tr ng vm h u Ph u thu t lm c ng l i vm h u; ngn ng a vm h u s p vo h ng. Ph u thu t ny thnh cng trong 44% tr ng h p ngng th v i ch s nh hn 24 v 50% tr ng h p ngng th v i ch s nh hn 10. 8.2.3. Ch nh s a l i g, vm h u, h ng Ph u thu t ngn ng a s s p xu ng c a vm h u, ami an v h ng. Ph u thu t ny thnh cng trong 50-60% tr ng h p ngng th . 8.2.4. Ph u thu t c t l i Ph u thu t lm gi m kch th c y l i v vng b s p xu ng l vng gi a y l i v thnh sau c a h ng. 8.2.5. Lm nh ra tr c c c m l i C c m l i y l i ra tr c, khi c n y gin ra khi ng , th ng kh b h p l i. 8.2.6. Treo xng mng Xng mng gip nng thanh qu n v l i trong c . 8.2.7. Lm nh ra tr c xng hm d i Ph u thu t n y lm di chuy n hm v rng trn ra pha tr c 8.2.8. Khai kh qu n Ph u thu t ny c m c ch lm ng vng qua ng kh b h p. 8.2.9. Ph u thu t bo ph: Ph u thu t n y lm gi m cn.
NGNG TH
1.
KHI NG TRUNG NG
nh ngha Ngng th khi ng trung ng l m t r i lo n trong hi n t ng th b ngng l i v b t u trong lc ng do thi u g ng s c h h p. Khng gi ng nh ngng th khi ng t c ngh n trong g ng s c th bnh th ng nhng khng th th c do t c ngh n ng h h p trn, ngng th khi ng trung ng x y ra khi no khng truy n tn hi u chnh xc n cc c ki m sot th . Ngng th khi ng trung ng t g p hn nh ng lo i khc, chi m kho ng t hn 10% ngng th khi ng . 2. Tri u ch ng Nh ng tri u ch ng th ng g p nh t c a ngng th khi ng trung ng bao g m: - Nh ng o n ngng th hay ki u th b t th ng trong lc ng - T nh gi c t ng t ph i h p v i th ng n - M t ng - Ng ngy nhi u - Th ng n t m th i ban m - Kh t p trung
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N u ngng th khi ng trung ng do th n kinh, c th c nh ng tri u ch ng sau: - Chng m t khi ng t m t t th ng i hay n m - Kh nu t - Y u hay t cng ton thn Ngy cng c th g p, nhng t hn trong ngng th khi ng t c ngh n. 3. Nguyn nhn Ngng th khi ng trung ng x y ra khi no khng lm trn nhi m v truy n tn hi u n nh ng c th . Ngng th khi ng trung ng c th do m t s b nh l nh h ng n kh nng c a thn no qua k t n i no v i t y s ng v ki m sot nhi u ch c nng nh nh p tim, nh p th ki m sot th . Nguyn nhn thay i theo type c a ngng th khi ng trung ng, bao g m: 3.1. Ngng th khi ng trung ng khng r nguyn nhn Bi u hi n v i nh ng s ngng g ng s c th v lu l ng th l p i l p l i. 3.2. H h p ki u Cheynes-Stokes Type ny th ng ph i h p nh t v i suy tim sung huy t hay t qu , v c c i m l s g ng s c th v lu l ng gia tng r i gi m d n d n c chu k. Trong lc g ng s c th y u nh t, m t s thi u ton b lu l ng kh c th x y ra. 3.3. B nh l n i khoa Ngoi suy tim sung huy t v t qu , nh ng b nh n i khoa c th gy nn ngng th khi ng trung ng. B t k m t t n thng no c a ph n no ki m sot th (thn no) hay nh ng dy th n kinh cung c p nh ng tn hi u th nh u no, ch n thng, nhi m trng (v d nh b nh b i li t) hay t n thng thoi ha no c th l suy km qu trnh th . Thm vo , nh ng t n thng nh h ng n c nh x c ng c t bn teo c, lo n d ng c hay nh c c cng c th gy ngng th khi ng trung ng hay th y u lc ng . 3.4. Th nh k cao Th nh k x y ra ph n l n nh ng ng i s ng cao trn 15.000 feet (1 feet = 0,3048m). S thay i p l c phong v bi u cao n y c th gy nn th nhanh. Ki u th n y c th gi ng nh h h p ki u Cheynes-Stokes, nhng th i gian ng n hn. 3.5. Thu c Opioids nh morphine, oxycodone hay codeine c gy nn nh p th khng u. 4. Tri u ch ng lm sng - Th ng n nh th c t gi c ng - Ngng th cch kho ng trong lc ng - Kh n m ng - Bu n ng nhi u ban ngy, c th gy ng khi lm vi c, xem truy n hnh hay li xe.
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H i bc s v v n gi c ng b t k l i m t m i, bu n ng hay kch thch. Bu n ng ban ngy nhi u c th do nh ng b nh khc nh cn ng thong qua. 5. Nh ng tt nh gi v ch n on 5.1. Theo di ban m b ng a k gi c ng
Ngng th khi ng trung ng v i h h p ki u Cheynes-Stokes Trong tt ny, ng i ta theo di tim, ph i, ki u th , c ng chn tay v m c ng oxy mu khi ng . Tt ny c gip cho bc s lo i t nh ng b nh khc nh c chn tay nh k hay cn ng thong qua, c th gy nn ng ban ngy nhi u nhng yu c u i u tr khc. 5.2. Theo di oxy mu b ng oxy k Theo di v ghi l i m c oxy mu khi ng . Tuy nhin oxy k khng th pht hi n t t c nh ng tr ng h p ngng th khi ng , do bc s c th yu c u th c hi n a k gi c ng ngay c k t qu oxy mu bnh th ng. 5.3. Tt th xch tay Bc s c th cung c p nh ng tt t i nh pht hi n ngng th khi ng . Nh ng tt ny th ng l oxy k o lu l ng th v ki u th . C n ph i c nh gi thm b ng bc s tim m ch hay bc s th n kinh tm nguyn nhn. 6. Bi n ch ng 6.1. Tim m ch S t t t ng t m c oxy mu x y ra trong ngng th lm gia tng huy t p v lm vi c qu m c h th ng tim m ch. Nh ng thay i ny lm gia tng nguy c suy tim v t qu . N u c b nh tim c s n, nh ng tnh tr ng thi u kh n y lm x u i tin l ng v lm gia tng nguy c r i lo n nh p tim. 6.2. M t ban ngy Nh ng l n nh th c l p i l p l i ph i h p v i ngng th lm cho b nh nhn khng th ng bnh th ng v h i ph c c. Ng i b ngng th th ng b bu n ng
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ban ngy n ng, m t v kch thch. B nh nhn c th kh t p trung v ng khi lm vi c, xem truy n hnh hay li xe. 7. i u tr 7.1. i u tr cc v n n i khoa: nh suy tim, bnh th n kinh c. 7.2. Gi m s d ng opioids: c th gi m li u 7.3. Th oxy: khi ng 7.4. Thu c: acetazolamide phng ng a ngng th khi ng trung ng do cao . 7.5. p l c ng kh dng tnh lin t c (xem ph n Ngng th khi ng t c ngh n) 7.6. p l c ng kh dng tnh hai m c (xem ph n Ngng th khi ng t c ngh n) 7.7. Thng kh cung c p thch h p: thi t b theo di ki u th bnh th ng v tch tr thng tin trong my tnh. Sau khi b nh nhn i ng , my s d ng p l c i u ha ki u th c a b nh nhn v phng ng a nh ng lc ngng th .
NGNG TH
KHI NG H N H P V PH C T P
M t s ng i b ngng th khi ng c s ph i h p c hai lo i. Khi ngng th khi ng t c ngh n n ng v ko di, i khi pht tri n nh ng o n b ngng th khi ng trung ng. C ch chnh xc c a m t pht ng h h p trung ng trong lc ng c a ngng th khi ng t c ngh n l khng r, nhng th ng lin quan m t thi t v i thng b ng toan-ki m, v m t ch c nng ph n h i kh cacbonic do suy tim. C m t nhm b nh v tri u ch ng lin quan n kh i c th , r i lo n tim m ch, h h p v th n kinh. B nh nhn b ngng th khi ng ph c t p c ngng th khi ng t c ngh n nhng do s d ng p l c ng kh dng tnh, b nh nhn l i b ngng th khi ng trung ng th ng xuyn. Lo i ngng th khi ng trung ng th ng c ghi nh n khi b nh nhn s d ng p l c ng kh dng tnh, sau khi ngng th khi ng t c th i u tr ngh n c lo i tr . Thng kh cung c p thch h p c a vo lo i ngng th khi ng ph c t p n y.
TI LI U THAM KH O
1. Wikipdia; Apne du sommeil; Ce document provient de http://fr. ikipedia.org/wiki/Apn%C3%A9e du sommeil; Dernire modification de cette page le 25 novembre 2008. 2. S.H.Onen. Syndrome dapne du sommeil de ladulte; Journal du jeune praticien; 2007. 3. Reginald H.B.Goodday, DDS, MSc, FRCD; David S. Precious, DDS, MSc, FRCD; Archibald D. Morrison, DDS, MSc, FRCD ; Chad G. Robertson, DDS. Le syndrome dapne obstructive du sommeil : Diagnostic et traitement; Le centre de documentation de lADC ; 2001. 4. Huw Thomas. Questionnaire Epworth sleepness scale; Sonoring and sleep Apnoea, 2008. 5. MayoClinic .com. Bookstore. Central sleep apnea; Jan 3, 2009. 6. Wikipedia. Sleep apnea. Last modified on 22 November 2008. 7. Andrew Verneuil MD. Sleep apnea; Medicine Net.com; last editorial 9/2/2005.
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CH N L A STATIN NO L T I U TRONG D PHNG TIN PHT V TH PHT B NH TIM M CH?

Tr n Vn Huy B nh vi n a khoa t nh Khnh Ha L i ch: Nhi u nghin c u cho th y t m quan tr ng c a l i ch i u tr statin l lin quan n cc y u t nguy c tim m ch c a t ng c nhn v m c lm h cholesterol hn l n ng cholesterol ban u [1-7]. M t phn tch t ng h p v t t c cc th nghi m lm sng statin chnh bao g m c d phng tin pht v th pht v i 90.056 i t ng trong 14 th nghi m statin ng u nhin th y r ng gi m m i mmol/L cholesterol c lipoprotein t tr ng th p (LDL) tng ng gi m 12% t l t vong do m i nguyn nhn (t s chnh [RR] 0.88, 95% CI 0.84-0.91; p<0.0001). i u n y ph n nh gi m 19% t vong m ch vnh c ngha v gi m khng c ngha trong t vong khng do m ch vnh (0.93, 0.83-1.03; p=0.2) v t vong khng do m ch mu (0.95, 0.90-1.01; p=0.1). C m t s gi m tng ng c ngha trong nh i mu c tim (NMCT) v t vong do m ch vnh (0.77, 0.74-0.80; p<0.0001), trong nhu c u ti lu thng m ch vnh (0.76, 0.73-0.80; p<0.0001), trong t qu t vong ho c khng t vong (0.83, 0.78-0.88; p<0.0001), v t ng h p chung gi m 21% trong b t k m t bi n c m ch mu l n (0.79, 0.77-0.81; p<0.0001). T l gi m cc bi n c m ch mu l n khc bi t c ngha theo s gi m LDL cholesterol t c. Nh ng l i ch trn c ghi nh n l c ngha ngay t nm u i u tr v l n hn trong nh ng nm v sau [3]. K t qu t nghin c u lm sng d phng tin pht l n nh t (n = 10.305), so snh atorvastatin v i placebo i u tr trn hn 3 nm cho th y s c n i u tr (number trnh m t tr ng h p t vong do b nh m ch vnh ho c needed to treat) (NNT) NMCT khng t vong nh ng i t ng khng b nh m ch vnh l 95 (95% CI 60 i v i d phng th pht, k t qu t 3 th nghi m l n nh ng ng i c 216).[21] b nh m ch vnh (n = 9014 [pravastatin], n = 4444 [simvastatin] v n = 4159 [pravastatin]), theo di g n 5-6 nm, g i s NNT c n trnh m t tr ng h p t vong do b nh m ch vnh ho c NMCT khng t vong nh ng i t ng c b nh m ch vnh l 29 (95% CI 20 - 48), 12 (95% CI 9 - 16) v 34 (95% CI 20- 96), l n l t [13]. C m t s khc bi t gi a cc statin trong vi c lm h m c LDL cholesterol, qua phn tch t ng h p 164 th nghi m ghi nh n t l ph n trm h LDL cholesterol gi a cc statin v li u hng ngy c ghi nh n theo b ng 1 [6]. Tuy nhin v l i ch lm sng, d a vo nh ng d li u c s n, cho n nay cha c m t statin no ch ng t u vi t hn h n cc statin khc trong vi c gi m cc bi n c lm sng.[14] B ng 1: Ph n trm gi m LDL theo li u statin hng ngy ( c tnh t 164 th nghi m ng u nhin c i ch ng) [6] Tc h i: Khng c b ng ch ng statin lm tng t l ung th. M t phn tch t ng h p 23 th nghi m statin v i 309.000 ng i/nm, ghi nh n khng c s lin quan c ngha gi a i u tr h LDL cholesterol v tng men gan (R2 < 0.001, p = 0.91), tiu c (R2 = 0.05, p = 0.16), ho c t l ung th (R2 = 0.09, p = 0.92)[7-8]. C m t t l men
39
gan tng cao hn c ngha khi dng statin li u cao so v i nhm i u bnh ho c th p [7-8] Ph n trm gi m LDL* 5 mg 10 mg 20 mg 40 mg Lovastatin (Mevacor) 21% 29% 37% Pravastatin (Pravachol) 15% 20% 24% 29% Fluvastatin (Lescol) 10% 15% 21% 27% Simvastatin (Zocor) 23% 27% 32% 37% Atorvastatin (Lipitor) 31% 37% 43% 49% Rosuvastatin (Crestor) 38% 43% 48% 53% * Ph n trm gi m c l p v i m c LDL tr c i u tr .
tr li u trung 80 mg 45% 33% 33% 42% 55% 58%
Chi ph v hi u qu : Ngoi vi c xem xt tnh l i ch v tc h i trn lm sng c a m t li u php i u tr , ngy nay quy t nh i u tr cn c n ph i xem xt v m t kinh t gi a tnh chi ph v hi u qu v lu di c a li u php i u tr . Trong d phng b nh tim m ch, dng thu c lm h cholesterol khng ch c l i ch r r t m cn g n nh lun lun c hi u qu khi xt gi a chi ph v tnh hi u qu trong c d phng tin pht l n th pht.[9-14] c tnh m i nm t i Hoa K v i li u php i u tr lm h lipid mu thch ng b nh nhn c b nh m ch vnh c th th ti t ki m hng t dollar.[9] M t phn tch t ng h p h th ng nh gi v gi tr kinh t c a statin trong d phng cc bi n c m ch vnh ghi nh n r ng trong d phng th pht b nh m ch vnh, s ti n l i t t l chi ph-hi u qu (ICERs) (incremental cost-effectiveness ratios) gia tng v i tu i khc bi t t 10.000 b ng Anh n 17.000 b ng Anh cho m i nm i s ng c ch t l ng (QALY) (quality adjusted life year) i v i tu i 45 v 85 l n l t. Trong d phng tin pht, c m t s khc bi t gi a ICERs theo tu i v cc y u t nguy c cng hi n di n. Ti n l i ICERs ty theo m c nguy c c s khc bi t t i v i nam v t 21.000 n 57.000 b ng Anh i v i 20.000 n 27.000 b ng Anh n .[10] Theo k t qu c a th nghi m Incremental Decrease in Endpoints Through Aggressive Lipid Lowering (IDEAL), cho th y m t s gi m c ngha cc bi n c tim m ch v i li u cao atorvastatin (80mg/ngy) so v i li u simvastatin generic thng th ng 20-40mg nh ng b nh nhn c b nh m ch vnh v i gi m 11% t vong b nh m ch vnh v nh i mu c tim (RR 0.89; 95% CI 0.781.01), gi m 13% cc bi n c m ch mu l n (RR 0.87; 95% CI 0.770.98) v 16% b t k bi n c m ch vnh no (RR 0.84;95% CI 0.760.91). Xt chi ph-hi u qu ghi nh n m c d u gi thnh m i li u c a atorvastatin cao hn nhng xt theo ICERs th li u php li u cao ti t ki m kho ng 50.000 b ng Anh cho m i QALY t i cc n c an M ch, Na Uy v Th y i n v gi tr n y cao hn n a t i Ph n Lan (gi tr 2005).[11,12] M t phn tch g p khc t i Hoa K bao g m c IDEAL v nh ng ngu n d li u khc cho th y atorvatatin li u cao c ICER l 33.400 dollar cho m i QALY, v s khc bi t gi l i ch thu c gi a li u cao atorvastatin so v i li u simvastatin thng th ng theo ngy l 1,40 dollar/ngy (gi tr 2005).[12] Phn tch chi ph-hi u qu d a trn nh ng th nghi m l n so snh atorvastatin v i placebo, chm sc n i khoa thng th ng, simvastatin ho c pravastatin cho th y chung r ng atorvastatin l g n li n m t gi tr ICER thch h p nh t, so v i li u php th ng dng.[9] Khuynh h ng k toa c a cc statin, t i Hoa K trong m t nghin c u m i y nghi nh n trong 2003-2004, 56% ang dng atorvastatin; 10%,
40
22%, v 12% ang dng pravastatin, simvastatin, v cc statin khc (cerivastatin, fluvastatin, lovastatin, or rosuvastatin), l n l t [20]. T i Anh, atorvastatin c k toa trong 49% ch nh d phng th pht v 45% trong d phng tin pht.[14] Tuy nhin, theo khuy n co c a Vi n S c Kh e V Ch t L ng Lm Sng Qu c Gia (NICE) c a NW London Anh Qu c nm 2006 xem xt ch ng c lm sng v chi ph-hi u qu , thng tin v s ho t ng, ngu n thu c v gi c cng nh ki n c a cc chuyn gia trong vi c xem xt ch n l a s n ph m statin no i v i d phng tin v th pht b nh tim m ch khuy n co r ng simvastatin c ch p nh n nh l statin hng u ch n l a trong c d phng tin l n th pht.[13] Trong l n c p nh t l i nm 2008, b ng h ng d n n y i u ch nh m t s b nh c nh m atorvastatin c xem nh ch n l a hng u.[14] i v i rosuvastatin, c m t vi bi bo ghi nh n c m t l i ch ICERs c c tnh i v i thu c nhnh rosuvastatin so v i thu c nhnh atorvastatin, simvastatin generic v pravastatin.[15-17] Li u rosuvastatin i v i ng i chu theo khuy n co NICE c a Anh th li u kh i u l 5mg v li u t i a l 20mg.[14] Tuy nhin, nh ng ch ng c lm sng trn t vong chung v cc bi n c tim m ch trong d phng th pht cha c. Chnh v v y c n c nh ng nghin c u c l p v ch ng c lm sng v tnh chi ph-hi u qu r rng hn n a m i ng c cho thu c ch n l a hng u trong c d phng tin v th pht. Hnh 1: So snh gi c a cc statin cho 28 ngy t i Anh 5/2006 ( n v ti n t B ng Anh) [14]
B ng 2: Gi cc lo i statin thng d ng c c p php lu hnh t i Vi t Nam (gi tr 3/2009) Thu c Atorvastatin: 10mg 20mg Gi 1v Thu c Nhnh 14.760 VND 21.083 VND Thu c generic VN (Domesco, Pym, Has ..) 2.000VND 2.500-3.500VND Thu c generic Chu (India, Pakistan) 3.000 VND 4.000VND
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Rosuvastain:10mg 16.070 VND 6.000 VND 9.000VND Simvastatin 20mg 10.600 VND 2.500-3.100VND 3.500VND i v i th c t Vi t Nam cng nh Chu , hi n c nh ng gi i h n v ch ng c lm sng c a cc statin c nghin c u ring i v i ng i Chu , cng nh gi a cc li u chu n hay li u cao l i ch nh th no, theo nghin c u JELIS c th c hi n t i Nh t B n cho th y li u th p pravastatin 10mg -20mg k t h p v i ti t th c cho th y gi m cc bi n c tim m ch 33% so v i ti t th c m t mnh v cc tc gi k t lu n hi u qu tng t nh li u cao ng i phng Ty [19], tuy v y c ch ng c hn c n ph i c nh ng nghin c u so snh c l p gi a hai li u m i thuy t ph c hn. Ring v gi gi a cc lo i statin v cc li u th c m t s khc bi t l n, hi n t i Vi t Nam, atorvastatin, rosuvastain, simvastatin ch ph m generic u c cho php lu hnh m cc thu c n y s n xu t ng ch t l ng k thu t theo cc tiu ch GMP/WHO, GLP, GSP.... B ng gi thu c cc statin ang c php lu hnh t i Vi t Nam c p nh t thng 3/2009 theo b ng 2. ng d ng th c hnh: Do cha c m t ch ng c lm sng no s n c ch ng t m t lo i statin no u vi t hn h n cc lo i statin khc trong gi m cc bi n c tim m ch. Cc khuy n co c a NICE cng nh c a T ch c Y T Th gi i nh b t bu c, cn khng th ch n (WHO) u khuy n co tr phi c nh ng ch l a lo i statin no i u tr lc u ph i l lo i c chi ph - hi u qu l i ch nh t (theo li u hng ngy v gi m i li u) [13,18]. H ng d n k toa statin no lc u trong d phng tin v th pht b nh tim m ch c a khuy n co NICE 2008 (Anh qu c), d a vo th c t t i y atorvastatin nm 2011 m i h t quy n b o h , h h ng d n r ng khi b nh nhn c ch nh statin th xem dng statin no cha, n u cha th xem c ang s d ng thu c c ch men CYP3A4 ho c cyp450 n u c dng pravastatin, khng th xem m c LDL n u > 5mmol/L ch nh atorvastatin 20mg/ngy, n u LDL <5mmol/L th simvastatin 40mg (n u b nh nhn c nguy c ph n ng ph v c th dng li u 20mg r i tng d n ln 40mg), trong tr ng h p khng dung n p simvastatin ho c suy th n v i l c c u th n <30ml ho c khng t m c tiu v i li u simvastatin t i a th chuy n sang atorvastatin. Cn trong tr ng h p ang dng m t lo i statin no r i th xem xt s p ng m c tiu nh th no, v n u c cc bi n c m ch vnh c p g n y th xem xt li u cao atorvastatin v c th tham kh o thm chuyn gia i u tr lipid.[14] Tr l i th c t Vi t Nam, atorvastatin generic gi r c php lu hnh th c n xem xt nh thu c hng u theo tiu ch c a WHO [18] v NICE [13] trong c d phng tin pht l n th pht, tuy nhin c n ch chu n thu c generic qu c t v th tng ng sinh h c. Trong m t nghin c u g n y nh t (2-2009) nh gi v s tun th statin v t l t vong chung trong d phng tin pht 136.952 b nh nhn khng c b nh tim v i th i gian theo di trung bnh 4 nm, v trong d phng th pht 93.866 b nh nhn theo di trung bnh 5 nm, ghi nh n n u s tun th dng statin lin t c 90% th i gian trong th i k theo di th g n li n v i gi m 45% trong d phng tin pht v 51% trong d phng th pht v nguy c t vong khi so v i nh ng c nhn ch dng 10%. (b ng 3).[22] Chnh v v y s tun th trong i u tr statin l r t quan tr ng cho vi c d phng c hi u qu . Qua tiu ch
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ch n l a m t statin gi thnh th p nh t v i ch ng minh c t chi ph - hi u qu cao l s ch n l a t i u. B ng 3: T l ngy dng statin v t vong chung [22] T l ngy dng statin trong th i k nghin c u, % <10 10 - 19 50 - 59 90 T Hazard (95% CI), T Hazard (95% CI), d phng tin pht secondary-d phng th pht 1 (tham kh o) 1.35 (1.22 - 1.50) 0.77 (0.67 - 0.88) 0.55 (0.49 - 0.61) 1 (tham kh o) 1.28 (1.18 - 1.39) 0.69 (0.63 - 0.76) 0.49 (0.46 - 0.53)
TI LI U THAM KH O
1. Lewington S, Whitlock G, Clarke R, et al. Blood cholesterol and vascular mortality by age, sex, and blood pressure: a meta-analysis of individual data from 61 prospective studies with 55,000 vascular deaths. Lancet 2007;370:1829 39. 2. Cobain MR, Pencina MJ, DAgostino RB Sr., Vasan RS. Lifetime risk for developing dyslipidemia: the Framingham Offspring Study. Am J Med 2007;120:623 30. 3. Baigent C, Keech A, Kearney PM, et al. Efficacy and safety of cholesterollowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins. Lancet 2005; 366:126778. 4. Thavendiranathan P, Bagai A, Brookhart MA, Choudhry NK. Primary prevention of cardiovascular diseases with statin therapy: a meta-analysis of randomized controlled trials Arch Intern Med 2006;166:2307-2313. 5. Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report. Circulation 2002;106:31433421. 6. Law MR, Wald NJ, Rudnicka AR. Quantifying effect of statins on low density lipoprotein cholesterol, ischaemic heart disease, and stroke: systematic review and meta-analysis. BMJ 2003;326:1423-30. 7. Alsheikh-Ali, A; Maddukuri, PV; Han, H, et al. Effect of the magnitude of lipid lowering on risk of elevated liver enzymes, rhabdomyolysis, and cancer: insights from large randomized statin trials. J Am Coll Cardiol. 2007;50:40918. 8. Kapur NK, Musunuru K. Clinical efficacy and safety of statins in managing cardiovascular risk. Vasc Health Risk Manag. 2008 April; 4(2): 341353. 9. Plosker GL ; Lyseng-Williamson KA Atorvastatin: a pharmacoeconomic review of its use in the primary and secondary prevention of cardiovascular events. Pharmacoeconomics. 2007; 25(12):1031-53
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10. Ward S, Lloyd Jones M, Pandor A, et al. A systematic review and economic evaluation of statins for the prevention of coronary events Health Technol Assess 2007;11:1-160iii - iv. 11. Lindgren P, Graff J, Olsson AG, Pedersen TJ, Jnsson B, on behalf of the IDEAL trial investigators. Cost-effectiveness of high-dose atorvastatin compared with regular dose simvastatin. Eur Heart J (2007) 28:14481453. First published on March 19, 2007, doi:10.1093/eurheartj/ehm020. 12. Chan PS ; Nallamothu BK ; Gurm HS et al. Incremental benefit and costeffectiveness of high-dose statin therapy in high-risk patients with coronary artery disease. Circulation. 2007; 115(18):2398-409 13. NICE. Statins for the prevention of cardiovascular events Assessment Report: Coronary Heart DiseaseStatins http://www.nice.org.uk/pdf/statins_assessment_report.pdf 20082005. Accessed October 14, 2008. 14. Frances Horne, - 2 - Prescribing Adviser, on behalf of the NWLCN. Guidance on Prescribing of Statins in Primary & Secondary Care across NW London. http://www.nwlcn.co.uk/pdfs/amendedfinalstatinpresguide41207.pdf 15. Costa-Scharplatz M, Ramanathan K, Frial T, Beamer B, Gandhi S. Costeffectiveness analysis of rosuvastatin versus atorvastatin, simvastatin, and pravastatin from a Canadian health system perspective. Clin Ther. 2008 Jul;30(7):1345-57. 16. BL Tran YB; Frial Y, Miller PS Statin's cost-effectiveness: a Canadian analysis of commonly prescribed generic and brand name statins. Can J Clin Pharmacol. 2007 Summer;14(2):e205-14. Epub 2007 Jun 5. 17. Ohsfeldt RL,Gandhi SK, Fox KM, McKenney JM Statin Cost-Effectiveness Comparisons Using Real-World Effectiveness Data: Formulary Implications. Value in Health. 2008, vol 11, 7; 10611069. 18. World Health Organization. Prevention of Cardiovascular Disease. Guidelines for assessment and management of cardiovascular risk. Geneva, 2007. 19. Yokoyama M, Origasa H, Matsuzaki M, et al. Effects of eicosapentaenoic acid on major coronary events in hypercholesterolaemic patients (JELIS): a randomised open-label, blinded end point analysis Lancet 2007;369:1090-1098 20. Mann D, Reynolds K, Donald D, Muntner P. Trends in Statin Use and LowDensity Lipoprotein Cholesterol Levels Among US Adults: Impact of the 2001 National Cholesterol Education Program Guidelines. Published Online, 22 July 2008, www.theannals.com, DOI 10.1345/aph.1L181. 21. Sever PS, Dahlof B, Poulter NR, Wedel H, Beevers G, Caulfield M, Collins R, Kjeldsen SE, Kristinsson A, McInnes GT, et al; ASCOT investigators. Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower than-average cholesterol concentrations, in the Anglo-Scandinavian Cardiac Outcomes TrialLipid Lowering Arm (ASCOTLLA): a multicentre randomised controlled trial.Lancet 2003;361:11491158. 22. Shalev V, Chodick G, Silber H, et al. Continuation of statin treatment and all-cause mortality. Arch Intern Med 2009; 169:260-268.
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KHUY N CO 2008 SUY TIM C P C A H I TIM M CH CHU U

Tr ng I. Nguy n Anh V i h c Y D c Hu
NH NGHA Suy tim c p l b nh c nh kh i pht ho c bi n i nhanh chng cc tri u ch ng v d u ch ng gy ra do suy ch c nng tim c n thi t ph i i u tr c p c u k p th i. y l tnh hu ng n ng n c th gy t vong v th c n c p c u. Ng i b nh c th c ho c khng c b nh tim tr c . R i lo n ch c nng tim c th do r i lo n ch c nng tm thu ho c tm trng, b t th ng nh p tim ho c tng ti n gnh ho c h u gnh.
Phn lo i lm sng c a suy tim c p II. LM SNG BN l l n, chi l nh, ti u t c cung l ng tim th p, p l c lm y mu cao, tng s c c n m ch h th ng. Hay km chong tim. Nghe ph i + xem tnh tr ng ph ng tnh m ch c nh gi nhanh th tch mu v p l c lm y mu, phn bi t suy th t tri v ph i. Quan tr ng v i u tr khc nhau (truy n d ch ho c l i ti u) Khm m m tim, nghe ti ng tim b nh l (ng a phi, h van, T2 ). III. C N LM SNG ECG Ch n on r i lo n nh p tim H i ch ng m ch vnh c p Tr ng thi t i c a tim X quang v KT hnh nh khc Ch p phim x quang: nh gi kch th c tim, tnh tr ng k t qu i u tr . Phn bi t suy tim v vim ph i CT v x hnh ph i: t c MP CT, TEE v MRI: phnh tch ng m ch ch .
mu ph i. Theo di
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Siu m tim: l thm d nh t thi t ph i c nh gi c u trc ch c nng th t cng nh h/c m ch vnh c p. Thng s : hnh thi tim, ch c nng th t v van tim, d ch mng ngoi tim, p l c ng m ch ph i, bi n ch ng c h c NMCT, cung l ng tim. IV. CH N ON 4.1. Cc b c ch n on
4.2. Phn lo i lm sng (D a vo tu n hon ngo i vi t c s t i mu v nghe ph i)
Lo Lo Lo Lo
i I: kh v m i II : m v m i III: kh v l nh i IV: m v l nh
V. I U TR 5.1. M c tiu i u tr 5.1.1. T c th - C i thi n tri u ch ng - Ph c h i oxy - C i thi n huy t ng v t i mu cc c quan - H n ch cc t n thng c a th n v tim - Gi m th i gian i u tr t i n v i u tr tng c ng.
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5.1.2. Trung h n (t i b nh vi n) - n nh b nh nhn v h p l ha chi n l c i u tr - Kh i ng i u tr thu c thch h p - Cn nh c s d ng cc thi t b i u tr nh ng b nh nhn c ch nh thch h p - Gi m th i gian n m vi n 5.1.3. i u tr tr c khi xu t vi n v di h n - nh k ho ch chi n l c theo di - Gio d c v b t u i u ch nh l i s ng - Phng ti nh p vi n s m phng b nh th pht - t t t ch - C i thi n ch t l ng cu c s ng v s ng cn c a b nh nhn. 5.2. i u tr c th 5.2.1. Oxy v thng kh h tr Yu c u bo ha oxy trong kho ng 95-98% c th chu c p oxy y cho t ch c. - Thng kh h tr khng t ng n i kh qu n: c 2 phng cch l p l c dng lin t c ng th (CPAP-continuous positive airway pressure) v thng kh p l c dng khng xm nh p (NIPPV-noninvasive positive pressure ventilation) gp ph n lm gi m nhu c u t ng n i kh qu n. t ng n i kh qu n: ch nn th c hi n n u nh suy h h p c p khng p ng v i thu c gin m ch, li u php oxy v/ho c CPAP ho c NIPPV. 5.2.2. L i ti u quai Tng th i mu i natri, n c v cc ion khc lm gi m th tch huy t tng v d ch ngo i bo, gi m p l c lm y mu th t tri v th t ph i v v y b t xung huy t ngo i vi cng nh b t ph ph i. Tim tnh m ch l i ti u cng gy gin m ch nhng v i li u cao (>1mg/kg) l i gy co m ch ph n x . Furosemide 20-40mg t i 40-100mg tim bolus v truy n 5-40mg/h. Thu c c a chu ng tim tnh m ch. C th ph i h p Dobutamine, Dopamine v/ho c Nitrates. 5.2.3. c ch beta Suy tim c p xem nh ch ng ch nh. Ch ng c nghin c u no cho th y c i thi n suy tim c p v i c ch beta. Trong nh i mu c tim c p, c ch beta tc d ng lm gi m kch th c nh i mu, lo n nh p tim v au ng c. Gi m t l m c b nh v t vong b nh nhn c xung huy t ph i. Cch s d ng: n u c suy tim m n cho sau khi n nh suy tim c p(>4 ngy). Th n tr ng trn b nh nhn suy tim c p r v nhi u ran y ph i. Cn nh c Metoprolol n u thi u mu c c b ti n tri n, nh p tim nhanh. B nh nhn nh i mu c tim c p suy tim c p n nh c th kh i ng c ch beta s m. 5.2.4. Cc thu c tng co bp c tim c ch nh trong tr ng h p gi m t i mu ngo i vi (h huy t p, ch c nng th n gi m). Tuy cc thu c ny c th r t ch l i c i thi n huy t ng nhng l i d sinh lo n nh p, c th gy thi u mu c c b c tim, m t khc khi s d ng lu di c th c r i lo n ch c nng c tim do tng qu m c tiu t n nng l ng. T l nguy c-c l i khc nhau ty theo thu c, nh ng thu c tc d ng qua c ch kch thch 1 giao c m lm tng n ng canxi trong tng bo c nguy c cao nh t.
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- Dopamine: l m t cathecholamin n i sinh, ti n ch t c a Norepinephrine. N tc ng ln c m th quan cc h dopaminergic, adrenergic, adrenergic. V i li u th p < 2 g /kg/pht tc d ng trn c m th quan dopaminergic gy gin m ch tr i m ch th n, m ch vnh, m ch no, m ch lch. li u ny thu c lm tng dng mu th n, tng l c c u th n, l i ti u th i mu i natri, tng p ng v i thu c l i ti u b nh nhn c gi m t i mu th n, suy th n. Li u >2 g /kg/pht gy tng co bp c th t v cung l ng tim do kch thch h giao c m tr c ti p v gin ti p. Li u >5 g /kg/pht tc ng ln c h gy co m ch lm tng s c c n ngo i vi v v th c ch n u huy t p t t. ng d ng th c ti n: Dopamine dng li u >2 g /kg/pht n u suy tim c p c h huy t p, li u < 2-3 g /kg/pht n u suy tim m t b c huy t p th p v thi u ni u. - Dobutamine: l thu c co c kch thch c m th quan 1 v 2 v i t l 3:1. Hay c dng tng cung l ng tim. Kh i u 2-3 g /kg/pht khng c li u n p. Tng t i 20 g/kg/pht. ng i b nh ang dng c ch c th c n li u cao hn (1520g/kg/pht). C th dng ph i h p v i PDEi. Thu c th i nhanh chng sau khi ngng truy n. Lu l truy n ko di (>24-48h) s d n t i dung n p thu c v m t m t ph n hi u qu ln huy t ng. - PDEi ( c ch phosphodiesterase): thu c ny c c ch tc d ng thng qua c ch chuy n AMP vng thnh AMP. Khi s d ng thu c lm tng co c, gin m ch ngo i vi, tng cung l ng tim, th tch t ng mu, gi m ng th i p l c ng m ch ph i, mao m ch ph i, s c c n m ch ph i v h th ng. Ph tc d ng c a n trung gian gi a thu c gin m ch nh Nitroprusside v thu c co c nh Dobutamine. Ch nh: khi gi m t i mu ngo i vi v i c ho c khng c tr tr v i i u tr l i ti u, gin m ch li u thch h p v huy t p b o t n. Thu c ny a s d ng hn Dobutamine trong tr ng h p i u tr c ch ng th i v/ho c p ng khng y v i Dobutamine. Tim li u n p 25-75g/kg trong 10-20 pht, Enoximone 0,25-0,75mg/kg sau truy n (Milrinone 0,375-0,75 g/kg/pht, Enoximone 1,25-7,5g/kg/pht). - Levosimendan: tc d ng tng co c (lm protein co bp tng nh y c m v i canxi) v gin m ch ngo i vi (m knh Kali). Thu c ch nh trong suy tim cung l ng th p c tri u ch ng th pht sau gi m ch c nng tm thu nhng khng c t t p huy t n ng (khng cho khi huy t p tm thu <85mmHg). Li u truy n lin t c 0,05-0,1g /kg/pht, tr c c li u n p 12-24g/kg trong 10 pht. 5.2.5. Ch ng ng Ch nh trong h i ch ng m ch vnh c p ho c rung nh v i c ho c khng c suy tim c p. Ni chung t c b ng ch ng bi n minh cho s d ng thu c ny trong suy tim c p v i b nh c nh khc. 5.2.6. Thu c gin m ch - Nitrate c tc d ng lm nh b t xung huy t ph i nhng khng lm gi m th tch t ng mu v cng khng lm tng nhu c u oxy c tim trong suy tim tri c p, c bi t l ng i b nh c h i ch ng vnh c p. li u th p n ch gy gin tnh m ch. Tuy nhin v i li u tng ln th n gin c ng m ch bao g m m ch vnh. V i li u thch h p thu c tc ng cn b ng gin c ng m ch tnh m ch lm gi m ti n gnh l n h u gnh c a th t tri m khng lm gi m t i mu m. N u nh huy t p n nh th c th cho Glyceril trinitrat (20-200g/pht) ho c IDN 1-10mg/h.
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- Nitroprusside li u 0,3-5g/kg/pht. Ch nh: suy tim n ng c tng h u gnh (tng huy t p, h van hai l). Khi dng ph i i u ch nh li u c n th n c theo di huy t p lin t c cng nh gim st ch t ch b nh nhn. Trnh dng b nh nhn c suy gan th n n ng. Trong h i ch ng m ch vnh c p, Nitrates t t hn do khng gy h i ch ng tr m mu m ch vnh nh Nitroprusside. - Nesiritide: l thu c gin m ch m i, t h p peptide no ng i (BNP) c tc d ng gin tnh m ch, ng m ch, m ch vnh qua lm gi m ti n gnh v h u gnh, tng cung l ng tim. Ch nh trong suy tim m t b c p (li u tim n p 2g/kg + truy n 0,015-0,03 g/kg/pht. ang cn t kinh nghi m s d ng lm sng thu c ny. - Morphine: ch nh trong giai o n s m c a suy tim n ng nh t l n u c km tri u ch ng b t an v kh th . Thu c c tc d ng gin tnh m ch cng nh gin nh ng m ch, gi m t n s tim. Li u dng 3 mg tim tnh m ch c th nh c l i n u c n. 5.2.7. Thu c v n m ch Khi ph i h p thu c tng co c tim v d ch truy n m v n khng c i thi n cung l ng tim, khu ch tn cc c quan th c n s d ng thu c v n m ch. Ngoi ra trong m t s tnh hu ng s ng cn th thu c v n m ch duy tr t i mu do ch ng l i hi n t ng h p. V l chong tim th ng ph i h p v i tnh tr ng s c c n m ch mu cao cho nn thu c v n m ch ph i s d ng th n tr ng v ch nh t th i do n lm tng h u gnh (lm n ng thm tim suy) v lm gi m l ng mu t i cc c quan. - Epinephrine: c i l c cao v i c m th quan 1, 2 v . Li u dng 0,050,5g/kg/pht khi c hi n t ng tr v i Dobutamine huy t p th p. - Norepinephrine: c i l c cao v i c m th quan v c dng tng s c c n m ch mu h th ng. T n s tim t tng v i Norepinephrine hn l Epinephrine, li u s d ng tng t . Ch n l a hai thu c ny ty thu c tnh hu ng lm sng. Norepinephrine (0,21g/kg/pht) a dng trong tr ng h p huy t p th p c s c c n m ch h th ng gi m nh chong nhi m trng. Norepinephrine hay ph i h p v i dobutamine c i thi n huy t ng.
Khuy n co 2008 c a H i tim chu u i u tr suy tim c p d a vo huy t p tm thu
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5.2.8. Digitalis C l trong suy tim c p ch nh thu c ny khi nh p nhanh gy suy tim (rung nh ki m sot t n s th t khng b ng thu c khc ch ng h n c ch beta). Ch ng ch nh: nh p tim ch m, bloc nh th t 2 v 3, h i ch ng nt xoang b nh l, h i ch ng WPW, h kali, tng canxi mu, h i ch ng xoang c nh, b nh c tim ph i. Ni chung digitalis khng khuyn trong suy tim c p, nh t l trong nh i mu c tim.
Khuy n co 2008 c a H i tim chu u i u tr suy tim c p d a vo p l c lm y th t tri. 5.2.9. Thu c c ch men chuy n Khng c ch nh nh m n nh s m tnh tr ng b nh trong suy tim c p. Tuy v y nh ng b nh nhn c nguy c cao, thu c c vai tr trong i u tr s m b nh nhn suy tim c p v nh i mu c tim c p. Hi n nay v n cn tranh lu n v ch n l a b nh cng nh th i i m b t u cho thu c. Thu c cho ng u ng (khng cho tnh m ch) li u kh i u th p tng d n c theo di huy t p v ch c nng th n. C n th n s d ng thu c b nh nhn c cung l ng tim ng ng th p v c th lm gi m l c c u th n. 5.2.10. D ng c nng c h c v thay tim S d ng d ng c tr gip tu n hon c n thi t trong tr ng h p suy tim c p khng p ng v i cc phng ti n kinh i n nhng c tim c kh nng ph c h i ho c l bi n php c u n i v i thay tim ho c can thi p c th lm ph c h i ch c nng tim. - Bng n i ng m ch ch : tr thnh phng ti n chu n i u tr b nh nhn chong tim ho c suy tim tri c p n ng khng p ng nhanh v i truy n d ch, thu c gin m ch, thu c tng co bp c tim. Ch ng ch nh: phnh tch ng m ch ch , h van ch quan tr ng. Cng khng nn dng b nh nhn c b nh m ch mu ngo i vi n ng, suy tim khng i u ch nh c nguyn nhn, suy a ph t ng. - D ng c h tr th t: l bm c h c thay th ho t ng th t. Ch nh ng b nh nhn c c may cao ph c h i ch c nng tim m i nn s d ng phng ti n ny: nh i mu c tim, s c sau ph u thu t tim, vim c tim c p, lo n ch c nng van tim, ng i ch thay tim. 5.2.11. Suy tim c p v cc b nh l n n - H i ch ng m ch vnh c p: bi n ch ng suy tim c ch nh ch p m ch vnh ngay v n u ti thng m ch vnh s lm c i thi n r ho c phng ng a suy tim. N u nh can thi p m ch vnh khng th c hi n c ho c lm c nhng ch m tr th c ch nh thu c tiu s i huy t s m.
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- B nh van tim: h c p van hai l v van ch n ng nn ph u thu t nhanh chng. Tuy nhin n u c th i k h c p ko di v ch s tim <1,5l/pht/m2, phn su t t ng mu <35% th ph u thu t c p c u ch ng c i thi n tin l ng. Lc ny bng n i m ch ch c gi tr l n n nh b nh nhn. B nh nhn vim n i tm m c nhi m trng bi n ch ng h c p n ng van ch c ch nh m c p c u. - T c van nhn t o: i u tr cn cha th ng nh t. Thu c tiu s i huy t v i van tim bn ph i v b nh nhn nguy c cao, a chu ng ph u thu t v i t c van tim bn tri. Li u thu c: rTPA tim TM 10mg sau truy n 90 mg trong 10 pht. Streptokinase 250.000-500.000 UI trong 20 pht sau 1-1,5 tri u UI truy n 10 gi . Sau li u php tiu s i huy t s d ng Heparine khng phn o n cho m i b nh nhn (PTA 1,5-2 l n ch ng). C th dng Urokinase 4.400UI/kg/h trong 12h khng c Heparine ho c 2000UI/kg/h v i Heprine trong 24h. - Lo n nh p tim: nh p nhanh th t n u khng n nh th s c i n cn n u n nh th th dng Xylocaine, Amiodarone. Nh p nhanh k ch pht trn th t gy suy tim v t t c t cn nhanh. B nh nhn rung nh c suy tim c p c n huy t p cng c n s c i n cho thu c ch ng ng. N u rung nh k ch pht ph i chuy n nh p b ng thu c ho c s c i n. N u rung nh >48h c n cho thu c ch ng ng v ki m sot t n s th t thch h p trong 3 tu n tr c khi chuy n nh p. N u nh huy t ng khng n nh th c n chuy n lo i tr c c c nh p c p c u nhng tr c ph i lm siu m tim qua th c qu n mu ng (gy t c m ch sau khi chuy n v nh p xoang). Thu c Amiodarone v c ch c tc d ng ki m sot t n s th t t t trong rung nh. Cn nh c s d ng digitalis c bi t n u nh rung nh th pht sau suy tim. - Bi n ch ng c h c trong nh i mu c tim c p: + Rch thnh t do th t: th ng t vong tr c khi ch n on. C th lm huy t ng n nh nh t th i b ng ch c ht mu mng tim, truy n d ch, thu c tng co c tim sau nn ph u thu t ngay. + Thng lin th t: a s c n ph u thu t v thng do hi n t ng khuy t vch lan r ng gy chong tim. Cng c th v b ng d ng c qua thng tim. + H van hai l: do t m t ph n hay hon ton c nh, lo n ch c nng c nh. B nh nhn h c p n ng van hai l c ph ph i chong tim c n ph u thu t c p c u.
TI LI U THAM KH O
1. ESC guidelines for the diagnosis and treatment of acute and chronic heart failure 2005-2008.
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VAI TR C A KHNG ALDOSTERONE TRONG D PHNG TIN PHT T T DO TIM

Tr n Lm BV K t nh Qu ng Nam H renin-angiotensin-aldosterone (RAA) ng m t vai tr trung tm trong vi c duy tr s m t cn b ng th n kinh-th d ch thc y s ti n tri n c a suy tim. S ho t ha th n kinh th d ch ko di lm bi n i c u trc v ch c nng c a tim, lu di d n n ph i th t tri v ti c u trc m ng collagen, lm tng t t b nh v t vong tim m ch. Cng v i nh ng thnh ph n khc c a h RAA, aldosterone tr c ti p thc y qu t i-ph i th t tri, p ng vim v x ha c tim [1]. b nh nhn suy tim do nh ng nguyn nhn khc nhau, s pht tri n c a i u tr n i khoa nh m n nh ng b t th ng th n kinh th d ch v i u bi n di n ti n c a b nh lm thay i nguyn nhn ch y u c a t vong t suy bm ti n tri n t i t t s c kh e c ng ng quan do tim ( TDT) do lo n nh p. V v y, TDT l m t v n tr ng [2,3]. M c d u cc thu c tc ng vo h RAA u lm gi m ho c ngay c o aldosterone th ng ng c ti c u trc th t tri v c i thi n tin l ng nhng n ng v n cn cao ho c th m ch tng b nh nhn suy tim do hi n t ng thot aldosterone V v y, vai tr c a khng aldosterone ngy cng c quan tm. Hai nghin c u lm sng l n g n y ch ng minh khng aldosterone lm gi m TDT ng h gi thuy t cho r ng tng aldosterone trong suy tim c th ng vai tr ti n sinh lo n nh p [3,4,5]. M c ch c a bi bo ny nh m trnh by vai tr, c ch tc d ng c a khng aldosterone, chnh xc hn l ch n th th corticoid khong (MRB-mineralocorticoid receptor blockade) trong d phng tin pht TDT b nh nhn suy tim m n tnh n ng (STMTN) v r i lo n ch c nng tm thu th t tri (RLCNTTTT), b nh nhn RLCNTTTT v suy tim sau nh i mu c tim (NMCT), v b nh nhn nguy c cao khng c suy tim ho c RLCNTTTT. T T DO TIM C A KHNG ALDOSTERONE I. HI U QU GI M 1. B nh nhn suy tim m n tnh n ng v r i lo n ch c nng tm thu RALES (Randomized Aldactone Evaluation Study) l m t nghin c u ng u nhin, m i bao g m 1663 b nh nhn b suy tim n ng v i EF< 35% do b nh tim thi u mu c c b (TMCB) ho c b nh c tim gin tin pht. Ngoi nh ng i u tr chu n nh nhm ch ng ( c ch men chuy n (CMC), l i ti u, ch n v digoxin), nhm nghin c u cn c b sung spironolactone li u 12.5 -50 mg/ngy. Nghin c u c php ngng s m sau th i gian theo di trung bnh 24 thng do nh ng ch l i quan tr ng c a spironolactone. So v i nhm ch ng, nhm dng spironolactone gi m TDT 29% (P=0.02), gi m t vong ton b 30% (P<0.001), k c gi m t vong do suy tim ti n tri n [2,3,4]. 2. B nh nhn b r i lo n ch c nng tm thu v suy tim sau nh i mu c tim. EPHESUS (Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study) l m t nghin c u m i c i ch ng, bao g m 6632 b nh nhn h u NMCT b RLCNTTTT (EF< 40%) v suy tim. Sau 16 thng theo di, so v i nhm ch ng, nhm s d ng eplerenone v i li u 25 - 50 mg/ngy lin quan v i gi m 15% (P=0.008) t vong ton b , v c bi t, gi m 21% (P=0.02) TDT. Nh v y, ph n l n
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gi m t vong tim m ch trong EPHESUS l do gi m 21% TDT. Cc tc gi cho r ng ch l i quan tr ng ny m t ph n l do tc d ng c a eplerenone trn cn b ng i n gi i ( c bi t l kali v magn). Nh ng c ch khc c c p n l gi m tnh tr ng vim m ch vnh, x ha kho ng k , ngng t p ti u c u, trng l c giao c m v stress oxy ha; c i thi n ch c nng n i m c, ti c u trc th t, bi n thin t n s tim (HRV) v s thu nh n norepinephrine c a t bo c tim. Eplerenone cng c hi u qu gi m TDT nh ng b nh nhn c i u tr t i u v i aspirin, ti t i mu, statin, ch n , c ch men chuy n v/ ho c c ch th th angiotensine; i u ny g i khng TTCK b sung hi u qu vo i u tr chu n trong vi c lm gi m TDT v t vong ton b [2,3,5]. b nh nhn NMCT v i RLCNTTTT v/ ho c suy tim, 30 ngy u l th i k c nguy c TDT cao nh t. Trong nghin c u EPHESUS, eplerenone li u 25 mg/ngy (tng ng v i spironolactone 12,5 mg/ngy) c hi u qu lm gi m c TDT (37%; P=0.051) v t vong ton b (31%; P=0.004) trong giai o n nguy c cao ny [6]. Trong nghin c u ny, eplerenone c b t u s d ng ngy 3-14 sau NMCT(trung bnh 7 ngy). Nh v y, hi u qu gi m TDT c th s cao hn n u thu c c dng aldosterone huy t tng s m hn. b nh nhn NMCT c ST chnh ln, tng n ng lc nh p vi n d on nguy c t vong tim m ch c l p v i tu i, tnh tr ng ti t i mu ho c suy tim [7]. 83% b nh nhn trong nghin c u EPHESUS khng c b ng ch ng suy tim lc nh p vi n, i u ny g i vai tr quan tr ng c a vi c dng s m khng TTCK cho b nh nhn NMCT cho d c suy tim trn lm sng hay khng. Trong m t nghin c u khc, nh ng b nh nhn l n u b NMCT thnh tr c v i ST chnh ln c can thi p m ch vnh qua da tin pht ngy u sau nh i mu, sau c phn ng u nhin tim TM canreonate (m t thu c khng TTCK ng tim), r i ti p t c u ng spironolactone trong 30 ngy. K t qu , li u php khng TTCK c dung n p t t v c lin quan v i s c i thi n ng k hi n t ng ti c u trc th t v hnh thnh collagen [8]. Nh v y, s d ng s m khng TTCK sau NMCT hy v ng s d phng c RLCNTTTT. 3. B nh nhn suy tim NYHA II v r i lo n ch c nng tm thu th t tri So v i suy tim n ng (NYHA III-IV), vai tr c a khng TTCK trong gi m TDT b nh nhn suy tim nh (NYHA II) v RLCNTTTT t c c p hn. AREA INCHF (Anti-remodelling Effect of Canrenone in Patients with Mild Chronic Heart Failure) l m t nghin c u ng u nhin, m i, c i ch ng nh m nh gi hi u qu c a canrenone b nh nhn suy tim NYHA II. Nghin c u bao g m 382 b nh nhn, b nh nhn nhm nghin c u ngoi li u trnh chu n i u tr suy tim nh nhm ch ng cn c b sung canrenone li u 25-50 mg/ngy. K t qu sau 12 thng cc thng s sau y c a nhm canrenone c i thi n c ngha so v i nhm ch ng: EF tng hn (p = 0,04), n ng BNP (Brain natriuretic peptide) gi m hn (-37% so v i -8%, p = 0,0001), ng knh nh tri gi m hn (-4% sv 0,2%; p = 0,02), k t c c ph i h p t vong v nh p vi n do nguyn nhn tim th p hn (8% sv 15%; p = 0,02), t t trong nhm canrenone cng th p hn (4 b nh nhn so v i 7 b nh nhn), ch c 0,9% b nh nhn c a nhm canrenone ti n tri n t NYHA II ln NYHA III-IV so v i 3,8% c a nhm ch ng, M c d u cha th rt ra k t lu n ch c ch n no do c m u tng i nh v th i gian theo di ng n, nhng cc tc gi cho r ng canrenone c ti m nng c i thi n tin l ng b nh nhn suy tim nh [1].
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Hi u qu gi m TDT c a eplerenone b nh nhn suy tim NYHA II v RLCNTTTT ang c nh gi trong m t nghin c u a trung tm, quy m l n hn l EMPHASIS-HF (Effect of Eplerenone versus Placebo on Cardiovascular Mortality and Heart Failure Hospitalization in Subjects With NYHA Class II Chronic Systolic Heart Failure) [9]. Nghin c u ny s hon thnh vo nm 2011. 4. B nh nhn suy tim v i ch c nng tm thu th t tri b o t n (STCNTTBT) T l m i m c STCNTTBT ngy cng gia tng lin quan v i tng tu i th , tng bo ph v i tho ng [10]. Khc suy tim m n v i RLCNTTTT, i u tr n i khoa khng lm gi m t vong ton b v TDT b nh nhn STCNTTBT. Trong nghin c u CHARMPreserved Trial (Candesartan in Heart Failure Assessment of Reduction in Mortality and Morbidity in Patients with Preserved Systolic function), thu c ch n th th angiotensin l candesartan c ch trong vi c gi m t l nh p vi n do suy tim nhng khng lm gi m t vong ton b hay TDT [11]. Vai tr c a m t thu c ch n th th angiotensin khc l irbesartan cng m i c cng b g n y trong nghin c u IPRESERVE (Irbesartan in Patients with Heart Failure and Preserved Systolic Function trial) [12]. Theo nghin c u ny, so v i nhm ch ng, irbesartan khng c i thi n k t c c tim m ch b nh nhn STCNTTBT (EF 45%). Ring v i ch n TTCK, m c d u b ng ch ng cho th y spironolactone c i thi n ch c nng tm trng c a b nh nhn STCNTTBT [13], nhng hi n cha c d li u v hi u qu c a khng TTCK trong gi m TDT qu n th b nh nhn ny. Y gi i ang ch i k t qu t nghin c u TOPCAT (Treatment of Preserved Systolic function in Cardiac Failure with an Aldosterone Antagonist) d ki n cng b vo nm 2012 [14] . 5. B nh nhn khng c RLCNTTTT ho c suy tim Vai tr c a khng TTCK trong d phng TDT b nh nhn khng c RLCNTTTT, ch ng h n b nh nhn THA nguyn pht km x ha v/ ho c ph i c tim, cha c ch ng minh. C x ha v ph i c tim u d n n TDT. X ha c tim gy gia tng s khng ng b i n h c v lm bi n i ch c nng d n truy n. Ph i th t v x ha c tim lin quan v i gi m d tr vnh, thi u mu c tim, v nh v y c TDT. Hi n t i cha c m t nghin c u quy m l n no ch ng minh ch l i c a khng TTCK i v i TDT b nh nhn THA khng c RLCNTTTT ho c suy tim. Tuy nhin, m t phn tch d li u c a EPHESUS cho th y h u nh t t c ch l i c a eplerenone trong vi c gi m TDT b nh nhn b RLCNTTTT v suy tim sau NMCT x y ra b nh nhn c ti n s THA ngay c khi h khng c bi u hi n THA th i i m NMCT [15]. i u ny c th c gi i thch b i kh nng ngn ch n hi n t ng ti c u trc i n h c b t l i lin quan v i tng ho t ng TTCK. Khng TTCK cng c th ng m t vai tr trong vi c d phng TDT b nh nhn b b nh ng m ch vnh t c ngh n nhng khng c b t th ng c u trc tm th t. Trn th c nghi m, khng TTCK c i thi n ch c nng n i m c trong ch ng tng lipid mu, ngn ch n pht tri n x v a ng m ch chu t ApoE v loi linh tr ng [16,17]. Nh v y, m c d u cha c ch ng minh nhng hi u qu c a khng aldosterone trong d phng tin pht TDT c th c gi nh i v i b nh nhn c RLCNTTTT v i b t th ng c u trc tm th t (nh l s x ha v ph i) v c b nh nhn b b nh ng m ch vnh t c ngh n ho c thi u mu c tim nhng khng c b t th ng c u trc.
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II. C CH GI M T T DO TIM C A KHNG TH TH CORTICOID KHONG 1. Aldosterone gia tng s trnh di n c a men chuy n angiotensine (ACE) v i u ha ln th th AT1 [18]. Nh v y, n ng aldosterone huy t thanh tng trong b nh c nh suy tim ho c h u NMCT c th d n n tng n ng v tc d ng c a angiotensin II trn th th AT1, t o thnh m t m t vng l n qu n v i s ho t ha c a h RAA lm gia tng s n xu t aldosterone hn n a t tuy n th ng th n. M c d u thu c CMC v/ ho c ch n th th AT1 c th c ch t m th i s s n xu t aldosterone, tuy nhin, theo th i gian c hi n t ng thot c ch v n ng aldosterone ti p t c tng [19]. Hi n t ng ny c th c gi i thch b i ho t ng s n xu t angiotensine II c l p v i men chuy n (hi n t ng thot angiotensine), s s n xu t men chuy n khng b c ch b i thu c CMC, v s s n xu t aldosterone c l p v i angiotensine II. Trong nghin c u RESOLVD (Randomised Evaluation of Strategies for Left Ventricular Dysfunction), n ng aldosterone gi m ng k sau 17 tu n c 2 nhnh i u tr (candesartan v enalapril), tuy nhin, tu n th 43 u tr v m c ban u t t c cc nhm i u tr . Trong m t nghin c u khc bao g m 34 aldosterone 11 b nh nhn ti p t c tng m c d u men b nh nhn suy tim, n ng chuy n b c ch hon ton [2]. Nh ng d li u ny gi i thch l do t i sao c n ph i ph i h p thu c khng c hi u aldosterone v i thu c CMC cho b nh nhn suy tim. 2. b nh nhn suy tim, s s n xu t qu m c aldosterone gy natri v n c d n n qu t i th tch lm suy gi m hn n a kh nng bm mu ra ngo i bin. i u ny d n n hi n t ng co m ch h th ng v i gi m lu l ng mu n th n. Cu i cng, hnh thnh m t vng l n qu n v i tng phng thch angiotensine II t th n d n n tng aldosterone v qu t i th tch hn n a. Aldosterone gy tng nguy c lo n nh p th t do lm tng bi ti t kali v magn th n. i u ny l gi i t i sao aldosterone b nh nhn suy tim v b nh nhn sau NMCT. b nh nhn lm tng nguy c t t suy tim sung huy t, nh ng tc ng c a aldosterone trn kali ni u v magn ni u c th b ha gi i b i nh ng thu c khng TTCK, t c th d phng TDT [2]. 3. Tng ho t ha th th corticoid khong: S ho t ha c a TTCK t bo bi u m ng th n quan tr ng trong vi c i u ha n ng natri, kali v magn ng l n xa c a c u th n. M t s m khc ngoi th n cng trnh di n TTCK, ch y u l c tim, thnh m ch, v m no [2, 3, 18]. Nh ng pht hi n ny g i aldosterone c nh ng ho t ng t i ch nh ng m khc nhau. Trong suy tim, c tim tng trnh di n TTCK [20]. S gia tng s n xu t aldosterone v men chuy n angiotensine cng c pht hi n tm th t c a b nh nhn suy tim [3]. i u ny cho th y aldosterone tham gia vo nhi m c tim m ch c l p v i ho t ng c a angiotensine II, v c m t m i quan h gi a n ng aldosterone v i t t b nh v t vong tim m ch. Trong nghin c u CONSENSUS (Cooperative North Scandinavian Enalapril Survival Study), t l t vong 6 thng cao hn c ngha nhm b nh nhn c n ng aldosterone ban u cao hn gi tr trung bnh [2]. Ngoi ra, cortisol c th ho t ha TTCK m t s m nh ng th n v thnh m ch. Tuy nhin, nh ng m ny cng trnh di n men 11 -hydroxysteroid dehydrogenase-2 c tc d ng i u ha s chuy n i cortisol thnh cortisone, do v y, c th khng kch thch TTCK. Trong nh ng b nh l c s gia tng cc g c oxy ph n ng (nh suy tim, THA), men 11 -hydroxysteroid dehydrogenase-2 c th b i u ha
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xu ng d n n gi m chuy n i cortisol thnh cortisone. H u qu , cortisol tng c th ho t ha TTCK. C tim khng trnh di n men 11 -hydroxysteroid dehydrogenase-2, do v y TTCK c th trnh di n bnh th ng nhng khng b cortisol ho t ha. Tuy nhin, v i s gia tng pht sinh nh ng g c oxy ph n ng, ph c h p cortisol-TTCK b ho t ha thng qua nh ng c ch cha c bi t [3]. Ngoi ra, aldosterone cng i u ha xu ng men glucose-6-phosphate dehydrogenase (G6PD) d n n gi m d tr ch t ch ng oxy ha v tng nh ng g c oxy ph n ng [21], k t c c l tng ho t ha TTCK. S ho t ha TTCK c th tr c ti p nh h ng n nh ng c i m i n h c c a tm th t t o thnh m t c ch t cho lo n nh p v TDT. S trnh di n qu m c c a TTCK tim chu t th c nghi m d n n lo n nh p nguy hi m [22]. M t s y u t c th tham gia, trong , i n th ho t ng c a tm th t b ko di l d u hi u bo tr c c a lo n nh p, y l y u t nguy c c l p c a TDT b nh nhn suy tim [23]. Canrenone, m t ch t chuy n ha ho t ng c a spironolactone, c tc d ng lm gi m ng ng rung th t sau NMCT trn chu t th c nghi m [24]. 4. i u bi n ch c nng knh kali v knh canci: m c m, s ho t ha TTCK gy m t kali, gy ch t t bo theo chng trnh, x ha, ph i, v ho t ha h th n kinh giao c m trung ng. Aldosterone c m t ho t ng sinh x tr c ti p b ng cch tng s n xu t collagen t nguyn bo s i c a tim, tng b c l y u t PAI-1 (plasminogen activator inhibitor-1) [2,3,25]. Trong m t nghin c u chu t c HA bnh th ng, chuy n aldosterone trong 24 gi d n n tng hi n t ng ch t theo chng trnh c a t bo c tim, t bo c tim ho i t l i l y u t kch thch gy x ha c tim. V v y, tng ch t t bo theo chng trnh v ho i t c tim c th l m t c ch khc gi i thch hi n t ng x ha c tim qua trung gian aldosterone [2]. Trong suy tim, n ng aldosterone c th tng g p 20 l n bnh th ng v tham gia vo qu trnh pht huy t thanh c a PIIINP tri n x ha c tim. Trong nghin c u RALES, n ng (propeptide of type III collagen), m t ch i m huy t thanh c a s t ng h p collagen, gi m c ngha nhm b nh nhn c i u tr b ng spironolactone [26]. Nh ng b ng ch ng ny g i aldosterone c m t ho t ng ti c u trc b t l i trn c tim v thc y x ha c tim. Tng x ha c tim m h u qu l ti c u trc th t c th thc y s m t ng b i n h c v l c ch t pht sinh lo n nh p th t n ng. m c t bo, s trnh di n qu m c c a TTCK t bo c tim gy nn hi n t ng ti c u trc knh ion lm ko di ti c c th t lin quan v i s i u ha ln dng ICa v i u ha xu ng dng Ito, d n n lo n nh p th t nguy hi m. Tng dng ICa, gi m dng Ito, ho c c hai bi n i ny u ko di i n th ho t ng c a tim. Nh ng thay i ny x y ra trong tu n u c a NMCT tr c khi xu t hi n nh ng bi n i hnh thi tm th t, v c th d phng c b ng thu c ch n TTCK. Aldosterone cng lm gi m dng Ito t bo c tim c a b nh nhn ho c ng v t b suy tim [22, 27- 30]. 5. Tng trnh di n knh natri c a tim: Aldosterone cng i u ha ln knh natri tim (INa), ko di th i gian i n th ho t ng t bo c th t c a chu t, v tc d ng ny b tri t tiu khi dng spironolactone [5]. Ko di th i gian i n th ho t ng l m t y u t sinh lo n nh p quan tr ng trong b nh nguyn c a TDT b nh nhn suy tim [28-30]. M c d c ch m ki u i u ha ion ny tham gia vo sinh lo n nh p cha c lm r nhng n g i m t vai tr sinh lo n nh p trong H/C Brugada. y l m t b nh l di truy n do t bi n gen SCN5A m ha knh natri c a tim. Trong h i ch ng ny, TDT c th lin quan v i s hi n di n c a x ha c tim [31]. V trn m hnh ng v t, s x ha c tim c th lin quan v i gi m ch c nng c a gen SCN5A. Nh
56
v y, c kh nng s trnh di n c a knh natri v m c aldosterone quan h v i nhau theo ki u feedback, , s gi m dng natri d n n tng b tr s n xu t aldosterone v x ha c tim [32]. M c d u hi u qu cha c ch ng minh nhng vi c i u tr s m b ng thu c ch n TTCK cho b nh nhn b H/C Brugada hy v ng s ngn ng a s xu t hi n c a x ha c tim, v nh v y c TDT. 6. Tng n ng norepinephrine: S ho t ha TTCK cng gy c ch s thu nh n norepinephrine vo c tim d n n tng n ng norepinephrine lu hnh, tng ho t ng th n kinh giao c m v lo n nh p th t [2]. Aldosterone cng i u bi n trng l c ph giao c m d n n gi m bi n thin t n s tim (HRV). Gi m HRV lin quan v i tng t vong v TDT b nh nhn suy tim [2, 23]. Ng c l i, thu c ch n TTCK i u bi n s thu nh n norepinephrine v ho t ng ph giao c m thng qua vi c c i thi n bi n thin t n s tim, phn tn kho ng QT v ch c nng c a th th p l c, d n n gi m lo n nh p th t [2, 3, 28]. Trong m t nghin c u c a Ramires v cs b nh nhn b b nh c tim gin nguyn pht ho c do TMCB, khi b sung spironolactone vo i u tr chu n lm gi m t n su t ngo i tm thu th t v nh p nhanh th t khng b n b [2]. Nh ng thay i ny cng lin quan v i s gia tng tnh kh d ng c a NO, ch c nng n i m c v ti u c u [1,2,3]. 7. Thu c ch n TTCK cng lm gi m n ng y u t c ch ho t ha plasminogen, c i thi n tiu s i huy t v d phng huy t kh i, gi m t n s tim c bi t vo nh ng gi sng s m [2,25,28]. Pht hi n ny c bi t quan tr ng b i v n g i vi c c ch ho t ng c a aldosterone s lm gi m xu t hi n cn thi u mu c c b vo sng s m, th i i m m t n su t TDT x y ra g p 2,5 l n b nh nhn suy tim. 8. Aldosterone cn c nh ng ho t ng ti n vim, sinh x v a v thc y r i lo n ch c nng n i m c: p ng vim c a h th ng tim m ch i v i corticoid khong m c bi t l aldosterone c ch ng minh. p ng vim ny bao g m s i u ha ln nh ng ch t trung gian nh y u t nhn B, protein 1 ho t ha, nh ng phn t k t dnh t bo v endothelin 1, i u ha ln MAP kinases (mitogen-activated protein kinases) [18]. S gin m ch ph thu c n i m c b gi m khi p ng v i acetylcholine l do gi m tnh sinh kh d ng c a NO qua trung gian aldosterone c xem l c ch quan tr ng c a r i lo n ch c nng n i m c. b nh nhn suy tim, s gin m ch ph thu c n i m c qua trung gian NO b gi m (m gp ph n vo s gia tng khng l c m ch mu) c xem l y u t d on quan tr ng bi n c tim tng lai. Ng c l i, b nh nhn suy tim c i u tr b ng spironolactone trong 1 thng tng ng k lu l ng ng m ch c ng tay ph thu c n i m c [33]. Trn th c nghi m, nghin c u c a Carmem LS v cs ch ng minh thu c ch n TTCK c i thi n r i lo n ch c nng v n m ch v stress oxy ha chu t b suy tim sau NMCT [34]. Trong nghin c u ny, Eplerenone bnh th ng ha s gin m ch t i a ph thu c n i m c, ph c h i s phosphoryl ha eNOS, v gi m hnh thnh cc g c oxy ph n ng. Trn th c nghi m, s d ng thu c ch n TTCK ch n l c l eplerenone ngay sau NMCT chu t gia tng s xm nh p c a i th c bo v tng thong qua nh ng cytokine kch thch li n s o (protein ha ng ng b ch c u n nhn, y u t ho i t u (TNF), interleukin-1, interleukin-6, interleukin-10, v interleukin-4) v y u t XIIIa vng c tim nh i mu d n n tng tn sinh m ch mu, gi m hi n t ng gin-m ng thnh c tim b nh i mu, v c i thi n ch c nng th t tri [35]. C ch ny ph n no c
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th gi i thch hi u qu c a eplerenone trn t vong 30 ngy sau NMCT [36]. Hi n t ng m ng - gin ti n tri n l bi n c c a nh ng ngy u sau NMCT. S c i thi n b dy s o nh i mu lm gi m s c cng thnh, ngn ng a s lan r ng nh i mu v hi n t ng ti c u trc nh ng v tr khng nh i mu. Gi m hi n t ng ti c u trc s m c a tm th t c th c i thi n s ng b c a d n truy n th t, nh v y gi m lo n nh p th t nguy hi m. Tuy nhin, nh ng c ch khc nh ngn ng a ti c u trc i n h c v r i lo n ch c nng n i m c c vai tr c bi t quan tr ng [2,3,37]. Trn c s nh ng b ng ch ng ny, c th k t lu n r ng m c d u khng ph i l nhm thu c ch ng lo n nh p nhng cc thu c ch n TTCK c hi u qu d phng TDT. Ty theo b nh c nh lm sng, m t ho c nhi u hn trong s nh ng c ch ny c th c bi t quan tr ng trong d phng TDT. ch l i c a thu c ch n TTCK trong d phng s m TDT sau NMCT c th do nh ng tc ng c a n trn ti c u trc i n h c, trong khi , nh ng tc ng trn ti c u trc th t, hnh thnh collagen v ph i c tim c th c t m quan tr ng tng ng ho c l n hn trong d phng v lu di TDT b nh nhn suy tim v RLCNTTTT. D li u hi n nay ch y u t p trung vo nhm b nh nhn c EF th p v suy tim sung huy t, v v y, c n c nh ng nghin c u m i m r ng ch nh nh m d phng TDT cho nh ng nhm b nh nhn khc.
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9. Aldosterone Antagonist Therapy for Adults With Heart Failure and Preserved Systolic Function. http://www.clinicaltrials.gov. 2007. 10. Bursi F, Weston SA, Redfield MM, et al. Systolic and diastolic heart failure in the community. JAMA. 2006; 296: 220916. 11. Yusuf S, Pfeffer MA, Swedberg K et al. Effects of candesartan in patients with chronic heart failure and preserved left-ventricular ejection fraction: the CHARMPreserved Trial. Lancet. 2003; 362: 77781. 12. Barry MM, Peter EC, John JM. Irbesartan in Patients with Heart Failure and Preserved Ejection Fraction (I-PRESERVE). NEJM. 2008. 13. Mottram PM, Haluska B, Leano R. Effect of aldosterone antagonism on myocardial dysfunction in hypertensive patients with diastolic heart failure. Circulation. 2004; 110: 558565. 14. Aldosterone Antagonist Therapy for Adults With Heart Failure and Preserved Systolic Function (TOPCAT). http://www.clinicaltrials.gov. 2007. 15. Pitt B, Krum H, Niclau JC. The EPHESUS trial: effect of eplerenone in patients with a baseline history of hypertension. Circulation. 2003; 108 (suppl): 599. Abstract. 16. Rajagopalan S, Duquaine D, King S. Mineralocorticoid receptor antagonism in experimental atherosclerosis. Circulation. 2002; 105: 221216. 17. Takai S, Jin D, Muramatsu M, Kirimura K. Eplerenone inhibits atherosclerosis in nonhuman primates. Hypertension. 2005; 46: 113539. 18. Schiffrin EL. Effects of aldosterone on the vasculature. Hypertension. 2006; 47: 312318. 19. Pitt B. "Escape" of aldosterone production in patients with left ventricular dysfunction treated with an angiotensin converting enzyme inhibitor: implications for therapy. Cardiovasc Drugs Ther. 1995; 9: 145149. 20. Yoshida M, Ma J, Tomita T. Mineralocorticoid receptor is overexpressed in cardiomyocytes of patients with congestive heart failure. Congest Heart Fail. 2005; 11: 1216. 21. Leopold JA, Dam A, Maron BA. Aldosterone impairs vascular reactivity by decreasing glucose-6-phosphate dehydrogenase activity. Nat Med. 2007; 13: 189197. 22. Ouvrard-Pascaud A, Sainte-Marie Y, Benitah JP. Conditional mineralocorticoid receptor expression in the heart leads to life-threatening arrhythmias. Circulation. 2005; 111: 30253033. 23. Zipes DP, Camm AJ, Borggrefe M et al. ACC/AHA/ESC 2006 guidelines for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death. Circulation. 2006; 114: e385e484. 24. Cittadini A, Monti MG, Isgaard J. Aldosterone receptor blockade improves left ventricular remodeling and increases ventricular fibrillation threshold in experimental heart failure. Cardiovasc Res. 2003; 58: 555564. 25. Weber KT. Aldosterone in congestive heart failure. N Engl J Med. 2001; 345: 168997. 26. Zannad F, Alla F, Douset B et al. Limitation of excessive extracellular matrix turnover may contribute to survival benefit of spironolactone therapy in patients
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with congestive heart failure: insights from the randomized aldactone evaluation study (RALES). Circulation. 2000; 102:2700-06.
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KHNG INSULIN TRONG TAI BI N M CH MU NO

Hong Khnh*, L Thanh H i** * Tr ng i h c Y D c Hu , Ban b o v s c kh e t nh Th a Thin Hu
**
Hi n nay, ngoi nh ng y u t nguy c (YTNC) c i n v ang nghin c u trn nhm b nh tai bi n m ch mu no (TBMMN), th vi c nghin c u tnh tr ng khng insulin trn b nh TBMMN, s b sung thm m t YTNC m i vo b c tranh t ng th cc YTNC c a b nh TBMMN ni ring v b nh l m ch mu ni chung Vi t nam. V y c ch b nh sinh c a khng insulin trong b nh l m ch mu ni chung v trong TBMMN nh th no? I. C CH SINH B NH C A KHNG INSULIN M t cu h i c t ra l: Khng insulin v c ng insulin mu khi i v/ho c sau khi u ng glucose l m t d u ch i m n thu n hay l m t y u t nguy c th t s c a b nh l m ch mu? Khng insulin v c ng insulin mu c th c m t tc d ng nh h ng n qu trnh sinh x v a, ho c tr c ti p ho c gin ti p qua nh ng b t th ng chuy n ho, tng huy t p v bo ph trung tm. Trong th c nghi m vi c cho insulin v gy khng insulin c th thc y s ti n tri n c a nh ng t n thng x v a, ngn ch n s thoi tri n, th m ch c ch tc d ng b o v c a estrogen - Khng insulin v c ng insulin mu tc ng tr c ti p ln thnh ng m ch Insulin c tc d ng kch thch s tng sinh c a nh ng t bo thnh ng m ch. Tc d ng ny c th qua trung gian s gia tng s n xu t c a IGF1. Ngoi ra, l ng insulin mu cao c th lm gi m ho t tnh c a c a nh ng th th c hi u trn cc i th c bo i v i nh ng s n ph m cu i c a glycosyl ho (advanced glycosylation end products) v thc y cc tc d ng c h i c a nh ng s n ph m ny trn thnh ng m ch. Khng insulin hi n di n trong hai nhm b nh nh i mu no v xu t huy t no v IGF-1 huy t tng c th chi m m t vai tr quan tr ng trong KI b nh nhn TBMMN c p. Khng Insulin l y u t nguy c m nh nh t c a dy l p o trong - o gi a c a ng m ch c nh. M t v n c coi l pht hi n quan tr ng l h u h t cc thi u mu c c b no c ngu n g c t cc m ch l n vng c nh ng m ch c nh, ni ta c th can thi p d dng b ng ph u thu t c t b l p o trong gip d phng v i u tr thi u mu c c b no [1],[4],[5]. - Tc d ng gin ti p c a insulin qua trung gian cc r i lo n lipid S gia tng c a VLDL (nh t l do tng s n xu t gan) c tng quan thu n v i m c khng insulin v c ng insulin. Ngoi ra, n ng HDL ( c bi t l HDL2) l i c tng quan ngh ch v i c ng insulin. Cc r i lo n lipid khc cng c quan st th y trong c ng insulin: tch t cc ch t t n lu c a VLDL d b cc i th c bo b t gi v c c tnh sinh x v a m nh, tng LDL nh m c sinh x v a m nh hn, gi m ho t tnh cc th th i v i HDL [19]. - Tc d ng gin ti p c a insulin qua trung gian THA M i lin quan gi a THA v khng insulin-c ng insulin c ni n tr c y, ch nh n m nh y vai tr c a insulin trn m ch mu nh lm tng nh y c m
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c a m ch mu i v i cc kch thch c a cc ch t gy co m ch, gi m cc prostaglandine dn m ch v ph i thnh m ch qua trung gian IGF-1 [2],[3], [16]. - Tc d ng sinh huy t kh i do gi m qu trnh hu fibrine S gia tng c a PAI-1 (ch t c ch ho t ho plasminogen 1) c vai tr sinh x v a qua tc d ng lm gi m qu trnh hu fibrin. C s tng quan c l p gi a tng PAI-1 v insulin mu khi i ng i bnh th ng, bo ph, T hay c b nh m ch vnh. Ng c l i, cc bi n php lm gi m khng insulin s lm gi m song song insulin mu, PAI-1 v triglyceride. C s tng quan thu n gi KI v m t s y u t nguy c quan tr ng c a b nh TBMMN nh glucose, lipid, huy t p, t-PA (tissue type plasminogen activator), PAI-1(plasminogen activator inhibitor-1) [9], [11], [21]. Tuy nhin, cc gi thuy t ny c n c ki m ch ng v ng i ta nh n th y PAI-1 l i khng thay i khi cho insulin li u cao ng v t th nghi m, khi s d ng insulin tim d i da trong i u tr b nh nhn T PTI, trong u ti t insulin (insulinome), v trong cc tnh tr ng khng insulin th pht do c ng v th ng th n (hypercorticisme) v b nh to c c (acromegalie) [29]. - Insulin lm gi m n ng calcium n i bo v gi m co th t c a cc t bo c trn S dn m ch do insulin b suy gi m nh ng ng i m s b t gi glucose km do khng insulin. Cho t bo c trn c a ng m ch i ch phn l p ti p xc v i insulin ng n h n lm gi m lu ng Ca++ i vo t bo do serotonine v gi m Ca++ n i bo (Kahn v c ng s ). Trong m t nghin c u th c nghi m khc tc gi cng nh n th y n ng insulin sinh l s lm gi m lu ng Ca++ i vo t bo d i tc d ng c a 5hydroxytryptophane (5-HT) ng m ch i c a b. Tuy v y, lu ng Ca++ c ti t ra t ti l i n i bo th khng b nh h ng. Gernazich cng c ng s qua nghin c u lm sng t m t c ch sinh l b nh m i lin quan n s thay i huy t ng Ca++ trong cc ti u ng m ch no m c th d n n tai bi n m ch mu no. - S dn m ch do insulin v b t gi glucose do insulin c lin h v m t ch c nng Chuy n insulin li u sinh l vo trong ng m ch s lm dn ng m ch cnh tay, s dn m ch ny c lm m nh thm khi chuy n cng lc D-glucose. Hi n t ng ny g i m t m i lin h c ngha v m t ch c nng gi a tc d ng chuy n ho v m ch mu c a insulin trn cc t bo n i m (Cleland v c ng s ) [6], [7], [8], [20], [25]. - Vai tr dn m ch c a insulin do tc ng ln s d ch chuy n ion Ca (2+) v bm Na+/K+ Tack chuy n Ouabain, m t ch t c ch c hi u bm Na+/K+-ATPase, vo ng m ch cnh tay tr c v trong khi lm nghi m php km gi ng ng mu trong lc lm tng insulin. S tng ti t kali t t bo b c ch m t ph n b i insulin. K t qu ny cho th y insulin c tc d ng gy dn m ch b ng cch kch thch bm Na+/K+-ATPase. S ho t ho bm ny c th x y ra cc t bo n i m hn l t bo c trn thnh m ch, v do gp ph n vo s dn m ch ph thu c n i m khi p ng v i insulin. Insulin l m t hoc mn m ch mu, ngoi kh nng nh h ng ln chuy n ho trung gian, n cn ng vai tr quan tr ng trong i u ho tim m ch v sinh l b nh c a b nh tim m ch nh THA nguyn pht, suy tim sung huy t v x v a ng m ch. Insulin gy ra tng p qua c ch tng ho t giao c m, mu i v tng sinh c trn thnh m ch. Tri l i, m t s b ng ch ng cho r ng insulin lm gi m s c khng thnh m ch v lm tng dng ch y c a m ch c bi t l c
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vn, ch ng t insulin l m t ch t dn m ch. M t s c ch gy dn m ch do insulin c a ra. Insulin lm tng s i ra c a Ca++ t t bo c trn m ch mu qua ho t ho Ca(2+)-ATPase mng huy t tng v lm tng phn c c qua kch thch Na(+), K(+)-ATPase v bm Natri/Kali. Insulin cng kch thch t ng h p NO (Nitric Oxide) v tng gi i phng NO t t bo n i m c m ch mu lm dn m ch. Tng AMP vng do insulin gy ra. THA lin quan v i khng insulin v tng insulin mu. Khng insulin gy ra tng huy t p qua tng ho t giao c m, r i lo n ch c nng n i m c v lm gi m ho t tnh dn m ch c a insulin. V v y, insulin c xem nh l m t peptide ho t m ch, c n c nhi u nghin c u hn lm sng t vai tr nh h ng ln huy t ng c a n [13]. Tng t , Johnstone v c ng s nh n th y s dn m ch ph thu c n i m b t th ng trong T th c nghi m. p ng c a lu ng mu cnh tay i v i nitroprussiate v verapamil, v p ng co m ch i v i phenylephrine l gi ng nhau gi a ng i bnh th ng v T . ng i T , s dn m ch ph thu c n i m tng insulin huy t thanh nhng khng tng quan v i ng mu, quan ngh ch v i n ng GHb (glycated hemoglobine), hay th i gian m c b nh. i u ny gi thch t n su t cao c a b nh m ch mu cc b nh nhn T ph thu c insulin [22], [23], [27], [28]. - Khng insulin tc d ng lm r i lo n ch c nng knh K(+) qua th c nghi m Khng insulin lm tng nguy c TBMMN ng i, m t y u t chnh gy b nh l lm thay i ch c nng m ch mu no k t qu t thay i ch c nng knh K(+). Trong nghin c u ny tc gi xem xt kh nng dn m ch qua trung gian knh K(+) nh ng ng m ch b khng insulin no. Nghin c u c th c hi n trn nh ng ng m ch no gi a n c tng p c a nh ng con chu t c tnh tr ng khng insulin do n ch n giu fructose. K t qu nghin c u cho th y tnh tr ng khng insulin gy ra r i lo n ch c nng knh K(+) qua trung gian d ng oxygen ph n ng. S thay i p ng m ch ph thu c knh K+ v Ca++ c th lm tng nguy c cao nh ng bi n c m ch no trong tnh tr ng s n c khng insulin. i u tr tr c v i superoxide dismutase k t h p v i catalase lm c i thi n c p ng dn m ch nh ng ng m ch no c tnh tr ng khng insulin [26] - Tc d ng dn m ch vnh c a insulin v IGF-1 trong nghin c u th c nghi m Hasdai kh o st vai tr i u ho trng l c m ch vnh trn cc ng m ch vnh th ng tm m c c a heo. C insulin v IGF-1 u c tc d ng lm gi m trng l c c a ng m ch vnh th ng tm m c sau khi co th t d i kch thch c a endothelin-1. Vi c l y b l p n i m m ch mu khng lm thay i p ng ny. Nh v y, c insulin v IGF-1 u gy dn m ch vnh khng ph thu c n i m, c th qua c ch ho t ho knh kali [24]. - Insulin tc d ng ln s dn m ch qua trung gian acetylcholine Taddei v c ng s so snh tc d ng c a insulin khi tim vo ng m ch cnh tay ln nh ng thay i c a lu ng mu gy ra b i acetylcholine (m t ch t dn m ch ph thu c n i m) ho c Sodium Nitroprussiate (ch t dn m ch khng ph thu c n i m) ng i bnh th ng v b nh nhn THA nh v trung bnh. c 2 nhm tc gi nh n th y: - B n thn insulin khng nh h ng n lu ng mu cnh tay.
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- Insulin y m nh tc d ng dn m ch c a acetylcholine, hi u qu ny gi m i khi c ch s t ng h p oxide nitric c a t bo n i m ng i bnh th ng, ho c tim ouabain vo ng m ch cnh tay ng i THA (ch t c ch Na+/K+-ATPase). - Insulin khng c nh h ng ln s dn m ch do tc d ng c a Sodium Nitroprussiate. II. KHNG INSULIN L Y U T NGUY C C A X V A NG M CH Hai ch t gy dn m ch chnh, NO (nitric oxide) v prostacyclin, duy tr ho t ng m ch mu, c ch k t t p ti u c u v ch ng t o huy t kh i. Nh ng nghin c u g n y cho th y chng cn c kh nng ch ng vim v nh th c kh nng ch ng sinh x v a. G n y ng i ta ch th y insulin kch thch gi i phng NO b i n i bo. Insulin l m t ch t dn m ch , c ho t tnh ch ng k t t p ti u c u v ch ng vim. Ho t tnh ch ng vim tng t nh thiazolidinediones (TZDs), troglitazone v rosiglitazone, g i kh nng ti m tng ch ng x v a c a chng. Kh nng ch ng sinh x v a c a insulin v TZDs l quan tr ng do hai tnh tr ng khng insulin chnh, bo ph v i ng tp 2, c lin quan lm gia tng r BMV v TBMMN do x v a. Nh ng quan st g n y cho th y c s dnh lu r vai tr b nh sinh gy x v a c a tnh tr ng khng insulin v gip xy d ng h ng i u tr ton di n gip phng sinh x v a ng m ch v nh ng bi n ch ng c a chng [18], [22].
RL chuy n ho nguy n pht YTNC b nh m ch trung gian T ng hu y t p YTNCkhng thay -Di truy n -Tu i i R i lo n lipid mu B nh l n i m ch Bi n c lm s ng
Tng ng mu Tng insulin mu
X V A
KHNG I NSULI N
Vi m YTNC thay i -Ch n -Bo ph -t v n n g -Thu c Huy t kh i T iu fibrin R i lo n ch c nng n im c
NG M CH .No -M ch mu l n -M ch mu b . ng m ch ch .M ch vnh TNG NG MU
B NH TI M M CH
(Thi t k d a theo ng u n: K ern an W .N. Ins ulin R esist ance and ris k f or str oke. N eur ology 2002 ; 59:8 09- 81 5)
1.
khng insulin v bi n c tim m ch
III. NGHIN C U V T N SU T M C B NH - Y U T NGUY C GY TAI BI N M CH MU NO M c d c nhi u YTNC c nghin c u trn nhm b nh TBMMN song v n cha gi i thch m t cch y s khc bi t v t n su t m c b nh TBMMN cc khu v c khc nhau trn th gi i. Ph i chng s khc bi t ny l do t n su t phn b c a cc YTNC khc nhau gi a cc s c t c? Do s hi n di n m t s YTNC c tnh c th ring cho t ng s c t c khc nhau trn th gi i? y l m t cu h i l n c t ra cho cc nh nghin c u b nh tim m ch.
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Ring Chu y cng l m t v n ang c quan tm, nh ng nm g n y qua cc cng trnh nghin c u d ch t h c b nh tim m ch Chu cho th y t n su t m c b nh tim m ch trong c b nh TBMMN gia tng nhanh so v i Chu l c khc trn th gi i, trong khi cc nh nghin c u cng nh n th y c m t s YTNC c t n su t cao phng Ty nh bo ph, r i lo n lipid mu th khng ph i l YTNC n i tr i c ng ng c dn Chu . Ph i chng c s xu t hi n m t s YTNC mang tnh c th ring trong c ng ng c dn Chu so v i Chu l c khc? lm r v n ny, chng ta tr l i tm hi u m t s cng trnh nghin c u phn b c a cc YTNC b nh tim m ch trn th gi i. Cng trnh nghin c u c a Charturvedi (International Centre for Circulatory Health and Department of Epidemiology and Public Health- London) l m t trong nh ng cng trnh i su vo v n ny. i m thu n l i c a cng trnh nghin c u ny l c th so snh c t n su t cc YTNC cc s c t c khc nhau trong m t khng gian a l m t n c, do Anh l m t qu c gia thu c Chu u nhng l i c n 7% ng i nh c khng ph i g c Chu u. H u h t nh ng ng i ny l c dn Nam ( a s nt n ) hay ng i Chu Phi da en ( n t vng Ca ri b v Ty Phi) [24]. ng gc b nh tim thi u mu c c b , nghin c u cho th y ng i Nam c nguy c m c b nh v t vong cao hn. Anh, t l t vong do b nh tim thi u mu c cb ng i Nam c 2 gi i cao g p 1,5 l n so v i cc c ng ng c dn khc. S khc khau v s c t c ny th hi n r nh t nhm ng i tr tu i. Nh ng s khc bi t v s c t c c nghin c u m t cch r ng ri, trong khi nh ng YTNC c i n nh ht thu c l, THA, bo ph v cholesterol mu thay i v cn b n gi a cc nhm ng i Nam , nhng t n su t nh ng YTNC ny cho th y tng ng hay th p hn so v i ng i Chu u. Cn cc y u t nh r i lo n dung n p glucose, bo ph trung tm (xc nh b ng cch o vng b ng v vng mng), triglyceride lc i v n ng insulin cho th y cao hn ng i Chu u, nh ng y u t ny l bi u hi n chnh c a h i ch ng khng insulin, m t nhm cc r i lo n chuy n ho bao g m tng insulin mu, tng glucose mu, T v r i lo n lipid mu v i c trng tng triglyceride mu v gi m HDL. Vai tr ti m tng c a khng insulin trong nguyn nhn b nh sinh b nh m ch vnh ng i Nam thc y cc nh nghin c u i su vo khm ph u m i ny nh l m t c ch chnh xc c a m i lin quan gi a b nh tim thi u mu c c b v khng insulin. Tm i m c a nghin c u cng xoy vo y u t gy vim, nhi m khu n, cc y u t huy t ng v r i lo n ch c nng n i m c m ch mu. N ng CRP (C reactive protein) cng cho th y tng ng i Nam , CRP c tng quan m nh v i insulin lc i v sau khi kch thch b ng glucose v c gi tr tin on c l p nguy c b nh tim thi u mu c c b . Lipoprotein(a), PAI-1 v homocysteine mu cng gia tng ng i Nam v ch c nng n i m c suy y u cng l nh ng YTNC d ph n mang tnh c th s c t c. Ngoi vi c ch ra s khc bi t t n su t khc nhau c a cc YTNC trong cc s c t c trong b nh l tim thi u mu c c b , nghin c u ny c p n khc bi t trong t n su t cc YTNC v ch ra m t s YTNC c tnh c th c dn Chu trong b nh TBMMN. Nghin c u i n k t lu n ng i Nam c nguy c m c b nh TBMMN
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cao g p 1,5 l n khi so snh v i ng i Chu u s ng Anh. THA l YTNC c xc l p, ngoi ra nghin c u ch ra m t tri c a tnh tr ng khng insulin c th ng m t vai tr trong b nh sinh b nh TBMMN c ng ng c dn Nam , y l m t v n c n nghin c u lm sng t thm [10]. Tri v i t n su t m c b nh tim thi u mu c c b th p hn c ng ng ng i Ca ri b g c Phi so v i cc c ng ng c dn khc, th s c t c ny l i c nguy c cao m c b nh TBMMN g p 1,5 - 2,5 l n so v i c ng ng chung. a s nguyn nhn TBMMN l do thuyn t c m ch mu. Tuy nhin, kh nng s ng st sau TBMMN cao hn ng i Ca ri b g c Phi. Nh ng YTNC b nh TBMMN n cao hn nam, s khc bi t v s c t c c ph n nh qua s o huy t p, v i tr s huy t p trung bnh lc ngh gi i nam v n ng i Ca ri b g c Phi l cao hn 6 mmHg v 17mmHg so v i ng i Chu u. Thm n a, c b ng ch ng cho r ng m c thng t n c quan ch, dy th t tri, giai o n cu i c a b nh th n v b nh t ch c l i cao hn c th ng vai tr trong khc bi t s c t c C th t ng k t cc i m chnh trong s khc bi t s c t c c a b nh l tim m ch trong c b nh TBMMN c a nghin c u trn nh sau: - Ng i Nam c nguy c cao b nh tim m ch trong c TBMMN so v i ng i Chu u c l do tng tnh tr ng khng insulin v cc y u t lin quan nh vim v r i lo n ch c nng n i m c m ch mu - Ng i Ca ri b g c Phi c nguy c th p b nh tim m ch so v i ng i Chu u, m c d cng c tnh tr ng khng insulin tng, chnh s khc bi t v lipid v lipoprotein gi i thch cho s khc bi t ny - Trong m i nhm s c t c, nh ng y u t thi quen t p qun nh ht thu c v s d ng cholesterol lm tng nguy c cao Hajat v cs. cng ti n hnh nghin c u tm hi u s khc bi t v s c t c trong cc YTNC b nh m ch no v cc th TBMMN. M c ch c a nghin c u ny l xc nh t n su t nh ng YTNC b nh m ch no nh ng b nh nhn TBMMN c ng ng c dn Nam Lun n-Anh v tm hi u m i lin quan c a nh ng YTNC ny v i c y u t s c t c v th TBMMN. M u nghin c u 1.254 b nh nhn TBMMN thu th p t 1995-1998 trong c 995 b nh nhn (79,3%) ng i da tr ng, 203 b nh nhn (16,2%) ng i da en, 52 (4,1%) c ngu n g c s c t c khc v 4(0,3%) l khng r ngu n g c s c t c. S d ng phn tch a bi n, k t qu cho th y, tu i cao (p<0,001) v ti n s TBMMN l lin quan c l p v i NMN hn XHN. Rung nh lin quan v i nhm NMN khng khuy t (p=0,02), NMN tu n hon tr c ton b (p=0,007), NMN tu n hon tr c t ng ph n (p=0,02) so v i nhm do khuy t no. T t c cc YTNC l tng t trong cc th NMN. Cc YTNC l tng t trong cc th XHN d a vo k t qu phn tch a bi n. THA (p<0,001) v T (p<0,001) l chi m t n su t cao trong c ng ng ng i da en. K t lu n cho th y nh ng YTNC b nh TBMMN trong c ng ng ng i da en Anh l tng t nh YTNC b nh TBMMN trong c ng ng ng i da en M , nhng nh ng YTNC khc nhau gi a cc s c t c Anh [12]. Chnh nh ng nghin c u trn ph n no phc ho c s khc bi t c a cc YTNC b nh tim m ch trong c b nh TBMMN gi a cc s c t c v vng mi n khc nhau, v ch ra c m t s YTNC c tnh c th i v i c ng ng c dn Chu . C th nh n m nh n t m quan tr ng c a khng insulin
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c ng ng c dn Chu trong b nh sinh c a b nh TBMMN. Nghin c u tnh tr ng khng insulin b nh nhn TBMMN Vi t nam hy v ng s gip xc l p thm vai tr c a YTNC ny trn b nh TBMMN ni ring v b nh tim m ch ni chung Chu . IV. D CH T H C V TNH TR NG KHNG INSULIN 1. L c s v tnh tr ng khng insulin Vo nm 1988, Gerald Reaven gi i thi u h i ch ng X trong s k t chm v i cc YTNC b nh tim m ch nh THA, r i lo n dung n p glucose, triglyceride mu cao v n ng HDL th p. H i ch ng ny cng thay i nhi u tn g i khc nhau, bao g m h i ch ng chuy n ho, h i ch ng khng insulin, h i ch ng a chuy n ho v nhi u danh t mang y mu s c ch t chc khc. Tn g i "h i ch ng khng insulin" c s d ng r ng ri v cho th y lin v i khng insulin c xem nh l m t m u s chung c a h i ch ng ny. T n su t c a h i ch ng chuy n ho thay i r gi a cc nghin c u khc nhau, h u h t s khc bi t ny l do khng xc l p c tiu chu n nh ngha cho h i ch ng ny. ch p nh n chung Vo nm 1998, T ch c y t th gi i a nh ngha th ng nh t cho h i ch ng ny. c g i l khng insulin " khi l n hn t phn v cao nh t c a ch s HOMA trong nhm ch ng" [17]. Khng gi ng nh huy t p, glucose hay cholesterol c th o tr c ti p c o l ng m t cch tr c ti p. Nh ng nm tr c y ngoi ngay. Khng insulin l kh vi c kh khn trong xc nh tnh tr ng khng insulin, l i khng c m t nh ngha th ng nh t c a khng insulin lm cho cc cng trnh nghin c u d ch t khng insulin th c hi n khng c tnh th ng nh t cao d n n kh ti n hnh nh gi t n su t khng insulin trong c ng ng v trn cc nhm b nh l nghin c u, gy ra b t ti n trong so snh t n su t khng insulin gi a cc cng trnh nghin c u. M t s phng php c s d ng nh gi nh y c m insulin ng i, phng php c cng nh n tiu chu n vng l nghi m php km gi ng ng huy t c ng insulin (euglycemic hyperinsulinemic Clamp), do y l m t nghi m php o l ng tr c ti p ho t ng c a insulin trn b t gi glucose d i nh ng i u ki n c nh. Tuy nhin, k thu t ny ch ti n hnh thu n l i trong phng th nghi m v ch p d ng cho m t s l ng nh i t ng nghin c u. thu n l i cho nh ng nghin c u lm sng v d ch t h c, nhi u phng php gin ti p v n gi n c ngh nh gi tnh tr ng khng insulin, d a vo s xc nh n ng insulin lc i v sau khi kch thch ti t b ng glucose v d a vo t insulin/glucose c tnh ton v i nh ng cng th c ton h c khc nhau. Ph h p v i i h i ny c ch s HOMA (homeostasis model assessment), ch s QUICKI (quantitative insulin sensitivity check index) l nh ng ch s c s d ng r ng ri trong nghin c u d ch t khng insulin hi n nay, ngoi ra cn c ch s McAuley cng ang c th nghi m. c trong tay m t s ch s gin ti p nh gi tnh tr ng khng insulin v k t sau khi c nh ngha khng insulin c a TCYTTG vo nm 1998, hng lo t nghin c u d ch t tnh tr ng khng insulin c ti n hnh t o ra m t b c nh y v t v s l ng cng trnh nghin c u v phong ph v nhm i t ng b nh l c tnh tr ng khng insulin c a vo nghin c u. Khng insulin l YTNC chnh trong m t s b nh l, bao g m i ng tp 2, bo ph, THA, r i lo n lipid mu v nh ng b nh l tim m ch trong c TBMMN. Hi n nay khng insulin tr thnh v n quan tm c tnh th i s trong cc cng
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trnh nghin c u. M t trong nh ng h i ngh bn v h i ch ng khng insulin g n y nh t l H i ngh c a H i nh ng nh n i ti t lm sng Hoa k (American Association of Clinical Endocrinologists) t ch c t 25-26 thng 8 nm 2002 t i Washington DC. C th tm hi u cc cng trnh nghin c u d ch t h c khng insulin trong h i ngh (Reaven G. 2004). - Ele Ferrannini (Pisa, ) c p trong nghin c u The San Antonio Heart Study, m u nghin c u g m 3.000 ng i, cho th y c lin quan tuy n tnh gi a n ng insulin mu lc i v kh i m c th . Theo di lin t c trong 8 nm v i m u 1.000 ng i cho th y tng hay gi m tr ng l ng c th lin quan v i tng hay gi m n ng insulin, lin quan ny r nam hn n gi i, m t d n gp v n chung thu th p t 21 trung tm lin quan v i c ng ng 1.466 ng i "bnh th ng" khng m c b nh T , khng c r i lo n dung n p glucose, khng THA. T n su t tng insulin mu v khng insulin l 10% nh ng ng i c BMI < 25; 30% v 12% nam v n v i ng i c BMI < 28; 48% v 35% nam v n v i ng i c BMI < 35; 80% v 60% nam v n v i ng i c BMI > 35. ng i bo ph nguy c khng insulin tng g p 3 l n, nhng tc gi cng pht hi n c nhi u ng i bo ph khng c khng insulin. Nghin c u xc nh c tng quan ngh ch gi a nh y c m insulin v c huy t p tm thu v huy t p tm trng, kh ng nh THA nguyn pht lin quan v i khng insulin. - Ronald M. Krauss bn lu n v m i lin quan gi a h i ch ng khng insulin v r i lo n lipid. Phn tch y u t nguy c t Framingham Offspring Study xu t m t h i ch ng chuy n ho trung tm v i tng triglyceride, HDL th p, ch s vng b ng/vng mng v BMI tng, insulin lc i v sau 2 gi cao. K t qu nghin c u cho th y t t c cc y u t u c tng quan v i insulin, c bi t nh ng ch s xc nh bo ph. - John E. Nestler tm hi u m i lin quan gi a h i ch ng khng insulin v h i ch ng bu ng tr ng a nang. Nghin c u k t lu n khng insulin ng vai tr b nh sinh trong pht sinh b nh l ny. Tng insulin mu lm gia tng s n xu t androgen bu ng tr ng, thay i LH (Luteinizing hormone) v gi i phng FSH (follicle stimulating hormone), v gi m globulin k t g n hoc mn gi i tnh. - Om P. Ganda th o lu n h i ch ng khng insulin trong c ng ng c dn Chu , l nh ng ng i c t l bo ph th p nhng t n su t b T v b nh m ch vnh cao. Thu n l i chnh c a nghin c u l trung tm qu n l b nh t t th ng k c 60 nhm s c t c ng i Chu khc nhau ang nh c t i M , qua i u tra dn s M c 23% ng i Trung qu c, 18% ng i Philippin, 15% ng i n g c , 11% ng i Vi t nam, 11% ng i Hn qu c v 8% ng i Nh t. Ganda t ng k t m t s nghin c u lin quan n c ng ng c dn Chu M , k t qu cho th y nh ng ng i n g c v i ch s BMI trung bnh 24,5 l bnh th ng nhng tng l ng m c th , chi m trung bnh 33% tr ng l ng c th , tng cao l ng m trong n i t ng lin quan v i r i lo n lipid v khng insulin. T ch c SHARE (The study of health Assessment and Risk in Ethnic groups) nh gi 985 ng i, cho th y c t n su t cao m c b nh tim m ch v gia tng t n su t r i lo n dung n p glucose, tng LDL v cholesterol, tng triglyceride, gi m HDL v pht hi n c nhi u r i lo n trong cc YTNC m i bao g m tng fibrinogen, homocysteine, lipoprotein(a) v PAI-1 trong s nh ng ng i Nam so v i nh ng ng i Chu u.
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- James A. Davidson bn v m i lin h c a h i ch ng khng insulin v i c ng ng ng i thi u s Latinos, c n 36% c dn ny m c h i ch ng chuy n ho, lm cho nhm s c t c ny c t n su t khng insulin cao nh t M . R rng d ch t khng insulin ang tr thnh m t trong nh ng lnh v c m i khng nh ng cho nh ng nh d ch t h c, m cn l m i quan tm c a nhi u lnh v c khc nhau c a y h c nh tim m ch h c, n i ti t h c, th n kinh h c, dinh d ng h c... Chnh nghin c u d ch t h c tnh tr ng khng insulin trn cc nhm nghin c u khc nhau, cc s c t c khc nhau gip lm r thm c ch b nh sinh c a hng lo t b nh l, nh t l cc b nh l chuy n ho, gp ph n gi i thch s khc bi t v t n su t m c b nh tim m ch cc vng khc nhau trn th gi i v xy d ng chi n l c d phng nh m h n ch tnh tr ng khng insulin khng mong mu n ny. 2. D ch t h c tnh tr ng khng insulin trong tai bi n m ch mu no Ti p theo sau cc nghin c u d ch t tnh tr ng khng insulin ng i bnh th ng v trong cc nhm b nh l c tnh tr ng khng insulin nh i tho ng tp 2, tng huy t p, b nh m ch vnh v m t s nhm b nh l khc. Trong nh ng nm g n y c r t nhi u cng trnh nghin c u d ch t khng insulin trong TBMMN [1]. - D Angostino a ra k t lu n khng insulin c ph n nh qua ch s vng b ng/vng mng v tng n ng Insulin lc i l m t YTNC m nh trong NMN (D Angostino 1996). - Shinozaki nghin c u vai tr c a khng insulin trong m i lin quan v i tng b nh nhn nh i mu no, nghin c u pht hi n c tnh tr ng tng Insulin mu b tr n ng glucose mu c ngha th ng k nhm NMN do t c m ch so v i nhm ch ng v nhm NMN do l p m ch ngu n g c t tim, i u ny ch ng t c s hi n di n c a s khng insulin nh ng b nh nhn NMN do t c m ch. Nghin c u i n k t lu n khng insulin c lin quan v i tng insulin mu b tr v tng lipid mu, c th l m t y u t b nh sinh quan tr ng trong vi c hnh thnh NMN do t c m ch (Shinozaki 1996). - Chng trnh nghin c u b nh tim Honolulu (The Honolulu Heart program) cho th y khng insulin c th thc y cc YTNC tim m ch khc v l d u n c a tnh tr ng x v a ng m ch v huy t kh i ng m ch (Burchfiel 1998). - Kernan v nhm nghin c u t v n khng insulin cng th ng g p nh ng ng i khng m c b nh T , v y th khng insulin c ph i l m t y u t nguy c quan tr ng trong TBMMN hay khng? K t lu n cho th y khng insulin c th l m t y u t nguy c n i b t trong TBMMN. Nh ng thu c m i lm gi m khng insulin v c th ng m t vai tr trong phng ng a TBMMN (Kernan 2002). - Du X.P. v cs.(2000) nghin c u m i lin quan gi a khng insulin v nhm cc YTNC c a b nh TBMMN. Ti n hnh nh l ng glucose, lipid, o huy t p, t-PA (tissue type plasminogen activator), PAI-1(plasminogen activator inhibitor-1) mu 159 b nh nhn TBMMN v 40 ng i ch ng. K t qu cho th y trong nhm b nh nhn TBMMN c s l ng cc y u t nguy c cng cao th ch s nh y c m insulin cng gi m (Insulin sensitivity Index - ISI), i u ny ch ng t khng insulin c lin quan r v i nhm cc y u t nguy c c a b nh TBMMN. - Kain K v cs. nghin c u m i lin quan gi a nhm cc YTNC gy t c m ch v khng insulin nh ng b nh nhn ng i Nam b NMN, trong nghin c u s d ng ch s HOMA (Homeostatis Model Assessment) l ch s i di n cho s khng
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insulin, phn tch 6 y u t nguy c gy t c m ch 140 b nh nhn nh i mu no (ch p no c t l p vi tnh). K t qu cho th y c m t s tng quan r gi a ch s HOMA v i t vng b ng / vng mng (r=0,31; p=0,0001), triglycerid (r=0,22; p=0,03), huy t p tm thu (r=0,21; p=0,04), t-PA (r=0,22; p=0,04); PAI (r=0,26; p=0,02), Fibrinogen (r=0,25; p=0,02), y u t VII (r=0,21; p=0,06). Nghin c u cho th y c m t s m r ng nhm cc y u t nguy c lin quan chuy n ho v t c m ch v i khng insulin, m d n n lm tng t n su t b nh l m ch mu c ng ng c dn ny (Kain K 2002)[21]. - Rajala v cs. ti n hnh nghin c u nh gi lin quan gi a tnh tr ng x v a ng m ch c nh v i h i ch ng khng insulin, k t qu nghin c u cho th y c tng quan ngh ch gi a dy l p o trong ng m ch c nh chung v ch s QUICKI (r:0,158; p=0,027). Gi tr trung bnh c a ch s QUICKI l th p hn b nh nhn i ng (0,319 + 0,027) so v i b nh nhn c r i lo n dung n p glucose (0,334 + 0,022) hay c glucose mu bnh th ng (0,335 + 0,022; p=0,002) (Rajala 2002)[26]. Qua nh ng nghin c u d ch t tnh tr ng khng insulin trn nhm b nh TBMMN, c ch b nh sinh c a khng insulin trong b nh TBMMN kh r c th tc ng sinh x v a ng m ch tr c ti p hay gin ti p qua k t chm cc v i cc YTNC tim m ch khc m trong khng insulin ng vai tr trung tm. M t s nghin c u d ch t khc cng ch ra t n su t khng insulin cao c ng ng c dn Chu v l YTNC m i mang tnh c th cao c a b nh l tim m ch bao g m TBMMN i v i c ng ng c dn ny. Nhi u cng trnh nghin c u xc nh c tnh tr ng khng insulin v c ng insulin trong b nh tai bi n m ch mu no v i nh ng c ch tc ng tr c ti p ho c gin ti p qua cc y u t nguy c khc v g p n i b t trong th nh i mu no. C m t s cng trnh nghin c u sau: - D Angostino a ra k t lu n KI c ph n nh qua ch s vng b ng / vng mng v tng n ng insulin lc i l m t YTNC m nh trong nh i mu no (D Angostino 1996). - Shinozaki nghin c u vai tr c a KI trong m i lin quan v i tng insulin mu b tr b nh nhn nh i mu no, nghin c u pht hi n c tnh tr ng tng n ng glucose mu c ngha th ng k nhm nh i mu no do t c m ch so v i nhm ch ng v nhm nh i mu no do l p m ch ngu n g c t tim, i u ny ch ng t c s hi n di n c a khng insulin nh ng b nh nhn nh i mu no do t c m ch. Nghin c u i n k t lu n KI c lin quan v i tng insulin mu b tr v tng lipid mu c th l m t y u t b nh sinh quan tr ng trong vi c hnh thnh nh i mu no do t c m ch (Shinozaki 1996). - Chng trnh nghin c u b nh tim Honolulu (The Honolulu Heart program) cho th y KI c th thc y cc YTNC tim m ch khc v l d u n c a tnh tr ng x v a ng m ch v huy t kh i ng m ch (Burchfiel 1998). - Kernan v nhm nghin c u t v n KI cng th ng g p nh ng ng i khng m c b nh i tho ng, v y th KI c ph i l m t y u t nguy c quan tr ng trong TBMMN hay khng?. K t lu n cho th y KI c th l m t y u t nguy c n i b t trong TBMMN. Nh ng thu c m i lm gi m KI v c th ng m t vai tr trong phng ng a TBMMN (Kernan 2002).
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- Kain v nhm nghin c u ti n hnh nghin c u trn 80 b nh nhn vng Nam b nh i mu no ( c ch n on b ng ch p no c t l p vi tnh) v 80 ng i ch ng. K t lu n cho th y n ng insulin khng khc bi t c ngha trong hai nhm, nhng KI khc bi t c ngha th ng k trong hai nhm (p < 0,01). Nghin c u cng cho th y tng n ng m t s YTNC khc trong nhm nh i mu no nh glucose mu (p < 0,01), fibrinogen mu (p < 0,02), cholesterol mu (P < 0,0001), y u t Von Willebrand (p < 0,006), t-PA (p < 0,04). S thay i n ng c a nh ng YTNC v a nu c xc nh ch y u ph thu c vo nh ng bi u hi n c a h i ch ng khng insulin (Kain 2002)[26]. - Zhonghua nghin c u s lin quan gi a y u t tng tr ng gi ng insulin (IGF1-Insulin like Growth Factor-1) v KI trn b nh nhn TBMMN c p. Nghin c u cho th y IGF-1 v IGFBP-3 (IGF Binding Protein 3) ng gp vo vai tr sinh l b nh trong nh i mu no c p v xu t huy t no c p trong giai o n s m. Khng insulin th hi n di n trong hai nhm b nh v a nu v IGF-1 huy t tng c th chi m m t vai tr quan tr ng trong KI b nh nhn TBMMN c p (Zhonghua 2002). - Du XP, Xia J (2000) nghin c u m i lin quan gi a KI v nhm cc y u t nguy c c a b nh TBMMN. Ti n hnh nh l ng glucose, lipid, huy t p, t-PA (tissue type plasminogen activator), PAI-1(plasminogen activator inhibitor-1) mu 159 b nh nhn TBMMN v 40 ng i ch ng. K t qu cho th y trong nhm b nh nhn TBMMN c s l ng cc y u t nguy c cng cao th ch s nh y c m insulin cng gi m (Insulin sensitivity Index-ISI), i u ny ch ng t KI c lin quan r v i nhm cc y u t nguy c c a b nh TBMMN. - Kain K, Catto AJ nghin c u m i lin quan gi a nhm cc y u t nguy c gy t c m ch v KI nh ng b nh nhn ng i Nam b nh i mu no, trong nghin c u s d ng ch s HOMA (Homeostatis Model Assessment) l ch s i di n cho s KI, phn tch 6 y u t nguy c gy t c m ch 140 b nh nhn nh i mu no (ch p no c t l p vi tnh). K t qu cho th y c m t s tng quan r gi a ch s HOMA v i t vng b ng/vng mng (r=0,31; p=0,0001), triglycerid (r=0,22; p=0,03), huy t p tm thu (r=0,21; p=0,04), t-PA (r=0,22; p=0,04); PAI (r=0,26; p=0,02), fibrinogen (r=0,25; p=0,02), y u t VII (r=0,21; p=0,06). Nghin c u cho th y c m t s m r ng nhm cc y u t nguy c lin quan chuy n ho v t c m ch v i KI, m d n n lm tng t n su t b nh l m ch mu c ng ng dn c ny (Kain K 2002)[26]. - Kain K, Catto AJ, Grant PJ nghin c u cho th y khng insulin k t chm r r t v i cc y u t tiu s i huy t v ng mu c ng ng dn c Nam , c th chi ph i t n su t cao m c b nh m ch mu trong c ng ng ny (Kain K 2003) [26]. - Ninomiya JK nghin c u cho th y c m t s lin quan m nh v b n v ng c a h i ch ng chuy n ho c khng insulin ng vai tr trung tm v i t n su t m c b nh nh i mu c tim v tai bi n m ch mu no (Ninomiya JK 2004). - T i Hu L Thanh H i, Hong Khnh, L Nhn (2005-2007) nghin c u n ng c a insulin mu v glucose mu lc i v sau 2 gi p d ng nghi m php dung n p glucose b ng ng u ng trn 82 b nh nhn TBMMN v 74 ng i ch ng, th y c s hi n di n khng insulin b nh nhn tai bi n m ch mu no, nh i mu no v ch y mu no. Tnh tr ng khng insulin nh i mu no hi n di n r hn so v i ch y mu no v i t l khng insulin tnh theo ch s HOMA nhm nh i mu no (55,56%) cao hn nhm ch ng (25,68%) c ngha th ng k (p < 0,05). Ch y mu no (43,24%) cao hn
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nhm ch ng (25,68%), nhng khng c ngha th ng k (p > 0,05). T l khng insulin thay i theo cc ch s gin ti p s d ng v i nh i mu no t 33,33% n 55,56%, ch y mu no t 29,73% n 48,65%. Tng quan gi a khng insulin qua cc ch s gin ti p v i cc y u t nguy c b nh tim m ch trong tai bi n m ch mu no. Ch s HOMA, ch s QUICKI v m t s ch s gin ti p a vo kh o st c gi tr trong s d ng xc nh khng insulin v u c ngha nguy c i v i b nh tai bi n m ch mu no v nh i mu no. Ch s HOMA c ngha d bo nguy c cao i v i tai bi n m ch mu no v i OR=2,89 (p < 0,01) v nh i mu no v i OR=3,61 (p < 0,01). Ch s QUICKI c ngha d bo nguy c v a i v i tai bi n m ch mu no v i OR=2,49 (p < 0,05) v nh i mu no v i OR=2,68 (p < 0,05). Hai ch s HOMA v QUICKI t c gi tr d bo nguy c i v i ch y mu no v i OR=2,21 (p > 0,05) v OR=2,28 (p > 0,05) [30]. V. K T LU N Trong nh ng nm cu i th k XX v u th k XXI, tnh tr ng khng insulin c nghin c u v c p n nh m t v n th i s c a ngnh n i khoa ni chung v lnh v c b nh l m ch mu ni ring, m t ph n v s ph i h p gi a n v nhi u b nh l ph bi n nh t, v m t ph n v s lin quan gi a nh ng b nh l ny v i nhau. Ngoi m t s b nh hi m g p m trong khng insulin ng vai tr trung tm, c th nu ra y nh ng b nh l c lin quan nhn qu v i khng insulin nh bo ph, tng huy t p, i tho ng, r i lo n lipid mu, b nh m ch vnh, tai bi n m ch mu no v th ng ph i h p v i nhau t o thnh m t s h i ch ng c m t trn lm sng (h i ch ng X chuy n ho, h i ch ng X tim m ch, h i ch ng khng insulin...). S hi n di n c ngha th ng k c a tnh tr ng khng insulin trong nh ng b nh l lin quan t n thng m ch mu lm cho n tr thnh m t trong nh ng y u t nguy c b nh l m ch mu hng u. Tc ng gy b nh tr c ti p hay gin ti p qua k t chm v i cc y u t nguy c khc, tnh tr ng khng insulin l y u t nguy c mang tnh th i s v quan tm nhi u hi n nay, nh t l trong c ng ng c dn Chu . Khng insulin v c ng insulin t o nn nguy c r t cao c a b nh tai bi n m ch mu no, c bi t khi c s hi n di n c a nhi u b nh l chuy n ho ph i h p.
TI LI U THAM KH O
Ti ng Vi t 1. o Th D a (2005), Khng insulin ng i bo ph, K y u ton vn cc ti khoa h c. i h i H i N i ti t v i tho ng qu c gia Vi t nam l n th ba, Tr 526-530. 2. Nguy n C u L i. Nghin c u s khng Insulin, m t y u t nguy c b nh m ch vnh nam gi i. Lu n n Ti n s y khoa 2004. Hu . 3. Hunh Vn Minh. Nghin c u s khng Insulin, m t y u t nguy c b nh nhn tng huy t p nguyn pht. Lu n n Ti n s khoa h c y d c 1996. H N i. 4. Tr n Th a Nguyn, Tr n H u Dng (2005), Nghin c u ch s QUICKI ng i bo ph, K y u ton vn cc ti khoa h c. i h i H i N i ti t v i tho ng qu c gia Vi t nam, Tr 535-539.
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5. Nguy n Quang T n, L Quang C ng (2004), Nghin c u m i lin quan gi a r i lo n lipid mu v i cc th tai bi n m ch mu no, T p ch Y h c Vi t nam, S 301, Tr 70-74. 6. Nguy n H i Thu , Nguy n Vi t Quang (2005), Ch c nng t bo bta tu v khng insulin b nh nhn i tho ng pht hi n sau 40 tu i, K y u ton vn cc ti khoa h c. i h i H i N i ti t v i tho ng qu c gia Vi t nam l n th ba, Tr 656-663. 7. Quch H u Trung (2005), Nghin c u tnh tr ng dung n p glucose mu b nh nhn tng huy t p, K y u ton vn cc ti khoa h c. i h i H i N i ti t v i tho ng qu c gia Vi t nam l n th ba, Tr 880-884. 8. Nguy n B Vi t, Hong Trung Vinh (2005), nh gi khng insulin v ch c nng t bo bta d a vo n ng insulin v glucose lc i b nh nhn i tho ng tp 2, K y u ton vn cc ti khoa h c. i h i H i N i ti t v i tho ng qu c gia Vi t nam l n th ba, Tr 619-622. Ti ng Anh 9. Bloomgarden Z.T.(2004), Definitions of the Insulin resistance syndrome, Diabetes Care; 27:824-830. 10. Bloomgarden Z.T.(2005), Second World Congress on the Insulin resistance syndrome, Diabetes Care; 28:2073-2080. 11. Bloomgarden Z.T.(2005), Inflammation, Atherosclerosis, and Aspects of insulin action, Diabetes Care; 28:2312-2319. 12. Bloomgarden Z.T.(2005), Cardiovascular complications of insulin resistance, Metabolic Syndrome and Related Disorders; 3:305-315. 13. Ceriello A., Motz E. (2004), Is oxidative stress the pathogenic mechanism underlying insulin resistance, diabetes, and cardiovascular disease?The common Soil hypothesis Revisited, Arterioscler Thromb Vasc Biol; 24:816-823. 14. Cheal K.L. , et al. (2004), Relationship to insulin resistance of the Adult Treatment Panel III diagnostic Criteria for identification of the metabolic syndrome, Diabetes 53, 1195-1200. 15. Chen H, Sullivan G, Yue LQ, Katz A, Quon MJ: QUICKI is a useful index of insulin sensitivity in subjects with hypertension. Am J Physiol Endocrinol Metab 284:E804E812, 2003. 16. Gonzalez-Albarran et al. Correlation between insulin suppression test and quantitative insulin sensitivity check index in hypertensive and normotensive obese patients. Diabetes Care 24:19982000. 2001 ...
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NH NG HI U BI T HI N NAY V I U TR VIM GAN B M N

Hong Tr ng Th ng Tr ng i h c Y D c Hu I. D N NH P Kho ng 350 n 400 tri u ng i trn th gi i nhi m virus vim gan B b vim gan m n, y l m t v n l n trong y t th gi i. T n su t nhi m virus B M tng i th p hn cc n c khc, tu v y cng c n 1,25 tri u ng i nhi m virus B m n tnh. Tuy nhin s ng i nhi m m n ny cng cha c xc nh m t cch y do c nhi u ng i nh p c t chu , Trung ng v chu Phi. cc khu v c ny t l nhi m HBV ln n 5-15% trong dn chng. M t nghin c u g n y cho th y t l ng i Chu M nhi m HBV ln n 23%. Ng i b vim gan B m n b nhi m virus t lc cn nh th c n 25% c nguy c ch t s m do x gan ho c ung th bi u m t bo gan. Phn tch nh ng cng trnh nghin c u di hi c cng b g n y i loan cho th y x gan v ung HBV-DNA cao. Nh ng d ki n ny th gan gia tng nhm b nh nhn c n ng lm gi m m t HBV-DNA xu ng m c h tr cho gi thuy t cho r ng i u tr th p ho c khng cn pht hi n trong huy t tng gip lm gi m cc bi n ch ng ny. Th t v y i u tr lu di v i lamivudine lm gi m di n ti n c a b nh v lm h t l ung th gan c 3 pha c a nhi m vim gan B m n: dung n p mi n d ch, thanh l c mi n d ch (ho t ng mi n d ch), v khng ho t ng. Dung n p mi n d ch xu t hi n nh ng ng i nhi m b nh t khi cn tr , mang c i m l vim gan b v i HBeAg(+), HBV-DNA trong mu cao >105 copies/mL, men gan lun lun bnh th ng. Pha dung n p mi n d ch c ti p n i b i pha thanh l c mi n d ch cng cn c g i l vim gan B m n v i men gan tng cao, n ng HBV-DNA cao v sinh thi t c hnh nh vim gan m n. Pha 3 l tnh tr ng mang HBsAg khng ho t ng, c nh d u b i s thanh th i HBeAg v xu t hi n khng th khng HBe, cn g i l chuy n huy t thanh HBe v mang c i m l n ng HBV-DNA < 104 copies/mL, ALT tr l i m c bnh th ng, sinh thi t gan cho th y ho t ng vim t i thi u. Tuy nhin m t vi b nh nhn c t bi n virus trong pha thanh th i mi n d ch l khng s n xu t ho c s n xu t HBeAg v ti p t c nhn ln c a virus n ng cao. i u ny gy ra nhi m HBV m n v HBeAg(-), v ph i h p v i t n thng gan n ng hn l HBeAg(+). II. M C CH C A I U TR c chia thnh ng n h n v di h n. M c ch u tin trong i u tr ng n h n l c ch s nhn ln c a virus. N ng c a HBV-DNA l ch i m ng tin nh t v b nh t t v nguy c gy ung th gan, x gan v t vong do gan c lin quan n n ng HBV-DNA v p ng v i li u i u tr . Trong nghin c u REVEAL cho th y t n su t ung th gan l 108/100.000 ng i m i nm i v i ng i c n n c b n HBVDNA < 300 copies/mL v ln n 1.152/100.000 i v i nh ng ng i c n ng HBV-DNA > 1 tri u copies/mL. S ph i h p ny r t c ngha b t lu n n tnh tr ng HBeAg, ho t men ALT v s c m t hay khng c a x gan.
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M t m c tiu khc c a i u tr ng n h n l lm gi m t n thng vim ho i t cho gan, c ch ng minh b i s tr l i bnh th ng c a men ALT huy t thanh v s c i thi n v m b nh h c c a gan. b nh nhn c HBeAg-(+), m c ch xa hn c a i u tr l gy ra m t s chuy n huy t thanh. S bi n m t c a khng nguyn b m t virus B (HBsAg), ch ng t s lo i b tnh tr ng nhi m trng m n virus B, l i u c mong c nh t, nhng hi m khi t c i u ny. V lu di, m c ch c a i u tr l lm gi m t vong do lm ngn ng a ho c lm ch m l inh ng h u qu n ng n c a b nh l x gan, b nh l gan m t b, ung th gan v nhu c u c a tnh tr ng ghp gan. III. S CH NH I U TR VG B m n
HBV DNA ALT
HBV DNA ALT bnh th ng
HBV DNA ALT
i u tr
Sinh thi t gan
Khng i u tr
T n thng m h c n ng/trung bnh
T n thng m h c nh hay khng c
i u tr
Khng i u tr
IV. I U TR KHNG VIRUS TRONG VIM GAN B M N M c ch c a i u tr vim gan B m n l lm gi m thi u HBV-DNA trong huy t thanh n m c th p khng cn c pht hi n v ngn ng a i n ti n a n x gan, suy gan, v ung th gan. B nh nhn nhi m HBV m n v c ho t men ALT bnh th ng l ang dung n p mi n d ch ho c mang siu vi khng ho t ng th khng c n i u tr . Ng c l i b nh nhn v i n ng ALT cao, n ng HBV-DNA cao v c tnh tr ng vim ho i t t bo gan th c n ph i c i u tr .Hi n nay FDA ch p thu n 5 thu c i u tr vim gan m n virus B; Interferon alfa-2b (1992), lamivudine (1998), adefovir dipivoxil (2002), v entecavir (2005) v peginterferon alfa-2a (thng 5/2005). Tuy nhin, trn th c t lm sng, interferon alfa-2b c thay th b ng peginterferon alfa-2a b i v s c i thi n v phng di n d c ng h c c a
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peginterferon c nhi u thu n l i hn, v lamivudine b h n ch do b khng (70% sau 4 nm), i u ny lm gi m s l a ch n v hi u qu c a vi c l a ch n thu c u ng. V v y Adefovir, Entecavir v peginterferon l nh ng thu c u tin c ch n l a trong nm 2006. B ng 1: M t s nh ngha v khng thu c Bng pht Tng n ng HBV-DNA > 1 log so v i lc th p nh t c a p ng virus v i i u tr H i ph c Tng n ng HBV-DNA trong huy t thanh n 2.000.000UI/ml virus ho c trn m c i u tr sau khi c p ng v i i u tr Bng pht Tng ALT qu gi i h n trn c a ng ng bnh th ng sau khi sinh ha bnh th ng ho trong qu trnh i u tr Khng thu c Pht hi n cc t bi n in vitro khng v i cc nucleoside /nucleotide ki u gen Khng thu c C b ng ch ng in vitro t bi n gi m nh y c m v i cc ki u hnh nucleoside/nucleotide Th t b i i u Khng gi m HBV DNA qu 1 log sau 6 thng i u tr tr tin pht Khng cho t bi n khng qu 1 thu c trn in vitro V. PHNG TI N I U TR 5.1. Adefovir Dipivoxil T ch c FDA c a Hoa k ch p thu n adefovir vo i u tr t nm 2002 trn c s nh ng k t qu c a nh ng th nghi m cho th y tnh an ton v hi u qu c a n sau 1 nm i u tr v i li u 10mg/ngy so v i gi d c b nh nhn vim gan B m n v i HBeAg(+) v c HBeAg(). Nhi u nghin c u cho th y tnh an ton v hi u qu c a adefovir sau 4-5 nm i u tr . Hadziyannis v c ng s nghin c u v m t virus h c, ho sinh v m b nh h c c a adefovir sau 4-5 nm tr li u, kh ng nh tnh an ton, v dung n p c a thu c v c vi c nh gi t l khng thu c. K t qu cho th y r ng c s gia tng c i thi n v x gan, 55% b nh nhn i u tr 4 nm v 71% b nh nhn i u tr sau 5 nm cho th y c i thi n > 1 i m c a thang i m v x c a Ishak. Ph n l n b nh nhn bnh th ng ho men gan v lm gi m m t virus < 1.000 copiess/mL v 5% m t HBsAg. Ch c vi tr ng h p c tc d ng ph , v i 3% tr ng h p c gia tng creatinine >0,5mg/dL (t i a l tng 0,8mg/dL v tr s t i a l 1,5mg/dL). Virus B khng thu c l c th xy ra v i t t c cc analogue c a nucleotide v m t nghin c u c a Borroto-Esoda v c ng s nh gi t l t bi n khng men sao chp ng c v tr A181V/T v N236T b nh nhn vim gan m n B c HBeAg(-) sau 5 nm i u tr v i adefovir gia tng l: 0%, 3%, 11%, 18% v 29% sau 1, 2, 3, 4, v 5 nm i u tr v t bi n v tr N236T l th ng g p nh t. Trong khi t l tch lu t bi n gen c a adefovir km v i bng pht c a virus (> 1log copies /mL) l 16% v t n su t tch lu khng v m t gen c ng v i virus v hay l tng men ALT l 11%. B nh nhn khng v i adefovir c ph i h p v i lamivudine th t c s gi m HBV-DNA 2-6 log copiess/mL. Chang v c ng s c p nm tv n th c t v th i gian ko di c a chuy n i huy t thanh HBeAg sau i u tr b nh nhn vim gan m n virus B c HBeAg(+) i u tr v i adefovir. Trong s 45 b nh nhn c chuy n i huy t thanh
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HBeAg sang anti HBeAg khi i u tr adefovir li u 10mg/ngy, th chuy n huy t thanh duy tr 41 BN (91%) trong th i gian i u tr c theo di trung bnh l 3 nm. B n b nh nhn (9%) chuy n sang HBeAg(+) trong vng 16 tu n sau khi ngng thu c v nh ng b nh nhn ny c th i gian i u tr adefovir sau chuy n i huy t thanh ng n hn b nh nhn c chuy n huy t thanh c th di hn. M t bo co khc quan tr ng hn cho th y r ng ph i h p adefovir v lamivudine tr c v sau khi ghp gan ngn ng a ti nhi m b nh nhn ghp gan b nh nhn vim gan m n B khng v i lamivudine. Trong nghin c u ny 57 b nh nhan vim gan m n B khng v i lamivudine c i u tr v i adefovir v c ti p t c thm trung bnh 36 t n sau ghp gan, trn 80% b nh nhn khng bao gi tm th y HBV-DNA v 93% khng bao gi pht hi n c HBsAg(+). K t qu c l i ny c duy tr cho d c s d ng globulin mi m d ch virus B (HBIG) hay khng. S s d ng adefovir ni chung l c dung n p t t, ch c 7% b nh nhn ph i ngng thu c do tc d ng ph v t n su t tch lu c a khng thu c l 0%, 2%, v 2% sau 48, 96 v 144 tu n i u tr . 5.2. Entecavir M entecavir c php a vo i u tr HBV t thng 3/2005 d a trn th c nghi m lm sang cho th y an ton v hi u qu hn lamivudine, li u dng l 0,5mg/ngy trong vng 1 nm cho c b nh nhn HBsAg(+) v HBsAg(-), c i thi n ng k v m b nh h c, n ng HBV DNA < 300copies/mL, bnh th ng ha men ALT. Tuy nhin khng c s khc bi t trong vi c bi n m t HBeAg (22% so v i 20%), cng nh s chuy n huy t thanh c a HBeAg (21% so v i 18%) so v i lamivudine, sau 1 nm i u tr b nh nhn vim gan m n HBeAg(+). Sau 48 tu n i u tr cha h y c s khng ng tin c y entecavir. Hai bo co trong HN gan m t chu u cng cho th y cha b khng sau 96 tu n i u tr . Trong NC ng tin c y b nh nhn vim gan B c HBeAg(-), 85% b nh nhn i u tr v i entecavir v 78% i u tr b ng lamivudine c HBV DNA < 0,7mEq/mL v ALT < 1,25 tr s bnh th ng v ngng i u tr ; khng p ng v i HBV DNA > 0,7 mEq/mL vo cu i tu n l 48 cng ngng i u tr . Shouval v c ng s nghin c u nh ng b nh nhn c n l i (26 ng i dng entecavir, 28 ng i lamivudine) nh ng ng i ch c p ng virus v hon t t i u tr vo nm th 2. V i nh ng b nh nhn ny 96% l i u tr b ng entecavir v 64% i u tr b ng lamivudine c n ng HBV DNA < 300copies/mL, l 94% cho entecavir v 77% cho lamivudine. Cng c n bi t r ng khng v i lamivudine lm gi m s nh y c m v i entecavir n 8 t n, v s bng d y c a virus do khng v i entecavir i h i s hi n di n c s n c a lamivudine c ng thm v i s thay i v tr T184, S202 v hay M250 c a men sao chp ng c c th ch n l c b i lamivudine. Colono v c ng s a ra nh ng d ki n cho th y r ng khng c b ng ch ng v khng entecavir vo tu n l 96 b nh nhn khng c i u tr v i lamivudine. Trong NC ny Colono ch n ng u nhin nh ng b nh nhn (81% b nh nhn), t t c b nh nhn c b ng pht virus, v t t c nh ng b nh nhn khng gi m l ng virus xu ng d i 300copies/mL c xc nh genotype. xc nh l khng c khng entecavir lin quan n s c ch nhanh
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v b n v ng s nhn ln c a virus, n ng cao c a entecavir trong n i bo, v c n nhi u s thay th t c n ng khng entecavir c ngha. 5.3. Telbivudine K t qu nm u trong i u tr 2 nm nghin c u GLOBE v i Telbivudine so v i lamivudine trong i u tr vim gan m n B trn 1367 b nh nhn v i li u Telbivudine 600mg/ngy ho c Lamivudine 100mg/ngy. Sau 1 nm cho th y Telbivudine lm gi m n ng HBV DNA cao hn c ngha 60% so v i 40% nhm b nh nhn HBeAg(+) v 88% so v i 71% nhm HBeAg(-). Ngoi ra t xu t hi n khng Telbividine hn Lamivudine 3% so v i 8% b nh nhn HBeAg(+) v 2% so v i 7% b nh nhn HBeAg(-) sau 1 nm i u tr . Trong m t NC phn tch c a GLOBE, ch ng minh r ng c ch HBV s m t i a l tin on cho hi u qu t i u virus trn lm sng. Games v cs bo co tnh an ton v hi u qu vo tu n l 52 v 76 c a Telbivudine b nh nhn vim gan B m n c HBeAg(+). Vo tu n l 76 s gi m trung bnh c a log10 HBV DNA l 6,6 so v i 5,2 v t l b nh nhn c HBV DNA m tnh l 69% so v i 41%. Thm vo , t l m t HBeAg c a Telbivudine cng l n hn (40% so v i 26%), cha c khng vo tu n l 76. 5.4. Tenofoviir Hai th nghi m c ki m sot cho th y tenofovir hi u qu hn adefovir trong i u tr b nh nhn HBV c HBeAg(+) v c HBeAg(-). Trong 1 nghin c u 266 b nh nhn HBeAg(+), k t qu HBV DNA khng cn pht hi n sau 1 nm i u tr l 74% so v i 12%, m t HBsAg l 3%. Khng c tr ng h p no khng v i tenofovir. nhm b nh nhn HBeAg(-) c 375 b nh nhn th k t qu khng cn pht hi n HBV DNA l 93% so v i 63%. Khng c tr ng h p no khng. Cc b nh nhn ny s c theo di trong 5 nm nh gi hi u qu v khng thu c. 5.5. Clevudine L m t thu c khng virus m nh d ng nh c kh nng p ng b n v ng virus sau khi ngng thu c. Kh nng khng virus b n v ng sau khi ngng clavudine c th lin quan n kh nng tc d ng c a clavudine trn cccDNA. C n c thm nh ng nghin c u nh gi hi u qu lu di c a clavudine cng nh t n su t khng thu c ny. 5.6. Peginterferon ALFA-2A FDA c a M cho php peginterferon alfa 2a i u tr vim gan B m n d a trn c s nh ng th nghi m v an ton v hi u qu v i li u 180mcg/tu n, dng n c hay ph i h p v i lamivudine 100mg/ngy trong vng 1 nm b nh nhn HBV c HBeAg(+) v HBeAg(-).Trong bo co t i HN Chu u v vim gan 2006, Cooksley v c ng s phn tch c p i tr c i u tr v 24 tu n sau i u tr c sinh thi t 207 b nh nhn HBeAg(+) v 143 b nh nhn HBeAg(-) v i li u interferon alfa-2a 180mcg/tu n. Trong s b nh nhn HBeAg(-), 33% c i thi n c tnh tr ng x (gi m > 1 i m trong ch s x) v 33% khng thay i. T c i thi n ho c n nh x cao hn c ngha v i p ng b n v ng huy t thanh v siu vi sau 72 tu n. VI. KHI NO I U TR ? i u tr c ch nh b nh nhn vo th i k thanh th i v ti ho t ng v d b nh nhn c n ng HBV DNA huy t thanh cao, men gan cao v hay l c tnh
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tr ng vim ho i t trn sinh thi t gan, v b nh nhn c d on c c may p ng t t v i i u tr . Trn th c t th sinh thi t gan khng c lm th ng xuyn nhng n c ch b nh nhn cha c ch nh i u tr y nh l ang c ch n on phn bi t gi a ng i mang siu vi khng ho t ng ho c vim gan B m n v i HBeAg m tnh ho c xc nh b nh gan c nhi u khng ng i gi v i men gan bnh th ng. M c ch u tin c a i u tr vim gan m n B v lu di l lm gi m HBV DNA trong huy t thanh, i u ny s lm gi m di n ti n a n x gan v ung th gan, cn c vo k t qu c a nhi u nghin c u i loan cho th y r ng n ng n nc a HBV DNA 104copies/L th k t h p v i h u qu c a cc bi n ch ng x gan v ung th gan cao hn trong 10 nm t i. Hn n a b nh nhn b gan x n ng ho c b x gan th vi c s d ng lamivudine > 3 nm s lm gi m tnh tr ng m t b v gi m t n su t K gan. B ng 2: H ng d n i u tr cho b nh nhn HBeAg(+) HBeAg HBV DNA < 20.000 ALT Chi n l c i u tr Khng i u tr Theo di m i 6-12 thng Xem xt i u tr khi c t n thng m h c gan cho d nhn ln virus th p i u tr th chuy n huy t thanh HBeAg th p B nh nhn tr th ng dung n p mi n d ch Xem xt sinh thi t, c bi t > 35-40 tu i; i u tr n u c thng t n, trong tr ng h p khng sinh thi t theo di s gia tng c a ALT N u i u tr th nn dng entecavir, adefovir, Pegint. alfa-2a, telbivudine c th cho n ng HBV DNA khng pht hi n c sau 24 tu n i u tr . V i b nh nhn i u tr , ti p t c thm 6-12 thng sau khi chuy n huy t thanh HBeAg v HBV DNA (-) Entecavir, adefovir, ho c pegint alfa-2a c u tin ch n, telbivudine c th cho php khng pht hi n HBV DNA sau 24 tu n i u tr . N u HBV DNA cao, entecavir, adefovir ho c telbivudine c chu ng hn pegint alfa-2a. V i b nh nhn c i u tr , ti p t c thm 6-12 thng sau khi chuy n huy t thanh v HBV DNA (-)
(+)
BT
(+)
20.000
BT
(+)
20.000
Cao
79
Theo FDA th thu c c ch p nh n hi n nay l interferon alfa-2b, interferon alfa-2a, v cc thu c u ng ng v n c a nucleoside/nucleotide nh lamivudine, adefovir dipivoxil, entecavir, v telbivudine l c s d ng trong nm 2008. M i lo i thu c ny u c nh ng ti n l i v b t l i. V n xt n trong i u tr l: hi u qu , tnh an ton, s khng thu c, cch th c s d ng, v gi thnh. Peginterferon alfa-2a c l i i m l c th i gian i u tr c xc nh 1 nm, c chuy n i huy t thanh HBeAg cao hn, khng b khng, v d ng nh c chuy n i huy t thanh HBsAg cao hn. i u b t l i l ph i dng b ng ng tim, th ng c tc d ng ph nh: tri u ch ng nh c m cm, tr m c m ho c ch thch, gi m t bo mu. C n ph i theo di k hn v ch ng ch nh trong b nh gan n ng, gi thnh cao. C n nh genotype gip cho vi c i u tr b ng interferon alfa 2a c hi u qu cao genotype A v th p nh t genotype D. Cc thu c nucleoside/nucleotide c l i i m l dng ng u ng, dung n p t t, v n dng c khi gan b n ng, kh nng lm gi m HBV DNA cao. Nh ng l i i m ny c a thu c c n c dng lu di v gy ra khng thu c. Cc thu c c tc d ng m nh v t khng l th ng c s d ng cho nh ng b nh nhn khng thu c[7,8,16]. Thu c c u chu ng trong i u tr 2008 l HBV DNA pginterferon alfa-2a, entecavir, tenofovir v telbivudine gip cho n ng khng pht hi n c sau 24 tu n i u tr , i u ny d bo cho t l khng cc thu c ny l r t th p sau 2 nm i u tr , Interferon alfa-2b t cn c dng do b t ti n v khng thu c c a n nhi u hn l entecavir v telbivudine. G n lamivudine th do s y tenofovir cho th y t t hn adefovir v s thay th cho adefovir trong i u tr u tay trong nm 2008. B ng 3: H ng d n i u tr cho b nh nhn HBeAg(-) HBeAg HBV DNA ALT Chi n l c i u tr Khng i u tr , ph n l n l ng i mang HBsAg khng ho t ng Theo di 6-12 thng i u tr cho b nh nhn c t n thng m h c d s nhn ln virus th p Sinh thi t gan, n u t n thng. N u khng c sinh thi t th theo di s gia tng men ALT N u i u tr , th ch n entecavir, adefovir, pegint,alfa-2a. Telbivudine c th lm HBV DNA khng pht hi n c sau 24 tu n i u tr . V i bnh nhn i u tr , n u li u trnh 1 nm th pegint alfa-2a, n u i u tr lu di th dng thu c u ng
(-)
< 2000
BT
(-)
2.000
BT
80
(-)
Entecavir, adefovir ho c pegint. alfa-2a c a ch n, telbivudine c th lm HBV DNA khng cn pht hi n c sau 24 thng i u tr . Tng i v i b nh nhn c i u tr li u php peginterferon l 1 nm. i u tr lu di th c n dng thu c u ng
Trong s b nh nhn vim gan m n B v i HBeAg(+) v gan cn b v i n ng HBV DNA 20.000IU/ml km v i ALT cao hn tr bnh th ng v/hay l sinh thi t gan c thng t n th c ch nh i u tr . i v i b nh nhn HBeAg(-) v gan cn b, n ng HBV DNA th p v i ng ng HBV DNA 2.000IU/ml cng v i ALT tng cao v /hay l sinh thi t gan c t n thng ng k th c ch nh i u tr . i v i b nh nhn x gan cn b, ng ng huy t thanh HBV DNA l 2.000IU/ml l i u tr , b t lu n HBeAg v ALT th no cho d ALT cao nh trong b n sau. V i b nh nhn vim gan m n B v x gan m t b, n ng HBV DNA b t u i u tr b ng thu c u ng cng nh ng k cho vi c ghp 200IU/ml l gan. Khuynh h ng hi n nay l i u tr cho b nh nhn x gan cn b hay m t b ph i c a HBV DNA b t lu n m c no. Cc thu c u ng h p v i vi c pht hi n n ng c a chu ng hn khi b x gan cn interferon th ch ng ch nh tng i hay tuy t i i t ng ny. Cng c khuynh h ng ph i h p gi a cc nucleoside v nucleotide b nh nhn x gan cng nh b nh nhn ng nhi m HBV v HIV v b nh nhn ghp gan sau nhi m HBV. KHUY N CO I U TR HBeAg(+) HO C (-) B ng 4: H ng d n i u tr Tnh trang HBV DNA HBeAg (+) ho c(-) (+) ho c (-) < 2.000 2.000 X GAN Cn b Cn b B NH NHN X GAN
b nh nhn x gan
chi n l t i u tr C th i u tr , ho c theo di Nn ch n Entecavir ho c Adefovir L a ch n u tin l Entecavir ho c Adefovir Nn i u tr lu di v i u tr ph i h p Nn ph i h p i u tr C n i u tr ko di. Ch ghp gan
(+) ho c (-)
< 200IU/ml M t b ho c 200UI/ml
Cu i cng b nh nhn c n ho tr ung th ho c i u tr b ng khng TNF alfa m c HBsAg th cho d l ng i mang virus khng ho t ng ho c vim gan B m n th nn i u tr b ng thu c u ng phng ti ho t ng c a virus B. Thu c khng virus nn cho ngay tr c v 6-12 thng sau ngng ho tr li u ho c thu c khng TNF alfa, ho c nn i u tr lu di n u b nh nhn tiu chu n c a i u tr vim gan m n.
81
VII. KHI NO NGNG I U TR B nh nhn nn c theo di t nh t m i 3-6 thng trong khi i u tr b ng thu c u ng v dy hn khi i u tr b ng interferonalfa-2a v tc d ng ph nhi u hn v t dung n p thu c hn. B nh nhn i u tr b ng peginterferon alfa-2a th c th i gian c h n l 1 nm, nhng cng c th ng n hn, ch c cha y 5% b nh nhn ph i rt ng n i u tr do khng dung n p c. Ng ng i u tr i v i b nh nhn vim gan m n B c HBeAg(+) l khi chuy n huy t thanh HBeAg ph i h p v i n ng HBV DNA th p ho c khng pht hi n c. D a trn kinh nghi m v i lamivudine cho th y r ng t l ti pht th p khi ti p t c i u tr thm 6-12 thng c a i m d ng ny, th c t ny cng p d ng cho nh ng thu c u ng khc. M t s h ng d n cho r ng v i b nh nhn x gan th i u tr di h n v i thu c u ng cho d khi chuy n huy t thanh HBeAg t c trnh nguy c ti pht. Do b nh nhn vim gan m n HBeAg(-) s ti pht 1 nm sau ngng i u tr l khng thay i, cho d khi m HBV DNA khng cn pht hi n , h ng d n hi n nay l i u tr di h n. Cho d nh ng nghin c u g n y cho th y r ng t n su t ti pht l th p n u ng ng i u tr b ng lamivudine ho c adefovir sau nhi u nm khi HBV DNA khng cn pht hi n n a. Khuy n co hi n nay v vim gan B v i HBeAg(-) l i u tr di h n. VIII. KHI NO THAY I LI U TRNH Th i gian thch h p thay i i u tr ho c ph i h p thu c l khi i u tr th t b i ho c p ng khng . nh ngha c a th t b i i u tr tin pht l khi HBV DNA huy t thanh gi m < 1 log10 IU/ml sau 12 tu n i u tr , trong khi p ng khng v m t virus c nh ngha l khi HBV DNA huy t thanh 2.000IU vo tu n 24 c a i u tr . B c u tin c a vi c nh gi kh nng th t b i ban u trong i u tr l lo i b nh ng b nh nhn khng tun th i u tr . N u b nh nhn u ng thu c u n m v n b nh trn th g i l th t b i tin pht v ph i thay i sang thu c m nh hn ho c ph i h p thu c. b nh nhn c p ng virus khng l th ng g p trong vi c thay i i u tr hn v pht i u tr cho nh ng b nh nhn ny g n y cng c a ra. B nh nhn ph i c chuy n sang thu c m nh hn v khng c khng cho v i t c p ng virus m t thu c dng ho c thm m t thu c m i. b nh nhn ch ph n sau 24 tu n i u tr (HBV DNA huy t thanh n m trong kho ng 60IU v < 2.000IU) cng c n thay i pht i u tr , m t s ng i c n thm thu c th 2 khng c khng cho v i thu c th nh t. Tuy nhin n u b nh nhn c i u tr v i thu c t khng nh l entecavir, th cng c th i u tr ko di trn 48 tu n. Trong tnh hu ng ny b nh nhn nn c nh l ng HBV DNA m i 3-6 thng. M t s thu c nh adefovir cng c tc d ng khng virus ch m. nh ng b nh nhn ny nn xt nghi m HBV DNA huy t thanh m i 3 thng v nh gi sau 48 tu n i u tr , n u vo th i i m ny m p ng virus ch m t ph n ho c khng th ph i i i u tr . B nh nhn vim gan B m n c p ng khng sau 24 tu n khi i u tr v i nh ng thu c c nguy c khng nh telbivudine th c n chuy n sang thu c khc hi u qu hn, ho c l dng thm m t thu c th 2 khng c khng cho v i thu c u. B nh nhn nn c theo di m i 3 thng cho n 48 thng. N u HBV DNA huy t thanh khng pht hi n c sau 48 tu n th xt nghi m HBV DNA m i 6 thng. Tuy
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nhin b nh nhn n ng th ti p t c theo di m i 3 thng b t lu n p ng v i i u tr nh th no. M t th i i m thch h p khc thay i i u tr b ng cch chuy n ho c thm thu c l khi xu t hi n virus khng thu c. i u tr v i adefovir b nh nhn HBeAg(-) th sau 5 nm l 29% khng thu c. Entecavir th t l khng thuc tch lu th p sau 4 nm i u tr l < 4%. khng v i telbivudine th m c trung gian sau 2 nm i u tr l: 25% v i HBeAg(+) v 11% v i HBeAg(-). Th nghi m v i telbivudine cho th y r ng t l c ch virus tu n 24 cao hn, k t qu t t hn sau 1 v 2 nm i u tr v phng di n HBN DNA khng cn c pht hi n, chuy n huy t thanh, men gan tr v bnh th ng, v t l HBV khng thu c. Nguyn t c chung c a khuy n co c pht ho trn b ng sau: IX. NNG L C I U TR VIM GAN B KHNG THU C B ng 5: H ng d n i u tr khi khng thu c khng lamivudine Ti p t c lamivudine v thm adefovir ho c tenofovir Chuy n sang emtricitabine/ tenofovir khng adefovir Ti p t c adefovir v thm lamivudine ho c telbivudine Chuy n qua ho c thm entecavir (n u khng c khng lamivudine tr c y) Chuy n qua emtricitabine/tenofovir Chuy n qua ho c thm adefovir ho c tenofovir Chuy n qua emtricitabine/tenofovir
khng entecavir
khng telbivudine Ti p t c telbivudine v thm adefovir ho c tenofovir Chuy n qua emtricitabine /tenofovir X. K T LU N i u tr vim gan m n virus B c nhi u ti n b trong vng 10 nm nay k t khi lamivudine c ch p thu n nh l thu c u ng u tin vo nm1998. Vi n c nh trong tng lai c i thi n vi c i u tr l r t sng s a v s cho ra i nhi u thu c m i cng nh cch ti p c n v n ngy cng t t hn trong v n tr li u i u ny s gip lm gi m s khng thu c cng nh t i u ho cc k t qu t c. i u tr vim gan m n B trong tng lai c th c n ph i ph i h p nhi u thu c. L t ng l cc thu c ph i h p t t c n c nh ng tnh ch t sau: Chng ph i khc nhau v tr tc ng trn s nhn ln c a HBV DNA, thu c ph i an ton, thu c ph i c tc d ng p ng virus b n v ng v c th i gian i u tr c h n. Th t v y ch c s ph i h p peginterferon alfa 2a v i lamivudine cho th y c hi u qu khng virus hn h n so v i n tr li u. S k t h p peginterferon alfa 2a v i m t thu c ng ng tc d ng m nh hn nh entecavir, telbivudine, tenofovir ho c clavudine c n c nghin c u thm. S ph i h p hi u qu hn cng v i nh ng hi u bi t v c ch khng thu c l nh ng thch th c l n c i thi n hi u qu i u tr v gip lm gi m gnh n ng c a vimgan B m n trong tng lai. TI LI U THAM KH O
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1. Anna S. F, Brrian J. Mcmahon. Hepatology, 2007 2. Benhamou Y, Pleury H, Trimoulet P, Anti- hepatitis B virus efficacy of tenofovir disoproxil fumarate in HIV- infected patients. Hepatology. 2006. 3. Brian J. McMahon. Natural history of chrronic hepatitis B- Clinical implications. Gastroenterology- Original Articles. Medcape Med 2008. 4. Chakrradhar M, Paul Martin. Understanding resistance in hepatitis B. Clinical implications. CME 2008.
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DUY T XT L I CC THUY T NG MU TRN C S NH NG TI N B G N Y TRONG C M MU V HUY T KH I

Nguy n Ng c Minh Tr ng i H c Y D c Hu Tm t t: M c d quan ni m v dng thc ng mu l s ti n b ng k v hi u bi t ng mu v c s d ng nghin c u nhi u nm nh m t m hnh h u ch, nhng nh ng quan st lm sang v th nghi m g n y cho th y r ng gi thuy t dng thc khng ph n nh y v hon ton nh ng v n quan tr ng c a c m mu in ViVo. Nh m m t nh ng thay i x y ra trong cc qu trnh sinh l lin quan n c m mu, duy t xt l i cc ti n b c a cc thuy t ng mu v cc m hnh c s nh gi v m t l thuy t cng nh th c hnh c cng b trn ton c nh d ng c a cc thuy t ng mu khc nhau theo trnh t th i gian: - M hnh c i n c a Paul Morawits 1905 - M hnh dng thc ng mu - M hnh d a trn nh ng ti n b v sinh h c c m mu - M hnh ng mu trn c s t bo - Tng tc ti u c u protein T cc v n thu c l thuy t a n nh ng k t lu n v ng d ng: - C m mu l m t m ng l i tng tc cao - C nhi u phng php can thi p i u tr - K t qu can thi p khng d on tr c - Tc nhn i u tr khng gi i h n i v i cc y u t ng mu protein c i n. - Ti p t c pht hi n cc tng tc khc, c bi t lin quan n Vim v ung th. Abstract
REVIEW ON COAGULATION THEORIES BASED ON RECENT ADVANCES IN COAGULATION AND HEMOSTASIS

Although viewpoint on coagulation waterfall cascade is a considerable advance in coagulation knowledge and used as a helpful model for researche for many years, clinical observation and assays have made it clear that suppositions on coagulation diagram havenot reflected important issues of coagulation in vivo sufficiently and entirely. In order to describe changes in physiological process related to coagulation, review on advances in coagulation theories and models is done to evaluate theoretical and practical aspects published in the panorama of various coagualation theories in temporal order: - Classical model by Paul Morawits in 1905 - Model of coagulation waterfall cascade - Recent advances-based model in the biology of hemostasis - Cell-based model of coagulation - Platelet protein interactions, ... With above theoretical issues, conclusions are made: - Coagulation is an interactive network - A lot of intervention methods for treatment
85
- Unpredictable intervention results - Unlimited treatment agents for classical protein coagulation elements - Continuous detection of other interaction, especially inflammation and cancer. M c d quan ni m v dng thc ng mu l s ti n b ng k v hi u bi t ng mu v c s d ng trong nhi u nm nh m t m hnh h u ch, nhng nh ng quan st lm sng v th nghi m g n y cho th y r ng gi thuy t dng thc khng ph n nh y v hon ton nh ng v n quan tr ng v c m mu in vivo. Cc c ch cm mu c pht hi n d n d n nh m b o v ch ng l i s e d a c a xu t huy t n ng. S tng tc gi a ti u c u v cc y u t ng mu d n n s hnh thnh nt c m mu b o v v ch c nng c a n l s n nh (staunch) dng mu v tr c t n thng m ch mu. cn b ng hi n t ng ny, h th ng tiu s i huy t c ho t ha d n d n lm thng cc m ch mu, khi s lnh v t thng t c ph c h i s t i mu c a m t m ch mu t n thng sau khi c c ng b o v c hnh thnh. M c d c nhi u c ch i u ha c m mu, nhng cng c nhi u r i lo n c th i km v i tnh tr ng xu t huy t ho c ti n huy t kh i (Loscalzo, 2003). Nh m m t nh ng thay i x y ra trong cc qu trnh sinh l lin quan n c m mu, duy t xt l i s ti n b c a cc thuy t ng mu v cc m hnh c s d ng nh gi v m t l thuy t cng nh th c hnh c cng b trong b i c nh c a cc thuy t ng mu khc nhau theo trnh t th i gian. I. T NG QUAN V C M MU C m mu l m t qu trnh ng (dynamic process) qua s ng mu c kh i u v k t thc theo cch th c i u ha nhanh chng v ch t ch (Nathan, Orkin, Ginsburg, Look, 2003). ng mu (s ng ng ch y mu t m ch mu t n thng) l m t ph n c a c ch khng quan tr ng c a c th . Khi t n thng m ch mu, ti u c u bm vo cc i phn t m d i n i m ch t i v tr t n thng v sau ngng t p hnh thnh nt c m mu u tin. Cc ti u c u kch thch s ho t ha cc y u t ng mu huy t tng t i ch t d n n s hnh thnh c c ng fibrin lm v ng ch c hn n a nt ti u c u. V sau, khi s li n thng x y ra, nt ti u c u v c c ng fibrin s b ph hy v lo i b . S c m mu c i u ha b i 3 thnh ph n c b n l thnh m ch, ti u c u v dng thc ng mu. S c m mu bnh th ng x y ra nh l k t qu c a m t t p h p cc qu trnh i u ha th c hi n 2 ch c nng: th nh t l duy tr mu d ng l ng khng ng, th 2 l t o ra nt c m mu nhanh chng v khu tr v tr m ch mu t n thng. S c m mu x y ra khi enzym thrombin c sinh ra, sau enzym ny th y phn protein fibrinogen huy t tng d ng ha tan t o ra fibrin a phn khng ha tan hay c c ng. Cc c ch lm gi i h n s hnh thnh cc nt ngng t p ti u c u v c c ng fibrin nh ng v tr t n thng l c n thi t duy tr d ng l ng c a mu. II. S L C V L CH S C M MU Hippocrate, Aristotle, Celsicus v Galen nh n th c y v n l mu v a m i l y ra kh i lng m ch th ng ng l i trong vng vi pht. H m t chi ti t cc khuynh h ng ch y mu n i t ng v b m t khc nhau. M t nh n xt chung l mu ng l i khi l nh. Ng i ta ngh r ng b ng cch v t thng ti p xc v i khng kh, mu tr nn l nh s lm ng ng ch y mu. Tuy nhin h khng lin k t c
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gi a tnh ng mu (blood coagulability) v i quan ni m c m mu (concept of hemostasis) (Nichols and Bowie, 2001). Hai ngn nm sau vo u nh ng nm c a th p nin 1720, nh ph u thu t ng i Php Jean-Louis Petit ghi nh n r ng s c m mu sau khi c t c t chi c t o ra b i cc c c ng hnh thnh trong cc m ch mu. y l quan st u tin v c c mu ng c lin quan n c m mu. Vo nm 1828, m t bc s Th y S Friedrich Hopff ghi nh n r ng khuynh h ng ch y mu c tnh gia nh c bi t r nam gi i c lin quan n tnh tr ng gi m ng (hypocoagulability), hi n nay c g i l b nh hemophilia, b nh c lin quan n NST X. V v y, kh nng ng mu l c n thi t ngn ng a ch y mu. Vi c nh n bi t ng mu b t th ng ny v m i lin quan c a n v i ch y mu d n n s gia tng nhanh chng cc nghin c u v hi n t ng ng mu. Vo th k 19, nm 1860 nh b nh l h c ng i c Ruolf Virchow m t v huy t kh i (thrombi) v khuynh h ng gy ngh n m ch c a huy t kh i. Ng i ta pht hi n ti u c u v ch c nng c a chng cng v i nhi u thnh ph n khc nhau c a qu trnh ng mu. Nh ng pht hi n ny d n n thuy t ng mu c i n c m t b i Paul Morawits vo nm 1905. ng t p h p m t cch thuy t ph c 4 y u t ng mu ng mu c a ng (hnh 1). trong s Thrombokinnase Calcium Prothrombin Thrombin Fibrinogen Fibrin
Hnh 1: Thuy t ng mu c i n c ngh b i Paul Morawits trong prothrombin c ho t ha b i canxi s sinh ra thrombin. Thrombin s chuy n fibrinogen thnh fibrin. V i s hi n di n c a canxi v thromboplastin, prothrombin c tin l b chuy n thnh thrombin. R i n l t thrombin chuy n fibrinogen thnh fibrin c kh nng hnh thnh c c ng fibrin. Mozawitz cho r ng t t c cc thnh ph n c a c c mu ng hi n di n trong mu v mu lu hnh th ng khng ng do thi u b m t m t (wettable surface) trn m ch mu. Thuy t c i n ny t n t i trong su t 40 nm. III. DNG THC NG MU (THE COAGULATION/WATERFALL CASCADE) Hi u bi t hi n i v m t ha sinh c a ng mu b t u xu t hi n vo th p nin 1940, khi Paul Owren (1947 nh n ra r ng th tr ng ch y mu m t ng i ph n tr khng th gi i thch b ng quan ni m 4 y u t ng mu v cho r ng c ta thi u m t y u t ng mu th 5 trong huy t tng. Trong su t nh ng nm c a th p nin 1940 v 1950, nhi u y u t ng mu hn c khm ph. Cc y u t ng mu c t tn b ng ch s La m. i u quan tr ng l h th ng s c ch p nh n ch ra con s i v i y u t theo trnh t pht hi n v khng ch ra i m tng tc trong dng thc ng mu. Vo nm 1957, cc y u t sau y c m t : y u t von Willebrand (VWF: von Willebrand Factor, von Willebrand 1931), y u t V (FV; Owren, 1947), FVII (Alexander, Goldstein, Landwehr v Cook, 1951), FVII (Patek v Stetson, 1936),
87
FIX (Aggeler v Cs, 1952; Briggs v Cs,1952; Shulman v Smith 1952) v FXI (Rosenthal, Dreskinoff v Rosenthal, 1953). Hai nhm m t thi u y u t X (Hougie, Barrow v Graham nm 1957, Telfer, Denson v Wright 1956). Tuy nhin c i u cha r l lm th no nh ng y u t ny tng tc chuy n prothrombin thnh thrombin hnh thnh c c ng fibrin. Nh ng pht hi n ny l s ng gp quan tr ng vo vi c hi u r c ch ng mu (Roberts, 2003) Vo nh ng nm 1960, hai nhm nghin c u sinh c l p gi i thi u m hnh ng mu nh l m t chu i cc b c, trong s ho t ha y u t ng mu ny d n n s ho t ha y u t khc cu i cng sinh ra thrombin. Nm 1964, Macfarlane cng b m hnh dng thc (cascade model) trn t p ch T nhin v m t th i gian ng n sau m hnh thc n c (water fall model) c Davie v Ratnoff (1964) ng t p ch khoa h c.
CON NG N I SINH CON NG NGO I SINH
XII
Kallik
(y u t Hageman) HMWK, Collagen
M t n thng
Prekallikrein
XII Y u t m (TF) XI XIa IX IXa VII Y u t m X

Ca2
+
(Thromboplastin)
VII
Thrombin
VIIIa IIa
Ca2
+
VII
Ca2
+
Xa V (thrombin) Va
Ca2
+ +
XII
Ca2
(II
II (Prothrombin) IIa (Thrombin)
Ca
+ 2
XIIIa
Fibrinogen B m t phospholipid Ca2+ Ho t ha B t ho t

(I)
Fibrinogen Fibrin lin (Ia) k t
CON NG CHUNG
Hnh 2: M hnh dng thc ng mu i m g p nhau gi a con ng n i sinh v ngo i sinh trong m hnh ny x y ra khi c s ho t ha y u t IX. HMWWK: (High molecularr weight kininogen ki): Kininogen tr ng l ng phn t cao.
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M hnh ny (hnh 2) m t m i y u t ng mu nh 1 ti n enzym c kh nng c chuy n thnh 1 enzym ho t ng. Cc m hnh dng thc hay thc n c g i r ng cc chu i ng mu c phn thnh 2 con ng. Qu trnh ng mu c th c kh i u qua con ng n i sinh (intrinsic pathway). Ng i ta g i l n i sinh v t t c cc thnh ph n c a n hi n di n trong mu, ho c b ng con ng ngo i sinh (extrinsic pathway) trong protein mng t bo d i n i m ch, y u t m (TF: tissue factor), l c n thi t cng v i cc thnh ph n khc lu hnh trong mu. S kh i pht c a m i con ng d n n ho t ha y u t X v cu i cng sinh ra c c ng fibrin qua con ng chung (Luchtman-Jones Broze, 1995). 3.1. Con ng n i sinh (Intrinsic pathway) Con ng n i sinh bao g m 1 dng thc ph n ng c a cc protease c kh i u b i cc y u t c trong mu. Khi ti p xc v i b m t tch i n m nh th y tinh ho c mng ti u c u ho t ha, 1 protein huy t tng c g i l y u t XII (y u t Hageman) tr thnh y u t XII ho t ha (FXIIa) ( ti p v ng a dng ch ra r ng y l d ng ho t ha c a y u t XII). M t phn t khc c g i l kininogen cao phn t (HMWK: high molecular weight kininogen) l m t s n ph m c a ti u c u th t s c th c g n vo mng ti u c u, gip neo gi y u t XII vo b m t tch i n v v v y ng vai tr nh m t ng y u t (cofactor). Tuy nhin vi c chuy n i y u t XII d i h tr c a HMWK hnh thnh FXIIa b gi i h n v t c . Khi m t l ng nh FXIIa t p h p l i, protease ny s chuy n prekallikrein thnh Kallikrein cng v i HMWK c ch c nng nh l m t m neo. R i n l t, kallikrein v a m i hnh thnh l i thc y chuy n y u t XII thnh FXIIa, y l m t v d c a s ph n h i dng tnh (positive feedback). Cng v i s khuy ch i sinh ra FXIIa thng qua kallikrein, FXIIa (cng v i HMWK) phn c t y u t XI theo ki u th y phn protein hnh thnh FXIa. n l t, FXIa (cng c g n vo b m t tch i n b i HMWK) phn c t FIX theo ki u th y phn protein t o ra FIXa, FIXa cng l m t protease. FIXa v 2 s n ph m g n ph n thp c a dng thc t o ra FVIIIa, FVIIIa l m t ng y u t trong ph n ng g c k ti p. Cu i cng, FIXa v FVIIIa cng v i Ca2+ (c ngu n g c ph n l n t cc ti u c u ho t ha v cc l p phospholipids tch i n m ) cc thnh ph n chnh c a mng t bo) s t o thnh m t ph c h p tam phn (trimolecular complex) c g i l tenase. Sau tenase chuy n FX thnh FXa cng l 1 protease. Trong m t lo t cc tng tc song hnh, FXa g n vo ng y u t Va, chnh n l 1 y u t thu c ph n th p c a dng thc tham gia v s ph n h i dng tnh v i ph n ng ngay khi sinh ra m t ph c h p c ho t tnh enzym c g i l prothrombinase. Ph c h p ny chuy n ti n enzym prothrombin thnh d ng enzym c a n l thrombin. Thrombin tc ng trn fibrinogen sinh ra fibrin n phn, cc fibrin n phn nhanh chng a trng h p hnh thnh c c ng fibrin. Trong qu trnh xt nghi m ng mu, con ng ng mu n i sinh c nh gi b ng xt nghi m th i gian thromboplastin t ng ho t ha (PTT: Activated partial Thromboplastine time) (R.Hoffman v CS, 2005). 3.2. Con ng ngo i sinh (Extrinsic pathway)
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Con ng ngo i sinh cng bao g m cc ng y u t protein v cc enzym. Con ng ny c kh i u b i s hnh thnh ph c h p gi a TF trn b m t t bo v FVIIa n m ngoi h th ng m ch mu. Cc t bo khng thu c m ch mu b c l ch y u protein mng c n thi t l TF ( c bi t nh l y u t III hay thromboplastin m), y l th th c a y u t VII huy t tng (Kumar v CS, 2005). Khi t n thng l p n i m ch, y u t VII s ti p xc v i TF, TF s ho t ha FVII thnh FVIIa khng theo ki u th y phn protein. C ch chuy n i ban u c a ti n men FVII thnh FVIIa v n cn c bn ci nhng g n nh ch c ch n l do s ho t ha ki u t th y phn v khng do hi u qu TF. S k t h p FVIIa vo TF t o ra m t ph c h p enzym lm ho t ha FX thnh FXa. Ph c h p FVIIa/TF gi ng ch c nng c a ph c h p tenase s chuy n FX thnh d ng ho t ha c a n l FXa. FXa s k t h p v i ng y u t FV v c g n ln cc b m t mng v i s hi n di n c a canxi sinh ra ph c h p prothrombinase. Ph c h p prothrombinase ny chuy n prothrombin thnh thrombin, sau thrombin chuy n fibrinogen thnh fibrin sinh ra cc c c ng fibrin. Trong qu trnh xem nghi m ng mu phng th nghi m, con ng ng mu ngo i sinh c nh gi b ng th i gian prothronbin (PT: Prothrombin time). B t k FXa c hnh thnh t con ng n i sinh hay ngo i sinh, khi dng thc ng mu ti p di n theo con ng chung. 3.3. Con ng chung (common pathway) Con ng chung b t u v i s ho t ha c a FX trong con ng n i sinh, con ng ngo i sinh ho c c hai. FX sinh ra t con ng n i sinh ho c ngo i sinh l protease u tin c a con ng chung. FX v i s hi n di n c a FV, Ca2+ v phospholipid s chuy n prothrombin thnh d ng ho t ng c a n l thrombin. Ho t ng chnh c a thrombin l th y phn fibrinogen d ng ha tan thnh fibrin n phn ha tan. Cc fibrin n phn sau a trng h p t o thnh cc a phn fibrin c kh nng b t gi cc t bo mu. Thrombin cng ho t ha FXIII chuy n thnh FXIIIa v i u ha lin k t cho ng ha tr c a cc fibrin a phn t o thnh fibrin d ng l i n nh t ha tan hn d ng fibrin a phn. Thrombin c th th y phn prothrombin t o thm FVa v FVIIIa, t khuy ch i qu t o thm thrombin v th y phn trnh ng mu m t cch hi u qu . V con ng chung c ch a cc y u t FX, FV v FII (b t k m t thi u h t no v cc y u t trong con ng c th d n n b nh l xu t huy t) nn cc y u t ny c th c theo di b i c 2 xt nghi m PT v PTT (Harmening, 2002). M c d nh ng quan ni m ny l s ti n b ng k v hi u bi t ng mu v ph c v trong nhi u nm nh 1 m hnh h u ch, nhng nh ng quan st v lm sng v th c nghi m g n y hn cho th y r ng gi thuy t dng thc hay thc n c (Cascade/waterfall hypothesis) khng ph n nh m t cch y v ton di n nh ng s ki n c m mu in vivo. Trong nh ng nm g n y, nhi u thi u st c a s ny tr nn r rng. Th nh t l khng c s gi i thch no v tnh tr ng khng c khuynh h ng ch y mu lm sng v nh ng thi u h t y u t XII, prekallikrein ho c HMWK m c d nh ng thi u h t v b t k 1 trong nh ng y u t ny lm ko di r r t nh ng nghi m php ng mu ho t ha b m t (surface-activated coagulation assays) khi thm d c m mu in vivo. Th hai l khng c s gi i thch no v l do t i sao thi u h t FVIII ho c FIX gy ra ch y mu n ng trn lm sng, m c d con ng ngo i sinh cho l b qua nhu c u y u t VIII v FIX (Hoffbrand v CS, 2005).
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Nh ng quan st quan tr ng ny d n n vi c xem l i nh ng m hnh s m hn c a ng mu. M t quan st mang tnh quy t nh l ph c FVIIa v TF khng ch l ho t ha FX m c FIX. Nhi u quan st g n y a n k t lu n r ng ho t tnh c a ph c h p FVIIa/TF l hi n t ng kh i u ch y u c a c m mu in vivo (M.Hoffman and Monzoe, 2005). IV. NH NG TI N B M I V SINH H C C M MU (RECENT ADVANCES IN THE BIOLOGY OF HAEMOSTASIS). T cc hi u bi t c b n v l thuy t dng thc ng mu nh nu trn cho php hnh dung m t chu i cc b c ho t ho tiu protein,m i b c g m m t enzym ho t ng trn m t ch t n n, sau ch t n n ny l i tr nn ho t ho c t m t tiu enzym (cn g i l Zymogen) k ti p trong chu i ho t ho ny. t c i u , m ng l i ng mu c kh i pht v i u ho b i m t m ng l i cc tng tc ph c h p d i s ki m sot c a cc vng ph n h i dng tnh v m tnh, k t qu l l ng ng fibrin c ki m sot v ho t ho ti u c u ch x y ra t i v tr t n thng. M c ch c a m ng l i ng mu l s n xu t t nhng c tnh khu tr c a fibrin thnh l p c c mu ng v tr t n thng m ch mu ng nhin, qu trnh ny ph i di n ra ngn c n nh ng h u qu c kh nng e do nhanh chng v c ki m sot ch t ch c a ng mu r i rc qua h m ch nguyn v n. Nh ng hi u bi t m i c b sung v s thnh l p cc ph c h p i phn t b t ngu n t php ghi hnh tinh th x quang v i n t , v c ng h ng t h t nhn, lm sng t hnh nh c u trc qua p d ng cc k thu t l sinh, cung c p nh ng hi u bi t v ng h c enzym, gi i thch cc thng tin v t bi n in Vitro v cc nghin c u v di truy n lm sng. Cc hi u bi t c n lu l: - Qu trnh ng mu ti p di n v k t thc b i s t o n i ti p cc ph c h p i phn t : t p trung vo 3 ph c h p y u t ho t ho chnh lin quan n qu trnh sinh thrombin. l cc ph c h p y u t m (TF) v y u t VII ho t ho (FVIIa) ph c h p y u t VIIIa/y u t IXa, ph c h p y u t Va/Xa. Cc ph c h p ny l n l t ho t ho y u t IXa v /ho c y u t Xa, y u t Xa v Prothrombin. - Cc ph c h p i phn t c ch qu trnh ng mu, xt n: + Vai tr c a ch t c ch con ng y u t m (TFPI) + Vai tr c a Antithrombin + Con ng Protein C Chnh cc hi u bi t ny lm c s cho vi c ng d ng i u tr ng mu r i rc trong lng m ch, nh m l p l i s qun bnh sinh h c, trnh d n t i s l ng ng fibrin qu m c t o thnh huy t kh i vi m ch v h u qu l suy a n i t ng. Chnh c s nh ng ti n b trn y d n t i b ng s p x p cc Protein huy t tng v Protein mng c a c m mu, v s qu trnh ng mu c hnh thnh theo c s m i. V. M HNH NG MU TRN C S T BO (CELL-BASED MODEL OF COAGALUTION) Pht tri n quan tr ng trong 15 nm qua l vi c pht hi n mu ti p xc v i cc t bo b c l TF trn b m t c a chng l c n thi t v kh i pht ng mu in vivo. Pht hi n ny d n n vi c tin t ng r ng con ng n i sinh (h th ng ti p xc)
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khng c vai tr sinh l th c s v c m mu. B ng ch ng m i y g i r ng m c d thi u y u t XII khng d n n nh ng v n ch y mu, nhng thi u FXII khng b o v ch ng l i huy t kh i b nh l. Gi thuy t ny v b ng ch ng th c nghi m c trnh by qua nhi u bi bo c a nhm nghin c u t khoa b nh l ih c Duke v i h c B c Carolina. Trong m hnh d a trn c s t bo, c m mu i h i s hnh thnh nt ti u c u v fibrin khng th m v tr t n thng m ch mu, nhng n cng i h i cc ch t ti n ng mu c ho t ha trong qu trnh ny ti p t c khu tr v tr t n thng. Qu trnh ng mu c kh i pht do s ti p xc c a cc t bo bi u hi n TF v i dng mu. TF c bi u hi n ch y u trn nhi u t bo nh t bo c trn, nguyn bo s i nhng khng bi u hi n cc t bo n i m ch ngh . TF hi n di n mng cc t bo bao quanh gi ng m ch nhng bnh th ng khng ti p xc v i dng mu. N c ti p xc dng mu do n i m ch khng lnh l n ho c s ho t ha c a cc t bo n i m ho c monoxit. Nhi u b ng ch ng g i r ng TF c trong mu trn cc h t t bo (cellular microparticles). Cc m nh mng ny b t ngu n t nhi u lo i t bo khc nhau: b ch c u, n i m m ch mu v ti u c u. Cc m nh ny c th ng vai tr quan tr ng hn trong c m mu b nh l (pathological hemostasis) (huy t kh i) i l p v i ng mu bnh th ng (Osterud and Bjorklid, 2006). T t nh t l xem xt s an xen ch t ch c a cc qu trnh v t l, t bo v sinh ha gp ph n vo c m mu nh m t lo t cc giai o n ti p di n (cc pha) hn l nh ng con ng. Cc pha kh i u (initiation), lan r ng (propagation) v k t thc (termination) minh h a cc qu trnh ph c t p lin quan n vi c duy tr tnh v n ton m ch mu. 4 pha ng mu t o thnh thuy t ng mu d a trn c s t bo hi n nay c tm t t b ng 1 B ng 1: Tm t t 4 pha ng mu theo thuy t ng mu d a trn c s t bo hi n nay Pha kh i u Pha khuy ch i Pha nhn ln S n xu t 1 l ng thrombin ng k , hnh thnh nt c m mu n nh v tr t n thng v ng ng m t mu Pha k t thc Qu trnh ng mu c gi i h n trnh ngh n m ch huy t kh i cc vng m ch bnh th ng xung quanh
N i m m ch mu v t bo mu lu hnh b r i lo n; tng tc c a FVIIa c ngu n g c t ti u c u v i y u t m
Thrombin ho t ha ti u c u, cc ng y u t Va v FVIII trn b m t ti u c u v FXI trn b m t ti u c u
5.1. Pha kh i u (Initiation phase) Pha kh i u khu tr cc t bo b c l TF, th ng c pht hi n ngoi lng m ch. Ph c h p FVIIa/TF ho t ha m t l ng nh FIX v FX. FXa ph i h p v i ng y u t c a n l FVa v t o ra ph c h p prothrombinase trn b m t cc t bo mang TF (TF bearing cell). FV c th c ho t ha b i FXa ho c b i cc protease khng thu c ng mu (noncoagulation protease) t o ra FVa c n t p h p prothrombinase. Ho t tnh m c th p c a con ng y u t m (TF pathway) lun lun x y ra trong khoang ngo i m ch. Cc protein ng mu r i m ch mu th m vo cc m v c pht hi n trong d ch b ch huy t g n nh t l v i kch th c phn t . H u nh
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ch c ch n l y u t VII c g n v i TF ngo i m ch ngay c khi khng c t n thng v FX v FIX ngo i m ch c th b ho t ha khi chng i qua cc m. Qu trnh ng mu ti p di n n pha khu ch i ch khi t n thng n h m ch cho php ti u c u v FVIII ( c g n v i vWF) trn vo cc m ngo i m ch v g n vo cc t bo mang TF v tr t n thng. Thu t ng extrinsic (ngo i sinh) l m t tn thch h p i v i con ng TF v n c th c ngh l ho t ng bn ngoi h m ch. 5.2. Pha khuy ch i (Amplification phase) M t l ng nh thrombin c sinh ra trn t bo mang TF c nhi u ch c nng quan tr ng. Ch c nng chnh l ho t ha ti u c u, b c l cc th th v g n vo cc v tr dnh cho cc y u t ng mu ho t ha. Do s ho t ha ny, cc ti u c u gi i phng m t ph n y u t V trn b m t c a chng. M t ch c nng khc c a thrombin c t o ra trong pha kh i u l s ho t ha cc y u t FV v FVIII trn b m t ti u c u ho t ha. Trong qu trnh ny ph c h p FVIII/vWF c phn tch, cho php vWF lm trung gian cho s k t dnh v ngng t p ti u c u hn n a t i v tr t n ng th i, m t l ng nh thrombin ho t ha FXI v FXIa trn b m t ti u thng. c u trong su t pha ny. 5.3. Pha nhn ln (Propagation phase) Khi m t l ng l n ti u c u c t p h p vo v tr t n thng, pha lan r ng hnh thnh c c ng x y ra trn b m t ti u c u ho t ha. u tin, FIXa c ho t ha trong pha kh i u lc ny c th g n v i FVIIIa trn b m t ti u c u. Th 2 l FIXa b sung c th c cung c p b i FXIa g n v i ti u c u. Th 3 l v FXa khng th di chuy n m t cch hi u qu t t bo mang TF n ti u c u ho t ha, Fxa ph i c cung c p tr c ti p trn b m t ti u c u b i ph c h p FIXa, FVIIIa. Th 4 l Fxa nhanh chng k t h p v i FVa c g n vo ti u c u trong pha khuy ch i. Cu i cng, ton b t p h p prothrombinase ti u c u ny d n n s bng pht sinh thrombin m c lm ng fibrinogen. 5.4. Pha k t thc (Termination phase) M t khi c c mu ng ti u c u fibrin c t o ra trn vng t n thng, qu trnh ngh n m ch huy t kh i cc vng m ch trnh ng mu ph i c gi i h n bnh th ng xung quanh. N u khng c ki m sot s ng mu c th lan r ng ra ton b h m ch mu. Ba lo i ch t ch ng ng t nhin i u ha ng mu l antithrombin (ATIII) c ch ho t tnh c a thrombin v cc serrin protease khc nh FIXa, Fxa, FXIa v FXIIa . Protein C v Protein S c c tnh b t ho t cc ng y u t ng mu FVa v FVIIIa. Protein C l m t glycoprotein huy t tng ph thu c Vitamin K c ch c nng (khi ho t ha) nh m t ch t ch ng ng b ng cch b t ho t FVa v FVIIIa. Ho t tnh protein C c gia tng b i m t ng y u t c ch ph thu c vitamin K khc l protein S. Protein S c ch c nng nh m t ng y u t c a protein C b ng cch gia tng ho t tnh c a protein C ch ng l i FVa v FVIIIa. Y u t c ch con ng TF (TF pathway inhibitor: TFPI), l m t protein c ti t b i cc t bo n i m ch, t o ph c h p v i FXa v ph c h p v i TF/FVIIa lm b t ho t chng gi i h n s ng mu m t cch nhanh chng. Thrombin sau khi g n vo 1 protein xuyn mng l thrombomodulin (TM) trn b m t t bo n i m ch nguyn v n s ho t ha protein C. Trong huy t tng ng i, kho ng 30% protein S lu hnh d ng protein t do, ph n cn l i c g n vo 1 protein i u ha b th l protein g n C4b (C4b -
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binding protein). Ch c d ng t do c a protein S c ch c nng nh m t i v i protein C ho t ha.
ng y u t
VI. TNG TC TI U C U - PROTEIN (PLATELET - PROTEIN INTERACTIONS) Nh th o lu n ph n tr c, c m mu k u c kh i u p ng v i t n thng thnh m ch v s ti p xc c a mu v i m d i n i m ch. Nhi u tng tc ph i h p trong s cc thnh ph n m, cc protein huy t tng v cc th th trn ti u c u d n n s hn g n u tin c a cc thnh m ch t n thng. Ti u c u l nh ng t bo mu c hi u ng vai tr quan tr ng trong cc qu trnh sinh l c m mu. S hnh thnh nt ti u c u u tin c tnh t m th i v c lin quan v m t khng gian v i s ho t ha c a h th ng ng mu. Qua qu trnh bm dnh v ngng t p thng qua vWF v fibrinogen, ti u c u hnh thnh nt hay c c ng c m mu. v tr thnh m ch t n thng, ti u c u tr i qua m t lo t cc bi n c nh bm dnh, ngng t p, gi i phng cc thnh ph n h t v thay i hnh d ng d n n hnh thnh nt ti u c u. S bm dnh ti u c u u tin ph thu c vo s tng tc gi a ti u c u v vWF (1 protein huy t tng a phn t c ch a nhi u n phn lin k t disulfua). VWF tr i qua qu trnh th y phn protein trong huy t tng; qu trnh ny c i u ha b i 1 metalloprotease c t tn l ADAMTS 13. ADAMTS 13 sinh ra vWF a phn v i m i kch th c v c ch c nng khc nhau. Cc phn t a phn l n hn c hi u qu hn trong vi c k t dnh ti u c u so v i cc phn t a phn kch th c nh hn. VWF i u ha s bm dnh ti u c u qua vai tr nh m t c u n i gi a m v ti u c u, g n v i c collagen b c l cc v tr t n thng m ch mu v v i glycoprotein Ib-V-IX trn mng ti u c u (GPIbVIX). Ch y mu qu m c c th l h u qu gi m s c b n thnh m ch, thi u ho c r i lo n ch c nng ti u c u, r i lo n ng mu ho c ph i h p cc r i lo n ny. ngha sinh l c a cc con ng ng mu l r rng v nhi u khi m khuy t di truy n d n n h u qu b nh l ch y mu. Cc ho t tnh c a ti u c u v cc y u t ng mu c lin quan m t thi t v i nhau. S thi u h t m i y u t ng mu c bo co gy ra r i lo n ch y mu ngo i tr thi u h t y u t XII khng gy ch y mu. Ba b nh l ch y mu di truy n th ng g p l Hemophilia A (thi u FVIII), Hemophilia B (thi u y u t IX) v b nh von Willebrand (vWD). B nh vWD l b nh l th ng g p m c d t tri u ch ng. B nh Hemophilia A v Hemophilia B c gy ra do thi u ch c nng c a m t protein huy t tng, di truy n theo ki u lin k t nhi m s c th X. V m t sinh l, con ng y u t m ho t ha y u t X c n n FVIII v FIX sinh thrombin bnh th ng v khng c 1 trong 2 y u t ny gy t n thng n ng n kh nng sinh thrombin v fibrin. V thi u y u t ng mu nguyn pht trong b nh hemophilia A ho c B nn qu trnh hnh thnh c c mu ng b ch m l i v khng v ng ch c. V v y, nh ng b nh nhn Hemophilia khng ch y mu m t cch nhanh chng v trong m t ch ng m c no c s hnh thnh ch m c a c c mu ng b t th ng. Cc gen y u t VIII v IX n m gn vng telomer c a cnh di trn nhi m s c th X. V v y, c hai b nh Hemophilia A v Hemophilia B c di truy n theo ki u di truy n l n lin k t nhi m s c th X. Nhi u t bi n trong vng gen FVIII c xc nh c lin quan n b nh Hemophilia A. Bi n i di truy n ph bi n nh t l s
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o gen (inversion). nhi u gia nh c b nh nhn c ch n on b t th ng phn t th vi c sng l c di truy n v pht hi n ng i mang gen b nh s c chnh xc cao. Tri v i tnh ph c t p c a gen FVIII, gen FIX nh hn nhi u v nh ng khi m khuy t cng c nghin c u nhi u hn. Hn 60% nh ng khi m khuy t FIX l do cc t bi n i m nh m ngha (missense) v m t khi m khuy t c th xc nh gen ny c th c pht hi n h u h t b nh nhn. Y u t von Willebrand (vWF: von Willebrand factor) khng th thi u i v i s kh i u hi u qu c a vi c bm dnh ti u c u vo cc ch t n n giu collagen d i vng l c x cao (high shear). GPVI v integrin l 2 lo i th th quan tr ng c a ti u c u i v i collagen l (alpha 2 -beta -1). Hai th th ny tr nn c s d ng sau khi vWF g n vo GPIb v khuy ch i nhanh chng p ng ph thu c collagen. M t ch c nng khc c a vWF l lm n nh FVIII (m t ng y u t ti n ng mu) trong tu n hon v c ch c nng nh 1 protein t i c a FVIII trong huy t tng. FVIII l ng y u i u ha quan tr ng trong s l ng ng cu i cng c a c c ng fibrin. VWF b o v FVIII kh i s thoi ging s m qua s th y phn tiu protein c a protein C, ko di th i gian v tr t n bn h y c a FVIII trong tu n hon v khu tr FVIII m t cch hi u qu thng. B t k s thay i no v m c vWF trong huy t tng th ng d n n s thay i i km v n ng FVIII trong huy t tng. V v y, vWF th c hi n 2 ch c nng chnh trong c m mu. Th nh t l i u ha s bm dnh ti u c u vo v tr t n thng m ch mu, do vWF c n thi t i v i s hnh thnh nt ti u c u. Th 2 l th c hi n ch c nng nh m t protein t i gip n nh y u t VIII ng mu. B nh vWF l b nh l ch y mu th ng g p do r i lo n qu trnh a trng h p y u t vWF. B nh vWF ng ch l tnh khc bi t di truy n r r t v c s phn t c a n. S phn b m c vWF trong qu n th r t khc bi t v khng bi u hi n 1 c s di truy n n gi n. M c d nhi u nghin c u phn t t ra l thnh cng trong vi c xc nh nh ng khi m khuy t di truy n lin quan v i vWF type 2 v type 3, nhng vWF typ1 l 1 d ng th ng g p c a b nh vWF v n cn l m t thch th c. T nm 1989, khi c u trc c a gen vWF ng i c xc nh, nhi u nghin c u th xc nh nh ng khi m khuy t vWF nh m gip ch n on s m hn v chnh xc hn b nh vWF type 1. Do tnh ph c t p c a c u trc gen nn vi c nghin c u ny t ra l m t nhi m v kh khn. May m n l 2 nghin c u g n y Chu u v Canada em l i m t s hi u bi t v lnh v c ny. Cc nghin c u kh ng nh c s di truy n c a vWF type1 thay i r t nhi u v c nhi u gen cng ph i h p v i gen vWF c th d n n m c vWF huy t tng th p. Tuy nhin, cng vi c ny i h i s xc nh n trong nh ng nghin c u c l p v nh ng nghin c u b sung c n c ti n hnh trong ch ny (James and Lillicrap, 2006). Ng i ta hy v ng r ng v i nh ng ti n b v hi u bi t c m mu v ki n th c v h gen ng i c cng b s m ra m t con ng i n nh ng hi u bi t m i v tnh di truy n c a b nh l ch y mu v s mang l i nh ng cng c ch n on chnh xc hn cng nh nh ng ng d ng can thi p lm sng ngy cng hi u qu hn. TI LI U THAM KH O
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1. Aggler, P.M. White, S.G, Glendenning, M.B, Page, E.W, Leake, T.B & Bates, G (1952). Plasma thromboplastin component (PTC) defficiency: A new disease resembling hemophilia. Procceeding of the society of for Experimental Biology and Medicine, 79, 692-694. 2. Alexander, V, Goldstein, R, Landwehr, G & Cook, C (1951), Coagulation serum prothrombin conversion accelerator (SPCA) deficiency: A hitherto unrecognized coagulation defect with hemorrhage rectified by serum and serum fraction. Journal of clinical investigation, 30, 596-608. 3. Allen, D.H, & Tracy, P.B (1995). Human coagulation factor V is activated to the functional cofactor by elastase and cathepsin G expressed at the monocyte surface. Journal of Biological Chemistry, 270, 1408-1415 4. Allen.G.A. Monroe, D, Roberts,H.R & Hoffman,M (2000).The effect of factor of factor X level on throbin generation and the procoagulant effect of activated factor VII in a a cell-based model of coagulation, Blood coagulation Fibrinolysis, 11 (Suppl,1), S3-S7. 5. Boron W.F & Boulpaep E.L (2005). Medical physiology (updated ed.). Philadelphia: Elsevier 6. Briggs, R, Douglas, A.S, Macfarlane, R.G, Dacie, J.V, Pitney, W.R, Merskey, C, et al (1952). Chrismas disease: A condition previously mistaken for haemophilia. British Medical journal, 2, 1378-1382. 7. Brown, S.A, Aledort, L & Lee, C.A (2002). Haemostasis: from bench to bedside. Haemophilia, 8, 685-693. 8. Dahback, B (2005). Blood coagulation ad its regulation by anticoagulant pathways: Genetic pathogenesis of bleeding and thrombotic disease. Journal of Internal medicine, 257, 209-223 9. Davie, E.W, & Ratnoff, O.D (1964). Waterfall sequence for intrinsic blood clotting. Science, 145, 1310-1312 10. Gill,J.C (2004). Diagnosis and treatment of von Willebrand disease. Hematology/Oncology Clinics of North America, 18, 1277-1299. 11. Harmening, D.M (2002). Clinical hematology and fundamentals of hemostasis. Philadelphia: F.A. Davis.
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TNH HNH V XU TH TRUY N MU HI N NAY VI T NAM T M NHN CHI N L C V PHNG H NG PHT TRI N TRONG GIAI O N T I
Nguy n Ng c Minh Tr ng i h c Y D c Hu Tm t t: Trong vng 15 nm qua, chuyn ngnh Huy t h c - Truy n mu (HH-TM) Vi t Nam - trong c tr ng tm l cng tc truy n mu v c bi t l t ch c phong tro hi n mu tnh nguy n (HMTN) c nhi u ti n b ng k : - T ng s mu thu c nm 2008 l 564.401 n v (t c 155.857 lit) - T l ng i HMTN/l ng mu thu c l 411.817 n v , chi m 72,97%) - T l hi n mu chuyn nghi p l 114.040 n v , chi m 19,97%) - T l ng i nh hi n mu l 36.270 n v chi m 6,43% - T l hi n mu t thn l 2.275 n v chi m 0,40% Tnh theo t l % dn s th m i chi m 0,65% trong khi theo tnh ton c a WHO, ph i c 1-2% dn s m i m b o c nhu c u mu ph c v cho i u tr c a t ng qu c gia. i u cho th y Vi t Nam cn ph i ph n u cao m i m b o c nhu c u truy n mu. c n c quan tm ti p t c c t nhi u pha, c n Ni r ng ra, cn nhi u v n xy d ng chnh sch d ch v mu qu c gia Vi t Nam k c t ch c m ng l i, s i u k thu t ngn hng mu, v n tuy n ch n v lu gi hnh t m qu c gia, cc v n ng i hi n mu, ngn qu dnh cho truy n mu, lu t v truy n mu, cc v n ph i h p khu v c v qu c t Chnh nh ng v n l t m nhn chi n l c xy d ng chng trnh, chnh sch, chi n l c mu qu c gia Vi t Nam trong giai o n t i. Abstract: CURRENT TENDENCIES ON BLOOD TRANSFUSION IN VIETNAM STRATEGIES AND TRENDS FOR DEVELOPMENT IN THE FOLLOWING STEPS For the last 15 years, hematology and blood transfusion specialty in Vietnam of which blood transfusion has been a focus, especially voluntary blood donation (VBD) movement gains considerable fruits: Total blood collection in 2008: 564.401 units (equivalent to 155.857 litres) Rate of voluntary blood donation/total blood collection: 411.817 units, (with 72,97% for VBD) Rate of paid donation (PD)/total blood collection: 114.040 n v , (with 19,97% for PD ) Rate of replacement donation (RD)/total blood collection: 36.270 units (with 6,43% for RD) Rate of autologous donation (AD)/total blood collection: 2.275 units (with 0,40% for AD) Based on the percentage of population, the above achievement only reaches 0,65%. However, in accordance with the statistics of WHO, there is a need of 1-2% population which ensure the blood demand for health care and treatment of each nation. It means that Vietnam must highly effort to make sure of blood transfusion need.
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In other words, there are a lot of issues to be continuously focused in multi side: - Establish national blood program in Vietnam including network, national steerring committee, technical issuess in blood bank, recruitment and retention of blood donors, budget and laws for blood transfusion, regional and international relation, Therefore, those are suggestions to establish national program, policies and strategies in Vietnam in the following steps. M u: Hng nm ton th gi i c n kho ng 150 tri u n v mu ph c v cho c p c u, i u tr v d phng th m h a, an ninh qu c phng. Tuy nhin theo bo co c a T ch c Y t th gi i (WHO) m i nm ton th gi i m i thu c 82 tri u n v mu. Nm 2008 m i c 54 n c t 100% ng i hi n mu tnh nguy n khng nh n ti n. Trong vng 15 nm qua, phong tro hi n mu tnh nguy n t c k t qu r t l n, t l ng mu thu c n s l ng ng i tham gia hi n mu tnh nguy n ngy cng tng, ch t l ng ng i tham gia hi n mu ngy cng t t hn. T d i 10% ng i nh v ng i hi n mu tnh nguy n nm 1994, n nm 2008 t 72,97% ng i hi n mu tnh nguy n. M t s ki n r t c ngha: ngy 26 thng 2 nm 2008 Th t ng Chnh ph ban hnh Quy t nh s 235/Q -TTg thnh l p Ban ch o Qu c gia v n ng hi n mu tnh nguy n. Cho n nay 63/63 t nh, thnh ph tr c thu c Trung ng ki n ton, b sung v thnh l p Ban ch o v n ng hi n mu tnh nguy n. H th ng t ch c Ban ch o v n ng hi n mu tnh nguy n t Trung ng n a phng ang t ng b c th ng nh t v i m t c ch chnh sch ng b : M t chi n l c qu c gia v chng trnh hi n mu tnh nguy n giai o n 2009-2015 v t m nhn n nm 2020. Cng nh Quy ch tn vinh khen th ng nh ng t ch c, c nhn c thnh tch v n ng v hi n mu tnh nguy n. Nm 2008, nm u tin Ban ch o Qu c gia v n ng hi n mu tnh nguy n c thnh l p, th c hi n 5 nhi m v m Th t ng Chnh ph giao cho. Trn xu th , chng ta nhn l i nh ng thnh t u t c trong nm 2008, xy d ng chng trnh hnh ng c a 2009 v nh ng nm ti p theo. I. TNH HNH THU GOM MU NM 2008 1. Hi n nay c 4 trung tm truy n mu khu v c (trong d n WB), ngoi ra cn c trn 84 khoa huy t h c truy n mu c a cc b nh vi n a khoa t nh, thnh ph c dn y v l c l ng v trang thu gom mu. T 30/10/2007 n 30/10/2008, ton qu c thu gom c: B ng 1: K t qu thu gom mu trong ton qu c nm 2008 (so snh v i nm 2007) Nm 2008 K t qu Stt Cc ch tiu Ch tiu k K t qu t 2007 ho ch c 1 T ng s mu thu c 457.734 526.500 564.401 2 Tnh nguy n 65% 70% 72,97% 3 T l % dn s hi n mu 0,54% 0,61% 0,65% 4 T l % v t so v i 2007 100% 123,3% 5 T l % v t so v i k ho ch 0% 100% 107,2% 1. T ng s mu thu c : 564.401 n v = 155.859 lt 2. T l ng i hi n mu tnh nguy n: 411.817 n v = 72,97%
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3. T l ng i cho mu chuyn nghi p: 114.040 n v = 19,97% 4. T l ng i nh hi n mu : 36.270 n v = 6,43% 5. T l hi n mu t thn : 2.275 n v = 0,40% S n v mu theo phn lo i th tch l y mu: - Lo i 250 ml: 430.562,75 n v chi m 76,28 % - Lo i 350 ml: 116.572 n v chi m 20,65 % - Lo i 450 ml: 17.226,25 n v chi m 3,07 % B ng 2: Tnh hnh thu gom mu nm 2008 m t s Trung tm Truy n mu l n ( t t 10.000 v n 190.000 v mu) T l % hi n Trung tm S mu thu TT mu tnh Ghi ch TM v TP gom ( v) nguy n Thnh ph TTTMKV Ch R y + BV 1 185.156 85,25% (4) H Ch Minh ... 4TP H N i v cc t nh trong 2 H N i 135.401 60,81% (6) d n TTTMKV 3 C n Th 22.457 99,64% (1) 4 N ng 16.228 92,99% (2) 5 Hu 15.491 89,28% (3) 6 H i Phng 10.884 62,84% (5) Ghi ch: + 285.687 n v mu, chi m 68,33% t ng s mu trong ton qu c + C 04/06 t nh t 70% tnh nguy n B ng 3: Tnh hnh thu gom mu m t s t nh, thnh khc ( t t 5.000 n v mu n d i 10.000 n v mu) T l % Trung tm TM S mu Ghi ch TT hi n mu tnh v t nh, thnh ph thu gom ( v) nguy n 1 2 3 4 5 6 7 8 9 An Giang Bnh nh 9891 9331 7429 7129 6447 5633 5251 5261 5180 92,07% 75,18% 34,51% 52,0% 84,21% 43,30% 33,36% 89,74% 40,68%
Thanh Ho Kin Giang Khnh Ha Qu ng Ninh Thi Bnh k Lk Ti n Giang
Ghi ch:
+ 61.591 n v mu, chi m 10,91% t ng s mu thu c trong ton qu c.
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+ Trong c 04/09 t nh, thnh ph t 70% tnh nguy n. B ng 4: T l HMTN cc t nh, thnh ph T l % Trung tm TM hi n mu tnh TT Ghi ch v thnh ph nguy n 1 C n Th 99,64% 2 B n Tre 97,73% 3 Qu ng Tr 94,74% 4 k Nng 94,05% 5 N ng 92,99% 6 An Giang 92,07% 7 Ph Yn 91,11% 8 k Lk 89,74% 9 Th a Thin - Hu 89,28% 10 Ngh An 88,04% 11 Qu ng Nam 86,16% 12 TP. H Ch Minh 85,25% 13 Ha Bnh 85,08% 14 Khnh Ha 84,21% 15 Bnh Thu n 81,82% 16 Vnh Long 81,06% 17 Bnh nh 75,18% 18 Thi Nguyn 74,75% 19 Bnh Dng 20 Bnh Ph c Cc t nh n m trong d n 21 H Nam Trung tm truy n mu khu 22 Vnh Phc v c BV Ch R y v H N i 23 B c Ninh bo co nn khng tnh 24 Ty Ninh thm. 25 B R a -Vng Tu 26 ng Nai 27 B c Giang Hai t nh ny khng trong d n WB 28 Ph Th II. CC NH N XT CHUNG V PHONG TRO HMTN 2.1. Nh ng u i m t c 2.1.1. H th ng Ban ch o v n ng hi n mu tnh nguy n t Trung ng n t nh, thnh ph tr c thu c Trung ng c thnh l p, ki n ton v c ng c . - 63/63 t nh v thnh ph c Ban ch o, 62/63 t nh, thnh ph /c ph ch t ch UBND ph trch vn x l Tr ng Ban ch o (ch cn H u Giang tr ng ban l Gim c S Y t ). - 59/63 t nh, thnh ph tr c thu c Trung ng ph tr ng ban th ng tr c l Ch t ch H i Ch th p (H N i, B c Ninh ph tr ng ban l B th on TNCS H
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Ch Minh, H i Phng, Bnh Dng, Khnh Ho ph tr ng ban th ng tr c l Gim cS Yt . 2.1.2. Trong th i gian qua ng, chnh quy n cc b , ban ngnh, on th Trung ng v cc a phng quan tm ch o, u t cho cng tc truy n mu ni chung v cng tc hi n mu tnh nguy n ni ring. 2.1.3. Nh n th c c a ton x h i v l i ch c a cng tc hi n mu tnh nguy n c chuy n bi n tch c c, m ng l i tuyn truy n v n ng hi n mu tnh nguy n hnh thnh v t ng b c hon thi n v pht tri n v i nhi u hnh th c phong ph nh: Cu l c b hi n mu d b , nhm mu hi m, Cu l c b Sinh nh t H ng tu i 18 - hi n mu c u ng i, Cu l c b 25 - ng i hi n mu yu cu c s ng v.v... 2.1.4. tri n khai nhi u bi n php chuyn mn k thu t nh m m b o ch t l ng v hi u qu c a cng tc hi n mu tnh nguy n. 2.1.5. S ph i h p lin ngnh c hi u qu gi a H i Ch th p Vi t Nam v B Y T l u m i then ch t trong cng tc v n ng hi n mu tnh nguy n v ph i h p ch t ch v i cc trung tm truy n mu t Trung ng n a phng l thnh vin quan tr ng m b o s pht tri n b n v ng c a chng trnh hi n mu tnh nguy n. 2.1.6. S l ng mu thu c t ng i hi n mu tnh nguy n tng d n c s l ng v ch t l ng ngy cng t t hn. Nm 2007 t ng s mu ton qu c thu c l 457.734 n v ; ng i hi n mu tnh nguy n l 295.247 v t 65%. Nm 2008 t ng s mu thu c 564.401 n v , s mu tnh nguy n l 411.817, t 72,97%; t ng s mu thu c so v i k ho ch d ki n 2008 tng 7,2% v so v i nm 2007 tng 23,3%. 2.1.7. Nh c chng trnh hi n mu tnh nguy n, ngn sch nh n c ti t ki m c kho n kinh ph dng mua mu c th : nh n c chi tr cho 01 n v mu ph i mua l 150.000 ng cho m t n v , trong khi chi ph cho 01 n v hi n mu tnh nguy n l 110.000 ng D 40.000 ng ti t ki m c) n u nhn ln so v i n v thu c s l m t con s r t l n (g n 20 t ). Theo s li u bo co c a 20 t nh, thnh ph tr c thu c trung ng, trong s 87.527 ng i hi n mu tnh nguy n th t l nam gi i chi m 54,58%, n chi m 45,52%. tu i tham gia hi n mu tnh nguy n: t 18 n 25: 52,66%; t 26 n 40 tu i l 31,59%; trn 40 tu i l 15,75%. 2.1.8. Cng tc tn vinh khen th ng c Ban ch o v n ng hi n mu tnh nguy n cc c p quan tm, k p th i bi u dng, khch l ng i hi n mu v nh ng ng i lm cng tc v n ng hi n mu. 2.2. Nh ng t n t i, kh khn, thch th c v cc xu t: 2.2.1. Hnh lang php l v v n ng hi n mu tnh nguy n cha y , c n ti p t c hon thi n s m nh: - Chnh sch qu c gia v mu - Lu t hi n mu tnh nguy n - Quy ch tn vinh khen th ng, 2.2.2. V m t t ch c c n lu - Ban ch o Qu c gia v n ng hi n mu tnh nguy n c thnh l p. Quy ch t ch c v ho t ng c a Ban ch o qu c gia c ban hnh, tuy nhin ho t ng c a cc thnh vin trong Ban ch o cha ng u, cha pht huy hi u qu nh mong mu n. Cng tc v n ng hi n mu tnh nguy n c ng, chnh quy n cc
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c p quan tm nhng nhi u t nh, thnh ph Ban ch o ra i cn mang tnh hnh th c, cha t hi u qu cao. Cng tc tuyn truy n v n ng cha th c s su r ng trong c ng ng cho nn hi u qu c a phong tro hi n mu tnh nguy n cn h n ch . - Ban ch o v n ng hi n mu tnh nguy n nhi u t nh, thnh ph cha c phn b cho 1-2 bin ch theo di cng tc hi n mu tnh nguy n, cha c kinh ph xy d ng k ho ch, chng trnh ho t ng, tn vinh khen th ng. Trong khi Thng t s 40/TT-BTC ngy 23/4/2007 c a B Ti chnh ngu n kinh ph cn r t h n h p v r t kh th c hi n cho Ban ch o cc c p. S ph i h p cc thnh vin Ban ch o ch y u l ngnh Y t v Vn phng Th ng tr c Ban ch o cha t t trong vi c xy d ng ch tiu k ho ch thu gom mu a phng. Do v y tnh tr ng thi u mu x y ra th ng xuyn, nh t l vo ma h, d p thi c c a h c sinh, sinh vin l m t th c t c n c nghin c u tho g v t ch c h p l. - T l hi n mu tnh nguy n nhi u a phng cn qu th p m i t 20-30%. C a phng trong cng m t t nh, thnh ph b nh vin t t l s d ng mu tnh nguy n t 70-80%, c b nh vi n khng c mu t ng i hi n mu tnh nguy n (0%). - C n nng c p cc trung tm truy n mu v cc khoa HHTM c nhn l c, p ng s pht tri n c a chng trnh hi n mu tnh trang b cho vi c thu gom mu nguy n. 2.2.3. T cc t n t i trn, cc v n c n c xu t l: o Qu c gia v n ng hi n mu tnh nguy n ngh B Y t c k - Ban ch ho ch xy d ng Lu t hi n mu tnh nguy n. ngh B Y t xy d ng chnh sch qu c gia v mu. - Quy ch tn vinh khen th ng c n s m hon thi n th c hi n th ng nh t trn ton qu c. - Pht tri n, t ch c l i m ng l i cc trung tm huy t h c truy n mu (hi n nay cn qu nhi u khoa HHTM thu gom mu th m ch trn cng m t t nh, thnh ph ) r t kh khn cho Ban ch o cc c p ph i h p. - Nng cao nng l c c a H i Ch th p Vi t Nam l y u t then ch t trong v n ng hi n mu tnh nguy n thng qua o t o, tuy n ch n cn b , tng c ng cng tc qu n l trong v n ng hi n mu tnh nguy n. Ph i k t h p ch t ch cng v i cc ngnh c bi t l ngnh Y t xy d ng cc trung tm Truy n mu gp ph n m b o chm sc s c kh e nhn dn. - Cc c quan c th m quy n nh: B N i v , B Ti chnh quan tm b sung cn b lm cng tc qu n l gim st chng trnh hi n mu tnh nguy n cng nh kinh ph cho cng tc hi n mu tnh nguy n khng nn g n kinh ph cho ho t ng hi n mu tnh nguy n v i chi ph cho 1 n v mu t tiu chu n quy nh. III. T M NHN CHI N L C, PHNG H NG NHI M V NM 2009 V NH NG NM TI P THEO 3.1. Cng tc ch o v t ch c phong tro HMTN C n nhanh chng hon ch nh cng tc t ch c, Ban Ch o cc t nh, thnh ph tr c thu c Trung ng theo h ng d n c a Ban ch o qu c gia. Xc nh r rng nhi m v v trch nhi m, xy d ng quy ch t ch c v ho t ng c a 63 Ban ch o cc t nh v thnh ph . - Cc thnh vin Ban ch o Qu c gia xy d ng k ho ch hnh ng c a B , ban ngnh on th mnh trong cng tc v n ng hi n mu tnh nguy n.
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- Ban ch o Qu c gia s m thnh l p hai ti u ban: + Ti u ban tuyn truy n v n ng + Ti u ban hu n luy n - o t o Xy d ng chi n l c pht tri n chng trnh hi n mu tnh nguy n giai o n 2009-2015 v t m nhn n nm 2020 cng nh quy ch tn vinh khen th ng thnh tch v n ng v hi n mu tnh nguy n khi c ph duy t c n tri n khai s m cc chng trnh ho t ng. - T ch c t t cc s ki n trong n c v qu c t nhn d p 7/4 v 14/6; Lm t t cng tc tn vinh khen th ng ng vin phong tro. - C n t ch c m ng l i thng tin bo co s li u c p nh t v chnh xc (xy d ng ph n m m HMTN). 3.2. D ki n l ng mu thu gom trong nm 2009 Nm 2009 ph i thu c 610.000 n v mu, ph i t 75% ng i hi n mu tnh nguy n v 0,70% t l dn s hi n mu. Cn c vo tnh hnh c th c a a phng ti p t c lm t t cng tc v n ng hi n mu tnh nguy n, b o m an ton cho ng i hi n mu v cho ng i c truy n mu. 3.3. Xy d ng t m nhn chi n l c chng trnh mu qu c gia v d ch v truy n mu Vi t Nam theo h ng hi n i: t m v m, Nh n c c n hnh thnh Ban i u hnh Chng trnh d ch v mu Qu c Gia Vi t Nam. Xu h ng chung c a cc n c tin ti n u c chng trnh d ch v mu qu c gia v i cc nh h ng l n: - Xy d ng chnh sch, chi n l c mu qu c gia. - T ch c m ng l i truy n mu th ng nh t trong c n c. - C ngn qu ring cho d ch v mu qu c gia (tch ring s ph thu c vo cc c s ch a b nh c a B Y T ) - Lu t ha cng tc truy n mu. - Tng c ng s h p tc khu v c v qu c t trong lnh v c truy n mu. V t ch c m ng l i truy n mu th ng nh t t cc Vi n Qu c Gia, Trung tm Khu v c (lo i I), Trung tm Truy n mu khu vng (lo i II), Trung tm Truy n mu tuy n t nh (lo i III) chu n ha v trang thi t b , nhn s , ngn qu m t cch th ng nh t. V n i dung t ch c d ch v truy n mu, ph i quan tm n n i dung k thu t c a cc Ngn hng mu, cng tc ki m tra ch t l ng, cng tc sng l c cc tc nhn ly nhi m v b t ho t trong cc s n ph m mu, h th ng c nh bo v theo di truy n mu, xy d ng quy m ph h p s n xu t cc ch ph m mu t p trung theo quy trnh cng nghi p t nh n l n (s c cc chuyn c th cho t ng m c tiu) Nhn l i cc n c trong khu v c v cc n c pht tri n, h c lu t truy n mu, c chng trnh, chnh sch, chi n l c mu qu c gia, ti p t c hon thi n d ch v mu qu c gia v t ch c nghin c u ngy m t su v cc v n xung quanh d ch v v y h c truy n mu, h ang t p trung vo cc v n nh: - Cc tr ng tm i u hnh: Cc d ch v k thu t s n xu t thnh ph n plasma Ph n m m qu n l mu qu c gia Xy d ng chi n l c tng lai v truy n mu Chm sc v qu n l ng i hi n mu
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D ch v qu n l ch t l ng v y khoa D ch v y khoa An ton s n ph m mu v ng i hi n mu V n m b o ch t l ng - Pht tri n ngh nghi p v nghin c u Nghin c u ch t l ng cao v ngn hng mu, s u t v h tr cng ngh nghin c u ch ph m mu - Nghin c u v pht tri n M hnh cc knh m i Nghin c u i u hnh, lm th no cung c p mu v t t nh t Nghin c u v lm sng: s d ng mu an ton t i cc c s i u tr Nghin c u khoa h c v truy n mu - Nghin c u v pht tri n chi n l c m i - D ch v ghp qu c gia V n ng i cho t ng Labo xt nghi m m (tissue typing service) Ng i hi n tu p d ng cng ngh m i Ngn hng mu cu ng r n - Nhm nghin c u chi n l c v xy d ng k ho ch - Lin h qu c gia v qu c t - Xy d ng h th ng thng tin trong truy n mu - Xy d ng ngu n l c - Kinh t ti chnh c l p cho truy n mu ( d tr hng nm, kinh ph d phng, n v ho t ng) Lin h l i, chng ta v n ang trong nh ng b c kh i u, m i ch t p trung gi i quy t v n ng i hi n mu tnh nguy n, cn cc v n khc v n cn b t t h u kh xa. IV. K T LU N Trong vng 15 nm qua cng tc Huy t h c Truy n mu Vi t Nam c nhi u c g ng v c nh ng b c ti n quan tr ng - nh t l vi c pht tri n phong tro HMTN thu c k t qu h t s c t t p: t ch ngu n mu cung c p t nh ng th p k 50 n 90, ch y u l t nh ng ng i hi n mu chuyn nghi p (t c ng i bn mu) t l ng i HMTN v ng i nh hi n mu cn r t t. T l HMTN ngy cng tng v ch t l ng mu ngy cng t t qua sng l c, ki m tra nh cc ti n b khoa h c k thu tT l ng i hi n mu tnh nguy n tnh chung trong nm 2007 l 65%, nm 2008 tng ln 72,97%. l con s r t c ngha, m t thnh cng to l n c a ngnh HHTM Vi t Nam v c a ton x h i. Vai tr c a h th ng CT cc c p tham gia r t tch c c s ch o c a ng, Nh n c h t s c to l n. Tuy v y, chng ta m i t ch c c m t m ng ng i hi n mu, cn m ng t ch c m hnh d ch v truy n mu, k thu t ngn hng mu, an ton truy n mu trn lm sng v n l nh ng v n l n, cn nhi u kho ng tr ng, cn nhi u cch bi t xa so v i cc n c tin ti n trong khu v c v th gi i.
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T m nhn v xy d ng h th ng HHTM - nh t l d ch v truy n mu qu c gia v n l nh ng i h i c p bch, ph i nhanh chng ph c v cho l i ch tr c m t v lu di m b o m t cch h u hi u trong dy chuy n ph c v s c kho nhn dn.
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TI LI U KHAM KH O 1. Bo co t ng k t phong tro Hi n mu Tnh nguy n nm 2008 H i CT Vi t Nam, H i ngh Chuyn HMTN nm 2008 2. Vox Sanguinis Vol 2. N02 Nov. 2007 pp 41-45 3. Vox Sanguinis Vol 93 sup.2. Nov. 2007 pp 42-48 4. Vox Sanguinis Vol 2. N04 June. 2008 pp 63-66 5. Vox Sanguinis Vol 97 sup.2. June. 2008 pp 62-74
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NH NGHA L I NH I MU C TIM
*
Tr ng
Hunh Vn Minh*, Tr n V Vinh Sn** i h c Y D c Hu , ** B nh vi n a khoa t nh Khnh Ha
U L I NI Ti li u ny c tri n khai t i m t cu c h i ngh ng thu n c kh i x ng b i Kristian Thygesen, Joseph S. Alphert, sau khi c s ch p thu n chnh th c c a Lars Rydn, Ch t ch Hi p h i tim m ch Chu u (ESC), v Arthur Garson, Ch t ch Tr ng mn Tim m ch Hoa k (ACC). Ti li u ny c duy t l i b i cc thnh vin c a Ban Sng ki n Khoa h c v Lm sng c a ESC v cc thnh vin c a Ban i u hnh ESC v c ch p thu n vo ngy 15/04/2000. Ti p theo Hi p h i Tim m ch chu u (ESC)/ Tr ng mn Tim M ch Hoa k (ACCF) /H i Tim Hoa k (AHA)/ Lin on Tim m ch Th gi i (WHF) h p l i vo 2007 v a ra m t th ng nh t chung v nh ngha NMCT . KHI NI M V NH NGHA V NH I MU C TIM Nh i mu c tim (NMCT) c th c nh ngha t cc gc nhn khc nhau lin quan n c i m lm sng, i n tm , sinh ha v b nh l. Thu t ng nh i mu c tim cng mang cc ngha x h i v tm l, v c 2 u ch bo m t v n l n v s c kh e v l th c o t n su t b nh t t trong th ng k dn s v k t qu th nghi m lm sng. Trong cc nghin c u v th ng k b nh t t do WHO ti n hnh, Nh i mu c tim c nh ngha b ng s k t h p c a 2 trong s 3 c i m sau: cc tri u ch ng i n hnh (t c l kh ch u ng c), l ng enzyme tng v ki u i n tm i n hnh lin quan n vi c hnh thnh cc sng Q. Tuy nhin, vi c th c hnh lm sng hi n nay, cc h th ng chm sc t , cng nh cc nghin c u d ch t h c, ton b u i h i ph i c nh ngha chnh xc hn v nh i mu c tim. Thm vo , vi c xu t hi n chuyn v nh y, cng cc k thu t ch p cc ch d u sinh h c v huy t thanh c nh chnh xc t o i u ki n cho vi c xem xt l i cc nh ngha c thi t l p v nh i mu c tim. Cc ti n b k thu t sau c nh y cao trong vi c pht hi n cc cn nh i mu r t nh l ra khng c coi l nh i mu c tim m t giai o n s m hn. K thu t hi n nay c kh nng xc nh b nh nhn c cc vng ho i t c tim nh cn n ng d i 1,0 g. Do , n u chng ta ch p nh n khi ni m r ng b t k l ng ho i t c tim no do thi u mu c c b gy ra c n ph i xem l nh i mu (theo ki n ngh c a h i ngh ng thu n ny), th m t c nhn m tr c y c ch n on l b au th t ng c d d i, n nh ho c khng n nh, nay c th c ch n on l b nh i mu c tim nh . T , vi c tng nh y c a tiu ch nh ngha nh i mu c tim c ngha l s c thm nhi u ca b nh c nh n d ng; ng c l i, vi c tng c hi u s lm gi m s l ng tr ng h p nh i mu c tim dng tnh gi . Nh ng thay i nh trn v nh ngha c th c tc d ng su s c n cch theo di lu nay v m c v h u qu b nh t t. tr l i cc v n do vi c thay i kh nng xc nh nh i mu c tim t ra, ESC v ACC tri u t p m t h i ngh ng thu n trong su t thng 07/1999 cng xem xt l i nh ngha v NMCT. Cc ngha khoa h c v x h i c a m t nh ngha m i v NMCT c xem xt t 7 quan i m: b nh l, sinh ha, i n tm , ch n
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on hnh nh, th nghi m lm sng, d ch t v chnh sch x h i. T cc ki n cn nh c c a ban th ng nh t ki n, r rng l khng nn s d ng thu t ng nh i mu c tim m khng c thm cc tiu ch khc, d l v th c hnh lm sng, v miu t nh ng ng i chung quanh b nh nhn, ho c v nghin c u dn s . Cc tiu ch c n ph i c p n l ng t bo c tim b m t (kch c cn nh i mu), tr ng h p gy nn cn nh i mu (t pht ho c trong qu trnh ch n on ho c ch a b nh m ch vnh), v th i gian ho i t c tim so v i th i gian quan st (nh i mu c tim ang pht, ang lnh ho c ch a lnh). Tiu chu n Nh i mu c tim c p T nh i mu c tim c dng khi c b ng ch ng ho i t c tim trong b i c nh lm sng k t h p v i thi u mu c tim. Theo c m t trong y u t sau cho php ch n on nh i mu c tim: 1) C s tng v/ho c gi m cc ch t ch i m c tim (t t nh t l troponin) v i t nh t m t gi tr > 99% bch phn v c a gi i h n trn km theo b ng ch ng thi u mu c tim nh c t nh t m t trong nh ng d u ch ng sau: + Tri u ch ng lm sng thi u mu.c tim. + Thay i c a i n tim cho th y c d u thi u mu (ST-T m i bi n i i ho c bl c nhnh tri m i xu t hi n) ; + S xu t hi n c a cc sng Q b nh l trn i n tim. + Phng php ch n on hnh nh cho php xc nh m i m t i s s ng c a c tim ho c b t th ng v n ng vng. t t bao g m ng ng tim, th ng v i tri u ch ng g i thi u mu, km 2) theo s m i chnh ln c a ST ho c bl c nhnh tri m i xu t hi n, v/ho c b ng ch ng c a c c mu ng m i qua ch p m ch vnh v/ho c khi ph u thu t t thi nhng t vong x y ra l y mu ho c vo lc tr c khi xu t hi n cc ch t ch i m tim trong mu. 3) i v i can thi p m ch vnh qua da i v i b nh nhn c tr s troponin c b n bnh th ng, s gia tng ch i m tim trn bch phn v th 99 l m t ch i m ho i t c tim khi ti n hnh can thi p. Theo qui c s gia tng ch i m tim trn 3 l n bch phn v th 99 gi i h n trn c th xem nh l NMCT lin quan can thi p. M t nhm nh lin quan n thuyn t c stent. 4) i v i ph u thu t c u n i m ch vnh b nh nhn c tr s troponin bnh th ng s gia tng cc ch t ch i m tim trn 5 l n bch phn v th 99 gi i h n trn km theo sng Q b nh l m i xu t hi n ho c bl c nhnh tri m i c ho c ch p vnh cho th y t c r ng m ch vnh m i ho c c u n i m i ho c ch n on hnh nh cho th y m t tnh s ng c tim th c th xc nh NMCT lin quan ph u thu t c u n i. 5) Cc d u ch ng b nh h c cho th y NMCT. Tiu chu n nh i mu c tim c tr c (prior) Khi c m t trong nh ng tiu chu n sau: 1) C s xu t hi n sng Q b nh l m i km theo tri u ch ng ho c khng c tri u chng . 2) Ch n on hnh nh cho th y c vng m t s s ng c tim, nh m ng i ho c co rt, m nguyn nhn do thi u mu.
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3) Cc b ng ch ng b nh h c cho th y NMCT lnh ho c ang lnh. BI U HI N LM SNG Quan i m chung l nhi u ng i ch p nh n r ng thu t ng nh i mu c tim ph n nh vi c m t cc t bo c tim (ho i t ) do thi u mu c c b ko di. Thi u mu c c b l h u qu c a tnh tr ng m t cn i gi a cung v c u cho nhu c u oxy c tim. V lm sng, c th nh n d ng c thi u mu c c b t ti n s b nh c a ng i b nh v t i n tm . Cc tri u ch ng c th c c a thi u mu c c b l kh ch u ng c, th ng v , cnh tay, c tay ho c hm khi g ng s c ho c lc ngh ngi. C m gic kh ch u g n v i NMCT c p th ng ko di t nh t 20 pht, nhng c th ng n hn. C m gic kh ch u c th hnh thnh vng gi a ng c ho c bn tri ng c sau lan t a ra cnh tay, hm, lng ho c vai. C m gic kh ch u th ng khng d d i ho c mang tnh khu tr cao v c th g n li n v i tnh tr ng kh th , tot m hi, bu n nn, nn m a, ho c l m u c. C m gic kh ch u c th xu t hi n vng th ng v (th ng nh m v i ch ng kh tiu), cnh tay, b vai, c tay, hm ho c lng, m khng xu t hi n ng c, nhng d ng ny l i khng i n hnh. C m gic kh ch u khng b tc ng b i vi c c ng cc c vng b kh ch u, v khi ht su cng khng th y kh ch u hn. C th ni, c m gic kh ch u ny khng mang tnh ch t v tr. Cc tri u ch ng c th g m c bu n nn, nn m a khng r l do, th g p ko di do suy th t tri, v c m gic y u t, vng v t, l m ho c ng t khng r nguyn nhn, ho c k t h p c a t t c cc tri u ch ng trn M c d nhi u b nh nhn c nh ng tri u ch ng nh v a miu t trn y, nhng c th b nh nhn khng c m nh n th y ho c cc tri u ch ng c th b gn nh m cho m t th b nh khc, nh kh tiu ho c h i ch ng do vi rt gy ra. Ho i t c tim cng c th x y ra m khng c tri u ch ng no, v ch c th pht hi n th y qua i n tm , ch p hnh tim ho c b ng cc nghin c u khc. B ng 1. Cc bi u hi n nh i mu c tim theo cc phng php ch n on
B nh h c Sinh ha i n tm Ch t t bo c tim Cc ch d u v tnh tr ng ch t t bo c thu c t cc m u mu Ch ng c thi u mu c c b c (thay i o n ST T) Ch ng c v tnh tr ng m t ho t ng i n c a m (sng Q) Gi m ho c m t t i mu m Cc b t th ng chuy n ng vch tim tim tim tim tim
Ch n on hnh nh
CC PHNG PHP PHT HI N HO I T T BO C TIM Vi c c hay khng c v kh i l ng c tim t n thng do thi u mu c c b ko di c th nh gi c b ng m t s cc phng ti n khc nhau, bao g m xt nghi m b nh l, nh l ng protein c tim trong mu, k t qu i n tm (cc thay i sng o n ST-T, sng Q), cc phng php ch n on hnh nh nh hnh nh t i mu c tim, siu m tim v ch p c c n quang bu ng th t. i v i m i k thu t ni trn, c th phn bi t c m t gradien t l ng ho i t c tim nh nh t n nh r i n l n nh t. M t s nh lm sng phn lo i ho i t c tim thnh: lo i c c nh , nh , v a ph i v l n, d a vo nh n ng c a m t ch d u sinh h c c bi t. nh y v c hi u c a
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m i m t k thu t ni trn dng pht hi n tnh tr ng m t t bo c tim, nh l ng m c m t v nh n ra trnh t s ki n qua th i gian c nh ng khc bi t r t r r t . 1. B nh h c Nh i mu c tim c nh ngha l tnh tr ng ch t t bo c tim do thi u mu c c b ko di. V m t b nh l, ch t t bo c phn thnh ho i t ng c ho c ho i t co rt, ho c c hai th ng pht tri n qua qu trnh tiu h y m, nhng c th d nv m tm c th p hn t tnh tr ng ch t l p trnh. C n ph i c chuyn gia quan st c kinh nghi m phn tch c n th n cc lt c t m m i phn bi t c cc th b nh ny. Sau khi kh i pht tnh tr ng thi u mu c c b c tim, tnh tr ng ch t t bo khng di n ra ngay t c kh c nhng ph i c m t kho ng th i gian nh t nh m i di n ra (c th ng n n 15 pht m t s sc v t lm m u th nghi m, nhng th m ch y cng c th l con s c tnh qu cao). Ph i m t 6 ti ng m i c th nh n d ng c tnh tr ng ho i t c tim b ng xt nghi m chu n i th v vi th sau khi ch t. Tnh tr ng ho i t hon ton c a t t c cc t bo c tim c nguy c ho i t c n n 4-6 ti ng ho c lu hn, ty vo vi c c tu n hon bng h ch y vo vng thi u mu c c b , tnh tr ng ngh n m ch vnh dai d ng ho c khng lin t c v nh y c m c a cc t bo c. Nh i mu th ng c phn lo i theo c vi th (ho i t ), nh (<10% th t tri), trung bnh (10-30% th t tri), ho c l n (>30% th t tri) cng nh theo v tr (tr c, bn, d i, sau ho c vch, ho c k t h p cc v tr). Trong ng c nh b nh h c, thu t ng nh i mu c tim nn c cc t c p, ang lnh, ho c ch a tr b ngha. c i m c a m t cn nh i mu c p l s hi n di n cc b ch c u a nhn. N u qung th i gian gi a kh i pht nh i mu v t vong l ng n (v d : 6 ti ng) c th th y s b ch c u a nhn r t t ho c khng c. S hi n di n cc t bo n nhn v nguyn bo s i v khng c cc b ch c u a nhn l c i m c a m t cn nh i mu ang lnh. M t cn nh i mu lnh c th hi n b ng m s o khng c hi n t ng thm nhi m t bo. Ton b qu trnh d n n cn nh i mu lnh c n n 5-6 tu n ho c hn. Thm vo , vi c ti t i mu lm thay i hnh d ng t ng th v vi th c a vng ho i t qua vi c t o ra cc t bo c v i cc d i co rt v l ng l n cc h ng c u trn ra. V th i gian, cn nh i mu c phn lo i: c p (6 ti ng n 7 ngy); ang lnh (7 n 28 ngy); lnh (29 ngy ho c hn). C n lu c a m t tr ng h p thi u mu c c b c p c th th i gian lm sng v i n tm khng c cng chung kho ng th i gian b nh l c a m t cn nh i mu c tim c p. V d : i n tm c th v n c cc thay i ang di n ra c a o n ST-T v l ng troponin tim v n c th tng ln (cho th y c nh i mu g n y) vo m t th i i m khi m v m t b nh h c cn nh i mu giai o n ang lnh. 2. Cc ch t nh d u sinh ha ho i t c tim
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Ho i t c tim c th pht hi n qua vi c xu t hi n trong mu cc lo i protein khc nhau c phng thch vo mu do cc t bo c b t n thng nh myoglobin, cc troponin T v I c tim, creatin kinaza, dehydrogenaza lactat, cng nh nhi u lo i khc Nh i mu c tim c ch n on khi cc m c ch t nh d u sinh h c nh y v c hi u trong mu, nh troponin c tim v phn o n MB c a creatin kinaza (CK-MB) tng ln trong b i c nh lm sng c a thi u mu c c b c p. Cc ch d u sinh h c ny cho th y m c thng t n c tim nhng khng bi u th c ch t n thng. Do , ch s tng ln khi khng c ch ng c lm sng c a thi u mu c c b ph i tm ki m thm cc nguyn nhn khc c a t n thng c tim nh vim c tim. Ch t ch i m sinh h c c miu t g n y nh t v c chu ng nh t i t n thng c tim l troponin c tim (I ho c T), lo i c tnh c hi u m c tim g n nh tuy t i, cng nh c nh y cao, pht hi n c ngay c cc vng ho i t c tim c c nh . M t ch s troponin c tim tng ln c n ph i xc nh l s o ph i v t qu 99% so v i m t nhm i ch ng. Cc ch s tham kh o ph i c xc nh m i phng th nghi m b ng cch s d ng nh ng th nghi m i ch ng ch t l ng ph h p, nh c bo co trong cc c san c ng nghi p duy t l i. khng chnh xc c th ch p nh n c (h s bi n thin) 99% i v i m i th nghi m c n c xc nh l 10%. M i phng th nghi m c n ph i xc nh ch s tham kh o trong b i c nh c th c a mnh. Do cc ch s troponin c tim c th duy tr m c tng ln trong vng 7-10 ngy ho c lu hn sau khi ho i t c tim, cho nn c n ph i c n tr ng trong vi c gn m c troponin c tim tng ln v i cc s ki n lm sng r t g n . B ng 2: Cc ch i m sinh ha trong pht hi n ho i t c tim Sau y l cc ch i m sinh ha pht hi n ho i t c tim: 1) N ng t i a troponin T ho c I v t qu gi i h n xc nh (bch phn v th 99% tr s i v i m t nhm i ch ng tham chi u) t nh t 1 l n trong su t 24 ti ng u tin sau bi u hi n lm sng. 2) Ch s CK-MB t i a (t t nh t l tnh kh i l ng CK-MB) v t qu bch phn v th 99% i v i m t nhm i ch ng tham chi u 2 m u lin t c nhau, ho c ch s t i a v t 2 l n gi i h n bnh th ng trn i v i vi c quan st c th m t tr ng h p trong su t cc gi u sau bi u hi n lm sng. Cc ch s CK-MB ph i tng r i gi m; cc ch s tng ln v khng h khng bao gi l do nh i mu c tim.
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Trong tr ng h p khng c s n xt nghi m troponin c tim, phng n thay th t t nh t l CK-MB ( o b ng th nghi m kh i l ng). Ch t ny t mang tnh c hi u v m so v i troponin c tim, nhng d ki n ghi l i tnh c hi u lm sng i v i t n thng khng o ng c th cao. Cng nh i v i troponin c tim, ch s CK-MB tng ln (t c l trn gi i h n quy t nh i v i nh i mu c tim) c xc nh l m t ch s v t qu bch phn v th 99% cc ch s CK-MB trong m t nhm i ch ng tham kh o. Trong a s tr ng h p, cc ch s ch i m sinh h c tng ln c n ph i c ghi l i t 2 m u mu lin ti p ch n on nh i mu c tim. Vi c o CK ton ph n khng c khuy n co khi ch n on thng l nh i mu c tim c p do m c phn b m r ng c a enzyme ny. Tuy nhin, CK ton ph n c m t l ch s lu di, v m t s bc s c th ch n ti p t c s d ng vo cc m c ch d ch t v khoa h c. Trong m t b i c nh nh v y, CK ton ph n nn c k t h p thm v i m t lo i ch d u sinh h c c nh y cao hn, nh troponin c tim ho c CK-MB, ch n on nh i mu c tim c p chnh xc hn. Cc ng ng c a CK ton ph n ph i tng i cao hn troponin c tim ho c CK-MB (t nh t g p i gi i h n trn i v i CK). Khng nn s d ng transaminaza glutamic-oxaloacetic (ASAT [transferaza ch n on aspartat amin]), dehydrogenaza lactat, v isoenzym dehydrogenaza lactat t n thng c tim. Cng v i cc y u t lm sng khc (v d : t n d ch c nng th t chnh ln c a m c ch d u sinh ha c lin quan n nguy c lm sng. Nn tri), t n thng c tim (c c nh , nh , trung bnh ho c l n), m c s d ng phn lo i m c d cha c m t h th ng c cng nh n chung v x p lo i kch th c cn nh i mu. i v i a s b nh nhn, c n ph i l y mu xt nghi m khi nh p vi n, trong kho ng th i gian t 6-9 ti ng v l y m t l n n a trong kho ng 12-24 ti ng n u cc m u tr c c k t qu m tnh v ch s nghi ng lm sng cao. i v i cc b nh nhn c n ch n on s m, th khuy n co nn dng m t lo i ch t nh d u sinh h c hi n nhanh (nh ch t ng d ng CK-MB ho c myoglobin), c ng v i m t ch t nh d u xu t hi n ch m hn (v d troponin c tim) kh ng nh k t qu ch n on. Vi c pht hi n ti nh i mu r t quan tr ng v lm sng v n lm tng nguy c i v i b nh nhn. Ti nh i mu c th gy nn nhi u kh khn c bi t cho vi c ch n on, v s tng troponin c tim c th ko di lu, v khi troponin c tim v n m c cao, th kh xc nh c qung th i gian t n thng c tim ban u. N u m u u tin c ch s troponin c tim cao, th c th s d ng cc m u ch t nh d u sinh h c sau c th i gian ng n hn xc nh th i gian cn nh i mu. 3. i n tm i n tm c th cho th y cc d u hi u thi u mu c c b c tim, c th l cc thay i o n ST v sng T, cng nh cc d u hi u ho i t c tim, c th l ph c b QRS. M t nh ngha h p l i v i nh i mu c tim c p ho c ang di n ti n v i s xu t hi n h i ch ng ph h p v lm sng, nh c minh h a b ng i n tm chu n v i 12 i n c c, c thi t l p b ng cch s d ng cc d ki n t cc nghin c u tng quan v lm sng v gi i ph u b nh l. Cc tiu ch i n tm sau (khi khng c cc y u t trung gian QRS [t c l: bl c nhnh tri, ph i th t tri, h i ch ng Wolff-Parkinson-White]) xu t hi n nh l cc y u t xc nh r rng tnh tr ng thi u mu c c b c tim (B ng 3). Cc thay i v thi u mu c c b nh th c th do nh i mu c tim ang di n ti n. B ng 3. Cc thay i i n tm thi u mu c c b c th di n ti n thnh nh i mu c tim
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1. B nh nhn c ST chnh ln: chnh ln c a o n ST m i ho c cho l m i t i i m J t i 2 ho c hn 2 i n c c k nhau c ng ng 0,2 mV t i cc i n c c V1, V2 ho c V3 v 0,1 mV t i cc i n c c khc (tnh li n k nhau m t ph ng tr c c xc nh b ng chuy n o aVL, I, aVR o ng c, II, aVF, III). 2. B nh nhn khng c ST chnh ln: a. ST chnh xu ng b. Ch c cc b t th ng c a sng T Hi n t ng ST chnh xu ng m i ho c cho l m i ho c cc b t th ng sng T, ho c c 2, c n ph i c quan st 2 ho c hn 2 i n c c k nhau. Cng th , b c o ng c sng T m i ho c cho l m i 1 mm ph i xu t hi n t nh t 2 i n c c k nhau. Cc tiu ch i n tm B ng 3 ph n nh tnh tr ng thi u mu c c b c tim v t chng cha xc nh nh i mu c tim. Vi c ch n on cu i cng v ho i t c tim ph thu c vo vi c pht hi n ra m c chnh ln c a cc ch t nh d u sinh ha trong mu, nh bn lu n trn. chnh ln c a o n ST cc b nh nhn nghi ng c nh i mu c tim c p c th m t i nhanh chng m t cch t nhin ho c sau khi i u tr . Hi u qu c a li u php ti t i mu i v i cc thay i o n ST c n c ch n on nh i mu c tim. Ho i t c tim khng xem xt khi s d ng i n tm hnh thnh m t s b nh nhn c vi c o ng c nhanh chnh ln c a o n ST. Bn c nh , vi c ST chnh xu ng t t i a cc chuy n o t V1 n V3 m khng c ST chnh ln cc chuy n o khc c n ph i c xem xt l d u hi u thi u mu c c b pha sau ho c nh i mu, ho c c hai, nhng th ng c n c cc nghin xc nh n s hi n di n c a tnh tr ng thi u mu c c b ho c nh i mu c u ch p nh t ng b nh nhn. Khi c bl c nhnh tri m i ho c cho l m i, chnh ln c a o n ST c th i km bl c nhnh, gy kh khn ho c khi n khng th nh n ra tnh tr ng nh i mu c tim c p, nn c n ph i nghin c u thm xc nh cc tiu ch bi u th nh i mu c tim c p. Cc sng T cao v c nh (sng T t i c p) c nh n th y trong su t cc giai o n r t s m c a nh i mu c tim c p. B ng 4. Thay i i n tm nh i mu c tim xc nh 1. B t k sng Q cc i n c c V1 qua n V3, sng Q 30 ms (0,03 s) t i cc chuy n o I, II, aVL, aVF, V4, V5, ho c V6. (Cc thay i sng Q ph i c 2 i n c c k nhau b t k, v ph i 1 mm v chi u su. Hi n t ng ST chnh xu ng s m ho c c coi l s m ho c cc b t th ng sng T, ho c c hai, c n ph i c quan st 2 ho c hn 2 i n tm lin ti p cch nhau t nhau vi ti ng ng h . Ho i t c tim ho c nh i mu c tim c thi t l p v lm sng c th c nh ngha t tiu ch i n tm 12 chuy n o khi khng c cc y u t nhi u c a QRS (v d : bl c b nhnh, ph i th t tri, h i ch ng Wolff-Parkinson-White) ho c ngay sau khi m n i b c c u m ch vnh, b ng cch dng cc thay i QRS . M t i n tm n l th a cc tiu ch sng Q B ng 4 bi u th m t cn nh i mu c tim c tr c . Cc sng Q < 30 ms g n v i hi n t ng ST-T chnh xu ng c th bi u th nh i mu, nhng cc pht hi n ny yu c u ph i nghin c u thm kh ng nh. Khi c c 3 ho c hn 3 k t qu i n tm , th t nh t 2 i n tm lin t c nhau ph i bi u th b t th ng ang xem xt. Cc tiu ch v su sng Q c n ph i c nghin
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c u thm, cng nh cc tiu ch QRS xc l p ch n on nh i mu c tim pha sau. Bl c b nhnh c km theo cc sng Q n m trong cc miu t ny. Bl c b nhnh ph i s khng can thi p vo kh nng ch n on cc sng Q; bl c b nhnh tri th ng lm m cc sng Q; cc sng Q m i v i s hi n di n c a bl c b nhnh tri c n ph i xem l c tnh ch t b nh l. Khng ph i t t c m i b nh nhn hnh thnh ho i t c tim cng u th hi n cc thay i trn i n tm . Do , m t i n tm bnh th ng khng lo i tr kh nng ch n on nh i mu c tim. Do cc ch t nh d u sinh ha nh y, m i cho php pht hi n hi n t ng ho i t c tim qu nh lin h v i cc b t th ng QRS, m t s b nh nhn s c cc tr s nh n m trong qung ph (subrange) c a cc thay i QRS. Ch nn xem cc b nh nhn y c nh i mu c c nh , nhng cc kha c nh c n ph i c lm sng t thm. 4. Ch n on hnh nh Cc k thu t hnh nh c dng h tr : 1) lo i b ho c xc nh n tnh tr ng nh i mu c p ho c thi u mu c c b t i Khoa C p c u; 2) xc nh cc tnh tr ng khng ph i thi u mu gy au ng c; 3) xc nh tin l ng ng n h n v di h n; v 4) nh n d ng cc bi n ch ng c a nh i mu c p. C s c a ch n on hnh nh chnh xc c s d ng cc k thu t siu m tim ho c k thu t h t nhn b nh nhn nghi ng b thi u mu c c b c p l thi u mu c c b d n n tnh tr ng gi m t i mu c tim, a n s c c th bao g m r i lo n ch c nng c tim v cu i cng l d n n ch t t bo. Trong ti li u ch bn th o n cc phng php quy c nh siu m m t c t ngang tim, ch p phng x , v ch p SPECT, ch khng bn n cc phng php hi n ang c th nghi m trong cc nghin c u lm sng. M t trong cc thu n l i chnh c a siu m tim l phng php ny cho php nh gi a s cc nguyn nhn khng do thi u mu c c b gy au ng c, nh vim mng ngoi tim, b nh van tim (h p ng m ch ch ), thuyn t c m ch ph i v cc b nh ng m ch ch (phnh bc tch ng m ch ch ). l v Cc k thu t phng x h t nhn cho php bc s nh gi tnh tr ng t i mu vo th i i m b t u i u tr b nh nhn. Vi c nh gi ny c th ti n hnh b ng cch tim ng v tr c ti p, v vi c c c hnh nh c th b tr n 60-90 pht. Phn tch nh l ng l m t thu n l i c a k thu t. Tnh chnh xc trong cc nghin c u l cao khi c di n gi i b i nh ng nh quan st c kinh nghi m. Cc nghin c u ny ng th i cng cho cc thng tin v t i mu v ch c nng c tim. Cc ch t ch i m sinh h c t ra nh y hn, c hi u hn v t t n km hn cc k thu t hnh nh khi ch n on ho i t c tim. Tr c khi pht hi n c b t th ng trong r i lo n v n ng vng b ng siu m tim, th ph i c t n thng > 20% b dy vch c tim. Ni chung, tr c khi c th gi i quy t khi m khuy t t i mu phng x h t nhn, th >10 g m c tim ph i b t n thng. Khng c k thu t no ni trn c th phn bi t c gi a thi u mu v nh i mu. 4.1 Thi u mu c p v nh i mu c p ho c nh i mu ang ti n tri n. V i kh nng pht hi n cc b t th ng r i lo n v n ng vng trong vng vi pht sau khi b tn thng do thi u mu c c b , siu m tim 2 chi u c th t ra h u ch trong vi c ch n on nh i mu c tim c p. C nh i mu khu tr v m c lan r ng nh i mu u c th xc nh c. M t hnh nh siu m tim ho c nuclit phng x c s m sau khi kh i pht cc tri u ch ng t ra c tc d ng l n trong vi c nh gi cc b nh nhn nghi ng b nh i mu c p v c i n tm khng ch n on c ho c khng di n gi i
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c. V i vi c ch p nh chnh xc cc b nh nhn ny, siu m tim bnh th ng ho c m t nghin c u SPECT bnh th ng c s d ng ch t phng x technetium-99m t ra h u ch trong vi c lo i tr nh i mu c p, do c gi tr tin on m 95-98% khi CKMB c dng l tiu chu n vng. Tuy nhin, v n cha bi t c l cc k thu t ny c cng gi tr tin on m cc b nh nhn c l ng troponin tng v m t tr s CKMB bnh th ng. M t b t th ng chuy n ng vch tim trn hnh nh siu m tim ho c nuclit phng x c th c nguyn nhn l nh i mu c tim c p ho c do m t trong s cc i u ki n thi u mu c tim, bao g m m t cn nh i mu c tim c, thi u mu c c b c p, chong ho c khng ho t ng, ho c k t h p c hai. Tr s tin on dng c a siu m tim l ~50% i v i ch n on nh i mu c tim, cc i u ki n ni tr c v cc nguyn nhn b nh khc khng lin quan n nh i mu c a cc b t th ng chuy n ng vch tim (v d : b nh c tim gin). Tr s tin on dng i v i phng php Gated SPECT cng b h n ch , v tnh tr ng t i mu cho t ng vng b t th ng v/ho c m t cn nh i mu c tim c, thi u mu c c b c p, chong v/ho c khng ho t ng c th gy r i lo n ch c nng t ng vng. D ng c gi m nhi u v ng i c thi u kinh nghi m cng c th d n n l gi i k t qu qut dng gi t o. 4.2 Nh i mu c tim hnh thnh. Siu m tim c ch sau m t s c t xu t c n n phn tch t n st ch c nng th t tri. Vi c xc nh ch c nng th t tri c gi tr tin l ng. Ch c nng th t tri c th c nh gi b ng nghi m php g ng s c ho c stress dobutamine; cc k t qu c a vi c xt nghi m nh th a ra cc thng tin v kh nng c tim. S phn thy c lin quan cho php tnh ton i m s chuy n ng vch tim dng lm s o ch c nng t n st th t tri c gi tr tin l ng s m v mu n trong vi c tin on cc bi n ch ng v kh nng s ng st. Cng d dng nh n d ng cc tri u ch ng cng xu t hi n nh r i lo n ch c nng van 2 l, m r ng khu v c nh i mu, huy t kh i thnh tim v cc bi n ch ng c h c c a nh i mu. Siu m tim l quy trnh c ch n l c trong ch n on nh n d ng cc bi n ch ng c h c c a nh i mu c tim. Cc k thu t phng x h t nhn cng c th c dng trong cc giai o n nh i mu ang lnh ho c i u tr lnh bo tr c. Cng v i t p luy n ho c stress gin m ch, vi c o l ng m c kh ngh ch khuy t t t c th nh n d ng c m c thi u mu c c b . Pht hi n cc khuy t t t t i hn 1 vng m ch vnh c th nh n d ng c b nh nhi u m ch. Nhi u pht hi n tin l ng khc nhau c th c nh n d ng (v d : m c ph i dung n p ch t thallium-201, gin bu ng th t tri do thi u mu, kch th c khuy t t t tng ng kch th c khu v c nh i mu). Cu i cng, m c v kh nng ho t ng c a c tim c th c c tnh b ng cng ngh t o nh t p trung nh l ng v i cc ch t phng x thallium-201 ho c technetium-99m. Phn lo i cc type NMCT - Type 1: NMCT ng u pht lin quan thi u mu do bi n c m ch vnh nguyn pht nh bong mng v a v/ho c n t, rch ho c bc tch m ch vnh. - Type 2: NMCT th pht sau thi u mu do tng nhu c u tiu thu O2 ho c gi m cung c p O2, v d co th t m ch vnh, t c vnh, thi u mu, r i lo n nh p, tng HA, ho c t t HA. - Type 3: t t do tim, bao g m ng ng tim, th ng c d u hi u g i thi u mu c tim, km theo ST m i chnh ln, bl c nhnh tri m i xu t hi n, ho c b ng
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ch ng m i c c c mu ng trong m ch vnh xc nh nh ch p m ch vnh v/ho c m t thi, tuy nhin t vong x y ra tr c khi l y mu ho c th i i m tr c khi xu t hi n cc ch i m tim trong mu. + Type 4a: NMCT ph i h p can thi p qua da. + Type 4a: NMCT k t h p t c m ch trong stent xc nh b ng ch p m ch ho c m t thi. - Type 5: NMCT ph i h p ph u thu t c u n i m ch vnh.
TI LI U THAM KH O 1. Alpert JS, Thygesen K, Antman E, Bassand JP, et al. Myocardial infarction redefineda consensus document of the Joint European Society of Cardiology/American College of Cardiology Committee for the Redefinition of Myocardial Infarction. J Am Coll Cardiol 2000;36:959-969. 2. Joint European Society of Cardiology/American College of Cardiology Committee. Myocardial infarction redefineda consensus document of the joint European Society of Cardiology/American College of Cardiology Committee for the Redefinition of Myocardial Infarction. Eur Heart J 2000;21:1502-1513. 3. P. Kavsak, A. MacRae, V. Lustig, R. Bhargava, R. Vandersluis, G. Palomaki, M. Yerna, A. Jaffe. The impact of the ESC/ACC redefinition of myocardial infarction and new sensitive troponin assays on the frequency of acute myocardial infarction American Heart Journal, Volume 152, Issue 1, Pages 118-125 4. KaiM. Eggers, MD, PhD, Lars Lind, MD, PhD, Per Venge, MD, PhD, Bertil Lindahl, MD, PhD.Will the Universal Definition of Myocardial Infarction Criteria Result in an Overdiagnosis of Myocardial Infarction? 5. Joint European Society of Cardiology/American College of Cardiology Committee for the redefinition of myocardial infarction. A consensus document Myocardial infarction redefined. Eur Heart J 2002;21:150213. 6. Hasdai D, Behar S, Wallentin L et al. A prospective survey of the characteristics, treatments and outcomes of patientswith acute coronary syndromes in Europe and the Mediterranean basin: The Euro Heart Survey of Acute Coronary Syndromes (Euro Heart Survey ACS). Eur Heart J 2002;23:1190201. 7. Gillum RF, Fortmann SP, Prineas RJ et al. International diagnostic criteria for acute myocardial infarction and stroke. Am Heart J 1984;108:1508. 8. Dargie H. Myocardial infarction: redefined or reinvented? Heart 2002;88:13. 9. Jaffe AS, Ravkilde J, Roberts R et al. It's time for a change to a troponin standard. Circulation 2000;102:121620. 10. White HD. Things ain't what they used to be: Impact of a new definition of myocardial infarction. Am Heart J 2002; 144:9337
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N I THO NG
Tr ng Nguy n Th Nh n i h c Y D c Hu
P.Gross ni r ng N u bo ph lm ci gi ng cho i tho ng, th ng c l i bo ph c nh gic cc nh chuyn khoa i tho ng ph i tm hi u n. T i sao ng i bo ph c ti m nng thnh ng i i tho ng? V t i sao ng i bc s chuyn khoa i tho ng th ng b th t b i trong i u tr ? Th t v y khi b nh nhn b bo ph t c ng ngha v i s qu t i l ng m trong c th , nh t l m b ng v th ng ko theo s r i lo n lipides mu, nh t l tng VLDL, gi m HDL, cng nh c ng insuline lc i v sau n v khng insuline.., t t c c xem nh l nh ng i tho ng. Hn n a, trong m t vi qu n th c y u t nguy c cao lm ti n tng huy t p, r i lo n lipide mu, r i lo n dung n p glucose mu, ph i h p v i h i ch ng chuy n ha. Nhi u d li u c nh gi g n y trn qu n th nguy c ti n i tho ng nh t l c bo ph, th y c s khng insuline x y ra r t s m. Bo ph th ng km c r i lo n trung tm cao g n nhn b ng c a vng d i i (VMH: ventral medium hypothalamus), ni xu t pht c a th n kinh t ng, v s m nh t gy c ng th n kinh ph giao c m kch thch tng ti t insuline, sau l khng insuline v i tho ng. Nm 1921, Elliot P.Joslin l ng i u tin thng bo s ph i h p gi a T v bo ph. Qua nhi u nghin c u ng i ta ghi nh n c s lin quan gi a bo ph v s pht tri n c a T th 2. Theo John H. Karam v Peter H. Forsham c hn 85% T th 2 b bo ph. Theo Marie Laure Auciaux v c ng s th t l ny l 70-80%. Nm 1985, WHO cng cho k t lu n tng t : bo ph t lu c xem l y u t nguy c c a T th 2. I. M I QUAN H GI A BO PH D NG NAM V I THO NG Bo ph c vai tr khng nh trong c ch b nh sinh c a T . Bo ph km bo b ng, t c tng m b ng, m t bo m hi n nay c xem nh l c quan n i ti t, ti t ra r t nhi u hormone trong c m t s hormone lm tng khng insuline v m t s cytokine gy vim v ch t t bo theo chng trnh. H u qu lc u tng khng insuline v tng ti t insuline, d n d n nhi u nm sau n u khng i u ch nh cc r i lo n do bo ph, bo b ng th s a n thi u tng i insulin m ch y u l do gi m s l ng th th cc t ch c ph thu c insulin, d n n gi m tnh th m c a mng t bo i v i glucose t ch c c v t ch c m , gy c ch qu trnh phosphoryl ha v oxy ha glucose, lm ch m qu trnh chuy n ha hydrate carbon thnh m , gi m t ng h p glycogen trong gan, tng tn t o ng m i. T t c cc nguyn nhn trn u lm tng glucose mu l tri u ch ng c b n c a b nh T . Theo tc gi RC. Bonadonna v R.A Defronzo: Bo ph v T th ng x y ra ng th i, ; nhng cng c r t nhi u nghin c u cho th y bo ph l m t y u t nguy c i km v i h i ch ng khng insulin, ti n pht tri n ti n i tho ng v b nh T type 2. N ng acid bo cao trong mu c nh h ng t i khng insulin c a T th 2, c ch qu trnh oxy ha glucose, gi m nh y c m c a insullin v i t ch c m v c ch
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g n insulin v i th th c hi u t bo ch. Acid bo t do c s n xu t nhi u hn c s n, do s oxy ha trong gan, s tn t o ng v s s n xu t glucose ton ph n s c kch thch v t qu gi i h n sinh l. Ng c l i v i ng i g y, gan ng i bo c dung n p glucose bnh th ng n u b qu t i lipid th v n s n xu t glucose v ngay c trong tr ng h p c tng insulin mu. V v y m t s tng glucose mu nh v tng cung c p acid bo t do c th gi i thch cho s hi n di n c a tam ch ng bi n d ng hormone sau: - Gi m ti t insuline c kch thch b i glucose. - Tng s n xu t glucose gan ngay c giai o n c b n v trong gi i h n th p c a tng insulin mu sinh l. - Gi m h p th glucose qua trung gian insulin. Chu i sinh l b nh ny c kh nng thc y v tr thnh m t vng xo n b nh l, cu i cng c th a n m t s tng ng mu r r t. ACID BO T S d ng glucose mu Ti t insuline Tng glucose mu TNH NH Y C M INSULIN S 1: Chu i b nh sinh gy tng glucose mu tng acide bo t do. b nh nhn bo ph DO S n xu t glucose mu
Th t v y, khi bo ph d ng nam, m b ng qu nhi u, gy h u qu x u, v t bo m c xem nh l c quan n i ti t. T lu, m m c xem l ni d tr nng l ng th ng. n nm 1987: ni chuy n ho steroid sinh d c, s n xu t adipsin., n nm 1994, pht hi n leptin m m , v Leptine c xem nh gen bo ph, mang k hi u gn ob. Hi n nay: autocrin, paracrin, endocrin, c th th p ng hormon t ni khc, v ni chuy n ho nng l ng, th n kinh- n i ti t, mi n d ch, v ngy cng pht hi n nhi u hormone n i ti t khc, m a ph n gy khng insuline lm ti n cho ti n i tho ng v i tho ng (nh hnh 2) : - Protein h RAS: t m n i t ng, gy THA, n u c ch RAS: gi m khng insulin, gi m HA - IL-6: t m n i t ng, gy khng insulin, tng lipid, gi m ti t adiponectin. - TNF-: m m d/da, gy vim ch t t bo theo chng trnh, n ng thm bo ph, khng insulin - MCP-1: (macrophages and monocyte chemoattratant protein): gy p/ vim, khng insulin, tng sinh n i m c m ch mu gy x v a.
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- PAI-1: (plasminogen activator inhibitor): t m m n i t ng, c ch tiu fibrin, tng sinh m ch gy x v a, khng Insulin, bo ph, HCCH - Adiponectin: t m d i da, lm gi m khng insulin (gi m T ), c ch dnh monocyte, ch ng vim, ch ng x v a - Adipsin v ASP/acylation stimulating protein: tng song song v i bo ph, khng insulin, rl lipid, nguy c TM - Resistin: t m n i t ng gy khng insulin - Leptin: gne c a bo ph, l m t lo i protein, c m ho b ng gne ob, ch c trong m m tr ng. Leptin c vai tr i u ha th tr ng, thng qua vng d i i, leptin i u ch nh thi n u ng v s i, thn nhi t v s tiu hao nng l ng, leptine cng i u nh s h p th th c n, G mu, insuline mu. Theo Catherine-Le Stunff, ng i bo ph, Leptine tng 10 l n cao hn l ng Leptine ng i bnh th ng, v t l v i kh i l ng m , do c s khng Leptine ng i bo ph, v h u qu l tng hi u qu c a cc ch t ti n vim, ti n thuyn t t, tng phng thch a.nitric, tng stress oxide ha v tc d ng gi ng giao c m lm tng khng insuline
Hnh 2. T bo m v cc hormone n i ti t II. LIN QUAN HNH THI V I S BI N I S L NG V CH T L NG M NG I BO PH S.Lillioja trnh by thuy t v lin quan hnh thi v i s bi n i s l ng v ch t l ng m ng i bo ph. 2.1. V phng di n s l ng m : S gia tng kh i l ng m lun ko theo m t s gia tng kh i l ng c lin quan n tng ng knh s i c. Hi n t ng ny c 2 h u qu : - Th nh t l gi m cc ch t t i glucose qua mng. - Th hai l s l ng mao m ch /mm2 c a m c gi m m t cch t l v i s gia tng m m , i u ny cng th y r hn v s phn b m ng i bo ph d ng nam. Nh v y, m t mao m ch s ph trch nui d ng m t vng r ng hn ng i bo ph so v i ng i khng bo ph, do v y vng pha ho tan c a insuline ph thu c c a mao
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m ch ny s r t quan tr ng v n ng insuline trong d ch t ch c k (t c l n ng sinh l) s gi m. 2.2. V phng di n ch t l ng m : Bn c nh bi n i v s l ng, cng c t n thng v ch t l ng c a m c ng i bo ph. C n nh c l i r ng, tr c tin c 3 lo i s i c: 1, 2A v 2B. T l s i c lo i 1 c quy t nh m t cch di truy n, khi m s phn b gi a lo i 2A v 2B d b dao ng trn cng m t b nh nhn. Nh ng s i c lo i 1 co ch m v v n hnh theo cch oxy ho. Nh ng s i lo i 2A co nhanh v cng v n hnh theo cch oxy ho, v nh ng s i 2B v n hnh theo cch ng phn. ng v t nh ng s i oxy ho (1 v 2A) c tnh nh y c m v kh nng p ng v i insuline l n hn s i 2B. ng i bo ph, t l s i lo i 1 gi m, v t l s i lo i 2B tng. Song song, tnh nh y c m v i insuline d ng nh tng quan thu n v i ph n trm s i lo i 1 v tng quan ngh ch v i ph n trm s i lo i 2B (clamp tng insuline mu b nh nhn c b t k th tr ng no). Cng v y, ng i bo ph, ngoi m c c a h t nh y c m v i insuline hn so v i ng i khng bo ph, ng i ta cn th y m c khng c cung c p insuline m t cch d dng. S gi i thch ny v s khng insuline ng i bo ph l hon ton c thuy t ph c. M t khc, c n ch r ng n u s gi m tnh nh y c m c a insuline l tng quan v i s thi u h t s i c lo i 1, v trong khi th s l ng s i c lo i 1 c quy t nh m t cch di truy n, nn ng i ta duy tr gi i thch th b nh nguyn trong s pht tri n bo ph v nh ng h u qu c a n trn chuy n ho glucose. III. T KHNG INSULINE N I THO NG S v ti n trnh t nhin c a T th 2 ng i bo ph c De Fronzo a ra. Nghin c u c trnh by so snh gi a 5 nhm i t ng: (1) ch ng bnh th ng, (2) T th 2 c th tr ng bnh th ng, (3) bo ph khng T , (4) bo ph c T v i tng insuline mu v (5) bo ph c T v i gi m insuline mu (c n ch r ng tng v gi m insuline mu c kh o st su t 3 gi lin ti p v i chuy n glucose). m i nhm c th c hi n xt nghi m kch thch tng ti t insuline trong khi truy n TM glucose) ng th i v i o calo gin ti p. Protocole ny cho php nh gi v l ng, kh nng b t gi glucose c a t bo v s tr v c a glucose c b t gi , c ngha l nh gi kh nng d tr v s oxy ho. - K t qu u tin: + ng i T th 2 c th tr ng bnh th ng: gi m s b t gi glucose c a t bo; s d tr glucose cng b ng l ng glucose oxy ha. + ng i bo ph khng T : cng c nh n th y nh ng i T th 2 c th tr ng bnh th ng, nhng c thm khng insuline. V nh ng ng i bo ph c a nhm ny khng b T , nn nh ng t bo bta o Langerhans c a h ng c v i nh ng t bo bta c a ng i T khng bo ph l c kh nng ti t nhi u insuline, b ng cch b s l ng do gi m ch t l ng. Nh v y, k t qu u tin ny cho php nh n m nh r ng s khng insulin c a m ngo i bin ng i bo ph khng th m t mnh n gy T n u ph n ng t bo bta cn bnh th ng. - K t qu th 2 c a nghin c u ny so snh gia 2 nhm bo ph c i tho ng v i insuline mu cao v bo ph i tho ng v i insuline mu th p. Ng i ta
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th y r ng s b t gi glucose c a m gi m so v i ch ng v s b t gi ny cng th p hn so v i ng i i tho ng th 2 c tr ng l ng bnh th ng v ng i bo ph khng i tho ng. i u ng ng c nhin l khng c s khc bi t gi a bo ph c i tho ng tng insuline v gi m insuline mu: gi m s b t gi glucose c a m c 2 nhm gi ng nhau v l ng. S tng glucose mu r nh t g p trong nhm gi m insuline mu, y chnh l nh h ng x u c a ng mu trn chuy n ho glucose. i tho ng th 2, gi m insuline mu th ng c m c chuy n ho ng mu m c cao > 2g/l lc i. - Hai k t qu ny c th c a vo trong s m t l ch s t nhin c a ti n trnh b t th ng i u ho ng mu b nh nhn bo ph. S ny khng gi i quy t r rng cu h i thi t y u v b nh sinh b t th ng ny, c bi t l t i sao c s gi m ti t insuline x y ra? Ph i chng c vai tr di truy n, trong c l do b t th ng v l ng c a t bo bta? Ng c l i trong quan ni m c nh t ph i chng l do tng glucose mu? Gi thuy t th hai ny c th ch p nh n c, b i v quan ni m nhi m c ng Glucotoxicit c xc nh. G n y ng i ta ch ng minh r ng tng glucose mu m n tnh con chu t b c t tu bn ph n c gy b t th ng v s ti t insuline. P.B. Arner t ng trnh k t qu nghin c u v tc d ng c a insuline trn s ng i bo ph v khng bo ph, lc i v 1 gi sau u ng glucose: thoi bi n m + ng i khng bo ph lc i, insuline c ch s thoi bi n m v i n ng 10U/ml. M t gi sau u ng glucose, nh ng b nh nhn khng bo ph ny, tnh nh y c m c a tc d ng khng thoi bi n m c a insuline trn t bo m tng r t cao, v i n ng insuline 1U/ml l c hi u qu r i. + ng i bo ph lc i th ng c l i, insuline c tc d ng khng- thoi bi n m v i n ng r t th p so v i ch ng bnh th ng, tc d ng ny c c v i n ng insuline l 1U/ml. Sau khi u ng glucose, kh nng c ch thoi bi n m c a insuline cng gi ng nh khi i. Tc gi k t lu n r ng tnh nh y c m insuline c a t bo m ng i bo ph d ng nh khng i u bi n theo i u ki n dinh d ng, v v n cn gia tng trong m i tnh hu ng, c bi t l lc i. C n nh c l i r ng, ng i bo ph c tng insuline mu v khng insuline, ch c lin quan trn chuy n ho ng (s g n insuline trn t bo m c l khng gi m ng i bo ph so v i ch ng khng bo ph v i m i l a tu i, gi i v v tr c a m m ). Cng v y, c s lin k t c a 3 tnh hu ng lm duy tr kch th c gia tng c a t bo m , c bi t l m b ng, so v i m vng i th m b ng nh y c m hn nhi u v i tc d ng khng-thoi bi n m c a insuline. E. Ferrannini cng trnh by nghin c u gi ng nh J.P. Felber trnh by trn. E. Ferrannini so snh ng i bnh th ng v i 4 nhm b nh nhn: (1) bo ph v i dung n p glucose mu bnh th ng, (2) bo ph v i khng dung n p glucose, (3) bo ph v i T th 2 v (4) T th 2 c th tr ng bnh th ng. Nghin c u th c hi n o oxy-ho glucose v lipide b ng calo k gin ti p trong 3 tnh hu ng: lc i, giai o n ng ng v trong qu trnh lm nghi m php tng glucose mu. K t qu r t r rng l c s gia tng oxy-ho lipide trong t t c cc nhm v trong c 3 tnh hu ng so v i ch ng. i u ny xc nh r ng chuy n ho ng i bo ph c bi t b ng s s d ng u th lipide, v i r i loan ng (c s tng quan ngh ch gi a oxy-ho lipide v oxy-ho glucose). M c khc, s d tr glucose c xem nh b t n thng ng i bo ph khng dung n p glucose, trong su t th i gian
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xt nghi m k p tng glucose mu (t c ngn ch n s tng glucose) nhng bnh th ng trong su t lc lm nghi m php tng ng mu: nh v y tng glucose mu ng vai tr b. ng i bo ph b T th ng c l i, s d tr glucose cng b t n thng su t th i gian k p tng glucose mu, nhng khng bnh th ng trong su t th i gian lm nghi m php tng ng mu: s tng glucose mu b tr ngng, gi ng nh vng lu n qu n c m t b i Felber. IV. K T LU N BO PH NG VAI TR QUAN TR NG TRONG C CH B NH SINH I THO NG. Bo ph gy h u qu thi u tng i insuline, ch y u do gi m s l ng th th cc t ch c ph thu c insuline. Do gi m insuline t bo m , c, nn gi m tnh th m mng t bo i v i glucose t ch c c v m , c ch qu trnh phosphoryl ho glucose gi m ho t tnh men hexokinase) v oxy ho glucose, lm ch m qu trnh chuy n ha ( ng thnh m , gi m t ng h p glycogne trong gan, tng tn t o ng m i). T t c nh ng nguyn nhn ny lm tng glucose mu R i lo n chuy n ho glucose trong b nh T ch y u do cc r i lo n sau y: - C n tr v n chuy n glucose vo t ch c c v m . - c ch oxy ho glucose theo con ng phosphoryl ho, v lm gi m men hexokinase, glucokinase. - Gi m t ng h p glycogne gan do gi m ho t tnh c a men glycognesynthetase Tng tn t o ng m i (t o ng t m v m ). H u qu nh ng r i lo n trn, s lm cho glucose mu tng. Con ng c b n bi n i glucose trong i u ki n sinh l l con ng phosphoryl ho, th c hi n d i tc d ng c a insuline. Ngoi ra trong c ch b nh sinh do thi u insuline, cn do cc hormone khng insuline ho c ch t khng insuline cng r t quan tr ng. T n su t T th 2 tng song song v i s pht tri n kinh t cng ngy cng tng, i u ny g i c s lin quan gi a bo ph v T . Nghin c u c a M. Reaven v m t s tc gi khc cho th y c s ti n tri n lin t c t bo ph n i tho ng, t c ng insuline mu, khng insuline r i n gi m ti t insuline v gi m dung n p glucose. S r i lo n ny c ph n do gia tng oxy ho lipide c giai o n s m c a bo ph. N ph n nh s tng s d ng acide bo cung c p nng l ng ng i bo ph. ng i bo ph khng T , s khng insuline c th ch ng minh b i s c ch d tr glucose trong su t giai o n qun bnh glucose mu v tng insuline mu. S khi m khuy t trong d tr glucose khng c nh n th y trong khi lm nghi m php dung n p glucose b ng ng u ng, v n c b tr b i tng insuline mu v tng glucose mu trong khi lm dung n p glucose. S gi m dung n p glucose xu t hi n do c ch oxy ho glucose, b ng s oxy ho lipide gia tng n a ch ng, i u ny lm gi m s d ng glucose ngo i bin, lm ch m l i s d tr glycogene do c ch glycogen phosphorylase, v a n T . Sau cng, ti n tri n t bo ph n r i lo n dung n p glucose mu, d n n gi m ti t insuline, r i i tho ng. Bo ph ph thu c T , v i b ng ch ng tng acetyl-CoA m bo l nguyn nhn d n n s b t th ng v t bo bta ng i bo ph khng T v k t qu cu i cng d n n bo ph ph thu c T . Nhi u cng trnh nghin c u cho th y gi m
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nh y c m insuline c 2 nhm b nh nhn bo ph v T , i u ny c ch ng minh sau m t th i gian theo di st trong cng m t i u ki n b nh nhn bo ph khng T . K t qu cu i cng bo ph c xem nh l thnh vin c a T th 2. Bo ph gia tng s khng insuline, s khng ny k t h p v i tng insuline mu. C c i u ny do thay i trong vi c phng thch insuline c a t bo bta hn l ng ng kch thch glucose. Gi m s l ng receptor gp ph n trong khng insuline. Ki u gen ti t ki m Bo ph Tng insuline mu v/hay l khng insuline Tnh t i Tu i, ti t th c....
Thi u h t t bo Bta Tng Glucose mu Nhi m Kch thch t bo-bta Gi m insuline mu Cn b + ? Di truy n T th 2 M t b Hnh 3. Ti n trnh t nhin v cch th c chuy n t bo ph thnh T th 2 TI LI U THAM KH O 1. A. Lonardo, S.Lombardini, M.Ricchi, F.Scaglion and P. Review article: hepatic steatosis and insulin resistance. 2005 2. Adipose tissue and adipokines in Health and Disease, Edited by Giamilia Fantuzzi, Ph.D. 2007 3. Catherine Le Stunff, Pierre Bougnre. Obsits lies des dfauts molculaire de la voie: Leptine-hypothalamus. Endocrinologie volume 1, 5, 6/1999 4. Chantal Simon. Existe il un poids idal . Prcise de nutrition et dittique. Page 3-11 c Glucose Ki t qu t bo bta
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5. Froguel Philippe. Gntique du diabte non insulinodpendant . Glcorama, No 27, 1-9 6. Jaques Haoune. Un gne pour lobsit ?. Le Journal Fax de lEndocrinologue21/11/1995 7. George A. Bray, MD. The Metabolic Syndrome and Obesity 8. Gross P. De lobsit au diabte . Glucorama.LActualit diabtolopique. 1987, No 13, 1-9 9. Guerci B. Ziegler O., Drouin P. Hyperlipidmie au cours du diabte notions rcents . Presse Medicale-Hand Book off Obesity. Edited by George A.Bray, Claude Bouchard, 2007 10. Haring H.U.Mahmert. Pathogenesis of type 2 diabetes mellitus: candidate for a signal transmitter defect causing insuline resistance of the skeletal muscle. Diabetologia (1993) 36, 176-182. 11. Manuela Merli, Frida Leonetti and al. Glucose inolerance and insuline Resistance in cirhossis are normalized after liver transplanttion 12. Nimantha Mark Wilfred de Alwis, Christopher Paul Day. Genetics of alcoholic liver disease and nonalcoholic fatty liver disease, 2007 13. Obesity and Diabetes. Edited by Christos S. Mantroz, 14. Ronald F. Fletcher. Pancreas and carbohydrate. Obesity. Endocrinology 15. Thomas L. Mcknight. Obesity Management in family pratice 16. WHO. Prevention of diabetes mellitus. 1994, 1-66
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R I LO N CH C NNG N I M C M CH MU V I THO NG
Tr ng SUMMARY Endothelial dysfunction often marks an early stage in the development atherosclerosis and can be observed in coronary and peripheral arterial beds. Endothelial dysfunction comprises of abnormalities in vascular tone, balance in thrombosis and fibrinolysis, control of inflammatory response and the growth of smooth muscle. Data suggest that vascular endothelial dysfunction may contribute to the pathophysiology of clinical ischemia, especially angina pectoris, mI, and sudden cardiac death, as it emerges as one of the initial stages in the development of atherosclerosis. Endothelial dysfunction has been documented in type 2 and type 1 diabetic patients and obese individuals with insulin resistance, particularity those who have microalbuminuria. Recent data also showed its existence in individuals at high risk for developing diabetes. Several therapeutic interventions have been tested both in vitro and /or in vivo aim to improve endothelial function in patients with diabetes mellitus. This includes insulin sensitizers, angiotensin converting enzyme inhibitor, lipid lowering medications and antioxidants. Estrogen therapy has also been studied in postmenopausal women. Finally, exercise and weight loss improve insulin resistance and potentially improve endothelial function I CNG N I M C M CH MU N i m c m ch mu (vascular endothelium) l m t l p t bo n m gi a lng m ch mu v l p t bo c trn m ch mu. V phng di n chuy n ho l p n i m c ho t ng v s n xu t m t s ch t trung gian lin quan n v n m ch trong ch t nitric oxide (NO) d n xu t t t bo n i m c l ch t c b n trong duy tr s h ng nh n i mi m ch mu. N i m c m ch mu l m t c quan c n n i ti t l n, n ti t ra nhi u y u t i u ha trng l c m ch mu, gip pht tri n c a t bo, cc tng tc c a b ch c u v ti u c u v c tnh sinh ng. Nh ng nh n c m v p ng c a n i m c i v i v s cc kch thch bn ngoi v bn trong thng qua cc ph c h p th th mng t bo v nh ng c ch truy n t i tn hi u, d n n s t ng h p v phng thch cc ch t ho t m ch, cc y u t pht tri n v i u ha ng mu. Vai tr c a n i m c m ch mu trong b nh l ng i g n y tr thnh tm i m nghin c u c a cc nh khoa h c. Suy gi m ch c nng n i m c c lin quan v i m t s tnh tr ng b nh l nh i tho ng, r i lo n lipid mu, tng huy t p, bo ph R i lo n ch c nng n i m c l m t trong nh ng d u hi u chnh v s m c a b nh sinh x v a m ch, d bo nh ng thay i x v a ng m ch .. II. I THO NG V CH C NNG N I M C Trong i u ki n sinh l tc d ng insulin trn t bo thnh m ch bao g m s k t h p glucose thnh glucogen,v n chuy n Acid amin, trnh di n Endothelin, trnh di n v ho t ho eNOS, trnh di n VEGF trong t bo c trn thnh m ch, phosphoryl ho tyrosine cc lo i protein., xu t bo (exocytosis) v v n chuy n t bo (transcytosis) qua I. Nguy n H i Thu i H c Y D c Hu
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trung gian th th , t ng h p mng c b n, tng y u t c ch ho t ho plasminogen-1 (PAI-1), trnh di n c-myc, c-fos, t ng h p protein, t ng h p DNA v tng sinh t bo 2.1. i tho ng type 1: Trong T type 1, b nh nhn c th i gian b nh 5-10 nm v ng i c s bi ti t albumin ni u bnh th ng so snh v i ng i khng T c trng b i s gia tng p l c mu, c ng cc m ch mu l n v r i lo n th n kinh t ng v m t vi ho c h u h t r i lo n ch c nng n i m c v gia tng ph n ng vim c p th p. Cc b t th ng ny x u hn khi trong giai o n microalbumin ni u. Cng cha r chng tng tc v i nhau nh th no ho c r i lo n ch c nng n i m c l ti n chung hay l h u qu , nhng nhi u nghin c u ghi nh n ch c nng tim m ch bao g m ch c nng n i m c r i lo n tr c khi xu t hi n microalbumin ni u c xc nh khi microalbumin ni u 30 mg/24 gi . R i lo n ch c nng n i m c x y ra tr c microalbumin ni u. tuy nhin r i lo n ch c nng n i m c l bi u hi n c a T type 1 khng v tng ng mu trung bnh r i lo n ch c nng n i m c khng?.N ng vWF khng tng b nh nhn T type 1 khng c bi n ch ng s m v i u ch nh h p l xu t ch c nng n i m c bnh th ng. Ch ng c khc l s gin m ch ph thu c n i m c qua trung gian NO b r i lo n b nh nhn T khng bi n ch ng ng n h n v tng ng mu gy r i lo n c p gin m ch ph thu c n i m c c p ng i khng T khng c y u t nguy c khc.C m t s xu t: b nh nhn T type 1 ki m sot t t, gin m ch khng v d n i b r i ph thu c v khng ph thu c n i m c c a cc ng m ch lo n ho c khng gia tng. B nh nhn T type 1 khng bi n ch ng s m th ng i km gin m ch khng b co m ch t i cc m ch mu l n v nh v c s gia tng dng mu t i vi m ch trn ng i v sc v t th nghi m. Gin vi m ch c th gy tng p l c mao m ch v i km gi thi t v huy t ng h c c a b nh l vi m ch. Tng p l c mao m ch s gy t n thng n i m c vi m ch v v th kh i u cho cc giai o n b nh l vi m ch nh l xu t hi n albumin ni u. Trong giai o n ny, ch c nng n i m c r i lo n ton th bao g m r i lo n gin m ch ph thu c n i m c c th dng quan st r rng m c d u ch c nng n i m c i khi bnh th ng ngay c nh ng ng i c microalbumin. c bi t cc ch t trung gian ph trch lo i gin m ch c a T type 1 s m v n cha c xc nh v khng r n i m c c lin quan khng. Cc d ki n xu t r ng r i lo n gin m ch ph thu c n i m c c th x y ra s m b nh nhn i tho ng T type 1 c l ph thu c vo cc y u t mi tr ng v di truy n khc nh l gen a d ng th th Ang II type I. 2.2. i tho ng type 2 R i lo n ch c nng n i m c xc nh b i r i lo n gin m ch ph thu c n i m c qua s gia tng n ng huy t tng c a cc ch t ch i m c a ch c nng n i m c th ng g p b nh nhn T type 2 s m v khng bi n ch ng. Th d : n ng cc ch t vWF v VCAM-1 ho tan u gia tng v ghi nh n ph i h p v i s gia tng nguy c t vong tim m ch v pht tri n v ti n tri n c a microalbumin n c ti u. c bi t r i lo n ch c nng ni m c th ng n ng ph n b i ng. V n cha r s pht tri n r i lo n ch c nng n i m c ny gy ra b i tng ng mu. T type 2 i n hnh x y ra trong b i c nh c a m t t p h p cc y u t nguy c tim m ch, c bi t s bo ph, tng huy t p, tng TG, gi m HDL, b t th ng c u trc LDL, tng insulin mu, khng insulin v ph n ng vim c p th p ko di, t t c u c th lm r i lo n cl pv i ch c nng n i m c. R i lo n ch c nng n i m c trong T type 2 c v r i lo n ch c nng gy ra b i bo ph nhng vai tr v n cha xc nh. M t i u quan
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tr ng l gia tng tc ng c a vim. R i lo n ch c nng n i m c, ph n ng vim v th i albumin n c ti u T type 2 th ng ti n tri n v lin quan ch t ch v i nhau. Tuy nhin, khc v i T type 1, microalbumin trong T type 2 c th x y ra khi khng c r i lo n ch c nng n i m c n ng v v th d h u tng i t t. 2.3. Khng insulin v h i ch ng chuy n ho v r i lo n ch c nng n i m c Khng insulin th ng kh i u c a T type 2 v i km theo m t chm y u t nguy c c tc ng n khng insulin v r i lo n ch c nng n i m c. Khng insulin kh i u T type 2, tng huy t p v r i lo n lipid v r i lo n ch c nng n i m c hi n di n trong b i c nh tng ng mu v cc y u t h i ch ng chuy n ho. D a theo s ng thu n ny, r i lo n ch c nng n i m c trong cc ng m ch l n m bi n c s m v u th trong b nh l x v a ng m ch, song song b i r i lo n ch c nng n i m c trong m ch mu khng v v phng di n chuy n ho h th ng mao m ch quan tr ng gp ph n vo pht tri n h i ch ng chuy n ho. 2.4. R i lo n ch c nng n i m c gy r i lo n s d ng glucose lin quan insulin b ng cch no? 1. Insulin l hormone v n m ch, insulin lm gia tng lu ng mu n c ng lc thng qua c ch lin quan lin k t th th insulin trn v t o hnh ph thu c n ng mng t bo n i m c. Tuy nhin tng thu nh n glucose do insulin v lu ng mu ton hi u qu khc nhau cng nh th i gian ng th c cc ng c t (curves) v n ng h c.V th gia tng lu ng mu ton th do insulin c th gia tng s d ng gluose. 2. Trong ti n trnh t p trung mao m ch, insulin c th a lu ng mu n c vn t cc mao m ch khng nui d ng n mao m ch nui d ng v v th gia tng s d ng glucose ngay c khi khng tng lu ng mu ton th . Ngoi ra tc d ng gin m ch c a insulin ghi nh n b r i lo n trong cc tnh tr ng khng insulin c i n c bi t T type 2, bo ph, tng huy t p v b gi m i b i cc ch t trung gian ph i h p ch t ch v i khng insulin nh l ch t TNF alpha, NEFAs v r i lo n tc d ng ph thu c NO. Nhi u nghin c u ghi nh n r i lo n ch c nng n i m c v r i lo n ph c h i mao m ch c th gy khng insulin km lin quan s d ng glucose khi n i m c mao m ch lnh m nh nhng khng th ph n ng v i insulin (khng insulin n i m c) v khi n i m c mao m ch b t n thng do cc c ch khc nh l gi m mao m ch lin quan tu i tc (gi m m (rarefaction) v d gi m m t mao m ch cho n v th tch c a t ch c), c bi t gi m m mao m ch v r i lo n ph c h i mao m ch c th lm gi m thu nh n glucose qua trung gian insulin b ng s gia tng kho ng cch phn ph i glucose v insulin chuy n ho glucose t ch c b i s r i lo n v n chuy n insulin xuyn mng. n u y ph i l di n tch b m t ph thu c v b i r i lo n t p trung t ch c c phn ph i km tr c . Gi m m t mao m ch v r i lo n t p trung mao m ch c th c vai tr trong s pht tri n cc thay i sinh x v a trong n ng lipoprotein thng qua r i lo n tc d ng c a LPL (lipoprotein lipase) lin k t n i m c. LPL l enzym lin quan n h n ch t c cho s d ng triacyglycerol v v tr tc d ng sinh l chng l b m t n i m c mao m ch. Gi m b m t n i m c mao m ch c th lm gi m ti p xc lipoprotein giu TG i v i LPL. C ch trn c th gi i thch t i sao r i lo n lipid trong r i lo n chuy n ho c xc nh ch triaglycerol (TG) v HDL. Cc con ng phn t qua insulin lm gia tng t ng h p NO, gin m ch ph thu c n i m c, t p trung mao m ch v n cha hi u
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m t cch y . Lm th no TNF alpha, NEFAs v c l c c ng insulin b n thn gy r i lo n tc d ng ny c a insulin. III. C CH R I LO N CH C NNG N I M C TRONG I THO NG Tng glucose mu gy r i lo n ch c nng n i m c thng qua nhi u hnh th c bao g m: Ho t ho con ng chuy n ho polyol, tng cc s n ph m ng ho khng enzyme, ho t ho dng thc DAG-PCK, tng stress oxy ho, thc y chuy n ho qua con ng hexosamine, vim thnh m ch, bi n i s trnh di n v tc d ng c a y u t pht tri n v cytokine 3.1. S n ph m sau cng c a s ng ho b c cao S hnh thnh s n ph m cu i cng c a ng ho b c cao (AGEs=Advanced glycation end-products) hay cn c g i s g n glucose khng c n enzyme c a cc protein (glycosylation non enzymatic) do tng glucose mu mn tnh. Cc ph n ng t o AGEs s s n xu t cc g c t do; AGEs ph n ng v i NO lm m t i tc d ng gin m ch v ch ng ng c a NO; s tng tc gi a AGEs v i t bo n i m c lm gia tng k t dnh b ch c u n nhn vo l p t bo n i m c m ch; s tch lu AGEs t i cc s i collagen lm x ho v thay i tnh ch t c a thnh m ch; s g n glucose c a apolipoprotein B v lipoprotein khc s c ch s thanh th i TG. Hi n t ng lin k t glucose v i fibrinogen v fibrin lm chng t nh y c m v i plasmin, g n glucose v i antithrombin III v heparin lm gi m i ho t tnh c a chng. S tng tc gi a AGEs v i LDL khi n chng d b th c bo thu n p t o thnh cc t bo b t. 3.2.Con ng chuy n ho sorbitol (Sorbitol pathway) Chuy n ho glucose theo ng polyol do thi u h t insulin lm tng chuy n ho glucose theo con ng sorbitol d i tc d ng c a enzyme aldose reductase; sau sorbitol s ti p t c bi n i thnh fructose d i tc d ng c a enzyme sorbitol dehydrogenase. Sorbitol c tc d ng lm tng p l c th m th u, lm gi m l ng myoinositol d n n r i lo n chuy n ho phospholipid v gi m ho t tnh c a enzyme Na+/K+ ATPase. Tng p l c th m th u do tch lu sorbitol l m t nguyn nhn gy dy mng y (membrane basale) c a mao m ch. M t khc, ch t fructose c kh nng g n v i protein khng c n enzym ti p t c t o thnh AGEs. Ngoi ra, con ng chuy n ho polyol cn th hi n tnh nhi m c qua cc c ch can thi p vo tnh c tnh c a cc g c t do v con ng chuy n ho ny s d ng nicotinamid adenidine nucleotid phosphatasase (NATPH) l enzyme quan tr ng chuy n ho cc ch t ch ng oxy ha. Hi n t ng tng cc g c t do d n n thoi bi n cc protein t bo n i m c v cc ti u c u qua trung gian c a hi n t ng oxy ha lipid ho c t n cng tr c ti p ln cc protein c bi t l cc protein g n glucose. Ngoi ra hi n t ng t oxy ho c a glucose v a m i c khm ph g n y glucose c th b oxy ho t d ng chuy n ti p n d ng d ha b i ch t trung gian c a glucose. Ni m t cch t ng qut con ng glucose t oxy ha l i u ki n g n oxy vo cc phn t n c. Hi n t ng ny s t o thnh cc g c hydroxyl t do gy t n thng cc protein v cc t bo, c bi t l protein c a mng y v t bo n i m c m ch mu. Nh ng ch t trung gian c a ph n ng t oxy ho glucose nh cc g c hydroxyl v cc ceto-aldehyd ti p t c c nh trn cc protein t o thnh d ng cetoaminomethylol. Ch t ny c th t oxy ho v t o thnh cc g c hydroxyl t do.
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b nh nhn T hi n t ng gi m ch c nng c a t bo n i m c m ch mu l d u hi u s m nh t c a hi n t ng x v a ng m ch v x y ra r t s m nay t giai o n ti n lm sng c a T th 2. Thng t n t bo n i m c m ch trong T th 2 c l khng insulin. lin quan n tng glucose mu, tng huy t p, r i lo n lipid mu v V th r i lo n ch c nng t bo n i m c m ch l d u hi u c trng s m c a bi n ch ng vi m ch v m ch mu l n c a T th 2 Hi n nay c nhi u phng php nh m nh gi kh nng ph n ng thnh m ch, nh vi c kh o st ch t NO (Nitric oxide) l d n ch t t t bo n i m c m ch. S lin h m t thi t trn lm sng v ho t ng sinh h c bao g m khuynh h ng dn m ch qua trung gian c a n i m c m ch. Trong T th 2, t n thng s dn m ch qua trung gian ch t NO, gy ra s co m ch, vim v t o huy t kh i trong b nh l x v a ng m ch. Nhi u nghin c u cng ghi nh n r i lo n ch c nng c a t bo n i m c m ch mu xu t hi n s m khi kh i u xu t hi n microalbumine ni u. Ngoi ra cc i t ng c r i lo n dung n p glucose, thn nhn b c nh t c a Bn T th 2 cng l i c ghi nh n qua siu m m ch mu nh gi s dn m ch ghi nh n hi n t ng gi m p ng i v i ch t acetylcholine khi kh o st s bi n i ng knh ng m ch vng cnh tay qua trung gian kh o st lu l ng mu. 3.3. Con ng chuy n ho DAG/PKC Tng glucose mu qua con ng stress oxy ha, s n xu t ch t diacylglycerol (DAG) hay cc s n ph m cu i c a s ng ha b c cao AGEs, cng cho th y ho t ho protein kinasa C (PKC). Con ng chuy n ho CPK (protein kinase C) c c trng v ph i h p v i m t vi b t th ng ch c nng t bo, bao g m gia tng co m ch v r i lo n ch c nng t bo n i m c m ch. Ch c nng ny qua trung gian c a endothelin-1 (ET-1), Angiotensin II, enzyme t ng h p NO n i m c (enzyme eNOS=endothelial NO synthetase). Trn th c nghi m ghi nh n m c d ki m sot t t n ng glucose mu nhng cng khng th gi m n ng DAG ho c ho t ho CPK ng m ch ch c a chu t b T , s t bi n c a CPK ny lm c i thi n s dy mng y c u th n, lu l ng mu v ho t ho t bo n nhn. Ngoi ra vi c s d ng cc ch t c ch enzyme chuy n cng duy tr c s dn m ch ph thu c n i m c m ch b nh nhn T type 1 v 2 khng tng huy t p. 3.4. Con ng chuy n ho hexosamine. Cc nh h ng m ch mu c a con ng chuy n ho hexosamine trong fructose 6-phosphate bi n i thnh glucosamine nh enzyme glutamine:fructose 6 phosphate amidotransferase. Trong t bo n i m c ng m ch ch , tng ng mu lm gia tng n ng hexosamine 6-phosphate v GlcNAc(N-acetylglucosamine). Do s thm vo c a GlcNAc n serine v threonine, gia tng s ng ho lin k t O (Olinked glycosylation) c a s sao chp y u t SP-1, lm gi m phosphoryl ho SP-1 v gia tng ho t ho SP-1.ng c l i i u ny c th tng sao chp PAI-1 v TGF-1. Cc protein khc nh PKC v NOS t bo n i m c c th b bi n i theo cch tng t . V d bi n i c a v tr Akt c a NOS t bo n i m c cho th y gi m ho t ho enzyme. 3.5. Cc cytokine R i lo n ch c nng n i m c m ch lin quan n s lu hnh cc thnh ph n cytokine vim. Qua m t s nghin c u s gia tng n ng cn b n c a cc cytokine
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nh ch t Interleukine (IL-6) v CRP v i s pht tri n T type 2 v bo ph d ng nam. Nghin c u g n y ghi nh n s bi n i cytokines ho c l b ng tc nhn d c l ho c lm gi m l ng m b ng, c k t qu lm c i thi n r ch c nng t bo n i m v gi m n ng cytokines lu hnh v cc ch t ch i m ho tan c a ho t ho t bo n i m c m ch. 3.6. M t s ch t ch i m gy r i lo n ch c nng n i m c trong i tho ng M t s nghin c u ghi nh n b nh nhn T type 2, b nh nhn r i lo n dung n p glucose v thn nhn b c nh t c a b nh nhn T type 2 c s hi n di n trong mu m t s ch t ch i m lin quan r i lo n ch c nng n i m c m ch nh: - Phn t k t dnh t bo thnh m ch d ng ho tan (sVCAM=solube vascular cell adhesion molecule). - Phn t dnh gi a t bo d ng ho tan (sICAM=solube intercellular adhesion molecule) - Endothelin-1 v vWF (y u t Von Willebrand). V i cc d ki n trn y cho th y cc nguy c gy t n thng thnh m ch mu l n x y ra tr c khi xu t hi n T type 2 lm sng. S khng insulin v/hay l giai o n ti n T gp ph n vo cc nguy c m ch mu kinh i n. V phng di n sinh h c b nh nhn T type 2 c s thay i ch c nng n i m c m ch mu tng i a d ng bao g m gi m s n xu t ch t NO, gia tng b t ho t do ph n ng oxy ho, r i lo n s sao chp Tm t t cc c ch v r i lo n gin m ch ph thu c n i m c trong i tho ng R i lo n t ng h p/ s nh y c a ch t NO - Gi m hi u l c c a arginine - R i lo n Gi protein ki m sot tn hi u chuy n i trong t bo n i m c -Gi m hi u l c c a cc ng y u t c a t ng h p NO (Ca++, calmodulin, tetrahydrobioprotein, NDPH) c ch n i sinh c a NO synthase (ADMA=asymmetric dimehtylarginine) Gia tng b t ho t NO v /ho c phn hu - Tng s n ph m ng ho khng enzym (AGE) - Ho t ho chuy n ho ng polyol - Ho t ho DAG-PKC (diacylglycerol-protein kinase C) - Khng lin k t eNOS Gia tng s n xu t y u t co m ch d n xu t n i m c - cc prostnoid co m ch. IV. NH GI R I LO N CH C NNG C A N I M C.
Ch c nng n i m c khng th nh gi tr c ti p ng i, nh gi cc lo i r i lo n ch c nng n i m c c th t c gin ti p b ng nh gi gin m ch ph thu c n i m c, n ng huy t tng c a protein i u ho d n ch t t n i m c v c th qua microalbumine ni u. M t vi thu c tnh m ch mu nh c ng ng m ch v dy l p n i trung m c (IMT) ng m ch c nh c l m t ph n ph thu c n i m c. Nhi u nghin c u ngang ghi nh n r i lo n gin m ch ph thu c n i m c v n ng cao c a cc protein i u ho dn ch t n i m c cc b nh nhn c cc b nh lin quan n t n thng n i m c nh l x v a- huy t kh i, ti n s n gi t v vim m ch mu cng nh nh ng c
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nhn c cc nguy c x v a-huy t kh i. Ngoi ra nh ng b nh nhn c r i lo n gin m ch ph thu c n i m c, n ng c a cc protein i u ho d n ch t n i m c ho c microalbumin ni u c d h u x u v tim m ch. B ng nh gi r i lo n ch c nng n i m c ng i Gi i thch v t n thng r i lo n ch c nng R i lo n gin m ch ph thu c n i m c Gi m s n xu t ch t gin m ch v/hay tng s n xu t ch t co m ch Tng t thot qua mng mao m ch c a Gia tng th m v i ch t c phn t l n albumin nh d u phng x chch tnh m ch, microalbumin ni u v sCD146 Tng s n xu t ch t co m ch Endothelin vWF Tng ho t ti n huy t kh i v ti n ng mu sThrombomodulin Gi m ho t ch ng ng t-PA v PAI-1 Gi m ho t ti n tiu s i huy t sE-selectin v sVCAM-1 Tng dnh v th m i v i b ch c u sICAM-1 Ho t ho ph n ng vim fibronectin t bo v collagen lo i IV R i lo n t ng h p c ch t ngo i bo Trong b ng nh gi r i lo n ch c nng n i m c 1. Cc test nh gi gn m ch ph thu c n i m c qua trung gian NO nh gi tc d ng c a cc ch t gin m ch n i m c nh prostacyclin v EDHF (endothelium derived hyperpolarizing factor) v c th nh m r i lo n ch c nng t bo c trn m ch mu 2. Ch p nh n n ng cao trong huy t tng c a cc ch t trung gian d n ch t n i m c ph n nh r i lo n ch c nng n i m c trong cc b nh m ch mu (m ch vnh, m ch c nh) i h i - Cc lo i t bo khc khng l ngu n quan tr ng - T ng h p quan trong hn l thanh th i tr phi ch t sau ph thu c n i m c - Ch c nng n i m c trong vi m ch tng ng ch c nng trong m ch mu l n, thnh ph n ny, do s vi c l h th ng n i m c vi m ch v i di n r ng v kh nng t ng h p, l quan tr ng kh ng nh n ng huy t tng c a cc ch t trung gian d n xu t n i m c. Lu PAI-1 khng nh ng c th s n xu t t t bo n i m c m cn t bo gan, t bo m v t bo c trn m ch mu. 3. T l xuyn mng c a albumin c kh ng nh khng nh ng b i n i m c m l i cn b i thu c tnh ho h c v c h c c a c ch t ngo i bo v b i p l c huy t ng d li u g n y ch t ho tan CD146 thnh ph n globulin mi n d ch lin quan n ki m sot lin k t t bo v t bo (cell-cell cohesion) v tnh th m n i m c, cung c p nhi u thng tin lin quan c a n i m c v i tnh th m m ch mu. Tm t t cc i u ki n ph i h p r i lo n ch c nng n i m c, chi n l c can thi p r i lo n ch c nng n i m c v ch t ch i m r i lo n ch c nng n i m c. nh gi Cc i u ki n X v a ng m ch, tng cholesterol mu, tng LDL.C, gi m ph i h p v i r i HDL.C, tng Lp(a), tng LDL.sd, LDL.C oxy ho, tng huy t p, lo n ch c nng tng homocystein, tu i, vim m ch mu, ti n s n gi t, h i ch ng n im c chuy n ho, au th t ng c khng n nh, i tho ng, ht thu c l ch ng v th ng, ti t i mu sau thi u mu, x v a
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ng m ch, bypass tim ph i, mn kinh, b nh Kawasaki, b nh Chagas, ti n s gia nh b nh m ch vnh, nhi m khu n, tr m c m, t ho t ng, bo ph, suy th n, tng CRP, suy tim sung huy t, ph i th t tri, sau n Can thi p nh m c ch enzym chuy n, c ch th th angiotensin, c ch c i thi n ch c endothelin, statin, tetrahydrobiopterin, folate, t p th d c, tng nng n i m c nh y insulin, gi m LDL, tng HDL, chng oxy ho, L-arginine, desferoxamine, glutathione, gi m homocystein, gi m CRP, gi m FFA Cc ch t ch CAMs, y u t von Willebrand, nitrite, khng tng thch i m ho tan (asymetric) dimethylarginine , CRP, tPA, fibrinogen, amyloid A c a r i lo n ch c nng n i m c V. NH GI T N THNG N I M C M CH MU TRONG LM SNG Th nghi m nh gi ch c nng n i m c m ch trn ng i i h i nhi u thch th c. N i m c m ch phng thch m t s s n ph m, nhng v n cha c m t xt nghi m mu n c no ch ng minh c tnh h u d ng trong vi c xc nh ch c nng n i m c bnh th ng hay b t th ng, nh t l giai o n s m. Cc th nghi m th ng c dng nh t nh gi ch c nng n i m c trn c th s ng u d a vo vi c o s gin m ch ph thu c n i m c khi m ch mu p ng v i nh ng kch thch bng d c ch t ho c v t l. c tnh ny d a vo kh nng c a n i m c phng thch NO, n khng ch l m t ch t gy gin m ch m cn l m t y u t ch ng ngng t p ti u c u, s k t dnh i th c bo, v s tng sinh c a t bo c trn. Ch c nng n i m c c th o c tr c ti p ng m ch vnh v ng m ch ngo i bin b ng cch o ch c nng v n m ch sau khi truy n vo trong lng ng m ch m t s ch t lm gia tng phng thch NO n i m c. i u b t ti n c a phng php ny l b n ch t xm nh p c a n. V nh gi ch c nng n i m c m c l do ny, nh ng phng php khng xm nh p c hnh thnh. Phng php c s d ng r ng ri nh t l d a vo siu m 2D o ng knh ng m ch kh u l n khi n p ng v i p l c p tr c gy ra gin m ch ph thu c n i m c. Gin m ch khng ph thu c n i m c cng c th nh gi b ng vi c o ng knh ng m ch sau khi dng nitroglycerin ng m d i l i. Trong th p nin 90, v i siu m t n s cao kh o st ng m ch cnh tay nh gi s gin m ch qua trung gian dng ch y (Flow Mediated Dilation) ph thu c n i m c pht tri n. y l m t k thu t nh gi ch c nng n i m c. K thu t ny kch thch phng thch nitric oxide (NO), gy ra gin m ch. M c gin m ch c th tnh ton c nh m t ch s c a ch c nng v n m ch (vasomotor function). Thm d khng xm nh p c a k thu t cho php l p l i nhi u l n nghin c u hi u qu c a nh ng can thi p khc nhau c nh h ng ln s lnh l n c a m ch mu. M c d khng ph i l tiu chu n vng nh gi ch c nng n i m c hi n h u, o FMD ng m ch cnh tay ho c ng m ch i qua siu m 2D l phng php nghin c u dng nhi u nh t trn lm sng 5.1. Gin m ch qua trung gian dng ch y (Flow Mediated Vasodilation FMD): M ch mu c kh nng co gin nh m p ng v i nh ng kch thch ha h c v v t l tc ng trong lng m ch c g i l kh nng t i u ha trng l c nh m
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i u ch nh phn b cng nh dng ch y c a mu p ng v i nh ng thay i mi tr ng t i ch . Nhi u m ch mu p ng v i s gia tng dng ch y ho c p l c chn p gy t c hon ton b ng cch gin ra. Hi n t ng ny c g i l FMD. NO ngu n g c n i m c l ch t trung gian c b n c a hi n t ng FMD. C ch chnh xc c a vi c pht hi n c p th i c a l c p v s d n truy n tn hi u n sau i u chnh trng l c m ch mu v n cha c bi t y . Mng t bo n i m c c ch a cc knh ion chuyn bi t, nh cc knh kali c ho t ha b i calcium, n m ra p ng v i p l c p. Hi u qu c a vi c m knh kali lm c ng phn c c t bo n i m c, gia tng dng calcium i vo. Calcium tc d ng nh 1 enzyme t ng h p NO, v s hnh thnh NO sau gy ra FMD. T bo n i m c m ch b t n thng lm m t kh nng ch ng ng do gi m gi i phng v gi m t ng h p thnh ph n Prostacyclin (PGI2); gi m t ng h p v gi m ho t tnh sinh h c c a protein C, protein S v thrombomodulin; gi m tiu s i huy t do r i lo n t ng h p t-PA, PAI-l; ti p qu nhi u protein thu n l i cho s k t dnh ti u c u (y u t VIII-Willebrand); gi m s n xu t NO. - Mng y m ch mu b t n thng d n n hi n t ng tng t ng h p cc protein c b n ngoi t bo m ch y u l collagen type IV. Proteoglycan, fibronectin v lamilin m h u qu c a chng l lm gi m tnh n h i v lm r i lo n kh nng l c c a mng y. - Bn T t bo c trn pht tri n m nh, ph i, tng sinh v lo n s n cng gp ph n lm r i lo n ng mu v tng sinh huy t kh i. - H th ng th n kinh m t qun bnh gi a giao c m v i giao c m: km nh y i giao c m nh acetycholin, do hi n c m v i cc ch t trung gian ho h c c a h t ng co m ch chi m u th . Phng php o FMD: Do c nhi u nghin c u FMD nh ng v tr ng m ch khc nhau trn c th cng nh cc cch ti n hnh gy p l c p v i kho ng th i gian khc nhau. Nm 2002 . T ch c Tim M ch i H c M (American College of Cardiology Foundation) ng thu n v k thu t c a phng php o FMD. Trang thi t b chnh l my siu m Doppler 2D mu c ph n m m m ch mu v i u d t n s cao (trn 7,5 MHz). V tr c ch n o ng knh tr c v sau khi t o ra kch thch p l ng m ch cnh tay o n trn h khu u. Khi kch thch p gy t c dng ch y c t o ra b ng m t my o huy t p v i bng o c qu n v tr cnh tay trn ch ng m ch c o ho c v tr c ng tay d i. Th i gian nh t s gin m ch t i a l 50 giy sau khi lm ngng dng ch y ng m ch c ng tay v 70 giy i v i ng m ch cnh tay. Do s gin m ch t n m c t i a khi ng m ch b t t trong 5 pht, th i gian ny c ch n lm th i gian lm ngng dng ch y. Bm p l c b ng my huy t p ln m c v t qu huy t p tm thu 50mmHg lm t c dng ch y t o ra kch thch v gi trong 5 pht. Sau x nhanh p l c huy t p t o ra ph n ng c ng mu. ng knh ng m ch cnh tay c o tr c v sau khi x p l c c o t i cng v tr. T l ph n trm gi a ng knh sau khi t o kch thch v ng knh tr c g i l FMD. Cng th c tnh FMD = (D2 D1)/D1* 100 (%) C suy gi m ch c nng n i m c khi FMD < 5,0 %. 5.2. Kh o st b dy l p n i trung m c (Intima Media Thickness) Sau phng php nh gi p ng n i m c qua trung gian dng ch y, t n thng s m x v a ng m ch c th pht b ng o b dy l p n i trung m ch (IMT)
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b ng siu m 2D v i u d c ly gii cao 7,5 MHz t i cc ng m ch nng nh ng m ch c nh, ng m ch ch , ng m ch i, ng m ch kheo.Phng php o IMT b ng siu m 2D c Pignoli P. (1986) l n u tin xu t. V phng di n hnh nh siu m, h th ng m ch mu chia lm 2 nhm bao g m nhm A trong v phng di n i th lng m c bnh th ng ho c c gii m (fatty streak) v nhm B trong c t n thng x v a ng m ch. Trong nhm A c trng m ch mu bi u hi n d i hnh nh hai ng h i m song song (parallel echogenic lines) c phn cch nhau b i m t kho ng gi m h i m ho c khng c h i m (hypoechogenic or anechoic space). Bi u m t c t c xc nh nh l bi u 2 ng trong ng bn trong (pha lng m ch) th ng u d n, m m m i v m ng hn so v i ng bn ngoi. Tng quan v i cc hnh ny v i m u tiu b n l n c ch p nh n v i ng bn trong l n i m c, ng gi m h i m l trung m c v ng h i m bn ngoi l ngo i m c. V v y khi o kho ng cch t ng h i m bn trong n kho ng phn gi i (interface) gi a ng gi m h i m v ng h i m th hai g i l b dy n i trung m c (IMT) c a thnh m ch. VI. I U TR R I LO N CH C NNG N I M C TRONG I THO NG R i lo n ch c nng n i m c l giai o n s m c a x v a ng m ch ni ring v t n th ng m ch mu ni chung. Khi xu t hi n cc d u ch ng lm sng c a b nh x v a m ch th ng l b nh giai o n b c pht v khi vi c x tr th ng l ch lm gi m nh b nh ho c nh m vo vi c b o v th pht. V v y phng ng a b nh x v a ng m ch giai o n s m c th t c b ng cch pht hi n v i u tr r i lo n ch c nng n i m c, m t trong nh ng thay i quan tr ng nh t giai o n ti n lm sng c a b nh x v a ng m ch. B nh nhn T c bi t l T type 2 l m t b nh l v i nhi u y u t nguy c ph i h p trn cng b nh nhn. V th song song v i ki m sot ng huy t vi c d phng v i u tr cc y u t nguy c ph i h p r t quan tr ng. 6.1. Thay i l i s ng v ki m sot ch ti t th c M t s nghin c u ghi nh n thay i l i s ng v ki m sot ch ti t th c l m t trong nh ng bi n php h tr v gp ph n c i thi n tnh tr ng r i lo n ch c nng n i m c, Lavrensic A v CS (2000) nghin c u hi u qu c a t p th d c ln FMD i t ng 29 ng i c h i ch ng chuy n ha tu i t 40 n 60. K t qu 3 l n t p th d c m i tu n trong 12 tu n th FMD gia tng ng k so v i tr c t p (5,3 2,8% tr c t p so v i 7,3 2,7% sau t p, p < 0,05). Nicholas Tentoluris v CS (2008) nghin c u tc d ng c a b a n giu acid bo b o ha v khng b o ha i v i FMD b nh nhn i tho ng type 2. K t qu sau b a n giu acid bo b o ha, FMD gi m c ngha th ng k. Ng c l i nhm dng b a n c acid bo khng b o ha (d u liu) th FMD thay i khng ng k . Nghin c u ny g i ch n v i ch t bo khng b o ha c th gip c i thi n r i lo n ch c nng n i m c. 6.2. Ki m sot ng huy t Tng ng huy t l m t trong nh ng nguy c gy r i lo n ch c nng n i m c. V th vi c ki m sot t t ng huy t d i m i hnh th c l i u tr c b n nh m h n ch t n thng n i m ch b nh nhn T . Nhi u nghin c u ghi nh n tng n ng glucose mu gy r i lo n gin m ch ph thu c n i m c. Gi m n ng glucose mu
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ngoi lm gi m n ng insulin cn gp ph n c i thi n ch c nng n i m c. V th i u tr c n nh m n l h ng huy t v tng nh y c a insulin. Cc thu c h ng huy t nh Metfomine ghi nh n c i thi n ch c nng ph thu c n i m c ng m ch m c treo c a chu t b khng insulin. Sulfolnyl Urea trong nhm gliclazide c i thi n s gin m ch ph thu c n i m c ng m ch ch c a th b T (gy ra do alloxan). Tuy nhin cc nghin c u lm sng nh gi tc d ng c a cc thu c h ng huy t trn ch c nng n i m c khng th y c s khc bi t ho c gi m ph n ng v i acetyl cholin khi cc thu c ny ngng s d ng. Nhm Thiazolidinedione (TZDs) v i cc nghin c u g n y cho th y nhm TZDs c i thi n ch c nng n i m c v khng insulin b nh nhn T type 2 bo ph, v th vi c ngh i u tr khng insulin c th c i thi n tnh tr ng r i lo n ch c nng n i m c T type 2 khng insulin. Asnani S v CS (2006) nghin c u s c i thi n FMD b nh nhn T type 2 c i u tr b ng insulin. K t qu , vi c s d ng pioglitazone cng v i insulin b nh nhn i tho ng type 2 c nh h ng thu n l i n ch c nng n i m c m ch mu, ngay c nhm sau nhi u nm c c ng glucose mu v khng insulin. 6.3. c ch PKC Tng ng mu c th gia tng ho t ho PKC trong gia tng stress oxy ho. S d ng cc ch t c ch PKC c th ph c h i ch c nng m ch mu v cng lm gia tng s trnh by mRNA c a eNOS trong t bo n i m c ng m ch ch . G n y, ch t c ch PKC, LY33531 c s d ng. Thu c ny lm bnh th ng lu l ng mu vng m c, t l l c c u th n song song v i tc d ng c ch PKC. Beckman v c ng s nh n th y c ch PKC lm gi m s r i lo n gin m ch ph thu c n i m c ng i kho m nh c lm tng ng mu. 6.4. Cc ch t c ch t ng h p AGEs. S n ph m AGE l k t qu r i lo n v lu di c a protein i v i tng ng mu v i cc tc d ng lm gi m NO tr c ti p v gia tng stress oxy ho. Ch t AGEs v c i aminoguanidine, ch t c ch t ng h p AGEs cho th y lm gi m n ng thi t ch c nng n i m c ng v t th nghi m. 6.5. Tetrahydrobiopterin Tng ng mu lm tng stress oxy ho c th lm gia tng bi n i NO thnh peroxynitrite, ch t lm t n thng ch c nng thnh m ch. Gi m stress oxy ho c th ph c h i ch c nng thnh m ch hn l cung c p NO. Tng ng huy t ko di v tng cholesterol mu gy ra s khng lin k t c a eNOS v lm gi m s n xu t NO. Nghin c u trn ng v t b T th c nghi m v b nh nhn tng Cholesterol ghi nh n s d ng ch t Tetrahydrobiopterin lm ph c h i gin m ch ph thu c n i m c. Tuy nhin cha kh ng nh cc nghin c u b nh nhn T . 6.6. L-arginine L-arginine cung c p c ch t cho NO, s d ng L arginine t ra c hi u qu cho ng i l n ng v t. Ti t th c L arginine trong 10 tu n cho th y d phng dy n i m c ng m ch vnh v gi m ph n ng ti u c u th b tng cholesterol. Dng L arginine ng u ng lm gi m tn sinh n i m c t n thng sau khi nong bng th tng v khng tng cholesterol mu. ng i s d ng L arginine lm gi m s tng ho t ng ti u c u ng i tng cholesterol mu. Dng L arginine tnh m ch gi m khng m ch ngo i bin v gi m huy t p tm thu v tm trng, c i thi n gin m ch vnh ph
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thu c n i m c nh m p ng acetylcholin trong m ch vnh ng i tng cholesterol v c i thi n lu ng mu ng m ch chi d i b thi u mu. Nhm Deanfield ghi nh n cung c p L-arginine khng c i thi n gin m ch qua trung gian dng ch y b nh nhn T ph thu c insulin. 6.7. Estrogen T n su t b nh ng m ch vnh ph n ti n mn kinh th p hn nam gi i cng tu i trong gi i thch m t ph n nh nh h ng Estrogen. Estrogen c cc tc d ng quan tr ng trn ch c nng thnh m ch m khng hon ton gi i thch d a trn s c i thi n lipid mu. B nh nhn n T c cng nguy c tim m ch nh l ng i nam khng T c xu t r ng, h b gi m tc d ng b o v tim m ch c a Estrogen nh l ng i ph n ti n mn kinh khc. Estrogen c nh ng tc d ng c l i, khng nh ng c ch ngng t p ti u c u m cn c tc d ng ch ng oxy ho v tc d ng ch ng tn sinh trn c trn m ch mu. Nhi u nghin c u ch ng t r ng Estrogen c i thi n s gin m ch ph thu c n i m c ng v t b c t bu ng tr ng v ph n h u mn kinh. C ch c th l do thc y s n xu t eNOS ho c l do c ch co m ch ph thu c Prostaglandine H synthase prostanoid. Lim v c ng s ghi nh n r ng li u php hormone thay th c i thi n cc ph n ng vi m ch ph n sau mn kinh kho m nh. Tc d ng ny c v y u ph n T type 2. Tuy nhin li u php hormone thay th c i thi n ho t ho n i m c c quy t nh b i m t phn t k t dnh n i bo ho tan T type 2. nh ng ph n 6.8. Cc ch t c ch enzym chuy n Cc ch t c ch enzym chuy n cho th y c i thi n ch c nng n i m c v lm gi m s pht tri n x v a ng m ch cc ng v t th nghi m c tng cholesterol mu d a vo tc d ng c l p v i tc d ng h huy t p. Tng t , nghin c u HOPE (Heart Outcomes Prevention Evaluation) ch ng t r ng ch t ramipril ( c ch enzim chuy n) trong d phng cc bi n c tim m ch b nh nhn T m c d c ch c a tc d ng ny cha r. Cc th nghi m lm sng ch ng t r ng ch t quinapril ( c ch enzym chuy n) c i thi n ch c nng n i m c b nh nh n khng T c b nh m ch vnh. Cc nghin c u nh gi tc d ng c a c ch men chuy n trn b nh nhn T type 1 c nh ng k t lu n bn ci trong m t s nghin c u ch ng t r ng c ch enzym chuy n khng c tc d ng trn ch c nng thnh m ch b nh nhn T type 1 sau 6 thng i u tr . Tuy nhin, ODriscoll v cng s ghi nh n c i thi n ch c nng n i m c do c ch enzym chuy n b nh nhn T ph thu c insulin. c ch men chuy n cng c i thi n ch c nng n i m c ph thu c NO c b n v kch thch b nh nhn T type 2 bao g m b nh nhn b tng huy t p v b nh th n T . Tuy nhin, khng th y hi u qu c a c ch enzym chuy n trn b nh nhn c h i ch ng khng insulin. Cc ch t c ch enzym chuy n c m t s tc d ng c l i trn c u trc v ch c nng m ch mu. c bi t, chng thc y hi u qu sinh h c c a NO. Ch t sau ny c th l do gi m s n xu t qua trung gian angiotensin II c a superoxides ho c thng qua c ch ging ho bradykinin, m t ch t c ti m nng kch thch NO phng thch. 6.9. c ch HMG CoA Reductase Nhi u th nghi m lm sng kh ng nh r ng nhm Statins lm gi m ng k t l t vong v m c b nh tim m ch. Ngoi ra, i u tr gi m lipid mu cng c i thi n ch c nng n i m c. C i thi n r i lo n gin m ch ph thu c n i m c x y ra trn b nh nhn T c r i lo n lipid l r t t v ph i h p. Akalin A v CS (2008) nghin c u tc d ng c a Atorvastatin ln FMD ng I i tho ng type 2. K t qu cho th y
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Atorvastatin c i thi n c ngha ch c nng n i m c (thng qua FMD) b nh nhn i tho ng type 2. R i lo n gin m ch ph thu c n i m c b nh nhn T type 2 c r i lo n lipid mu c ghi nh n l c i thi n v i i u tr fibrate (ch t lm gi m n ng triglyceride huy t thanh) nhng khng ph i v i statins. 6.10. Arginine ngh ch l (Arginine paradox) Cc tc d ng c l i c a L-Arginine ngo i sinh trn m ch mu c a m t s tnh tr ng b nh l v i s gia tng n ng nitrate v cGMP huy t tng trong qu trnh i u tr L-arginine xu t s cung c p nhi u L-arginine c th kch thch ho t ng NOS. Tuy nhin i u ang th c m c l s d ng arginine ngo i sinh s a n s n xu t nitric oxide khi n ng arginine ngo i bo lun ph h p trong s gia tng qu m c nhu c u c a NOS, m t hi n t ng g i l arginine ngh ch l. i u ny l n u tin c ch ng t th b tng cholesterol mu v cng c quan st trn b nh nhn tng p ph i. nhi u gi i thuy t i v i hi n t ng ny. y l c th l do ch t c ch n i sinh c a NOS,ADMA, c th i khng v i n ng n i bo bnh th ng c a L-arginine. kh c ph c s khi m khuy t c a c ch t V cung c p thm arginine c i h i NOS. Th hai. V eNOS nh v u th v tr n i bo c bi t c bi t l caveolae, t i ch c a L-arginine trong vi mi tr ng ny c th khc v i n i m ch. V n n ng cha r lm th no s nh v c hi u c a eNOS b i caveolae c th nh h ng n ng nh v c a eNOS c a m t c ch t t i ch thch h p, nhng c ch lin quan s vi ch t v n chuy n arginine (v d v n chuy n acid amine cation -1 (cationic amino acid transporter-1). S thnh l p c a ph c h p caveolar nh th c v thu n l i chuy n nh n bi t l tc d ng gin m ch c a Lgiao arginine t Enos. i u quan tr ng arginine khng hon ton trung gian tr c ti p b i nitric oxide. L-arginine c th c ch trng l c giao c m ngo i bin a n gin m ch qua s chuy n ho c a n, ch t abmatine, kch thch th th alpha2 trung ng. Thm vo arginine cng kch thch phng thch nhi u hormone nh glucagon, prolactin v growth hormone c th gy tc d ng gi n m ch. Ngoi ra m t vi m ch mu v tc d ng khc c a argnine b phn chia b i lo i ng phn hnh thi c a chng, D-arginine, khng ph i c ch t c a NOS. C ch ph c t p qua L-arginine c th c i thi n ch c nng m ch mu trong m t vi tnh hu ng ng c thm d sau ny. 6.11. Nitrovasodilator/Nitric oxide donor Cc lo i gin m ch nitro (Nitrovasodilator) nh amyl nitrite, glyceryl trinitrate, sodium nitroprusside v molsidomine l ti n ch t v c tc d ng sau khi chuy n ho thnh nitric oxide. V th c g i l cho nitric oxide (nitric oxide donor). D a trn cc thu c tnh gin tnh m ch cc thu c c s d ng trong suy tim v au th t ng c. Nitrosoglutathion l ph c h p c a nhm nitrosothiol nghin c u r ng r i trn ng i. thu c c tc d ng khng ngng t p ti u c u, cn b ng gin ng v tnh m ch hn nitrate h u c. Nitrosoglutathione c ch ho t ho ti u c u trong ng m ch vnh sau khi nong vnh v lm c u n i. V th nitrosothiol c thu c tnh d c h c trong i u tr thi u NO v c th ch t cho nitric oxide lo i c th c tri n khai khc hn thu c hi n t i. 6.12. Nitric oxide d ng ht ( Inhalation of nitric oxide) Nitric oxide d ng ht c i thi n m t s tr n h p mao m ch ph i, bao g m tng p ph i dai d ng tr s sinh, tng p ph i th phi sau thi u kh m n, h i ch ng suy h h p ng i l n. Thu c cn c ti m nng trong c i thi n ph ph i c p v ch ng methaemoglobinaemia.
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6.13.Ch ng oxy ho ( Antioxidants) T khi stress oxy ho gy bi n ch ng r i lo n ch c nng n i m c, nhi u nghin c u v vai tr thu c ch ng oxy ho trn ch c nng m ch mu v d phng bi n ch ng tim m ch. R i lo n ch c nng n i m c trong T type 1 v 2 l do b t ho t ch t NO b i cc g c t do d n xu t oxy. C m t s gi m n ng ch t ch ng oxy ho n i sinh bao g m ch t superoxide dismutase v catalase ng v t T th nghi m. Ngoi ra nhi u nghin c u lm sng ghi nh n c s gi m n ng vitamin C v E n i sinh T type 1 v type 2. B t c cc phng ti n lm gi m stress oxy ho u c ti m nng c i thi n gin m ch ph thu c n i m c. Timimi v c ng s , Ting v c ng s ghi nh n khi truy n vo trong vitamin C vo trong ng m ch c i thi n s gin m ch ph thu c n i m c b nh nhn T type 1 v type 2. Ngoi ra, truy n vitamin C c i thi n r i lo n ch c nng n i m c nh ng ng i kho m nh c gy tng ng mu. Chnh vitamine C (ascorbic acid) ng tnh m ch cnh tay c i thi n gin tnh m ch ph thu c n i m c b nh nhn T type 2, ng i ht thu c l v tng cholesterol mu. Tng t dng vitamin C b nh nhn b nh m ch vnh c i thi n gin m ch qua trung gian dng ch y. Tc d ng ny c l i x y ra nhanh sau 2 gi v ko di 30 ngy. ng m ch Ngoi ra dng vitamin C cn c i thi n gin m ch ph thu c n i m c th ng tm m c b nh nhn tng huy t p khng c b nh m ch vnh. b nh nhn b nh m ch vnh ph i h p vitamin C v L-arginine gy gia tng gin m ch ng k . Ngoi ra vitamin C c m t s tc d ng ti n oxy ho (pro-oxidant effects) trong m t s tnh hu ng. 6.14. Chuy n i gen (Gene transfer) Chuy n i tr c ti p gen NOS ng d ng n thnh m ch b r i lo n v n m ch v c vai tr trong i u tr cc b nh tim m ch . S ti p c n ny cho th y hi u qu trong cc th nghi m v b nh m ch mu c a cc ng v t th nghi m. i u tr gen m ch mu c a d n ch t eNOS n t ch c c bi t thc y s n xu t NO v tr c n quan tm. ng Chuy n gen NOS th c hi n l n u tin nm 1995, khi eNOS cDNA, l y t m ch c nh c a chu t sau khi t n tng do nong bng. trong m t ph c h p v i virus ngng k t c a Nh t B n. i u ny t o ra m t s gi m tn sinh n i m c ngy th 14. Sau m t k t qu tng t c kh ng nh b i m t nhm nghin c u khc ng m ch v tnh m ch ch u v vnh ghp. Gen tr li u cng lan r ng t chuy n giao t i ch cho n h th ng. a m t li u eNOS cDNA c a r n vo h th ng tu n hon qua tnh m ch ui c a chu t b tng huy t p t pht k t qu tng s n xu t v bi ti t cGMP v nitrite/nitrate, v gi m ng k huy t p tm thu ko di 12 tu n. 6.15. c ch NOS Dng c ch iNOS cho th y c i thi n thay i huy t ng qua trung gian v i NO trong th c nghi m c a chong nhi m khu n. i u tr tnh m ch L-NMMA d n ch t arginine (arginine analogue l-NMMA) lm c i thi n s gi m khng m ch mu ngo i bin v gi m huy t p ng m ch ch nhi m n i c t . Cc tc d ng tng t v i LNMMA cng kh ng nh ng i. Tuy nhin tng p ph i v gi m cung l ng tim cng ghi nh n sau khi dng c ch NOS. Trong tng lai pht tri n thu c trong l nh v c ny nh m vo d ng NOS ng d ng c hi u cng nh c p c a c ch i h i s n xu t cc d c ph m c hi u qu t i u. TI LI U THAM KH O
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1. Akalin A, Temiz G, Akcar N, Sensoy B. Short term effects of atorvastatin on endothelial functions and oxidized LDL levels in patients with type 2 diabetes. Endocr J. 2008. 55(5):861-6. 2. Asnani S, Kunhiraman B, Jawa A, Akers D, Lumpkin D. Pioglitazone restores endothelial function in patients with type 2 diabetes treated with insulin. Metab Syndr Relat Disord. 2006. Fall. 4(3): 179-84. 3. Balletshofer BM, Braun B, Rittig K et al. Urinary albumin excretion and noninvasive assessment of peripheral endothelial dysfunction with high-resolution ultrasound in type 2 diabetic subjects and nondiabetic controls. Med Klin (Munich). 2003. Apr 25; 98(5);253-8. 4. Baykan M, Erdogan T, Erem C, Hasihasanoglu A et al. The relationship between flow-mediated dilatation and left ventricular function in type 2 diabetic patients with microalbuminuria. Endocrine. 2006 Oct; 30(2):197-202. 5. Bots ML, Westerink J, Rabelink TJ, de Koning EJ. Assessment of flowmediated vasodilatation (FMD) of the brachial artery: effects of technical aspects of the FMD measurement on the FMD respond. Eur Heart J. 2005;26(4):363-8. 6. Casper G. Schalkwijk, Coen D.A. Stehouwer. Vascular complications in diabetes mellitus: the role of endothelial dysfunction. Clinical Science. 2005. 109: 143159.
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M TS
V N C P NH T SINH B NH H C V I U TR DUY TR B NH PH I T C NGH N M N TNH NGOI CN C P

Nguy n Vn Thnh BV KTW C n Th
TM T T B nh ph i t c ngh n m n tnh (COPD) l b nh l vim m n tnh c a ph i v i s tham gia ng th i c a nhi u y u t . Cc y u t thnh ph n trong sinh b nh h c COPD k t h p v i nhau m t cch ph c t p, t t o ra cc bi n i v ch c nng ph i, tri u ch ng h h p, cc t c p, nh h ng t i tnh tr ng s c kho chung v cu i cng l lm tng t vong. Cc ti p c n i u tr h p l c n tc ng vo cc y u t thnh ph n ny. K t h p ICS v m t hay nhi u thu c dn ph qu n tc d ng ko di d ng ht l phng php mang nhi u h a h n cho COPD. T kha: B nh ph i t c ngh n m n tnh ; Sinh b nh h c; i u tr duy tr. Abstract: UPDATES IN PATHOGENESIS AND CONTINUOUS THERAPY FOR STABLE CHRONIC OBSTRUCTIVE PULMONARY DISEASE. Chronic obstructive pulmonary disease (COPD) is chronic inflammation in the lung with participating of a lot of factors. The components in pathogenesis of COPD is complicated combination and caused lung dysfunction, respiratory symptoms, acute exacerbation and affected patients health and increased the mortality. A new approach has to intervent these components. The inhaled combination therapy with corticosteroid and one or more long-acting bronchodilator agents is potential therapy in continuous management for stable COPD. Key words: Chronic Obstructive Pulmonary Disease; Pathogenesis; Continuous therapy. I. SINH B NH H C COPD s c kh e M c d b nh ph i t c ngh n m n tnh ang l m t trong nh ng v n chnh, mang tnh t n c u v ang c xu h ng gia tng (1) nhng cho n nay chng ta cn cha hi u bi t v sinh b nh h c b nh l ny m t cch th u o v cha c cch ti p c n i u tr hi u qu nh m lm ch m ti n trnh x u i c a b nh (2). Nm 2001, l n u tin trong nh ngha, GOLD (Global Initiative for Chronic Obstructive Lung Disease) c p khi ni m vim m n tnh c a ph i trong COPD (3). COPD bao g m c vim cc ti u ph qu n t c ngh n m n tnh v i x ha, thu h p ng th nh v kh ph thng v i m r ng cc kho ng kh ngo i vi, ph h y c u trc ph i, m t n h i ph i v ng cc ng th nh (4). H u h t b nh nhn COPD u c y cc d ng t n thng nh v y v nguyn nhn ch y u l do thu c l. Tuy nhin t ng b nh nhn, cc bi u hi n ny c th tr i hn t n thng kh ph thng ho c tr i hn t n thng vim ti u ph qu n t c ngh n. B n ch t qu trnh vim trong COPD v hen ph qu n khc nhau v lo i t bo tham gia, cc ch t trung gian h h c, cch p ng vim, v tr t n thng, do v y m cch p ng v i thu c khng vim cng khc nhau (5). M t s b nh nhn c bi u hi n b nh l k t h p v a nh hen, v a nh COPD. Tuy nhin, nhi u kh nng y khng ph i l tnh tr ng n ng c a m t b nh l no m l s k t h p ng th i c hai b nh l ny (4). Hi n t ng h p ng th c nh, kh ph
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thng v bt t c lng ng th do qu ti t d ch nh y l cc y u t tham gia ng th i t o ra h i ch ng t c ngh n khi o ch c nng ph i. Tuy nhin c ch no l chnh, chng ng vai tr nh th no trong s thay i gi a b nh nhn ny v i b nh nhn khc v gi a cc giai o n c a s ti n tri n b nh. Cho n nay chng ta cha c cu tr l i chnh xc. Nghin c u v m b nh h c trong COPD cho th y c bi u hi n u th t n thng ng th ngo i vi v nhu m ph i. C hi n t ng t c ngh n c a cc ng th ngo i vi (bronchioles) v i cc bi u hi n x ha, thm nhi m i th c bo v cc Tlymphocyte. C bi u hi n ph h y c u trc nhu m ph i v i tng s l ng cc i th c bo v cc T-lymphocyte, trong CD8+ (T gy c t bo) tng nhi u hn CD4+ (T h tr ). Trn cc tr ng h p COPD n ng, sinh thi t ph qu n cng cho th y c cc bi n i tng t . Trong m v trong d ch r a ph qu n b nh nhn ht thu c l v COPD c bi u hi n tng r r t i th c bo, b ch c u a nhn trung tnh. Khng tng b ch c u i toan tr trong giai o n c p ho c c bi u hi n hen nh l m t b nh ng pht. Phn tch t bo ph nang v cc ng th nh cng cho th y c s tng ln c a t t c cc d ng t bo c lin quan trong COPD, g m: i th c bo, T-lymphocyte, B-lymphocyte v b ch c u a nhn trung tnh. M c d s b t th ng v s l ng cc d ng t bo vim c ch ng minh trong COPD nhng cho n nay s t n t i cng nh m i lin quan c a chng nh th no chng ta cng cn cha bi t r. M i m t hi khi thu c ch a kho ng 1017 cc m nh oxy ph n ng (reactive oxygen species ROS). ng th i cc m nh oxy ph n ng cng c t o ra n i sinh t cc t bo vim (b ch c u a nhn trung tnh, i th c bo). Cc m nh oxy ph n ng c lin quan trong sinh b nh h c COPD g m: superoxide anion (O2-), hydrogen peroxide (H2O2), g c hydroxyl (OH-), peroxinitride (ONOO-). Tnh tr ng oxy ha qu m c (oxidative stress) x y ra khi m cc m nh oxi ph n ng c sinh ra v t qu kh nng i u ha c a c ch b o v ch ng oxy ha. H u qu l t o ra s ph h y c u trc lipid, protein, ADN. Cng ngy ng i ta cng c b ng ch ng v vai tr quan tr ng c a tnh tr ng oxy ha qu m c trong sinh b nh h c COPD. Tnh tr ng oxy ha qu m c lm gi m ch c nng c a cc men ch ng phn h y protein (nh 1- antitrypsin). Cc m nh oxy ph n ng, c th l peroxinitride, lm gi m s k t h p c a corticosteroid receptor v i ADN v lm gi m kh nng d ch chuy n c a cc receptor ny t bo tng t i nhn t bo. ng i ht thu c l v b nh nhn COPD, ng i ta nh n th y c hi n t ng gi m ho t tnh c a histone deacetylase (HDAC), gi m HDAC2 i th c bo ph nang v m ph i ngo i vi. Vi c gi m ho t tnh HDAC2 s d n n gi m c ch qu trnh vim v gi m hi u qu khng vim c a corticosteroid. Tnh tr ng oxy ha qu m c cng lm thc y qu trnh ch t theo chng trnh (apoptosis) c a cc t bo c u trc ph i nh t bo n i m c m ch mu, t bo bi u m v lm tng h y ho i c u trc ph i, nh t l ngo i vi. Cc men phn h y protein (protease) lm ph v m lin k t ph i v hnh thnh kh ph thng. Elastin c th l protein c u trc ph i quan tr ng nh t trong vi c t o ra n h i c a ph i v protein ny l ch c a cc men phn h y protein. M c d lc u ng i ta ch nhi u t i elastase c a b ch c u a nhn trung tnh nhng hi n nay ng i ta cng a bi t nhi u men phn h y protein khc c vai tr trong sinh b nh h c COPD nh Serine protease, Cysteine protease, Matrix metalloproteinase (5).
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Cc gi thuy t v c ch no duy tr v m r ng qu trnh vim ph i c nhi u nghin c u c p n. Ht thu c lin t c l tc nhn kch thch duy tr cc ph n ng vim ph i. Nhi m virus ti m tng lm tng p ng vim c a ph i. Trn th c nghi m ng i ta cng th y nhi m Adenovirus ti m tng lm tng p ng vim c a ph i v i kch thch c a khi thu c. Gi m ho t tnh HDAC i th c bo ph nang v tng ho t tnh y u t nhn ch u trch nhi m d ch m di truy n (NF-kB) lm tng c ng t ng h p cc protein vim TNF-, IL-8. M c d khi thu c l tc nhn chnh trong sinh b nh h c COPD nhng COPD giai o n n ng, ngng ht thu c l cng khng ch m d t c cc ph n ng vim ph i. C th ph n ng vim c a ph i hnh thnh m t c ch nh vnh vi n. C A VI C DNG THU C DN PH QU N V II. HI U QU CORTICOSTEROID I U TR DUY TR: M c tiu c a vi c i u tr COPD ng i cn c p l c i thi n tnh tr ng s c kh e, gi m cc t c p v gi m t l t vong. Cc thu c hi n nay ang c s d ng i u tr cho COPD bao g m: cc thu c kch thch 2 tc d ng ng n (short-acting 2 agonists SABAs) (th d salbutamol, terbutalin), cc thu c kch thch 2 tc d ng di (longacting 2 agonists LABAs) (th d formoterol, salmeterol), khng cholinergic tc d ng ng n v tc d ng di (th d ipratropium, tiotropium), theo phyllin, corticosteroid d ng ht (Inhaled-corticosteroid - ICS) (th d beclomethasone dipropionate, budesonide and fluticasone propionate), cc d ng k t h p c nh li u ICS/LABA v SABA/khng cholinergic v glucocorticosteroid t n thn. Tr c y nh gi hi u qu i u tr ng i ta th ng t p trung trn hi u qu ch c nng h h p v lm gi m tri u ch ng. Hi n nay ng i ta ch ngy cng nhi u hi u qu i u tr trn tnh tr ng s c kh e v gi m t vong. V i mong mu n ny, c v nh l ICS, nh t l ICS k t h p v i LABA s em l i nhi u h a h n. Cho n nay chng ta cn thi u b ng ch ng t cc nghin c u lm sng ng u nhin xc nh hi u qu c a ICS trn t l t vong. Chng ta ch m i c cc thng tin t cc nghin c u h i c u/ m t cho r ng ICS c hi u qu lm gi m t l t vong trong COPD. S hi u bi t thm v hi u qu c a ICS c cung c p t cc nghin c u lm sng ti n c u ng u nhin. Nghin c u ISOLDE (Inhaled steroids in Obstructive lung disease) l nghin c u m i, ki m ch ng ng u nhin fluticasone propionate v i placebo trn 751 b nh nhn COPD t m c trung bnh n n ng. Trong nghin c u ny, fluticasone propionate gi m m t cch c ngha cc t c p v tc ng c ngha trn ch t l ng cu c s ng. Tuy nhin nghin c u khng ch ng minh c i u tr c i thi n c t c gi m FEV1. Briggs AH v cs (2006) v i fluticasone propionate cng khng ch ng minh c hi u qu gi m c ngha t l t vong. M t phn tch h i c u 3 nm (nghin c u EUROSCOP) trn b nh nhn COPD nh t i trung bnh cho th y nguy c thi u mu c c b c tim gi m c ngha v i i u tr b ng budesonide so v i placebo. Tuy nhin l i ch gi m t vong cha ch ng minh c. Nghin c u TORCH (toward a revolution in COPD health) nh gi hi u qu fluticasone propionate sau 3 nm trn 6000 b nh nhn COPD trung bnh t i n ng khng cho th y gi m t vong chung. M c d v i i u tr b ng ICS s l n vim ph i nhi u hn nhng t l t vong do vim ph i khng tng m t cch c ngha. LABA c vai tr quan tr ng trong i u tr tri u ch ng COPD. M t phn tch meta-analysis ng u nhin c ki m ch ng nh gi hi u qu s d ng LABA th i gian t
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nh t 3 thng cho th y i u tr ny lm tng t vong do h h p so v i placebo. Tuy nhin cc nghin c u ng u nhin g n y cho th y cc thu c LABA c b nh nhn COPD dung n p t t v an t n trong i u tr . Nghin c u TORCH cng cho r ng LABA (salmeterol) an t n, khng lm tng tc d ng ph v cn cho th y khuynh h ng gi m t vong khi i u tr b ng salmeterol trn 3 nm so v i placebo (hazard ratio 0.879, 95% CI 0.729-1.061). Thu c khng muscarinic tc d ng ko di (long-acting muscarinic antagonist LAMA) tiotrpium cng c kh nng ki m sot tri u ch ng v gi m t c p COPD. M t phn tch post h c trong th i gian 1 nm cho th y tiotropium c kh nng gi m t c suy gi m FEV1. N u hi u qu ny l th c th LAMA c kh nng lm gi m t vong. B ng m t nghin c u so snh ng u nhin, m i, Casaburi R v cs (2005) k t lu n tiotropium k t h p v i t p ph c h i ch c nng h h p lm tng kh nng g ng s c v c i thi n tnh tr ng s c kh e so v i t p n thu n. Hi u qu ny cn duy tr sau khi ngng t p 3 thng. Nm 2004, m t thi t k nghin c u th nghi m lm sng l n, c i ch ng v i tiotropium nh m nh gi hi u qu trn ch c nng ph i, tnh tr ng s c kh e, tc ng trn s t c p, c th c hi n ko di trong 4 nm v c cng b cu i 2008, nghin c u UPLIFT (Undstanding the potential long-term impact on function with tiotropium). Nghin c u ny k t lu n: k t h p tiotropium v i cc thu c i u tr khc khng khng cholinergic gip c i thi n ch c nng ph i, c i thi n ch t l ng cu c s ng, gi m s t c p trong th i gian nghin c u. Tuy nhin tr li u ny l i khng gi m ct c gi m FEV1 hng nm c ngha (10). K t h p ICS v LABA l m t i u tr mang nhi u h a h n sau khi cc nghin c u th nghi m lm sng ch ng minh k t h p thu c mang l i hi u qu hn b t k thu c no dng n c. Khi c cc d ng bo ch k t h p k t h p ICS v LABA li u c nh th tng lai cho vi c i u tr lu di COPD tr nn c nhi u tri n v ng t t. M t nghin c u ng u nhin c ki m ch ng trn 812 b nh nhn cho th y k t h p thu c budesonide/formoterol trong 12 thng lm gi m s l n c cc t c p n ng ( t c p c n s d ng corticosteroid v/ho c khng sinh v/ho c nh p vi n v tri u ch ng h h p) 24% so v i placebo, 23% so v i formoterol n thu n, c i thi n m t cch c ngha ch t l ng cu c s ng so v i placebo. Trong m t nghin c u khc, trn 1022 b nh nhn i u tr b ng budesonide/formoterol cho th y th i gian xu t hi n t c p n ng u tin di hn, s l n xu t hi n t c p n ng t hn, ch t l ng cu c s ng c i thi n hn so v i nhm placebo. K t qu thu c cng tng t nh v y i v i cc nghin c u TRISTAN (trial of inhaled-steroid and long-acting beta-agonists), nghin c u TORCH. Trong m t nghin c u khc, nghin c u VIVACE, so snh hi u qu k t h p salmeterol/fluticasone propionate v salmeterol n thu n cho th y lm gi m s l n t c p trn b nh nhn COPD n ng. Cng nh i v i ICS, cho n nay, trong khi m t s nghin c u h i c u cho th y k t h p ICS/LABA lm gi m c t l t vong th cha c nghin c u ti n c u no cng b kh ng nh c k t lu n ny. M t nghin c u h i c u /m t so snh trn 3620 b nh nhn trong 3 nm kh ng nh k t h p salmeterol/ fluticasone propionate lm gi m t vong so v i nhm i u tr khng ICS, ho c so v i LABA hay ICS n c. M t phn tch k t h p (pooled analisis) trn 1800 b nh nhn i u tr v i ho c budesonide/formoterol ho c budesonide hay formoterol n c ho c placebo trong 1 nm. Phn tch ny cho th y budesonide n c ho c k t h p v i formoterol lm gi m
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c ngha (p=0.039) nguy c t vong do t t c cc nguyn nhn trong m t nm so v i formoterol ho c placebo. Hi u qu ny c nh n th y trn t t c cc nhm khc nhau v FEV1, gi i v tu i. Nhm nghin c u TORCH cng thi t k ti n c u theo h ng ch ng minh hi u qu ny trong m t nghin c u so snh ng u nhin trong 3 nm. B ng m t thi t k c nh gi l ch t ch , nghin c u ny cho k t lu n l k t h p salmeterol /fluticasone propionate gi m nguy c t vong 17.5% so v i placebo, nhng so snh ny l i khng th c s c ngha th ng k (p=0.052). S khc bi t v hi u qu i u tr i v i t l t vong gi a nghin c u TORCH v cc nghin c u tr c c l gi i theo nhi u cch, c bi t l s khc nhau trong thi t k nghin c u. Tuy nhin cng c cc tc gi b ng phn tch th pht ti n chuyn bi t (prespecified secondary analysis) cho th y t vong gi m m t cch c ngha, hazard ratio l 0.811 (95% CI 0.670-0.982; p=0.03) v cho r ng hi u qu lm gi m t vong c a k t h p LABA/ICS l th c s . Hi u qu i u tr c a corticosteroid u ng trong COPD khng r rng nh trong hen ph qu n. M t s khuy n co cho r ng s d ng corticosteroid u ng trong hai tu n gip tin l ng c b nh nhn s c hi u qu t t v i i u tr lu di ICS. C s c a khuy n co ny d a trn k t qu nghin c u c a Callahan CM et al (1991) nh n th y corticosteroid u ng ng n ngy gip tin l ng c di n bi n c a FEV1 v i i u tr corticosteroid u ng di ngy. Ng i ta cng cho r ng v i tr li u corticosteroid u ng ng n ngy s gip xc nh m t s tr ng h p hen ph qu n m tnh tr ng t c ngh n ch c i thi n v i thu c dn ph qu n sau khi s d ng corticosteroid u ng ng n ngy. Tuy nhin, ngy cng nhi u b ng ch ng cho th y corticosteroid u ng ng n ngy c gi tr r t th p trong vi c tin l ng s d ng ICS ko di i v i COPD. C hai nghin c u h i c u phn tch hi u qu c a vi c s d ng corticosteroid u ng trn s thay i lu di FEV1 cho r ng v i li u 10mg/ngy trong 14-20 nm v i COPD trung bnh v li u trn 7.5mg/ngy trong 14-18 nm v i COPD n ng cho th y i u tr lm ch m t c gi m FEV1. Tuy nhin thi t k c a hai nghin c u ny l h i c u, khng i ch ng v thi u nh ngha COPD m t cch r rng lm cho nh ng k t lu n khng nhi u tnh thuy t ph c. Bn c nh , nhi u c tnh do s d ng corticosteroid u ng ko di c bi t r nn cc thi t k nghin c u ti n c u nh m xc nh hi u qu i u tr lu di i v i thu c ny l r t h n ch . Theophyllin c s d ng t lu trong lm sng b nh ph i t c ngh n m c d c ch tc ng phn t c a thu c cn cha c bi t r rng. Bn c nh tc d ng dn ph qu n, theo phyllin cn c cc tc d ng ng i dn ph qu n. B ng m t thi t k nghin c u so snh ng u nhin v m i v i placebo, Sarah V v cs (2002) cho r ng sau 2 tu n s d ng theophyllin 150-300mg/ngy tnh tr ng vim v ph h y ph i thng qua vai tr c a b ch c u a nhn trung tnh s gi m v i b ng ch ng l c hi n t ng gi m b ch c u a nhn trung tnh cng nh gi m s l ng v ho t tnh cc y u t ha h ng ng trong m v trong mu ngo i vi. c b ng ch ng v i li u th p theophylline lm gi m cc t c p. Cho n nay tr ng i chnh khi s d ng theophylline v n l v n c tnh nn thu c khng c khuy n co nh l l a ch n u tin trong COPD. Tuy nhin y l thu c r ti n, d ng u ng, nn c n c nh ng nghin c u thm v kh nng v hi u qu s d ng thu c ny trong i u ki n kinh t x h i c a chng ta hi n nay.
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III. K T LU N COPD l m t b nh l vim m n tnh c a ph i v i s tham gia ng th i c a nhi u y u t . Cc y u t thnh ph n trong sinh b nh h c COPD k t h p v i nhau m t cch ph c t p, t t o ra cc bi n i v ch c nng ph i, tri u ch ng h h p, cc t c p, nh h ng t i tnh tr ng s c kh e chung v cu i cng lm tng t vong. M t ti p c n i u tr h p l c n tc ng vo cc y u t thnh ph n ny. D a trn cc b ng ch ng, GOLD khuy n co vi c ti p c n i u tr theo b c tng d n c a m c n ng. Cho n nay, cha c b ng ch ng v i u tr b ng thu c c th thay i c s suy gi m FEV1. Tuy nhin, thu c dn ph qu n v n l thu c chnh lm gi m tri u ch ng trong COPD. Trong s cc thu c dn ph qu n hi n nay, thu c dn ph qu n tc d ng ko di l thu c c nhi u ti n ch nh t. M c d v y, nhi u b nh nhn v n cn tri u ch ng khi dng thu c dn ph qu n m t cch t i u. Trong tr ng h p ny, k t h p nhi u lo i thu c l c n thi t. Nhi u b ng ch ng cho r ng k t h p thu c s lm tng hi u qu v gi m tc d ng ph so v i tng li u c a m t thu c t c hi u qu ngh r t th n tr ng v vi c dng corticosteroid d ng tng ng. GOLD c nh ng ht duy tr. Ch nh ny ch c t ra v i COPD n ng v r t n ng (b c III v IV) n u c nhi u t c p ti di n. ICS c th lm gi m nguy c t vong do t t c cc nguyn nhn, tuy nhin k t lu n ny cn c n ph i c cc nghin c u ti n c u kh ng nh. ICS k t h p LABA s c hi u qu i u tr t t hn vi c dng thu c ring l . TI LI U THAM KH O: 1. Lopez AD et al. The global burden of disease, 1990-2020. Nat Med 1998; 4: 12411243. 2. P.J. Barnes et al. Chronic obstructive pulmonary disease: molecular and cellular mechnisms. Eur Respir J 2003; 22: 672-688. 3. Pauwels RA et al. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease. NHLBI/WHO Global Initiative for Chronic Obstructive Lung Disease (GOLD). Worshop summary. Am J Respir Crit Care Med 2001; 163:1256-1276. 4. PJ Barnes et al. Chronic obstructive pulmonary disease: molecular and cellular mechanisms. Eur respir J 2003; 22: 672-688. 5. PJ Barnes. New concept in COPD. Ann Rev Med 2003; 54: 113-129. 6. Saetta M et al. CD8+ T-lymphocytes in peripheral airways of smokers with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1998; 157: 822826. 7. Di Stefano A et al. Severity of airflow limitation is associated with severity of airway inflammation in smokers. Am J Respir Crit Care Med 1998; 158: 12771285. 8. Pesci A et al. Inflammatory cells and mediators in bronchial lavage of patients with chronic obstructive pulmonary disease. Eur Respir J 1998; 12: 380386. 9. Keatings VM et al. Differences in interleukin-8 and tumor necrosis factor-a in induced sputum from patients with chronic obstructive pulmonary disease or asthma. Am J Respir Crit Care Med 1996; 153: 530534. 10. Donald P. Tashkin et al. A 4-year trial of Tiotropium in chronic obstructive pulmonary disease. N Engl J Med 2008; 359; 15 (www. NEJM.ORG).
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NHN M T TR NG H P VIM TUY N GIP NUNG M C P C NHI M

Tr ng
C GIP
Nguy n Th Nh n i h c Y D c Hu
Tm t t: Vim tuy n gip c p nhi m khu n l m t b nh t g p. Vi khu n gy b nh th ng xm nh p theo nhi u ng nh ng mu, b ch huy t, ng tr c ti p t h u h ng, ho c do ch n thng xuyn th ng tuy n gip hay ng i suy gi m mi n d ch. Tri u ch ng chnh l s t, au c , nu t au, ni au, tuy n gip l n lan t a nng v hi m khi c nhi m c gip. Nhn m t tr ng h p nh p vi n t i khoa n i BV Tr ng i h c Y D c Hu , b nh nhn n 21 tu i, kh i pht b nh g n 15 ngy, kh i u v i s t nh , m i c, m t, nu t au h ng g n 5 ngy, sau s t cao tng d n, nu t au nhi u, km h i ch ng nhi m v ni r t au. Nh p vi n v i tuy n gip l n, nng c gip tng i r v i nh p nhanh 150 l n/pht, run tay, kch thch kh ch u, h i h p. C n lm sng: BC tng cao 18.800c/mm3, Neutro 76%; CRP = 96.8mg/l (0.1 5); VS: 1h: 37mm; 2h: 83mm. TSH= 0.1IU/ml (0.4 6); FT4 = 2.5 ng/dl (0.8 - 2), ch p nh p nhy tuy n gip (-), I131: 2h l 11%; 24h: 15%. Siu m tuy n gip tr c khi nh p vi n: thy ph i kch th c bnh th ng; thy tri: 254720 mm, k t lu n l vim tuy n gip. Siu m tuy n gip sau i u tr khng sinh tnh m ch 4 ngy: thy tri c u trc gi m m, khng ng nh t, nhi u h c dnh, h ch d c M c nh. K t lu n siu m: vim p xe ha thy tri tuy n gip. c h i ch n khoa ngo i ch c ht d n lu, c y tm vi khu n nhng cha th c hin. Ti p t c i u tr n i khoa b ng khng sinh TM, propanolol, b nh nhn kh e, h t s t, m ch 76 l n pht, tuy n gip nh khng s th y l n. CLS: BC, CRP, TSH, FT4 tr l i bnh th ng. Summary: Acute bacterial thyroditis is rare. Bacteria can get into the gland by hematogenous, lymphatic route, or by direct spread, penetrating trauma or in immunosuppressive individuals. The main symptoms of thyroiditis: local pain, fever, chill, odynophagia, and dysphonia. Gland is enlarged, tender, firm, and the symptoms of thyrotoxicosis are rare. A presentation case: A 21 year-old female have been hospitalized at Internal Medicine Deaprtment of Hue College of Medicine and Pharmacys Hospital. 15 days admission, prodrome had been pharyngitis, generalized myalgias, mild fever, and fatigue; then symptomes had become more severily: high fever and severe neck pain, swelling neck, chill, tired, odynophagia and dysphonia. On clinical examination: thyroid gland is enlarged, tender, and firm, with the symptoms of thyrotoxicosis: palpitation, heart rate: 150 beats/min. W.B. counts 18.800/mm3 with N: 76%, and erythrocyte sedimentation rate is elevated. Suppurative areas appear cold on scintigraphy. The 24-hour 131 I uptake is low: 15%. The CRP concentration is elevated. TSH= 0.1IU/ml (0.4 6); FT4 = 2.5 ng/dl (0.8 - 2). Thyroid echography on admission: thyroiditis, second echography (4 days later): abscess on the left of thyroid gland. Treatment: antibiotics pIV and propanolol. Result: patient gets better, pulse and temperature turn back to normal; the thyroid gland returns normally in size and other laboratory tests are normal.
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I.
TV N C nhi u lo i vim tuy n gip nh: - Vim tuy n gip t mi n Hashimoto - Vim tuy n gip bn c p De Quervain (do virrus), (cn g i l vim TG au bn c p) - Vim tuy n gip khng au sau sinh - Vim tuy n gip nhi m khu n c p cn g i l vim tuy n gip nung m c p - Vim x tuy n gip Riedel - Vim tuy n gip do thu c V vim tuy n gip c phn lo i nh sau: C p, bn c p v m n Vim tuy n gip nhi m khu n c p (Acute Bacterial Thyroditis) cn g i l vim tuy n gip nung m /Acute (suppurative) thyroiditis. ng xm nh p vi trng c th g p: theo ng mu, b ch huy t, theo ng tr c ti p h u h ng (vim h ng), ch n thng xuyn th ng tuy n gip hay ng i b suy gi m mi n d ch. Vi trng gy b nh th ng g p l Streptococcus pneumonia, Staphylococcus aureus, S. pyogenes, k kh, n m. Vim TG nhi m khu n hi m x y ra do nhi u l do: tuy n gip c bao b c b i l p v , trong tuy n ch a y ch t iode, giu h th ng m ch mu, v c tr i r ng xung quanh nhi u h b ch huy t nn r t kh x y ra nhi m trng. Lm sng c hi u l au c r t nhi u, s t, run l nh, nu t au, ni cng au, tuy n gip l n lan t a, nng au. Di n ti n t n thng t i gip l d p xe ha; nhng b nh l ny t g p so v i vim tuy n gip c p De Quervain. Ch c nng gip th ng l binh th ng, tuy nhin theo Elizabeth N. Pearce v cs th c m t s nhi m c gip hay suy gip c ghi nh n. Sau y chng ti xin trnh by m t tr ng h p vim tuy n gip nhi m khu n c p kh i n hnh: B nh nhn G. Th T. N. 21 tu i, ti n s khng c b u gip, nh p vi n ngy 29 thng 11 nm 2008, s nh p vi n 8757, kh i pht nh g n 10 ngy tr c khi nh p vi n v i s t lc u nh , m i m t, nu t au rt c trong 5 ngy u, cha dng thu c g, sau , au gia tng khi nu t, khi ni, ng th i cng th y c to ra, b nh nhn i khm t i phng khm n i ngy 23/11/08 v i s t 38oC, m ch nhanh 150 l n/ pht, run tay, tuy n gip l n c hai thy, sng, nng au r t nhi u, nu t au c ch n on v i vim tuy n gip c p nhi m khu n, gim bi t v i vim tuyn gip c p De Quervain, v c i u tr b ng hai lo i khng sinh u ng, trong khi cho XN thm TSH, FT4 vo ngy 25/11/08, k t qu TSH = 0.3IU/ml (0.4 6); FT4 = 2.1 ng/dl (0.8 - 2), v i k t qu siu m TG ngy 23/11/08 l tuy n gip l n c hai thy theo di vim tuy n gip; ECG ngy 25/11/08 nh p nhanh xoang, t n s 140-150 l n/pht, ngy 29/11 b nh nhn cn s t cao, nn nh p vi n v i s t 40oC, m ch 150 l n/pht, HA 110/70mmHg. Di n ti n c n lm sng theo di: 16.600/mm3; N: 74%, L 26% (24/11/08) 18.800/mm3; N: 78%, L 22%, E; 0.3% (29/11/08) 8.300/mm3; N: 64%, L 36% (6/12/08) 7.400/mm3; N: 58%, L 42% (16/12/08) CRP: 96.8mg/l (0.1 5) (ngy 1/12/08); 0.9 mg/l (12/12/08), VS: 1h: 37mm; 2h: 83mm CTM: BC:
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ECG: nh p xoang 140 l n/pht (ngy 25/11/08) 100 l n/pht (ngy 29/11/08) l n/pht (ngy 12/12/08) SA tim: bnh th ng TSH: 0.3IU/ml (0.4 6) FT4: 2.1 ng/dl (0.8 - 2) (ngy 25/11/08) 0.1IU/ml FT4 2.5 ng/dl (ngy 1/12/08) 0.4IU/ml FT4 2.0 ng/dl (ngy 16/12/08) Scintigraphy TG (23/11/08): tr ng khng ghi hnh c. t p trung iode phng c t i tuy n gip: th p; 2h 11%; 24h: 15%. Siu m tuy n gip:
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Siu m TG (23/11/08): Thy ph i kch th c bnh th ng. Thy tri: 25 x 7 x 20mm. Vim tuy n gip
Siu m TG (5/12/08): Thy tri c u trc gi m m, khng ng nh t, nhi u h c dnh, h ch d c M c nh. Vim p xe ha thy tri tuy n gip
Siu m TG (10/12/08): Vim p xe ha thy tri tuy n gip
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Siu m TG (18/12/08): Vim thy tri tuy n gip p xe ha i u tr b ng khng sinh ng TM: Cephalosporine th h 3, Likacine, propanolol, khng vim. Di n ti n: sau 1-2 tu n i u tr b nh nhn h t s t d n, h t au c , tuy n gip nh l i d n, h t , n h t au, nu t bnh th ng, nh p tim tr l i bnh th ng 80 l n/pht. C n lm sng ch c nng gip tr l i bnh th ng, b ch c u v CRP tr l i bnh th ng, tuy nhin p xe v n cn khu tr, d ch m kh d n, cho chuy n i u tr ngo i d n lu. II. BN LU N: B nh nhn nh p vi n v i b nh l tuy n gip c h i ch ng nhi m c gip th ng g p nh t l Basedow, lm sng g i khi c h i ch ng nhi m c gip r m r r rng, tuy n gip l n lan t a, r nh t l c ti ng th i tm thu t i b u, m t l i ho c sng long lanh. Tuy nhin cng c m t s b nh khc c h i ch ng nhi m c gip nh u tuy n gip c, ho c a u tuy n gip c, vim tuy n gip bn c p De Quervain, nhng vim tuy n gip nhi m khu n c p th hi m g p. Tr ng h p b nh nhn ny khi m i n khm, lm sng gi ng nh vim tuy n gip c p De Quervain, m theo nhi u tc gi cn g i l vim tuy n gip au: nh s t, m i m t, ho, nu t au c ; tuy n gip sau 5 ngy l n nhanh, lan t a, nng v au tng, siu m c hnh nh vim tuy n gip, scintigraphy tuy n gip khng ghi hnh c v t p trung iode phng x qu th p; lm sng c h i ch ng nhi m c gip l b nh nhn h i h p, nng n y kh ch u, da r n m hi, run tay, nh p tim 140-150 l n/pht, TSH gi m (0.1IU/ml); FT4 tng (2.5 ng/dl), VS tng cao (1h: 37mm; 2h: 83mm); nhng c i m khng ph h p l cng th c mu c b ch c u tng cao d n, ch y u l neutrophile (BC: 18.800c/mm3; N: 78%,), CRP tng cao (CRP = 96.8mg/l); v di n ti n siu m l m thy tri tuy n gip, i u ny kh ng nh xc nh ch n on l vim tuy n gip nhi m khu n c p p xe ha ho c vim tuy n gip c p nung m . V ch nh i u tr : c 3 ch nh chnh : - Khng sinh - Khng vim - Gi m ng ng nhi m c gip (n u c) b ng ch n bta: + Propanolol 40mg/vin ho c Propranolol (Inderal ) LA: 60-320 mg/ngy + Atenolol (Tenormin ): 50-100 mg/ngy + Metoprolol (Lopressor ): 50-100 mg ngy 2 l n + N u ch ng ch nh ch n bta th s d ng Verapamil (Calan ) 40-80 mg
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* Ch ng ch nh dng thu c khng gip, v nhi m c gip trong tr ng h p ny khng do tng ho t tuy n gip. - D n lu m . V tiu i m nhi m trng: tr ng h p ny r t g i t h ng, v tr c khi tuy n gip l n b nh nhn c au h ng nhi u ngy. V ch n khng sinh: t t nh t d a vo khng sinh t d ch m , nhng do cha th c hi n c (ph i c ti n hnh Khoa Ngo i); do v y chng ti s d ng khng sinh ph r ng; v b nh c i thi n t t v v phng di n lm sng v c n lm sng: nh tuy n gip nh l i r, h t nng, , au; b nh nhn kh e, nh p tim tr l i bnh th ng; ch c nng tuy n gip bnh th ng; BC, VS, CRP cng hon ton bnh th ng. Ring k t qu siu m v n cn t d ch thy tri TG, Sau chng ti cho chuy n i u tr ngo i tr v theo di, v k t qu siu m c i thi n d n. Sau y chng ti trnh by m t bi u cho th y s thay i TSH, T4 huy t 131 tng v I b nh nhn vim tuy n gip bn c p De Quervain
Tng T4 HTh TSH HTh TT I131
Bnh th ng
Gi m
Thng
Hnh 1: S
v s thay i TSH, T4, v I b nh nhn vim tuy n gip bn c p De Quervain (theo Jeffrey Medland, Andrews AFB, 6/2007)
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Nh v y di n ti n c a VTG bn c p De Quervain khng bao gi c p xe ha, pha u c nhi m c gip ko di trong 3 thng u v i TSH gi m, T4 tng, t p trung iode phng x gi m; theo sau l suy gip kho ng ch ng 3 thng, v r i th ng tr v bnh gip. Nh v y tr ng h p b nh nhn chng ti trnh by ngoi nh ng i m khc bi t v c n lm sng nu, cn c s khc bi t v di n ti n: tr v bnh gip r t nhanh sau cha y 2 tu n i u tr . TI LI U THAM KH O: 1. Alan Cowan, MD, Shawn Newlands, MD, PhD, May 2006, Morning Report 08/06/07, University of Texas Medical Branch, Dept of Otolaryngology, 2. Dipak Shah, Department of Pathology, UWI, Mona 3. Elizabeth N. Pearce, M.D., Alan P. Farwell, M.D., and Lewis E. Braverman, M.D, N Engl J Med 2003;348:2646-55 4. Kamal Al-Shoumer , DIC (UK), PhD (UK), MRCP (UK), FRCP (UK), ViceDean-Associate Professor, Faculty of Medicine - Kuwait University, Consultant & Head of Division of Endocrinology & Metabolic Medicine
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KHUY N CO M I 2009 C A H I SIU M TIM HOA K (A.S.E) V R I LO N CH C NNG TM TRNG TH T TRI V C Y TH T TRI L NG P L C LM
Tr ng I. Ch c nng tm trng th t tri R i lo n ch c nng tm trng c chia lm 3 : nh (gi m th gin), v a (gi bnh th ng) v n ng (h n ch ). Lu khi l ng gi ph i ch t i tu i v t n s tim (v n t c sng E, t E/A, v n t c e (m vng van hai l) s gi m khi t n s tim tng ln. c bi t ng i gi khng c b nh tim ph i cn nh c khi k t lu n gi m ch c nng tm trng I b i v th ng khi >60 tu i hay c t E/A<1 v Dt >200ms. Trong nh ng tr ng h p ny n u nh khng c ch i m b nh tim m ch (t c dy th t tri) ch nn coi l bnh th ng theo tu i. Trong th gi m nh ch c nng tm trng c t l E/A<0,8, DT>200ms v IVRT 100ms. Doppler dng ch y tnh m ch ph i c tr i sng S (t c S>D), e vng van hai l <8 v E/e<8 (vch v bn). Tuy nhin gi m t l E/A nhng c Doppler m bnh th ng c th g p ng i bnh th ng c gi m th tch mu v v y t l E/A<0,8 cng khng nn s d ng i tr k t lu n gi m ch c nng tm trng. Ni chung khi t l E/A<0,8 th p l c trung bnh nh khng tng ngo i tr khi gi m n ng kh nng th gin th t nh trong b nh c tim ph i ho c tng huy t p qu lu. Nguy n Anh V i h c Y D c Hu
Hnh 1: M i lin h gi a t l E/A, th i gian gin ng th tch (IVRT), th i gian gi m t c Dt v p l c nh tri. i v i b nh nhn c gi m ch c nng tm trng m c v a (gi bnh th ng) c t l E/A 0,8-1,5, thao tc Valsalva gi m v n t c >50%, t l E/e (trung bnh) 9-12 v e<8 cm/s. m t s thng s khc ph thm nh v n t c sng Ar >30cm/s (tnh m ch ph i), t l S/D<1. m t s b nh nhn r i lo n v a ch c nng tm trng ch c p l c cu i tm trng th t tri tng ln (c ngha l p l c trung bnh nh tri bnh th ng) v c Ar-A 30ms. R i lo n ch c nng tm trng II c suy gi m kh nng th gin th t v tng nh -v a p l c lm y th t tri. Trong lo i gi m ch c nng tm trng III c hi n t ng h n ch lm y th t v i t l E/A 2, Dt<160ms, IVRT<60ms, phn su t lm y tm thu <40% (tnh d a trn sng S v D dng ch y tnh m ch ph i: VTIS / (VTIS+ VTID)), th i gian sng A
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ng n hn Ar, t l E/e trung bnh >13 (ho c E/e vch 15 v E/ebn >12). C th chia lm hai phn nhm : h i ph c lm y th t tri sang th gi m th gin sau khi i u tr (IIIa) v h n ch khng h i ph c IIIb. Lo i IIIb ni ln nguy c cao m c b nh v t vong do tim. Tuy nhin khng nn ni IIIb ch d a trn m t thm khm m ph i d a vo nhi u thm khm sau khi s d ng cc bi n php i u tr thch h p. Th tch nh tri tng ln v i II v III nhng bnh th ng trong I.
r i lo n ch c nng tm trng theo khuy n co m i c a A.S.E 2009 Hnh 2: Phn Ghi ch: t l E/e l t l trung bnh c a e vch v e bn. Th tch nh tri: o m t c t 4 bu ng ho c 2 bu ng m m cu i tm thu. Cc nghin c u cho th y nh tri 34ml/m2 l y u t nguy c c l p ni ln t l t vong, suy tim, rung nh v t qu do thi u mu c c b . Tuy nhin nh tri c th l n ng i b nh c nh p ch m xoang, l n 4 bu ng tim, thi u mu, suy tim cung l ng cao, b nh van hai l, rung nh, cu ng ng nh m ch c nng tm trng bnh th ng. m t khc nh c th l n tim v n ng vin khng c b nh tim m ch. Chnh v v y ph i k t h p v i tnh tr ng lm sng, th tch cc bu ng tim khc cng nh cc thng s Doppler nh n nh.
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o th tch nh tri cu i tm thu (l n nh t) trn m t c t 4 bu ng m m (ho c 2 bu ng) II. P L C LM Y TH T TRI: v k thu t v ngha c a cc k thu t M ts v n Thao tc Valsalva: - Th c hi n b ng cch b o ng i b nh th ra g ng s c t i a khi b t mi ng v mi. Ng i lm siu m ph i c gi c ng l y m u Doppler n m gi a nh l van hai l. - B nh nhn b nh tim c gi m 50% t l E/A l ch d n r t c hi u ni ln tng p l c lm y th t tri. Tuy nhin v i bin th p hn khng ph i lun ch d n ch c nng tm trng bnh th ng. Dng ch y tnh m ch ph i: - C ng l y m u 2-3mm t >0,5cm trong tnh m ch ph i t i m t c t 4 bu ng thu c ph Doppler t t. - L y cc thng s v n t c sng S v D, t l S/D, phn su t lm y tm thu, v n t c v th i gian sng Ar, hi u Ar-A. - Khi tng p l c cu i tm trng th t tri c tng bin v th i gian sng Ar cng nh hi u th i gian cc sng Ar v A hai l (Ar-A). - B nh nhn gi m EF v phn su t lm y tm thu gi m <40% c gi m s c ch a (compliance) nh tri v tng p l c trung bnh nh tri. Khi c rung nh, b nh van hai l, b nh c tim ph i, EF>50% th m i lin h trn gi m chnh xc. V n t c lan truy n dng ch y M-mode mu: - Dng m t c t 4 bu ng dng ch y mu. - Thanh c t M-mode t trung tm dng ch y xui dng t van hai l t i v n t c cao nh t m m. g t thanh qut mu (baseline) sao cho gi m ng ng Nyquist trung tm c mu xanh. - Vp l d c o t van hai l t i 4cm trong th t tri ho c l d c d ch chuy n t khng mu sang c mu. - Vp > 50cm/s coi nh l bnh th ng. - ng i c EF gi m, gi m Vp v i E/Vp 2,5 ni ln p l c mao m ch ph i (p l c bt) > 15mmHg v i chnh xc ch p nh n c. - ng i c EF v th tch th t tri bnh th ng nhng c p l c lm y th t tng c th c thng s Vp bnh th ng lm nh m l n. Doppler m: - Doppler m xung l y m m m t c t 4 bu ng o v n t c vng van hai l. - L y v n t c c vng van vch v bn cng nh trung bnh c a hai thng s ny. - o cu i k th ra v trung bnh c a 3 chu chuy n tim k ti p. v n t c qut 50-100cm/s. - Ng i c b nh tim th e dng ch nh l i k t qu o E dng ch y qua van hai l v E/e dng nh gi p l c lm y th t tri.
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- T l E/e khng chnh xc d bo p l c lm y mu ng i bnh th ng ho c b nh nhn c vi ha n ng vng van hai l, b nh van hai l, vim mng ngoi tim co th t.
ng i b nh c gi m th gin th t v i Ve<50cm/s c p l c lm y th t bnh th ng. N u nh t E/A n m trong kho ng 1-2 th c n c cc d ki n sau ni c tng p l c lm y th t tri: thao tc Valsalva thay i 0,5, S/D dng ch y tnh m ch ph i <1, Ar-A 30ms, E/Vp 2,5, E/e (s d ng trung bnh e) 15, IVRT/TE-e<2, p l c tm thu ng m ch ph i 35mmHg (n u khng c b nh ph i). Ng c l i n u nh thao tc Valsalva thay i < 0,5, S/D dng ch y tnh m ch ph i >1, Ar-A<0ms, E/Vp<1,4, E/e (s d ng trung bnh e) <8, IVRT/TE-e>2, p l c tm thu ng m ch ph i <30mmHg th c p l c lm y bnh th ng.
ng i b nh c EF bnh th ng nh gi p l c lm y kh hn. Nn s d ng t l E/e. T l trung bnh 8 ni ln p l c lm y th t tri bnh th ng trong khi n u t l ny 13 ni ln tng p l c lm y th t tri. N u t l ny n m gi a 9-13 th c n thm nh ng thng s khc nh gi. Tng p l c lm y khi: Ar-A 30ms, thay i
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t l E/A v i Valsalva 0,5, IVRT/TE-e<2, p l c tm thu ng m ch ph i 35mmHg (n u khng c b nh ph i), th tch nh tri c c i 34ml/m2. chnh xc tng khi c 2 tr s o b t th ng. Tr ng I. Nguy n Anh V i h c Y D c Hu
KHUY N CO 2008 SUY TIM C P H I TIM M CH CHU U
NH NGHA L b nh c nh kh i pht ho c bi n i nhanh chng cc tri u ch ng v d u ch ng gy ra do suy ch c nng tim c n thi t ph i i u tr c p c u k p th i. y l tnh hu ng n ng n c th gy t vong v th c n c p c u. Ng i b nh c th c ho c khng c b nh tim tr c . R i lo n ch c nng tim c th do r i lo n ch c nng tm thu ho c tm trng, b t th ng nh p tim ho c tng ti n gnh ho c h u gnh.
Phn lo i lm sng c a suy tim c p II. LM SNG BN l l n, chi l nh, ti u t c cung l ng tim th p, p l c lm y mu cao, tng s c c n m ch h th ng. Hay km chong tim. Nghe ph i + xem tnh tr ng ph ng tnh m ch c nh gi nhanh th tch mu v p l c lm y mu, phn bi t suy th t tri v ph i. Quan tr ng v i u tr khc nhau (truy n d ch ho c l i ti u) Khm m m tim, nghe ti ng tim b nh l (ng a phi, h van, T2 ) III. C N LM SNG 3.1. ECG Ch n on r i lo n nh p tim H i ch ng m ch vnh c p Tr ng thi t i c a tim 3.2. X quang v KT hnh nh khc
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Ch p phim x quang: nh gi kch th c tim, tnh tr ng mu ph i. Theo di k t qu i u tr . Phn bi t suy tim v vim ph i CT v x hnh ph i: t c MP CT, TEE v MRI : phnh tch ng m ch ch . Siu m tim: l thm d nh t thi t ph i c nh gi c u trc ch c nng th t cng nh h/c m ch vnh c p. Thng s : hnh thi tim, ch c nng th t v van tim, d ch mng ngoi tim, p l c ng m ch ph i, bi n ch ng c h c NMCT, cung l ng tim. IV. CH N ON 4.1. Cc b c ch n on
4.2. Phn lo i lm sng (D a vo tu n hon ngo i vi t c s t i mu v nghe ph i)
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Lo i I: kh v m Lo i II : m v m Lo i III: kh v l nh Lo i IV: m v l nh V. I U TR 1. M c tiu i u tr : 1. T c th: - C i thi n tri u ch ng - Ph c h i oxy - C i thi n huy t ng v t i mu cc c quan - H n ch cc t n thng c a th n v tim - Gi m th i gian i u tr t i n v i u tr tng c ng. 2. Trung h n (t i b nh vi n): - n nh b nh nhn v h p l ha chi n l c i u tr - Kh i ng i u tr thu c thch h p - Cn nh c s d ng cc thi t b i u tr nh ng b nh nhn c ch nh thch h p - Gi m th i gian n m vi n 3. i u tr tr c khi xu t vi n v di h n - nh k ho ch chi n l c theo di - Gio d c v kh i ng i u ch nh l i s ng - Phng ti nh p vi n s m - t t t ch phng b nh th pht - C i thi n ch t l ng cu c s ng v s ng cn. 2. i u tr c th : 2.1. Oxy v thng kh h tr : yu c u bo ha oxy trong kho ng 95-98% c th chu c p oxy y cho t ch c. - Thng kh h tr khng t ng n i kh qu n: c 2 phng cch l p l c dng lin t c ng th (CPAP-continuous positive airway pressure) v thng kh p l c dng khng xm nh p (NIPPV-noninvasive positive pressure ventilation) gp ph n lm gi m nhu c u t ng n i kh qu n. t ng n i kh qu n: ch nn th c hi n n u nh suy h h p c p khng p ng v i thu c gin m ch, li u php oxy v/ho c CPAP ho c NIPPV. 2.2. L i ti u quai: tng th i mu i natri, n c v cc ion khc lm gi m th tch huy t tng v d ch ngo i bo, gi m p l c lm y mu th t tri v th t ph i v v y b t xung
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huy t ngo i vi cng nh b t ph ph i. Tim tnh m ch l i ti u cng gy gin m ch nhng v i li u cao (>1mg/kg) l i gy co m ch ph n x . Furosemide 20-40mg t i 40100mg tim bolus v truy n 5-40mg/h. Thu c c a chu ng tim tnh m ch. C th ph i h p Dobutamine, Dopamine v/ho c Nitrates. 2.3. c ch beta: suy tim c p xem nh ch ng ch nh. Ch ng c nghin c u no cho th y c i thi n suy tim c p v i c ch beta. Trong nh i mu c tim c p, c ch beta tc d ng lm gi m kch th c nh i mu, lo n nh p tim v au ng c. Gi m t l m c b nh v t vong b nh nhn c xung huy t ph i. Cch s d ng: n u c suy tim m n cho sau khi n nh suy tim c p(>4 ngy). Th n tr ng trn b nh nhn suy tim c p r v nhi u ran y ph i. Cn nh c Metoprolol n u thi u mu c c b ti n tri n, nh p tim nhanh. B nh nhn nh i mu c tim c p suy tim c p n nh c th kh i ng c ch beta s m. 2.4. Cc thu c tng co bp c tim: c ch nh trong tr ng h p gi m t i mu ngo i vi (h huy t p, ch c nng th n gi m). Tuy cc thu c ny c th r t ch l i c i thi n huy t ng nhng l i d sinh lo n nh p, c th gy thi u mu c c b c tim, m t khc khi s d ng lu di c th c r i lo n ch c nng c tim do tng qu m c tiu t n nng l ng. T l nguy c-c l i khc nhau ty theo thu c, nh ng thu c tc d ng qua canxi trong tng bo c nguy c cao c ch kch thch 1 giao c m lm tng n ng nh t. - Dopamine: l m t cathecholamin n i sinh, ti n ch t c a Norepinephrine. N tc ng ln c m th quan cc h dopaminergic, adrenergic, adrenergic. V i li u th p < 2 g /kg/pht tc d ng trn c m th quan dopaminergic gy gin m ch tr i m ch th n, m ch vnh, m ch no, m ch lch. li u ny thu c lm tng dng mu th n, tng l c c u th n, l i ti u th i mu i natri, tng p ng v i thu c l i ti u b nh nhn c gi m t i mu th n, suy th n. Li u >2 g /kg/pht gy tng co bp c th t v cung l ng tim do kch thch h giao c m tr c ti p v gin ti p. Li u >5 g /kg/pht tc ng ln c h gy co m ch lm tng s c c n ngo i vi v v th c ch n u huy t p t t. ng d ng th c ti n: Dopamine dng li u >2 g /kg/pht n u suy tim c p c h huy t p, li u < 2-3 g /kg/pht n u suy tim m t b c huy t p th p v thi u ni u. - Dobutamine: l thu c co c kch thch c m th quan 1 v 2 v i t l 3:1. tng cung l ng tim. Kh i u 2-3 g /kg/pht khng c li u n p. Hay c dng Tng t i 20 g/kg/pht. ng i b nh ang dng c ch c th c n li u cao hn (1520g/kg/pht). C th dng ph i h p v i PDEi. Thu c th i nhanh chng sau khi ngng truy n. Lu l truy n ko di (>24-48h) s d n t i dung n p thu c v m t m t ph n hi u qu ln huy t ng. - PDEi ( c ch phosphodiesterase): thu c ny c c ch tc d ng thng qua c ch chuy n AMP vng thnh AMP. Khi s d ng thu c lm tng co c, gin m ch ngo i vi, tng cung l ng tim, th tch t ng mu, gi m ng th i p l c ng m ch ph i, mao m ch ph i, s c c n m ch ph i v h th ng. Ph tc d ng c a n trung gian gi a thu c gin m ch nh Nitroprusside v thu c co c nh Dobutamine. Ch nh: khi gi m t i mu ngo i vi v i c ho c khng c tr tr v i i u tr l i ti u, gin m ch li u thch h p v huy t p b o t n. Thu c ny a s d ng hn Dobutamine trong tr ng h p i u tr c ch ng th i v/ho c p ng khng y v i Dobutamine. Tim li u n p 25-75g/kg trong 10-20 pht, Enoximone 0,25-0,75mg/kg sau truy n (Milrinone 0,375-0,75 g/kg/pht, Enoximone 1,25-7,5g/kg/pht).
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- Levosimendan: tc d ng tng co c (lm protein co bp tng nh y c m v i canxi) v gin m ch ngo i vi (m knh Kali). Thu c ch nh trong suy tim cung l ng th p c tri u ch ng th pht sau gi m ch c nng tm thu nhng khng c t t p huy t n ng (khng cho khi huy t p tm thu <85mmHg). Li u truy n lin t c 0,05-0,1g /kg/pht, tr c c li u n p 12-24g/kg trong 10 pht. 2.5. Ch ng ng: ch nh trong h i ch ng m ch vnh c p ho c rung nh v i c ho c khng c suy tim c p. Ni chung t c b ng ch ng bi n minh cho s d ng thu c ny trong suy tim c p v i b nh c nh khc. 2.6. Thu c gin m ch: - Nitrate c tc d ng lm nh b t xung huy t ph i nhng khng lm gi m th tch t ng mu v cng khng lm tng nhu c u oxy c tim trong suy tim tri c p, c bi t l ng i b nh c h i ch ng vnh c p. li u th p n ch gy gin tnh m ch. Tuy nhin v i li u tng ln th n gin c ng m ch bao g m m ch vnh. V i li u thch h p thu c tc ng cn b ng gin c ng m ch tnh m ch lm gi m ti n gnh l n h u gnh c a th t tri m khng lm gi m t i mu m. N u nh huy t p n nh th c th cho Glyceril trinitrat (20-200g/pht) ho c IDN 1-10mg/h. - Nitroprusside li u 0,3-5g/kg/pht. Ch nh: suy tim n ng c tng h u gnh (tng huy t p, h van hai l). Khi dng ph i i u ch nh li u c n th n c theo di huy t p lin t c cng nh gim st ch t ch b nh nhn. Trnh dng b nh nhn c suy gan th n n ng. Trong h i ch ng m ch vnh c p, Nitrates t t hn do khng gy h i ch ng tr m mu m ch vnh nh Nitroprusside. - Nesiritide: l thu c gin m ch m i, t h p peptide no ng i (BNP) c tc d ng gin tnh m ch, ng m ch, m ch vnh qua lm gi m ti n gnh v h u gnh, tng cung l ng tim. Ch nh trong suy tim m t b c p (li u tim n p 2g/kg + truy n 0,015-0,03 g/kg/pht. ang cn t kinh nghi m s d ng lm sng thu c ny. - Morphine: ch nh trong giai o n s m c a suy tim n ng nh t l n u c km tri u ch ng b t an v kh th . Thu c c tc d ng gin tnh m ch cng nh gin nh ng m ch, gi m t n s tim. Li u dng 3 mg tim tnh m ch c th nh c l i n u c n. 2.7. Thu c v n m ch: khi ph i h p thu c tng co c tim v d ch truy n m v n khng c i thi n cung l ng tim, khu ch tn cc c quan th c n s d ng thu c v n m ch. Ngoi ra trong m t s tnh hu ng s ng cn th thu c v n m ch duy tr t i mu do ch ng l i hi n t ng h p. V l chong tim th ng ph i h p v i tnh tr ng s c c n m ch mu cao cho nn thu c v n m ch ph i s d ng th n tr ng v ch nh t th i do n lm tng h u gnh (lm n ng thm tim suy) v lm gi m l ng mu t i cc c quan. - Epinephrine: c i l c cao v i c m th quan 1, 2 v . Li u dng 0,050,5g/kg/pht khi c hi n t ng tr v i Dobutamine huy t p th p. - Norepinephrine: c p l c cao v i c m th quan v c dng tng s c c n m ch mu h th ng. T n s tim t tng v i Norepinephrine hn l Epinephrine, li u s d ng tng t . Ch n l a hai thu c ny ty thu c tnh hu ng lm sng. Norepinephrine (0,2-1g/kg/pht) a dng trong tr ng h p huy t p th p c s c c n m ch h th ng gi m nh chong nhi m trng. Norepinephrine hay ph i h p v i dobutamine c i thi n huy t ng.
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Khuy n co 2008 c a H i tim chu u i u tr suy tim c p d a vo huy t p tm thu 2.8. Digitalis: c l trong suy tim c p ch nh thu c ny khi nh p nhanh gy suy tim (rung nh ki m sot t n s th t khng b ng thu c khc ch ng h n c ch beta). 2 v 3, h i ch ng nt xoang b nh l, Ch ng ch nh: nh p tim ch m, bl c nh th t h i ch ng WPW, h kali, tng canxi mu, h i ch ng xoang c nh, b nh c tim ph i. Ni chung digitalis khng khuyn trong suy tim c p, nh t l trong nh i mu c tim.
Khuy n co 2008 c a H i tim chu u i u tr suy tim c p d a vo p l c lm y th t tri 2.9. Thu c c ch men chuy n: khng c ch nh nh m n nh s m tnh tr ng b nh trong suy tim c p. Tuy v y nh ng b nh nhn c nguy c cao, thu c c vai tr trong
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i u tr s m b nh nhn suy tim c p v nh i mu c tim c p. Hi n nay v n cn tranh lu n v ch n l a b nh cng nh th i i m b t u cho thu c. Thu c cho ng u ng (khng cho tnh m ch) li u kh i u th p tng d n c theo di huy t p v ch c nng th n. C n th n s d ng thu c b nh nhn c cung l ng tim ng ng th p v c th lm gi m l c c u th n. 2.10. D ng c nng c h c v thay tim: s d ng d ng c tr gip tu n hon c n thi t trong tr ng h p suy tim c p khng p ng v i cc phng ti n kinh i n nhng c tim c kh nng ph c h i ho c l bi n php c u n i v i thay tim ho c can thi p c th lm ph c h i ch c nng tim. i u tr b nh nhn - Bng n i ng m ch ch : tr thnh phng ti n chu n chong tim ho c suy tim tri c p n ng khng p ng nhanh v i truy n d ch, thu c gin m ch, thu c tng co bp c tim. Ch ng ch nh: phnh tch ng m ch ch , h van ch quan tr ng. Cng khng nn dng b nh nhn c b nh m ch mu ngo i vi n ng, suy tim khng i u ch nh c nguyn nhn, suy a ph t ng. - D ng c h tr th t: l bm c h c thay th ho t ng th t. Ch nh ng b nh nhn c c may cao ph c h i ch c nng tim m i nn s d ng phng ti n ny: nh i mu c tim, s c sau ph u thu t tim, vim c tim c p, lo n ch c nng van tim, ng i ch thay tim. 2.11. Suy tim c p v cc b nh l n n: - H i ch ng m ch vnh c p: bi n ch ng suy tim c ch nh ch p m ch vnh ngay v n u ti thng m ch vnh s lm c i thi n r ho c phng ng a suy tim. N u nh can thi p m ch vnh khng th c hi n c ho c lm c nhng ch m tr th c ch nh thu c tiu s i huy t s m. - B nh van tim: h c p van hai l v van ch n ng nn ph u thu t nhanh chng. Tuy nhin n u c th i k h c p ko di v ch s tim <1,5l/pht/m2, phn su t t ng mu <35% th ph u thu t c p c u ch ng c i thi n tin l ng. Lc ny bng n i m ch ch c gi tr l n n nh b nh nhn. B nh nhn vim n i tm m c nhi m trng bi n ch ng h c p n ng van ch c ch nh m c p c u. - T c van nhn t o: i u tr cn cha th ng nh t. Thu c tiu s i huy t v i van tim bn ph i v b nh nhn nguy c cao, a chu ng ph u thu t v i t c van tim bn tri. Li u thu c: rTPA tim TM 10mg sau truy n 90 mg trong 10 pht. Streptokinase 250.000-500.000 UI trong 20 pht sau 1-1,5 tri u UI truy n 10 gi . Sau li u php tiu s i huy t s d ng Heparine khng phn o n cho m i b nh nhn (PTA 1,5-2 l n ch ng). C th dng Urokinase 4.400UI/kg/h trong 12h khng c Heparine ho c 2000UI/kg/h v i Heprine trong 24h. - Lo n nh p tim: nh p nhanh th t n u khng n nh th s c i n cn n u n nh th th dng Xylocaine, Amiodarone. Nh p nhanh k ch pht trn th t gy suy tim v t t huy t p cng c n s c i n c t cn nhanh. B nh nhn rung nh c suy tim c p c n cho thu c ch ng ng. N u rung nh k ch pht ph i chuy n nh p b ng thu c ho c s c i n. N u rung nh >48h c n cho thu c ch ng ng v ki m sot t n s th t thch h p trong 3 tu n tr c khi chuy n nh p. N u nh huy t ng khng n nh th c n chuy n nh p c p c u nhng tr c ph i lm siu m tim qua th c qu n lo i tr c c c mu ng (gy t c m ch sau khi chuy n v nh p xoang). Thu c Amiodarone v c ch c tc d ng ki m sot t n s th t t t trong rung nh. Cn nh c s d ng digitalis c bi t n u nh rung nh th pht sau suy tim.
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- Bi n ch ng c h c trong nh i mu c tim c p: + Rch thnh t do th t: th ng t vong tr c khi ch n on. C th lm huy t ng n nh nh t th i b ng ch c ht mu mng tim, truy n d ch, thu c tng co c tim sau nn ph u thu t ngay. + Thng lin th t: a s c n ph u thu t v thng do hi n t ng khuy t vch lan r ng gy chong tim. Cng c th v b ng d ng c qua thng tim. + H van hai l: do t m t ph n hay hon ton c nh, lo n ch c nng c nh. B nh nhn h c p n ng van hai l c ph ph i chong tim c n ph u thu t c p c u.
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SILDENAFIL TRONG I U TR SUY TIM

Hunh Vn Minh Thnh vin H i Tim m ch Hoa k (ACC) Thnh vin H i Tim m ch ng nam (ASCC) C ch tc d ng Sildenafil l ch t c ch ch n l c c a phosphodiesterase type 5 (PDE5), c tc d ng dn m ch qua vi c t o thnh nitric oxide nh ng b nh nhn c ho c khng c suy tim b ng s c ch thoi ging GMP vng, l cha kho thng tin th hai n i bo.[1] Vi c c ch cyclic AMP vng phosphodi esterase type 3 c hi u (PDE3, bao g m cc thu c tng co bp tim nh milrinone, vesnarinone, v enoximone) s tng m c n i bo AMP vng v gia tng t vong b nh nhn suy tim,[2] sildenafil c tc d ng ch n l c cao (>4000-l n) i v i PDE5 ng i, khng lm tng AMP vng, v khng c tc d ng co bp tim; do khng c xem phn chia c tnh k t h p v i s c ch PDE3.[3]
Phosphodiesterase Type-5 Inhibitors: Mechanism TypeProstacyclin Pathway
Arachidonic Acid
Endothelin Pathway
Big Endothelin Endothelinconverting Enzyme Endothelin-1
Nitric Oxide Pathway

Arginine
Prostacyclin Synthase
Nitric Oxide Synthase
Prostacyclin cAMP Prostacyclin Prostacyclin Derivatives Derivatives
Nitric Oxide cGMP Exogenous Nitric Oxide
Endothelin Receptor Antagonists Endothelin Receptor A Endothelin Receptor B
Phosphodiesterase Type-5 Type-
Phosphodiesterase Type-5 Inhibitors
Vasodilatation and Antiproliferation
Vasoconstriction and Proliferation
Vasodilatation and Antiproliferation
Humbert M et al. N Engl J Med. 2004;351:1425-1436.
Hnh 1: C ch tc d ng c a thu c c ch PDE5 Tc d ng ln m ch mu c a PDE5 r khi n c th a nh n nh l m c tiu i u tr ban u. c ch PDE5 t bo c trn c a tnh m ch th hang dng v t c xem nh l tc d ng chnh trong i u tr r i lo n dng cng [4] Tuy nhin, nhi u d li u cho th y PDE5 cng c m t trong t bo c tim v c th c tc d ng trong i u ho ho t tnh GMP vng trong b nh l tim m ch.[5] Th t v y i u ho ng c GMP vng c bo co trong m t s tnh hu ng tim m ch nh tng p ph i,[6] suy tim sung huy t,[7] v ph i th t ph i,[8] cho th y kh nng i u tr suy tim b ng sildenafil cng nh cc bi n ch ng. Sildenafil v suy tim M t s nghin c u c n lm sng v lm sng ng n h n ng h vai tr sildenafil trong i u tr suy tim. Tc d ng c a Sildenafil ln s c c n m ch ph i. S thch ng th t ph i (performance) l ch s quan tr ng trong tin l ng v kh nng g ng s c c a b nh nhn suy tim, t , gi m s c c n m ch ph i l m c tiu quan tr ng c a i u tr . b nh nhn tng p ph i, sildenafil c tc d ng dn m ch ch n l c trn m ch ph i tng
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t khi ht nitric oxide (NO).[9] Qua sildenafil cho th y c i thi n kh nng g ng s c, huy t ng khi ngh, v ch c nng b nh nhn c tng p ph i (TAP) v cn v TAP ph i h p b nh m lin k t ho c b nh tim b m sinh n i t t h th ng- ph i c s a ch a.[10] Cc d li u t nh ng nghin c u huy t ng nh , c p tnh g i trong suy tim m n (c ho c khng c ph i h p tng p ph i), sildenafil gi m s c c n ph i khi ngh v p l c ph i b , lm tng ch s tim m khng tng h huy t p ton th .[11-13] C i thi n c p th i ch s t ng mu th t ph i v hi u qu thng kh khi g ng s c s n i b t b nh nhn suy tim km v i p l c ph i trung bnh > 25 mm Hg.[14] M c d cc d li u lu di v s d ng sildenafil trong suy tim cn gi i h n, cc hi u qu trn p l c ph i v hi u qu k kh cho th y duy tr n 6 thng.[15]
Hnh 2: Tc d ng gi m p l c m ch ph i v i PDE5 Tc d ng Sildenafil ln p ng tim i v i Stress. Cc d li u cho th y c ch PDE5 c th c vai tr quan tr ng trong vi c ch ng ph i, ch ng ch t t bo chng trnh, v tc d ng ti n thch nghi do thi u mu c th lm gi i h n ti c u trc c tim p ng v i stress v gi m i s pht tri n ti n ch t suy tim. Trong m hnh trn chu t c a tng gnh p l c c tim gy ra do ch n ng m ch ch , c ch PDE-5 ph i h p s gi m ph i c tim v tim, gi m x ho m k , duy tr ch c nng tim, v b t ho t s ph i khc nhau bi u th s thoi ging.[16] S c ch PDE5cng gy ra s m knh KATP ty l p th (mitochondrial),[17] ch c cho l c a c ch t oxygen ph n ng gy nn s c thi u mu/ t i mu v i u tr b ng doxorubicin, v gi m doxorubicin ho c ch t chng trnh gy ra do thi u mu/ti t i mu .[18,19] Theo , cho sildenafil c c tc d ng gi i h n kch th c nh i mu c tim gy ra trong khi thi u mu/t i mu, v gi m s pht tri n r i lo n ch c nng th t tri trong m hnh trn chu t c a nhi m c tim do doxorubicin .[5,19-21] Tc d ng Sildenafil ln p ng tim i v i ho t tnh th n kinh n i ti t. S c c n i v i ho t tnh c a peptides l i ti u l m u ch t c a tnh tr ng b nh l c a mu i nh trong x gan, suy tim, v h i ch ng th n h. S ging ho c a GMP vng do PDE5 p ng v i kch thch angiotensin II c th l c ch quan tr ng c a s gi m p ng peptide l i ti u .[7] T l lu hnh peptide l i ti u huy t tng type B i v i GMP vng, m t ch t nh d u s gi m nh y c m peptide l i ti u, gia tng ng k trong suy tim, nhng duy tr m c bnh th ng sau khi c ch PDE5. Theo , trong
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m hnh trn ch b suy tim, ti p xc v i thu c c ch PDE5 lu di cho th y c i thi n s p ng th n c p v i peptides l i ti u. M c d nh ng nh n xt cn i k t qu trn ng i nhng g i s c ch PDE5 v i sildenafil c th b t ch c ho c gy nn tc d ng peptide l i ti u trong suy tim.
Sildenafil: Change from Baseline in 6MW Test

80 60 40 Mean change from baseline 20 (m) 0 Week 4 -20 -40 Placebo (n=65) Sildenafil 20 mg tid (n=65) Sildenafil 40 mg tid (n=63) Sildenafil 80 mg tid (n=65) Week 8 Week 12 *P<0.001 * * *
45 m
46 m
Gali N et al for the Sildenafil Use in Pulmonary Arterial Hypertension (SUPER) Study Group. N Engl J Med. 2005;353:21482157.
Hnh 3: Tc d ng c i thi n kh nng g ng s c qua TN i b 6 pht theo li u PDE5 c th gi vai tr trong bi n i p ng kch thch giao c m . c ch PDE5 c p tnh c th k t h p s suy y u p ng co bp tim v lusitropic i v i nh ng kch thch beta-adrenergic c p tnh b ng dobutamine ng i v trn ch.[5] M c d c bo co ny nhng sildenafil khng lm bi n i co bp tim khi ngh ho c khi th gin b nh nhn suy tim v c i thi n kh nng tim khi g ng s c b nh nhn r i lo n ch c nng tm thu. [15] Cc bo co ny l b ng ch ng ch ng l i b t k tc d ng lm sng n i b t no trn d tr co bp tim. Tc d ng Sildenafil trn ch c nng m ch mu. B t th ng ch c nng n i m c l m t bi u hi n suy tim v c th ng gp vo vi c co m ch ton th , gi m d tr gi m m ch, v t i mu c xng b t th ng do kh nng lm bi n i s m thnh chuy n ho k kh v lm tng p ng thng kh v i g ng s c. Gia tng thng kh v kh th b nh nhn th ng km tin l ng x u trong suy tim c l p ch s t ng mu . c ch PDE5 ph i h p s c i thi n ch c nng n i m c b nh nhn suy tim do r i lo n tm thu th ng lin h ch c ch v i s c i thi n s t i mu c xng, gi m tng thng kh khi g ng s c (VE/VCO2), v lm gia tng hi u qu hi u kh. Vi c gi m ph i h p c ng ng m ch l n c quan st khi i u tr b ng sildenafil gp ph n c i thi n v sau ch c nng th th v s t o ra s h i ph c nh p tim b nh nhn suy tim. S c i thi n ch c nng m ch mu v s co m ch ph i c th gp ph n vo kh nng g ng s c v ch t l ng cu c s ng khi cho lu di thu c sildenafil trong i u tr suy tim. K t lu n Nhi u b ng ch ng ng h vai tr i u tr c ch PDE5 b ng sildenafil trong suy tim. Tuy nhin, nh ng th nghi m trn ng i v n cn h n ch v cc nghin c u sinh l b nh nhn suy tim v gi m ch s t ng mu (th ng km tng p ph i) i km th i gian tng i ng n. Do nhi u nghin c u c ch c a thu c c ch PDE5 lin quan
50 m
165
n ph i th t tri, s c ng m ch mu-tm th t, suy th n, v tng p ph i c th c bi t n i b t b nh nhn suy tim c ch s t ng mu duy tr, c s h p l khi m r ng tc d ng c l i trong i u tr suy tim tm thu sang nhm suy tim tm trng. Nghin c u RELAX ang ti n hnh nh m tr l i cu h i trn b ng ch n ng u nhin 190 b nh nhn c ch n on suy tim v ch s t ng mu th t tri 50% i u tr b ng sildenafil ho c placebo trong 24 tu n, v i m c tiu l kh nng g ng s c. Tuy v y hi n nay vi c s d ng lu di nh m nh gi an ton, s ch u ng, hi u qu l r t c n thi t. TI LI U THAM KH O 1. Semigran MJ. Type 5 phosphodiesterase inhibition: the focus shifts to the heart. Circulation. 2005;112(17):2589-2591. 2. Nony P, Boissel JP, Lievre M, Leizorovicz A, Haugh MC, Fareh S, de Breyne B. Evaluation of the effect of phosphodiesterase inhibitors on mortality in chronic heart failure patients. A meta-analysis. European journal of clinical pharmacology. 1994;46(3):191-196. 3. Cheitlin MD, Hutter AM, Jr., Brindis RG, Ganz P, Kaul S, Russell RO, Jr., Zusman RM. ACC/AHA expert consensus document. Use of sildenafil (Viagra) in patients with cardiovascular disease. American College of Cardiology/American Heart Association. Journal of the American College of Cardiology. 1999;33(1):273-282. 4. Goldstein I, Lue TF, Padma-Nathan H, Rosen RC, Steers WD, Wicker PA. Oral sildenafil in the treatment of erectile dysfunction. Sildenafil Study Group. The New England journal of medicine. 1998;338(20):1397-1404. 5. Senzaki H, Smith CJ, Juang GJ, Isoda T, Mayer SP, Ohler A, Paolocci N, Tomaselli GF, Hare JM, Kass DA. Cardiac phosphodiesterase 5 (cGMP-specific) modulates beta-adrenergic signaling in vivo and is down-regulated in heart failure. Faseb J. 2001;15(10):1718-1726. 6. Corbin JD, Beasley A, Blount MA, Francis SH. High lung PDE5: a strong basis for treating pulmonary hypertension with PDE5 inhibitors. Biochemical and biophysical research communications. 2005;334(3):930-938. 7. Kim D, Aizawa T, Wei H, Pi X, Rybalkin SD, Berk BC, Yan C. Angiotensin II increases phosphodiesterase 5A expression in vascular smooth muscle cells: a mechanism by which angiotensin II antagonizes cGMP signaling. Journal of molecular and cellular cardiology. 2005;38(1):175-184. 8. Nagendran J, Archer SL, Soliman D, Gurtu V, Moudgil R, Haromy A, St Aubin C, Webster L, Rebeyka IM, Ross DB, Light PE, Dyck JR, Michelakis ED. Phosphodiesterase type 5 is highly expressed in the hypertrophied human right ventricle, and acute inhibition of phosphodiesterase type 5 improves contractility. Circulation. 2007;116(3):238-248. 9. Lepore JJ, Maroo A, Pereira NL, Ginns LC, Dec GW, Zapol WM, Bloch KD, Semigran MJ. Effect of sildenafil on the acute pulmonary vasodilator response to inhaled nitric oxide in adults with primary pulmonary hypertension. The American journal of cardiology. 2002;90(6):677-680. 10. Galie N, Ghofrani HA, Torbicki A, Barst RJ, Rubin LJ, Badesch D, Fleming T, Parpia T, Burgess G, Branzi A, Grimminger F, Kurzyna M, Simonneau G. Sildenafil citrate therapy for pulmonary arterial hypertension. The New England journal of medicine. 2005;353(20):2148-2157.
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11. Lepore JJ, Maroo A, Bigatello LM, Dec GW, Zapol WM, Bloch KD, Semigran MJ. Hemodynamic effects of sildenafil in patients with congestive heart failure and pulmonary hypertension: combined administration with inhaled nitric oxide. Chest. 2005;127(5):1647-1653. 12. Guazzi M, Tumminello G, Di Marco F, Fiorentini C, Guazzi MD. The effects of phosphodiesterase-5 inhibition with sildenafil on pulmonary hemodynamics and diffusion capacity, exercise ventilatory efficiency, and oxygen uptake kinetics in chronic heart failure. Journal of the American College of Cardiology. 2004;44(12):2339-2348. 13. Guazzi M, Tumminello G, Di Marco F, Guazzi MD. Influences of sildenafil on lung function and hemodynamics in patients with chronic heart failure. Clinical pharmacology and therapeutics. 2004;76(4):371-378. 14. Lewis GD, Lachmann J, Camuso J, Lepore JJ, Shin J, Martinovic ME, Systrom DM, Bloch KD, Semigran MJ. Sildenafil improves exercise hemodynamics and oxygen uptake in patients with systolic heart failure. Circulation. 2007;115(1):5966. 15. Guazzi M, Samaja M, Arena R, Vicenzi M, Guazzi MD. Long-term use of sildenafil in the therapeutic management of heart failure. Journal of the American College of Cardiology. 2007;50(22):2136-2144. 16. Takimoto E, Champion HC, Li M, Belardi D, Ren S, Rodriguez ER, Bedja D, Gabrielson KL, Wang Y, Kass DA. Chronic inhibition of cyclic GMP phosphodiesterase 5A prevents and reverses cardiac hypertrophy. Nature medicine. 2005;11(2):214-222. 17. Ockaili R, Salloum F, Hawkins J, Kukreja RC. Sildenafil (Viagra) induces powerful cardioprotective effect via opening of mitochondrial K(ATP) channels in rabbits. American journal of physiology. 2002;283(3):H1263-1269. 18. Das A, Xi L, Kukreja RC. Phosphodiesterase-5 inhibitor sildenafil preconditions adult cardiac myocytes against necrosis and apoptosis. Essential role of nitric oxide signaling. The Journal of biological chemistry. 2005;280(13):1294412955. 19. Fisher PW, Salloum F, Das A, Hyder H, Kukreja RC. Phosphodiesterase-5 inhibition with sildenafil attenuates cardiomyocyte apoptosis and left ventricular dysfunction in a chronic model of doxorubicin cardiotoxicity. Circulation. 2005;111(13):1601-1610. 20. Salloum FN, Takenoshita Y, Ockaili RA, Daoud VP, Chou E, Yoshida K, Kukreja RC. Sildenafil and vardenafil but not nitroglycerin limit myocardial infarction through opening of mitochondrial K(ATP) channels when administered at reperfusion following ischemia in rabbits. Journal of molecular and cellular cardiology. 2007;42(2):453-458.
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VAI TR C A ROSUVASTATIN TRONG I U TR X V A NG M CH

Tr ng Tr n H u Dng i h c Y D c Hu
Summary The HMG-CoA reductase inhibitor (statin) rosuvastatin is widely available for use in the management of dyslipidemia, and was recently approved in the US to slow the progression of atherosclerosis as part of a strategy to lower low-density lipoproteincholesterol (LDL-C) and total cholesterol (TC) to target levels. Rosuvastatin has greater lipid-lowering efficacy than any of the other currently available statins, and significantly more patients receiving rosuvastatin than other statins achieve LDL-C goals. Rosuvastatin delayed theprogression of carotid atherosclerosis in patients with subclinical carotid atherosclerosis, moderately elevated cholesterol levels, and a low risk of cardiovascular disease in a primary prevention trial (METEOR). The results of METEOR suggest a possible role for the earlier use of rosuvastatin in primary prevention. Significant regression of atherosclerosis was seen with rosuvastatin 40 mg/day in patients with established coronary heart disease (CHD) in the ASTEROID trial, supporting the use of intensive lipid lowering in secondary prevention patients. Rosuvastatin is generally well tolerated, with a similar tolerability profile to that of other currently available statins. Thus, rosuvastatin is an important lipid-lowering treatment option that has been shown to cause regression of atherosclerosis in secondary prevention patients, and has a potential future role in delaying atherosclerosis in primary prevention patients. Tm t t Rosuvastatin thu c c ch men HMG-CoA reductase (statin), c dng ph bi n hi n nay i u tr r i lo n lipid mu, g n y thu c c cng nh n Hoa k cn c tc d ng lm ch m qu trnh x v a thng qua tc d ng gi m LDL-C v Cholesterol ton ph n. Rosuvastatin c tc d ng c i thi n r i lo n lipid mu t t hn m i lo i thu c statin khc, nhi u b nh nhn dng Rosuvastatin t c k t qu gi m LDL-C hn cc thu c khc. Rosuvastatin lm ch m di n bi n x v a ng m ch c nh nh ng b nh nhn b x v a c pht hi n qua c n lm sng, tng cholesterol v a, v nguy c b nh tim m ch th p trong th nghi m phng ng a ban u (METEOR). Nh ng k t qu c a METEOR cho th y Rosuvastatin c th dng s m trong d phng ban u. Tc d ng lm gi m mng x v a ghi nh n c v i li u rosuvastain 40mg/ngy trn nh ng b nh nhn b thng t n m ch vnh trong th nghi m ASTEROID, g i nn dng thu c gi m lipid m nh nh ng b nh nhn phng b nh b c 2. Rosuvastatin c dung n p t t tng ng so v i cc statin khc. Nh v y rosuvastatin l m t phng ti n i u tr gi m lipid quan tr ng lm thoi lui mng x v a nh ng b nh nhn phng b nh b c 2, v c tri n v ng lm ch m l i ti n trnh x v a nh ng b nh nhn d phng ban u.
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Thu c c ch men HMG-CoA reductase (statin), c dng ph bi n hi n nay i u tr tng LDL-C. i u tr tch c c tnh tr ng r i lo n lipid mu l yu c u c n thi t trn nh ng b nh nhn b b nh m ch vnh m m c ch quan tr ng l lm gi m LDL-C. Lin quan n phng ng a ban u, vi c dng thu c cn c trn n ng LDL-C v nguy c b nh m ch vnh. V i nh ng b nh nhn c nguy c b nh m ch vnh th p v LDL-C ch tng nh th cha c n dng thu c. Tuy nhin m t s b nh nhn c nguy c tim m ch th p ny th c t c x v a ng m ch qua thm d c n lm sng. Pht hi n v i u tr s m trn nh ng b nh nhn ny gip c i thi n tin l ng ng k cc bi n ch ng tim m ch. Rosuvastatin, m t lo i statin c dng ph bi n hi n nay i u tr r i lo n lipid mu, g n y thu c c cng nh n Hoa k cn c tc d ng lm ch m qu trnh x v a thng qua tc d ng gi m LDL-C v Cholesterol ton ph n. Rosuvastatin c tc d ng c i thi n r i lo n lipid mu t t hn m i lo i thu c Statin khc, nhi u b nh nhn dng Rosuvastatin t c k t qu gi m LDL-C hn cc thu c khc. Rosuvastatin lm ch m di n bi n x v a ng m ch c nh nh ng b nh nhn b x v a c pht hi n qua c n lm sng, tng cholesterol v a, v nguy c b nh tim m ch th p trong th nghi m phng ng a ban u (METEOR). Nh ng k t qu c a METEOR cho th y Rosuvastatin c th dng s m trong d phng ban u, tuy thu c c n d c ti p t c th nghi m c thm thng tin. Tc d ng lm gi m mng x v a ghi nh n c v i li u rosuvastain 40mg/ngy trn nh ng b nh nhn b thng t n m ch vnh trong th nghi m ASTEROID, g i nn dng thu c gi m lipid m nh nh ng b nh nhn phng b nh b c 2. Rosuvastatin c dung n p t t tng ng so v i cc statin khc. Nh v y rosuvastatin l m t phng ti n i u tr gi m lipid quan tr ng lm thoi lui mng x v a nh ng b nh nhn phng b nh b c 2, v c tri n v ng lm ch m l i ti n trnh x v a nh ng b nh nhn d phng ban u. Rosuvastatin tng i ho n c v c tnh ch n l c cao trn t bo gan. S thu n p rosuvastatin qua trung gian ch t v n chuy n anion c h c c th gan OATP-C, in vitro, i l c c a rosuvastatin v i OATP-C m nh hn pravastatin ho c simvastatin. nhi u th nghi m l n, rosuvastatin c tc d ng lm gi m LDL-C m nh hn nhi u so v i simvastatin, pravastatin, ho c atorvastatin nh ng b nh nhn tng cholesterol mu, k c nh ng b nh nhn c nguy c cao b nh l m ch vnh nh H i ch ng chuy n ha, ho c r i lo n lipid b nh nhn i tho ng, b nh nhn ng i M g c Phi, ng i M g c Ty ban nha c nguy c b nh l m ch vnh cao ho c trung bnh, v b nh nhn Nam c nguy c b nh m ch vnh cao. Rosuvastatin lm gi m cholesterol ton ph n nhi u hn so v i tc d ng c a simvastatin, pravastatin, ho c atorvastatin, cng nh lm c i thi n HDL-C t t hn so v i simvastatin, pravastatin, ho c atorvastatin m t cch c ngha h u h t cc nghin c u, m t s nghin c u cn cho th y hi u qu hn c a rosuvastatin trn tc d ng i v i triglyceride. Cn c trn chu n i u tr c a NCEP ATP III (National Cholesterol Education Program Adult Treatment Panel III), chu n c a Chu u nm 2003, ho c chu n v LDL-C c a Chu u nm 1998 Rosuvastatin t ra hi u qu hn trn s ng b nh nhn v i li u 10mg/ngy so v i atorvastatin 10 mg/ngy, simvastatin 20 mg/day, ho c pravastatin 40 mg/ngy. Hn n a nh ng nghin c u thay i i u tr cho th y chu n LDL-C c a Chu u 1998 ho c ATP
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III ni chung t c d dng khi chuy n i u tr v i rosuvastatin 10 ho c 20mg/ngy so v i duy tr atorvastatin, simvastatin, ho c pravastatin. Ngoi tc d ng lm gi m lipid mu, rosuvastatin cn c nh ng tc d ng khc h u ch hn nh tc d ng khng vim trn nh ng b nh nhn c r i lo n lipid mu ho c b nh l m ch vnh, thu c lm gi m r Hs-C-reactive protein, fibrinogen, cc cytokine ti n vim nh TNF-, interleukin-6, v interferon-. Rosuvastatin cng c ch ng minh c tc d ng ch ng oxy ha v m t s tc d ng c l i ln ch c nng n i m c m ch mu v ti u c u
Changes in lipids and Hs-CRP

120 LDL-C (mg/dL) 100 80 60 40 20 0 0 1 2 3 Year 4 5 p<0.0001 TG (mg/dL) LDL-C: 43% reduction 200 160 120 80 40 0 0 1 2 3 Year 4 5 p<0.0001 Rosuvastatin Placebo TG: 16.2% reduction
60 HDL-C (mg/dL) 50 40 30 20 10 0 0
HDL-C: 2.9% increase Hs-CRP (mg/L)
7 6 5 4 3 2 1
Hs-CRP: 11.5% decrease P<0.0001 Rosuvastatin Placebo
p=0.045
0 Baseline 3 months 1 year 3 4 5 Year Values are means (95% CI) for LDL-C, TG and HDL-C and medians (95% CI) for Hs-CRP; % change from baseline at 3 months is quoted and p values are for change at 3 months versus placebo 1 2
Hi u qu i u tr K t qu t ba nghin c u (METEOR, ORION, v ASTEROID), nh gi hi u qu c a rosuvastatin trn x v a. METEOR l m t th nghi m phng b nh ban u, c ti n hnh qua 2 nm, a trung tm, c so snh v i gi d c, m i, ng u nhin. Ch n ng u nhin 984 b nh nhn l a tu i trung nin b x v a ng m ch c nh c pht hi n b ng c n lm sng, km tng cholesterol trung bnh v m c nguy c tim m ch cn th p. Rosuvastatin 40mg/ngy c dng, lm ch m di n bi n x v a ng m ch c nh m t cch c ngha. dy l p o gi a gi m 0,0145mm/nm so v i nhm ch ng. M t nghin c u trn 129 b nh nhn i u tr rosuvastatin so v i nhm dng gi d c k t qu cho th y thay i c ngha l p o gia c a ng m ch c nh chung. ORION l m t th nghi m nh (33 b nh nhn), ng u nhin, m i, a trung tm, th i gian 2 nm, th nghi m phng b nh ban u trn nh ng i t ng 18 tu i v i thng t n m ch c nh cha c tri u ch ng km tng cholesterol v a. Lc u cc b nh nhn c ch n ng u nhin cho dng rosuvastatin li u th p (5mg/ngy) ho c li u cao (40mg/ngy n 80mg/ngy) trong 2 nm, tuy nhin sau nh ng tr ng h p dng 80mg/ngy c i u ch nh cn 40mg/ngy. Nhm dng rosuvastatin 5 v 40mg/ngy th tch vch ng m ch c nh khng thay i c ngha. Tuy nhin ph n li ho i t giu lipid c a mng x v a gi m c ngha n 41,4% v m s i gia tng c ngha n 1,8%.
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ASTEROID l m t th nghi m khng so snh, a trung tm, th i gian 2 nm, th nghi m phng ng a b c hai. Th nghi m c sng l c t 1.183 b nh nhn, 507 b nh nhn 18 tu i, t t c c ch nh lm sng ch p m ch vnh, v c t nh t m t v tr t c m ch vnh v i m c h p > 20% ng knh m i c ch n nghin c u, c 158 b nh nhn c rt kh i nghin c u do khng ng tham gia, do m t s l do khc ho c do tc d ng ngo i . 349 b nh nhn cn l i c dng rosuvastatin 40mg/ngy. B nh nhn c nh gi mng x v a b ng siu m n i m ch sau 2 nm. K t qu cho th y: Mng x v a gi m c ngha v i li u rosuvastatin 40mg/ngy th nghi m ASTEROID. C 63,6% b nh nhn dng rosuvastatin gi m mng x v a. Th tch trung bnh mng x v a gi m t 212,2mm3 lc u xu ng cn 197,5mm3 , nh th trung bnh gi m c 14,7mm3.
ASTEROID Trial: Secondary Endpoint ASTEROID Trial: Secondary Endpoint

Mean Normalized Total atheroma volume (mm3)
240 210 180 150 120 90 60 30 0
212.2
197.5
At follow-up, total followatheroma volume was reduced from 212.2 mm3 at baseline to 197.5 mm3 (an absolute change of -14.7 mm3).
mm3
Baseline Baseline
Follow-up
Presented at ACC 2006 Presented at ACC 2006
ASTEROID Trial: Principal Findings ASTEROID Trial: Principal Findings

Mean LDL level decrement and HDL level increment (mg/dL) p<0.00
1
132 132
LDL/HDL mg/dL mg/dL
130.4 130.4
110 110 88 88 66 66 44 44 22 22 0 0 LDL Levels LDL Levels

Baseline Baseline
60.8 60.8
p<0.00 1
43.1 43.1
49.0 49.0
LDL Levels were reduced from 130.4 mg/dL at baseline mg/dL to a mean of 60.8 mg/dL at 2 year mg/dL follow-up follow(p<0.001), with 75% of patients achieving an LDL <70 mg/dL. mg/dL. HDL levels were increased from 43.1 mg/dL at mg/dL baseline to a mean of 49.0 mg/dL at mg/dL follow-up follow(p<0.001).
HDL Levels HDL Levels

Follow-up Follow-up
171
ASTEROID Trial: Primary Endpoint cont. ASTEROID Trial: Primary Endpoint cont.
64 64 56 56
Regression vs. progression change in % atheroma volume (%) 63.6 63.6 Regression in percent atheroma volume was observed in 63.6% of patients; whereas, progression was observed in 34.6%.
% patients
48 48 40 40 32 32 24 24 16 16 8 8 0 0 Regression Regression Progression Progression 34.6 34.6
Cc ghi nh n khc qua th nghi m ny cho th y LDL-C trung bnh ban u l 130,4mg/dL sau 2 nm gi m xu ng cn 60,8mg/dL, HDL-C trung bnh ban u l 43,1mg/dL tng ln 49,0mg/dL sau 2 nm i u tr . Ngoi cc th nghi m trn y, m t th nghi m khc mang tn JUPITER do Paul M. Ridker, MD, MPH (Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts) th c hi n trn 17.802 ng i c b ngoi kh e m nh v i LDLC < 130 mg/dL (3.4 mmol/L) nhng hsCRP 2,0 mg/L, i u tr v i rosuvastatin qua 2 nm, k t qu cho th y lm gi m t l m i m c c a nh i mu c tim, t qu v t vong do tim m ch 47%, v gi m t l t vong chung 20%. Dung n p thu c Phn tch k t qu t nghi m lm sng trn 16.876 b nh nhn dng rosuvastatin 5 40mg/ngy, c kho ng 2% b nh nhn c cc tc d ng khng mong mu n, th ng g p l au c, au u, vim mi h u, au kh p, bu n nn, vim ng h h p trn. ALT tng ( >3 l n trn m c bnh th ng qua t nh t 2 l n nh l ng) ghi nh n t l 0,6%, 0,2%, 0,2%, v 0,4% trn nh ng b nh nhn dng 5, 10, 20, v 40mg/ngy. ALT tng th ng ch t m th i s gi m ho c tr v bnh th ng sau khi ngng i u tr . Creatinekinase tng ghi nh n t l 0,4%, 0,2%, 0,3%, v 0,6% trn nh ng b nh nhn dng 5, 10, 20, v 40mg/ngy. Tri u ch ng au c g p kho ng 3,5%, Protein ni u t m tnh n dng tnh >2+ ch g p kho ng <1% cc b nh nhn dng rosuvastatin t 5 20mg/ngy v 1,5% nhm dng 40mg/ngy. Rosuvastatin 40 mg/ngy ni chung dung n p t t cc th nghi m METEOR v ASTEROID. Tri u ch ng th ng g p th nghi m METEOR l au c (12,7% nhm dng thu c so v i 12,1% nhm gi d c). th nghi m ASTEROID cc tc d ng khng mong mu n th ng g p l au c ho c y u c chi m t l 3,7% c khi ph i ng ng i u tr . Khng c tr ng h p no b tiu c. ALT tng >3 l n qua 2 l n nh l ng, creatinekinase tng > 10 l n, protein ni u t m tnh n dng tnh 2+ l n l t ghi nh n v i 0,6% nhm rosuvastatin v 0,7% nhm gi d c trong th nghi m METEOR v 0,2% nhm dng rosuvastatin trong t nghi m ASTEROID. Nhi u phn tch h i c u trn cc nghin c u l n cho th y khng c s
172
khc nhau c ngh th ng k v t l ph i nh p vi n v bi u hi n tiu c, au c, thay i ch c nng th n, thay i ch c nng gan trn cc nhm dng rosuvastatin so v i cc statin khc. TI LI U THAM KH O 1. Schuster H. The GALAXY program: an update on studies investigating efficacy and tolerability of rosuvastatin for reducing cardiovascular risk. Expert Rev Cardiovasc Ther 2007 Mar; 5 (2): 177-93. 2. Nissen SE, Nicholls SJ, Sipahi I, et al. Effect of very high-intensity statin therapy on regression of coronary atherosclerosis: the ASTEROID trial. JAMA 2006 Apr 5; 295 (13): 1556-65. 3. AstraZeneca. Crestor (rosuvastatin calcium): US prescribing information [online]. Available from URL: http://rosuvastatininformation.com [Accessed 2007 Nov 19]. 4. AstraZeneca. First head to head study comparing Crestor and Lipitor effects on the treatment of atherosclerosis [media release]. Available from URL: http:// www.astrazeneca.com [Accessed 2008 Jan 24]. 5 Furman C, Copin C, Kandoussi M, et al. Rosuvastatin reduces MMP-7 secretion by human monocyte-derived macrophages: potential relevance to atherosclerotic plaque stability. Atherosclerosis 2004 May; 174 (1): 93-8. 6. Nissen SE, Nicholls SJ, Sipahi I, et al. Effect of very high-intensity statin therapy on regression of coronary atherosclerosis: the ASTEROID trial. JAMA 2006 Apr 5; 295 (13): 1556-65. 7. Davidson M, Ma P, Stein EA, et al. Comparison of effects on low-density lipoprotein cholesterol and high-density lipoprotein cholesterol with rosuvastatin versus atorvastatin in patients with type IIa or IIb hypercholesterolemia. Am J Cardiol 2002 Feb 1; 89 (3): 268-75
173
C CH THI U MU C C B NO LIN QUAN I U TR N I KHOA HI N NAY

Tr ng I. C CH SINH B NH Khi thi u mu c c b th y m t vng trung tm b ho i t c lu l ng mu 10 15 ml/100g no/pht v khu v c bao quanh vng ho i t c lu l ng mu 23 ml/100g/pht, v i lu l ng ny cho t bo khng ch t nhng khng ho t ng c g i l vng tranh t i - tranh sng hay cn g i l vng i u tr v n u h i ph c lu l ng mu th t bo no ho t ng tr l i bnh th ng. Trong vng trung tm cc t bo hnh sao t n thng s m nh t, ph no xu t hi n vo kho ng 3 gi sau tai bi n v ti n t i t i a 4 gi , t n t i hn 72 gi , cn nron b t n thng ch m hn ch th y sau 6 gi v c bi t r sau 24 gi v ko di kho ng m t thng. K l th c bo do b ch c u a nhn v cc i th c bo ko di m t thng ho c hn. Thi u mu c c b no Ng ng cung c p O2 v glucoza Ho t ha phospholipase Gi i phng glutamate Khng t ng h p AND v proteine Hong Khnh i h c Y D c Hu
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T n thng v h y ho i t bo
NMDA=N-methyl-D-aspartate; AMPA=-amino-3-hydroxy-5-methyl-4-Isoxazolepropionic acid. S 1. C ch thi u mu c c b no
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174
ln do s lan r ng vng nh i mu. Ngoi ra m ch mu trong vng thi u mu b t n thng khi ti l p tu n hon d gy xu t huy t th pht, ph no n ng. Ng i ta ch ng minh vai tr ion canxi kch thch men phospholipase lo i A lm t n thng mng t bo. Vng tranh t i tranh sng t n t i 2 - 3 gi .
Lu l ng mu no (ml/100g/pht)
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M lnh
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Tranh t i tranh sng
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Ch ho i t t bo
Ho i t
0 0 Ho i t 30 60 90 120 pht 3 4 5 6 24 48 gi
Tranh t i tranh sng
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Ngoi ra cn th y trong nh i mu no ho t ha qu m c m-Calpain nn khng th no ki m sot s phn hu v ti c u trc c a protein t o nn khung t bo t lm gi m cc y u t d ng th n kinh nn kh nng tnh m m d o tuy t i c a h th n kinh b sa st. T i vng nh i mu no c ph n ng vim gy tng cytokin m c bi t l interleukin, t lm gia tng th th k t dnh b ch c u CD-18 v th th phn t k t dnh t bo (ICAM-1, Intercellular Adhesion Molecular) gy h u qu ngh n vi tu n hon t i ni t n thng t lm tr m tr ng hn t n thng. II. I U TR Nh m b n m c tiu: duy tr i s ng, gi i h n t n thng, h n ch di ch ng v bi n ch ng Trn th c t c hai lo i bi n php sau y: 2.1. Cc bi n php ti l p tu n hon no
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2.1.1. Cc thu c tiu huy t kh i Gi i phng t c m ch c tc d ng n u dng tr c 6 gi t t nh t l tr c 3 gi m i c hi u qu , tuy nhin c nguy c ch y mu. Cc thu c trong nhm ny l streptokinase 1,5 tri u U; plasminogne (rt-PA)1,1mg/kg v nay cn c pro-rt-PA. B ng 4.15: M t s th nghi m lm sng i u tr tiu huy t kh i. 1,5 tri u UI streptokinase khng c ti p t c sau 270 b nh nhn v c t l cao c a ch y mu no. ASK 1,5 tri u UI streptokinase trong 4 gi , c ti p t c s d ng. MASTI 1,5 tri u UI streptokinase trong 6 gi , c ti p t c s d ng. ECASS1 rtPA trong 6h, li u 1,1mg/kg tr ng l ng c th (li u t i a), 10% tim tr c ti p trong 2 pht, ngh trong 1 gi , s s ng c c i thi n trong nhm nghin c u. NINDS 1291 b nh nhn, rtPA trong 3 gi , 0,9mg/kg tr ng l ng c th , dng t i a 90mg, 10% tim tr c ti p trong 1 pht, ngh trong 1 gi , khng dng heparin trong 24 gi . ngh i u tr tiu huy t kh i trong thi u mu c c b no theo Hi p h i Th n kinh Hoa K (AAN): - Tiu chu n nh n i u tr T 18 80 tu i (n u i u ki n sinh h c t t th c th trn 80 tu i). t qu thi u mu c c b no trn l u. Cc tri u ch ng kh i u t i a 3 gi tr c khi i u tr tiu huy t kh i. M c n ng c a tri u ch ng: li t nhn t p trung khng ko di, khng c cn co gi t , khng b hn m. - Xem xt HA: 185/110mmHg ho c th p hn cho n khi i u tr tiu huy t kh i. Glucoza mu t i a 22,2 mmol/L cho n khi tiu huy t kh i. Hematocrit trn 25%. CTscan khng c ch y mu no. t qu t i a b ng m t ph n ba c a khu v c ng m ch no Vng nghi ng gi a. - Tiu chu n lo i tr : Lo i tr n u b nh nhn tr c c: ch y mu d i nh n, ch y mu trong no, d d ng ng tnh m ch, u no, ch y mu th n. Lo i tr n u trong 3 thng cu i c t qu thi u mu c c b no, ch n thng s no, ph u thu t n i s ho c n i t y s ng. Lo i tr n u trong thng cu i c ph u thu t l n b t k v tr no trn c th , ch n thng, sinh thi t, ch y mu sau ch c ven m kh c m mu, ch y mu d dy ru t ho c ng ni u. Lo i tr n u trong tu n cu i c ch c s ng lng, tim trong ng m ch. Lo i tr n u g n y ho c hi n t i c suy tim xung huy t m t b (CHF), lo n nh p c tnh, ho n ng, mang t2, c khuynh h ng ch y mu, nh i mu c tim g n y, i u tr ch ng ng v i th i gian prothrombin INR trn 1,7; dng heparin, lm sng h i ph c nhanh. Cc tri u ch ng khng r th i gian kh i pht khi b nh nhn ng . Theo David O.Wierber g i ch ng ch nh dng tiu huy t kh i: MASTE
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ang dng ch ng ng, c th i gian prothrombin INR trn 1,7. Nh n heparin trong su t 48 gi v i th i gian PTT t 60 70 giy. C ti u c u d i 100.000. t qu ho c ch n thng s trong 3 thng g n y. Ph u thu t l n trong 14 ngy g n y. HA trn 185/110mmHg, m c d i u tr h HA v n c dng cho n khi tiu c c huy t c ngh . Ph c h i lm sng nhanh tr c khi i u tr tiu c c huy t. Ch y mu trong no tr c . Glucoza mu d i 2,75mmol ho c trn 22,2mmol/L th i k dng tiu c c huy t. Cn co gi t ng kinh. Ch y mu d dy ho c ti t ni u trong 21 ngy g n y. Nh i mu c tim g n y. - Quy trnh i u tr Tr c khi ti n hnh i u tr tiu huy t kh i c n ti n hnh kh n c p: Ch p CTscan kh n c p, xt nghi m sinh ha mu v ng mu, CTM, nhm mu. Ngy ti p theo: ch p l i CTscan sau 24 gi , xt nghi m mu c bi t dng mu, theo di HA, tnh tr ng tim, tnh tr ng h h p. Li u dng: 0.9mg rtPA (actilyse)/kg tr ng l ng c th (li u t i a 90mg), l 50mg/50ml dung d ch n c tim (1ml = 1mg). Tim tr c ti p 10% c a t ng li u trong 1 2 pht, tnh m ch, 90% cn l i, truy n trong 60 pht. Heparin li u th p c sau 24 gi n u c ch nh (xem ch b t u dng ngay (2 x 5000 UI). Heparin y d n dng heparin). Khng ti n hnh trong 24 gi ng tnh m ch trung tm, ch c vo ng m ch, lu n sonde mi, ch c s ng th t lng. Bi n ch ng ch y u c a dng rtPA l ch y mu. Theo th ng k, c m t t l 5 10% nguy c c a ch y mu trong s ho c ch t. N u x y ra t i t th n kinh ho c au u m i xu t hi n, tng huy t p c p, nn ho c bu n nn do nghi ng m t ch y mu trong s , rtPA s c d ng l i ngay l p t c v ti n hnh ch p CTscan, xt nghi m th i gian prothombin, th i gian thromboplastin m t ph n, m ti u c u, fibrinogen s c xc nh l i ngay. X tr khi c bi n ch ng ch y mu b ng chuy n huy t tng ti ng l nh, Aprtinin (trasylol) 500.000 KIU ( n v kallikrein khng ho t ng), truy n tnh m ch tr c, sau 200.000 KIU m i 4gi (5ml/pht). Tranexamic acid (cyclo caprol), 15mg/kg tr ng l ng c th , truy n tnh m ch s m, nh c l i m i 6 gi . Thng th ng, ch kho ng t hn 10% b nh nhn c i u ki n cho i u tr tiu c c huy t kh i. C n lu , heparin tnh m ch s khng c dng trong 24 gi , huy t p (HA) s c gi th p hn 180/105mmHg v c theo di th ng xuyn. Urokinase v streptokinase do c nhi u tai bi n ch y mu nn cc tc gi g n y ch trng dng li u nh a tr c ti p vo v tr ng m ch b t c trong 6 gi u kh i pht b nh. 2.1.2. Ch ng ng cc b nh nhn v i nh i mu no m c v a v nh ho c kh nng x u ln c a cc thi u h t ban u, vi c dng heparin tnh m ch ngay l p t c s c xem xt. C ch ho t ng ch y u c a heparin l g n k t v i antithrombin III, s g n k t ny lm tng ho t tnh c ch c a khng ch thrombin m c y u t Xa, IXa, XIa, v XIIa.
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- Ch nh i u tr . + L a ch n 1: heparin truy n tnh m ch. Kh i u tim tr c ti p 5000 UI/kg, tnh m ch; ti p theo truy n nh gi t 1000UI/gi , m c ch t c s duy tr th i gian PTT l 1,5 2 l n so v i bnh th ng ho c PTT t 60 70 giy, ki m tra PTT h ng ngy l c n thi t. + L a ch n 2: heparin tr ng l ng phn t th p (fragmin, lovenox, warfarin) hai l n, hng ngy, 100UI/kg tr ng l ng c th , tim d i da (ho c lovenox 0,4 x 2 l n/24 gi , d i da x 5 7 ngy). - Cc ch ng ch nh c bi t. + Ch y mu trong s , ch y mu d i nh n. + T n thng r ng. + B nh th n, gan ho c t y n ng, thi u mu n ng. + B nh nhn c ph u thu t th n kinh ho c ph u thu t m t. - Bi n ch ng v x tr N u x y ra h u qu ch y mu lin quan n heparin th s d ng vitamin K v i m t li u 5ml dung d ch 1% pha l n v i 20ml dung d ch mu i ng trng tim tnh m ch ch m, khng qu 50mg trong 10 pht ho c 200mg trong hai gi . Nguy c ch y mu c a heparin l b t k v tr no, nhng th ng x y ra ng tiu ha, c th mng b ng v c hai th n. - Ghi ch Heparin tr ng l ng phn t th p (enoxaparin), th ng c dng d phng huy t kh i tnh m ch su v cc b nh tim m ch khc n a bao g m t qu . c hng ngy Enoxaparin dng d hn heparin nhi u do li u dng n (0,4mg/24 gi , m i 12 gi ), theo di l khng nh t thi t. M t s nghin c u g n y k t lu n r ng cc b nh nhn v i t qu thi u mu c c b nh v v a, m t IRN c a 2,0 3,0 l h p l. 2.1.3. Ch ng ngng t p ti u c u Cc thu c ch ng ti u c u bao g m: aspirin, dipyridamol, ticlopidin, clopidogrel, abciximab... Hi u qu c a aspirin trong gi m nguy c t qu , nh i mu c tim so v i gi d c c xc nh r. Trong nghin c u d phng t qu chu u 2 (ESPS2), n u dng aspirin n c, nguy c c a t qu gi m c ngha (21,2%); 19,4% v i dipyridamol; n u dng k t h p aspirin v dipyridamol, s gi m c ngha nguy c t qu t i 37%; ticlopidin gi m x p x 33%, clopidogrel gi m x p x 34%. T i Trung tm t qu no B nh vi n Trung ng Qun i 108 th ng dng phc ph i h p (aspirin 0,1g + dipyridamol 250mg/24 gi ) ho c plavix 75mg/24gi i u tr d phng t qu c k t qu , khng c tai bi n. 2.1.4. Lm lo ng mu Nh m gi m nh t c a mu nn tng lu l ng mu ln no (pentoxifiline, dextran) nhng nhi u nghin c u g n y cho th y khng c hi u qu . 2.1.5. Cc thu c gin m ch no Naftidrofuryl (praxilne) l c hi u qu v i li u 600 mg/ngy. 2.2. Cc bi n php b o v t bo no Cc ch t ch n Ca++ (knh Ca++ ph thu c) nn cho trong 12 gi u sau tai bi n nh t l nhm nimodipine v i li u 120mg/ngy, ngoi ra c th s d ng nicardipine, lifarisine.
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Cc thu c khng glutamat lm ngh n s gi i phng glutamat ho c phong t a cc th th NMDA nh aptiganel, YM90K, tuy nhin cc thu c ny gy o gic. Thu c b o v mng (monoganglioside) tc ng ln s gi i phng glutamat. C th dng i khng morphine nh naloxone v n c n tr dng canxi qua mng, peroxy ha lipit, ch ng oxy ha, tng lu l ng mu no, ch ng ngng t p ti u c u v chng ph no. Cc thu c c ch g c t do nh tirilazad, clomethiazole, superoxide dismutase ang cn trong giai o n nh gi. i u bi n con ng NO: lubeluzole ( ang cn th nghi m) Magnesium sulphate v i li u ban u l 16mmol chuy n trong 15 pht sau duy tr 65 mmol trong 24 gi . Vinpocetine (Cavinton) ngy nay c s d ng r ng ri v thu c ny t c ba m c tiu l ti l p tu n hon thng qua ch ng ngng t p ti u c u, ch ng vim, ch ng ph n , gi m nh t mu v gi n m ch t i ch ; hai l b o v t bo no v lm b n mng t bo, gi m tch ly g c t do v gi m h y m; ba l khi ph c l i qu trnh chuy n ha nh s d ng t t O2 v glucoza nn lm gi m lactat t i ch nh i mu. Vin 5 mg, 3 vin ngy trong 2 - 3 thng; ng 10 mg ngy 2 ng chuy n tnh m ch trong 10 - 14 ngy. Khng dng khi c t2, thi u mu c tim c c b v lo n nh p. Cerebrolysin chi t su t t protein no l n c vai tr th nh t l i u bi n chuy n ha b ng cch tng hi u qu chuy n ha nng l ng trong mi tr ng y m kh, tc ng ln qu trnh t ng h p protein v c bi t lm g m axit lactic, c ch m-calpain, kh cc g c t do; th 2 l c vai tr gi ng y u t tng tr ng th n kinh (Nerve Grow Factor -NGF) v cu i cng l c tc d ng i u bi n th n kinh. Li u th ng dng ng 10 ml ngy 2 - 3 ng tim tnh m ch trong th i gian 2 - 4 tu n. H u nh khng c tc d ng ph no. Ngoi ra c th s d ng Tanakan 40 mg ngy 3 vin hay Nootropyl 400mg ngy 3-6 vin trong 2 - 4 tu n. Xu h ng m i trong i u tr nh i mu no l s d ng khng ICAM-1, ch ng k t dnh b ch c u b ng doxycycline 10mg/kg cn n ng v thu c ny g n vo cc ion dng c a th th CD-18 lm cho b ch c u khng k t dnh v i ph c h p b th .
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PHT HI N S M X V A NG M CH QUA KH O ST R I LO N CH C NNG & C U TRC N I M C M CH MU

Tr ng Nguy n H i Thu i H c Y D c Hu
I. R I LO N CH C NNG N I M C N i m c m ch mu (vascular endothelium) ho t ng v s n xu t m t s ch t trung gian lin quan n v n m ch trong ch t nitric oxide (NO) d n xu t t t bo n i m c l ch t c b n trong duy tr s h ng nh n i mi m ch mu .N i m c m ch mu l m t c quan c n n i ti t l n, n ti t ra nhi u y u t i u ha trng l c m ch mu, gip pht tri n c a t bo, cc tng tc c a b ch c u v ti u c u v c tnh sinh ng. Nh ng nh n c m v p ng c a n i m c i v i v s cc kch thch bn ngoi v bn trong thng qua cc ph c h p th th mng t bo v nh ng c ch truy n t i tn hi u, d n n s t ng h p v phng thch cc ch t ho t m ch, cc y u t pht tri n v i u ha ng mu.
T n thng
T bo ch t H vng n i m
Hnh 1: C ch t n thng n i m c v vai tr NO Trong t n thng thi u mu/ti t i mu, c s r i lo n phng thch NO do khi m khuy t tn hi u chuy n i qua mng. T bo n i m c duy tr kh nng c a s n xu t v phng thch NO. Vai tr c a n i m c m ch mu trong b nh l ng i g n y tr thnh tm i m nghin c u c a cc nh khoa h c. Suy gi m ch c nng n i m c c lin quan v i m t s tnh tr ng b nh l nh i tho ng, r i lo n lipid mu, tng huy t p, bo ph R i lo n ch c nng n i m c l m t trong nh ng d u hi u chnh v s m c a b nh sinh x v a m ch, d bo nh ng thay i x v a ng m ch ..
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N i m c m ch mu i u ho trng l c v tnh th m thnh m ch, gip cn b ng gi a ng mu v tiu s i huy t, tc ng c u thnh c ch t l p d i n i m c, lin quan n s k t dnh v xuyn m ch b ch c u v ho t ng vim c a thnh m ch. Chng cng tc ng trn ch c nng c a m t s t bo khc nh t bo c trn m ch mu, ti u c u, b ch c u, bi u m gic m c, t bo trung m th n v i th c bo ng m ch l n, ng c l i cc t bo ny cng tc ng tr l i trn t bo n i m c. th c hi n ch c nng trn t bo n i m c m ch s n xu t m t s cc c u thnh c a c ch t ngo i bo nh l collagen v s n ph m i u ho bao g m ch t NO, prostanoids, endothelin-1 (ET-1), angiotensin II (Ang II), ho t ho plasminogen t ch c (tissuse type plasminogen activator = t-PA), c ch ho t ho plasminogen-1 (plasminogen activator inhibitor -1 = PAI-1), von Willebrand factor (vWF), phn t k t dnh v cytokine. Cc ch t t n i ti t v c n n i ti t phng thch t n i m Tc d ng Gin m ch Cc ch t t n i ti t v c n n i ti t NO, prostacyclin, y u t tng kh c c d n xu t n i m, bradykinin, adrenomedulin, y u t l i ni u C Co m ch ET-1, angiotensin II, thromboxane A2, g c oxy ho, prostaglandin H2. Ch ng tn sinh NO, prostacyclin, y u t pht tri n chuy n giao , heparin sulphate. Ti n tn sinh ET-1, angiotensin II, g c oxy ho, y u t pht tri n d n xu t t ti u c u, y u t pht tri n nguyn bo s i c b n, y u t pht tri n gi ng insulin, interleukin Ch ng huy t kh i NO, prostacyclin, ho t ho plasminogen, protein C, y u t c ch t ch c, y u t von Willebrand. Ti n huy t kh i ET-1, g c oxy ho, PAI-1, thromboxane A2, fibrinogen, y u t t ch c Ch i m vim CAMs (P v E-selectin, ICAM,VCAM) chemokine, y u t nhn -B Tnh th m Th th cho s n ph m sau cng ng ho b c cao (AGEP). Tn sinh m ch Y u t pht tri n n i m c m ch
Bnh th ng ho t ng t bo n i m c m ch lm gi m trng l c m ch mu, h n ch s k t dnh b ch c u cng nh cc ph n ng vim trong cc thnh m ch, duy tr tnh th m m ch mu i v i ch t dinh d ng, hormone, cc ch t tr ng l ng phn t l n khc, b ch c u, c ch k t dnh v ngng t p ti u c u b ng cch s n xu t prostacyclin v NO, h n ch ho t ng c a qu trnh ng mu b i thrombomodulin/protein C, heparan sulfate/antithrombin v y u t t ch c/tng tc c ch con ng y u t t ch c v i u ho tiu s i huy t b ng s n xu t t-PA v ch t c ch PAI-1 c a chng. M t trong cc phn t quan tr ng c t ng h p t i t bo n i m c l NO c tc d ng gy gin m ch, ch ng ngng t p ti u c u, ch ng tn sinh, gi m tnh th m v thu c tnh khng vim. Ch t NO c ch k t dnh b ch c u v lin quan trnh di n ch t VCAM-1(vascular cell adhesion molecule-1) do cytokine v ch t MCP-1 (monocyte
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chemotactic protein-1), cc h u qu m c t nh t m t ph n tham gia c ch sao chp y u t NF-B (nuclear factor B). T n thng n i m c c th gy r i lo n ch c nng n i m c c bi u hi n khi thu c tnh b thay i theo chi u h ng khng tng thch trong tr ng thi c b n ho c sau khi kch thch. R i lo n ch c nng n i m c c vai tr quan tr ng khng nh ng trong kh i u x v a ng m ch m cn trong ti n tri n v h u qu lm sng. Cc nguy c nh tng cholesterol mu, r i lo n lipid mu, ht thu c l, i tho ng u lin quan n ho t ho n i m c v r i lo n ch c nng n i m c. V th ho t ho n i m c c ch p nh n nh l s chuy n i (transducer) c a cc y u t nguy c x v a. Cc y u t nguy c x v a th ng lm cho NO n i m c gi m st ho c l do gi m s n xu t ho c l do tng ging ho.. V d n ng cao LDL tng s n xu t s n ph m oxy ph n ng ROS ( reactive oxygen species) v cc NO d n d p nhng cng gia tng tng tc gi a NOS (NO synthetase) v caveolin-1 ch t lm gi m s n xu t NO. Ch t angiotensin II lm gia tng NAD(P)H oxidase m ch mu, s n xu t superoxide v NO thu d n v nh th gi m hi u l c NO. Cc ti n trnh trn dn n ho t ho n i m c bi u hi n b i gia tng trnh di n cc phn t k t dnh IV. NH GI R I LO N CH C NNG C A N I M C. B ng nh gi r i lo n ch c nng n i m c ng i
nh gi R i lo n gin m ch ph thu c n i m c
Gi i thch v t n thng r i lo n ch c nng Gi m s n xu t ch t gin m ch v/hay tng s n xu t ch t co m ch Tng t thot qua mng mao m ch c a Gia tng th m v i ch t c phn t l n albumin nh d u phng x chch tnh m ch, microalbumin ni u v sCD146 Tng s n xu t ch t co m ch Endothelin vWF Tng ho t ti n huy t kh i v ti n ng mu sThrombomodulin Gi m ho t ch ng ng t-PA v PAI-1 Gi m ho t ti n tiu s i huy t sE-selectin v sVCAM-1 Tng dnh v th m i v i b ch c u sICAM-1 Ho t ho ph n ng vim fibronectin t bo v collagen lo i IV R i lo n t ng h p c ch t ngo i bo Ch c nng n i m c khng th nh gi tr c ti p ng i, nh gi cc lo i r i lo n ch c nng n i m c c th t c gin ti p b ng nh gi gin m ch ph thu c n i m c, n ng huy t tng c a protein i u ho d n ch t t n i m c v c th qua microalbumine ni u. M t vi thu c tnh m ch mu nh c ng ng m ch v dy l p n i trung m c (IMT) ng m ch c nh c l m t ph n ph thu c n i m c. Nhi u nghin c u ngang ghi nh n r i lo n gin m ch ph thu c n i m c v n ng cao c a cc protein i u ho dn ch t n i m c cc b nh nhn c cc b nh lin quan n t n thng n i m c nh l x v a- huy t kh i, ti n s n gi t v vim m ch mu cng nh nh ng c nhn c cc nguy c x v a-huy t kh i. Ngoi ra nh ng b nh nhn c r i lo n gin m ch ph thu c n i m c, n ng c a cc protein i u ho d n ch t n i m c ho c microalbumin ni u c d h u x u v tim m ch Trong b ng nh gi r i lo n ch c nng n i m c
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1. Cc test nh gi gin m ch ph thu c n i m c qua trung gian NO nh gi tc d ng c a cc ch t gin m ch n i m c nh prostacyclin v EDHF (endothelium derived hyperpolarizing factor) v c th nh m r i lo n ch c nng t bo c trn m ch mu 2. Ch p nh n n ng cao trong huy t tng c a cc ch t trung gian d n ch t n i m c ph n nh r i lo n ch c nng n i m c trong cc b nh m ch mu (m ch vnh, m ch c nh) i h i - Cc lo i t bo khc khng l ngu n quan tr ng - T ng h p quan trong hn l thanh th i tr phi ch t sau ph thu c n i m c - Ch c nng n i m c trong vi m ch tng ng ch c nng trong m ch mu l n, thnh ph n ny, do s vi c l h th ng n i m c vi m ch v i di n r ng v kh nng t ng h p, l quan tr ng kh ng nh n ng huy t tng c a cc ch t trung gian d n xu t n i m c. lu PAI-1 khng nh ng c th s n xu t t t bo n i m c m cn t bo gan, t bo m v t bo c trn m ch mu. 3. T l xuyn mng c a albumin c kh ng nh khng nh ng b i n i m c m l i cn b i thu c tnh ho h c v c h c c a c ch t ngo i bo v b i p l c huy t ng d li u g n y ch t ho tan CD146 thnh ph n globulin mi n d ch lin quan n ki m sot lin k t t bo v t bo ( cell-cell cohesion) v tnh th m n i m c, cung c p nhi u thng tin lin quan c a n i m c v i tnh th m m ch mu. Tm t t cc i u ki n ph i h p r i lo n ch c nng n i m c, chi n l c can thi p r i lo n ch c nng n i m c v ch t ch i m r i lo n ch c nng n i m c. Cc i u ki n X v a ng m ch, tng cholesterol mu, tng LDL.C, gi m ph i h p v i r i HDL.C, tng Lp(a), tng LDL.sd, LDL.C oxy ho, tng huy t p, lo n ch c nng tng homocystein, tu i, vim m ch mu, ti n s n gi t, h i ch ng n im c chuy n ho, au th t ng c khng n nh, i tho ng, ht ng v th ng, ti t i mu sau thi u mu, x v a thu c l ch ng m ch, bypass tim ph i, mn kinh, b nh Kawasaki, b nh Chagas, ti n s gia nh b nh m ch vnh, nhi m khu n, tr m c m, t ho t ng, bo ph, suy th n, tng CRP, suy tim sung huy t, ph i th t tri, sau n Can thi p nh m c ch enzym chuy n, c ch th th angiotensin, c ch c i thi n ch c endothelin, statin, tetrahydrobiopterin, folate, t p th d c, tng nng n i m c nh y insulin, gi m LDL, tng HDL, chng oxy ho, L-arginine, desferoxamine, glutathione, gi m homocystein, gi m CRP, gi m FFA Cc ch t ch CAMs, y u t von Willebrand, nitrite, khng tng thch i m ho tan (asymetric) dimethylarginine , CRP, tPA, fibrinogen, amyloid A c a r i lo n ch c nng n i m c V. PHT HI N S M T N THNG X V A NG M CH QUA GI T N THNG N I M C TRONG TH C HNH LM SNG 1. nh gi r i lo n ch c nng n i m c m ch NH
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Th nghi m nh gi ch c nng n i m c m ch trn ng i i h i nhi u thch th c. N i m c m ch phng thch m t s s n ph m, nhng v n cha c m t xt nghi m mu n c no ch ng minh c tnh h u d ng trong vi c xc nh ch c nng n i m c bnh th ng hay b t th ng, nh t l giai o n s m. Cc th nghi m th ng c dng nh t nh gi ch c nng n i m c trn c th s ng u d a vo vi c o s gin m ch ph thu c n i m c khi m ch mu p ng v i nh ng kch thch bng d c ch t ho c v t l. c tnh ny d a vo kh nng c a n i m c phng thch NO, n khng ch l m t ch t gy gin m ch m cn l m t y u t ch ng ngng t p ti u c u, s k t dnh i th c bo, v s tng sinh c a t bo c trn. Ch c nng n i m c c th o c tr c ti p ng m ch vnh v ng m ch ngo i bin b ng cch o ch c nng v n m ch sau khi truy n vo trong lng ng m ch m t s ch t lm gia tng phng thch NO n i m c. i u b t ti n c a phng php ny l b n ch t xm nh p c a n. V l do ny, nh ng phng php khng xm nh p nh gi ch c nng n i m c m c c hnh thnh. Phng php c s d ng r ng ri nh t l d a vo siu m 2D o ng knh ng m ch kh u l n khi n p ng v i p l c p tr c gy ra gin m ch ph thu c n i m c. Gin m ch khng ph thu c n i m c cng c th nh gi b ng vi c o ng knh ng m ch sau khi dng nitroglycerin ng m d i l i. nh Trong th p nin 90, v i siu m t n s cao kh o st ng m ch cnh tay gi s gin m ch qua trung gian dng ch y (Flow Mediated Dilation) ph thu c n i m c pht tri n. y l m t k thu t nh gi ch c nng n i m c. K thu t ny kch gin m ch c th tnh thch phng thch nitric oxide (NO), gy ra gin m ch. M c ton c nh m t ch s c a ch c nng v n m ch (vasomotor function). Thm d khng xm nh p c a k thu t cho php l p l i nhi u l n nghin c u hi u qu c a nh ng can thi p khc nhau c nh h ng ln s lnh l n c a m ch mu. M c d khng ph i l tiu chu n vng nh gi ch c nng n i m c hi n h u, o ng m ch cnh tay ho c ng m ch i qua siu m 2D l phng php FMD nghin c u dng nhi u nh t trn lm sng Gin m ch qua trung gian dng ch y (Flow Mediated Vasodilation FMD): M ch mu c kh nng co gin nh m p ng v i nh ng kch thch ha h c v v t l tc ng trong lng m ch c g i l kh nng t i u ha trng l c nh m i u ch nh phn b cng nh dng ch y c a mu p ng v i nh ng thay i mi tr ng t i ch . Nhi u m ch mu p ng v i s gia tng dng ch y ho c p l c chn p gy t c hon ton b ng cch gin ra. Hi n t ng ny c g i l FMD. NO ngu n g c n i m c l ch t trung gian c b n c a hi n t ng FMD. C ch chnh xc c a vi c pht hi n c p th i c a l c p v s d n truy n tn hi u n sau i u chnh trng l c m ch mu v n cha c bi t y . Mng t bo n i m c c ch a cc knh ion chuyn bi t, nh cc knh kali c ho t ha b i calcium, n m ra p ng v i p l c p. Hi u qu c a vi c m knh kali lm c ng phn c c t bo n i m c, gia tng dng calcium i vo. Calcium tc d ng nh 1 enzyme t ng h p NO, v s hnh thnh NO sau gy ra FMD. T bo n i m c m ch b t n thng lm m t kh nng ch ng ng do gi m gi i phng v gi m t ng h p thnh ph n Prostacyclin (PGI-2); gi m t ng h p v gi m ho t tnh sinh h c c a protein C, protein S v thrombomodulin; gi m tiu s i huy t do r i lo n t ng h p t-PA, PAI-l; ti p qu nhi u protein thu n l i cho s k t dnh ti u c u (y u t VIII-Willebrand); gi m s n xu t NO.
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- Mng y m ch mu b t n thng d n n hi n t ng tng t ng h p cc protein c b n ngoi t bo m ch y u l collagen type IV. Proteoglycan, fibronectin v lamilin m h u qu c a chng l lm gi m tnh n h i v lm r i lo n kh nng l c c a mng y. - Bn T t bo c trn pht tri n m nh, ph i, tng sinh v lo n s n cng gp ph n lm r i lo n ng mu v tng sinh huy t kh i. - H th ng th n kinh m t qun bnh gi a giao c m v i giao c m: km nh y c m v i cc ch t trung gian ho h c c a h i giao c m nh acetycholin, do hi n t ng co m ch chi m u th . Phng php o FMD : Do c nhi u nghin c u FMD nh ng v tr ng m ch khc nhau trn c th cng nh cc cch ti n hnh gy p l c p v i kho ng th i gian khc nhau. Nm 2002 . T ch c Tim M ch i H c M (American College of Cardiology Foundation) ng thu n v k thu t c a phng php o FMD. Trang thi t b chnh l my siu m Doppler 2D mu c ph n m m m ch mu v i u d t n s cao (trn 7,5 MHz). o ng knh tr c v sau khi t o ra kch thch p l V tr c ch n ng m ch cnh tay o n trn h khu u. Khi kch thch p gy t c dng ch y c t o ra b ng m t my o huy t p v i bng o c qu n v tr cnh tay trn ch ng m ch c o ho c v tr c ng tay d i. Th i gian nh t s gin m ch t i a l 50 giy sau khi lm ngng dng ng m ch c ng tay v 70 giy i v i ng m ch cnh tay. ch y Do s gin m ch t n m c t i a khi ng m ch b t t trong 5 pht, th i gian ny c ch n lm th i gian lm ngng dng ch y. Bm p l c b ng my huy t p ln m c v t qu huy t p tm thu 50mmHg lm t c dng ch y t o ra kch thch v gi trong 5 pht. Sau x nhanh p l c huy t p t o ra ph n ng c ng mu. ng knh ng m ch cnh tay c o tr c v sau khi x p l c c o t i cng v tr. T l ph n trm gi a ng knh sau khi t o kch thch v ng knh tr c g i l FMD. Cng th c tnh FMD = (D2 D1)/D1* 100 (%) C suy gi m ch c nng n i m c khi FMD < 5,0 %.
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Hnh 2 v 3: S minh ho hnh nh siu m ng m ch cnh tay kh o st p ng dng ch y trch d n theo Corretti, M. C. et al. J Am Coll Cardiol 2002;39:257-265 2. Kh o st b dy l p n i trung m c ( Intima Media Thickness)
Hnh 4 v 5: siu m 2D b dy l p IMT bnh th ng (ph i) v dy ln (tri) Sau phng php nh gi p ng n i m c qua trung gian dng ch y, t n thng s m x v a ng m ch c th pht b ng o b dy l p n i trung m ch (IMT) b ng siu m 2D v i u d c ly gii cao 7,5 MHz t i cc ng m ch nng nh ng m ch c nh, ng m ch ch , ng m ch i, ng m ch kheo.Phng php o IMT b ng siu m 2D c Pignoli P. (1986) l n u tin xu t V phng di n hnh nh siu m, h th ng m ch mu chia lm 2 nhm bao g m nhm A trong v phng di n i th lng m c bnh th ng ho c c gii m (fatty streak) v nhm B trong c t n thng x v a ng m ch. Trong nhm A c trng m ch mu bi u hi n d i hnh nh hai ng h i m song song c phn cch nhau b i m t kho ng gi m h i m ho c khng c h i m . Bi u m t c t c xc nh nh l bi u 2 ng trong ng bn trong (pha lng m ch) th ng u d n, m m m i v m ng hn so v i ng bn ngoi. Tng quan v i cc hnh ny v i m u tiu b n l n c ch p nh n v i ng bn trong l n i m c, ng gi m h i m l trung m c v ng h i m bn ngoi l ngo i m c. V v y khi o kho ng cch t ng h i m bn trong n kho ng phn
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gi i (interface) gi a ng gi m h i m v ng h i m th hai g i l b dy n i trung m c (IMT) c a thnh m ch. VI. KT LU N R i lo n ch c nng v c u trc n i m c m ch l nh ng thng t n u tin c a ti n trnh x v a ng m ch. Ngoi s h n ch v ki m sot cc y u t nguy c gy r i lo n v ch c nng v c u trc c a n i m c,vi c pht hi n s m t n thng x v a ng m ch b ng 2 thm d khng xm nh p nh nh gi p ng gin m ch qua trung gian dng ch y (FMD) ng m ch cnh tay v o b dy l p n i trung m c (IMT) c a cc ng m ch nng nh ng m ch c nh ho c ng m ch i gp ph n c i thi n tin l ng b nh nhn c nguy c cao b x v a ng m ch. TI LI U THAM KH O 1. Bots ML, Westerink J, Rabelink TJ, de Koning EJ. Assessment of flowmediated vasodilatation (FMD) of the brachial artery: effects of technical aspects of the FMD measurement on the FMD respond. Eur Heart J. 2005;26(4):363-8. 2. Corretti MC, Anderson TJ, Benjamin EJ, Celermajer D, Charbonnaeu F et al. Guidelines for the ultrasound assessment of endothelial-dependent flow-mediated vasodilation of the brachial artery. J Am Coll Cardiol, 2002;39:257-265. 3. De Roos NM, Bots ML, Schouten EG, Katan MB. Within-subject variability of flow-mediated vasodilation of the brachial artery in healthy men and women: implications for experimental studies. Ultrasound Med Biol. 2003 Mar; 29(3):401-6. 4. Donald AE, Halcox JP, Charakida M, Storry C et al. Methodological approaches to optimize reproducibility and power in clinical studies of flow-mediated dilation. J Am Coll Cardiol. 2008 May 20;51(20):1965-6. 5. Faulx MD, Wright AT, Hoit BD. Detection of endothelial dysfunction with brachial artery ultrasound scanning. Am Heart J. 2003 Jun;145(6):943-51. 6. Fronek A, Allison M. Non-invasive assessment of endothelial activity in patients with coronary heart disease and cardiovascular risk factors. Vasa. 2008 May;37(2):137-42. 7. Hasan Korkmaz, Orhan Onalan. Evaluation of endothelial dysfunction: FlowMediated Dilation. Endothelium. Volum 15, Issue 4 July 2008, pages 157-163. 8. Hiroyoshi Komai, Yayoi Higami, Hisaharu Tanaka et al. Impaired flowmediated endothelium-dependent and endothelium-independent vasodilation of the brachial artery in patients with artherosclerotic peripheral vascular disease. Angiology, 2008. Vol 59, No1:52-56. 9. Jadhav UM, Sivaramakrishnan A, Kadam NN. Noninvasive-Assessment-ofEndothelial duysfunction by brachial artery flow-mediated dilatation in prediction of coronary artery disease in Indian subjects. Indian Heart J. 2003;55:44-48. 10. Juonala M, Viikari JS, Laitinen T, Marniemi J, Helenius H, et al. Interrelations between brachial endothelial function and carotid intima-media thickness in young adults : the cardiovascular risk in young Finns study. Circulation. 2004 Nov 2;110(18):2918-23.
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11. Korkmaz H, Onalan O. Evaluation of endothelial dysfunction: flowmediated dilation. Endothelium. 2008 Jul-Aug;15(4):157-63.
I U TR R I LO N CH C NNG N I M C M CH
Tr ng Nguy n H i Thu i H c Y D c Hu
I. B NH NGUYN R I LO N CH C NNG N I M C N i m c m ch mu (vascular endothelium) l m t l p t bo n m gi a lng m ch mu v l p t bo c trn m ch mu.V phng di n chuy n ho l p n i m c ho t ng v s n xu t m t s ch t trung gian lin quan n v n m ch trong ch t nitric oxide (NO) d n xu t t t bo n i m c l ch t c b n trong duy tr s h ng nh n i mi m ch mu . N i m c m ch mu l m t c quan c n n i ti t l n, n ti t ra nhi u y u t i u ha trng l c m ch mu, gip pht tri n c a t bo, cc tng tc c a b ch c u v ti u c u v c tnh sinh ng. Nh ng nh n c m v p ng c a n i m c i v i v s cc kch thch bn ngoi v bn trong thng qua cc ph c h p th th mng t bo v nh ng c ch truy n t i tn hi u, d n n s t ng h p v phng thch cc ch t ho t m ch, cc y u t pht tri n v i u ha ng mu. Vai tr c a n i m c m ch mu trong b nh l ng i g n y tr thnh tm i m nghin c u c a cc nh khoa h c. Suy gi m ch c nng n i m c c lin quan v i m t s tnh tr ng b nh l nh i tho ng, r i lo n lipid mu, tng huy t p, bo ph R i lo n ch c nng n i m c l m t trong nh ng d u hi u chnh v s m c a b nh sinh x v a m ch, d bo nh ng thay i x v a ng m ch Nguyn nhn gy r i lo n ch c nng n i m c Cc i u ki n ph i X v a ng m ch, tng cholesterol mu, tng LDL.C, gi m h p v i r i lo n HDL.C, tng Lp(a), tng LDL.sd, LDL.C oxy ho, tng huy t ch c nng n i m c p, tng homocystein, tu i, vim m ch mu, ti n s n gi t, h i ch ng chuy n ho, au th t ng c khng n nh, i tho ng, ht thu c l ch ng v th ng, ti t i mu sau thi u mu, x v a ng m ch, bypass tim ph i, mn kinh, b nh Kawasaki, b nh Chagas, ti n s gia nh b nh m ch vnh, nhi m khu n, tr m c m, t ho t ng, bo ph, suy th n, tng CRP, suy tim sung huy t, ph i th t tri, sau n Can thi p nh m c ch enzym chuy n, c ch th th angiotensin, c ch c i thi n ch c endothelin, statin, tetrahydrobiopterin, folate, t p th d c, tng nng n i m c nh y insulin, gi m LDL, tng HDL, chng oxy ho, Larginine, desferoxamine, glutathione, gi m homocystein, gi m CRP, gi m FFA Cc ch t ch i m CAMs, y u t von Willebrand, nitrite, khng tng thch ho tan c a r i (asymetric) dimethylarginine , CRP, tPA, fibrinogen, amyloid lo n ch c nng n i A m c II. I U TR R I LO N CH C NNG N I M C R i lo n ch c nng n i m c l giai o n s m c a x v a ng m ch ni ring v t n th ng m ch mu ni chung. Khi xu t hi n cc d u ch ng lm sng c a b nh x
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v a m ch th ng l b nh giai o n b c pht v khi vi c x tr th ng l ch lm gi m nh b nh ho c nh m vo vi c b o v th pht. V v y phng ng a b nh x v a ng m ch giai o n s m c th t c b ng cch pht hi n v i u tr r i lo n ch c nng n i m c, m t trong nh ng thay i quan tr ng nh t giai o n ti n lm sng c a b nh x v a ng m ch. B nh nhn T c bi t l T type 2 l m t b nh l v i nhi u y u t nguy c ph i h p trn cng b nh nhn. V th song song v i ki m sot ng huy t vi c d phng v i u tr cc y u t nguy c ph i h p r t quan tr ng 1. Thay i l i s ng v ki m sot ch ti t th c ti t th c l M t s nghin c u ghi nh n thay i l i s ng v ki m sot ch m t trong nh ng bi n php h tr v gp ph n c i thi n tnh tr ng r i lo n ch c nng n i m c, Lavrensic A v CS (2000) nghin c u hi u qu c a t p th d c ln FMD i t ng 29 ng i c h i ch ng chuy n ha tu i t 40 n 60. K t qu 3 l n t p th d c m i tu n trong 12 tu n th FMD gia tng ng k so v i tr c t p (5,3 2,8% tr c t p so v i 7,3 2,7% sau t p, p < 0,05). Nicholas Tentoluris v CS (2008) nghin c u tc d ng c a b a n giu acid bo b o ha v khng b o ha i v i FMD b nh nhn i tho ng type 2. K t qu sau b a n giu acid bo b o ha, FMD gi m c ngha th ng k. Ng c l i nhm dng b a n c acid bo khng bo ha (d u liu) th FMD thay i khng ng k . Nghin c u ny g i ch n v i ch t bo khng b o ha c th gip c i thi n r i lo n ch c nng n i m c. 2. Ki m sot ng huy t Tng ng huy t l m t trong nh ng nguy c gy r i lo n ch c nng n i m c. V th vi c ki m sot t t ng huy t d i m i hnh th c l i u tr c b n nh m h n ch t n thng n i m ch b nh nhn T . Nhi u nghin c u ghi nh n tng n ng glucose mu gy r i lo n gin m ch ph thu c n i m c. Gi m n ng glucose mu ngoi lm gi m n ng insulin cn gp ph n c i thi n ch c nng n i m c. V th i u tr c n nh m n l h ng huy t v tng nh y c a insulin. 3. c ch PKC Tng ng mu c th gia tng ho t ho PKC trong gia tng stress oxy ho. S d ng cc ch t c ch PKC c th ph c h i ch c nng m ch mu v cng lm gia tng s trnh by mRNA c a eNOS trong t bo n i m c ng m ch ch . G n y, ch t c ch PKC, LY33531 c s d ng. Thu c ny lm bnh th ng lu l ng mu vng m c, t l l c c u th n song song v i tc d ng c ch PKC. Beckman v c ng s nh n th y c ch PKC lm gi m s r i lo n gin m ch ph thu c n i m c ng i kho m nh c lm tng ng mu. 4. Cc ch t c ch t ng h p AGE. S n ph m AGE l k t qu r i lo n v lu di c a protein i v i tng ng mu v i cc tc d ng lm gi m NO tr c ti p v gia tng stress oxy ho. Ch t aminoguanidine, ch t c ch t ng h p AGE cho th y lm gi m n ng AGE v c i thi t ch c nng n i m c ng v t th nghi m. 5. Tetrahydrobiopterin Tng ng mu lm tng stress oxy ho c th lm gia tng bi n i NO thnh peroxynitrite, ch t lm t n thng ch c nng thnh m ch. Gi m stress oxy ho c th ph c h i ch c nng thnh m ch hn l cung c p NO. Tng ng huy t ko di v
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tng cholesterol mu gy ra s khng lin k t c a eNOS v lm gi m s n xu t NO. Nghin c u trn ng v t b i ng th c nghi m v b nh nhn tng Cholesterol ghi nh n s d ng ch t Tetrahydrobiopterin lm ph c h i gin m ch ph thu c n i m c. Tuy nhin cha kh ng nh cc nghin c u b nh nhn T . 6. L-arginine L-arginine cung c p c ch t cho NO, s d ng L arginine t ra c hi u qu cho ng i l n ng v t. Ti t th c L arginine trong 10 tu n cho th y d phng dy n i m c ng m ch vnh v gi m ph n ng ti u c u th b tng cholesterol. Dng L arginine ng u ng lm gi m tn sinh n i m c t n thng sau khi nong bng th tng v khng tng cholesterol mu. ng i s d ng L arginine lm gi m s tng ho t ng ti u c u ng i tng cholesterol mu. Dng L arginine tnh m ch gi m khng m ch ngo i bin v gi m huy t p tm thu v tm trng, c i thi n gin m ch vnh ph thu c n i m c nh m p ng acetylcholin trong m ch vnh ng i tng cholesterol v ng m ch chi d i b thi u mu. Nhm Deanfield ghi nh n c i thi n lu ng mu cung c p L-arginine khng c i thi n gin m ch qua trung gian dng ch y b nh nhn T ph thu c insulin. 7. Estrogen T n su t b nh ng m ch vnh ph n ti n mn kinh th p hn nam gi i cng tu i trong gi i thch m t ph n nh nh h ng Estrogen. Estrogen c cc tc d ng quan tr ng trn ch c nng thnh m ch m khng hon ton gi i thch d a trn s c i thi n lipid mu. B nh nhn n T c cng nguy c tim m ch nh l ng i nam c xu t r ng, h b gi m tc d ng b o v tim m ch c a Estrogen khng T nh l ng i ph n ti n mn kinh khc. Estrogen c nh ng tc d ng c l i, khng nh ng c ch ngng t p ti u c u m cn c tc d ng ch ng oxy ho v tc d ng ch ng tn sinh trn c trn m ch mu. Nhi u nghin c u ch ng t r ng Estrogen c i thi n s gin m ch ph thu c n i m c ng v t b c t bu ng tr ng v ph n h u mn kinh. C ch c th l do thc y s n xu t eNOS ho c l do c ch co m ch ph thu c Prostaglandine H synthase prostanoid. Lim v c ng s ghi nh n r ng li u php hormone thay th c i thi n cc ph n ng vi m ch ph n sau mn kinh kho m nh. Tc d ng ny c v y u ph n T type 2. Tuy nhin li u php hormone thay th c i thi n ho t ho n i m c c quy t nh b i m t phn t k t dnh n i bo ho tan nh ng ph n T type 2. 8. Cc ch t c ch enzym chuy n Cc ch t c ch enzym chuy n cho th y c i thi n ch c nng n i m c v lm gi m s pht tri n x v a ng m ch cc ng v t th nghi m c tng cholesterol mu d a vo tc d ng c l p v i tc d ng h huy t p. Tng t , nghin c u HOPE (Heart Outcomes Prevention Evaluation) ch ng t r ng ch t ramipril ( c ch enzim chuy n) trong d phng cc bi n c tim m ch b nh nhn T m c d c ch c a tc d ng ny cha r. Cc th nghi m lm sng ch ng t r ng ch t quinapril ( c ch enzym chuy n) c i thi n ch c nng n i m c b nh nh n khng T c b nh m ch vnh. Cc nghin c u nh gi tc d ng c a c ch men chuy n trn b nh nhn T type 1 c nh ng k t lu n bn ci trong m t s nghin c u ch ng t r ng c ch enzym chuy n khng c tc d ng trn ch c nng thnh m ch b nh nhn T type 1 sau 6 thng i u tr . Tuy nhin, ODriscoll v c ng s ghi nh n c i thi n ch c nng n i m c do c ch enzym chuy n b nh nhn T ph thu c insulin.
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c ch men chuy n cng c i thi n ch c nng n i m c ph thu c NO c b n v kch thch b nh nhn T type 2 bao g m b nh nhn b tng huy t p v b nh th n T . Tuy nhin, khng th y hi u qu c a c ch enzym chuy n trn b nh nhn c h i ch ng khng insulin. Cc ch t c ch enzym chuy n c m t s tc d ng c l i trn c u trc v ch c nng m ch mu. c bi t, chng thc y hi u qu sinh h c c a NO. Ch t sau ny c th l do gi m s n xu t qua trung gian angiotensin II c a superoxides ho c thng qua c ch ging ho bradykinin, m t ch t c ti m nng kch thch NO phng thch
S 9.
c ch tc d ng c ch enzyme chuy n trn n i m c m ch
c ch HMG CoA Reductase Nhi u th nghi m lm sng kh ng nh r ng nhm Statins lm gi m ng k t l t vong v m c b nh tim m ch. Ngoi ra, i u tr gi m lipid mu cng c i thi n ch c nng n i m c. C i thi n r i lo n gin m ch ph thu c n i m c x y ra trn b nh nhn T c r i lo n lipid l r t t v ph i h p. Akalin A v CS (2008) nghin c u tc d ng c a Atorvastatin ln FMD ng I i tho ng type 2. K t qu cho th y Atorvastatin c i thi n c ngha ch c nng n i m c (thng qua FMD) b nh nhn i tho ng type 2. R i lo n gin m ch ph thu c n i m c b nh nhn T type 2 c r i lo n lipid mu c ghi nh n l c i thi n v i i u tr fibrate (ch t lm gi m n ng triglyceride huy t thanh) nhng khng ph i v i statins
191
C ch tc d ng nhm statin trn t bo n i m c 10. Arginine ngh ch l (Arginine paradox) Cc tc d ng c l i c a L-Arginine ngo i sinh trn m ch mu c a m t s tnh tr ng b nh l v i s gia tng n ng nitrate v cGMP huy t tng trong qu trnh i u tr L-arginine xu t s cung c p nhi u L-arginine c th kch thch ho t ng NOS. Tuy nhin i u ang th c m c l s d ng arginine ngo i sinh s a n s n xu t nitric oxide khi n ng arginine ngo i bo lun ph h p trong s gia tng qu m c nhu c u c a NOS, m t hi n t ng g i l arginine ngh ch l. i u ny l n u tin c ch ng t th b tng cholesterol mu v cng c quan st trn b nh nhn tng p ph i. nhi u gi i thuy t i v i hi n t ng ny. y l c th l do ch t c ch n i sinh c a NOS,ADMA, c th i khng v i n ng n i bo bnh th ng c a L-arginine. V cung c p thm arginine c i h i kh c ph c s khi m khuy t c a c ch t NOS. Th hai. V eNOS nh v u th v tr n i bo c bi t c bi t l caveolae, n ng t i ch c a L-arginine trong vi mi tr ng ny c th khc v i n i m ch. V n cha r lm th no s nh v c hi u c a eNOS b i caveolae c th nh h ng n c ch t t i ch thch h p, nhng c ch lin quan s ng nh v c a eNOS c a m t vi ch t v n chuy n arginine (v d v n chuy n acid amine cation -1 ( cationic amino acid transporter-1). S thnh l p c a ph c h p caveolar nh th c v thu n l i chuy n giao arginine t eNOS i u quan tr ng nh n bi t l tc d ng gin m ch c a L-arginine khng hon ton trung gian tr c ti p b i nitric oxide. L-arginine c th c ch trng l c giao c m ngo i bin a n gin m ch qua s chuy n ho c a n, ch t abmatine, kch thch th th alpha2 trung ng. Thm vo arginine cng kch thch phng thch nhi u hormone nh glucagon, prolactin v growth hormone c th gy tc d ng gi n m ch. Ngoi ra m t vi m ch mu v tc d ng khc c a argnine b phn chia b i lo i ng phn hnh thi c a chng, D-arginine, khng ph i c ch t c a NOS. C ch ph c t p qua L-arginine c th c i thi n ch c nng m ch mu trong m t vi tnh hu ng ng c thm d sau ny. 11. Nitrovasodilator/Nitric oxide donor
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Cc lo i gin m ch nitro (Nitrovasodilator) nh amyl nitrite, glyceryl trinitrate, sodium nitroprusside v molsidomine l ti n ch t v c tc d ng sau khi chuy n ho thnh nitric oxide. V th c g i l cho nitric oxide (nitric oxide donor). D a trn cc thu c tnh gin tnh m ch cc thu c c s d ng trong suy tim v au th t ng c. Nitrosoglutathion l ph c h p c a nhm nitrosothiol nghin c u r ng r i trn ng i. thu c c tc d ng khng ngng t p ti u c u, cn b ng gin ng v tnh m ch hn nitrate h u c. Nitrosoglutathione c ch ho t ho ti u c u trong ng m ch vnh sau khi nong vnh v lm c u n i. V th nitrosothiol c thu c tnh d c h c trong i u tr thi u NO v c th ch t cho nitric oxide lo i c th c tri n khai khc hn thu c hi n t i 12. Nitric oxide d ng ht ( Inhalation of nitric oxide) Nitric oxide d ng ht c i thi n m t s tr ng h p mao m ch ph i, bao g m tng p ph i dai d ng tr s sinh, tng p ph i th phi sau thi u kh m n, h i ch ng suy h h p ng i l n. Thu c cn c ti m nng trong c i thi n ph ph i c p v ch ng methaemoglobinaemia. 13. Chuy n i gen (Gene transfer) Chuy n i tr c ti p gen NOS ng d ng n thnh m ch b r i lo n v n m ch v c vai tr trong i u tr cc b nh tim m ch . S ti p c n ny cho th y hi u qu trong cc th nghi m v b nh m ch mu c a cc ng v t th nghi m. i u tr gen m ch mu c a d n ch t eNOS n t ch c c bi t thc y s n xu t NO v tr c n quan tm. Chuy n gen NOS th c hi n l n u tin nm 1995, khi eNOS cDNA, l y t ng m ch c nh c a chu t sau khi t n tng do nong bng. trong m t ph c h p v i virus ngng k t c a Nh t B n. i u ny t o ra m t s gi m tn sinh n i m c ngy th 14. Sau m t k t qu tng t c kh ng nh b i m t nhm nghin c u khc ng m ch v tnh m ch ch u v vnh ghp. Gen tr li u cng lan r ng t chuy n giao t i ch cho n h th ng. a m t li u eNOS cDNA c a r n vo h th ng tu n hon qua tnh m ch ui c a chu t b tng huy t p t pht k t qu tng s n xu t v bi ti t cGMP v nitrite/nitrate, v gi m ng k huy t p tm thu ko di 12 tu n. 14. c ch NOS Dng c ch iNOS cho th y c i thi n thay i huy t ng qua trung gian v i NO trong th c nghi m c a chong nhi m khu n. i u tr tnh m ch L-NMMA d n ch t arginine (arginine analogue l-NMMA) lm c i thi n s gi m khng m ch mu ngo i bin v gi m huy t p ng m ch ch nhi m n i c t . Cc tc d ng tng t v i L-NMMA cng kh ng nh ng i. Tuy nhin tng p ph i v gi m cung l ng tim cng ghi nh n sau khi dng c ch NOS. Trong tng lai pht tri n thu c trong l nh v c ny nh m vo d ng NOS ng d ng c hi u cng nh c p c a c ch i h i s n xu t cc d c ph m c hi u qu t i u. 15. Ch ng oxy ho (Antioxidants) T khi stress oxy ho gy bi n ch ng r i lo n ch c nng n i m c, nhi u nghin c u v vai tr thu c ch ng oxy ho trn ch c nng m ch mu v d phng bi n ch ng tim m ch. Chnh vitamine C (ascorbic acid) ng tnh m ch cnh tay c i thi n gin tnh m ch ph thu c n i m c b nh nhn T type 2, ng i ht thu c l v tng cholesterol mu. Tng t dng vitamin C b nh nhn b nh m ch vnh c i thi n gin m ch qua trung gian dng ch y. Tc d ng ny c l i x y ra nhanh sau 2 gi v ko di
193
30 ngy. Ngoi ra dng vitamin C cn c i thi n gin m ch ph thu c n i m c ng m ch th ng tm m c b nh nhn tng huy t p khng c b nh m ch vnh. b nh nhn b nh m ch vnh ph i h p vitamin C v L-arginine gy gia tng gin m ch ng k . Ngoi ra vitamin C c m t s tc d ng ti n oxy ho (pro-oxidant effects) trong m t s tnh hu ng. Vitamin C R i lo n ch c nng n i m c trong T type 1 v 2 l do b t ho t ch t NO b i cc g c t do d n xu t oxy. C m t s gi m n ng ch t ch ng oxy ho n i sinh bao g m ch t superoxide dismutase v catalase ng v t T th nghi m. Ngoi ra nhi u nghin c u lm sng ghi nh n c s gi m n ng vitamin C v E n i sinh T type 1 v type 2. B t c cc phng ti n lm gi m stress oxy ho u c ti m nng c i thi n gin m ch ph thu c n i m c. Timimi v c ng s , Ting v c ng s ghi nh n khi truy n vo trong vitamin C vo trong ng m ch c i thi n s gin m ch ph thu c n i m c b nh nhn T type 1 v type 2. Ngoi ra, truy n vitamin C c i thi n r i lo n ch c nng n i m c nh ng ng i kho m nh c gy tng ng mu. Vitamin E Vitamine E (- tocopherol) tan trong m , trong thin nhin g m 8 d ng khc nhau c a hai h p ch t l tocopherol v tocotrienol. (1)Tocopherol c phn b r ng ri nh t trong thin nhin, n c c u trc vng v i m t chu i di bn c nh, v c b n d ng l -toco, -toco, - toco, v - tocopherol (chng c phn bi t b ng s l ng v v tr g ng c a nhnh methyl trn vng). Trong -tocopherol l ch t c ho t tnh sinh h c nhi u nh t v (2) Tocotrienol cng c b n d ng nh v y v c phn bi t v i tocopherol b ng chu i di khng bo ha. D ng vitamin E c ngu n g c t ng h p chnh l t t c cc racemic--tocopherol l m t h n h p g m 8 ng phn quang h c. C hai d ng t nhin v t ng h p c a vitamin E u c cng cng th c phn t , nhng khc nhau v c u trc khng gian ba chi u. Ch c nng chnh c a Vitamin E trong c th l tc ng nh l ch t ch ng oxy ha - n c xem l hng phng th tr c tin ch ng l i qu trnh peroxyd ha lipid. m c t bo Vitamin E tc ng b o v mng t bo kh i s t n cng c a g c t do lm t n h i n mng t bo n th c s h i nh p vo l p lipid kp xung quanh t bo. Nh l m t ch t thu d n g c t do, Vitamin E b o v cc acid bo khng bo ha (PUFA) v cholesterol trong mng t bo. Cc t bo h ng c u (RBCs) c hm l ng PUFA cao v Vitamin E c nhi m v b o v h ng c u kh i b huy t tn. Nh l m t ch t ch ng oxy ha n i t bo, Vitamin E ti t ki m selenium, ch t ny ch a trong enzym glutathion peroxydase. y l thnh ph n khc c a h th ng phng th ch ng oxy ha c a c th v b o v nh ng ch t tng t ch t bo khc nh Vitamin A kh i b phn h y. Vitamin E gi vai tr l m t ch t thu d n v ch ng oxy ha, n c i thi n c ch c nng t bo n i m c, b y cc g c oxy t do, c ch s k t dnh v phng thch cytokine c a cc t bo n nhn l p n i m c. M t s nghin c u ghi nh n Vitamine E c tc d ng c ch s k t dnh v ngng t p ti u c u qua c ch ph thu c protein kinase C. Vitamin E cn i u ha s ngng t p ti u c u b ng tc ng c ch ho t ng c a cyclooxygenase v lm gi m s sinh t ng h p prostaglandin (throm boxan). Trn th nghi m cng nh trn th c t , nhi u b ng ch ng cho th y khi i u tr b ng vitamin E c th lm o ng c ho t ng c a protein kinase C m chng ta bi t
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ho t ng ny ch u trch ni m chnh trong r i lo n ch c nng n i m c m ch mu b nh nhn T . Ngoi ra, vitamin E cn c i thi n c ch c nng gy gin ng m ch qua NO v duy tr s ton v n, tnh n nh protein c a mng t bo. Theo Pathania v cs (1998) v Lang v cs (2000) c nh ng minh ch ng v vai tr c a vitamin E ng m ch ch , ph i v nhi u c quan khc Vitamin E l ch t u tin ch ng l i hi n t ng peroxy ha c a acide bo a khng bo ho (polyunsaturated) ch a trong phospholipid c a mng t bo v mng n i bo b i v n g n k t v i cc g c peroxyl t do. Vitamin E cn k t h p v i hng lo t cc s n ph m oxy ho t ng nh oxy n d ng, cc g c peroxy t do. NO c th tng tc v i cc anion superoxide (O2 ), t o ra nhn peroxynitrite oxy c (ONOO ). Peroxynitrite do s nitrat ha cc residues tyrosine lm thay i c ch c nng v c u trc protein trong nh ng con ng tn hi u. Tr c y, ng i ta bi t c tnh tr ng tng peroxynitrite v s hi n di n qu m c c a nitrotyrosine trong protein b nh nhn T . M ph n ng dng tnh v i nitrotyrosine c dng nh l ch t ch i m gin ti p c a stress oxy ha. Trong Y vn cng cho th y vai tr h ng th n kinh m nh c a vitamin E nh ng ng v t b tnh tr ng thi u mu. Do v y n c tc d ng gi m stress oxy ha b nh nhn suy tim xung huy t, c ch th cha c r nhng c th n tham gia m t ph n vo vi c c i thi n p l c trong coporal. Tm l i, c nhi u b ng ch ng cho th y tc d ng t t c a vitamin E trong qu n th b nh nhn T . Evans v cs (2002) ghi nh n tng ng mu c th a n ho t ha cc kinase v cc protein kinase ho t tnh stress ch u trch nhi m trong nhi u thay i b nh l c bi t trn qu n th ny. Vitamin E d ng nh c i thi n tc ng c a insulin ng i b i tho ng. Nh l tc ng c a m t ch t ch ng oxy ha, n c th b o v c u trc mng t bo l ng l o kh i s gia tng peroxy ha lipide v ngn c n s h h ng ch c nng c a cc tc nhn v n chuy n glucose. Cc cng trnh nghin c u v tc ng c a Vitamin E trn b nh nhn T s d ng li u t 100 IU n 900 IU. Trong m t th nghi m lm sng, nhm b nh nhn T i u tr nh n 100 IU Vitamin E k t qu gi m 10% l ng HbA 1C v gi m 24% n ng glucose mu trn cc b nh nhn ny. Ngoi vitamin E m t s ch t cng c c p c tc d ng ch ng oxy ho c trnh by nh vitamin C, Betacaroten, selenium, magnesium... Ch t c ch PDE type 5 Nh ng k t qu nghin c u g n y v Vardenafil, Tadalafil, Sildenafil cho th y tc d ng c a cc ch t trn c th gi m stress oxy ha lin quan v i tc d ng h ng mu v h lipid mu c a chng b nh nhn T , bn c nh nh m t y u t xc tc, chng c th lm gi m hi n t ng peroxy ha lipid. Vi c i u tr ph i h p ch ng oxy ha v ch t c ch PDE type 5 l m t ti p c n i u tr r t h u ch. M c d c nhi u nghin c u cho th y ch ng oxy ha trn T khng k t qu , nhng v n cn qu s m kh ng nh i u ny. Alpha lipoic acid c k t qu trong b nh l th n kinh. B nh nhn T c nguy c stress oxy ha nhi u hn qu n th chung. D a trn nh ng hi u bi t m i v sinh l b nh c a stress oxy ha, c n c nh ng nghin c u v ch t c ch thnh l p cc g c ph n ng. Cc tc nhn d ki n l ty th tr ng l ng phn t th p, SOD bo tng, ng v n catalase, L-prropionyl carnitine,
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PKC- beta inhibitor LY-333531, peroxynitrite catalyst FP15 v DNP khng g n ty th . K t lu n nhi u ch ng c v tc d ng c h i c a stress oxy ha trn ch c nng m ch mu v lin k t v i c ch b nh sinh i v i bi n ch ng T r t thuy t ph c. Trong khi thi u cc ch ng c v tc d ng c l i ch ng oxy ha c a cc vitamine. V th h i T Hoa K nh n m nh vai tr vitamine ch ng oxy ha v i b nh l tim m ch cha thuy t ph c. V th c n c nhi u nghin c u v sinh l b nh c a stress oxy ha v vai tr c a i u tr ch ng oxy ha s c ti p c n trn lm sng. TI LI U THAM KH O 1. Akalin A, Temiz G, Akcar N, Sensoy B. Short term effects of atorvastatin on endothelial functions and oxidized LDL levels in patients with type 2 diabetes. Endocr J. 2008. 55(5):861-6. 2. Asnani S, Kunhiraman B, Jawa A, Akers D, Lumpkin D. Pioglitazone restores endothelial function in patients with type 2 diabetes treated with insulin. Metab Syndr Relat Disord. 2006. Fall. 4(3): 179-84. 3. Ennio Ongini, Francesco Impagnatiello, Albino Bonazzi, Massimillano Guzzetta. Nitric oxide (NO)-releasing statin derivatives, a class of drugs showing enhanced antiproliferative and antiinflammatory properties. PNAS. June 1,2004, vol.101. no 22: 8497-8502. 4. Hink U; Tsilimingas N; Wendt M; Munzel. T. Mechanisms underlying endothelial dysfunction in diabetes mellitus: Therapeutic implictions. Treatments in Endorinology, volume 2, number 5, 2003: 293-304 5. Lavrensic A, Salobir BG et al. Physical training improves flow-mediated dilation in patients with the polymetabolic syndrome. Arteriosclerosis, Thrombosis, and Vascular Biology. 2000,20:551. 6. Nicholas Tentolouris, Christina Arapostathi, Despoina Perrea et al. Differential effects of two isoenergietic meals rich in saturated or monounsaturated fat on endothelial function in subjects with type 2 diabetes. Diabetes Care, 2008 Dec;31(12):2276-8. 7 Jeannette Schultz Johansen, Alex K Harris, David J Rychly and Adviye Ergul (2005). Oxidative stress and the use of antioxidants in diabetes: Linking basic science to clinical practice. Cardiovascular Diabetology. 8 Michael Phillips, Renee N. Cataneo, Taseer Cheema, Joel Greeberg. (2004) Increased breath biomarkers of oxidative stress in diabetes mellitu. Clinica Chimica Acta 344, pp 189-194. 9 Giugliano D, Cerillo A, Paolisso G.(1998) Oxdative stress and diabetic vascular complication. Diabetes Care. 10. A.C Maritim, R.A. Sanders, J.B. Watkins III (2003). Diabetes, oxidative stress, and antioxidants: A review. Research Article- Journal of Biochemical and Molecular Toxicology. Volume 17, issue 1, pp 24-38. 11. Ray D. Strand (2005). Oxidative Stress. Health Concepts, PO Box 9226, Rapid city, SD 57709. 12. Dan Rutheford,GP (2005). Antioxidants and oxidative stress. Diet and nutrition.
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B NH SINH X V A V B NH M CH MU TRONG I THO NG TYPE 2

Tr ng Nguy n Th Nh n i h c Y D c Hu
KHNG INSULIN L G? Vai tr ch y u c a insulin l lm d cho glucose vo t bo c, h n ch tn sinh glucose t gan. tr ng thi bnh th ng, l ng insulin c n thi t duy tr m c glucose ph thu c vo kh i c v l ng glucose tn sinh t gan. Tuy nhin, m c insulin huy t tng i khi c ti t nhi u hn g p hai l n bnh th ng m i duy tr c m c glucose mu bnh th ng (Hollenbeck and Reaven, 1087). S thay i l ng insulin ny c g i l khng insulin, nh v y ng i c n l ng insulin cao hn so ng i c n l ng insulin th p hn th g i ng i b " khng insulin". B nh sinh khng insulin l i m c trng chnh c a T type 2, v khng insulin i tr c pht tri n lm sng c a b nh T t 10 n 20 nm (Warram et al, 1990). khng insulin l do gi m tnh dung n p c a m ch ngo i bin (m c, ch ng l i s gan) i v i m c insulin bnh th ng. u tin t y tng ti t insulin l khng insulin v nh v y duy tr glucose bnh th ng. Tuy nhin, l ng d tr c a t y gi m so v i nhu c u ngo i bin, v nh v y glucose mu tng cao, nguy c a n r i lo n glucose mu i, r i lo n dung n p hay i tho ng type 2
i tho ng tp 2 Nguy c b nh tim
T n thng MM lin quan n tng Glucose mu ch lm tng nh d c c a nguy c
khng insulin Nh y c m insulin
Nh ng y u t nguy c lin quan n khng insulin, bo ph, a n ti nT : -RL lipid, -THA -Rl ng mu -RL ch c nng n i m c -Vim
Th i gian
Hnh 1: khng insulin tng d n theo tu i, t y th ng ti t tng l ng insulin trong nhi u nm, duy tr glucose mu. m t s b nh nhn, t y lm vi c n ki t s c, nn sau glucose mu cao ng ng ti n T hay T . Tuy nhin, nhi u y u t nguy c khc nh tng TG, THA th ng lm n ng thm tnh tr ng khng insulin. Chnh cc r i lo n ny l nguy c b nh tim m ch v i u ny cng gi i thch t i sao nguy c b nh tim m ch th t s cao ngay khi ch n on T type 2. Tuy nhin tng
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glucosse mu ch l m t trong nhi u y u t nguy c tim m ch, do n u ch i u tr tng glucose mu thi, th ch m i gi m nh nguy c tim m ch m t ph n. VAI TR C A INSULIN C s lin k t gi a nhi u thng s nguy c v s gia tng nguy c cho i tho ng type 2. Trong insulin tc ng trn m c, m m , m gan, n i m c m ch mu v c t bo mi n d ch (Ritchie v cs 2004, Bloomgarden 2005, Reaven 2005). Nh v y insulin khng ch gip a glucose vo t bo, chuy n ha, m cn c nh ng ch c nng sau: - Ngn c n phng thch acide bo t do t m m , nn duy tr l ng th p a.bo t do, bnh th ng ha lipide - H n ch t ng h p triglyceride gan, nn gi m TG v tng HDL-C - Duy tr huy t ng n i m c, tc d ng dn m ch, ngn ngh n m ch - Gi m cytokines, nn i u ha vim
Hnh 2: Ho t ng c a insulin trn m c, m m , m gan, v nh h ng trn c trn n i m c MM, ch c nng t bo mi n d ch. ng i kh e m nh, tnh nh y c m insulin t t, gip duy tr c m c acide bo t do (FFAs) mu th p, nh v y bnh th ng ha c lipids, l p n i m c bnh th ng, m c cytokine th p. Tri l i, ng i c khng insulin, m p ng km v i insulin, th t t c y u t trn s o ng c R I LO N LIPIDS V I THO NG TYPE 2 V i s gia tng bo ph, nh t l bo b ng, t bo m gia tng v tr nn t nh y c m v i insulin. M t ng gia tng ng i bo ph s tng phng thch nhi u acid bo t do vo tu n hon c a, gy tng tch t v tng t ng h p triglycerid (TG) gan, d i d ng VLDL (VLDL c l ng TG cao nh t), h u qu tng n ng TG huy t tng. R rng r ng trong ti n trnh ti n T type 2, ngoi glucose mu, s gia tng TG huy t tng l ch ng c r nt ti n sinh ha c a nguy c m c b nh T type 2 (Freeman et
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al.2002). Th c v y, Theo Wilson v cs (2005) s tng TG l nguy c cao T type 2 hn l b nh tim m ch. Ng c l i, s gia tng TG d i d ng VLDL, lm thc y cc phn t lipids khc sinh x v a. c bi t VLDL trao i TG cho c LDL v HDL-Cholesteryl ester, y l c ch chnh gy gi m HDL-C v tng TG trong mu. c bi t cc phn t LDL sinh x v a, trong khi HDL l y u t b o v tim. Cc r i lo n sinh x v a trn th ng c lm n ng thm sau khi n, do lm gia tng cc remant VLDL giu cholesterol trong huy t tng, cng lm gi m HDL v gi m kch th c cc LDL thm. Khng dung n p TG (t n thng thanh th i lipid mu sau n) l d bo c l p c a s xu t hi n b nh tim m ch (Eberly et al. 2003). Ni chung, tng acide bo t do v TG, gi m HDL-C v tng u th LDL m c, nh ; th th ng ph i h p r t cao v i i tho ng tp 2 v khng insulin. C nhi u c ch , b ng nh ng c ch ny, lipid c th lm gia tng b nh sinh x v a, nh nhi u nghin c u g n y m t chi ti t trong B ng 2.1 (theo Sattar et al.1990). c bi t, cc phn t LDL m c, nh (small, dense LDL particles) i vo n i m c m ch mu d dng hn do kch th c n nh hn. N c gi l i ho c k t dnh b ng cch k t dnh v i m t protein, v nh v y n c oxyde ha, v r i th chng tr thnh khng nguyn v s phng thch tn hi u li ko n bo (monocyte) v d dng bi n chuy n thnh t bo b t (foam cell) do g n vo ch t th th trung gian. M c khc, oxyde ha LDL l tn hi u cha kha u tin c a mng x v a. Oxyde ha phn t LDL cng cho th y c vai tr c t bo, m t ph n do p ng i v i t bo n i m c b t n thng v thoi ha i th c bo t i mng x v a. i u ng ch hi n nay l nhi u nghin c u cho th y t Apo B /ApoA1 cao tin on b nh tim m ch m nh hn t cholesterol/HDL-C (Walldius et al. 2001; Siniderman 2004). Apolipoprotein B l m t protein cha kha v i phn t LDL, ng c l i, Apolipoprotein A1 l m t protein cha kha v i phn t HDL, tc d ng ch ng x v a. G n y, ng i ta ch ng minh r ng Apo B c tng quan r v i khng insulin hn l LDL, v Apo B tng r b nh nhn i tho ng v l ti n t gy b nh l tim m ch. B ng 2.1. S lin k t r rng gi a b nh sinh x v a (theo Sattar et al.1990) Phn t C ch t n thng Lipoprotein giu Triglyceride v phn Tng oxide ha t mnh th a Gy c tr c ti p n l p n i m c C th c n tr hng ro n i m c Kch thch t bo n i m c s n xu t PAI-1 Ho t ha y u t VII Gia tng s k t dnh vo n i m c LDL nh , m c Tng tnh nh y c m t n thng oxyd ha Tng th i tr ngh c a ng m ch Tng tnh th m n i m c m ch mu Tng k t dnh protein vo l p n i m c Acid bo t do (FFA) Tng stress oxyd ha Gip LDL v mnh th a giu choplesterol d dng i vo l p n i m c Gi m c tnh b o v albumin, do lm bi u l VLDL c.
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HDL (hight-density lipoproteins)
Gi m t bo n i m c s n xu t prostacyclin v nitric oxide T n thng kh nng c ch ti u c u c a t bo n i m c Ch ng oxyde ha Men ch ng oxyd ha n i sinh H n ch n i m c nhi m c b i mnh th a VLDL
TNG HUY T P: Nhi u nghin c u v ti li u cng cho r ng tng HA l y u t nguy c b nh sinh x v a. Theo nghin c u c a UKPDS (United Kingdom Prospective Diabetes Study), hn 1/3 b nh nhn T lc ch n on c tng HA (Mattheww, 1999). B nh sinh b nh tim m ch do tng HA theo nhi u cch, y u t nguy c sinh x v a b ng cch lm bi n d ng cc mng v do lm cho cc mng khng n nh. THA l nguyn nhn ph i th t tri, tng nhu c u dng mu c tim, v t n thng lm y th t tri k tm trng, v do cng l y u t nguy c suy tim. X quanh m ch mu (Perivascular) trong THA lm t n thng chuy n v n oxy xuyn qua thnh m ch. t lu ng i ta bi t r ng: r t c th tng HA nguyn pht l do tng insulin mu, c b t th ng dung n p glucose, v do c khng insulin. Nhng theo M. Reaven 2006, s lin k t gi a tng HA v khng insulin th t g p hn l tng HA, r i lo n lipid v bo ph. Tuy nhin ng i ta nh gi hn m t n a b nh nhn c khng insulin l c tng HA ch y u. Theo Freeman v cs 2002, tng HA c tm thu v tm trng l d bo kh nng d c T . G n y, siu phn tch, ng i gi v trung nin, huy t p lin quan tr c ti p v r t m nh n t vong tim m ch, t t nh t d i ng ng pha th p 115/75mmHg (Lewington et al, 2002). Do v y, m t s gia tng HA r t nh ti n T cng l nguy c cao cho tim m ch. C ch tng HA trong T v ti n T khng c nh ngha chnh xc, nhng ch c ch n l do nhi u y u t : r i lo n ch c nng n i m c, m m phng thch cc ch t ho t m ch nh angiotensin, c ng insulin do th n kinh giao c m v tng ti h p thu sodium ng th n (Mlinar et al, 2007) . R I LO N CH C NNG N I M C V I THO NG TP 2 L p n i m c ng vai tr quan tr ng trong i u ha trng l c m ch mu v c ch k t dnh b ch c u v ngng t p ti u c u, do n phng thch ch t trung gian ha h c nh nitric oxide v prostacyclin. Nitric oxide (NO) d n xu t t L-Arginine thng qua ho t ng c a enzyme nitric oxide synthetase (eNOS) (Schram and Stehouwer, 2005). NO c ch ngng t p v k t dnh ti u c u, i u ha s ph i c a t bo c trn, s n sinh endothelin, v gi m k t dnh b ch c u vo n i m c. Do , r i lo n ch c nng n i m c c th b i t n thng tnh th m mao m ch, tng k t dnh cc phn t , cc b ch c u, t n thng p ng dn m ch. R i lo n ch c nng n i m c cng ph i h p v i tng ngh n m ch NH GI CH C NNG N I M C NH M T TI N T C A I THO NG HO C TI N- I THO NG Nhi u y u t d n xu t t n i m c, cc phn t k t dnh t bo v t-PA l ti n nguy c T tp 2, c l p v i cc ti n t khc (Meigs v cs, 2006), Steinberg v cs
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(1996) cho th y r ng b nh nhn bo ph n ng (BMI=34) c khng insulin, dung n p glucose bnh th ng, c cng m c t n thng dng ch y v ph n ng m ch mu nh nh ng ng i b i tho ng tp 2. Cng tng t , Caballero v cs kh o st ch c nng n i m c v ph n ng m ch mu 2 nhm c nguy c pht tri n T tp 2: l nhm c r i lo n dung n p glucose v nhm dung n p glucose bnh th ng nhng gia nh c ng i b T ; h th y r ng ph n ng vi m ch v m ch mu l n u b gi m c hai nhm so v i nhm ch ng kh e m nh, nhng v n t t hn so v i nhm b nh nhn b T tp 2 (xem s sau). i u ny ch ng t r ng t n thng ch c nng n i m c c s m ngay giai o n c h i ch ng khng insulin
% tng trn ng cn b n c a K M cnh tay 16 14 12 10 8 6 4 2 0 Ch ng G b T IGT T 13.7 10.5 9.8 8.4
Hnh 3: T n thng dn m ch l p n i m c b nh nhn c nguy c b T tp 2. ng knh M cnh tay thay i theo ph n ng c a tng glucose mu, c 3 nhm c s gi m ng knh M cnh tay so ch ng p<0.0 (Theo Caballero AE 2003. Obesity Research 11, 1278-89) R I LO N CH C NNG N I M C TRONG I THO NG Hin nay v i nhi u k thu t khc nhau c dng trong nghin c u v T , t n thng c ng M nhi u v tr bao g m m ch vnh, M cnh tay, m ch mu d i da (Hnh 2001). Nhi u d ng c a h i ch ng chuy n ha c th tham gia vo r i lo n ch c nng n i m c bn T , g m tng acide bo t do, c bi t l tng lipide, bo ph v tng HA, cc y u t vim. Ngoi ra, tng glucose mu cng lm t n thng ch c nng m ch mu thm n a. Cu i cng, g n y ng i ta th y r r ng, chnh insulin kch thch c co m ch v dn m ch nh h ng n l p n i m c. i u hi n nhin l c nhi u y u t nguy c lin k t nhau, nh h ng b t l i n ch c nng n i m c b nh nhn T theo nhi u con ng khc nhau ALBMINE NI U VI TH C PH I L D U CH I M LM SNG C A R I LO N CH C NNG N I M C TRONG T ? Albumine ni u vi th l tn hi u nguy c l n cho b nh tim m ch b nh nhn c hay khng c i tho ng. Albumine ni u vi th c nh ngha khi m c ti t albumin n c ti u th p kho ng 30-300mg/ngy. qu n th b nh nhn tng huy t p hay i tho ng, t n su t albumine ni u vi th dng tnh l 10-40%. i u ng ch l nh ng nh ng ng i trng b ngoi c v kh e m nh, cng c kho ng 5-7% albumine ni u dng tnh. R i lo n ch c nng n i m c m ch mu c xem l y u t quan tr ng trong b nh sinh vi m ch v m ch mu l n i tho ng (Basi and Lewis 2006).
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VIM Nh ng nm g n y, vim l y u t nguy c m i v quan tr ng trong b nh sinh b nh m ch mu. D u ch i m pha c p nh tng b ch c u, amyloid A v C-reactin (CRP) huy t thanh. Ngoi ra, nh ng y u t nh tu i, thu c l, v c bi t l bo ph cng quan tr ng, cc y u t ti n vim cng ng gp vo b nh l m ch mu. b nh nhn c h i ch ng chuy n ha, CRP c tng quan v i b nh l m ch vnh Ngoi CRP, cc cytokins cng gy t n thng m ch mu; cytokins i u ha p ng mi n d ch, nh h ng n chuy n ha nh r i lo n lipids, khng insulin ngo i bin, r i lo n ch c nng n i m c CC D U CH I M TNG TRONG PHA C P B NH NHN C NGUY C I THO NG TYPE 2 Hi n nay, c nhi u d ki n cho th y cc d u ch i m vim tng r b nh nhn nam, n v tr em c bo ph. Ngoi ra, nh ng nhm khc c nguy c i tho ng bao g m ph n c h i ch ng bu ng tr ng a nang (PCOS/polycystic ovarian syndrome), nam n c ngu n g c nam , n Pimas, ph n c ti n s gia nh T tp 2, t nh t i u c cc ch t vim tng, v c l p v i BMI (Ziegler, 2005; Stattar, khng insulin, ti n t T type 2. 2006). Cc ch t ch i m vim tng quan v i Do v y, r i lo n vim c tr c i tho ng nhi u nm, v nh l ch t lin quan tng x v a. ADIPOKINES-ADIPONECTIN C s lin quan gi a adiponectin v i c i tho ng type 2 v b nh tim m ch. Adiponectin l m t protein c 244 acid amin, m c d ch c ti t ra t m m , nhng l i gi m m t cch ngh ch l ng i bo ph (Greenberg v Obin, 2006). ng i, n ng adiponectin t 0.5-30g/ml, cao hn 1000 l n m c leptin v insulin. Nghin c u v d ch t cho th y n ng adiponectin gi m, ph i h p v i khng insulin cao hn, v tng nguy c i tho ng type 2, d ng nh c l p v i bo ph (Lindsay et al.2002). Do v y, m c adiponectin cao c xem nh l m c tiu c i thi n tnh nh y c m insulin v dung n p glucose, v c th ngn ch n b nh tim m ch. b nh nhn i tho ng, adiponectin c vai tr b o v ch ng l i b nh tim m ch b ng nhi u c ch khc nhau. Adiponectin ch ng vim, gi m k t dnh cc phn t t bo n i m c v lm tng thanh th i lipids. chu t thi u h t ApoE, adiponectin ngo i sinh cho vo s b o v ch ng l i s pht tri n mng x v a (Greenberg and Obin, 2006). K t qu nghin c u trn 266 b nh nhn nh i mu c tim c p, cho th y r ng gi m adiponectin l m t lin k t chnh gi a i tho ng v b nh tim m ch v r rng r ng m t s gi m adiponectin b nh nhn T s lin quan n tng x v a
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C P NH T M T S
TC D NG C A NHM STATINS
Tr ng Nguy n H i Thu i H c Y D c- i H c hu
I. D C NG H C CA STATINS HMG CoA (3-hydroxy-3-methylglutaryl coenzyme A) reductase l enzyme h n c a con ng mevalonate thng qua cc t bo t ng h p cholesterol t ch t c acetate. c ch enzyme HMG CoA reductase v gi m t ng h p cholesterol lm t bo gan gia tng trnh di n th th LDL b m t t bo gan, v th tng thu nh n LDL lm gi m LDL huy t tng v gi m cholesterol huy t tng l tc d ng chnh c a nhm statins. Ngoi tc d ng gi m t c ti t ApoB t i gan, Statins cn c tc d ng thng qua kh nng lin k t ch y u HMG-CoA reductase hn l HMG-CoA. Tuy nhin nh ng khc bi t t n t i gi a cc thu c trong nhm statins l kh nng lin k t c a chng v i HMG CoA, ti m nng c a chng v u th thu ht ch t m (lipophilic) ho c thu ht n c (hydrophilic) v i u ny c th nh h ng n cc tc d ng nhi u h ng c a statins. M t s thu c thu c nhm satins hi n nay th ng s d ng trn lm sng bao g m: Rosuvastatin (Crestor) Fluvastatin (Lescol) Lovastatin (Mevacor) Simvastatin (Zocor, Lodal,Vida) Pravastatin (Elisor, Vasten, Pravachol, Lipostat) Atorvastatin (Lipitor) Ngoi gi m t ng h p cholesterol, s can thi p con ng chuy n ha mevalonate cng d phng t ng h p ch t trung gian c a isoprenoid bao g m FPP (farnesylpyrophosphate) v GGPP (geranylgeranylpyrophosphate). Geranylgeranyl v farnesyl l nh ng lipid quan tr ng trong bi n i h u v n chuy n c a cc tn hi u protein, bao g m protein GTPase Rho nh , Rac v Ras v protein G. GTPase Rho nh ho t ng nh l phn t chuy n m ch ng c dng c a nhi u ng d n truy n c th nh h ng n t bo c vn (cell cytoskeleton), tnh ch t t bo, v n chuy n mng v ho t ha y u t sao chp, S isoprenyl ha (Isoprenylation) thu n l i lin k t cng ho tr , nh v trong t bo v v n chuy n qua mng c a cc protein bo tng v th ng vai tr ch o trong ho t ng sinh h c c a chng. V th c ch hi n t ng isoprenyl ha gy tch ly Rho v Ras bo tng a n thay i t bo c vn m t cch ng k . i u ny lm r i lo n tn hi u t bo, v n chuy n qua mng, sao chp gen v tnh n nh mng. Trong t bo n i m c m ch mu, s chuy n i Ras ph thu c vo s farnesyl ha, ng c l i s geranylgeranyl ha lin quan chuy n i Rho. Cc ch ng c trn cho th y cc tc d ng khng ph thu c vo cholesterol c a statins qua trung gian c ch s isoprenyl ha Rho (Rho isoprenylation)
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II. STATINS V CH C NNG T BO N I M C M CH Cc b t th ng m n tnh c a ch c nng t bo n i m c m ch mu gy ra do cc y u t nguy c bao g m thu c l, tng lipid, tng huy t p, i tho ng ho c tng homocystein c vai tr b nh sinh x v a ng m ch. RLCN n i m c m ch c th c th kh o st b ng nh gi s r i lo n gin m ch qua trung gian dng ch y (FMD), y l bi u hi u s m c a b nh sinh x v a v cng l bi u hi n c a m t s cc b nh l vim nh lupus ban , th p kh p v h i ch ng Behcet. Tng n ng LDL th ng ph i h p RLCN n i m c v s gi m LDL do statins ho c trch huy t tng c th h i ph c hi n t ng ny. Tuy nhin cc tc d ng c l i trn n i m c m ch sau khi i u tr v i pravastatin v simvastatin ghi nh n trong vng 1 thng k t sau i u tr v khng s d ng gi m lipid mu. Cc tc d ng ny bao g m c i thi n s t i mu c tim, tnh th m vi m ch vnh v c u trc m ch nui m ch c a m ch vnh. i u ny ch ng t s c i thi n ch c nng n i m c m ch sau s d ng statins khng nh ng lin quan n tc d ng gi m lipid mu c a thu c m thu c cn c cc tc d ng khng ph thu c gi m lipid mu. Gi thi t trn c cng c sau 2 th nghi m 1/Tc d ng ng n h n c a cerivastatin trn ch c nng n i m c m ch ng i gi T v i 27 b nh nhn T l n tu i khng v c tng nh n ng cholesterol c i u tr trong 3 ngy. S gin m ch qua trung gian dng ch y ph thu c n i m c m ch c i thi n do cerivastatin trong khi khng thay i n ng lipid mu. Cc tc d ng lin quan m t ph n n gia tng kh nng sinh h c c a NO. cholesterol mu 2/Th nghi m th hai th c hi n trn 8 i t ng nam gi i c n ng bnh th ng, dng 80 mg atorvastatin hng ngy. C s gia tng lu ng mu cnh tay ph thu c n i m c (FMD) c ghi nh n trong vng 24 gi v hi n t ng ny x y ra tr c khi gi m n ng cholesterol v CRP. Tuy nhin ngng atorvastatin sau 30 ngy i u tr , dng mu l i tr l i nh lc ban u. III. STATINS V VAI TR NO (NITRIC OXIDE) NO c vai tr quan tr ng trong duy tr ch c nng n i m c bnh th ng v c t o ra nh m p ng cc stress tc ng n l p m ng thnh m ch (laminar shear stress). Ch t NO n i m c l m t ch t c tc d ng gin m ch, c ch s tn sinh t bo c trn, c ch ngng t p ti u c u, trnh di n phn t k t dnh v i n i m c v tng tc gi a b ch c u-n i m c (leucocyte-EC interaction). Ch ng t statins c kh nng thc y s n sinh NO t i ch trong t bo n i m c b ng s gia tng th i gian n a i c a mRNA c a enzyme NO synthase n i m c (eNOS) l minh ch ng c b n v cc hi u qu khng ph thu c vo lipid c a statin.. Statin c kh nng lm gia tng eNOS trong s hi n di n LDL b oxy ha v trong i u ki n thi u oxy. Ngoi ra statins c cc tc d ng c l i trn n i m c thng qua c ch s trnh di n ch t co m ch endothelin-1. Cc tc d ng ny ghi nh n trn nh ng lo i thu c khc nhau bao g m simvastatin, lovastatin, atorvastatin, pravastatin v fluvastatin in vivo l n in vitro. Phn tch chi ti t c a cc thm d qua statins nh h ng ln trnh di n eNOS v endothelin-1 c ghi nh n GGPP, nhng khng v i FPP, squalene ho c cholesterol, c thm vo tc d ng c a statins
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c ch c a s Rho geranylgeranyl ha lm thc y tnh n nh eNOS mRNA, nhng khng hi u qu trn s sao chp gene eNOS. Nghin c u in-vivo trn ng v t ghi nh n s i u ha ng c eNOS do statins c ngha lm sng, lm gi m s thi u mu no v b o v th n kinh v h n ch s r i lo n ch c nng co bp c tim trong tr ng thi thi u mu/ti t i mu. Kh ng nh statins lm gia tng s sinh t ng h p NO do tc d ng chng trn eNOS cng c ghi nh n in vivo. Tuy nhin t m quan tr ng c a NO l i c ch ng t qua s th t b i c a statins b o v ch ng l i thi u mu no ho c c ch s tng tc b ch c u-n i m c m ch mo b gi m eNOS. IV. STATINS V I HUY T KH I V TIU S I HUY T (THROMBOSIS AND FIBRINOLYSIS) Ch t c ch enzyme HMG-CoA reductase c nhi u tc d ng trn s n nh n i mi (haemostasis) v huy t kh i, thu n l i cho d tiu s i huy t qua cc c ch ti n huy t kh i, m t ch c nng m c bi t quan tr ng cc v tr c a m ng x v a b n t. Statins c tc d ng ch ng huy t kh i b ng ngn ng a trnh di n v ho t ha y u t t ch c (TF=tissue factor). Tc d ng ny u tin ghi nh n t bo n nhn v i th c bo in vitro v in vivo. K t qu tng t cng ghi nh n t bo n i m c ng m ch ch ng i v t bo c trn m ch mu trong simvastatin ngn ng a s c m ng TF b i thrombin, t nh t m t ph n thng qua c ch s kh phosphoryl c a Akt ph thu c Rho-kinase (Rho-kinase-dependent Akt dephosphorylation). S c ch TF c a statins cng ghi nh n in vivo v i thu c fluvastatin lm gi m trnh di n TF cc t n thng ng m ch c nh th c nui b ng cholesterol. Nghin c u lm sng cng h tr cho tc d ng ch ng huy t kh i c a statins khng ph thu c cc tc d ng gi m cholesterol. M t tc d ng ch ng huy t kh i quan tr ng khc l c ch s ho t ha v ch c nng c a ti u c u ph n nh c s nh h ng v khng nh h ng c a statins ln lipid. C ch ny bao g m tng eNOS v NO t i ch , gi m t ng h p thromboxane A2 v thay i trong thnh ph n cholesterol c a mng ti u c u. Cc nghin c u g n y ghi nh n lovastatin lm tng ho t ha v trnh di n mng c a Ecto-5-Nu (ecto-5-nucleotidase) trn t bo n i m c m ch, v th thc y c ch ngng t p ti u c u b m t t bo n i m c thng qua tc d ng c a ecto-5-Nu product adenosine. Tc d ng ny khng ph thu c vo cc thay i vo l ng cholesterol mng. S c ch ch c nng ti u c u ghi nh n in vivo c nghin c u trn ng v t l n ng i. Ngoi ra atorvastatin v rosuvastatin thng qua tc d ng c a chng trn eNOS v ho t ha ti u c u, b o v ch ng l i thi u mu no v tai bi n m ch no chu t c n ng cholesterol bnh th ng. Thm vo cc tc d ng trn s h ng nh n i mi v huy t kh i, statins c tc d ng thu n l i trn s tiu s i huy t. S d ng Lovastatin, fluvastatin, atorvastatin v simvastatin cho th y tng y u t ti n tiu s i huy t tPA (tissue plasminogen activator), trong khi c ch t ng h p ch t ch ng tiu s i huy t, ch t c ch ho t ha plasminogen1 (PAI-1) do t bo n i m, i th c bo v t bo c trn. Cc tc d ng ny c b t ch c b i C3 exoenzyme c ch RhoA (RhoA inhibitor C3 exoenzyme) v c d phng b i GGPP nhng l i khng d phng i
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v i ch t FPP, ch ng t tc d ng c a statins qua trung gian c ch s geranylgeranyl ha. Trong khi cho r ng cc lo i statins tc ng nh nhau, i u quan tr ng ghi nh n r ng m c d ph n l n cc nghin c u h tr tc d ng ch ng huy t kh i u th , m t vi tc d ng i ngh ch ho c trung l p cng c ghi nh n. Ngoi ra khng ph i t t c statins u tc ng tiu s i huy t trn cng c p v c khc bi t qua m t s nghin c u. V th cc k t qu trn xu t statins c th gy tiu huy t kh i v tr m ng v a r n n t v c n nhi u th nghi m lm sng v sau nh m kh ng nh i u ny V. STATINS V I T N THNG M CH MU V DI CHUY N B CH C U X v a ng m ch c ch p nh n l m t th b nh vim nhi m v cc ch ng c v cc tc d ng khng ph thu c cholesterol c a statins t ra cu h i li u ch t c ch HMG CoA reductase c tc d ng khng vim khng?. y l v n khng nh ng nh cho i u tr x v a ng m ch m cn cho vim nhi m m ch mu m t cch t ng qut v s lan r ng c a cc b nh l nh l nh vim kh p, lupus, vim m ch mu, quan tm hi n nay vim c u th n, i tho ng v x c ng r i rc. C nhi u v n trong lnh v c ny v i nh ng d ki n tm th y in vitro v m t s minh ch ng in vivo. i u tr cc t bo n i m trong mi tr ng c y v i pravastatin, simvastatin, fluvastatin v cerivastatin lm gi m s t ng h p cc ch t ti n vim cytokines nh IL-1 beta, TNF, IL-6 v cc th quy n p c a cyclo-oxygenase. Tng t k t qu ghi nh n c t bo c trn m ch mu sau khi i u tr v i thu c atorvastatin v trong t bo b ch c u qua cc bo co ghi nh n c s gi m ti t cc ch t TNF, IL-1 beta, IL-6, IL-8, MCP-1 (monocyte chemotactic protein -1) v MMP (matrix metalloprotease). i u ny gy ra cc thay i s trnh di n cc phn t k t dnh bao g m c ch ch t P selectin n i m c m ch, phn t k t dnh gian bo lo i 1 (ICAM-1=intercellular cell adhesion molecule 1) v i u ha ng c phn t k t dnh t bo thnh m ch (VCAM-1=vascular cell adhesion molecule) v gi m b ch c u trung tnh v gi m trnh di n v ho t ha b ch c u trung tnh v t bo n nhn. Nghin c u g n y ghi nh n khi s d ng ch t simvastatin 18 gi tr c khi dng n i c t (endotoxin), k t qu tng 50% ch t eNOS m ch mu ru t c a chu t, gi m ng k trnh di n ch t P selectin n i m c m ch v gi m v n chuy n v di tr b ch c u vo m ch mu ru t c a chu t. Ngoi ra, s phn tch vi th ang c b t u nh n ra s s p x p gen c th c i u ha b i i u tr v i statins. M t nghin c u nam gi i v i n ng cholesterol trn 5 mmol/l v/hay triglycerides trn 2 mmol/l v i u tr v i ch t Atorvastatin ghi nh n c trn 200 gen c i u ha b i statins, trong cc gen ny ph i h p v i ph n ng vim bao g m cc gen lin quan n chuy n ha lipid, thu nh n b ch c u, huy t kh i, hi n t ng ch t theo chng trnh v x v a ng m ch. i u tr b ng simvastatin ho c fluvastatin cho th y gi m ng k s k t dnh b ch c u vo t bo n i m c c a mao m ch c a tnh m ch ru t chu t v i n ng cholesterol tng ho c bnh th ng. Trong cc nghin c u v s tng tc gi a b ch c u v n i m ch d i lu l ng mu m c sinh l, i u tr tr c ch t U937 t bo n nhn v i cerivastatin ho c atorvastatin lm gi m s k t dnh.
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i u ny l k t qu c a i u ha xu ng c a t t p b ch c u, c ch chuy n v tr c a ch t RhoA v gi m thnh ph n ch t F actin. Ng c l i simvastatin ghi nh n c ti m nng gy c m ng ch t E-selectin, ICAM-1 v VCAM-1 trn ch t TNF ho c IL-1 beta t bo n i m c in vitro. C ch tc d ng C ch lin quan tc d ng c a statins trn s trnh di n phn t k t dnh t bo do cytokine v k t dnh b ch c u c xc nh y v c l nhi u y u t . S c ch c a statins v i y u t nhn B (NK (nuclear factor) B) c l quan tr ng i u ha ng c cc th th nhn PPAR alpha v beta. Tuy nhin, i u ha c a s s n xu t eNOS v NO do statins lm gi m k t dnh b ch c u vo t bo n i m c v i u ny c th m t ph n ph n nh s c ch qua trung gian NO v ch c nng v trnh di n phn t k t dnh. C ch c nghin c u g n y trong ch t atorvastatin, cerivastatin v pravastatin c ch trnh di n CD40 kch thch b i TNF alpha/interferon gamma do t bo n i m c, lm gi m s trnh di n IL-12 do lin k t CD40. Phn tch y u t sao chp xu t r ng y l k t qu c a s c ch NFB v t ng h p ph thu c chuy n i tn hi u c a sao chp lo i 1 (STAT-1 = signal transducer of transcription-1) c a y u t 1 i u ho interferon Sau cng m t s quan tm c bi t c quan st th y lovastatin l ch t c ch allosteric v ch c nng c a 2 integrin LFA-1 (leucocyte function antigen-1, CD11a/CD18). Lovastatin, simvastatin v mevastatin lin k t vo v tr trong ph n I c a LFA-1 locking th th trong c u t o b t ho t, v th d phng lin k t v i th th i l p ICAM-1 c a chng, m t c ch k t dnh quan tr ng i v i k t dnh b ch c u i v i n i m c v s kch thch ph c a lympho T. Cc nghin c u in vivo m hnh th b x v a ng m ch, atorvastatin lm gi m s vim n i m c m ch m i km c ch s ho t ha NF-B, s t ng h p MCP-1 v s thm nhi m i th c bo vo thnh m ch. Cc nghin c u g n y s d ng ch t simvastatin v ch t pravastatin kh ng nh r ng cc tc d ng ny khng ph thu c vo gi m cholesterol. T n thng x v a ng m ch c i u tr v i statin ch a t IL-1 beta, VCAM-1 v TF v gi m thm nh p i th c bo. Vai tr c a NO qua trung gian tc d ng ch ng vim c a ch t statins cng ch ng t trong cc nghin c u in vivo s d ng ch t rosuvastatin, cerivastatin v pravastatin. Cc minh ch ng cng xu t r ng ch t statins c cc tc d ng khng vim quan tr ng tr ng nh ng mi tr ng khc bao g m vim do carregeenan, vim do vim kh p v t n thng thi u mu/ ti t i mu th n v c tim. Ngoi ra, thng t n vim h th ng th n kinh trung ng, lovastatin v cc ch t c ch c a protein prenylation u c i thi n vim no th c nghi m. Ti m nng c a statins khi i u tr cc b nh l vim trong cc nghin c u g n y ghi nh n vi c s d ng atorvastatin trong vim no t mi n th c nghi m, x c ng ri rc qua trung gia ch t Th-1. Atorvastatin li u i u tr ng u ng c kh nng d phng v h i ph c li t. Ch t Atorvastatin t o ra Th2 bias bao g m phosphoryl ho STAT-6 v ti t cytokine Th2, trong khi c ch STAT-4 v t ng h p cytokine Th1. i u tr statins cng gy bi t ha t bo ThO thnh Th2 v v n chuy n cc t bo ny ch ng l i b nh.
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K t qu t cc m hnh b nh t t xu t r ng ch t statins c ti m nng ch ng l i vim c p v mn tnh m khng ph thu c cholesterol v ngn c n v i dng thc k t dnh b ch c u. i u quan tr ng hi n nay l xc nh ch t statins no c cc tc d ng ch ng vim nghin c u ng i khng. Tc d ng nhanh c l i c a ch t statins m t vi nghin c u lm sng xu t r ng y c th l tr ng h p, khi cc nghin c u g n y v n ng ch t CRP gi m do ch t statins khng ph thu c v tc d ng c a chng trn ch t cholesterol VI. STATIN V I I U HA MI N D CH V S GHP C QUAN Tng cholesterol mu th ng ghi nh n b nh nhn ghp c quan v s d ng thu c c ch mi n d ch bao g m cyclosporine v corticoid u c khuynh h ng tng n ng lipid. V v y ph i h p ti m nng gi m lipid, ch ng vim v c ch mi n d ch xu t thu c statins c kh nng s d ng nh ng b nh nhn ghp n i t ng v g n y trong lnh v c ghp n i t ng nh n m nh v n ny. Tuy nhin khng nghin c u no v s d ng thu c statins trong ghp n i t ng cholesterol lm cho kh khn khi gi i thch tc d ng quan tr ng ki m sot n ng khng ph thu c vo lipid ny. C ch tc d ng Kh nng c a statin gy c ch ch c nng t bo n nhn/ i th c bo, ho t ho v tn sinh t bo lympho B, lympho T v c t t bo gi t t nhin (natural killer cell cytotoxity) g i v d phng trong th i m nh ghp. Ngoi ra pravastatin, lovastatin v atorvastatin cho th y c ch s trnh di n gy ra do IFL gammma c a MHC lo i II trong i th c bo, t bo n i m c v t bo c trn nhng khng c trong t bo B ho c t bo s i nhnh (dendriticcell). C ch c a tc d ng ny c thng qua c ch c a tc nhn IV c a CIITA (MHC class II transactivator = ch t v n chuy n MHC lo i II) i u ho sao chp gene MHC lo i II. M c d u s p ng ny i h i li u cao statin v v n cn c kh ng nh in vivo, v n cn bi u hi n c m t tc d ng quan tr ng c a cc thu c ny. Gi m trnh di n MHC lo i II trn t bo n i m c m ch mu, t bo c trn v thm nhi m i th c bo l do gi m tn sinh v bi t ho t bo T. S b c l quan tr ng c a h th ng mi n d ch trong b nh sinh X v a ng m ch y l m t nh h ng quan tr ng trong qu trnh ti n tri n c a b nh. Tuy nhin cc l i ch c th tc ng n cc b nh l vim khc nh l vim a kh p, x c ng ri rc v th i m nh ghp m n tnh. M hnh th c nghi m trn ng v t Simvastatin v pravastatin cho th y gi m s th i m nh ghp m n tnh v s gia tng x v a ng m ch c a m ch mu m nh ghp t i tim v gan c a chu t. Cc thu c ny lm gi m b t cc tc d ng c h i c a thi u mu, ti t i mu trong c tim c a chu t c cholesterol mu bnh th ng v trong th n, trong ghi nh n c s gia tng ch t eNOS. Ngoi tc d ng i u ho mi n d ch v khng vim c m t trn, kh nng c a statin c ch tn sinh t bo c trn c vai tr quan tr ng trong lm gi m X c ng ng m ch ph i h p trong ghp. Cc nghin c u In vitro ghi nh n statin lm ng ng
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chu k t bo G1 n giai o n di chuy n S trong t bo c trn c i u tr v i y u t pht tri n d n xu t ti u c u (PDGF) Tc d ng trn s tn sinh t bo c trn c h i ph c b i GGPP nhng khng b i FPP ho c cholesterol. Ngoi ra c ch c a Rho b i C3 exoenzyme ti hi n tc d ng c a statin. Cc nghin c u ny xu t c ch khng ph thu c cholesterol gp ph n cc tc d ng b o v c a statin sau ghp, nhng c n ph i kh ng nh trn nghin c u in vivo Th nghi m lm sng M t s th nghi m trn b nh nhn ghp tim ghi nh n c i thi n tin l ng v s ng st v x c ng m ch mu c quan ghp. So snh b nh nhn i u tr v i pravastatin v i nhm ch ng nh n thu c c ch mi n d ch n c cho th y gia tng 1 nm s ng st v gi m th i ghp. Tng t dung simvastatin c i thi n 4 nm s ng st, gi m phng cytokine ti n vim t i ch bao g m TNF alpha, gi m b nh l m ch mu v c i thi n ch c nng n i m c. k t qu nghin c u ban u cng ghi nh n statin c i thi n i s ng 24% sau khi ghp th n. VII. STATINS V CH NG OXY HO Tng cholesterol th ng k t h p tng oxy ho LDL v thnh l p g c t do. T bo n i m c l ngu n s n xu t cc superoxide lm b t ho t NO gy r i lo n ch c nng n i m c. Gi m lipid huy t tng b ng thu c hay ti t th c c th h i ph c hi n t ng trn b ng gi m stress oxy ho v thay i thnh ph n LDL.C, lm gi m i s m n c m v i oxy ha. Tc d ng khng ph thu c gi m lipid c a statins cng c vai tr trong v n ny b ng cch gia tng sinh t ng h p NO n i m c, gi m sinh s n ph m oxy ph n ng thng qua c ch ho t ho NAD(P)H oxidase. K t qu ny lm gi m LDL oxy ho v stress oxy ho n i bo. M t c ch ti m nng thm vo l ho t ho Ecto-5-Nu thc y b i statin (statin enhanced Ecto-5-Nu) gia tng do thi u kh. i u ny cng ch ng t in vitro li u pravastatin khng lm gi m cholesterol, lm gia tng ho t ng c a Ecto-5-Nu trong c tim th b thi u mu v gi m kch th c nh i mu. S n xu t adenosine ngo i bo do Ecto-5-Nu c vai tr quan tr ng trong bo v thnh m ch ch ng l i stress do thi u kh. Kh nng d n d p cc g c t do d n ch t t oxygen c c tham d s b i m t s thu c nhm statin bao g m simvastatin, fluvastatin, atorvastatin, pravastatin v cerivastatin v cng c bi u hi n trn m t s lo i t bo bao g m i th c bo, b ch c u trung tnh, t bo n i m c v t bo c trn. Cc tc d ng ch c nng c a gi m stress oxy ha thay i. Simvastatin, fluvastatin v pravastatin c ch stress oxy ho gy ra b i lysophosphatidylcholine trong mi tr ng c y t bo c trn v y l s ph n nh b i kh nng c a cc thu c ny trn s c ch s di chuy n t bo c trn in vitro. Atorvastatin d phng thnh l p superoxide do tng ng mu ng m ch vnh. In vivo, simvastatin c th lm y u i stress oxy ho v thi u kh trong thnh ng m ch vnh, duy tr ch c nng n i m c m ch th ng tm tm m c v m ch nh c a ng m ch vnh khng lin quan n gi m cholesterol. B o v t bo c ch ng t v i rosuvastatin lm tng s n xu t eNOS m ch mu v gi m i ho i t c tim sau thi u mu v ti t i mu m c nh nhng
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khng th y chu t b gi m eNOS. Ngoi ra rt lui i u tr statin gy stress oxy ho v r i lo n ch c nng n i m c chu t. C ch n m bn d i lin quan ho t ho c a gp91phox ch a NAD(P)H oxidase do Rac1 lm s n sinh superoxide, ch t d n d p eNOS. Rac1 thnh vin c a dng Rho l m t thnh ph n i u ho c a NAD(P)H oxidase v s c ch s isoprenyl ho Rac1 do statin lm c ch phng thch cc s n ph m oxy ph n ng trong t bo n i m c m ch. Statins c tc d ng thng t trn t bo c trn v c tim, c ch cc s n ph m oxy ph n ng do angiotensin II thng qua c ch geranylgeranyl ha Rac1. Cc tc d ng ny c k t qu quan tr ng ch ng t kh nng c a statin c ch ph i c tim chu t i u tr v i angiotensin II ho c i t ng co th t ng m ch ch . Tc d ng c a statin trn cc p ng qua trung gian angiotensin II c th do c gi m lipid mu v tc d ng ngoi gi m lipid mu c a statin. LDL c th lm AT1 (Ang II type 1 receptor) i u ho ng c ln t bo c trn m ch mu in vitro v c trong tng cholesterol th v ng i u lm tng trnh di n AT1. Tuy nhin cc nghin c u sau ghi nh n s gi m lipid do statin i u ho xu ng trnh di n AT1. Statin cng ghi nh n gi m trnh di n AT1 v v v y ngn c n v i cc c ch tn hi u c a th th khng ph thu c gi m cholesterol mu. VIII. STATINS V B O V T BO M CH MU CH NG L I T N THNG QUA TRUNG GIAN B TH khng ch ng l i nhi m khu n Chu i b th ng vai tr tr ng tm trong s v i u ho v p ng mi n d ch. Tuy nhin b th cng lin quan n b nh sinh c a nhi u b nh l vim bao g m vim c u th n, vim kh p, lupus v x v a ng m ch. d phng t n thng bn ngoi n v i t ch c v t ch sau ho t ho b th , m t s ch t ho tan v protein i u ho ph c h p lin k t mng t bo cng b lin quan. Bao g m protein b m t t bo DAF (decay-accerelating factor, CD 55), CD44 (membrane cofactor protein), CD59 (protectin) v CD35 (complement receptor 1). Ch t DAF t trn b m t t bo n i m c v thc y s b o v t bo ch ng l i t n thng qua trung gian b th trong vim, huy t kh i, tn sinh m ch mu. Ngoi ra vi c i u tr t bo n i m c c a c a tnh m ch r n ng i, vi m ch da v ng m ch ch v i atorvastatin ho c simvastatin a n gia tng ng k s trnh di n DAF v c ch hu ho i t bo qua trung gian b th . C ch tc d ng Tc ng nhi u h ng c a statins trn n i m c m ch mu ph i h p u th v i gia tng NO d n ch t eNOS v/hay l ho t ho c a PI3K (phosphoinositide 3-kinase)/Akt. Ng c l i, s i u ho ng c ln c a DAF b i statin khng lin quan v i con ng ny. S i u ho ng c DAF i h i sao chp gen, gia tng u n mRNA v t ng h p protein m i, nhng khng b gi m sau khi c ch c a NOS ho c PI3K/Akt. i u ho ng c ln khng ph thu c vo cc tc d ng c ch trn t ng h p cholesterol v c t o ra b i C3 exoenzyme v ch t c ch geranylgaranyl transferase (GITT286) v c c i thi n nh GGPP m khng ph i l FPP. M c d i u ho ng c gy ra b i statin c a DAF v n cn c ki m ch ng in vivo, hi n t ng ny c bi u th phng th c qua v phng di n i u tr , n i
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m c m ch mu c th l i u ki n cho i u tr v d phng x v a b nh l vim m ch mu khc lin quan ho t ho b th .
ng m ch v cc
Vai tr b th trong b nh l m ch mu Vai tr b th trong b nh sinh c a x v a ng m ch, nh i mu c tim v gia tng x v a sau khi ghp c quan c m t v m t s c ch qua b th c th b ho t ho trong thnh m ch c xc nh. Bao g m ho t ho b i CRP, cng nh v v i C5b-9 MAC (C5b- 9 membrane attack complex) trong thnh m ch x v a v cho th y ho t ha b th in vivo l n in vitro. V th n ng CRP c th i di n l m t trong nh ng phng th c qua ph n ng vim m n c th t n cng trn thnh m ch mu. N ng CRP trn m c ng phn v c a gi tr bnh th ng th ng ph i h p v i gia tng nguy c cao nh i mu c tim v b nh m ch vnh trong ng i bnh th ng. Tuy nhin tnh a d ng c a statin v cho th t gi m n ng CRP khng ph thu c tc d ng statin trn cholesterol v d phng bi n c m ch vnh b nh nhn c n ng cholesterol th p nhng l i tng CRP. Gi m ho t ho b th trong thnh mng v a c th l y u t gp ph n cho v n ny. i u ny c th qua trung gian 2 ng (1) qua s i u ho ng c ln trnh di n DFA v (2) gi m ho t ho b th qua trung gian CRP. c bi t n i u tr b nh nhn v i b nh l vim S tc ng ny c th quan h h th ng ph i h p ho t ha b th nh l lupus v vim kh p trong gia tng t n su t ch t tr do nh i mu c tim c ghi nh n. Thm vo tc d ng c l i trn ch c CRP, ch t c cc tc d ng ti n khng vim nng n i m c c th do t gi m n ng tr c ti p trn n i m c m ch mu. IX. STATINS V TN SINH M CH MU Cc k t qu g n y v tc d ng trn m ch mu khng lin quan gi m lipid c a statins bao g m cc bo co v tc d ng ti n v khng tn sinh m ch (pro-anti angiogenic effects). u tin ghi nh n ch t simvastatin ho t ho con ng PI3K/Akt, gy hi n t ng phosphoryl ho eNOS, c ch hi n t ng ch t t bo theo chng trnh v gia tng tn sinh m ch in vivo v in vitro. Nghin c u sau theo cch th c murin (murine model) pht hi n p ng tn sinh m ch in vivo t nh t m t ph n lin quan n k t qu c a s di chuy n ph thu c PI3K/Akt c a cc thnh ph n nguyn thu n i m tu xng (bone marrowendothelial progenitors) v m t s gia tng lu hnh t bo n i m nguyn thu (EPC=endothelial progenitor cell). S gia tng ny trong t bo nguyn thu n i m lu hnh cng c ghi nh n b nh nhn b nh m ch vnh dng statins. Kh nng c a statins lm gia tng lu hnh t bo n i m c nguyn thu lu hnh a n gi thuy t l chng c th lm thu n l i ti t o n i m c ho (reendothelialization) v lm gi m b dy n i m c tn sinh pha thnh m ch t n thng thng qua s di chuy n v thu nh n thm t bo nguyn thu n i m c. Cc nghin c u g n y cng minh ch ng i u ny. Tuy nhin ng c l i v i nh ng bo co cc tc d ng ti n tn sinh m ch c a statins, m t ch t statin c tc d ng thu nh n ch t m , ch t cerivastatin c ghi nh n c ch tn sinh m ch mu in vitro qua cc c ch khc, g i l c ch c a Rho.
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Cc nghin c u ti p theo ghi nh n cerivastatin lm ng ng pht tri n trong t bo n i m c cc giai o n G1/S theo sau s gia tng ch t c ch kinase ph thu c cyclin p21 Waf1/Cip1 v c ch tn sinh m ch in vivo. Tc d ng 2 pha c a statins Cc gi i thch v s khc bi t lin quan n tc d ng 2 pha c a statins trn s tn sinh m ch. Cc nghin c u ghi nh n n ng th p (0,002-0,05 M i cerivastatin v 0,002-0,2M i v i atorvastatin) c a cc thu c ny tc d ng ti n tn sinh m ch, trong khi n ng cao tc d ng ti n ch t t bo theo chng trnh (pro-apoptotic) v n nh m ch mu (angiostatic). V th i u tr li u th p v trung bnh c a cc thu c ny ng i c tc d ng tn sinh m ch v li u cao c tc d ng n nh n i m ch. Nghin c u in vitro ghi nh n li u th p thc y tn sinh v di chuy n t bo n i m c thong qua phng thch c a y u t pht tri n n i m c m ch, ng c l i li u cao lm gi m y u t pht tri n n i m c m ch v k t qu gy hi n t ng ch t t bo theo chng trnh. Cc tc d ng li u th p qua trung gian b i s ho t ho c a PI3K/Akt v tc d ng li u cao lin quan n c ch s geranylgeranyl ho. Ngoi ra s n nh c a eNOS mRNA ch t c b i li u cao. Cc tc d ng ph thu c li u dng ny a ra trong cch th c murine c a s tn sinh m ch trong cerivastatin gi m pht tri n kh i u v m ch mu trong ch ng ung th ph i d ng Lewis. Tuy nhin nghin c u g n y xu t r ng cch th c ny khng ng trong m i tnh hu ng. Cc tc gi ghi nh n r ng li u th p cerivastatin (0,005 M) c ch tn sinh m ch do cc s n ph m ng ho b c cao in vitro thng qua c ch ph thu c vo s c ch c a FPP v khng lin quan GGPP. Ti m nng i u tr Kh nng statins i u ho s tn sinh m ch a ra m t ti m nng i u tr c a thu c i v i b nh tim m ch, K, vim kh p, b nh vng m c T . M c d nhi u xu t h p d n, chng c n c nghin c u k tr c khi ng d ng lm sng do cha r rng li u gi m lipid hi n nay c a statin ng i hi n ang m c ti n ho c m c ch ng tn sinh m ch. Ngoi ra trong b nh XV M c nhi u ti m nng c l i c a cc tc d ng n nh m ch mu, d n n r i lo n pht tri n h vi m ch trong mng x v a, cng nh s tc ng ti n tn sinh m ch thu n l i cho pht tri n m ch mu ph . Thm vo khng c k t qu a ra v gia tng c tnh b nh nhn i u tr v i li u statins khuy n co hi n nay c th di n d ch r ng b t c tc d ng no v ti n tng sinh m ch invo u r t y u. Tuy nhin c n xc nh m t cch th n tr ng cc hi u qu trn s tn sinh m ch c a li u statin hi n nay, gi i thch m t cch y hn cc tc d ng c l i v cc nguy c ti m tng. X. STATINS V N NH M NG X V A NG M CH V phng di n ch p m ch mu qua cc th nghi m phn tch v i u tr gi m lipid mu i v i b nh m ch vnh ghi nh n gi m cc bi n c tim m ch trong tng lai
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qu m c hn s mong mong i t s gia tng t i thi u c a ng knh ng m ch vnh. i u ny d n n s ng thu n s n nh m ng v a c m t qua s thay i sinh h c c a mng v a, bao g m n p x collagen dy hn, kho ch a lipid t hn, tng t bo c trn v t bo vim t hn. K t qu cc cc thay i ny lm cho nguy c v mng v a v h u qu huy t kh i a n h i ch ng vnh c p c gi m i. C ch ng c quan tr ng l gi m n ng lipid c kh o st b ng cch phng php bao g m ti t th c, dng hay khng dng statins, thc y tch lu t bo c trn thnh th c, gi m i s vim m ch mu t i ch , tch ly cholesterol trong i th c bo v sinh t ng h p c ch t MMP (matrix metalloproteinase) b i cc i th c bo v t bo c trn, t t c cc kha c nh lm cho mng v a n nh. Kh nng c a statins t o thu n l i cho n nh mng v a c th c hi n trn th nghi m ng v t, k t qu i u tr lm gi m tch lu v ho t ho i th c bo km gi m trnh di n y u t pht tri n, sinh t ng h p ch t trung gian ti n vim v c ch t MMP th c nui ch t bo Ngoi ra c m t vi ch ng c c l i tng t b nh nhn dng pravastatin v simvastatin. Phn tch mng v a m ch c nh ghi nh n gia tng l ng ng collagen, gi m thnh ph n lipid, thm nhi m b ch c u v c ch t MMP. M c d cc tc d ng c l i c a vi c i u tr statins khng cn bn c i, Cc xu t v hi u qu khng ph thu c lipid l r t quan tc d ng nhanh c a chng tr ng trong s n nh m ng v a. i u ny gi i thch kh nng c a statins b o v ch ng l i thi u mu b nh m ch vnh, m c d n ng LDL.C l d u hi u ngho nn khi d bo bi n c . Pravastatin ch ng t c i thin gin m ch do acetylcholine c a ng m ch vnh ng v t linh tr ng v tc ng t i t ch c mng v a b r i lo n chuy n sang n nh, khng ph thu c vo thay i n ng lipid huy t tng M t nghin c u g n y cho th y pravastatin v simvastatin c tc d ng gi m v tc ng trn m ng v a theo chi u h ng n nh bao g m tng thnh ph n collagen v t bo c trn v gi m t ng h p MMP. Tng t ghi nh n chu t thi u apolipoprotein E trong simvastatin lm cho n nh m nh v a khng ph thu c vo gi m lipid mu V n cn s hoi nghi v ngha lm sng c a tc d ng khng ph thu c lipid c a statin trn s n nh mng x v a cn l i b i v s kh khn phn cch v i cc tc d ng trn v i cc hi u qu do gi m lipid mu. Tuy nhin cc nghin c u th c hi n nghim tc ghi nh n tc d ng gi m cholesterol v nhi u h ng tc ng khc c a statins gp ph n vo s n nh m ng v a v gi m tai bi n lm sng b nh nhn s d ng v i cc thu c trn XI. K T LU N Vai tr statins trong i u tr b nh l vim hi n ang c quan tm. B nh l vim h th ng nh l b nh vim kh p v Lupus ngoi tc d ng th pht cn gy x v a ng m ch s m v tng t vong tim m ch. i u ny a ra cu h i li u Statins c s d ng d phng cho b nh nhn khng, khng ch n b i c nh Lupus lm gi m nguy c t vong tim m ch. y l v n m cc bo co lin quan n khng vim khng ph thu c cholesterol v tc d ng b o v m ch mu. S d ng bisphotphonate d phng lo ng xng do corticoid cho b nh nhn c xem nh l b i c nh tng t . Tuy nhin, cc phn quy t cha t ra v qu
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nhi u i u khng ch c ch n i h i s d ng r ng ri nh ng b nh nhn c n ng cholesterol mu bnh th ng. Khi s d ng statins nh ng b nh nhn c b nh l vim mn tnh cc thm d ph i c ch n h u qu b nh l bn d i nh l nguy c tim m ch, i tho ng. M t i u quan tr ng ch p nh n do cc tc d ng khc nhau c a statins cng c ti m nng c h i v c th c b nh l do qu li u. V v y c n ph i xc nh li u statin c ch nh c khc so v i li u c k t qu t c h lipid mu l t ng. Ngoi ra, m t d u cc thu c ny tng i an ton nhng s rt lui g n y c a cerivastatin v n cn lu ti p t c c n c c nh gic. V v y, ti p t c nghin c u ch n m t thu c m i c hi u d a trn nhm Statin v c n xc nh m c tiu l quan tr ng. Ngoi ra, cc k t qu ki m sot tnh c th nghi m lm sng i h i phn bi t tc d ng ph thu c v khng ph thu c cholesterol c a Statin hi n nay v thi t l p ti m nng s d ng trong cc tnh tr ng b nh l khc nhau ang c mong i. TI LI U THAM KH O 1/ John P Kane (1997). Disorders of lipoprotein metabolism. Basic and clinical endocrinology. 2/ John A Farmer, Antonio M Gotto (1998). Dyslipidemia and other risk factors for coronary artery disease. Heart disease.(Eugene Braunwald) 3/Justin C. Mason. Statins and their role in vascular protection. Clinical Science (2003) 105: 251- 266. 4/ David M. Kendal (2005), Clinical management of metabolic syndrome; 65th scientific sessions of American Diabetes Association, Medscape. 5/Huy Van Tran, Olabode Oladeinde, Nguyen Hai Thuy, Huynh Van Minh, Dao Duy An, Dat Nguyen Tran, Thach N. Nguyen, Adolphus Anekwe and Matthew J Sorentino (2007) Integrated Primary Prevention of Cardiovasscular Disease. Management of Complex Cardiovascular Problems. The Evidence-Based Medicine Approach. Third Edition. Blackwell. Futurapp:129-190 6/ Sammuel Klein, Johannes A Romijn (2008). Obesity. William textbook Endocrinology 11th edition. 2008, pp 1563-1580. 7/ Robert W. Mahley, Karl H. Weisgraber, Robert V. Farese (1998). Disorders of Lipid Metabolism. Williams Textbook of Endocrinology, nineth edition. W.B. Saunders Company. 1998: 1099 - 1155. 8/ Stanley H Hsia (2002). Disorders of lipid metabolism Manual of Endocrinology and Metabolism. Norman Lavin. 3th Lippicott Williams and Wilkins. 2002: 520 - 550. 9/ Mary J Malloy, John P Kane (2004). Disorders of Lipoprotein Matabolism. Basic and Clinical Endocrinology. Francis S Greenspan. Seventh edition. A Lange Medical book 2004: 766 - 793. 10/ Marc K Hellerstein, Elizabeth J Parks (2004). Obesity and Overweight Basic and Clinical Endocrinology. Francis S Greenspan. Seventh edition. A Lange Medical book 2004: 794 - 813.
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11/ Daniel J. Rader, Helen H. Hobbs (2008). Disorders of lipoprotein metabolism. Harrisons Internal Medicine. 17th edition 2008: 2416-2429.
KI M TRA MY T O NH P TH T V I I N TM
Tr n Th ng Division of Biomedical Engineering, Oregon Health & Science University Tm t t M c tiu: Trong bi ny, chng ti s bn v m t s nguyn t c c b n m t bc s tim m ch, khng chuyn v i n sinh l tim, c th dng ch n on m t b nh nhn c c y m t my t o nh p bu ng th t. Phng php: Phng ti n ch n on bc s tim m ch th ng c s n l i n tm . V i m t nam chm m nh v hi u bi t c b n v ho t ng c a my t o nh p, bc s s c th quy t nh l my t o nh p ho t ng chu n hay b nh nhn c n tr l i khm v i bc s c y my. K t qu : Chng ti s gi i m t s tr ng h p i n hnh cng v i cc i bi u. K t lu n: Bc s tim v m t nam chm m nh c th ch n on h u h t cc s m ch v i my i n tm ki n m t my t o nh p bu ng th t. Abstract Objective: In this paper we would like to review some basic principles for the practicing cardiologist, without extensive cardiac electrophysiology experience, to be able to diagnose a patient with a basic ventricular pacemaker implant. Method: The main tool available to such a cardiologist is the electro-cardiogram. With a strong magnet and some basic understanding of the operation of the pacemaker, the cardiologist can, in most cases, determine whether the pacemaker is operating satisfactorily, or further consultation with the implanting cardiogist would be required. Results: We will go over a number of examples of troubleshooting with the audience. Conclusion: A cardiologist with his electrocardiogram machine and a magnet can diagnose most ventricular pacemaker problems. TV N Chng ti c on l s b nh nhn c y my t o nh p Vi t Nam nm 2009 s ln n kho ng 1000 ng i. Cc trung tm c y my u cc thnh ph l n. M t s kh l n cc BN c y my s t cc t nh ln. V v y, sau khi c y my, cc BN ny s tr v t nh v khi BN c s ki n, cc BS t i t nh l tuy n u quy t nh my t o nh p c a BN c ho t ng chu n hay BN c n ph i i khm BS c y my BV thnh ph c ki m tra v i cc my chng trnh c a cng ty s n xu t. V y BS khng c my chng trnh c a cng ty s n xu t c th no ch n on tnh tr ng ho t ng c a my t o nh p c khng ? II. PHNG PHP Cc BS tim m ch u c my i n tm . My ny, cng v i nam chm m nh, gip BS ch n on cc BN c c y my t o nh p m t bu ng th t c t o nh p theo phng cch VVI. Trong ph n ny chng ti s trnh bi m t s khi ni m c b n v my t o nh p gip bc s hi u ho t ng c a m t my t o nh p VVI. 2.1. C b n t o nh p VVI [1] I.
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T o nh p VVI l t o nh p bu ng th t b ng nh ng xung v i nh p c nh, th ng l 70nh p/pht. trnh t o nn lo n nh p, my t o nh p c ch c nng nh n c m cc sng R, ng hn l sng kh c c c pht hi n t i u dy i n c c mm tim hay thnh lin th t. N u my pht hi n sng kh c c ny, my s khng pht xung, v s b t u chu k ch tr l i, th ng l 850 ms (70 n/p). V i nh n c m t t, my s khng c nh tranh v i nh p n i t i, n u nh p ny >70 n/p. 2.2. Nh n c m l m (Oversensing) V my dng i n tim nn cc sng my pht hi n c khng nh t thi t l tng ng v i sng R trn i n tm . Th d cc sng khc c my pht hi n l m l sng R: Ngo i tm thu th t Sng i n t cc c xung quanh tim, th d sng pht t c honh, ho c sng t cc c ng c. Sng nhi u t bn ngoi, th d khi BN ng g n m t my n p i n m nh. Trong hai tr ng h p u, my s b c ch v chu k th i gian (850 ms) s b l pl it u. N u cc sng ny ti p t c, my s khng ho t ng c v BN ty thu c my s ng t. Trong tr ng h p th ba, khi cc sng t i v i nh p cao hn 360 n/p (100 ms), my s pht xung theo nh p c nh (70 n/p) m khng b nh p n i t i c a BN c ch , c th a n lo n nh p n u xung nh vo sng T c a nh p n i t i c a BN. Trong tr ng h p cc sng t cc c ngoi tim c ch my, th BN c n ph i tr l i BS c y my i u ch nh nh y c a my. M t tr ng h p oversensing n a l khi dy i n c c b o n m ch (open circuit), 2.3. Khng nh n c m (undersensing) My dng m t m ch i n ng ng (threshold) pht hi n sng R c a i n tim. V v y sng R trong i n tim ph i cao hn nh y (sensitivity) c l p trnh. pht hi n sng trn 2,5 mV. Sng R trn Thng th ng th cc my c l p trnh i n tm c th r t cao, m sng R trong i n tim nhi u khi l i d i 2,5 mV, nn my s khng pht hi n c nh p n i t i. Trong tr ng h p ny, my s pht xung ng chu k (850 ms sau sng R tr c, hay sau pht xung tr c) m c d c m t ph c b QRS ngay tr c ! N u undersensing x y ra th ng xuyn, BN c n tr l i BS c y my i u ch nh nh y c a my. Ngoi sng R qu nh , undersensing cng c th x y ra do: Dy i n c c b o n m ch ( t) ho c ch p m ch i n c c b st 2.4. Th i gian tr (refractory) H u trnh pht hi n cc sng ph , sau khi my pht hi n m t sng R, hay sau khi pht xung, my s l i m t kho ng th i gian, th ng l 300 ms. V v y n u c m t ngo i tm thu th t ho c m t ph c b QRS x y ra trong kho ng th i gian 300 ms sau m t xung, my s l i m khng l p l i chu k. Ngoi th i gian tr my, cc c tim cng c th i gian tr. V v y m t th i gian ng n sau m t ph c b QRS, ~200-300 ms, t o nh p s khng thnh cng. 2.5. T o nh p khng thnh cng Khi c y my, bin xung c l p trnh t 2X n 3X ng ng t o nh p (bin xung th p nh t c th t o nh p thnh cng). Tuy nhin ng ng c th thay i do tc d ng ph c a thu c BN dng i u tr m t b nh khc, th d c m, b nh bao t , ho c
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do x ha u i n c c. V v y khi my khng t o nh p thnh cng, c n ph i h i xem c thay i g trong tnh tr ng s c kh e c a BN. N u BN ch m i c tri u ch ng do tnh tr ng s c kh e thay i, th trong tr ng h p tri u ch ng khng tr m tr ng l m, c th ch cho qua cn b nh. L n ti khm sau v i BS c y my, BN c n lu BS v s c qua , BS tng bin xung ln i cht. M t l do khc t o nh p khng thnh cng l do s c v i dy i n c c: i n c c st, dy i n c c b o n m ch ho c ch p m ch, v dy i n c c b n t ho c rch. Tr ng h p ny c n tr l i BS c y my i u ch nh. 2.6. C honh b kch thch N u bin xung qu cao, c honh c th b kch thch. BN c n ph i c l p trnh bin xung tr l i. 2.7. Hi n t ng nam chm [2] Khi nam chm m nh c t trn my, my s t o nh p c nh, khng b c ch . Biotronik: nh p c b n c a my. N u pin y u, th nh p s gi m 11% (70 n/p -> 62,3 n/p) Medtronic: 85 n/p. N u pin y u th 65 n/p. 2.8. Nh p qu th p N u nh p BN qu th p, th ngo i tr nguyn nhn c bn ph n II.2, cn c cc nguyn nhn sau y: My c l p trnh nh p v i hi n t ng tr (hysteresis). Th ng nh p v i hi n tng tr c dng v i BN c nh p n i t i khng qu 10-20 n/p th p hn so v i nh p my. M y l nh p n i t i, khng ph i nh p my! My c l p trnh v i nh p m. N u BN bo co l nh p tr c khi ng th p hn nh p c b n, l nh p m! Th ng l 45-50 n/p. My s p h t pin. C n tr l i BS c y my v s p s ph i thay my. o My Biotronik s gi m nh p 11% khi pin y u (70 n/p -> 62.3 n/p). Thng th ng my c l p trnh v i nh p v i con s ch n 70, 65, 60! Con s l nh 62,3 l b t th ng! o My Medtronic s t o nh p 65 n/p. N u c nam chm m nh t trn my, s th y my t o nh p 65 n/p c nh m khng b c ch . N u pin t t, th v i nam chm my s t o nh p c nh 85 n/p! 2.9. H ng d n ki m tra my 1. Yu c u BN trnh gi y my (Patient ID card). Lu tn my v ngy c y my.
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Ghi thng s my t s theo di c a BN, n u c.
2. Nh n d ng ph c b QRS, xung t o nh p, ngo i tm thu, nhi u. 3. T i m i xung, o ng c l i kho ng th i gian c b n (th ng: 1000 ms (60 n/p), 850 ms (70 n/p)). y l th i gian my ch pht xung. N u c ph c b QRS hay ngo i tm thu th t trong kho ng th i gian ny, c n tm hi u nguyn nhn t i sao my khng pht hi n v c ch xung. 4. Sau m i xung/QRS c nh n c m, c kho ng th i gian tr, ~200-300 ms. Trong kho ng ny cc sng s b my l i. 5. Nh n d ng sng sau xung phn bi t t o nh p thnh cng, khng thnh cng v nh p dung h p (fusion beat). 6. Dng nam chm ki m tra nh p c b n. Khi dng nam chm, cc ph c b QRS b my l . Tuy nhin n u t o nh p thnh cng th trong vng ~400 ms sau xung s khng c QRS. N u nh p nam chm th p hn bnh th ng [3], th pin my y u. Lu sau th i gian ho t ng >7 nm. III. TH C HNH V I I N TM 3.1. VVI, 60 n/p (1) [3]
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V. K T LU N BS tim m ch v i i n tm v nam chm c th ki m tra my t o nh p m t bu ng th t c ho t ng chu n hay khng, nh v y trnh BN ph i i ln thnh ph
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ki m tra my khi khng c n thi t. N u v n v i my khng ph i l do tc d ng ph c a thu c, th BN s c n tr l i khm v i BS c y my. TI LI U THAM KH O 1. Nguy n S Huyn, Tr n Th ng, Nguy n Ph Du, T Ti n Ph c, My t o nh p tim: c b n & th c hnh, T p Ch Tim M ch H c Vi t Nam, S 16-1998. 2. 2009 Medtronic Pacemaker and ICD Encyclopedia (6.26 MB) https://wwwp.medtronic.com/medtronicconnect/resources/presentationtools/MDT_Pac em akerandICD_EncyclopediaJune2009.pdf 3. Janet R. Christiansen, David L. Hayes, Transtelephonic Electrocardiography and Troubleshooting: A Case Approach, in David L Hayes, Paul J Wang, eds, Cardiac Pacemakers and Implantable Defibrillators: A workbook in 3 Volumes, Futura Publishing Company, Inc., Armonk, NY, 1998. Disclosure Ts Tr n Th ng l Gim c k thu t CT Trang Thi t B Y-T Tm Thu, nh cung c p cc my t o nh p tim vnh vi n v t m th i v cc my ph rung v i u tri c, t i Vi t N m - www.tamthuvn.com suy tim c a cng ty Biotronik, CHLB
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T O NH P TH T V I MY HAI BU NG: L I HAY H I ?

Tr n Th ng Division of Biomedical Engineering, Oregon Health & Science University Tm t t M c tiu: Nghin c u DAVID v i cc b nh nhn my ph rung hai bu ng nh th c gi i t o nh p v nguy h i t o nh p th t khi k t qu c cng b nm 2002. Bi ny s tm t t v s hi u bi t v nguy c do t o nh p th t t o ra cho t i th i i m thng 5, 2009. Phng cch: Trong bi ny, chng ti s bn v cc nghin c u ti p theo DAVID v l i/h i t o nh p th t. Nghin c u INTRINSIC RV nm 2007 gi i thch r l t o nh p th t ch khi c n thi t, th t ra khng c h i m l i c l i ch cho b nh nhn. Ngoi ra cc nghin c u MOST, DAVID II, MVP cng gip thm vo s hi u bi t v t o nh p th t. K t qu : Sau khi k t qu nghin c u DAVID c cng b , cc nh s n xu t my t o nh p v my ph rung tung ra m t s chng trnh trong cc my hai bu ng nh m gi m t o nh p th t. Chng ti s gi i thi u cc chng trnh ny v s bn v i v i cc nghin c u sau DAVID. hi u qu K t lu n: vo th i i m ny, ch c m t s nh my t o nh p v ph rung hai bu ng ang c cc cng ty gi i thi u Vi t Nam t c cc tiu chu n c n thi t gi m nguy c suy tim do t o nh p th t. TV N Chng ti c on l s b nh nhn c y my t o nh p Vi t Nam nm 2009 s ln n kho ng 1000 ng i. S b nh nhn ch n my 2 bu ng s kho ng 1/3, m t con s ng k ! i a s BN c y my m t bu ng u c t o nh p theo phng th c VVI(R ). Trong tr ng h p ny, t o nh p th t khng th trnh c. Trong cc nghin c u so snh t o nh p VVI v i t o nh p AAI cc BN suy nt xoang, t l suy tim v rung nh cc BN t o nh p VVI lc no cng cao hn BN t o nh p AAI [1]. Tuy nhin t o nh p AAI ch p d ng mcho <50% cc BN - ch trong tr ng h p BN c d n truy n nh-th t t t. Ngoi ra c y dy i n c c nh cng tng i kh hn l c y dy th t, v nh t l trong tr ng h p cc BN l n tu i, BS lo ng i l BN s b bl c nh-th t trong tng lai. V th t o nh p VVI an ton hn. Trong nghin c u MOST [2], t o nh p 2 bu ng DDDR c so snh v i t o nh p 1 bu ng VVIR. K t qu l khng c khc bi t v phng di n s c (t vong hay stroke), nhng DDDR cng c tc d ng gi m b t cc nguy c. I.
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Hnh 1. T l t n vong v i t o nh p [1]. Hnh 2. T l t n vong - MOST [2].
Hnh 3. So snh cc nguy c - MOST [2]. N u so snh hnh 1 v hnh 2, chng ta nh n th y l AAI v n t t hn DDD, trong tr ng h p cc BN b suy nt xoang. Nghin c u DAVID dng cc BN c c y my ph rung (ICD) 2 bu ng v c l p trnh DDDR-70 (70 n/p) ho c VVI-40 (VVI d phng 40 n/p). Ni chung cc BN ny khng c n t o nh p v nh v y c nt xoang tng i t t v v i d n truy n nh-th t t t. c tnh cc BN ny l tim b t u suy y u, v i LVEF < 40%! Cc BN ny r t nh y c m suy tim, so v i cc BN t o nh p bnh th ng. K t qu DAVID lm si ng gi i t o nh p v i khm ph l t o nh p 2 bu ng a n t l suy tim cao g p 2 l n t o nh p VVI-40!
Hnh 4. Xc su t s c - DAVID [3]. V y l, vo th i i m nm 2006, chng ta bi t l T o nh p AAI sinh l v c t l s c th p hn VVI. T o nh p VVIR tng ng v i DDDR v s c nghim tr ng (t vong, suy tim). Tuy nhin t o nh p 2 bu ng c nh ng l i ch [2] nh trnh h i ch ng my t o nh p, tng ch t l ng cu c s ng. Chng ta cng c th k t lu n l t o nh p DDDR khng c t t b ng t o nh p AAI v i cc BN suy nt xoang v i d n truy n nh- th t t t. DDDR v i t o nh p th t tng hi m h a suy tim g p 2X so v i VVIR,
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trong nhm BN khng c n t o nh p. II. PHNG PHP 2.1. Nghin c u INTRINSIC RV Sau khi nghin c u k t qu nghin c u DAVID, m t nhm BS i n k t lu n l cc v n v i t o nh p 2 bu ng do t o nh p th t khng c n thi t gy nn! Nhm BS ny ngh chng trnh nghin c u INTRINSIC RV [4]. gi m t o nh p th t, cc BS ch n my ph rung 2 bu ng Vitality AVT c a cng ty Guidant (Boston Scientific) v c i m sau y My c hi n t ng tr th i gian nh- th t (AV hysteresis) t i 300 ms My c ch c nng tm nh p th t n i t i th ng xuyn sau m t th i gian t o nh p th t - AV Search Hysteresis (AVSH, ho c AVS+). Ch c nng ny r t quan tr ng trnh my t o nh p lin t c sau khi m t nh p th t n i t i. V nghin c u ch ch tr ng n cc BN khng c n t o nh p, c nh ngha l BN v i t o nh p <20% th i gian, nn trong s 1530 BN c tuy n, ch c 988 BN (65%) tham gia chng trnh nghin c u [5] v c phn chia ng u nhin gi a hai nhm DDDR 60-130 v VVI-40. K t qu l INTRINSIC RV nh AVS+ gi m t o nh p xu ng cn trung bnh (average) l 10% v i i m gi a (median) 4%, so v i t o nh p 3% trung bnh v 0% i m gi a cho nhm VVI-40, o ng c k t qu c a DAVID.
Hnh 5. T l khng s c - INTRINSIC RV [5]. Hnh 6. Tm t t k t qu INTRINSIC RV [6]. Olshansky sau nghin c u INTRINSIC RV c lm thm m t nghin c u ph [7] dng t t c cc BN c l p trnh DDDR, k c nhm v i t o nh p th t >20% khng c dng trong nghin c u nguyn th y. Nhm 106 BN v i t o nh p t 10%-19% c t l s ki n th p nh t, xem hnh 7. T l ny tng d n ln v i t l t o nh p > 20%. Tuy nhin nhm 344 BN v i t o nh p th p nh t (0-9%) l i c t l s kin cao, 8.1%! Nh v y, i v i cc BN khng c n t o nh p ny, t o nh p m c 10-19% l t i u!
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Hnh 7. T l s c v i t o nh p th t trong nhm DDDR [7]. T i sao 10-19% t i u? M t gi thuy t c ngh l cc BN, m c d u c nt nh-th t t t, v n c nh ng khi thong b bl c c p II ho c III, v s m t i m t s chu k co bp th t, ho c bl c c p I qu di (> 300 ms). Trong cc tr ng h p ny t o nh p th t 300 ms sau sng p (ho c t o nh p nh) s gip huy t lu khng suy gi m. Ngoi cc s ki n trn (t vong, nh p vi n do suy tim), nhm >50% t o nh p th t cng l nhm v i nhi u lo n nh p c i u tr , 17%, k n l nhm 0-9% v i 12% lo n nh p. B n nhm cn l i ch c t l lo n nh p 5,6%! so snh, trong DAVID, t o nh p th t trong nhm DDDR70 l 59%, v ch kho ng 4% trong nhm VVI-40. V i k t qu INTRINSIC RV, chng ta khng c g ng c nhin v k t qu DAVID. Nghin c u chi ti t hn, cc BN DDDR70 trong DAVID v i t o nh p <40% c t l s ki n th p hn hm VVI-40. 2.2. Nghin c u DAVID II Nghin c u DAVID II [8] mu n tm hi u xem t o nh p AAI-70 c an ton so v i VVI-40. K t qu l khng c khc bi t v t l s ki n.
Hnh 8. T l s ki n - DAVID II. T l t o nh p nh l 47% v t l t o nh p th t l 2%. Nh v y l t o nh p nh trong nhm BN khng c n t o nh p ny, khng c h i m cng khng c l i ch g so v i t o nh p d phng th t. Nh v y cc s ki n khng t t trong nho/m DDDR c a DAVID l hon ton do t o nh p th t! Gom gp cc k t qu c a DAVID, INTRINSIC RV, v DAVID II, chung ta c th k t lu n l i v i nhm BN ICD khng c n t o nh p ny T o nh p nh khng khc t o nh p d phng T o nh p hai bu ng c h i so v i t o nh p d phng VVI-40. T o nh p hai bu ng v i ch c nng AVS+ dng nh p th t n i t i t i a s gi m t l s ki n so v i VVI-40. T i u l t o nh p th t 10-19%. II.3. Nghin c u
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MVP. K t qu nghin c u MVP v a c cng b h i nghi HRS, ngy 15 thng 5,2009,http://wwwp.medtronic.com/Newsroom/NewsReleaseDetails.do?itemId=12423 90431212&lang=en_US. Chng ti cn ang ch bo co chi ti t s c ng trn cc t p ch tim m ch. Theo bo co t i HRS, th t o nh p MVP khng c hi u qu hn VVI-40! Managed Ventricular Pacing l phng cch t o nh p c a ring cng ty Medtronic. V i MVP my s t o nh p theo d ng AAIR cho t i khi m t nh p n i t i th t 4 chu k lin ti p, th s chuy n qua t o nh p DDDR. Sau 2 chu k nh m khng c nh p n i t i th t, my s pht m t xung an ton th t. T t c cc ICD hai bu ng c a Medtronic, t th h Intrinsic tr v sau, u dng ch c nng ny. V i k t qu ny, MVP t ra khng cng hi u b ng AVS+, m c d u cng hi u gi m t o nh p th t xu ng kho ng 4% [10]. Tuy nhin n u nhn k t qu c a INTRINSIC RV, chng ta cng khng c g ng c nhin v nhm v i 0-9% t o nh p c t l s ki n kh cao, ch hi th p hn nhm VVI-40 i cht. II.4. Hi m h a t o nh p th t BS Sweeney v c ng s [13] phn tch tr l i nghin c u MOST[2] v tm c s quan h gi a t o nh p th t v suy tim v i rung nh cc BN suy nt xoang. Chng ta th y trong b ng d i y l t o nh p th t v i DDD <50%, v n t t hn l t o nh p VVI. Nhng m t khi qu 50%, thi c 2 phng cch t o nh p c tai h i nh nhau. V khi >90%, th DDD khng t t b ng VVI!
Hnh 9.T o nh p th t v suy tim v i rung nh [13]. Tm hi u su xa hn Sweeney v Hellkamp [14] gi i thch r ng t o nh p t mm th t gy suy tim v rung nh do ln sng kh c c khng c sinh l. Khi so snh t l nh p vi n do suy tim c a BN suy tim v BN t o nh p dng r ng c a QRS, chng ta th y hai ng th c d ng gi ng nhau.
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r ng QRS [13]. Hnh 10. Hi m h a suy tim v i Nh kh e hn, cc BN t o nh p c th ch u ng m t r ng QRS khi t o nh p th t l n hn so v i cc BN suy tim. 2.5. T o nh p VDDR Cc nghin c u c bn trn u nh m vo cc BN suy nt xoang, v th ng c d n truy n nh-th t t t. V y cn tr ng h p BN c nt xoang t t nhng b bl c th sao? Trong [15], chng ti c bo co r ng t o nh p VDDR t t hn DDDR v VVIR v phng di n rung nh. V suy tim th ng x y ra m t th i gian lu sau khi BN c t o nh p, nn chng ta ch c th c on l t l suy tim sau m t th i gian di, cng s theo t l rung nh. III. T O NH P 2 BU NG V I CH C NNG GI M T O NH P TH T 3.1. Boston Scientific (Guidant) Cc my t o nh p v ph rung hai bu ng c a Guidant u dng ch c nng AV Search Hysteresis (AVS+) gi m t o nh p th t. V i ch c nng ny, cc BN khng c n t o nh p th t (c d n truy n nh-th t t t) s tm c t o nh p kho ng 10% th t, theo k t qu INTRINSIC RV. AVS+ dng Hi n tng tr th i gian nh-th t (AV hysteresis) n 300 ms, Chng trnh tm th ng xuyn nh p n i t i sau m t th i gian t o nh p. Boston Scientific khng c m t th tr ng Vi t Nam. 3.2. Biotronik T t c cc my t o nh p v ph rung 2 bu ng Biotronik ang cung c p Vi t Nam u c ch c nng Intrinsic Rhythm Support plus (IRS+) v i AV hysteresis n 300 ms, ho c IOPT (ch ICD thi) v i AV hysteresis n 400 ms. IRS+ dng AV hysteresis n 300 ms AV scan s tm nh p n i t i sau 180chu k t o nh p th t AV repetitive, s nh tr chuy n qua AV delay thng th ng (ng n hn AV hysteresis) khi b t u t o nh p trong vng m t s chu k Cc BN khng c n t o nh p (AV < 200 ms) s c t o nh p th t kho ng 6-9% (trung bnh 7%) [9]. So v i AVS+, IRS+ trong cng BN th ng s c t l t o nh p th p hn v ch c nng AV repetitive s c g ng tm nh p n i t i th t trong vng 5 chu k sau khi m t nh p n i t i th t. Nh v y l IRS+ s tng ng v i vng 1019% t i u c a INTRINSIC RV. 3.3. Medtronic 3.3.a. Managed Ventricular Pacing
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Ch c dng cao c p my t o nh p Advanta c a Medtronic l c ch c nng MVP. Cc my ICD t Intrinsic tr i cng c MVP. Tuy nhin hi n th i Medtronic ch cung c p Maximo ICD th tr ng Vi t Nam. My Maximo khng c ch c nng gi m t o nh p th t. MVP gi m t o nh p th t xu ng cn kho ng 4% [10], g n b ng t l c a t o nh p VVI d phng. V nh k t qu MVP Trial cho th y, m c ny qu th p, khng gip BN nh ng khi b bl c nh-th t. L do l t i MVP c n 4 chu k khng c nh p n i t i th t m i chuy n t AAIR sang DDDR. M c d u c t o nh p an ton ngay sau 2 chu k khng pht hi n nh p n i t i th t, nhng d sao th t cng m t m t chu k co bp! 3.3.b. Search AV plus Search AV hysteresis l ch c nng Medtronic dng trong cc my t o nh p 2 bu ng, ngoi tr dng Advanta. SAV+ khng c dng trong cc my ph rung. SAV+ gi m t o nh p th t xu ng cn kho ng 23% [12], hi cao hn vng t i u 10-19%. L do SAV+ khng hi u qu b ng AVS+ ho c IRS+ l do SAV+ ch tng th i gian AV hysteresis ln t ng b c 10 ms, trong lc AVS+ v IRS+ u dng hysteresis n 300 ms!
Hnh 9. T o nh p MVP [11] Sau nghin c u MVP, c th cng ty Medtronic s chuy n cc my ph rung sang SAV+ ?? Theo hnh 7, t o nh p t l 20- 39% t t hn l 0-9%! Ho c s thay i qua chng trnh nh AVS+ ?? 3.4. StJude 3.4.a. AutoIntrinsic Conduction Search: Sau m t s chu k t o nh p, my s tng th i gian nh-th t b ng s c l p trnh (t 10 n 120 ms). Ch c nng ny ch ho t ng n nh p 90 n/p. L do AICS khng cng hi u b ng AVS+ l t i v th i gian nh-th t ch c tng thm v i s c l p trnh. Theo bo co th AICS hi u qu gi m t o nh p th t xu ng cn kho ng 49.7% 3.4.b. Ventricular Intrinsic Preference VIP gi ng AVS+ v khi tm nh p n i t i th t th ko di th i gian nh-th t n 350 ms. VIP c th ho t ng n nh p 110 n/p. Chng ti ngh l VIP s tng t nh AVS+. VIP ch c trong cc my t o nh p dng Victory (2006) v Zephyr (2007). Cc my ny cha c lu hnh Vi t Nam.
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IV. K T LU N T cc chng trnh nghin c u c bn trn, chng ti m n php ngh gi thuy t l phng cch t o nh p c t t t nh t l t o nh p m t bu ng (nh ho c th t) v i t o nh p d phng bu ng kia, v i m t nh p ch hi th p hn cht nh. T o nh p hai bu ng v i AVS+ v IRS+ h p v i gi thuy t trn. T o nh p MVP tr t i u l nh p d phng th t ch l nh p nh! Theo gi thuy t trn, th m t phng cch t o nh p i v i BN b bl c t t hn VDDR l t o nh p DDDR v i hysteresis nh p (ratehysteresis) v i ch c nng tm nh p n i t i. Ch c nng ny c trong cc my: Rate hysteresis scan (c ng v i Rate repetitivehysteresis nh tr tr l i nh p c b n) c a Biotronik, Sinus preference c a Medtronic (ch trong Adapta, khng c trong Sensia), Hysteresis search c a StJude. Ph i l p trnh bao nhiu hysteresis? Chng ti ngh -20 n/p l . nh p 60n/p, voi rate hysteresis -10 n/p, m ch i n nh s ch thm 200 ms tr c khi pht xung . T cc nghin c u c bn trong bi ny, v kinh nghi m t o nh p VDD [15], chng ta c th i n k t lu n sau y: i v i cc BN cn d n truy n nh-th t t t, t o nh p hai bu ng v i ch c nng t n d ng nh p th t n i t i t i a dng AV hysteresis di 300+ ms, l t i u, t t hn c t o nh p AAIR. Hi n nay th tr ng Vi t Nam, ch c cc my cng ty Biotornik t c tiu chu n ny. i v i cc BN b bl c v i nt xoang t t, t o nh p VDDR [15] hi n nay l t t nh t. H u h t cc my 2 bu ng c th dng phng cch t o nh p ny. Theo gi thuy t c a ra trn, th chng ti ngh l t o nh p 2 bu ng DDDR, v i hysteresis nh p v v i ch c nng tm nh p n i t i. c tri n v ng gi m t l s ki n th p hn VDDR v i nhm BN b bl c! i u ny c n c ch ng minh! Cc my c a cng ty Biotronik v StJude, v my Adapta c a Medtronic c th l p trnh t o nh p theo hng cch ny. N u c th nn ch n i m c y dy i n c c th t thnh lin th t h u t o cc QRS h p [16, 17]. K t lu n trn ch p d ng cho t o nh p v nh p ch m. i v i BN suy tim, ang c i u tr b ng phng php ti t o ng b tim (CRT), th t o nh p th t 100% l m c ch i u tr . TI LI U THAM KH O 1. HR Andersen, JC Nielsen, PEB Thomsen, et al., Long term follow-up of patients from a randomised trial of atrial versus ventricular pacing for sick-sinus syndrome, The Lancet 1997; 350: 1210-1216. 2. AS Hellkamp, KL Lee, MO Sweeney, et al., Treatment crossovers did not affect randomized treatment comparisons in the Mode Selection Trial (MOST), JACC 2006; 47: 2260-2266. 3. The DAVID Trial Investigators, Dual-chamber pacing or ventricular backup pacing in patients with an implantable defibrillator, JAMA 2002; 288: 3115-3123. 4. B Olshansky, J Day, M McGuire, et al., Reduction of right ventricular pacing in patients with dual-chamber ICD, PACE 2006; 29: 237-243. 5. B Olshansky, JD Day, S Moore, et al., Is dual-chamber programming inferior to single- chamber programming in an implantable cardioverter-defibrillator?
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Results of the INTRINSIC RV (Inhibition of unnecessary RV pacing with AVSH in ICDs) Study, Circulation 2007; 115: 9-16. 6. S Stiles, INTRINSIC-RV: Dual-chamber and ventricle-only pacing can achieve similar clinical outcomes in ICD patients, Heart Wire, May 23, 2006. http://www.theheart.org/article/703891.do 7. B Olshansky, JD Day, DR Lerew, et al., Eliminating right ventricular pacing may not be best for patient requiring implantable cardioverter-defibrillator, Heart Rhythm 2007; 4:886-891. 8. BL Wilkoff, PJ Kudenchuk, AE Buxton, et al., The DAVID (Dual chamber and VVI Implantable defibrillator) II Trial, JACC 2009; 53: 872-880. 9. A Puglisi, S Favale, P Scipione, et al., Overdiver versus conventional or closed-loop rate modulation pacing in the prevention of atrial tachyarrhythmias in brady-tachy syndrome: on behalf of the Burden II study group, PACE 2008; 31: 14431455. 10. MO Sweeney, KA Ellenbogen, D Casavant, et al., Multicenter, prospective, randomized safety and efficay study of a new atria-based managed ventricular pacing mode (MVP) in dual chamber ICDs, J Cardiovasc Electrophysiol 2005; 16: 811-817.
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LIN QUAN GI A MU I N V HUY T P

o Duy An Tm t t Mu i n g m hai ion Na+ (natrium) v Cl- (chlor) v n ng vai tr quan tr ng trong i u ha th tch ngo i bo v l y u t chnh i u ha huy t p. L ng mu i n t i a l 6 g/ngy; n u v t ng ng ny, lu ngy s d n n m t s nguy c v b nh, c bi t l tng huy t p. L ng mu i th c s c n thi t cho c th c l l 0,5 g/ngy, c s n trong th c ph m t nhin. Gi a mu i n v huy t p c m i quan h ti n tri n v lin t c, khng c ng ng r rng. L ng mu i n cng nhi u th huy t p cng tng: c tng m i 100 mmol mu i n hng ngy th huy t p tm thu tng 12 mm Hg v huy t p tm trng tng 7 mm Hg. Cc b ng ch ng nhn h c, d ch t h c, di dn, can thi p d a trn c ng ng, th c nghi m, nhin c u gene ng i, th nghi m i u tr v phn tch g p cho th y m i quan h nhn qu gi a hm l ng mu i v ch s huy t p. Ng i nguyn th y kh p cc ni khng n mu i nn khng b tng huy t p v huy t p khng tng theo tu i tc gi ng nh cc n c cng nghi p. Nh ng c ng ng bi t l p n < 1g natrium/ngy th t l hi n m c tng huy t p ch b ng 1% c a cc c ng ng c l i s ng cng nghi p. Nh ng ng i t cc vng phi cng nghi p n ni th th c HA cao hn ng i l i. Cc nghin c u trn chu t, ch, g, th , c u, kh u ch v tinh tinh u cho th y mu i n lm tng huy t p trong qu n th . i m i l a tu i gi m mu i u lm gi m huy t p. Gi m mu i n th gi m huy t p v cc bi n ch ng lin quan cng nh ngn ng a tng huy t p ng th i gip thu c h huy t p tc d ng t t hn, ki m sot huy t p t t hn v tc d ng gi m mu i n tng ng thu c l i ti u li u th p. Gi m mu i gip ng i ang u ng thu c h huy t p ng ng thu c m huy t p v n ki m sot t t.Vi c gi m mu i trong c ng ng c tnh l i chi cao v t ra ph h p v i b i c nh Vi t Nam. N l c gi m mu i ki m sot huy t p v tng huy t p t t ph thu c chnh ph , c ng ng, c nhn v m i th y thu c tng huy t p; y l m t trong nh ng thay i hnh vi n quan tr ng v kh khn nh t. T kho: mu i n, natrium, huy t p, tng huy t p, lin quan Abstract Salt includes sodium and chloride which have an important role in regulating the volume of extracellular fluid and are major regulators of blood pressure. Maximum recommended salt intake is 6 g/day; if daily salt intake is over this threshold permanently, some risks and diseases, especially hypertension will be evolved. Daily salt need for good health is probably close to the natural salt content of unprocessed food, about 0.5 g per day. Relationship between sodium intake and blood pressure is progressive and continuous without an apparent threshold. The more salt intake rises is the more blood pressure increases: an increase in sodium intake of 100 mmol caused an increase in systolic pressure of 12 mm Hg and diastolic pressure of 7 mm Hg. Evidence resulting from anthropic, epidemiological, migration, population-based intervention, animal, human genetic studies, clinical trials and meta-analyses of trials shows the causal relationship between salt intake and blood pressure. Preimitive people from wildly parts of the world did not eat sodium have no hypertension and blood pressure does not rise with age as it does in all industrialized populations. In isolated societies where the consumption of sodium is less than 1 g per day, the prevalence of
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hypertension is only 1% of that in industrialized communities. Migrants from a nonindustrialized environment to an urban setting manifested an increase in blood pressure compared with those left behind. Numerous studies in rat, dog, chicken, rabbit, sheep baboon and chimpanzee have all shown that a high salt intake is essential for blood pressure to rise. For all varies of ages, sodium reduction related to blood pressure decrease. Sodium reduction induces the decrease of the level of blood pressure and related consequences as well as prevention of hypertension. A low-salt diet combined with anti-hypertensive therapies facilitates blood pressure reduction and the control of hypertension. The effect of salt reduction is equivalent to low-dose thiazide diuretic. Reduction of sodium intake may help people on antihypertensive drugs to stop their medication while maintaining good blood pressure control. Community salt intake reduction is cost-effective and applicable in todays Vienamese social condition. The effort to control the level blood pressure and hypertention by sodium reduction depends on the government, communities, individuals and hypertension specialists. Eating behavior change is one of the most important and difficult part in the life style modification program. Key words: salt intake, sodiium, blood pressure, hypertension, relation. D n nh p Mu i n g m hai ion Na+ (natrium) v Cl- (chlor) v n ng vai tr quan tr ng trong i u ho th tch ngo i bo v l y u t chnh i u ho huy t p (HA) [1, 2]. L ng mu i n t i a l 6 g/ngy [3 - 6]; n u v t ng ng ny, lu ngy s d n n m t s nguy c v b nh nh ph i th t tri, hen, s i th n, long xng, [7], t qu b nh m ch vnh v c bi t l tng huy t p (THA) [6, 8]. Hi n nay, THA l b nh l tim m ch ph bi n nh t trn ton c u cng nh t i Vi t Nam, gy t vong, bi n ch ng v di ch ng nhi u nh t: 26,4% dn s b THA, tnh ra 1,5 t ng i m c v 7,1 tri u ng i trn th gi i ch t s m m i nm [9 - 15]; trong khi , kh nng d phng v ki m sot THA r t cao. Tuy nhin, gi a mu i n v HA c m i lin h nhn qu v bi n php i u ch nh mu i ki m sot v d phng THA nh th no cng nh th c hnh gi m mu i c ng ng ra sao, cha th y tc gi no c p. Vai tr c a mu i trong i s ng v Bi u 1. Lin quan gi a th i natrium qua n c ti u v gi m huy t p tm thu t i m t phn trong c th tch g p th nghi m gi m mu i trung bnh tr Mu i n ng vai tr quan tr ng trong >/= m t thng. Vng tr ng ch tr huy t p bnh i s ng v s c kho con ng i [16]. Mu i c l th ng v vng en ch ng i tng huy t p. Cc d c c a o n th ng bi u th s thay i l gia v lu i nh t, th ng dng nh t m huy t p th c. Cc c vng tng ng l n khng t o nng l ng [6]. Hai tri u nm tr c, c a th nghi m. Ngu n: He et al [15]. t tin con ng i n < 0,25 g mu i m i ngy [7]. L ng mu i th c s c n thi t cho c th c l l 0,5 g/ngy v n c s n trong th c ph m t nhin [17]. Kho ng 5000 nm tr c, ng i Trung Hoa bi t dng mu i b o qu n th c ph m nh tnh nng mu i c c ch vi khu n. Ngy nay t l nh v cc k thu t b o
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qu n th c ph m ngoi mu i n kh ph bi n nhng do quen v m n c a mu i nn ng i ta c xu h ng thch th c ph m m n hn l lo i khng m n; v l i mu i gip th c n khng ngon tr nn d n v tng tr ng l ng th c ph m cng nh ko theo s c mua cc lo i n c gi i kht; v v y, x h i ng i v n tiu th mu i kh cao [6, 7]. Mu i lin quan huy t p nh th no T xa, bi t quan h nhn qu gi a mu i n v HA [18]. M t trm nm tr c d y ln nghi ng mu i n thc y THA [6]. Bi u 2. Lin quan gi a l ng mu i natrium th i 24 gi v t l Gi a mu i n v tng huy t p. HA c m i quan h ti n (Tng huy t p l huy t p tm thu >/= 140 mm Hg v/ho c huy t p tm trng >/= 90 mm Hg. Cc vng: Yanomamo (Brazil), New tri n v lin t c, khng Guinea highlands, Pukapuka v Rarotonga (Cook Islands), Marshall c ng ng r rng [6] d Islands, Eskimo (Alaska), United States (Dahl), United States (F), r ng v i l ng mu i n B , Naples, Italy, Renfrew, Scotland, Ph n Lan, Nh t-pha nam, Bantu (chu Phi), Nh t-pha b c. < 50 mmol/ngy th h u F = D li u t nghin c u Framingham theo hm l ng natrium th i nh khng c THA v ra.). Ngu n: Mac regor [2]. tng ch s HA do tu i tc [19]. L ng mu i n nh cng nhi u (xc b ng cch tnh l ng Bi u 3. Lin quan gi a huy t p tm thu v l ng mu i nm vo th c n hng ngy ng v i cc qu n th c tu i khc nhau. mu i n vo ho c l ng Ngu n: MacGregor [2]. natrium th i qua n c ti u 24 gi ) th HA cng tng [20, 21], d n n tng ch s HA v t l THA (Bi u 1 v 2). C tng m i 100 mmol mu i n hng ngy th HA tm thu (HATTh) tng 12 mm Hg v HA tm trng (HATTr) tng 7 mm Hg [2]. Mu i n vo c th thc y s thay i n i t i v th gin v khng c a m ch mu; hi u ng ny c tng cng b i s ng mu i b m sinh ho c m c ph i [22] ng th i tng th tch ngo i natrium huy t tng cng nh tng c ng ho t ng bm Na+/K+ [23], bo v n ng kch thch ti t steroid h ng tim v digitalis loi ng v t c v [16]. n qu nhi u mu i c th gy THA khng [11]. Cc b ng ch ng nhn h c, d ch t h c, di dn, b ng ch ng can thi p d a trn c ng ng, b ng ch ng th c nghi m, b ng ch ng nghin c u gene ng i, b ng ch ng th nghi m i u tr v phn tch g p cho th y m i quan h nhn qu gi a hm l ng mu i v ch s HA [15, 18, 20, 24, 25]. B ng ch ng nhn h c. Ng i nguyn th y kh p cc ni khng n mu i nn khng b THA v HA khng tng theo tu i tc gi ng nh cc n c cng nghi p [13], v d ng i Yanomano 40-49 tu i b c Brazil bi xu t ch m t mmol natrium m i ngy c HA 107/67 nam v 98/62 mm Hg n [2, 13, 26] (Bi u 3). B ng ch ng d ch t h c. C dn dng n c bi n ch bi n th c n th c HA cao hn c dn khng nh th qu n o Thi Bnh Dng . T i Nigeria trong 2 c ng ng nng thn c l i s ng
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gi ng nhau tr vi c x l h mu i l y mu i dng th c ng ng dng mu i c ch s HA cao hn. Qash'qai, m t b t c s ng Iran chuyn x l mu i t p trn m t t, c ch s HA cao v HA tng theo tu i gi ng nh cc n c phng Ty d cc c i m v l i s ng th gi ng cc c ng ng cha pht tri n m khng x l mu i t p [7]. Nh ng c ng ng bi t l p n < 1 g natrium/ngy th t l hi n m c THA ch b ng 1% c a cc c ng ng c l i s ng cng nghi p [14]. B ng ch ng di dn Nghin c u trn 20 c ng ng khc nhau, v n n t ho c khng dng mu i, th y HA t tng theo tu i v hon ton khng c THA [6] (Bi u 3). M t s nghin c u th y vi c di dn t vng n mu i t v c l p n mi tr ng th n mu i nhi u th lin quan v i tng ch s HA [7]. Nghin c u di dn b t c nng thn Kenya cho thy vi c di chuy n n vng th (ni n nhi u mu i) lm cho HA tng so v i nhm ch ng tng t nhng v n l i vng nng thn; thanh nin Kynia gia nh p qun i, n mu i th vi nm sau ch s HA tng [6, 7]. Nh ng ng i t cc vng phi cng nghi p n ni th th c HA cao hn ng i l i [25]. B ng ch ng can thi p d a trn c ng Bi u ng. 4. Tc d ng gi m mu i v b a n DASH ln HA C vi nghin c u can thi p d a trn tm thu (bi u A) v HA tm trng (bi u B). HA trung bnh tm thu/tm trng nhm ch n c ng ng trong c m t s nghin c u i ch ng. HA trung bnh thay i i v i nh ng khng th lm gi m l ng mu i c nn m c natrium khc nhau (v ch li n) v gi a hai ch HA khng gi m v cng c nghin c u lm n ng v i t ng m c natrium n vo khc nhau. Con s c nh v ch r i ch HA thay i trung bnh v tin gi m c l ng mu i n nn HA gi m theo. c y 95% n m trong ngo c n. Khc bi t c ngha Nghin c u can thi p thnh cng nh t l t i 2 v HA tm thu i v i pha natrium cao v th p trong b a n i ch ng (trung bnh, 6,7 mm Hg; kho ng lng B o Nha th hi n l gi m l ng tin c y 95% , 5,4 n 8,0; P<0,001) v trong b a mu i khc bi t gi a 2 lng n 50%. Sau 2 n DASH (trung bnh, 3,0 mm Hg; kho ng tin c y 95% , 1,7 n 4,3; P<0,001) v gi a pha natri cao nm can thi p, khc bi t HA gi a 2 lng l c a b a n i ch ng v i pha natri th p c a b a n 13/6 mm Hg. M i y, m t th nghi m can DASH (trung bnh, 8,9 mm Hg; kho ng tin c y 95%, 6,7 n 11,1; P<0,001). Khc bi t cng c thi p d a trn qu n th ng u nhin ti n hnh ngha gi a huy t p tm trng gi a pha natri cao v 550 c nhn t i 2 lng ng b c Nh t. pha natri th p c a b a n i ch ng (trung bnh, 3,5 Nghin c u cho th y t v n ch n m t mm Hg; kho ng tin c y 95%, 2,6 n 4,3; P<0,001) v b a n DASH (trung bnh, 1,6 mm Hg; nm gi m c 2,3 g mu i/ngy, o b ng kho ng tin c y 95%, 0,8 n 2,5; P<0,001) v l ng natrium th i qua n c ti u 24 gi , lin gi a pha natri cao c a b a n i ch ng v i pha natri th p c a b a n DASH (trung bnh, 4,5 mm Hg; quan gi m 3,1 mm Hg HATTh [7]. kho ng tin c y 95%, 3,1 n 5,9; P<0,001). D u B ng ch ng th c nghi m. sao (P<0,05), d u thnh gi (P<0,01)v d u thnh gi i (P<0,001) ch khc bi t c ngha v huy t p Nhi u nghin c u trn chu t, ch, g, gi a cc ch n ho c gi a cc b a n c m c th , c u, kh u ch v tinh tinh u cho th y natrium khc nhau. Vi t t t: DASH-the Dietary Approaches to Stop mu i n lm tng HA trong qu n th [ 2, 7, Hypertension. 27]. Con ng i v tinh tinh gi ng nhau n Ngu n: Sacks et al [29].
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98,8% v gen [15]; do v y thay i tinh tinh c th ph n nh th c tr ng ng i. Tinh tinh trong mi tr ng hoang d n mu i khng khc l m v i t tin ng i [6]. Elliott & CS nm 2007 [28] cng b k t qu nghin c u v l ng natrium thay i 17 con tinh tinh t i Franceville, Gabon v 110 tinh tinh t i Bastrop, Tex. Gabon, tinh tinh n bnh qui c d ng ch t c nh ngo i tr mu i thay i sau 3 nm t 75 xu ng 35 v ln 120 mmol/ngy. Bastrop, chia tinh tinh thnh 2 nhm: (1) nhm chu n n natrium 250 mmol/ngy trong 2 nm v (2) nhm ng ng n natrium. L ng natrium th c n th p lin quan HATTh, HATTr v HA trung bnh th p Gabon (P 2 chi u < 0,001, c/khng c i u ch nh theo phi, tu i v cn n ng ban u) v Bastrop (P < 0,01, khng i u ch nh; P = 0,08 n 0,10, c i u ch nh), v khng c ng ng xu ng n 35 mmol/ngy v natrium. i v i HATTh, c l ng gi m 12,7 mm Hg (kho ng tin c y [KTC] 95%: 16,9 n 8,5, i u ch nh) trn 100 mmol/ngy l ng natrium Gabon v gi m 10,9 mm Hg (KTC 95%: 18,9 n 2,9, i u ch nh) v gi m 5,7 mm Hg (KTC 95%: 12,2 n 0,7, i u ch nh) i v i l ng natrium gi m cn 122 mmol/ngy Bastrop. Huy t p tm thu ban u cao hn 10 mm Hg lin quan gi m m nh HATTh 4,3/2,9 mm Hg Gabon/Bastrop trn 100 mmol/ngy khi gi m l ng natrium. B ng ch ng nghin c u gene ng i. R t hi m gene gy THA. Nh ng gene ny lm cho th n gi m kh nng th i mu i (th n v n l c 180 L huy t tng m i ngy v ti h p thu 99% l ng mu i, tng ng 1 kg mu i), do gy HA tng. Huy t p tng cng m nh khi n mu i cng nhi u [7] (Bi u 3). B ng ch ng th nghi m i u tr v phn tch g p. Ambard v Beaujard, nm 1904, l nh ng ng i u tin ch ng minh gi m mu i m nh s lm gi m HA [7]. K t qu ny c vi nh nghin c u c ng c su t 30 nm sau nhng khng ph i i n khi Kempner h i sinh t ng h n ch mu i m nh n m i c ng d ng r ng ri trong i u tr THA. Th nghi m c a Sack & CS [29] v phn tch g p c a He & CS [30] ch ng minh nh h ng c a gi m natrium ln tnh tr ng HA ng n h n v di h n. Tc d ng gi m mu i ng n h n. B n trm m i hai ng i HA bnh th ng cao v THA giai o n 1 phn ng u nhin n b a n i ch ng i n hnh c a M ho c dng b a n DASH (the Dietary Approaches to Stop Hypertension) (g i ng l b a n h n h p, g m nhi u s i, khong ch t t tri cy v rau ti, nhi u c, th t g, t th t b, heo v t ch t bo bo ha) v trong m i ch n phn ti p ng u nhin i t ng n m t trong 3 ki u n theo l ng natri l cao (150 mmol/ngy), trung bnh (100 mmol/ngy) v th p (50 mmol/ngy) trong 30 ngy lin ti p. K t qu l khi l ng natri gi m t m c cao xu ng trung bnh th HATTh gi m 2,1 mm Hg (P < 0,001) i v i b a n ch ng v gi m 1,3 mm Hg (P = 0,03) i v i b a n DASH. L ng natri gi m t m c trung bnh xu ng th p th HA gi m thm 4,6 mm Hg trong b a n ch ng (P < 0,001) v gi m 1,7 mm Hg trong b a n DASH (P < 0,01). Tc d ng gi m natri x y ra ng i c/khng c THA, nam ho c n v b t k ch ng t c. Ch n DASH lm gi m c ngha HATTh t ng m c mu i v gi m HA m nh hn khi mui gi m nhi u hn. So v i nhm ch ng c n ng natri cao, b a n DASH v i m c natri th p s gi m c HATTh trung bnh 7,1 mm Hg ng i khng c THA v gi m 11,5 mm Hg ng i THA (Bi u 4) [29]. Tc d ng gi m mu i di h n.
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He & CS [30] tm trn h lu tr d li u MEDLINE, EMBASE, Cochrane cc nghin c u v t ng lu n v gi m mu i trung bnh >/= 4 tu n. K t qu l c 20 th nghi m trn ng i THA (n = 802) v 11 th nghi m ng i bnh th ng (n = 2220). trung v natrium th i qua n c ti u l 78 mmol/24 gi (4,6 Ng i THA c n ng g/ngy mu i), HATTh gi m trung bnh -5,06 mmHg (KTC 95%:-5,81 n -4,31) v HATTr gi m -2,7 mmHg (KTC 95%: -3,16 n -2,24). ng i bnh th ng, gi m trung v l ng natrium qua n c ti u l 74 mmol/24 gi (4,4 g/ngy mu i), HATTh gi m trung bnh -2,03 mmHg (KTC 95%: -2,56 n -1,5) v HATTr gi m -0,99 mmHg (-1,4 n -0,57). H i quy tuy n tnh c ngha gi a gi m natrium qua n c ti u v gi m HA. Trong kho ng t 3 n 12 g/ngy, l ng mu i cng gi m th HA cng gi m. tu i Gi m mu i v i cc i v i m i l a tu i gi m mu i u lm gi m HA [8]: Tr s sinh. Nghin c u c a Hofma & CS trn 500 tr s sinh H Lan trong su thng: nhm u ng s a c gi m mu i th g n 50% c HA gi m 2,1 mm Hg t i su thng tu i so v i nhm tr dng s a bnh th ng v HA nhm tr u v n gi m ko di sau 15 nm b t k l ng mu i n [8]. Tr em v thanh nin m i l n. C m i tng quan tuy n tnh gi a l ng natrium th i 24 gi v HATTh 73 tr 1114 tu i, t c l n cng nhi u mu i th HATTh cng tng v m i tng quan ny v n ngha sau khi lo i tr nh h ng c a tu i, phi, ch ng t c, m ch, chi u cao v cn n ng [7]. M t phn tch g p m i y 10 th nghi m gi m mu i v i 966 ng i cho th y gi m mu i trung bnh d n n gi m c ngha HA tr em v thanh nin m i l n. Khi gi m 42% mu i n trong 4 tu n, HATTh gi m 1,2 mm Hg (P < 0,001) v HATTr gi m 1,3 mm Hg (P < 0,001). K t qu ny quan tr ng b i tr em m HA cng cao th khi l n HA cng cng cao[7]. L a tu i trung nin. MacGregor & CS nghin c u th y l ng mu i gi m trung bnh (v d 80 mmol/ngy) th HA gi m, ti p t c gi m khi cng gi m mu i v gi m ko di cho n khi cn gi ch gi m mu i. Theo di 18 thng trn cc i t ng 30-54 tu i c HATTr 80-89 mm Hg th y HA gi m 1,4/0,9 mm Hg khi bi xu t natri gi m 100 mmol/ngy [8]. Ng i > 60 tu i. Huy t p gi m khi mu i gi m r rng hn, b t lu n HA ban u; v i m c gi m mu i trung bnh, HA gi m 7,2/3,2 mm Hg snh ngang m c gi m HA trong cc th nghi m dng thu c l i ti u thiazide. ng i > 60 tu i th HA gi m khi mu i gi m r rng hn, b t lu n HA ban u; v i m c gi m mu i trung bnh, HA gi m 7,2/3,2 mm Hg snh ngang m c gi m HA trong cc th nghi m dng thu c l i ti u thiazide [8].
Nhn chung, n gi m mu i trung bnh lm gi m HA ng i THA l 7,11/3,88 mm Hg (P < 0,001 i v i c HATTh v HATTr) v ng i bnh th ng l 3,57/1,66 mm Hg (P < 0,001 i v i c HATTh v P < 0,05 i v i HATTr) [31]. Phn tch g p c a Dumler [32] m i y th h n ch mu i ng i THA gip gi m HA cn tc d ng di h n c n kh o c u n a; tuy nhin, ph n a vi c gi m mu i di h n trong cc phn tch g p ny r t t [7].
Bi u
5. Tc d ng c a h huy t p. Ngu n: U.S. Department Of Health And Human Services [4].
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Tm t t ch l i gi m mu i Cc b ng ch ng cho th y gi m mu i n th gi m HA v ngn ng a THA [33]: nguy c tng i THA gi m kho ng 20% (c ho c khng c gi m cn n ng km theo) [20]. i m i l a tu i gi m mu i u lm gi m HA [8]. n mu i < 6 g/ngy lm gi m c HA t 2 8 mm Hg [4]. Tuy gi m mu i ng n v di h n d n n HA gi m 5) [4, 20]: (1) ch c n gi m HATTh 3 nh nhng l i ch c ng ng r t l n (Bi u mm Hg th t qu gi m 8%, b nh m ch vnh gi m 5% v t vong chung gi m 4%; (2) cc nghin c u quan st v th nghi m lm sng nh n th y HATTr gi m 2 mm Hg s gip gi m 17% t l hi n m c THA, 6% nguy c b nh m ch vnh v 15% nguy c t qu v thi u mu no thong qua [34]. Gi tr th c ti n. n t mu i ngn ng a THA c bi t hi u qu ng i nhi u nguy c nh ng i th a cn, THA gi i h n, ng i cao tu i, i tho ng v b nh th n m n ng th i gip thu c tr THA t t hn d l ch ng t c no. Tc d ng gi m mu i trung bnh tng tc v i cc nhm thu c h HA c ch men chuy n angiotensin, i khng th th angiotensin II v ch n beta giao c m tng ng thu c l i ti u nhm thiazide li u th p ngo i tr thu c c ch canxi [20, 35]. Gi m mu i gip ng i ang u ng thu c h HA ng ng thu c m HA v n ki m sot t t [36]. T i Ph n Lan, trong vng 30 qua, l ng mu i gi m trung bnh 1/3 d n n gi m c HA tm thu/tm trng >10 mm Hg trong dn chng v gi m 75% - 80% t vong do t qu v b nh m ch vnh. Khng th y b ng ch ng c h i khi gi m mu i [37]. Th c t ton c u. Brown & CS [21] m i y c l ng bi xu t natrium qua n c ti u 24 gi t nghin c u INTERSALT (198587) v INTERMAP (199699) v d li u t cc nghin c u quan st v can thi p cng b l ng mu i n kh p cc vng trn th gi i v t nhu c u sinh l (t c l 1020 mmol/ngy). H u h t ng i l n n natrium > 100 mmol/ngy v nhi u ng i ( c bi t l cc n c chu ) c l ng natrium n > 200 mmol/ngy. Cc n c sau th n t natrium: Cameroon, Ghana, Samoa, Ty Ban Nha, i Loan, Tanzania, Uganda v Venezuela. L ng natrium thng th ng > 100 mmol/ngy tr > 5 tu i v tng d n theo tu i. cc n c chu u v B c M , l ng natrium n vo n i tr i qua th c ph m ch bi n s n. Ngu n cung c p natrium l n nh t t i Anh v M l th c ph m t ng c c v bnh n ng cn t i Trung Qu c v Nh t l mu i nm n m khi n u, khi n v n c ch m. cc n c phng u-M , l ng mu i n ch c 10% t th c ph m thin nhin, 15% t tay thm cn 75% t th c n ch bi n s n [4, 6, 18, 21] v cc chnh ph ang n l c gi m 50% l ng mu i trong th c n cng nghi p nh M . M i nm Vi t Nam s n xu t 150 170 tri u lt n c m m (hm l ng mu i 270 290 g/L) v tiu th ch y u trong n c [38]. Th gi i c kho ng 400 tri u ng i dng n c m m [38]. Chng ta c th lm g? Chnh ph a ra chnh sch qu c gia v mu i [5]. Nm 1985, T ch c Y t Th gi i ngh m c mu i n l 5 g/ngy [7]. Th c t , l ng mu i n vo trung bnh : (1) ng i M nam n natri 4,2 g/ngy, n 2,75 g/ngy [4]; (2) ng i chu l > 200 mmol/ngy [21]; (3) ng i Vi t Nam l 18 22 g mu i/ng i/ngy v ty t ng vng m thi quen n m n l i khc nhau nh H Nam, Yn Bi l 13 15 g/ng i/ngy, trong khi cc vng bi n hay cc ni cn ngho, m c ny l i tng
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ln g p 2-3 l n [8, 39]. Nh t (1960-81), B (1968-81), Ph n Lan (1975 n nay), vng qu c Anh (2008 n nay) th c hi n cu c v n ng gi m mu i ton dn [7,18] v m i y M v n ng ton dn gi m n m n. M i m t n c trong C ng ng Chu u k k t gi m 16% mu i n trong 4 nm [7]. Nm 2005, World Action group (WASH - World Action on Salt and Health) thnh l p nm 2005 nh m c v gi m mu i ton c u v c trn 300 thnh vin qu c t v n ch y u l cc chuyn gia THA v nm 2007, nhm WASH t i c pht ng chi n d ch qu c gia gi m mu i cn 6 g/ngy vo nm 2012 [7]. D mu i gy tng t l hi n m c v m i m c THA nhng n th i i m 2009 v n t chnh ph c chnh sch qu c gia gi m mu i n. N l c gi m mu i i h i c nhn v c ng ng tch h p, c th l chnh ph , chnh quy n a phng, nh s n xu t th c ph m, nh hng, qun x, nhn vin y t , tr ng h c, ng i n i tr v m i ng i. Nng cao nh n th c dn chng thng qua truy n thng tr c ti p v/ho c gin ti p v tc h i c a mu i, c bi t nh n m nh nguy c b nh tim v t qu do n nhi u mu i [5]. Thuy t ph c cc nh s n xu t th c ph m v ng i bn hng n u ng gi m mu i trong th c n [5]. Hoa K t c tho thu n l cc nh ch bi n th c ph m gi m 50% l ng mu i trong th c n. M i th y thu c th c hnh gi m mu i cho mnh v t v n cho ng i b nh, ng i nh nh t l cc b m khng thm mu i khi n u n ng, khi n [40] v ch n th c ph m ch bi n s n c hm l ng natrium < 0,3 g/100 g th c ph m (0,75 g mu i/100 g th c ph m). Lu , 2,5 g mu i (1 g natrium) trong 100 g th c ph m c m n tng ng n c bi n [18, 20]. N l c gi m mu i ki m sot HA v THA t t ph thu c chnh ph , c ng ng (tr ng h c, cc h i, cc t ch c), c nhn v m i th y thu c THA. Vi t Nam l n c ngho nhng xu h ng th ho cao, t l THA tng nhanh [12], ng i b nh nhi u ni khng chi ph ch a THA v i u tr THA lu di; v v y, vi c p d ng gi m mu i c ng ng t ra l hi u qu nhn ti n v l i chi nh t. Chng trnh c ng ng gi m mu i v HA t i Ghana. T i chu Phi, THA v t qu th ng g p v tng d n nhng ki m sot th cn h n ch . Th c ph m ch bi n s n chu Phi cn hi m [41]. Cappuccio & CS [41] th c hi n th nghi m phn ng u nhin chm d a trn c ng ng 1013 ng i (628 n v 481 nam, trung bnh 55 tu i) t i 12 lng gi m mu i v HA. Huy t p trung bnh l 125/74 mmHg v l ng natrium qua n c ti u (Nat) l 101 mmol/ngy. Can thi p thc y s c kho qua 6 thng v i t t c lng v nh gi 3 v 6 thng. K t qu l c m i lin h ngha gi a l ng mu i v c HATTh (2,17 mmHg [KTC 95%: 0,44 3,91] trn 50 mmol Nat/ ngy, P < 0,001) l n HATTr (1,10 mmHg [KTC 95%: 0,08 1,94], P < 0,001) lc ban u. T i th i i m 6 thng, nhm can thi p c gi m HATTh (2,54 B ng1. Cc ch vi t t t DASH the Dietary Approaches to Stop Hypertension HA Huy t p HATTh Huy t p tm thu HATTr Huy t p tm trng INTERMAP The International Population Study on Macronutrients and Blood Pressure INTERSALT The International Study of Salt KTC Kho ng tin c y Nat Natrium th i qua n c ti u
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mmHg [KTC 95%: -1,45 n 6,54]) v HATTr (3,95 mmHg [KTC 95%: 0,78 n 7,11], P = 0,015) khi so snh v i nhm ch ng. Gi m khng c ngha thay i lng Nat. C khc bi t v Nat 24 gi trn 50 mmol v i gi m HATTh xu ng 2,12 mmHg (KTC 95%: 1,03 n 3,21) t i 3 thng v 1,34 mmHg (0,08 n 2,60) t i 6 thng (P < 0,001 v i c hai). Gc th c hnh Gi m mu i l b c quan tr ng trong i u tr THA [17]. d phng, l ng natri n < 2,3 g/ngy (100 mmol/ngy) cn v i ng i THA th 1495 g- 2,3 g (65 - 100 mmol) [3], th m ch </= 65 mmol/ngy [42, 43]. i v i ng i THA, gi m mu i cng nhi u cng t t, l t ng l mu i n m c 65 mmol Natri/ ngy [20]. K t c c, mu i n cung c p khong ch t c n thi t cho c th v i u ho HA nhng l ng mu i n v t ng ng 6 g/ngy s gy tng t l hi n m c v m i m c THA. n mu i thi qu l nguyn nhn c a kho ng 30% THA; n l t THA lin quan mu i gy 14% t qu v 9% nh i mu c tim [17]. B ng ch ng khoa h c t nhi u ngu n ch ng minh gi m mu i n th gi m huy t p v cc bi n ch ng lin quan cng nh ngn ng a tng huy t p ng th i gip thu c h huy t p tc d ng t t hn, ki m sot huy t p t t hn v tc d ng gi m mu i n tng ng thu c l i ti u li u th p. Vi c gi m mu i trong c ng ng c tnh l i chi cao v t ra ph h p v i b i c nh ki m sot HA v THA t t ph thu c chnh ph , c ng Vi t Nam. N l c gi m mu i ng, c nhn v m i th y thu c THA; y l m t trong nh ng thay i hnh vi n quan tr ng v kh khn nh t [44]. TI LI U THAM KH O [1] He FJ, Markandu ND, Sagnella GA, et al. Plasma sodium: ignored and underestimated. Hypertension 2005;45:98-102. Epub 2004 Nov 22. [http://www.ncbi.nlm.nih.gov]. [2] MacGregor GA. Sodium is more important than calcium in essential hypertension. Hypertension 1985;7;628-37. [http://hyper.ahajournals.org]. [3] Canadian Hypertension Education Program. 2009 CHEP Recommendations for the Management of Hypertension. [http://www.hypertension.ca]. (Accessed on May 17, 2009). [4] U.S. Department Of Health And Human Services. Complete Report: The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. NIH Publication No. 04-5230, Aug 2004. [http://www.nhlbi.nih.gov].(Accessed on Jun 1st, 2009). [5] Irish Heart Foundation Position Statement on Salt, Blood Pressure and Heart Disease. (April 2004). [http://www.irishheart.ie]. (Accessed on May 25, 2009). [6] Kenney JJ. Diet, Hypertension and Salt Toxicity. (Last updated 2/24/2004).[http://www.foodandhealth.com]. (Accessed on May 25, 2009).
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CC CH T C CH PHOSPHODIESTERASE V NH NG NG D NG TRN LM SNG

Hong Tr ng Th ng Tr ng i h c Y D c Hu Abstracts: Erectile Dysfunction (ED) has been defined as consistent inability to attain or maintain a penile erection sufficient for satisfactory sexual intercourse. Various disorders such as vascular (33%), endocrine (2-8%), metabolic and psychogenic dysfunction contribute to the etiology of ED. Diabetes is the leading cause of ED. The risk to develop ED is three times higher in diabetics than in non-diabetics with 20-85% of diabetic men manifesting ED. Frequently, atherosclerosis with micro- and macroangiopathy contributes to ED. Compromised venous compression against the tunica albuginea with consecutive venous leakage is a less frequent cause of ED. There are several endocrine causes of ED such as disorders of the hypothalamic-pituitary-axis, the adrenal or thyroid gland. ED often results from neurological diseases such as multiple sclerosis, Parkinsons disease (in 50-80%), brain and spinal tumors, spinal cord injuries, and polyneuropathies, especially diabetic (35-75%) neuropathy, and various disorders of the autonomic nervous system. ED is also a frequent side effect of many drugs, particularly antidiabetic (26%), antihypertensive (14%) or vasodilating agents (36%). Primary psychogenic etiology is rather rare. The majority of ED cases is due to an organic or a combined organic and secondary psychogenic pathophysiology. I. T NG QUAN Men phosphodiesterase l m t t p h p lin quan n phosphohydrolase c d ha th y phn ch n l c c a c u n i 3' phosphate vng c a cAMP v CcMP. Men cGMP c vai tr tn hi u c xc l p trong nim m c ru t non v c trn m ch mu. 1. Ch t c ch phosphodiesterase 4 v 5: i u tr suy n v COPD - Methylxanthines. - Theophylline: c x d ng r ng ri, do kha c nh tc d ng ph nn khng d c dng nhi u. - Cafein - Daxas (Romflumilast): ch t c ch phosphodiesterase 4 khng c dng v v i li u tc d ng th khng ch u c. - Airflo (Cilomast) cng v y 2. Ch t c ch phosphodiestease 3: Thu c ch ng ngng t p ti u c u - Pletal (Cilostazol)- vasodil, dng trong au c nh kh ang o n h i, ch ng ch nh b nh nhn suy tim. 3. Ch t c ch phosphodiesterase 5: Cng l thu c c ch ngng t p ti u c u PDE5 cGMP PDE3 cAMP Tc d ng khng ti u c u o Dipyridamole Cng v i aspirin d phng trong thi u mu no
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Cng v i Warfarin d phng huy t kh i b nh nhn thuyn t c v mang valve tim gi Ch t c ch PDE 5 trong lo n cng- ch ng ch nh dng cc nitrates o Viagra (sidenafil) o Levitra (varfenadil) o Cialis (tadalafil) Ch t c ch PDE 5 Trong tng p ng m ch ph i o Revatio (sidenafil) li u cao - Gy ra dn m ch ph thu c NO tng t nh viagra trong i u tr tng p ng m ch ph i PDE 3 inhibitors i u tr suy tim o Inamrinone o Primacor (milrinone) o Nitroprusside PDE 5 inhibitors hi n nay ang c NC i u tr suy tim. II. THU C V C CH TC D NG Thu c C ch tc X d ng Tc d ng(Kch thch/ c lm sng/ d ng nh ph ch ) ch i u tr 1. PDE 4 and 5: i u tr hen v COPD Methlyxanthi nes Theophylline - c ch PDE 4 & 5 (1 lo i c a => ngn ch n s ph methylxanthi h y c a cAMP v ne) cMP - c ch s t ng h p Caffeine is v ti t c a ch t trung another gian vim t h p bo v basophils qua vi c example c ch tng tranh v i PDE 4 t i th th adenosine, gy ra co ph qu n trong hen v gy ra phng thch h p bo t ph i.
Ch ng ng ch x nh d ng
Hen, COPD Hen c p v Kch thch m n, COPD tiu ha trn, b t an, r i lo n nh p tim, co gi t
Chuy n ha b i cytochro me P450 so p450 ch t c m ng: cimetidin e ho c ciproflox acin do gi m n ng theophyll ine huy t thanh B nh nhn suy tim b t
B gi i h n di ch s i u tr r t h p
2. PDE 3 (direct) and 5 (indirect): Khng ti u c u Pletal 3) (PDE Khng ngng t p ti u cn c u v v lm d dn cch c trn m ch mu ch au h i, lm
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(lm dn m ch). Dipyridamole - Tc ng m t cch (PDE 5) gin ti p khi c s hi n di n c a NO, t o thu n cho hi u qu c ch c a NO ln ngng t p ti u c u - c ch s b t gi c a adenosine, tc ng ln th th kch thch adenylyl cyclase ti u c u -Gia tng n ng cGMP gy ra tc d ng c ch c a PDE3 v k t qu gia tng cAMP
gi m tri u k lo i ch ng no Ngn R i lo n ng a thi u tiu ha, mu no ch y mu trong ph i h p v i aspirin - D phng thuyn t c b nh nhn mang valve tim gi trong vi c ph i v i h p warfarin c dng trong vi c d phng cn au th t ng c Cc Nitrates dn m ch, cc i ch t khng th th adrenergic gy ra nguy c h huy t p
3. Cc PDE 5: i u tr r i lo n cng Sidenafil T bo th hang s n xu t i u tr (Viagra) NO trong qu trnh cng d c ch ng b t trong p ng truyn th n cng Varfenadil kinh adrenergic v dng v t (Levitra) nonadrenergic, Tadalafil noncholinergic (Cialis) NO kch thch thnh l p cGMP, gy ra s dn c trn c a c th hang v ng m ch dng v t, lm cng th hang v cng dng. S tch ly GMP vng c th c lm d b i s c ch c a cGMPc hi u c a h PDE5
4/ Cc 3 PDE i u tr suy tim: lm gia tng s c co bp c tim v lm d cho s dn c a c trn m ch mu Amrinone i u tr ng n h n Bu n nn Lm gi m (inamrinone) tri u ch ng c a tri u ch ng
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Primacor (milirinone)
suy tim, khng thay i t su t
b nh nhn suy tim m t b
III. I U TR Gio d c b nh nhn v ch n l a thu c c kh nng c ch PDE-5, d ng tng ng phosphodiesterse l u th trn dng v t, r t hi u qu trong vi c gy cng dng sau kch thch. Kh i u tc d ng l sau 60-90 pht. C n ch nh li u cho ph h p ng i gi v suy th n ho c ang dng thu c c ch cytochrome P 3A4 qua ng chuy n ha gan nh Erythromycine, cimetidine, ketoconazole v chng c th gy tng n ng c a thu c, cc tc d ng ph ph i h p l: nh c u (19%), cn ph ng m t (9%), ch m tiu (6%), sung huy t xoang mi (4%), thay i mu th gic (7%). Ch t c ch PDE-5 ch ng ch nh b nh nhn ang i u tr nitrates trong b nh l tim m ch v nguy c shock n ng. Cng v y ch t c ch PDE-5 cng nn trnh ng i suy tim sung huy t, dng thu c h huy t p, v b nh tim v nguy c tr y m ch. 1/ T t c 3 lo i c ch PDE-5 : sildenafil, vardenafil v tadalafil gip gi n ng n nh GMP vng trong th hang dng v t gip cho ng i r i lo n cng dng c c s cng dng v t khi kch thch. Khng c dng ph i h p nitrates v i cc thu c c ch PDE-5 v gy h huy t p n ng c th trn 50/25 mmHg v gy ng t. Ch ng ch nh dng thu c i khng Alpha adrenergic antagonists (do gy h huy t p n ng khi ph i h p v i PDE) ngo i tr v i tamsulosin, c th an ton khi ph i h p v i tadalafil. Th i gian tc d ng khc nhau gi a cc lo i PDE-5. Sildenafil v vardenafil hi u qu sau cha y 30 pht v n 4 gi sau khi dng li u hi u qu , c a tadalafil l cha y 16 pht n 36 gi sau li u tc d ng. Sildenafil v vardenafil ph i c dng khi b ng i cn v i tadalafil c th dng b t k lc no. 2/ Sildenafil ch c dng khi l ng gi m t cch y v nguyn nhn c a r i lo n cng nh: h i b nh s , khm lm sng, nh l ng testosterone, prolactine, TSH. S hi n di n c a b nh ti m n c th i u tr c c th b b qua khi cho ch nh dng thu c ny. Kh th cng c th l d u hi u c a thi u mu c tim ti m n. 3/ Sildenafil khng c ch nh b nh nhn ang dng nitrate. N u b nh nhn dng sildenafil m c h i ch ng cn au th t ng c, th nitrate khng nn cho trong vng 24 gi ho c cn lu hn b nh nhn suy gan, suy th n. M c d dildenafil tc d ng b ng cch c ch type 5 phospjodiesterase, n c th nh h ng ln vng m c b ng cch c ch nh phosphodiesterase type 6, c n cho s bi n i kch thch nh sng thnh tn hi u i n. Trong m t bo co 5 b nh nhn nam dng 100mg sildenafil 1gi sau c s bi n i trn i n vng m c v h i ph c hon ton sau 6 gi . Khng c s bi n i trn nhu th gic. Sildenafil cng gy nhn xanh 3% b nh nhn ko di sau 2-3 gi v bi n m t m t cch t nhin. Trong nm 1998 ch c 23 tr ng h p b thi u mu ng m ch th tr c khng b b nh th n kinh (NAION) khi dng sildenafil v tadalafil. V v y khng bi t l do dng sildenafil hay do cc y u t nguy c m ch mu vng m c c s n nh i ng, tng huy t p, hay r i lo n lipid mu.
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4/ H i tim m ch Hoa k ng thu n r ng thu c c ch 5 phosphodiesterase l an ton cho b nh nhn c b nh m ch vnh n nh khi khng dng nitrate. Khng c d li u lm sng an ton cho b nh nhn c nh i mu c tim, t qu , ho c lo n nh p nguy hi m trong vng 6 thng v b nh nhn c huy t p > 170/110mmHG ho c < 90/50mmHg. Nh ng b nh nhn c n xem xt khi x d ng l nghi m php g ng s c (+). Nh ng b nh nhn c xem xt x d ng sildenafil nn h i c g ng s c c khng, n u t p th d c nh p i u l cng tng ng v i tiu t n nng l ng nh trong sinh ho t tnh d c. N u khng th ph i lm tr c nghi m g ng s c 5/ Sildenafil khc v i khi giao h p 2 i m: H p th t nh h ng b i th c n nhi u d u m v r u v tc d ng di hn. V i sildenafil v vardenafil th hi u qu t i a l khi u ng thu c b ng i (n nhi u m v r u lm ch m h p thu thu c) v sau 1 gi m i tc d ng. Tadalafil th u ng khi no cng c. Th i gian tc d ng c a sildenafil v vardenaffil l 4 gi . nh ng ng i lo n cng c th c p ng cng dng n 36 gi sau m t l n dng tadanafil. Trong 1 nghin c u cho th y 66,3% ng i thch dng tadanafil v 33,7% v i sildenafil khi i u tr r i lo n cng. B n nm sau khi cc c ch phosphodiesterse type V dng trong i u tr lo n cng cho th y thu c c hi u qu cao, an ton; thu c gip ngn ch n s phn chia c a GMP vng v gia tng n ng GMP vng. S gia tng GMP vng lm dn c trn dng v t ko theo a mu vo th hang v lm cng dng. Sildenafil khng ch lm cng dng m cn lm c i thi n ch t l ng s ng c a nhi u b nh nhn. Tc d ng ph c a sildenafil l nh v th ng g p l nh c u, ph ng m t, sung huy t mi, r i lo n nhn mu xanh li u cao. Khng nn dng sau nh i mu c tim ho c t qu cn ng n, b nh nhn c nguy c tim m ch, b nh nhn di truy n thoi ha vng m c, khng dng ph i h p v i nitrate ho c molsidomine. Hi n nay cc c ch phosphodiesterase khc nh Tadalafil, Vardenafil ang c s d ng. G n y, cc apomorphine ng v n Dopamine-D1-D2 tc d ng trung ng i u tr r i lo n cng. Thu c t d i l i (Ixense, Uprima) gy ng n c dng trnh cng dng qua kch thch vng c nh nhn b ng h khu no. Li u 2-6mg tc d ng ph c a apomorphine nh l bu n nn, v nn m a nh ng v n c 10% b nh nhn b bu n nn, ngp, bu n ng , nh c u, h huy t p Thu c lm dn c trn dng v t, lm dn m ch v cng khi a nh ng ch t v n m ch vo th hang ho c vo ni u o nh papaverine, phentolamine v prostaglandine PGE1 (Caverject). C nh ng nghin c u cho th y r ng ch ch c n tim Caverject 1 l n vo th hang hi u qu ln n 70-90%, nh ng c th c tc d ng ph a n cng c ng dng v t, au v x ha dng v t ln n 9,3% sau 2 nm x d ng. PGE1 cng c ch ph m a tr c ti p vo ni u o 125-1.000g (MUSE), tc d ng ph l au v c th ch y mu. IV. K T LU N Lo n cng dng khng ch l m t v n tm l, l m t r i lo n c th do h u qu c a nhi u b nh ti m n bn d i. Do m t khm nghi m ton th v y c th gip xc nh nguyn nhn ban u gy ra r i lo n ny nh: i ng, tng huy t p, x v a ng m ch, b nh l do r i lo n th n kinh tm th n... m t ch n on chnh xc v y s gip ngn ng a nh ng bi n ch ng khc c a cc lo i b nh l
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trn. Hi u qu c a i u tr s gip c i thi n ch t l ng s ng c a ng i b nh v cng c m i quan h gia b nh nhn v ng i Th y thu c. T y b nh nhn s dung n p t t hn v i ch i u tr cng nh tun th ti t ch h n ch cc ti t th c nh m m c ch trnh c nh ng nguyn nhn ban u c a r i lo n cng dng v d nh nh ng r i lo n v bi n d ng, bo ph ho c tng huy t p. TI LI U THAM KH O: 1. NIH consensus development panel on impotence. Impotence. JAMA 1993;270:83-90. 2. Feldmann HA, Goldstein I, Hatzichristou DG, et al. Impotence and its medical and psychosocial correlates: Results of the Massachusetts Male Aging Study. J Urol 1994;151:54-61. 3. Hilz MJ, Hecht M, Klsch C. Erektile Dysfunktion. Akt Neurologie 2000;27:1-12. 4. Stief CG, Hartmann U, Hfner K, Jonas U. Erektile Dysfunktion, Diagnostik und Therapie. Berlin, Heidelberg, New York: Springer; 1997. 5. Romeo JH, Seftel AD, Madhun ZT, Aron DC. Sexual function in men with diabetes type 2: association with glycemic control. J Urol 2000;163:788-791. 6. Hilz MJ. Neurologische und neurophysiologische Aspekte der erektilen Dysfunktion. Akt Neurol; Sonderband. Dtsch. Ges. fr Neurologie '98 1999:C3-1 - C310. 7. Porst H. Manual der Impotenz. Erektions-, Ejakulations- und Hormonstrungen, Peniserkrankungen, weibliche Sexualstrungen. Bremen: UniMed; 2000. 8. Fowler CJ. Electrophysiologic evaluation of sexual dysfunction. In: Low PA, editor. Clinical autonomic disorders. Boston, Toronto, London: Little, Brown and Company; 1992. p. 279-285. 9. Dula E, Bukofzer S, Perdok R, George M. Double-blind, crossover comparison of 3 mg apomorphine SL with placebo and with 4 mg apomorphine SL in male erectile dysfunction. Eur Urol 2001;39:558-553; discussion 564.
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R I LO N CH C NNG V C U TRC THNH M CH MU B NH NHN I THO NG

o Th D a B nh vi n TW Hu I. C CH R I LO N CH C NNG V C U TRC HNH M CH MU B NH NHN I THO NG 1. 1. S hnh thnh s n ph m cu i cng c a hi n t ng g n glucose v i protein b c cao (Advanced glycation end-products: AGPs) R | HC=O HC=N H2C-NHR HC=O AGEs | | | | HCOH HCOH C=O C=O | | | | RNH2 + HOCH HOCH HOCH CH2 | | | | HCOH HCOH HCOH HCOH | | | | HCOH HC HCOH HCOH Inactive | | | | metabolites CH2OC CH2OH CH2OC CH2OC
Amin
Glucosse N-Glucosylamin 1Amino-1deoxyketose 3Deoxyglucosone
S hnh thnh s n ph m cu i cng c a g n glucose (glycation) v i cc protein b c cao hay cn c g i s g n glucose khng c n enzyme c a cc protein (glucose s ph n ng v i nhm amin c a protein) do nh h ng c a tng glucose mu m n tnh. Qu trnh ny s t o ra nhi u lo i protein lin k t cho v hng lo t ph n ng sinh ho m hi n nay v n cha bi t h t. Theo Monti L.D. v Pozza G., tng n ng glucose mu b nh nhn T s x y ra ph n ng gi a glucose v cc phn t protein cng nh lipid, t o thnh AGEs v gy ra nhi u h u qu . Tnh tr ng tng glucose mu cng ko di v m c tng glucose mu cng tr m tr ng, th hi n t ng g n glucose khng c n enzyme cng d x y ra. Nhi u nghin c u xc nh n cc h u qu do AGEs gy ra b nh nhn T nh sau: cc ph n ng t o AGEs s gy s n xu t cc g c t do; AGEs ph n ng v i nitric oxid (NO) lm m t tc d ng gin m ch v ch ng ng mu c a n; AGEs lm thay i c u trc v ch c nng c a cc thnh ph n c b n trong huy t tng v thnh m ch: s tng tc c a AGEs v i t bo n i m c lm tng k t dnh b ch c u n nhn v i l p n i m c, hi n t ng ny s gy t ng h p v phng thch y u t tng tr ng v cc cytokin: phn t k t dnh m ch mu (vascular adhesion molecule), endothelin-1, y u t t ch c... l nh ng peptid co m ch, pht tri n v tng sinh t bo c trn,
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lm r i lo n ng mu, x v a ng m ch, t c m ch. S tch ly AGEs t i cc s i collagen lm x ho v thay i tnh ch t c a thnh m ch. S g n glucose v i cc protein lm h bi n ch c nng v c u trc c a chng c bi t l cc protein c a mng y b i hi n tng x ho. S g n glucose v i apolipoprotein B v cc protein khc s c ch s thanh l c triglycerid, hi n t ng g n glucose c a fibrinogen v fibrin lm chng t nh y c m v i plasmin, g n glucose c a antithrombin III v heparin lm gi m ho t tnh c a chng, tng tc c a AGEs v i cc lipoprotein t tr ng th p khi n chng d b i th c bo thu n p t o thnh cc t bo b t. Nh v y, s hnh thnh AGEs do qu trnh r i lo n chuy n ho b nh nhn T , c bi t nh ng i t ng khng c ki m sot glucose mu ch t ch , gp ph n quan tr ng trong c ch t n thng m ch mu. 1.2. Chuy n ha glucose theo ng polyol Tr ng thi thi u h t insulin tng i ho c tuy t i, d n n hi n t ng tng glucose mu b nh nhn T , gy ra m t lo t r i lo n chuy n ha: tng chuy n ha glucose theo con ng sorbitol d i tc d ng c a enzyme aldose reductase; sau sorbitol s ti p t c bi n i thnh fructose d i tc d ng c a enzyme sorbitol dehydrogenase. Sorbitol lm tng p l c th m th u, lm gi m myo-inositol d n n r i lo n chuy n ha phospholipid v gi m ho t tnh c a enzyme Na+/K+ATPase. Nhi u cng trnh nghin c u cho th y tng p l c th m th u do tch ly sorbitol l m t nguyn nhn quan tr ng gy dy mng n n (membrane basale) c a mao m ch. M t khc, fructose c kh nng g n v i protein khng c n enzyme ti p t c t o thnh AGEs. Ngoi ra, con ng chuy n ha polyol cn th hi n tnh c h i qua cc c ch khc, gi thi t c a Jennings P.E. gp ph n gi i thch v n ny: con ng chuy n ha polyol can thi p vo c tnh c a cc g c t do, v con ng chuy n ho ny s d ng nicotinamid adenin dinucleotid phosphat (NADPH) l enzyme quan tr ng chuy n ha cc ch t ch ng oxy ha. Theo Jennings P.E, khi s d ng c ch aldose reductase s ti t ki m c nicotinamid adenin dinucleotid phosphat v cc d ng chuy n ha c a glutation, vitamine C, vitamine E s c ph c h i v ch ng l i ph n ng oxy ha. Hi n t ng tng cc g c t do b nh nhn T d n n h bi n cc protein, t bo n i m c v TC qua trung gian c a hi n t ng oxy ha lipid ho c t n cng tr c ti p ln cc protein, c bi t l cc protein b g n glucose. Chuy n ha glucose theo con ng polyol v i nhi u c ch khc nhau, lm r i lo n qu trnh sinh ha - chuy n ha bn trong t bo, r i lo n qu trnh ng mu v t n thng thnh m ch. 1.3. Hi n t ng t oxy ha c a glucose Glucose c th b oxy ha t d ng chuy n ti p n d ng d ha b i ch t trung gian d ng ne - diol c a glucose. Ni m t cch t ng qut, con ng glucose t oxy ha l i u ki n g n oxy vo cc phn t n c. Hi n t ng ny s t o thnh cc g c hydroxyl t do gy t n thng cc protein v cc t bo, c bi t l protein c a mng n n v t bo n i m c m ch mu. Nh ng ch t trung gian c a ph n ng t oxy ha glucose nh cc g c hydroxyl v cc ceto-aldehyd ti p t c c nh trn cc protein t o thnh d ng ceto-aminomethylol. Ch t ny c th t oxy ha v t o thnh cc g c hydroxyl t do. Hunt J.V. v CS cng nh n nh chnh cc g c hydroxyl t do ny gp ph n gy t n thng cc protein v t bo, h u qu l t n thng cc thnh ph n c a m ch mu.
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II. CC BI U HI N T N THNG M CH MU B NH NHN I THO NG Trong nh ng nm g n y, nh s ti n b c a n n y h c, ng i ta ch ng minh c m i lin quan gi a tng glucose mu v b nh l m ch mu b nh nhn T , m r i lo n ch c nng v c u trc thnh m ch mu l nh ng c trng c a b nh l ny. 2.1. T bo n i m c ((TBNM) b t n thng TBNM c vai tr quan tr ng trong i u ho ng mu v ti t o thnh m ch. TBNM i u ho ng mu qua cc c ch sau: - T ng h p prostaglandin I2 (PGI2) ch ng ngng t p ti u c u - T ng h p y u t ho t ho plasminogen c a m (tissue plasminogen activator: t-PA) v y u t c ch ch t ho t ho plasminogen type 1 (plasminogen activator inhibitor-1: PAI-1) i u ho h th ng tiu s i huy t - T ng h p thrombomodulin lm tng s ho t ho h th ng protein C-protein S (h th ng c ch ng mu) TBNM tham gia vo s ti t o thnh m ch mu gip ph c h i m ch mu trong tr ng h p b t n thng. TBNM t ng h p protein c a thnh m ch m c bi t l protein c a mng y, ngoi ra TBNM cn tham gia vo i u ho s v n m ch. S t n thng TBNM d n n m t kh nng khng ng do gi m gi i phng v gi m t ng h p prostaglandin I-2; gi m t ng h p v gi m ho t tnh sinh h c c a protein C, protein S v thrombomodulin; gi m tiu s i huy t do r i lo n t ng h p t-PA, PAI-1; ti t qu nhi u cc protein thu n l i cho s k t dnh TC (y u t VIII-Willebrand); gi m s n xu t nitric oxid (NO) v gi m p ng c a cc ch t trung gian gin m ch, cc hi n t ng ny t o thu n l i cho s ng mu. Nhi u nghin c u ch ng t r ng t n thng TBNM x y ra tr c r i lo n v hnh thi c a cc m ch mu. Ng c l i, r i lo n ch c nng TBNM c ph c h i tr c so v i s thoi tri n c a x v a ng m ch, khi cc nguyn nhn c lo i b . 2.2. Mng n n m ch mu b t n thng Mng n n m ch mu b t n thng cng l m t c trng c a r i lo n ch c nng v c u trc thnh m ch mu b nh nhn T type 2. Theo Stenerg M. v CS, dy mng n n thnh m ch n c lin quan v i th i gian m c b nh v hi u qu ki m sot glucose mu. Qu trnh b nh l ny bao g m hi n t ng tng t ng h p cc protein c b n ngoi t bo (Extracellular matrix protein) m ch y u l collagen type IV, proteoglycan, fibronectin v laminin m h u qu c a chng l lm gi m tnh n h i v lm r i lo n kh nng l c c a mng n n. 2.3. T bo c trn b r i loan b nh nhn T t bo c trn pht tri n m nh, ph i, tng sinh v lo n s n cng gp ph n lm r i lo n ng mu v tng sinh huy t kh i c cc nghin c u xc nh n. S r i lo n t bo c trn cng do nh h ng c a tng glucose mu m n tnh ko theo r i lo n chuy n ha cc ch t trong c th . 2.3. H th n kinh m t qun bnh gi a giao c m v i giao c m. Nghin c u Veigh G.E. v CS cho th y m ch mu c a b nh nhn T type 2 km nh y c m v i cc ch t trung gian ha h c c a h i giao c m nh acetylcholin, do hi n t ng co m ch chi m u th . y l i u ki n thu n l i cho s hnh thnh huy t kh i, t n thng thnh m ch v ho t ha qu trnh ng mu.
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Nh v y, t n thng thnh m ch do tng glucose mu m n tnh b nh nhn T type 2 lm gi m kh nng khng ng v gi m tiu s i huy t, l m t trong nh ng nguyn nhn c a s hnh thnh huy t kh i, ti n cn c a x v a ng m ch, l y u t nguy c c a cc b nh l m ch mu b nh nhn T . TI LI U THAM KH O 1. Cohen R.A. (1997),Endothelial Dysfuntion in Diabetic vascular disease, Cardiovascular Complications of Diabetes Medicographia, Vol 19, (No 2),pp. 157161. 2. Harbarchuk O.I.(2000), The coagulogram characteristics of patients with non-insulin-dependent diabetes mellitus , Article in Ukrainian (1) , pp.62-64. 3. Monti L.D. and Pozza G. (1997), Advanced glycation end products (AGEs) : their role in diabetic vasculcar lesions , Cardiovascular Complication of Diabetes Medicographia, Vol 19, (No 2), pp.119-122. 4. Peter J. Grant(2001), Coagulation and fibrinolysis in type 2 diabetes:Relationship to Microcascular Complication, Univesity of leeds, UK, pp. 1526.
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R I LO N H TH NG TIU S I HUY T B NH NHN I THO NG

o Th D a B nh vi n TW Hu Tiu s i huy t l m t qu trnh ly gi i m ng l i fibrin do nhi u y u t tham gia. Trong , plasminogen l ti n t b t ho t c a plasmin ng vai tr quan tr ng, ho t ng c a plasminogen ph thu c v y u t c ch ch t ho t ho plasminogen type 1 (plasminogen activator inhibitor-1: PAI-1) v y u t ho t ha plasminogen c a m (tissue plasminogen activator: t-PA). Nm 1978, Almer L.O. v c ng s nghin c u 221 b nh nhn T ghi nh n kh nng tiu s i huy t gi m so v i nhm ch ng, nh t l nh ng b nh nhn km theo bo ph v c bi n ch ng m ch mu, tc gi cng ghi nh n gi m tiu s i huy t khng khc bi t gi a 2 th T v khng tng quan v i tu i
Plasmingen
Y ut ho t ho
t-PA Prourokinase-Urokinase Y u t XII-Prek-KHPM Plasmin
Fibringen Fibrin
PDF
2 antiplasmin
Y ut c ch ho t ho
PAI-1 PAI-2 C1-inactivator
: H th ng tiu s i huy t
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1. Y u t c ch ch t ho t ho plasminogen type 1 (plasminogen activator inhibitor type 1). Plasminogen activator inhibitor type 1 (PAI-1) c s n xu t b i t bo gan v t bo n i m c m ch mu. Ngoi ra, PAI-1 cn c pht hi n trong ti u c u. Ho t tnh sinh h c c a PAI-1 l c ch r t nhanh t-PA v urokinase, d n n gi m s ho t ho plasminogen thnh plasmin v h u qu gi m thoi bi n m ng l i fibrin nn t o thu n l i cho s ng mu. PAI-1 lu hnh trong huy t tng d i 3 d ng: - D ng ho t ng: ch c d ng ho t ng m i c kh nng c ch t-PA. - D ng b t ho t: c th lin k t v i t-PA ho c d ng t do. D ng ny th ng tm th y ti u c u sau khi c ho t ho. - D ng ti m n: ch c tm th y trong t bo nui c y, v tnh ch t sinh l h c c a n v n cha bi t r N ng PAI-1 c a huy t tng thay i trong ngy, t n ng t i a v lc 6 gi sng v t i thi u vo lc 16 gi . s t ng h p PAI-1 b i t bo n i m c m ch mu c kch thch b i cc lo i n i c t (endotoxin), interleukin-1, y u t ho i t u (tumor necrosis factor: TNF), thrombin v h u qu c a r i lo n chuy n ho lipid. PAI1 do t bo gan t ng h p th c kch thch b i insulin. Trong th i gian g n y, c nhi u cng trnh nghin c u v n ng PAI-1 huy t tng c a b nh nhn T , u nh n xt tnh tr ng gi m tiu s i huy t v tng ng mu c lin quan n tng n ng PAI-1. Chnh tng n ng PAI-1 s c ch m nh t-PA v urokinase, d n n gi m ho t ha plasminogen thnh plasmin, h u qu gi m tiu s i huy t. C ch tng PAI-1 b nh nhn T c lin quan n tnh tr ng khng insulin. Theo Juhan-Vague, chnh s tng n ng insulin b nh nhn T type 2 (do tnh tr ng khng insulin) kch thch t bo gan tng t ng h p PAI-1. Alessi M.C. v CS nghin c u tc d ng c a insulin ln t bo gan, tc gi nh n nh r ng insulin kch thch tr c ti p t bo gan t ng h p PAI-1. Kooistra T. v CS cng nghin c u v sinh t ng h p PAI-1 b ng cch cho insulin vo dng t bo gan nui c y, nh n nh r ng insulin kch thch t bo gan tng t ng h p PAI-1, nhng i v i t bo n i m c, insulin khng c tc d ng tr c ti p m n tc d ng gin ti p qua trung gian r i lo n chuy n ho lipid. Tng lipid mu, c bi t l cc lipoprotein c tr ng l ng phn t th p kch thch t bo n i m c m ch mu tng kh nng t ng h p PAI-1. Theo nghin c u c a Grant PJ. v CS, n ng PAI-1 b nh nhn T l 40,1ng/l v nhm ch ng (khng b T ) l 7,7ng/l (s khc bi t c ngha thng k). Nhi u nghin c u khc cng cho k t qu tng t . Tng n ng PAI-1 khng nh ng b nh nhn T m ngay c i t ng gi m dung n p glucose. Nghin c u c a Andreas F. v CS ghi nh n n ng PAI-1 b nh nhn T cao hn h n nh ng i t ng gi m dung n p glucose v nh ng i t ng gi m dung n p glucose l i cao hn h n ng i c glucose bnh th ng. i u ny kh ng nh tnh tr ng tng glucose mu tc ng r t r ln s s n xu t v gi i phng PAI-1. Nghin c u c a Juhan-Vague v m t s tc gi cho th y b nh nhn T type 2, n ng PAI-1 tng m t cch c ngha so v i i t ng kho m nh. Tc gi cng ghi nh n nh ng b nh nhn c bi n ch ng m ch mu th n ng PAI-1 tng nhi u hn. S tng n ng PAI-1 c lin quan v i tnh tr ng bo ph, tng huy t p, m c ki m sot glucose mu, tnh tr ng ht thu c l v r i lo n lipid mu.
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2. Y u t ho t ha plasminogen c a m (tissue plasminogen activator). Tissue plasminogen activator (t-PA) l m t serin protease c s n xu t t i t bo n i m c m ch mu v gi i phng vo huy t tng d i d ng b t ho t do t o ph c v i nh ng ch t c ch , hi u qu tiu s i huy t ph thu c vo s l ng c a t-PA hi n di n trn b m t c a fibrin. Nh ng ch t c hnh thnh trong qu trnh sinh huy t kh i gy gi i phng c p tnh t-PA t t bo n i m c m ch mu. Theo m t s tc gi , n ng t-PA b nh nhn T r t thay i (c th gi m ho c tng so v i ng i bnh th ng) tu theo gia o n ti n tri n c a b nh. b nh nhn T , s t ng h p t-PA gi m do t bo n i m c m ch mu b t n thng trong qu trnh ti n tri n c a b nh. Nhng th c t qua m t s nghin c u cho th y, n ng t-PA b nh nhn T c th gi m ho c tng, c bi t nh ng b nh nhn c bi n ch ng m ch mu th n ng t-PA th ng tng. Nghin cu c a Grant PJ. cho th y n ng t-PA b nh nhn T l 11,2ng/l v nhm ch ng (khng T ) l 7,6ng/l (s khc bi t c ngha th ng k). Nghin c u c a Mansfield MW. v CS cng ghi nh n tng n ng t-PA i t ng gi m b nh nhn T . Nghin c u Framingham Offspring cho th y ngay c dung n p glucose cng c hi n t ng tng n ng t-PA. Hi n t ng tng n ng tPA g i i t ng c a cc nghin c u ny c bi n ch ng m ch mu do huy t kh i. Hi n t ng ny c gi i thch nh sau: thnh m ch mu th ng xuyn ph n ng l i v i kch thch c a huy t kh i trong lng m ch v tng c ng kh nng lo i tr s hnh thnh fibrin t i v tr b t n thng, b ng cch tng gi i phng t-PA c th ch ng l i s hnh thnh huy t kh i trong lng m ch. M t khc, m t s ch t c hnh thnh trong qu trnh sinh huy t kh i gy gi i phng c p tnh t-PA t t bo n i m c m ch mu. Cc tc gi cng ghi nh n tc ng c a b nh l huy t kh i v x v a ng m ch ln s gi phng t-PA t t bo n i m c c a thnh m ch mu b nh nhn T r nt hn nhng i t ng b b nh l huy t kh i v x v a ng m ch nhng khng b T .V n ny c ch ng minh trong m t kh o st c a Moreno v CS : nh ng b nh nhn b b nh l m ch vnh km T c n ng t-PA cao hn b nh nhn b b nh l m ch vnh khng b T . M t s nghin c u khc th c k t qu ng c l i, nghin c u c a Zhang J., Ren S., v nghin c u c a Sobel B.E. u cho th y n ng t-PA gi m v d n n gi m tiu s i huy t, t o ti n cho s hnh thnh huy t kh i. Cc tr ng h p ny c gi i thch: do t n thng t bo n i m c d i nh h ng c a tang glucose mu lm gi m t ng h p t-PA. Qua m t s nghin c u, Ceriello A. nh n xt n ng t-PA b nh nhn T c th gi m ho c tng, nhng ho t tnh c a n lun gi m. V v y, c hi n t ng gi m tiu s i huy t nh ng b nh nhn ny. Chnh v v y, cc nghin c u v n ng t-PA b nh nhn T cho k t qu khc nhau. N cn tu thu c vo giai o n ti n tri n c a b nh, cng nh m c c a cc bi n ch ng m ch mu. Nghin c u khc c a Mansfield M.W. v CS ghi nh n nhm b nh nhn c bi n ch ng m ch mu, n ng t-PA tng cao hn h n so v i nhm khng c bi n ch ng ny, ng th i cng cho th y c m i lin quan gi a tng n ng t-PA v i t qu , bo ph, tu i. Ng c l i, tng n ng t-PA khng ph thu c vo type T v gi i tnh. Tnh tr ng r i lo n tiu s i huy t x y ra b nh nhn T ch y u l do tng n ng PAI-1, cn t-PA c th gi m ho c tng tu thu c vo giai o n ti n tri n c a b nh. Tng n ng PAI-1 s c ch cc y u t bi n i plasminogen thnh plasmin
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nh: t-PA v urokinase. V v y, tng n ng PAI-1 s d n n tnh tr ng gi m tiu s i huy t, d cho n ng t-PA c tng do ph n ng v i s t o huy t kh i trong lng m ch TI LI U THAM KH O 1. Mancfield M.W., Catto A.J., Carte A.M. and Grant P.J., (1998),Fibrinolytic measurements in type 2 diabetic patients with acute cerebral infarction. Unit of Molecular Vascular Medicine, Research School of Medicine,University of Leed, pp.953-957. 2. Peter J. Grant(2001), Coagulation and fibrinolysis in type 2 diabetes: Relationship to Microcascular Complication, Univesity of leeds, UK, pp. 15-26. 3. Rao A.K.,Chouhan V., Chen X.,et al (1999), Activation of the tissue factor parthway of blood coagulation during prolonged hyperglycaemia in young healthy men, Diabetes,(48),pp. 1156-1161. 4. Sobel B.E, Woodcock-mitchellJ., Schneider D.J. et al (1998), increased plasminogen activator inhibitor type 1 in coronary antery atherectomy spciments from type 2 diabetic compare with nondiabetic patients: a potential factor predisposing to thrombosis and its persistencer, Departement of Medicine, The University of Vermont College of Medicine, USA, pp,2213-2221.. 5. Sobel B.E. (2001), PAI-1 is a factor to be reckoned with in countering atherosclerolosis in patients with type 2 diabetes,Issues in Type 2 Diabetes,Vol.4, (Number2),pp. 1-5. 6. Juhan-Vague , Alessi et al (2004), Increased plasma plasminogen activator inhibitor 1 levels. A possible link between insulin resistance and atherothrombosis, Diabetologia, pp. 457- 462. 7. Maher, Vincent M. G. (2008) Plasminogen activator inhibitor-1 removal using dextran sulphate columns. Evidence of PAI-1 homeostasis. Journal of Thrombosis and Thrombolysis
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CH
I M NGUY C TIM M CH M I: NH NG V N LM SNG

Nguy n H u Trm Em B nh Vi n Hon M Tp HCM
Summary Heart disease is the leading cause of mortality in US and developed countries. However, cardiovascular mortality is now rapidly rising in developing countries, largely due to uptake of a Western lifestyle. Guidelines from the associations is to the target of the primary and secondary prevention of CV disease, especially coronary heart disease by reducing traditional CV risk factors. In our practice, a significant percentage (20%) of patients without traditional risk factors develops CV events regardless of using Framingham Risk Score for evaluating CV global risks. How to prevent CV events in individuals without traditional risk factors? During the past two decades, a large number of candidate risk factors have been proposed, evaluated and in most cases discarded. One typical example is the amino acid homocysteine. Today, hsCRP and Lp-PLA2 among many CV risk markers which are available in medical practice, may be candidates for CV risk factor in the future. BI B nh tim m ch l nguyn nhn hng u gy t vong t i Hoa K v cc n c pht tri n 1. Tuy nhin, cc n c ang pht tri n c khuynh h ng gia tng nhanh chng t l t vong do b nh l tim m ch do du nh p l i s ng phng Ty 2. Cc h ng d n c a cc hi p h i lun h ng n ngn ng a tin pht v th pht b nh tim m ch, c bi t l b nh m ch vnh thng qua vi c i u ch nh cc y u t nguy c tim m ch kinh i n. Trong th c hnh, c m t t l ng k 20% b nh nhn khng c cc y u t nguy c kinh i n v n ti n tri n n s c tim m ch m c d s d ng thang i m d on nguy c ton b 3. V n c t ra l lm sao c nguy c Framingham th d on v ngn ng a cc s c tim m ch nh ng ng i thi u cc y u t nguy c kinh i n. Trong hai th p nin qua, nhi u ch i m nguy c c ti m nng l y u t nguy c c xu t, nh gi nhng h u h t b cu c. M homocystein l v d i n hnh cho tr ng h p ny. Ngy nay, CRP, Lp-PLA2 trong s cc ch i m nguy c tim m ch c m t trong th c hnh, c th tr thnh nh ng ng vin y u t nguy c tim m ch trong tng lai. II. CH I M NGUY C TIM M CH M I nh ngha Ch i m sinh h c l thng s c th o l ng v xc nh s l ng c (n ng enzyme, hormone, phn b genotype trong qu n th ) m c vai tr nh m t ch s nh gi v s c kh e, tnh tr ng sinh l nh nguy c b nh, r i lo n tm th n, phi nhi m mi tr ng v tc ng c a n. 4 Ng i ta c th chia cc ch i m nguy c tim m ch (CV risk marker) thnh ch i m huy t thanh, c u trc v ch c nng. Ngoi ra, ng i ta cn phn lo i theo ng d ng lm sng: Ch i m tin on gip xc nh nguy c ti n tri n b nh tim m ch. I. M
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Ch i m t m sot h tr t m sot cc b nh cha bi u hi n r v lm sng (subclinical). Ch i m ch n on xc nh b nh ng i c tri u ch ng. Ch i m tin l ng tr gip d on ti di n, di ch ng, bi n ch ng b nh tim m ch ho c theo di i u tr . Phn bi t y u t nguy c tim m ch v i ch i m nguy c tim m ch4,5,6 Trong thu t ng hi n nay, nhi u tc gi s d ng khi ni m ch i m nguy c tim m ch (CV risk marker) nh m trnh nh m l n v i y u t nguy c tim m ch (CV risk factor). Y u t nguy c l thnh t tham gia vo qu trnh b nh sinh c a m t b nh m i u tr lm gi m m c c a n s lm gi m nguy c ti n tri n b nh. Tuy nhin, tu i v gi i cng l y u t nguy c khng th i u ch nh c v khng r m i lin h nhn qu gi ng nh tng huy t p, i tho ng, tng cholesterol muDo , khng c bi n php i u tr lm gi m nguy c v chng gp ph n theo m t c ch ph c t p v khng c hi u y . Tri v i y u t nguy c, ch i m nguy c l thnh t o m c c lin h v i s hi n di n ho c nguy c c a b nh m khng c n m i lin h nhn qu . xu t thnh y u t nguy c nhng v n M c d nhi u ch i m nguy c c cha ch ng c v ng thu n v tiu chu n nh gi nn cc ch i m nguy c tim xc minh m ch hs-CRP, Lp-PLA2, fibrinogen, Lp (a) v n ti p t c c nghin c u vai tr c a chng trong tng lai Cc ch i m nguy c tim m ch m i 1. Homocystein: Homocystein l m t acid amin c ch a nhm sulfhydryl c t o ra t vi c kh n. Thnh ph n ny lin quan v i r i lo n ch c methyl c a methionin trong ch nng n i m c, gia tng oxy ha LDL cholesterol, suy gi m y u t dn m ch, ho t ha ti u c u v stress oxy ha. Ng i ta ghi nh n c s x v a m ch mu n ng x y ra tr em v thanh nin c khi m khuy t men cystathione beta synthase v i n ng ra gi thuy t r ng ph i homocystein tng n >100mol/L. Do , McCully chng s gia tng nh v v a ph i c a homocystein huy t tng l y u t gp ph n b nh x v a m ch mu 7 . H u h t cc nghin c u (khng ph i l t t c ) ti n c u v b nh ch ng cho th y homocystein lin quan v i s c tim m ch ( B ng 1). Trong m t t ng phn tch qua 30 nghin c u, v i n ng homocystein th p i 25% c lin quan v i gi m ch 11% v nguy c b nh m ch vnh v 19% nguy c t qu 8. Do , homocystein ch l y u t d on s c m ch vnh v t qu m c v a ph i. T ng i ta ngh n gi thuy t r ng n u h th p c n ng homocystein b ng thu c (v i acide folic v cc vitamine B6, B12) s em n gi m c nguy c tim m ch. Tuy nhin, cc th nghi m lm sng l n 9,10,11 g n y cho th y r ng m c d c gi m c n ng homocystein mu v i i u tr b ng thu c nhng khng lm gi m c nguy c tim m ch (nh i mu, t qu v t vong tim m ch) khi so v i gi d c. Nh ng gi thuy t cho k t qu khng mong mu n ny l 12: 1/ Homocystein c th l i di n cho m t qu trnh no khc ho c con ng gy x v a khc m chng ta n gi n ha con ng chuy n ha ph c t p ny b ng cch n i k t homocystein v i mng x v a.
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2/ C th vi c a acide folic v B12 vo chu trnh methyl ha qu m c v i m c ch i u tr s t o ra ADMA (asymmetrical dimethylargine) n i m c, do tc d ng b t l i ch t ny s trung ha h t tc d ng h homocystein. V cha th ch ng minh c m i lin h nhn qu c a homocystein qua cc th nghi m lm sng nu trn, cho nn homocystein hi n nay v n ch l ch i m nguy c tim m ch n thu n. Tc gi Nghin c u Tiu ch nh gi K t qu Hopkins Nam-n , tu i B nh m ch vnh T su t khc bi t OR gi a n ng 38-68 gia nh s m HCY 9 mol/l so v i <9 162 b nh v (NMCT khng t mol/l l: 155 ch ng vong, ph u thu t OR:13.8 (95% CI, 3.555) v i m ch vnh s m) nam, OR: 12.8 (95% CI, 2.082) v i n Sau khi i u ch nh tu i, gi i, BMI, ti u ng, lipid mu, ht thu c l, n ng vitamin, thu c gi m m . Robinson N -nam, tu i H p MV 70% T su t khc bi t OR gi a n ng tb 62, 304 b nh 1 nhnh chnh HCY 14 mol/l so v i <14 v 155 ch ng mol/l l: OR:2.9(95%CI, 1.74.7) v i nam >65t OR:3.5(95% CI, 1.48.5) v i n >65t i u ch nh ti u ng , THA, ht thu c l, tng lipid. Arnesen Nam-n , tu i B nh m ch vnh t Nguy c tng i RR cho gia HCY: 12-61, 123 vong v khng t tng 4 mol/l n ng b nh, 492 vong 1.32 (95% CI, 1.051.65), sau ch ng khi i u ch nh lipid, HA tm Theo di 4 thu, ht thu c l, ti u ng v nm. au th t ng c. Malinow Nam-n , tu i NMCT khng t T s khc bi t cho ng phn v 25-64, 420 vong cao nh t v th p nh t: OR: 1.84 (95% CI, 0.84.5) cho b nh v 486 ch ng B c Ai len OR: 4.27 (95% CI, 2.09.3) cho Php Sau khi i u ch nh theo tu i, BMI, r u, thu c l, HA tm thu v lipid Graham Nam-n , <60t, B nh m ch mu x T s khc bi t cho ng phn v 750 b nh v v a( tim, no, cao nh t v i cc gi tr ng phn 800 ch ng ngo i bin) v khc:
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OR: 2.2 ((95% CI, 1.62.9) Sau khi i u ch nh tu i v trung tm nghin c u. Ivans Nam-n , 35- T l c ng d n T s khc bi t theo t phn v : MRFIT 57t, 93 NMCT NMCT khng t quartile 2: 1.03 (95% CI, 0.63 khng t vong, vong v BMV t 1.66) 186 i ch ng, vong. quartile 3: 0.84 (95% CI, 0.51 147 b nh MV 1.28) t vong, 286 quartile 4: 0.82 (95% CI, 0.55 i ch ng. 1.54) Theo di 11-17 i u ch nh theo tu i, ht thu c l, HA tm trng, lipid. nm. Whincup, Nam 40-59t, T l c ng d n T su t khc bi t theo ng phn British 386 b nh v NMCT khng t v cao nh t so v i gi tr ng Regional 454 ch ng. vong v BMV t phn v khc: Heart Theo di 12,8 vong. 1.76 (95% CI, 1.282.43). Study nm Sau khi i u ch nh tu i, HA tm thu, glucose, FEV1, cholesterol, ht thu c l, r u Stehouwer Nam tu i 64- NMCT khng t Nguy c tng i (RR) cho 84, 878 ng i, vong v BMV t tam phn v th 1 v th 3 l: theo di 10 vong. 1.81 (95% CI, 1.073.08) cho nm NMCT khng t vong v 1.58 (95% CI, 0.932.69)cho BMV t vong. i u ch nh theo tu i, BMI, HA tm thu, cholesterol, ti u ng, ht thu c l. B ng 1: Tm t t cc nghin c u l n v homocystein nh l ch i m nguy c x v a ng m ch v b nh tim m ch.(c i bin t Atherosclerosis and Heart Disease 2003, pp43-44) HCY: vi t t t c a Homocysteine. 2. hs-CRP hs CRP- m t phn t 5 ti u n v 1,15 kDa l ch t ph n ng trong phase c p kinh i n, c t o ra t gan khi p ng v i kch thch vim t cytokine (interleukin6) . Tuy nhin g n y, cc nh nghin c u nh n th y cc m khc nh t n thng x v a ng i, t bo c trn m ch vnh, t bo n i m MC, t bo m th n, neuron, i th c bo ph nang cng tham gia t o CRP 13. Cc xt nghi m th ng qui v ch pht hi n khi c tng CRP r r t th ng g p trong cc b nh l vim nhi m kinh i n. Tuy nhin nh n s pht tri n k thu t, xt nghi m v i nh y cao cho php pht hi n s gia tng d r t nh n ng CRP nh ng ng i c tnh tr ng vim nh ho c khng r rng (trong sinh huy t kh i x v a). Cc nghin c u ti n c u v vai tr c a hs CRP trong d on nguy c tim m ch K t nghin c u ti n c u u tin c a Kuller (1996) cho n nghin c u c a Boekholdt (2006) (Bi u 1) u cho th y CRP c m i lin h v i s c tim m ch nh ng ng i ban u khng c b nh tim m ch v m t lm sng. Tuy nhin, m t s
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nghin c u l n ti n hnh ng i cao tu i khng cho th y CRP khng c m i lin h v i s c tim m ch sau khi i u ch nh cc y u t nguy c khc. Trong m t t ng phn tch 11 nghin c u vo nm 2000 14, cho th y nguy c tng i l 2,0 v i s c tim m ch theo CRP, tri l i t su t khc bi t m t t ng phn tch khc15 sau ny l 1,5. i u cho th y vai tr c a CRP c th c nh gi qu m c trong cc nghin c u tr c.
Bi u 2: Cc nghin c u ti n c u v CRP v s c tim m ch. (trch l i t Biomarkers in Heart Disease-The AHA Clinical Series, 2008, p165). Ch thch: CHD death: t vong do b nh m ch vnh, CHD: b nh m ch vnh, Fatal stroke: t qu t vong, stroke: t qu , MI: NMCT, CVD: b nh tim m ch. PVD: b nh m ch mu ngo i bin. Trong cc ch i m vim nhi m, hs CRP l ch i m c gi tr d on cao NMCT khi so v i cc ch i m vim nhi m khc (fibrinogen, sICAM-1, interleukin-6), nhng n u k t h p v i TC:HDL th cho gi tr d on cao hn (Bi u 2).
Bi u 1: Cc ch i m vim nhi m v nguy c tng i NMCT trong tng lai nam gi i kh e m nh. (Theo Libby and Ridker. Circulation 1999;100:114850)
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sICAM-1: soluble form of intercellular adhesion molecule-1; hs-CRP: high sensitivity C-reactive protein; TC:HD: increased total cholesterol:high density lipoprotein cholesterol ratio D khng b ng v i cc y u t nguy c kinh i n khc (cholesterol tp, ht thu c l, HA tm thu), hs CRP cng c vai tr cung c p thm thng tin d on nguy c b nh m ch vnh (Bi u 3) 7.
Bi u 3: T su t khc bi t c a cc ch i m/y u t nguy c tim m ch trong d on b nh m ch vnh (Theo Mayo Clinical Cardiology-Concise Textbook 3rd Ed 2007, p728). CRP v s c tim m ch Cc th nghi m lm sng gi m n ng 16 Th nghi m CARE l th nghi m u tin ch ng t tr li u statin ngoi vi c h th p n ng LDL cn lm gi m n ng hsCRP. Nh ng t li u ny ph h p v i k t qu nghin c u phng xt nghi m ch ng minh vai tr khng vim cng nh tc d ng h lipid mu c a statin. Hn n a, m c gi m s c tim m ch s l n hn b nh hsCRP khi so v i b nh nhn tng lipid mu nhn tng lipid mu km tng n ng nhng n ng hsCRP th p. Trong m t phn tch post h c t nghin c u the Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS)17 cng cho th y nh ng ng i c LDL-C th p nhng hsCRP cao s c hi u qu v i i u tr statin trong khi nh ng ng i c LDL-C th p v hsCRP th p th khng cho th y hi u qu tng t . Pht hi n ny cng c th l ti n cho nghin c u JUPITER. Th nghi m JUPITER 18 d a trn m t gi thuy t cho r ng li u gi m n ng hsCRP v i statin ng i c LDH-C bnh th ng c lm gi m c nguy c cc s c tim m ch (t vong tim m ch, NMCT, t qu , ti thng ng m ch) hay khng? Nghin c u ti n hnh 17.802 ng i khng tri u ch ng (nam 50t, n 60t) v khng c ti n s BMV, t qu , ti u ng nhng c xt nghi m t m sot ban u HDLC130 mg/dL (3.36 mmol/L) v hsCRP 2.0 mg/L. Nh ng ng i tham gia nghin c u c ch n ng u nhin m i s d ng 20 mg/ngy v i rosuvastatin ho c gi d c v i d tr nghin c u s c theo di trong 4 nm. Tuy nhin, y Ban Theo Di D Li u c L p ch m d t th nghi m s m hn mong i vo thng 3 nm 2008 (sau 2 nm theo di) v hi u qu to l n c a rosuvastatin v i l do o c nghin c u. Th nghi m cho th y nh ng ng i khng tri u ch ng c hsCRP cao nhng LDH-
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C bnh th ng vi c i u tr phng ng a tin pht v i statin lm gi m nguy c s c tim m ch ph i h p 44% v gi m c nguy c t vong chung 20%. G n 80 nm sau khi pht hi n, CRP ang tr thnh m t ch i m m i v quan tr ng ngn ng a b nh tim, t qu v t vong chung. 19 V i k t qu nghin c u ny, ng i ta ngy cng quan tm n vai tr c a hsCRP nh l m t y u t nguy c vim m vi c can thi p lm gi m thnh ph n ny cng gp ph n lm gi m s c tim m ch. S d ng hs-CRP trong lm sng : Sau y l h ng d n c a Vi n Hn Lm Qu c Gia v Sinh Ha Hoa K 20: xc nh n ng hs-CRP c th th c hi n lc i ho c khng i, nh ng b nh nhn n nh v chuy n ha, khng m c cc b nh nhi m trng ho c b nh c p tnh. hs-CRP <3mg/L, khng c n xt nghi m l i. N u n ng >3mg/L N u n ng nn xt nghi m l i t nh t 2 tu n khi tnh tr ng chuy n ha n nh, khng c b nh nhi m trng v khng b nh c p tnh. V i 2 l n c tr s th p nn xem xt l gi tr th c c a b nh nhn. N u n ng 10mg/L, tr s ny c th lin quan v i nguy c b nh tim m ch. Tuy nhin nh ng tnh tr ng khc nh nhi m trng ang ho t ng, cc tnh tr ng vim nhi m khc c th ch u trch nhi m cho s gia tng ny V i xt nghi m hs-CRP chu n ng i ta c th phn lo i nh sau: a/ nguy c th p: <1,0mg/L b/ nguy c v a: 1,0-3,0mg/L c/ nguy c cao: >3,0mg/L d/ nguy c r t cao: >10mg/L Theo h ng d n c a CDC/AHA t nm 2003, 21 vi c th hsCRP nn h ng n nh ng b nh nhn khng tri u ch ng c thang i m Framingham nguy c trung bnh (10-20% nguy c s s tim m ch trong 10 nm). b nh nhn nguy c th p ho c cao, xt nghi m hsCRP l khng c n thi t. Nh ng b nh nhn nguy c trung bnh nhng hsCRP>3mg/L c n c i u tr nh b nh nhn nguy c cao. M t s v n cha gi i quy t c a hs CRP 22: a. C s khc bi t r r t v n ng CRP cc nhm tu i, gi i tnh v ch ng t c khc nhau. Do cha c gi tr ng ng chu n theo t ng nhm qu n th khc nhau. Trong m t nghin c u c a Canada, n ng CRP trung bnh 4 nhm ch ng t c l 3.74 mg/L ng i th dn, 2.59 mg/L ng i Nam , 2.06 ng i Chu u, v 1.18 mg/L ng i Trung hoa (p < 0.0001) . b. M c d CRP l ch i m c vai tr d on nguy c c l p nhng cha ph i l y u t tin l ng thm vo m nh m so v i cc y u t nguy c kinh i n v i t su t khc bi t a bi n ch kho ng 1,5. c. M t s nghin c u ch ng minh s d ng statin c th lm gi m hs CRP v gi m s c tim m ch, c l p v i n ng cholesterol mu nhng chng ta v n cha bi t c ch t c ch c hi u hs CRP lm gi m nguy c hn n a gip ngn ng a tin pht v th pht b nh tim m ch. 3. Lipoprotein-associated phospholipase A2 (Lp-PLA2) 23,24,25
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Lp-PLA2 l ch i m sinh h c tim m ch c FDA cng nh n trong vi c s d ng k t h p v i nh gi lm sng d on b nh m ch vnh v t qu . Lp-PLA2 l m t enzyme s n xu t ch y u b i cc i th c bo v b i m t s t monocyte, ti u c u, t bo mast. Lp-PLA 2 lu hnh v g n vo LDL (80%), HDL (15-20%).
i t ng Ngn ng nguyn pht Ngn ng nguyn pht Ngn ng nguyn pht Ngn ng nguyn pht Ngn ng nguyn pht Ngn ng nguyn pht a WOSCOPS a WHS a ARIC a ARIC a MONICA a Rotterdam Thu n t p B nh ch ng 97/837 308/1822 Nghin c u Thi t k B nh/ch ng (n) 580/1160 123/123 608/740 194/766 Tiu ch/ theo di T vong BMV, NMCT, ti thng /5 nm T vong BMV, NMCT, t qu T vong BMV, NMCT, ti thng/ 6 nm t qu thi u mu/6 nm T vong BMV, NMCT/14 nm T vong BMV, NMCT/ 7 nm So snh Lp-PLA2 Tng m t l ch chu n T phn v cao nh t so v i th p nh t Tam phn v cao nh t so v i th p nh t Tam phn v cao nh t so v i th p nh t Tng m t l ch chu n T phn v cao nh t so v i th p nh t Tng m i l ch chu n T phn v cao nh t so v i th p nh t Tng m t l ch chu n Ng phn v cao nh t so v i th p nh t Tam phn v cao nh t so v i th p nh t Adjusted HR (T su t nguy h i i u ch nh) 1.18 (1.051.33) 1.17 (0.453.05) 1.15 (0.811.63) 1.93 (1.143.27) 1.23 (1.021.47) 1.97 (1.283.02) 1.20 (1.041.39) 1.97 (1.033.79) 1.24 (1.021.52) baseline: 1.08 (0.861.36); 30 ngy: 1.33 (1.011.74) Ton b : 2.65 (1.474.76); Ho t ng: 2.40 (1.354.29)
B nh ch ng B nh ch ng B nh ch ng B nh ch ng
Ngn ng a nguyn pht
Rotterdam
B nh ch ng
110/1822
t qu thi u mu/6 nm
H i Ch ng Vnh C p Ngn ng a th pht
PROVE IT
Th nghi m lm sng B nh nhn b nh m ch vnh
3648
T vong, NMCT, ti thng, t qu , au th t ng c khng n nh/ 2 nm S c tim m ch/ 4 nm
Koenig et al.
1051
B ng 2: Cc nghin c u nh gi m i lin h gi a Lipoprotein-associated phospholipase A2 v B nh M ch Vnh & t Qu (c i bin t Biomarkers in Heart Disease AHA 2008) Lp-PLA2 l ch t kh i pht qu trnh vim v t o mng x v a c khuynh h ng v . Ch t ny t o ra b i i th c bo v c t bo b t v c gi i phng t mng x v a vo tu n hon, t i n g n v i lipoprotein. B m t phospholipid c a h t LDL b oxy ha. Lp-PLA2 s th y phn cc phospholipid oxy ha thnh acid bo oxy ha v lysophosphatidylcholine (lysoPC). Cc ch t ny kch thch phn t k t dnh v gi i phng cytokines, nh ng ch t ny thu th p b ch c u monocyte vo l p intima sau chng c ho t ha thnh i th c bo v t bo b t. Nh ng i th c bo v t bo b t c ho t ha s ti p t c s n xu t Lp-PLA2 v t o ra m t vng l n qu n.
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Lp-PLA 2 l ch i m c hi u cao cho t n thng m ch mu m n khng nh h ng b i nhi m trng thng th ng v b nh vim kh p, c bi n ng sinh h c th p. y l i m u th khi so v i hs CRP (ch i m c a vim nhi m h th ng). Qua 25 nghin c u ti n c u cho th y c s lin h gi a tng Lp-PLA 2 v i s c m ch vnh v t qu trong tng lai. 11 trong 12 nghin c u ti n c u cho th y c m i lin h c ngha th ng k gi a tng Lp-PLA 2 v i s c m ch vnh nguyn pht v s c tim m ch. 6 nghin c u cho th y c m i lin quan ch t ch gi a Lp-PLA 2 v i t qu (B ng 2). N ng Lp-PLA 2 c th gi m khi i u tr v i cc thu c h lipid mu nh statin, niacin, fenofibrate, acid bo omega-3 v ezetimibe. Tuy nhin, cha c d li u no v n ng ch khi i u tr v i cc thu c trn c i thi n h u qu lm sng. Hi n nay, ch t c ch Lp-PLA 2 ang ti n hnh nghin c u phase 2 v 3. N ng Lp-PLA2 theo b n ng thu n qu c gia (US) l 235ng/ml cao, tuy nhin theo cc xu t c a cc hang xt nghi m th n ng <200ng/ml l th p, 200235ng/ml l gi i h n cao, v trn 235ng/ml l cao. 4. Lipoprotein (a)3,7,26 M c d c nghin c u r ng ri hn 4 th p nin qua, s ph c t p v c u trc v chuy n ha c a Lp (a) lm c n tr vi c xc nh p d ng Lp(a) trong th c hnh lm sng. Lp(a) c c u trc tng t nh LDL nhng ch ch a glycoprotein duy nh t apo(a) m n g n v i apo (B) v i c u n i disulfide. Trong m t t ng phn tch 27 nghin c u ti n c u v i hn 5000 tr ng h p c Lp(a) cao nh t c ti m nng BMV v theo di 10 nm cho th y r ng ng i c n ng kh nng gia tng 70% nguy c b nh m ch vnh so v i ng i c n ng th p nh t. M t s nghin c u khc cho th y k t h p gia tng n ng cao Lp(a) v tng LDL cng lm gia tng s c tim m ch. Tuy nhin, thi u s chu n ha c a vi c nh l ng Lp(a) cng l ro c n l n trong vi c nghin c u v xc nh vai tr Lp(a) trong lm sng. Cho n nay, khng c nghin c u cho th y Lp(a) gi m v i i u tr statin. M t s tnh hu ng m xt nghi m Lp(a) cho th y ch l i nh m t ch i m nguy c ng i c nguy c trung bnh nhng c n phn t ng tch c c hn. 1. 2. Ti n s gia nh m c b nh tim m ch s m 3. M c b nh m ch vnh nhng xt nghi m lipid mu bnh th ng. 4. Tng cholesterol mu tr v i i u tr . 5. Ti n s ti h p nhi u l n. 5. Fibrinogen 3,7 Fibrinogen huy t tng l y u t nh h ng n k t dnh ti u c u, qunh c a mu v tng tc v i g n plasminogen huy t tng, ph i h p thrombin th c hi n b c cu i cng t o thnh c c mu ng v p ng v i t n thng m ch mu. Nh ng bo co u tin c c t cc nghin c u Gothenburg, Northwick Park v Framingham Heart Study cho th y c s lin quan thu n gi a n ng fibrinogen v i s c tim m ch. Trong m t t ng phn tch cho th y sau khi i u ch nh tu i v gi i th c m i gia tng 1 g/L fibrinogen th t su t nguy h i i v i b nh m ch vnh l 2,4 v i v i t qu l 2,1. M c d v y, vi c nh gi fibrinogen v n cn gi i h n v cha chu n ha v tnh h ng nh qua cc hng xt nghi m v n cn km. Cho n nay, m t s th nghi m lm sng nh The Bezafibrate Infarction Prevention Trial, the HERS trial v the Women's Health Initiative khng cho th y gi m c s c tim
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m ch m c d m t s fibrinogen mu.
nhm thu c (fibrate, hormone) c lm gi m c n ng
III. K T LU N M c d c nhi u ch i m nguy c tim m ch c nghin c u nhng tr thnh m t y u t nguy c tim m ch m i v n l nh ng thch th c cho cc nh nghin c u lm sng. chu n ha trong qui trnh nh gi ch i m nguy c m i, trong m t b n Tuyn B Khoa H c c a Hi p H i Tim Hoa K 27 g n y, a ra cc giai o n nh gi m t ch i m nguy c m i bao g m : n n t ng khoa h c c a ch i m nguy c, gi tr c a ch i m nguy c trong nghin c u ti n c u, gi tr tin l ng thm vo c a ch i m nguy c, gi tr ng d ng lm sng c a ch i m nguy c, vai tr c a ch i m nguy c trong c i thi n h u qu lm sng, gi thnh-hi u qu c a ch i m nguy c. Trong cc ch i m nguy c trn ch c m t s ch i m c th ti m nng tr thnh y u t nguy c l hsCRP v Lp-PLA2. Tuy nhin, nh ng ch i m ny hi n t i v n cha c ch t c ch c hi u nh m lm gi m s c tim m ch nh mong mu n. Do , vai tr c a cc ch i m nguy c hi n nay v n l gip ti phn nhm nguy c b nh nhn c nguy c trung bnh theo y u t nguy c kinh i n. TI LI U THAM KH O 1. FD Richard Hobbs and Bruce Arroll. Cardiovascular Risk Management. Blackwell Publishing. 2009 Hobbs FDR & Arroll B. ISBN: 978-1-405-15575-5 2. Paul M. Ridker Peter Libby. Novel Atherosclerotic Risk Factors in Braunwald's Heart Disease: A Textbook of Cardiovascular Medicine, 8th ed. p1012-1019. 3. E. Ingelsson, R. S. Vasan. New biomarkers of cardiovascular disease in Therapeutic Strategies in Cardiovascular Risk edited by Ian M. Graham, Ralph B. D'Agostino, Sr. Atlas Medical Publishing 2008, the 1st Edition. pp 111-136. 4. Helge Rsj2 and Torbjrn Omland. New cardiovascular risk markers: The race is on, but are there any winners?. The Scandinavian Journal of Clinical & Laboratory Investigation, Vol. 68, No. 8, December 2008, 673677 5. Meir J. Stampfer, Paul M Ridker and Victor J. Dzau. Risk Factor Criteria. Circulation 2004;109;IV-3-IV-5. 6. Iftikhar J. Kullo. Novel Risk Markers for Atherosclerosis in Mayo Clinic Cardiology-Concise Textbook edited by Joseph G. Murphy, Margaret A. Lloyd. 3rd Ed, 2007 by Mayo Foundation for Medical Education and Research. p725-733. 7. R. Clarke, R. Collins, S. Lewington, A. Donald et al. Homocysteine and Risk of Ischemic Heart Disease and Stroke: A Meta-analysis. JAMA. 2002;288:2015-2022. 8. Toole JF, Malinow MR, Chambless LE et al. Lowering homocysteine in patients with ischemic stroke to prevent recurrent stroke, myocardial infarction, and death: the Vitamin Intervention for Stroke Prevention (VISP) randomized controlled trial. JAMA 2004;291:565-75 9. Bnaa KH, Njlstad I, Ueland PM et al. Homocysteine lowering and cardiovascular events after acute myocardial infarction. N Engl J Med 2006; 354:1578-88 10. The Heart Outcomes Prevention Evaluation (HOPE) 2 Investigators. Homocysteine lowering with folic acid and B vitamins in vascular disease. N Engl J Med 2006;354:1567-77
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11. Patrick OCallaghan. Homocysteine is it the end of the line?Br J Cardiol 2007;14:6970. 12. Sridevi Devaraj, Uma Singh, and Ishwarlal Jialal. The Evolving Role of CReactive Protein in Atherothrombosis. Clinical Chemistry 55:2; 229238 (2009) 13. Danesh J, Whincup P, Walker M, Lennon L, Thomson A, Appleby P, et al. Low grade inflammation and coronary heart disease: prospective study and updated metaanalyses. BMJ 2000; 321: 199204 14. Danesh J, Wheeler JG, HirschfieldGM,Eda S, Eiriksdottir G, Rumley A, et al. C-reactive protein and other circulating markers of inflammation in the prediction of coronary heart disease. N Engl J Med 2004; 350: 13871397 15. Ridker PM, Rifai N, Pfeffer MA, Sacks F, Braunwald E. Long-term effects of pravastatin on plasma concentration of C-reactive protein. The Cholesterol and Recurrent Events (CARE) Investigators. Circulation 1999;100:230 5. 16. Ridker PM, Rifai N, Clearfield M, Downs JR, Weis SE, Miles JS, Gotto AM Jr. Measurement of C-reactive protein for the targeting of statin therapy in the primary prevention of acute coronary events. N Engl J Med 2001;344:195965. 17. Ridker PM, Danielson E, Fonseca FAH, Genest J, Gotto AM, Kastelein JJP, et al., for the JUPITER Study Group. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med 2008;359:2195207 18. Paul M Ridker. C-Reactive Protein: Eighty Years from Discovery to Emergence as a Major Risk Marker for Cardiovascular Disease. Clinical Chemistry 55:2 ; 209215 (2009). 19. NACB LMPG Committee Members. National Academy of Clinical Biochemistry Laboratory Medicine Practice Guidelines: Emerging Biomarkers for Primary Prevention of Cardiovascular Disease. Clinical Chemistry 55:2,378384 (2009). 20. Pearson TA, Mensah GA, Alexander RW, Anderson JL, Cannon RO 3rd, Criqui M, et al. Markers of inflammation and cardiovascular disease: application to clinical and public health practice. A statement for healthcare professionals from the Centers for Disease Control and Prevention and the American Heart Association. Circulation 2003;107:499 511. 21. Amit Khera. C-Reactive Protein in Biomarkers in Heart Disease, Edited by James A. de Lemos. 2008 American Heart Association. ISBN: 978-1-405-17571-5. pp 161-180. 22. Marshall A. Corson, Peter H. Jones, and Michael H. Davidson. Review of the Evidence for the Clinical Utility of Lipoprotein- Associated Phospholipase A2 as a Cardiovascular Risk Marker. Am J Cardiol 2008;101[suppl]:41F50F 23. Amir Lerman, and Joseph P. McConnell. Lipoprotein-Associated Phospholipase A2: A Risk Marker or a Risk Factor?. Am J Cardiol 2008;101[suppl]: 11F22F. 24. Michael H. Davidson, MD,a,b,* Marshall A. Corson, MD,c Mark J. Alberts. Consensus Panel Recommendation for Incorporating Lipoprotein- Associated Phospholipase A2 Testing into Cardiovascular Disease Risk Assessment Guidelines. Am J Cardiol 2008; 101[suppl]:51F57F.
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CH N ON NH P NHANH VO L I T I NT NH TH T B NG CC NGHI M PHP THM D I N SINH L V I U TR T B NG SNG CAO T N

T Hng Th y Trung tm Tim m ch - BVTW Hu Tm t t: Nh p nhanh vo l i t i nt nh th t (AVNRT) l th nh p nhanh k ch pht trn th t th ng g p nh t, lin quan n c ch vng vo l i t i nt nh th t. Th i n hnh l ch m- nhanh. Ch n on phn bi t v i cc nh p nhanh khc b ng cc nghi m php thm d i n sinh l l r t quan tr ng gip quy t nh ch n on v qua xc nh v tr c n t. i u tr b ng sng cao t n tri t b ng ch m cho k t qu t t. Summary: AV nodal reentrant tachycardia is the most common type of supraventricular tachycardia (excluding atrial fibrillation). AVNRT occurs in the presence of a reentrant circuit involving fast and slow pathways that connect to the AV node. Typical AVNRT is the slow-fast form. Standard diagnostic pacing maneuvers are very crucial to differentiate the various forms of paroxysmal supraventricular tachycardia in the electrophysiology laboratory. Once the diagnosis of AVNRT is confirmed, slow pathway ablation produces a high rate of success. Nh p nhanh vo l i t i nt nh th t (AVNRT) l th nh p nhanh k ch pht trn ( T ) khi ngh bnh th t th ng g p nh t (khng tnh rung nh) c i n tm th ng chi m 60% cc tr ng h p nh p nhanh c QRS h p ng i l n. AVNRT l r i lo n nh p nhanh c c ch vng vo l i. V c b n, m t vng vo l i bao g m 2 ng: ng beta c tnh d n truy n nhanh nhng th i gian tr ko di, ng anpha d n truy n ch m nhng th i gian tr ng n[1] (hnh A). Khc v i cn nh p nhanh vo l i nh th t (AVRT hay ORT) b nh nhn c ng ph c vng vo l i i t nh n th t v ng c l i, AVNRT nh tn g i c a n c vng vo l i t i nt nh th t (hnh B). AVNRT xy ra trn b nh nhn c s hi n di n c a 2 c u trc khc bi t v phng di n i n sinh l cng ch y n nt nh th t- l ng nhanh v ng ch m. ng nhanh l c u trc pha tr c n m g n nt nh th t v d c theo gn Todaro, trong khi ng ch m l c u trc n m pha sau v th ng c xc nh l n m d c theo vng van ba l g n l xoang vnh[2] (hnh 1). nh p xoang bnh th ng d n truy n nh th t x y ra qua ng nhanh. Thng th ng cn AVNRT c kh i pht b i 1 ngo i tm thu (NTT) nh n s m g p lc ng nhanh v n cn ang th i k tr nn b bl c ng nhanh, nhng n u lc ng ch m thot kh i th i k tr (th i gian tr hi u qu ERP c a ng nhanh di hn ng ch m) th xung ng c a ngo i tm thu nh c d n truy n xu ng qua ng ch m n nt nh th t. V th i gian n truy n qua ng ch m ko di hn so v i ng nhanh, nn xung ng b d n truy n ch m l i. Khi xung ng n v tr ng ba giao nhau v i ng nhanh, lc ny ng nhanh thot kh i th i k tr v s n sng d n xung ng ng c dng ln nh. Nh th lc ny, c 2 kh c c x y ra g n nh ng th i l kh c c th t theo chi u xui v v kh c c nh theo chi u ng c dng (hnh A). Kh c c nh l i nhanh chng theo ng ch m kh c c xui dng t o nn vng vo l i[3] (cn ch m-nhanh AVNRT i n hnh).
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Tnh hu ng lm sng M t b nh nhn n 63 tu i i khm v m t ng c, kh th . H i k tri u ch ng th b nh nhn than phi n c nhi u cn nh p nhanh h i h p. Nh ng cn ny th ng x y ra ban m lm b nh nhn th c gi c. Cn kh i pht t ng t khng c ti n tri u v k t thc t ng t. B nh nhn m t cn nh p nhanh h i h p ki u nhanh v u, trung bnh ko di 10 n 15 pht. B nh nhn ni r ng cn th ng ch m d t khi b lm cc ng tc ki u nh nghi m php Valsava. Khm pht hi n cn nh p nhanh r t i n hnh. T 12 chuy n o ghi nh n cn nh p nhanh v i QRS h p t n s 150 chu k/pht (hnh 2). T trong cn khng th y r sng P i tr c QRS. Tuy nhin n u quan st k , th c sng P kh c c ng c (retrograde) ch ng ln ph n sau ph c b QRS. Ch n on phn bi t ki u cn nh p nhanh v i RP ng n (short RP) ny l cn AVNRT ho c ORT (hay AVRT nh p nhanh do ng ph ) ho c nh p nhanh nh v i bl c nh th t c p 1. B nh nhn c ch nh lm thm d i n sinh l. a cc Catheter vo bu ng tim ghi i n th vng cao nh ph i (HRA), b His, v m m th t ph i. Catheter 20 i n c c c a vo xoang vnh v i i n c c 13,14 v tr l xoang vnh. o t cc kho ng cch c b n v cc gi tr n m trong gi i h n bnh th ng (hnh 3). Cc th thu t kch nh p ch n on diagnostic pacing c b n c th c hi n gy cn cng nh thm d cc tnh ch t d n truy n c b n. Kh o st ngoi cn nh p nhanh: Tr c tin l kch thch th t kh o st d n truy n ng c th t nh. Kch thch th t v i ventricular extrastimulus testing VEST g i t t l V extra ho c V stim plus 1 ho c 2 (ty theo c 1 hay 2 nht n s m) l th thu t kch nh p v i 8 nh p paced v i chi u di chu k (CL) c nh (drive train S1 th ng l 600 ms ho c 400 ms t o n n n nh) ngay sau l nht n s m[3]. C th c 1 (S2) ho c 2 (S3) ho c 3 (S4) nht n s m. Trn b nh nhn ny cho th y decremental concentric retrograde conduction kh i n th His v c c nh ng c dng ng tm concentric v i ho t ng nh s m nh t d n truy n ng c dng c t c gi m d n decremental. Thu t ng decrement c m t hi n t ng d n truy n ch m l i khi t n s tng ln (rate-dependent dng prolongation of conduction). y l tnh ch t c b n c a t bo t o nh p v i i n th ho t ng c kh c c ph thu c vo dng calcium i vo ch m ( y l nt nh th t) [3]. K ti p l kch thch nh nh gi d n truy n xui dng nh th t. Kch thch nh c nht n s m (AEST) tng t nh VEST nhng khc v tr paced l nh. D n truy n xui cng i qua nt nh th t nn cng c tnh decremental t c AH di ra khi ngo i tm thu (NTT) ng n l i. Th thu t ny cng dng nh gi th i gian tr ERP c a nt nh th t l CL c a ngo i tm thu nh hay kho ng ghp A1A2 di nh t nhng khng d n xu ng c His . Trn b nh nhn ny khi AEST s m th xu t hi n b c nh y AH. B c nh y c xc nh khi kho ng A2-H2 tng trn 50 ms khi kho ng ghp A1A2 ng n i 10ms. Khi c b c nh y th c th k t lu n nt nh th t c 2 ng nhanh v ch m dual AV node physiology ho c nm na l c ng ch m. Kho ng ghp A1A2 gy b c nh y c th coi l ERP c a ng nhanh. Khi ngo i tm thu nh n s m khi ng nhanh v n cn trong th i k tr hay khi kho ng ghp n m trong ERP c a ng nhanh, th xung ng chuy n sang d n truy n qua ng ch m[3]. Nh th , th i gian t nh n nt AV (kho ng AH) chuy n t ng nhanh sang ng ch m s t ng t di ra. Trong tr ng h p b nh nhn ny, khi kch thch nh c nht
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n s m, ghi nh n c b c nh y AH 85 ms. Cng v i b c nh y, nht echo cng r t quan tr ng trong ch n on AVNRT cng c ghi nh n b nh nhn ny (hnh 4). Nht echo nt nh th t l do xung ng sau khi theo ng ch m n nt nh th t th ngoi i xu ng kh c c th t l i ng th i kh c c ng c dng theo ng nhanh ln kh c c nh v lc ny ng nhanh ra kh i th i k tr nn kh c c nh v th t x y ra ng th i. Ti p t c lm AEST gy cn nh p nhanh c QRS h p v i chi u di chu k (CL cycle length) l 390 ms (hnh 5). Quan st trong cn nh p nhanh d n truy n VA h u nh khng i v i th i gian 40 ms (< 70ms) km d n truy n ng c ng c dng ng tm v gi m d n decremental concentric retrograde conduction kh o st tr c , g i kh nng cao l AVNRT [4]. xc nh ch n on, nhi u nghi m php kch nh p c ti n hnh. Cc nghi m php trong cn nh p nhanh: Sensed A l nghi m php kch thch nh s m c sau sensing m i 4 QRS c a cn nh p nhanh th s pht ra 1 kch thich nh n s m hn chi u di chu k c a cn nh p nhanh (TCL). C th c 1 ho c 2 NNT nh ty theo m g i l single hay double sensed A. Sau khi xc nh nht NNT nh b t c nh (captured), cn nh p nhanh v n ti p t c th so snh VA c a nht u tin tr l i cn nh p nhanh v i VA trong cn nh p nhanh. N u VA khng i hay thay i < 10ms th g i l VA c nh (hooked or fixed VA) g p trong AVNRT hay ORT v kh c c nh lin h m t thi t v i kh c c th t trong 2 th nh p nhanh ny. N u VA thay i > 10 ms (unhooked VA) th kh nng l nh p nhanh nh[4][5]. Trn b nh nhn ny, VA c nh. Nghi m php Morady r t quan tr ng trong thm d i n sinh l l entrainment. Th c ra entrainment l m t tnh ch t c b n trong i n sinh l c tim, l c i m r t quan tr ng nh gi c ch t vng vo l i c a r i lo n nh p. Entrainment l hi n t ng t n s nh v th t trong cn nh p nhanh tng ln theo chi u di chu k (CL) c a kch nh p v t t n s overdrive pacing t nh ho c th t v i chi u di chu k ng n hn CL c a cn nh p nhanh t 10 40 ms v tr v l i CL ban u sau khi d ng kch nh p[4][5]. V d trn b nh nhn ny CL c a cn nh p nhanh l 390ms. Overdrive pacing t th t v i CL = 360ms th y c entrainment c a nh, ngha l t n s nh trong cn nh p nhanh cng tng ln v i CL = 360ms. Ch ng t c ch nh p nhanh trn b nh nhn ny l vng vo l i. Lc ny quan st trnh t kh c c nh atrial activation sequence th y gi ng v i trnh t trong cn nh p nhanh. N u khc th th ng l nhanh nh ho c ng ph . Sau khi ng ng overdrive pacing, n u nh p nhanh khng ch m d t m ti p t c ta s nh gi ki u p ng v th i gian tr l i nh p nhanh sau kch nh p v t t n s post pacing interval PPI. Trn b nh nhn ny ki u p ng l VA-H-V hay V-A-V (hnh 6). p ng V-A-H-V gip lo i b c ch n on nh p nhanh nh[4](thng th ng c ki u p ng l V-A-A-V) nhng l i khng ch n on phn bi t c gi a 2 lo i nh p nhanh ph thu c vo nt nh th t l AVNRT v AVRT. o PPI v tnh PPI-TCL n u > 115ms th l AVNRT n u < 115 ms, th ng l ng ph [5][6] M t nghi m php n a gip ch n on phn bi t AVNRT v ORT qua ng ph l Zipes test hay sensed V hay sensed PVC, c ti n hnh nh sau c sau khi sensing 4 QRS c a cn nh p nhanh th s pht ra 1 kch nh p c n His parahisian pacing. Th thu t ny l kch nh p ngo i tm thu th t x y ra ng th i v i i n th His v v i c ng cao vng b His t o dng i n m nh b t c tr c ti p b His. M t m t gy kh c c th t, m t khc xung ng truy n ng c dng n tr c ti p
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nt nh th t v n th t qua b His ph i h p t o nn ph c b QRS h n h p. Lc ny His ang b tr nn n u c kh c c nh ng c dng t nht NTT th t ny th con ng duy nh t ch c th l qua ng ph v s ko kh c c nh n s m hn theo nht NTT th t [5]. Trong tr ng h p b nh nhn ny, kho ng AA trong cn nh p nhanh khng i, ngha l khng c kh c c nh n s m sau nht sensed PVC x y ra ng th i v i His, ta k t lu n Zipes test m tnh v c th lo i tr ng ph . Khi kch nh p c n His th ph i s d ng c ng cao. N u gi m c ng kch nh p, th lc ny xung ng khng cn b t c b His nn kh c c th t t vng vch cao nn QRS gin r ng. Xung ng i n m m th t Ph i r i quay tr ng c kh c c b His. Nh th lm tng th i gian c kh c c nh. Tuy nhin khi c m t ng ph th kh c c ng c dng ln nh x y ra r t nhanh t v tr kch nh p th t m khng ph thu c vo nt nh th t. Kh c c nh khi c ng ph r t nhanh d l His c c kch thch tr c ti p hay khng. Trn b nh nhn ny, theo hnh 7 th t kho ng cch t kch thch n sng nh A nht His khng b t c (QRS gin r ng) di hn kho ng cch t kch thch n sng nh A nht His bt c (QRS h p). i u ny kh ng nh kh c c nh ng c dng b nh nhn ny ch s d ng nt nh th t m khng s d ng ng ph . Ch n on nh p nhanh vo l i t i nt nh th t th ch m nhanh slow-fast, ti n hnh t ng ch m b ng sng cao t n. ng ch m l vng c nh n m d c theo vng van ba l v n m pha sau d i nt nh th t, v l ph n pha sau c a tam gic Koch n m trn ph n vch c xc l p b i l xoang vnh l y v 2 c nh l gn Todaro v vng van ba l [2][7]. t ng ch m c Jackman m t l n u tin trn bo vo nm 1992 nhng tr c David Ross Sydney l n u tin m t i u tr AVNRT b ng ph u thu t nm 1985. C 2 phng cch t ng ch m: mapping i n th ng ph v d a vo gi i ph u. i n th ng ch m c Jackman m t l sng bin th p, t n s th p theo st sau b i sng t n s cao bin cao nhng th p n m d i nt nh th t v tr c Haissaguerre m t l cc sng t n s th p, bin l xoang vnh. Tuy v y, v n cn nhi u tranh ci quanh i n th ng ch m. Mapping d a vo gi i ph u ang p d ng r t ph bi n. Catheter t n m d a vo m t nh c a van ba l n m tr c l xoang vnh v d i nt nh th t ghi c sng nh cao t n v t l sng nh/ th t < 0,5. V sao Catheter t n m nh l i ghi c c sng nh v th t. Cu h i ny r t t ti li u c p t i. Theo Kalman m t trong nh ng nh electrophysiologist hng u th gi i (Melbourne) th ng ch m n m trn vch c nh th t do van ba l n m th p hn so v i van hai l. K t h p v tr gi i ph u ( hi ln trn v ra tr c l xoang vnh) v hnh thi i n tm ( sng th t l n v sng nh nh nhng c d ng nh n v lm) th ng gip tm ra v tr ch. Hnh 8 cho th y p ng i v i t tri t b b ng sng cao t n. Khi t v i sng cao t n, th nh p b n i xu t hi n. S xu t hi n c a nh p b n i l d u hi n c a t tri t b ng ch m thnh cng. y l d u hi u c nh y c m cao nhng khng c hi u, ngha l khng c th kh nng khng thnh cng cao, nhng c th cng cha h n l thnh cng. M t nghin c u cho th y cc tr ng h p t thnh cng th 100% c nh p b n i, nhng l i c 65% nh ng tr ng h p t khng thnh cng c nh p b n i. Kalman cho r ng kh nng thnh cng n u nh p b n i ko di v c s nht nh p b n i nhi u[8]. Quan st s hi n di n lin t c c a kh c c nh ng c dng 1:1 l r t quan tr ng. N u th y c bl c VA ng c dng th ph i ngng t ngay v nguy c cao c a tai bi n b c nh th t (kho ng 0,5 n 1% n u t t i v tr l xoang vnh). N u xu t hi n nh p nhanh b n i
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th ph i ng ng t ngay v lo i nh p ny th ng i km v i bl c nh th t. Trn b nh nhn ny, t tri t b thnh cng, nh p nhanh khng cn xu t hi n d chuy n isoproterenol. Lu l hi n nay h u h t cc trung tm EP ch p nh n r ng n u nh p nhanh khng cn xu t hi n d chuy n oproterenol th d c cn 1 nht echo v n ch p nh n l tri t b thnh cng[8]. K t lu n y l tr ng h p i n hnh c a cn nh p nhanh vo l i t i nt nh th t th ch m nhanh, th hay g p nh t. Tri u ch ng lm sng, c t cn v i nghi m php Valsava v T 12 chuy n o l nh ng d u ch ng kinh i n c a th cn nh p nhanh ny. M t s tiu chu n ch n on bao g m s hi n di n c a ng ch m (dual AV physiology), kh i pht cn nh p nhanh ph thu c vo kho ng AH, s d ng cc nghi m php ch n on phn bi t v i nh p nhanh nh v ng ph gip xc nh ch n on. V t l t tri t b thnh cng AVNRT ln n 98%, nn v n ch n on chnh xc v i u tr t b ng sng cao t n ph i c n th n. Bi n ch ng tuy hi m v n c th x y ra. M t trong nh ng bi n ch ng n ng n nh t l Bl c nh th t chi m 1-2% cc tr ng h p. Hi u bi t y v gi i ph u c a nh ph i, c bi t l tam gic Koch l r t quan tr ng. B nh nhn ph i c gi i thch c n k nguy c bl c d n truy n d l th p km v i cc nguy c bi n ch ng khc khi ch c m ch v a catheter. Cc bi n th khc c a cn AVNRT i n hnh c th x y ra nh th fast-slow s d ng ng nhanh (c u trc n m pha tr c nt nh th t) d n truy n xui dng c a vng vo l i v ng d n truy n ng c dng. Th slow-slow v th n m bn tri cng c y ch m vn m t . D th no i n a th cng c th i u tr thnh cng b ng cch t bi n i ng ch m. an ton tng i v t V t ng ch m b ng sng cao t n l th thu t c l thnh cng cao nn t bi n i ng ch m l ch nh Class I v l li u php i u t bi n i ng ch m tr hng u trn b nh nhn c cn AVNRT c n i u tr . cng c khuy n co p d ng nh ng b nh nhn khng p ng ho c khng dung n p v i i u tr n i khoa. TI LI U THAM KH O: 1. Fogoros. The electrophysiology study in the evaluation and treatment of supraventricular. In: Electrophygiologic testing. Blackwell Publishing, 1999: p.115. 2. McElderry H, Kay N. Ablation of atrioventricular nodal reentry by the anatomic approach. In: Huang S, Wood M (eds). Catheter Ablation of Cardiac Arrhythmias. Philadelphia: Saunders/Elsevier, 2006: pp. 325-346 3. Murgatroyd. Dual AV nodal pathways and AV nodal reentry. In: Handbook of cardiac Physiology. A practical guide to invasive EP study and catheter ablation. ReMEDICA, 2002: p.71-85. 4. Bradley P. Knight, Fred Morady. Diagnostic value of tachycardia features and pacing maneuvers during paroxysmal supraventricular tachycardia. J. Am. Coll. Cardiol. 2000;36;574-582 5. Ziad Issa , Douglas P. Zipes. Approach to paroxysmal supraventricular tachycardias. In: Clinical arrhythmology and electrocardiography. Saunders, 2008: p.377-392.
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NG RA TH T PH I
T Hng Th y Trung tm Tim m ch - BVTW Hu
Tm t t: C r t nhi u nghin c u cho th y t o nh p m m th t ph i c nhi u h u qu tiu c c ln lm sng v huy t ng, gy rung nh v lm gi m ch c nng th t tri. Do , nhu c u tm ki m cc v tr t o nh p m i l m t v n th i s , trong t o nh p ng ra th t ph i t ra l m t v tr t o nh p l t ng. Bi vi t ny phn tch cng nh t ng h p cc d li u ch ng minh tnh u vi t c a t o nh p ng ra th t ph i. Summary: There have been emerging strong evidence showing the deleterious hemodynamic and clinical effects of right ventricular apical pacing due to atrial fibrillation and worsened left ventricle function following conventional permanent cardiac pacing, which directs our attention to alternate sites of pacing. The right ventricular outflow tract is a promising pacing site. Indeed, current convincing data on RVOT pacing as an alternate site ventricular pacing are encouraging and this approach should be actively pursued and further investigated in future studies. u T o nh p m m th t ph i (right ventricular apical pacing RVA pacing) l phng th c t o nh p c p d ng t khi k thu t t o nh p ra i cch y hn 50 nm c u s ng v c i thi n tri u ch ng hng tri u b nh nhn c r i lo n d n truy n kch thch i n c tim k ch pht ho c m n tnh (bl c nh th t, b nh l nt xoang). Tuy nhin, ki u t o nh p ny gy bl c cnh tri (LBBB) i km v i r i lo n ng b co bp (dyssynchony) gi a hai th t v trong th t. M t th p nin tr l i y c nhi u nghin c u cho th y tc ng tiu c c c a t o nh p RVA ln ch c nng c tim v huy t ng cng nh gy rung nh. Do trong nh ng nm g n y, c nhi u v tr t o nh p m i c nghin c u thay th t o nh p RVA, trong t o nh p ng ra th t ph i (right ventricular outflow tract pacing RVOT pacing) c nh c n nhi u nh t v ang c p d ng nhi u cc trung tm t o nh p trn th gi i. Bi vi t ny s phn tch cng nh c p nh ng nghin c u v h n ch c a t o nh p m m ng th i gi i thi u v t o nh p ng ra th t ph i v cc nghin c u so snh 2 v tr t o nh p trn. Nh ng h u qu x u c a t o nh p m m th t ph i T o nh p m m th t ph i gy ra bl c cnh tri v o ng c tr c kh c c bnh th ng c a c tim t m m ln y v t ph i sang tri. LBBB l bi u hi n v m t i n h c c a b t ng b c h c do thnh bn th t tri kh c c ch m hn, lm th i gian kh c c th t ko di ko theo hi n t ng vng kh c c s m vng kh c c mu n d n n tng s c p ln thnh tim lm cng v tiu th oxy c tim ng th i r i lo n ch c nng tm trng v tm thu th t tri[1]. Trong giai o n co ng th tch chi u di c a cc s i c tim thay i khc nhau. Cc s i c g n v tr t o nh p co ng n trong khi cc s i xa gin di, lm khng c a cc s i nng l ng kh c c t v tr t o nh p lan t a gi m d n v g p s c cha kh c c, i u ny gi i thch s b t ng b c h c v r i lo n v n ng vng. Th i gian co ng th tch ko di nh h ng n th i gian t ng mu c a th t. B t ng b gi a vch v thnh sau bn th t tri lm hai c nh kh c c khng ng th i nn hai l van M
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ng l ch nhau d n n h hai l. H hai l i km v i tng kch th c nh tri, sau l rung nh v lm n ng thm suy tim [2]. S b t ng b cng d n n ti phn ph i th tch kh i c tim, vng c g n v tr t o nh p c kh c c s m tr nn m ng i trong khi kh i c xa kh c c mu n dy ln, v lu di d n n r i lo n ti c u trc c tim th t tri, lm dn th t tri v ph i l ch tm th t tri [3]. Tr c kh c c b t th ng t m m ln y tim lm r i lo n dng mu, gi m th tch co bp, ch c nng tm thu v cung l ng tim d n n bi u hi n suy tim trn lm sng v suy tim huy t khng v i i u tr n i khoa [3][4]. Ngoi ra, b t th ng t i mu v v n ng vng, r i lo n nh p th t, tng ho t th n kinh giao c m cng c ghi nh n. C nhi u nghin c u ch ng minh cc h u qu x u c a t o nh p m m th t ph i. T lu t o nh p RVA c ghi nh n lm n ng thm suy tim trn b nh nhn c ch c nng th t tri km v b nh tim th c th , cc nghin c u g n y cn ch ng minh nh h ng c trn ng i c ch c nng th t tri bnh th ng [5]. Thambo theo di trn b nh nhn tr tu i b bl c nh th t hon ton b m sinh c t o nh p DDD v i i n c c th t ph i t i m m sau trung bnh 10 nm cc tr s ph n nh b t ng b trong th t, ti c u trc, dn v ph i th t tri km gi m cung l ng tim v kh nng g ng s c u bi n i c ngha so v i nhm ch ng [4]. Hitoshi v cs theo di 76 b nh nhn khng c b nh tim th c th c t o nh p DDD ( i n c c th t m m) v i 30 b nh nhn h i ch ng nt xoang b nh l c 3 6 % kch nh p th t (so v i nh p n i t i) v 46 b nh nhn bl c nh th t c 100% 2 % kch nh p th t. Ch s Tei th t ph i v tri, kch th c tm trng th t tri v BNP tng c ngha nhm kch nh p th t cao[5]. Nghin c u c a Nielsen trn 177 b nh nhn so snh t o nh p AAIR v DDDR/ VVIR cho th y l i ch lm sng r r t c a AAI v khng gy b t ng v n th t tri. Nhm b nh nhn DDDR c AV delay ng n gy kch nh p th t ph trn 90% th ghi nh n c nh tri dn, rung nh v co h i th t tri LVFS gi m. Khc bi t gi a VVIR v DDDR t r rng v c l tc d ng ng b nh th t c a DDDR b tc h i c a b t ng b th t do t o nh p m m th t ph i lm lu m [4][6]. B ng 1. Cc nghin c u lm sng v tc d ng khng c l i c a t o nh p m m th t ph i S l ng Tu i tr Th i Kch Ch c b nh bnh gian th c nh nng th t Suy Rung Nghin c u nhn tri tri tim nh (nm) (nm) Tantengco et al. Karpawich et al. 24 14 19.5 15.5 9.5 5.5 NA NA Thay i c u trc m /DS /MPD /SNA NA NA NA NA 2 NA NA NA
Thambo et al. Tse et al. Hamdan et al. DAVID MADIT II Substudy Wonisch et al. Thackray et al.
23 12 13 506 567 17 307
24 72 66 64 64 59 72
10 1.5 NA* 1 1.7 0.25 5.2
NA NA NA NA NA NA NA
NA NA NA **
NA NA NA NA NA NA
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MOST Nielsen et al.
1,339 177
74 74
6 2.9
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O'Keefe et al. 59 69 1.5 NA NA NA DS = dyssynchrony r i lo n ng b ; MPD = myocardial perfusion defects khi m khuy t t i mu c tim; NA = not available/ not assessed cha cng b /khng nh gi; SNA = sympathetic nerve activity ho t ng th n kinh giao c m. * Nghin c u trong giai o n u **T o nh p th t ph i lm gi m kh nng ho t ng th l c. Tc h i c a b t ng b do t o nh p th t ph i cn c ghi nh n cc nghin c u DAVID, MOST v nhnh c a nghin c u MADIT -II . N u nh p tim b nh nhn c > 40% t o nh p m m th t ph i th c t l rung nh, suy tim, nh p vi n v t vong gia tng [7][8]. Nghin c u MOST cho th y d duy tr ng b nh th t b ng t o nh p DDD, nhng nhm b nh nhn c t o nh p th t > 40% th i gian c nguy c nh p vi n do suy tim tng hn 2,6 l n so v i nhm c t l t o nh p th t th p hn. Nghin c u MADIT-II theo di t o nh p sau 20 thng trn b nh nhn c ch c nng th t tri gi m sau nh i mu, 369 b nh nhn c t l nht bp do t o nh p m m th t ph i > 50 % c t l suy tim m i ho c n ng ln cao hn (30% vs 17%, P = 0.002; hazard ratio 1.9), suy tim v t vong cao hn (50% vs 20%, P = 0.004; hazard ratio 1.8) so v i nhm c t l t o nh p m m th t ph i th p. n t ng hn c c l l nghin c u c a Thackray trn 307 c t o nh p m m th t ph i ghi nh n c 54% c tri u ch ng suy tim, 31% c EF <40% . Sau 10 nm t n su t suy tim tng t 24 n 38%, rung nh tng t 26% n 45% [9]. Theo Sweeney trong nhm nghin c u MOST, ngoi y u t b nh tim th c t n nh rung nh, suy tim, nh i mu, nguy c nh p vi n do suy tim cn nh h ng b i cc r ng QRS do t o nh p, t l nht bp do t o nh p th t ph i v y u t t o nh p nh th t o nh p lm m t ng b nh th t. Do kh ng ch t l t o nh p th t gip gi m nh p vi n do suy tim nh t l b nh nhn c EF th p v suy tim[10]. Karpawich so snh 8 m u sinh thi t tr c v 8 m u sau trung bnh 5,5 nm t o nh p RVA nhm b nh nhn tr tu i cho th y c s bi n i v c u trc m h c c tim[11]. Nghin c u c a Tse dng x c tim Dipyridamole Tl-201 v ch p th t b ng radionuclide trn b nh nhn t o nh p khng c b nh m ch vnh cho th y c r i lo n t i mu vng v v n ng vng sau 6 thng t o nh p m m th t ph i v i DDD v cng r r t hn sau 18 thng. R i lo n ch c nng tm trng th t tri v gi m s c co bp c th y nh ng vng c tim xa v tr t o nh p[12]. T o nh p ng ra th t ph i v tr t o nh p m i thay th T nh ng h u qu x u c a t o nh p m m, nn trong m t th p nin qua nhi u v tr t o nh p m i c nghin c u nh m h ng t i kh c c th t g n sinh l hn v ng tm hn. Ban u, t o nh p m m c s d ng ph bi n l v k thu t d th c hi n, i n c c th t c nh t t trong c b. Hi n nay, nh ng c i ti n c a cng ngh ch t o i n c c c ng v i s ra i c a i n c c c nh ch ng b ng l xo xo n gip cc nh t o nh p c th c y i n c c nhi u ni trong th t ph i. V bnh th ng vng vch l ni kh c c th t u tin, nn r t logic t o nh p t i y. T o nh p vng vch th t ph i c l p lu n l xung ng s xm nh p m ng Purkinje nhanh hn, rt ng n th i gian kh c c th t, v chi u kh c c sinh l hn. Th c t l h u h t cc v tr t o nh p m i ang p d ng hi n nay u n m vch th t ph i nh vng vch th p, vng
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gi a vch, b His v ng ra th t ph i[1]. Nhng t o nh p cc v tr ny cng g p m t s kh khn nh t nh nh cng ngh c a dy i n c c ph i h tr gip cho k thu t t thu n l i, k thu t t i n c c vo m t s v tr r t kh khn th i gian tia ko di, tn g i cc vng khc nhau trong th t ph i cha c chu n ha v kh khn lin quan n vi c xc nh t ng vo v tr mu n t i n c c hay cha. Vi c l a ch n v tr t o nh p m i cn ph thu c nhi u y u t khc nh k t qu v nh h ng trn lm sng v huy t ng (hi n v n cn ang ti p t c nghin c u), m c kh (th i gian th thu t, th i gian pht tia) hay d th c hi n (trn nhi u b nh nhn khc nhau v h u h t cc bc s c th th c hi n c), ho t ng i n c a dy i n c c nh ng ng, bin sng v i n tr thu n l i v n nh c trong th i i m t my l n v lu di. Trong s cc v tr t o nh p m i, t o nh p ph n vch ng ra th t ph i c nhin c u nhi u nh t. Cch y khng lu, cng khng ph i d t o nh p v tr th c s l vng vch ng ra th t ph i. Nhng hi n chng ta hi u r hn c u trc gi i ph u ng ra th t ph i v m i lin h v i hnh nh fluoro v i n tm , gip xc nh t dy i n c c vo v tr vch ng ra th t ph i [13]. ng ra th t ph i lu nay khng c m t k trong y vn. Tr c y ng i ta dng thu t ng t o nh p ng ra th t ph i ch nhi u v tr t o nh p khc nhau ng ra th t ph i th t s , gi a vch v vng trn m m. D c r t nhi u bao g m n l c chu n ha thu t ng cc v tr t o nh p khc ngoi m m [14], s l n l n ny v n cn ph bi n nn m t s k t qu nghin c u t o nh p ng ra th t ph i giai o n u v giai o n sau c nh ng k t qu khc nhau. Ngay c khi xc nh ng ng ra th t ph i, th b n thn c u trc ny cng kh ph c t p v r t c n phn bi t r u l vch, u l thnh t do v thnh tr c v chi u kh c c v d ng sng kh c c cng r t khc nhau khi t o nh p t cc v tr ny. Theo di ng n h n v trung h n t o nh p vng vch ng ra th t ph i u cho th y k t qu r t t t v lm sng v huy t ng so v i t o nh p m m[12][15] K t qu ny khc bi t v i k t qu c a m t s nghin c u cng g i l t o nh p ng ra th t ph i nhng khng xc nh chnh xc l t v tr no c a ng ra th t ph i[15][16]. i u ny ch ng t ch c t o nh p t vng vch c a ng ra th t ph i m i cho k t qu t t. Trn quan i m t o nh p, ng ra th t ph i c gi i h n pha trn l van ng m ch ph i pha d i l m t trn c a van ba l. ng ra th t ph i th ng c m t m t cch n gi n ha c b n m t l trn, d i, thnh t do v vch[14]. Th c ra, m t c g i l vch ng ra th t ph i l 1 thu t ng khng chu n v ph n l n m t ny n m trn van ng m ch ch . Theo nh ngha gi i ph u chu n th c u trc vch l c u trc khi c t b khng lm thng thng tim t trong ra ngoi nn ch c ph n d i c a vch m i ng l vch c a ng ra th t ph i. C u trc vch n m trn van ng m ch ch l nn ng m ch conus arteriosus c thnh trn lng nn khng thch h p c m y i n c c. D i m c mo trn th t (crista supraventricularis) l ph n d i c a vch. l c u trc n m bn tri b vch b septomarginal trabeculation d ng ti c nhi u c b vch thnh septoparietal trabeculations l v tr l t ng c m dy i n c c. T kinh nghi m thm d i n sinh l v t cc lo n nh p gy nh p nhanh ng ra th t ph i, chng ta c cc nghin c u v cc c i m v hnh d ng i n tm t cc v tr khc nhau ng ra th t ph i[17]. Cng v i hnh nh fluoro, hnh d ng i n tm s c ng d ng sang t o nh p v s gip phn bi t gi a t o nh p t vch
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v t m t tr c thnh bn[13]. T o nh p t m t tr c thnh bn s khng sinh l v m t i n h c gy b t ng b ( QRS dn r ng) m v tr ny cn r t g n v i ng m ch lin th t tr c. Do o c n h t s c trch v tr ny trong th c hnh. T o nh p t vch ng ra th t ph i cho vector m ho c ng i n DI trong khi t thnh tr c bn th vector dng DI, QRS dn r ng v c mc chuy n o sau d i, nh t l DIII. xc nh b ng fluoro th c n ch p cc t th tr c sau, ch ch ph i 40 gip trnh i vo xoang vnh v TM great cardiac v ch ch tri 40 gip phn bi t vch v thnh bn. N u u dy i n c c h ng ra sau th l vo vch v ng c l i. Ch p nghing tri 90 xc nh vo vch c c hi u 100% n u u dy i n c c lui sau [13]. Theo y vn, QRS do t o nh p t vng vch ng ra th t ph i h p hn b t k v tr no trong th t ph i c bi t l thnh bn c a ng ra th t ph i[13]. Nh th d khng l t ng nh d n truy n c a nh p n i t i, nhng vng vch ng ra th t ph i v n l v tr t o nh p ao c v t o ra QRS h p ngha l gi m th i gian kh c c th t do t gy b t ng b kh c c th t hn v r i lo n huy t ng th t tri[12][13][15][17]. Hn n a, theo Karparwich t o nh p vnh vi n t vng vch t gy bi n i v m t m t m t bo nh g p t o nh p m m nn mang l i l i ch lm sng nhi u hn. Th t v y, cc nghin c u ng n h n[11] v trung h n[12][15] ( di h n ang trong th i gian nghin c u) t o nh p ng ra th t ph i m xc nh r t vng vch th cho th y k t qu r t t t so v i t o nh p m m v lm sng, huy t ng v ch c nng i n h c c a i n c c. K thu t c m dy i n c c vo vng vch c a ng ra th t ph i s d ng i n ng h ng ra sau. C th dng Select Secure Medtronic Inc. c c xo n vt ch Minneapolis, US l i n c c khng lng 4,1 Fr a qua h th ng 10 Fr Select Site, Medtronic Inc. Tr ng i l n nh t l tnh an ton v ho t ng i n c a i n c c khng m b o. Hn n a h th ng ny khng quen i v i nh ng nh t o nh p v i h i th i gian o t o lu. Hi n nay, nhi u trung tm trn th gi i trong c Royal Melbourne (Australia) s d ng i n c c thng th ng 7 Fr u n v i hnh d ng c bi t c m vo vch ng ra th t ph i. Hary Mond t i Melbourne pht minh ra stylet t bi t mang tn ng ( FDA ch p thu n ) gip t thnh cng g n nh 100% tr ng h p v i learning curve r t ng n. Theo m t t ng k t v a c cng b th khng c tr ng h p no ri i n c c c i th l n vi th . Ho t ng i n c a i n c c r t ng khch l v i ng ng lc t trung bnh l 0,84 V 0,4, sau 1 ngy l 0.55 V, sau 6 thng 0.68 V v 0.71 V sau 1 nm. Khng c tr ng h p no tng ng ng b t th ng sau khi t v khng c exit bl c. nh n c m sng R v i n tr k t qu t t v n nh [18]. V c i m gi i ph u c a v tr vch ng ra th t ph i nn v l thuy t l khng th c bi n ch ng th ng tim, vim mng ngoi tim, trn mu mng ngoi tim, hay kch thch c honh x y ra. Th c t , t ng k t t i Royal Melbourne th cng khng ghi nh n bi n ch ng n ng n x y ra v khng c t vong lin quan n t my. K t qu ny cng tng t nh k t qu cng b c a Vlay ( New York)[16]. Hi n cc nghin c u v nh h ng c a t o nh p vnh vi n ng ra th t ph i trn lm sng v huy t ng ang d n c cng b . Nghin c u a trung tm Rennes v Clermont Ferrand Php trn b nh nhn c EF < 45% th t o nh p vng vch b o t n ch c nng th t tri hn l t o nh p m m (42 5% versus 37 4% P < 0.001)[15]. Theo Hung-Fat Tse v Chu Pak Lau, th t o nh p ng ra th t ph i b o t n kh c c ng b (134 4 ms vs. 151 6 , p < 0.03) v ngn ng a c h u qu b t th ng t i mu v
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gi m ch c nng th t tri sau t o nh p vnh vi n m m[12]. Theo cng b c a Haoying Shi v Fang Wang [19] (Th ng H i, Trung Qu c) so snh ch s global systolic contraction amplitude (GSCA) o trn siu m tissue Doppler d a vo bin co h i trung bnh c a 16 vng th t tri ghi nh n t o nh p ng ra th t ph i l 5.66 1.00 mm cao hn so v i m m (4.82 0.94 mm,p < 0.05) v vng vch th p (4.82 1.07 mm, p < 0.05). Quan st trn siu m cn th y gi m v n ng d c thnh bn, sau v d i t o nh p m m so v i t o nh p ng ra th t ph i v trn b nh nhn t o nh p m m v vng vch th p v n ng c tim theo d ng ch M v c sng m cu i th tm trng thnh bn, sau v d i. Nghin c u c a Marsh v Gammage [20] (Birmingham,UK) trn siu m cho th y t o nh p vng vch c ch c nng th t tri t t hn m m sau 18 thng t o nh p. Tm l i, t o nh p m m r rng c nh ng nh h ng n ng n ln lm sng, huy t ng ch c nng th t tri. D cc nghin c u di hi v nh h ng c a t o nh p vng vch ng ra th t ph i ln th t tri cha cng b , nhng r rng l v m t l lu n, v theo k t qu nghin c u ban u th t o nh p ng ra th t ph i cho k t qu t t hn t o nh p m m. Hy v ng trong th i gian t i, khi cc nghin c u lu di v nh h ng c a t o nh p vch ng ra th t ph i trn lm sng, huy t ng v ch c nng th t tri cho nh ng k t qu tch c c c ng v i nh ng k t qu r t kh quan v k thu t v cc thng s v ho t ng i n h c c a i n c c c cng b , c th ni t o nh p ng ra th t ph i h a h n l v tr t o nh p th t ph i c a hi n t i v tng lai. TI LI U THAM KH O 1. Kaye, Stampler, Yee. Search for the Optimal RV Pacing Site: Design and Implementation of Three Randomized Multicenter Clinical Trials. PACE 2009; 32:426433 2. S. Serge Barold; I. Eli Ovsyshcher. Pacemaker-Induced Mitral Regurgitation. Pacing Clin Electrophysiol. 2005;28(5):357-360. 3. Thambo JB, Bordachar P, Garrigue S, Lafitte S, Sanders P, Reuter S, Girardot R, et al. Detrimental ventricular remodelling in patients with congenital complete heart block and chronic right ventricular apical pacing. Circulation 2004; 110:37663772. 4. Barold SS. Adverse effects of ventricular desynchronization induced by longterm right ventricular pacing. Am J Cardiol 2003; 42:624626 5. Hitoshi Ichiki. Effect of Right Ventricular Apex Pacing on the Tei Index and Brain Natriuretic Peptide in Patients with a Dual-Chamber Pacemaker. PACE 2006; 29:985990 6. TNielsen JC, Kristensen L, Andersen HR. A randomized comparison of atrial and dual chamber pacing in 177 consecutive patients with sick sinus syndrome: echocardiographic and clinical outcome. J Am Coll Cardiol 2003;42: 61423. 7. The DAVID Trial Investigators. Dual-chamber pacing or ventricular backup pacing in patients with an implantable defibrillator: The dual chamber and VVI implantable defibrillator (DAVID) trial. JAMA 2002; 285:3115-3123. 8. Sweeney MO, Hellkamp AS, Ellenbogen KA, et al. for the MOST Investigators. Adverse effect of ventricular pacing on heart failure and atrial fibrillation among patients with normal baseline QRS duration in a clinical trial of pacemaker therapy for sinus node dysfunction. Circulation 2003; 107:2932-2937. 9. Thackray SDR, Witte KKA, Nikitin NP, Clark AL, Kaye GC, Cleland JGF. The prevalence of heart failure and asymptomatic left ventricular dysfunction in a
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typical regional pacemaker population. Eur Heart J 2003; 24:1143-1152. 10. Michael O. Sweeney, MD; Anne S. Hellkamp, MS. Heart Failure During Cardiac Pacing. Circulation. 2006;113:2082-2088. 11. Karpawich PP, Rabah R, Haas JE. Altered cardiac histology following apical right ventricular pacing in patients with congenital atrioventricular block. Pacing Clin Electrophysiol 1999; 22:1372- 1377. 12. Tse HF, Yu C, Wong KK, et al. Functional abnormalities with permanent right ventricular pacing. J Am Coll Cardiol. 2002;40:14511458 13. Hary Mond. Right Ventricular Outflow Tract Pacing: Radiographic and Electrocardiographic Correlates of Lead Position. PACE 2006; 29:10631068. 14. Lieberman, Mond, Gammage. Selective Site Pacing: Defining and Reaching the Selected Site. PACE 2004; 27[Pt. II]:883886 15. Victor F, Mabo P, Mansour H, et al., A randomised comparison of permanent septal versus apical right ventricular pacing:short-term results, J Cardiovasc Electrophysiol, 2006; 17:23842 16. Vlay SC, Right ventricular outflow tract pacing: practical and beneficial. A nine-year experience of 460 consecutive implants, Pacing Clin Electrophysiol, 2006; 29:105562. 17. Dixit, Marchlinski. Electrocardiographic Patterns of Superior Right Ventricular Outflow Tract Tachycardias: Distinguishing Septal and Free-Wall Sites of Origin. J Cardiovasc Electrophysiol, Vol. 14, pp. 1-7, January 2003 18. Hary Mond. Right Ventricular Outflow Tract Septal Pacing: Long-Term Follow-Up of Ventricular Lead Performance. PACE 2009; 32:172176. 19. Haoying Shi, Fang Wang. Improved lt ventricular mechanical synchrony and systolic performance during right ventricular outflow tract pacing versus apical and low septum. Heart Rhythm, Vol 3, No 5, May Supplement 2006. P3-43. 20. Marsh v Gammage.Benefits of right ventricular septal over apical lead placemenet after 18 months of pacing: implicat ions for echocardiographic assessment of leff ventricular function. Heart Rhythm, Vol 3, No 5, May Supplement 2006. P3-44.

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Bl c nhnh tri hon ton

HOI NGH TIM M CH MIEN TRUNG M RONG LAN TH V

HOI NGH TIM M CH MIEN TRUNG M RONG LAN TH V

HOI NGH TIM M CH MIEN TRUNG M RONG LAN TH V

B ng 11: Cc tiu chu n ph

i n th chuy n R I + S III RI R aVL R aVF Q ho c S aVR

HOI NGH TIM M CH MIEN TRUNG M RONG LAN TH V

i c bl c nhnh ph i o tr c tim (tr c

HOI NGH TIM M CH MIEN TRUNG M RONG LAN TH V

HOI NGH TIM M CH MIEN TRUNG M RONG LAN TH V

HOI NGH TIM M CH MIEN TRUNG M RONG LAN TH V

M T S Y U T NGUY C LIN QUAN N NGUY C B NH L M CH VNH TRONG 10 NM T I T I C NG NG T NH TH A THIN HU

HOI NGH TIM M CH MIEN TRUNG M RONG LAN TH V

HOI NGH TIM M CH MIEN TRUNG M RONG LAN TH V

HOI NGH TIM M CH MIEN TRUNG M RONG LAN TH V

7.79 4.35 2.34 R i loan Ht lipide t hu c l T HA Beo phi i t ho L i s ng ng t inh t ai

HOI NGH TIM M CH MIEN TRUNG M RONG LAN TH V

HOI NGH TIM M CH MIEN TRUNG M RONG LAN TH V

250 200 150 100 50 0 0

y = 1.5084x + 111.81 R2 = 0.3709

Hnh 3.2. Tng quan gi a nguy c BMV sau 10 nm v i huy t p tm thu

Hnh 3.3. Tng quan gi a nguy c BMV sau 10 nm v i huy t p tm trng

HOI NGH TIM M CH MIEN TRUNG M RONG LAN TH V

HOI NGH TIM M CH MIEN TRUNG M RONG LAN TH V

HOI NGH TIM M CH MIEN TRUNG M RONG LAN TH V

HOI NGH TIM M CH MIEN TRUNG M RONG LAN TH V

HOI NGH TIM M CH MIEN TRUNG M RONG LAN TH V

HOI NGH TIM M CH MIEN TRUNG M RONG LAN TH V

HOI NGH TIM M CH MIEN TRUNG M RONG LAN TH V

l i l p m lt thnh sau h ng h nh nhn l i ami an

HOI NGH TIM M CH MIEN TRUNG M RONG LAN TH V

HOI NGH TIM M CH MIEN TRUNG M RONG LAN TH V

HOI NGH TIM M CH MIEN TRUNG M RONG LAN TH V

HOI NGH TIM M CH MIEN TRUNG M RONG LAN TH V

HOI NGH TIM M CH MIEN TRUNG M RONG LAN TH V

HOI NGH TIM M CH MIEN TRUNG M RONG LAN TH V

HOI NGH TIM M CH MIEN TRUNG M RONG LAN TH V

HOI NGH TIM M CH MIEN TRUNG M RONG LAN TH V

HOI NGH TIM M CH MIEN TRUNG M RONG LAN TH V

HOI NGH TIM M CH MIEN TRUNG M RONG LAN TH V

CH N L A STATIN NO L T I U TRONG D PHNG TIN PHT V TH PHT B NH TIM M CH?

HOI NGH TIM M CH MIEN TRUNG M RONG LAN TH V

tr li u trung 80 mg 45% 33% 33% 42% 55% 58%

HOI NGH TIM M CH MIEN TRUNG M RONG LAN TH V

HOI NGH TIM M CH MIEN TRUNG M RONG LAN TH V

HOI NGH TIM M CH MIEN TRUNG M RONG LAN TH V

HOI NGH TIM M CH MIEN TRUNG M RONG LAN TH V

HOI NGH TIM M CH MIEN TRUNG M RONG LAN TH V