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DIABETIC CARDIOMYOPATHY
Prof. Nguyen Hai Thuy. MD, PhD DEMA-CVN.COM Hue College of Medicine and Pharmacy
Congestive heart failure in diabetic patient without CAD and HTN. HbA1c : 8%, BP: 110/70 mmHg IVSd: 1.06 cm, IVSs: 1.23 cm
LA: 4.29 cm, LVMI :180 g/m2, EF :20.5%
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I.INTRODUCTION
Diabetes is observed in 15% to 25% of HF patients in major clinical trials. Among all patients hospitalized for heart failure, 25% to 30% patient have DM as a comorbid condition In large-scale mortality trials, in HF patients with systolic dysfunction, diabetes was an independent risk factor for death.
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Framingham Study
1. A direct association between DM and HF was first demonstrated 2. Risk of developing symptomatic HF
2.4-fold in diabetic men 5-fold in diabetic women,
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Gender-specific cardiovascular protective effects can be considered to be mitigated once overt diabetes develops in women.
W H. Wilson Tang, MD, and James B. Young, MD ENDOCRINOLOGY AND METABOLISM CLINICS OF NORTH AMERICA, VOLUME 30 NUMBER 4 DECEMBER 2001
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Some diabetic patients do not have obvious ischemic insults that lead to progressive HF. A number study challenged that Diabetic patients may have more diffuse and severe coronary insufficiency than nondiabetic patients. Every 1% increase in the baseline glycosylated hemoglobin level translates into a 15% increase in risk of developing HF
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Leyden E.(1881) commented that HF was a frequent and noteworthy complication of diabetes mellitus. Mayer J. (1888) stated that heart disease in diabetes can be traced to an abnormality in metabolism. Rubler S.(1972) coined the term diabetic cardiomyopathy after performing post mortem studies in 4 diabetic patients with cardiac failure, having excluded alcohol, hypertension, and coronary and structural heart disease as possible aetiologies.
Diabetic Cardiomyopathy
Clinical Evidence
Over 30 years ago 4 diabetic patients with CHF, normal coronary arteries, and no other etiologies were proposed as having diabetic cardiomyopathy. (Rubler et al. , Am J Cardiol 1972) Diabetic cardiomyopathy is a unique entity, unassociated with coronary artery disease, characterized by diastolic dysfunction. It is rarely clinically apparent unless associated with hypertension (Bell, Diabetes Care 1995)
Diastolic dysfunction can be recognized in type II diabetics, in the absence of concomitant hypertension, in a proportion ranging from 30% to 60% (Nicolino 1995, Di Bonito 1996, Poirier 2001)
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1.Cardiomyocytes
cardiomyocyte hypertrophy and interstitial fibrosis in all except two samples. mitochondrial degeneration and fatty infiltration of the myofibrils to contraction band formation, perivascular and interstitial oedema and myocytolysis.
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Mild myocardial fibrosis stained with Masons trichrome. (A) Perivascular fibrosis in diabetic heart. (B) Mild fibrosis between myofibres.
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2.Myocardial microvessels
A study of human diabetic myocardium found two characteristic abnormalities in myocardial capillaries: endothelial swelling and/or degeneration and thickening of the capillary basement membrane
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Myocardial fragment stained with hematoxylin and eosin shows arteriolar hyalinization.
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Electronmicrograph of a myocardial capillary from a diabetic patient, demonstrating luminal occlusion with basement membrane thickening. DEMA-CVN.COM Diabetic cardiomyopathy. Clinical Science (2009)116:741-760
Fibrosis
HYPERGLICEMIA Accumulation of AGEs Disturbed Ca++ handling Cross linking of collagen FIBROSIS DIASTOLIC DYSFUNCTION
Hypertrophy
Bell Diabetes Care 2003
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MICRO vessels
TISSUE perfusion/metabolism
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2005 by American Physiological Society
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The metabolic pathways in cardiomyocyte. ADP, adenosine diphosphate; ATP, adenosine triphosphate; FFA, free fatty acids; CPT-1, carnitine palmitoyl transferase-1.
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Malonyl-CoA, inhibits CPT-1 and FA oxidation. AMP-activated kinase (AMPK) inhibits ACC, relieves its inhibition on CPT-1, and promotes FA oxidation. DEMA-CVN.COM Malonyl-CoA decarboxylase (MCD), through decreasing malonyl- CoA by decarboxylating it to acetyl-CoA, enhances CPT-1 and FA oxidation.
DEMA-CVN.COM insulin receptor substrate (IRS) , protein kinase-B (PKB). pyruvate dehydrogenase (PDH), Phosphofructokinase-1 (PFK1),
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1.Hyperglycemia
ROS : reactive oxygen species, PARP: poly(ADP-ribose) polmerase DEMA-CVN.COM GAPDH: enzyme Glyceraldehyde-3 phosphate dehydrogenase
ROS and NO
The elevation of ROS leads to cellular damage by oxidation, disruption of vascular homoeostasis through interference with NO and, most recently, by modulation of detrimental intracellular signalling pathways. ROS have been implicated in all stages of the development of HF, from cardiac hypertrophy to fibrosis, contractile dysfunction and failure. Increased ROS causes cardiac dysfunction by direct damage to proteins and DNA inducing PARP [poly(ADP-ribose) polymerase] as well as by promoting apoptosis. DEMA-CVN.COM
PARP
(Poly(ADP-ribose) polymerase)
PARP enzymes are overactivated in diabetes as a reparative response to ROS-induced oxidative damage to DNA. PARP inhibits GAPDH (glyceraldehyde- 3-phosphate dehydrogenase), which leads to accumulation of glycolytic intermediates, which inturn activate a series of transducers which inflict tissue damage via AGE formation and PKC (protein kinase C) activation PARP also promotes cardiac damage by activating NFB (nuclear factor B) and inducing overexpression of the vasoconstrictor ET (endothelin)-1 and its receptors . DEMA-CVN.COM
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Protein Kinase C
Increased cardiac Impaired relaxation; Increased hypertrophy; increased extra increased ventricular DEMA-CVN.COM protein kinase C cellular stiffness
Hexosamine pathway
Polyol pathway
Decreased regeneration of reduced Increased polyol glutathione leading flux to oxidative stress; increased DNA fragmentation sorbitol-induced AGE DEMA-CVN.COM
Increased AGE
Crosslink RyRs41; Decreased SR calcium release crosslink type III and myocyte contractility; DEMA-CVN.COM collagen increased ventricular stiffness;
2.NEFA
INSULIN RESISTANCE
K ATP Channel
Ceramide
ALTERED MYOCARDIUM
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APOPTOSIS
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3.Hyperinsulin
Cardiovascular targets and actions of insulin.
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Alternative pathways whereby compensatory hyperinsulinemia contributes to myocyte hypertrophy through the sympathetic nervous system activation and MAP kinase/ERK DEMA-CVN.COM pathways at a time when insulin receptor mediated Akt-1 activation is impaired.
Pathway-selective insulin resistance in PI3K signaling creates imbalance between prohypertensive and antihypertensive vascular actions of insulin exacerbated by compensatory hyperinsulinemia.
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2007 by Endocrine Society
Catechols, Cortisol
Lipolysis
Insulin
Phospholipids
Lysophospholipids
Membrane Damage
Ca2+ overload
Enzyme loss
Arrhythmias
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Endothelial dysfunction Impaired endothelial NO production and increased vasoconstrictor prostaglandins, glycated proteins, endothelium adhesion molecules and platelet and vascular growth factors enhance vasomotor tone and vascular permeability and limit growth and DEMA-CVN.COM remodelling
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Arterial stiffness Increased central aortic pressure and left ventricular afterload and lowered central diastolic and coronary perfusion pressures, leading to subendocardial ischaemia and interstitial fibrosis. DEMA-CVN.COM
Autonomic neuropathy
CAN (cardiac autonomic neuropathy)
Decreased sympathetic/parasympathetic myocardial innervation with impaired coronary resistance vessel vasodilator response DEMA-CVN.COM and impaired ventricular diastolic filling .
Study of heart rate variability (HRV) in type 2 diabetic patients by Holter ECG
NTDong, NHThuy, HVMinh, LTB Thun (2003-2005)
decreased HRV Normal HRV
n DM Non-DM Total 40 10 51
% 36,7 20,0
n 69 40 108
% 63,3 80,0
Total 109 50
2 = 4,43
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Aldosterone-induced fibrosis Myofibroblast growth with interstitial and focal perivascular accumulation of collagen.
HIF-1/VEGF HIF-1 activation via hypoxia/free radicals induces angiopoietin, PGF, PDGF- and VEGF but, in diabetes, VEGF and its receptors, VEGF-R1 and VEGF-R2, are decreased significantly , leading to impaired angiogenesis.
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80 70 60
T l (%)
Essex UK study
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Gi tr bnh thng
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LVMI of diabetic patient before and after treating with high doses of vitamin B1
(143 g/m2 vs 116 g/m2)
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1. DIASTOLIC DYSFUNCTION
Figure 2 Trans-mitral valve spectral Doppler flow pattern in a normal subject (upper panel), in a patient with mild diastolic dysfunction (abnormal relaxation; middle panel), and in a patient with severe (restrictive) diastolic dysfunction (lower panel) In the upper panel, the E/A wave ratio is approx. 1.5 to 1.0, and in the middle panel the E/A wave ratio is <1.0. In the lower panel, the E/A wave ratio is abnormally high and A wave velocity is very low.
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JACC 2006
Diastolic dysfunction
Echocardiography study of 48 nonhypertensive type 2 diabetic patients (Nguyen Hai Thuy, Nguyen Quoc Viet-2003) Prevalence of diastolic dysfunction : 81,25% in which first degree was 70,83%
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Normal
Normal diastolic function and diastolic dysfunction (obesity) by tissue doppler echography
Raev D.C. (1994) : diastolic dysfunction more frequent and early than systolic dysfunction in type 1 diabetic patients Poirier P and al (2001) : study of diastolic dysfunction in diabetic patients without HTN showed that diabetic cardiopathy is special cardiomypathy, independent with CAD and HTN.
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Prevalence of LVH with LVMI ( male >125g/m2 and female > 110 g/m2) was 40%
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3. SYSTOLIC DYSFUNCTION
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Christina Voulgari. (2010) , Diabetic cardiomyopathy Vascular health and risk DEMA-CVN.COM management 2010:6 883-903
There was correlation between (1) Tei index with duration of diabetes (r=0,243; p<0,05) and HbA1c (r=0,673 p<0,0001) (2) LVMI with duration of diabetes (r=0,465; p<0,01) and HbA1c (r=0,608; p<0,0001),
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MBF (ml/min/g)
, Bellina et al., J Nucl Med 1990
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Increased relative risk of 3.5 times in 5 yrs Dip MBF < 1.36 ml/min/g
6.Cardiac biomarkers
BNP is a cardiac hormone secreted in response to ventricular volume and pressure overload. Although it is both sensitive and specific for congestive HF, it cannot reliably distinguish between systolic and diastolic HF, which limits its diagnostic use in diabetic cardiomyopathy
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Study of plasma NT-proBNP levels in 104 diabetic patients (Nguyen Hai Thuy, Le Thanh Tung, 2010) NT-proBNP levels of diabetic patients with and without LVH (279 227,2 vs 45,72 31,5 pg/ ml, p = 0,001 ). with and without diastolic dysfunction (286,19 230,34 vs 48,44 34,53 pg/ml, p = 0,001 ) With and without systolic dysfunction ( 376,69 299,4 vs 89,75 91,8 pg/ml, p = 0,001 )
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Glycaemic control
Hyperglycaemia increases the level of FFA, oxidative stress,and growth factors, and causes abnormality in substrate supply and utilisation. Hence, diabetes control may be the most basic and important strategy for preventing the development of diabetic cardiomyopathy
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A1c (%)
Fasting (preprandial) plasma glucose Postprandial (after meal) plasma glucose
<7*
6.5
American Diabetes Association. Diabetes Care. 2010;33(suppl 1) Implementation Conference for ACE Outpatient Diabetes Mellitus Consensus Conference Recommendations: Position Statement at http://www.aace.com/pub/pdf/guidelines/OutpatientImplementationPositionStatement.pdf. Accessed January 6, 2006. AACE Diabetes Guidelines 2002 Update. Endocr Pract. 2002;8(suppl 1):40-82.
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Am Coll Cardiol, 2009; 54:422-428, doi:10.1016/j.jacc.2009.04.049 2009 by the American College of Cardiology Foundation
Relationship of Hemoglobin A1C and Mortality in Heart Failure Patients With Diabetes
David Aguilar, MD*,,*, Biykem Bozkurt, MD*,, Kumudha Ramasubbu, MD*, and Anita Deswal, MD, MPH*,,
At 2 years of follow-up, death occurred in 25% of patients in Q1 (HbA1C< 6.4%), 23% in Q2 (6.4% < HbA1c < 7.1%), 17.7% in Q3 (7.1% < HbA1c < 7.8%), 22.5% in Q4 (7.8% < HbA1c < 9.0%), and 23.2% in Q5 (HbA1c >9.0%). DEMA-CVN.COM
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Insulin-Resistant Cardiomyopathy.Clinical Evidence, Mechanisms, and Treatment Options Ronald M. Witteles, MD, Michael B. Fowler, MB, FACC. Stanford, California. Journal of the American College of Cardiology Vol. 51, No. 2, 2008 DEMA-CVN.COM 2008 by the American College of Cardiology Foundation
Tht bi vi OAD
Kt hp thm thuc vin s khng th t c mc tiu iu tr
Cc thuc ung ch lm gim A1c 1-2%
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Insulin Resistance
The extrapancreatic effect of Amaryl
Rate limiting step for glucose utilisation is glucose uptake via GLUT4 transporter Amaryl translocation of GLUT4 transporters from low-density microsomes to plasma membrane of insulin-resistant fat and muscle cells Amaryl appears to peripheral glucose uptake and to mimic the action of insulin
Plasma Adiponectin Plays an Important Role in Improving Insulin Resistance With Glimepiride in Elderly T2DM
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Plasma Adiponectin Plays an Important Role in Improving Insulin Resistance With Glimepiride in Elderly T2DM
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77
70 60 50 40 30 20
44 42
43
28 24
Baseline
Amaryl
Gliclazide
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Single center, openlabel, randomized, cross over study in 22 T2DM patients receiving digoxin (0.125-0.5 mg) for cardiac arrhythmia. After a 1-week runin phase, patients received Amaryl (46 mg QD, n=10) or Gliclazide (240-320 mg, n=12) for 2 weeks before crossing over for a further two weeks.
Ischemic Preconditioning
Protect myocardium independently of an increase in coronary collateral flow intensity of ischemic pain extent of ST segment deviation from baseline severity of regional wall abnormalities Initiate by opening of cardiac K ATP channels(adenosine, K channel openers) Glimeperide, Gliclazide
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The RAAS
Both ACE inhibition and treatment with ARBs reduce total and cardiovascular mortality in diabetic patients . There was a reduction in cardiovascular events in large studies such as RENAAL, HOPE and IDNT (Irbesartan Diabetic Nephropathy Trial), the effect being more pronounced in diabetic compared with nondiabetic patients. CHARM and Val-HeFT studies also demonstrated mortality and morbidity benefits with ARBs which were similar in diabetic and non-diabetic patients.
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ACE inhibitors
ACE -I facilitate blood flow through the microcirculation in fat and skeletal muscles. Improvement of coronary blood flow may be beneficial for microvascular disease related diabetic cardiomyopathy. ACE-I increases the number of perfused capillaries and epicardial perfusion rate, prevents the increase of coronary perfusion pressure and end-diastolic pressure in animal experiments
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ACE inhibitors
The action of ACE -I on angiotensin II may improve fibrosis in myocardium and functional and structural changes of small vessels in diabetes ACE inhibitors have been demonstrated to reduce cardiovascular disease in diabetic patients, particularly in presence of hypertension. Angiotensin receptor blockers may also have similar effects on myocardial fibrosis in diabetic DEMA-CVN.COM subjects
-Blockers
-Blockers (carvedilol) improved insulin resistance and had no effect on HbA1c, Although to date there has not been a study of -blockers in diabetic patients with HF,up to a quarter of patients in the major -blocker trials in HF were diabetic . Subgroup analysis of these trials demonstrated significant mortality and morbidity benefits in diabetic patients.
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Microvascular Dysfunction
A relevant mechanism of metabolic-inflammatory diseases A new target of innovative treatment
Dyslipidemias
Microvessels
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Metabolic
apo A-I, apo A-III HDL LPL TG-lipoprotein lipolysis apo C-III sdLDL apo A-V TG
vascular
ABCA- receptor cholesterol efflux CLA-1/SR-BI receptor reverse C transport transrepression NF-B proinflammatory, pro-leuco-adherent environment, TF transrepression AP-1 ET-1 transcription CYP450 AA metabolism antiinflammatory EET Angiostatic VEGF; bFGF-induced Akt activation; actin cytoskeleton
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Metabolic modulators
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Changing of metabolism in diabetic heart would you accept them? ADP, adenosine diphosphate; ATP, adenosine triphosphate; CPT-1, carnitine palmitoyl transferase-1; FFA, free fatty acids.
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C ch tc dng metformin
AMPK (Adenosine monophosphate activated protein kinase) ACC (Acetyl coa carboxylase) SREBP-1 (Sterol regulatory element binding protein-1)
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Metabolic modulators
Trimetazidine, inhibits an enzyme involved in the oxidation of NEFAs and has been shown to improve LVEF, NYHA functional class and QOL in patients with HF. Perhexiline has demonstrated substantial improvements in LVEF, Vo2max and QOL, but is associated with a risk of hepatotoxicity and peripheral neuropathy . Ranolazine, reduces intracellular Na+ and diastolic Ca2+ overload, thus improving diastolic function, but it has been associated with prolongation of the QT DEMA-CVN.COM interval.
Metabolic modulators
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FFAs are mobilized from adipose tissue to inhibit the uptake of glucose by muscle (including heart muscle). The result is hyperglycemia and increased insulin resistance. Elevated FFAs also act on mitochondria (mito) to cause excess oxygen wastage with formation of ROS. The consequences include mitochondrial and cellular dysfunction (ionic changes, increased cell calcium and sodium). Metabolic interventions decrease insulin resistance, hyperglycemia, and ROS formation to decrease the severity of heart failure DEMA-CVN.COM
PARP which inhibits GAPDH (glyceraldehyde-3-phosphate dehydrogenase). This leads to the accumulation of glucose and other glycolytic intermediates prior to their entry into the Krebs cycle. These intermediaries activate a number of major transducers of hyperglycaemic damage In addition to the direct cytotoxic pathway regulated by DNA injury and PARP activation, PARP also modulates the course of cardiovascular inflammation and injury by regulating the activation ofNF-B and inducing over-expression of ET (endothelin)-1 and ET receptors Blocking PARP activity with two different competitive PARP inhibitors provides a magic bullet approach as it blocks activation of all the major pathways thought to mediate tissue DEMA-CVN.COM diabetes damage in
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Congestive heart failure in diabetic patient before and after treating high doses of vitamin B1 at Hue University Hospital
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Published October 2nd, 2010 in General Interest, Health, Health News, Health and Wellness, Heart, Life, Medical News, Nutrition, Popular ACS.org Garlic oil has significant potential for preventing cardiomyopathy, a form of heart disease that is a leading cause of death in people with diabetes, scientists have concluded in a new study. Their report, which also explains why people with diabetes are at high risk for diabetic cardiomyopathy, appears in ACS bi-weekly Journal of Agricultural and Food Chemistry. Wei-Wen Kuo and colleagues : garlic might protect against heart disease , garlic oil possesses significant potential for protecting hearts from diabetes-induced cardiomyopathy,
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References
1.Sajad A. HAYAT, Billal PATEL, Rajdeep S. KHATTAR and Rayaz A. MALIK Diabetic cardiomyopathy: mechanisms,diagnosis and treatment Clinical Science (2004) 107, 539557 2.TK Mishra*, PK Rath**Diabetic Cardiomyopathy: Evidences, Pathophysiology, and Therapeutic ConsiderationsJournal, Indian Academy of Clinical Medicine Vol. 6, No. 4 October-December, 2005 3.Indu G. Poornima, Pratik Parikh, Richard P. ShannonDiabetic Cardiomyopathy.The Search for a Unifying HypothesisCirculation Research March 17, 2006 4.Ding An and Brian RodriguesRole of changes in cardiac metabolism in development of diabetic cardiomyopathyAJP-Heart Circ Physiol VOL 291 OCTOBER 2006 5.Omar ASGHAR, Ahmed AL-SUNNI, Kaivan KHAVANDI, Ali KHAVANDI, Sarah WITHERS, Adam GREENSTEIN, Anthony M. HEAGERTY and Rayaz A. MALIKDiabetic cardiomyopathy.Clinical Science (2009) 116, 741760 6.GF Gensini. VENTRICULAR DYSFUNCTION AND DIABETIC CARDIOMYOPATHY:Where The Devil Comes From?.2011 7.AMERICAN DIABETES ASSOCIATION. Standards of Medical Care in Diabetes 2011
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