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GII THIU

GII THIU CAC TAI NGHIN CU KHOA HOC TAI HI NGHI NI KHOA TOAN QUC TAI

THANH PH H CHI MINH THANG 7/ 2011

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Hue College of Medicine and Pharmacy Vietnam

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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%

Whats your diagnosis?

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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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New England Journal of Medicine 1999; 341(12): 857-865 DEMA-CVN.COM

 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,

SOLVD ( Studies of Left Ventricular Dysfunction)

1. Registry of 6791 patients with heart failure, 2. 1310 diabetic patients were more likely to be hospitalized for HF exacerbation and more likely to die.

3. independent of coexisting hypertension or ischemic heart disease.

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DM and younger HF study

Under 65 years old.
Four fold in diabetic men Eight fold in diabetic women

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.

Clinical Science (2009) 116, 741760 DEMA-CVN.COM

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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II. STRUCTURAL FEATURES OF DIABETIC CARDIOMYOPATHY AND THEIR FUNCTIONAL RELEVANCE

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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.

Microangiopathic changes of venules and capillaries in diabetic heart (magnified x360).

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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

Changes in Myocardial Structure

Myocellular and Interstitial Fibrosis
The extent and frequency of diastolic dysfunction is directly proportional to the HbA1c level (Devereux et al. Circulation 2000)

Fibrosis
HYPERGLICEMIA Accumulation of AGEs Disturbed Ca++ handling Cross linking of collagen FIBROSIS DIASTOLIC DYSFUNCTION

Hypertrophy
Bell Diabetes Care 2003
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III.DEFINITION OF DIABETIC CARDIOMYOPATHY (DCM)

A distinct entity characterized by the presence of abnormal myocardial performance or structure, in the absence of epicardial coronary artery disease, hypertension and significant valvular disease
Aneja Am J Med 2008

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Microvascular and tissue dysfunction in DCM

MACRO vessels

MICRO vessels
TISSUE perfusion/metabolism

<< Flow >> Glucose

In the absence of stenosis

blood flow can be reduced by Microvascular Dysfunction

causing ischemic metabolism and Tissue Dysfunction

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DIABETIC CARDIOMYOPATHY (DCM) and DIABETIC HEART DISEASE (DHD)

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Marwick, Heart 2004

IV. Myocardial substrate metabolism in the normal heart

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Stanley W C et al. Physiol Rev 2005;85:1093-1129

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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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Glucose utilization in the cardiomyocyte.

Phosphofructokinase-1 (PFK1) pyruvate dehydrogenase (PDH) Pyruvate dehydrogenase kinase (PDK)

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Control of fatty acid (FA) delivery and utilization in the cardiomyocyte.

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.

Inhibition of glucose oxidation by FA utilization.

DEMA-CVN.COM insulin receptor substrate (IRS) , protein kinase-B (PKB). pyruvate dehydrogenase (PDH), Phosphofructokinase-1 (PFK1),

Cardiovascular targets and actions of insulin.

Muniyappa R et al. Endocrine Reviews 2007;28:463-491 DEMA-CVN.COM

2007 by Endocrine Society

V.Pathophysiology of diabetic cardiomyopathy

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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

Increased hexosamine flux

Sp1-O-GluN acylation of transcription factors decreasing DEMA-CVN.COM SERCA2a expression45

Prolonged calcium transients; impaired relaxation

Polyol pathway

Decreased regeneration of reduced Increased polyol glutathione leading flux to oxidative stress; increased DNA fragmentation sorbitol-induced AGE DEMA-CVN.COM

Increased myocyte apoptosis; increased ventricular stiffness

Advanced Glycation End Products (AGEs)

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.

Muniyappa R et al. Endocrine Reviews 2007;28:463-491 DEMA-CVN.COM

2007 by Endocrine Society

FFA & insulin resistance

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Ceramide is a cardiotoxin in lipotoxic cardiomyopathy

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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.

Muniyappa R et al. Endocrine Reviews 2007;28:463-491

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2007 by Endocrine Society

Impact of Insulin Resistance on Myocardial Metabolism:

Importance of FF Acid Generation

CV Stress Coronary Occlusion

Catechols, Cortisol

Lipolysis

Insulin

TG FFA Acyl CoA Acylcarnitine

Plasma FFA Glucose

Phospholipids

Lysophospholipids
Membrane Damage

Glycolysis Glucose Oxidation

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Adapted from Oliver MF, Opie LH, Lancet 1994; 343: 155

Ca2+ overload

Enzyme loss

Arrhythmias

Renin Angiotensin Aldosterone System

RAS Cardiomyocyte hypertrophy and apoptosis .

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Activation of the Renin-Angiotensin System (RAS)

The role of activation of the RAS in the development of diabetic cardiomyopathy is well recognized. Angiotensin II receptor density and mRNA expression are elevated in the diabetic heart. Activation of the RAS during diabetes mellitus has been shown to be associated with increased oxidative damage and cardiomyocyte and endothelial cell apoptosis and necrosis in diabetic hearts, which contributes to the increased interstitial fibrosis.
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Abnormality in calcium homoeostasis

Diabetes impairs sarcoplasmic reticular calcium pump activities, which reduces the rate of Ca++ removal from the cytoplasm in diastole. Such alterations may contribute to the increased diastolic stiffness characteristic of diabetic cardiomyopathy. Accumulation of toxic molecules such as long chain acylcarnitine and free radicals contribute to alterationof calcium sensitivity of regulatory protein.

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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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Medial vascular calcification in diabetes mellitus

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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Thiamine dificiency in diabetes

[Plasma Thiamine] (nM) Subjects n Median Range P Control 20 61.4 44.6 - 93.7 ---Type 1 26 11.7 4.8 - 43.7 <0.001 Type 2 49 13.7 2.5 - 53.3 <0.001

80 70 60

T l (%)

50 40 30 20 10 0 0 20 40 60 80 100 120 Type 2 Control

Thiamine huyt tng (nM)

Essex UK study
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Mecanism of thiamine dificiency in diabetes

are excreted principally in the urine
Nng thiamine huyt tng (nM)
60 50 40 30 20 10 0 0 100 200 300 400 thanh thi Thiamine (ml/min)
thanh thi Thiamine (ml/min) Nhm n Median Range P Chng 20 3.7 2.6 - 26.2 ---T tp 1 26 86.5 12.8 - 228.4 (P<0.001) T tp 2 49 59.8 1.4 - 256.6 (P<0.001)

Gi tr bnh thng

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Hammes et al., Nature Medicine (2003) 9; 294-299

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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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VI. Diagnosis of DCM

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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

Screening the diabetic cardiomyopathy by evaluating diastolic function

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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2. Left ventricular hypertrophy (LVH)

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LVMI in type 2 diabetic patients without HTN

Tran Thi Van Anh,Nguyen Hai Thuy, Nguyen Anh Vu (2006-2007)

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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4.TEI (Total ejection isovolumic ) INDEX

Christina Voulgari. (2010) , Diabetic cardiomyopathy Vascular health and risk DEMA-CVN.COM management 2010:6 883-903

Echocardiography study of 39 non-hypertensive diabetic patients

( Nguyen Hai Thuy , Vo Th Quynh Nhu , 2007-2008) .

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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5.Positron Emission Tomography (PET)

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Positron Emission Tomography

Technology of choise to assess microvascular function
Quantitative Imaging of Microvascular Function (Myocardial Blood Flow MBF)

MBF (ml/min/g)
, Bellina et al., J Nucl Med 1990
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Microvascular Dysfunction in Idiopathic DC

75% of pts with microvascular dysfunction
Patients with more Severe Microvascular Dysfunction are at Increased Risk of Death and/or Heart Failure

MBF > 1.36 P = 0.0012 MBF < 1.36

Increased relative risk of 3.5 times in 5 yrs Dip MBF < 1.36 ml/min/g

Neglia et al., Circulation 2002 DEMA-CVN.COM

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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STAGES OF DIABETIC CARDIOMYOPATHY

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VII.Management of Diabetic Cardiomyopathy

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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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Goals of Glucose Management

Targets for glycemic (blood sugar) control in most non-pregnant adults
ADA AACE

A1c (%)
Fasting (preprandial) plasma glucose Postprandial (after meal) plasma glucose

<7*

6.5

70-130 mg/dL <110 mg/dL <180 mg/dL <140 mg/dL

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.

*<6 for certain individuals

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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%

Do , bnh nhn c A1c > 9% s khng th t mc tiu iu tr vi thuc vin

DEMA-CVN.COM DeWitt DE, Dugdale DC. Prim Care Clin Office Pract 2003;30:543-56

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

DEMA-CVN.COM Mller G, Wied S. Diabetes. 1993;42: 1852-1867

Plasma Adiponectin Plays an Important Role in Improving Insulin Resistance With Glimepiride in Elderly T2DM

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17 elderly T2DM,12 wks glimepiride

Diabetes Care 26:285289, 2003

Plasma Adiponectin Plays an Important Role in Improving Insulin Resistance With Glimepiride in Elderly T2DM

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17 elderly T2DM,12 wks glimepiride

Diabetes Care 26:285289, 2003

Cardiovascular Safety: Arrhythmia

Amaryl is associated with a lower incidence of cardiac arrhythmias than gliclazide in T2DM patients with heart failure Effect of Amaryl and gliclazide on mean (SD) number of ventricular beats/hour
Ventricular ectopic beats/hour

77
70 60 50 40 30 20

44 42

43

28 24

Baseline

Amaryl

Gliclazide

Pogatsa G et al. Diabetes. 2001;50 (suppl 1):A128. Abstract 513-P

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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 & ARBs

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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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Calcium channel blockers

Intracellular retention of calcium in diabetes is associated with the depletion of high-energy phosphate stores and a derangement of ultrastructure and cardiac dysfunction. Calcium channel blockers can reverse the intracellular calcium defects and prevent diabetes induced myocardial changes. Verapamil has been shown to significantly improve the depressed rate of contraction and rate of relaxation and lower peak LV systolic pressure. Verapamil can also improve the altered myofibrillar. ATPase activity, myosin ATPase and sarcoplasmic DEMA-CVN.COM reticular Ca++ pump activities.

Microvascular Dysfunction
A relevant mechanism of metabolic-inflammatory diseases A new target of innovative treatment
Dyslipidemias

Microvessels

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Fenofibrate, PPAR- agonism, PPRE / non-PPRE-mediated diabetic -vascular end-organ effects

Metabolic
apo A-I, apo A-III HDL LPL TG-lipoprotein lipolysis apo C-III sdLDL apo A-V TG

vascular

metabolic & vascular

mitochondrial -oxidation ectopic fat

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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Diabetic patient with hypertriglyceridemia

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Statins and HF: DCM

Node, Circulation 2003

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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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AMPK Signaling is Activated by Exercise

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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

NEW THERAPEUTIC DIRECTIONS

PARP inhibitors

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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Thank you for your attention

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