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DEMA-CVNGII THIU

GII THIU CC TAI NGHIN CU KHOA

HC TI HI NGH NI KHOA TOAN QUC TITHANH PH H CH MINH THNG 7/ 2011

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Hue College of Medicine and PharmacyVietnam

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DIABETIC CARDIOMYOPATHY

Prof. Nguyen Hai Thuy. MD, PhD

Hue College of Medicine and PharmacyDEMA-CVN.COM

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Congestive heart failure in diabetic patient withoutCAD and HTN. HbA1c : 8%, BP: 110/70 mmHg

IVSd: 1.06 cm, IVSs: 1.23 cmLA: 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 HFpatients in major clinical trials.

Among all patients hospitalized for heart

failure, 25% to 30% patient have DM as acomorbid condition

In large-scale mortality trials, in HF patients

with systolic dysfunction, diabetes was anindependent risk factor for death.

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

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Framingham Study

1. A direct associationbetween DM and HF wasfirst demonstrated

2. Risk of developing

symptomatic HF 2.4-fold in diabetic men 5-fold in diabetic women,

3. independent of coexisting

hypertension orischemic heart disease.

SOLVD ( Studies of LeftVentricular Dysfunction)

1. Registry of 6791 patients withheart failure,

2. 1310 diabetic patients weremore likely to be hospitalized

for HF exacerbationandmore likely to die.

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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 cardiovascularprotective effects can be considered tobe mitigated once overt diabetesdevelops 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 coronaryinsufficiency than nondiabetic patients.

Every 1% increase in the baseline glycosylatedhemoglobin level translates into a 15% increase in

risk of developing HF

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Leyden E.(1881) commented that HF was afrequent and noteworthy complication of diabetes

mellitus. Mayer J. (1888) stated that heart disease indiabetes can be traced to an abnormality inmetabolism.

Rubler S.(1972) coined the term diabeticcardiomyopathy after performing post mortemstudies in 4 diabetic patients with cardiac failure,

having excluded alcohol, hypertension, andcoronary and structural heart disease as possibleaetiologies.

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

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Diabetic cardiomyopathy is a unique entity, unassociated with coronary arterydisease, characterized by diastolic dysfunction. It is rarely clinically apparent

unless associated with hypertension

(Bell, Diabetes Care 1995)

Over 30 years ago 4 diabetic patients with CHF, normal coronary arteries, and noother etiologies were proposed as having diabetic cardiomyopathy.

(Rubler et al. , Am J Cardiol 1972)

Diastolic dysfunction can be recognized in type II diabetics, in the absence ofconcomitant hypertension, in a proportion ranging from 30% to 60%

(Nicolino 1995, Di Bonito 1996, Poirier 2001)

Diabetic CardiomyopathyClinical Evidence

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II. STRUCTURAL FEATURES OF DIABETICCARDIOMYOPATHY 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 contractionband formation, perivascular and interstitial oedema and myocytolysis.

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Mild myocardialfibrosis stained with

Masons trichrome.(A) Perivascularfibrosis in diabeticheart.

(B) Mild fibrosisbetween myofibres.

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2.Myocardial microvessels

A study of human diabetic myocardiumfound two characteristic abnormalities inmyocardial capillaries:

endothelial swelling and/or degeneration and thickening of the

capillary basement membrane

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Myocardial fragment stained withhematoxylin and eosin shows arteriolarhyalinization.

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

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Electronmicrograph of a myocardial capillary from a diabetic patient, demonstratingluminal occlusion with basement membrane thickening.

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Changes in Myocardial StructureMyocellular and Interstitial Fibrosis

Fibrosis

Hypertrophy

The extent and frequency of diastolicdysfunction is directly proportional to the

HbA1c level

(Devereux et al. Circulation 2000)

HYPERGLICEMIA Accumulation of AGEsDisturbed Ca++ handling Cross linking of

collagen FIBROSIS DIASTOLICDYSFUNCTION

Bell Diabetes Care 2003DEMA-CVN.COM

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III.DEFINITION OF DIABETICCARDIOMYOPATHY (DCM)

Adistinctentity characterized bythe presence ofabnormal myocardial performance or structure,

in theabsence of epicardial coronary arterydisease, hypertension and significant valvulardisease

Aneja Am J Med 2008

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Microvascular and tissue dysfunction in

DCM

TISSUE perfusion/metabolism

In the absence ofstenosis

MACRO vesselsMICRO vessels

blood flow can be reduced

by Microvascular Dysfunction causing ischemic metabolism

and Tissue Dysfunction

> Glucose

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Marwick, Heart 2004

DIABETIC CARDIOMYOPATHY (DCM) andDIABETIC HEART DISEASE (DHD)

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IV. Myocardial substrate metabolismin the normal heart

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.

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

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Glucose

utilization in thecardiomyocyte.

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

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Inhibition of glucose oxidation by FA utilization

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Inhibition of glucose oxidation by FA utilization.

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

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Cardiovascular targets and actions of insulin.

Muniyappa R et al. Endocrine Reviews 2007;28:463-4912007 by Endocrine Society

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V.Pathophysiology of

diabetic cardiomyopathy

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ROS : reactive oxygen species, PARP: poly(ADP-ribose) polmerase

GAPDH: enzyme Glyceraldehyde-3 phosphate dehydrogenase

1.Hyperglycemia

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ROS and NO The elevation of ROS leads to cellular damage by

oxidation, disruption of vascular homoeostasisthrough interference with NO and, most recently, bymodulation of detrimental intracellular signallingpathways.

ROS have been implicated in all stages of thedevelopment of HF, from cardiac hypertrophy tofibrosis, contractile dysfunction and failure.

Increased ROS causes cardiac dysfunction by directdamage to proteins and DNA inducing PARP[poly(ADP-ribose) polymerase] as well as bypromoting apoptosis.

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PARP

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PARP(Poly(ADP-ribose) polymerase)

PARP enzymes are overactivated in diabetes as areparative response to ROS-induced oxidative damageto DNA.

PARP inhibits GAPDH (glyceraldehyde- 3-phosphate

dehydrogenase), which leads to accumulation ofglycolytic intermediates, which inturn activate a seriesof transducers which inflict tissue damage via AGEformation and PKC (protein kinase C) activation

PARP also promotes cardiac damage by activating NF-B (nuclear factor B) and inducing overexpression ofthe vasoconstrictor ET (endothelin)-1 and its receptors.

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Protein Kinase C

Increased

rotein kinase C

Increased cardiac

hypertrophy; increased extra

cellular

Impaired relaxation;

increased ventricular

stiffnessDEMA-CVN.COM

H i th

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Hexosamine pathway

Increased hexosamine

flux

Sp1-O-GluN acylation of

transcription factors decreasing

SERCA2a expression45

Prolonged calcium transients;

impaired relaxation

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P l l th

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Polyol pathway

Increased polyol

flux

Decreased regeneration of reduced

glutathione leading

to oxidative stress; increased DNA

fragmentation sorbitol-induced AGE

Increased myocyte apoptosis;

increased ventricular

stiffness

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Advanced Glycation End Products (AGEs)

Increased

AGE

Crosslink RyRs41;

crosslink type III

collagen

Decreased SR calcium release

and myocyte contractility;

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2.NEFA

ALTERED MYOCARDIUM

INSULINRESISTANCE K ATP Channel

APOPTOSIS

Ceramide

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3 H i li

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3.HyperinsulinCardiovascular targets and actions of insulin.

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

2007 by Endocrine Society

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FFA & i li i

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FFA & insulin resistance

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Ceramide is a cardiotoxin

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Ceramide is a cardiotoxinin 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

pathways at a time when insulin receptor mediated Akt-1 activation is impaired.DEMA-CVN.COM

Pathway-selective insulin resistance in PI3K signaling creates imbalancebetween prohypertensive and antihypertensive vascular actions of insulin

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between prohypertensive and antihypertensive vascular actions of insulinexacerbated by compensatory hyperinsulinemia.

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

2007 by Endocrine Society

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Impact of Insulin Resistance on Myocardial Metabolism:

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Impact of Insulin Resistance on Myocardial Metabolism:

Importance of FF Acid Generation

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

CV Stress

Catechols, Cortisol

Lipolysis

Plasma FFA

Glucose

Insulin

CoronaryOcclusion

Lysophospholipids

Ca2+ overload Enzyme loss

Glycolysis Glucose Oxidation

MembraneDamage

Arrhythmias

Phospholipids

TG

FFA

Acyl CoAAcylcarnitine

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R i A i i Ald S

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Renin Angiotensin Aldosterone System

RAS Cardiomyocyte hypertrophy and apoptosis .DEMA-CVN.COM

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Activation of the Renin-Angiotensin System(RAS)

The role of activation of the RAS in the developmentof 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 oxidativedamage and cardiomyocyte and endothelial cell

apoptosis and necrosis in diabetic hearts, whichcontributes to the increased interstitial fibrosis.

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Ab lit i l i h t i

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Abnormality in calcium homoeostasis

Diabetes impairs sarcoplasmic reticular calcium pumpactivities, which reduces the rate of Ca++ removalfrom the cytoplasm in diastole.

Such alterations may contribute to the increased

diastolic stiffness characteristic of diabeticcardiomyopathy.

Accumulation of toxic molecules such as long chainacylcarnitine and free radicals contribute to

alterationof calcium sensitivity of regulatory protein.

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Endothelial dysfunctionImpaired endothelial NO production and increased vasoconstrictor prostaglandins,glycated proteins, endothelium adhesion molecules and platelet and vascular growthfactors enhance vasomotor tone and vascular permeability and limit growth and

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Medial vascular calcification in diabetes mellitus

Arterial stiffnessIncreased central aortic pressure and left ventricular afterloadand lowered central diastolic and coronary perfusion pressures,leading to subendocardial ischaemia and interstitial fibrosis.

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Autonomic neuropathy

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Autonomic neuropathyCAN (cardiac autonomic neuropathy)

Decreased sympathetic/parasympathetic myocardial innervationwith impaired coronary resistance vessel vasodilator response

and impaired ventricular diastolic filling .DEMA-CVN.COM

St d f h t t i bilit (HRV) i

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Study of heart rate variability (HRV) intype 2 diabetic patients by Holter ECG

NTDong, NHThuy, HVMinh, LTB Thun (2003-2005)

decreased HRV Normal HRVTotal

n % n %

DM 40 36,7 69 63,3 109

Non-DM 10 20,0 40 80,0 50

Total 51 108 2 = 4,43

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Aldosterone-induced fibrosis Myofibroblast growth with interstitial and focal

perivascular accumulation of collagen.

HIF-1/VEGF HIF-1activation via hypoxia/free radicals induces

angiopoietin, PGF, PDGF- and VEGF but, indiabetes, VEGFand its receptors, VEGF-R1 andVEGF-R2, are decreased significantly , leading to

impaired angiogenesis.

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Thiamine dificiency in diabetes

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y

0 20 40 60 80 100 120

Control

Type 2

0

10

20

30

40

50

60

70

80

T

l(%)

Thiamine huyt tng (nM)

[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

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0

10

20

30

40

50

60

0 100 200 300 400

thanh thi Thiamine (ml/min)

Nng

t

hiamin

ehuyttng(n

M)

are excreted principally in the urine

thanh thi Thiamine (ml/min)

Nhm n Median Range PChng 20 3.7 2.6 - 26.2 ----T tp 1 26 86.5 12.8 - 228.4 (P

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

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LVMI of diabetic patient before and aftertreating with high doses of vitamin B1

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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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S O C

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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

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JACC 2006DEMA-CVN.COM

Diastolic dysfunction

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Normal

Screening the diabetic

cardiomyopathy byevaluating diastolic

function

Echocardiography study of 48 non-hypertensive type 2 diabeticpatients (Nguyen Hai Thuy, Nguyen

Quoc Viet-2003) Prevalence ofdiastolic dysfunction : 81,25% inwhich first degree was 70,83%

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Normal diastolic function and diastolic dysfunction

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Normal diastolic function and diastolic dysfunction(obesity) by tissue doppler echography

Raev D.C. (1994) : diastolic dysfunction more frequent and early than systolicdysfunction in type 1 diabetic patientsPoirier P and al (2001) : study of diastolic dysfunction in diabetic patients withoutHTN showed that diabetic cardiopathy is special cardiomypathy, independent withCAD and HTN.

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2. Left ventricular hypertrophy (LVH)

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LVMI in type 2 diabetic patients without HTN

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LVMI in type 2 diabetic patients without HTNTran 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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3. SYSTOLIC DYSFUNCTION

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4 TEI (T l j i i l i ) INDEX

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4.TEI (Total ejection isovolumic ) INDEX

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

Echocardiography study of

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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

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g p y ( )

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Positron Emission Tomography

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MBF (ml/min/g)

Bellina et al., J Nucl Med 1990,

Technology of choise to assess microvascular function

Quantitative Imaging of Microvascular Function(Myocardial Blood Flow MBF)

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Microvascular Dysfunction in Idiopathic DCf h l d f

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75% of pts with microvascular dysfunction

P = 0.0012

MBF < 1.36

MBF > 1.36

Patients with more Severe Microvascular Dysfunctionare at Increased Risk of Death and/or Heart Failure

Neglia et al., Circulation 2002

Dip MBF< 1.36 ml/min/g

Increasedrelative risk of

3.5 timesin 5 yrs

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6 C di bi k

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6.Cardiac biomarkers

BNP is a cardiac hormone secreted inresponse to ventricular volume andpressure overload.

Although it is both sensitive and specificfor congestive HF, it cannot reliablydistinguish between systolic and diastolic

HF, which limits its diagnostic use indiabetic cardiomyopathy

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Study of plasma NT-proBNP levels in 104 diabeticpatients (Nguyen Hai Thuy, Le Thanh Tung, 2010)

NT-proBNP levels of diabetic patients

with and without LVH (279 227,2 vs 45,72 31,5pg/ 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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STAGES OF DIABETIC CARDIOMYOPATHY

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VII.Management of

Diabetic Cardiomyopathy

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Glycaemic control

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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 diabeticcardiomyopathy

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G l f Gl M t

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Targets for glycemic (blood sugar) control inmost non-pregnant adults

ADA AACE

A1c (%)

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Am Coll Cardiol, 2009; 54:422 428,doi:10.1016/j.jacc.2009.04.049

2009 by the American College ofCardiology FoundationRelationship of Hemoglobin A1C and Mortality

in Heart Failure Patients With DiabetesDavid Aguilar, MD*,,*, Biykem Bozkurt, MD*,, Kumudha Ramasubbu,

MD*, and Anita Deswal, MD, MPH*

,,

At 2 years of follow-up, death occurred in25% of patients inQ1 (HbA1C< 6.4%),23% in Q2 (6.4% < HbA1c < 7.1%),17.7% inQ3 (7.1% < HbA1c < 7.8%),22.5% in Q4 (7.8% < HbA1c < 9.0%),and23.2% in Q5 (HbA1c >9.0%).

DEMA-CVN.COM
http://content.onlinejacc.org/misc/terms.dtlhttp://content.onlinejacc.org/misc/terms.dtlhttp://content.onlinejacc.org/misc/terms.dtlhttp://content.onlinejacc.org/misc/terms.dtl

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Insulin-Resistant Cardiomyopathy.Clinical Evidence, Mechanisms, and Treatment OptionsRonald M. Witteles, MD, Michael B. Fowler, MB, FACC. Stanford, California. Journal of the American College ofCardiology Vol. 51, No. 2, 2008

2008 by the American College of Cardiology Foundation

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Tht bi vi OAD

Kt hp thm thuc vin s khng th t c mctiu iu tr

Cc thuc ung ch lm gim A1c 1-2% Do , bnh nhn cA1c > 9% s khng th t

mc tiu iu tr vi thuc vin

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

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Insulin Resistance

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

The extrapancreatic effect of Amaryl

Rate limiting step for glucoseutilisation is glucose uptake viaGLUT4 transporter

Amaryl translocation of GLUT4transporters from low-densitymicrosomes to plasma membraneof insulin-resistant fat and musclecells

Amaryl

appears to peripheralglucose uptake and to mimic theaction of insulin

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Plasma Adiponectin Plays an Important

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Role in Improving Insulin Resistance

With Glimepiride in Elderly T2DM

Diabetes Care 26:285289, 200317 elderly T2DM,12 wks glimepirideDEMA-CVN.COM

Plasma Adiponectin Plays an Important

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Role in Improving Insulin Resistance

With Glimepiride in Elderly T2DM

Diabetes Care 26:285289, 200317 elderly T2DM,12 wks glimepirideDEMA-CVN.COM

Cardiovascular Safety: Arrhythmia

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Effect of Amaryland gliclazide on mean (SD) number ofventricular beats/hour

Baseline Amaryl Gliclazide

Amarylis associated with a lower incidence of cardiac arrhythmias

than gliclazide in T2DM patients with heart failure

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

Single center, open-

label, randomized,cross over study in22 T2DM patientsreceiving digoxin(0.125-0.5 mg) forcardiac arrhythmia.After a 1-week run-

in phase, patientsreceived Amaryl(4-6 mg QD, n=10) orGliclazide (240-320mg, n=12) for 2weeks beforecrossing over for afurther two weeks.

20

30

40

50

24

28

60

7077

434244

Ven

tricularectopic

beats/hour

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Ischemic Preconditioning

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g Protect myocardium independently

of an increase in coronarycollateral flow

intensity of ischemic pain

extent of ST segmentdeviation

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

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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 effectbeing more pronounced in diabetic compared withnondiabetic patients.

CHARM and Val-HeFT studies also demonstrated

mortality and morbidity benefits with ARBs which weresimilar in diabetic and non-diabetic patients.

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ACE inhibitors & ARBs

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ACE inhibitors & ARBs

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ACE inhibitors

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ACE -I facilitate blood flow through themicrocirculation in fat and skeletal muscles.Improvement of coronary blood flow may be beneficialfor microvascular disease related diabetic

cardiomyopathy. ACE-I increases the number of perfused capillaries

and epicardial perfusion rate, prevents the increase ofcoronary perfusion pressure and end-diastolic

pressure in animal experiments

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ACE inhibitors

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ACE inhibitors

The action of ACE -I on angiotensin II mayimprove fibrosis in myocardium and functionaland structural changes of small vessels indiabetes

ACE inhibitors have been demonstrated toreduce cardiovascular disease in diabeticpatients, particularly in presence of

hypertension.

Angiotensin receptor blockers may also havesimilar effects on myocardial fibrosis in diabetic

sub ectsDEMA-CVN.COM

-Blockers

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-Blockers (carvedilol) improved insulin resistance

and had no effect on HbA1c, Although to date therehas not been a study of-blockers in diabeticpatients with HF,up to a quarter of patients in themajor-blocker trials in HF were diabetic .

Subgroup analysis of these trials demonstratedsignificant mortality and morbidity benefits in diabeticpatients.

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Calcium channel blockers

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Intracellular retention of calcium in diabetes isassociated with the depletion of high-energyphosphate stores and a derangement of ultrastructureand cardiac dysfunction.

Calcium channel blockers can reverse the intracellular

calcium defects and prevent diabetes inducedmyocardial changes.

Verapamil has been shown to significantly improve thedepressed rate of contraction and rate of relaxationand lower peak LV systolic pressure.

Verapamil can also improve the altered myofibrillar.ATPase activity, myosin ATPase and sarcoplasmic

reticular Ca++ pump activities.

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Microvascular DysfunctionA relevant mechanism of metabolic-inflammatory diseases

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A relevant mechanism of metabolic inflammatory diseases

A new targetof innovative treatment

Microvessels

Dyslipidemias

MyocarditisDEMA-CVN.COM

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

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vascular end organ effects

Metabolic

apo A-I, apo A-III HDL LPL TG-lipoprotein lipolysis apo C-III sdLDL apo A-V TG metabolic & vascular mitochondrial -oxidation ectopic fat

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-1transcription

CYP450 AA metabolism antiinflammatoryEET

Angiostatic VEGF; bFGF-induced Akt

activation; actin cytoskeleton

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Diabetic patient with

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abet c pat e t thypertriglyceridemia

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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, adenosinediphosphate; 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 dngmetformin

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 improveLVEF, NYHA functional class and QOL in patientswith HF.

Perhexiline has demonstrated substantialimprovements in LVEF, Vo2max and QOL, but isassociated with a risk of hepatotoxicity andperipheral neuropathy .

Ranolazine, reduces intracellular Na+ and diastolicCa2+ overload, thus improving diastolic function, butit has been associated with prolongation of the QT

interval

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FFAs are mobilized from adiposetissue to inhibit the uptake of glucoseby muscle (including heart muscle)

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by muscle (including heart muscle).The result is hyperglycemia and

increased insulin resistance.Elevated FFAs also act onmitochondria (mito) to cause excessoxygen wastage with formation ofROS. The consequences includemitochondrial and cellulardysfunction (ionic changes,increased cell calciumand sodium).

Metabolic interventions decreaseinsulin resistance, hyperglycemia,and ROS formation to decrease theseverity of heart failure

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NEW THERAPEUTIC DIRECTIONSPARP i hibit

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PARP inhibitors

PARP which inhibits GAPDH (glyceraldehyde-3-phosphate

dehydrogenase). This leads to the accumulation of glucoseand other glycolytic intermediates prior to their entry into theKrebs cycle.

These intermediaries activate a number of major transducers

of hyperglycaemic damage In addition to the direct cytotoxicpathway regulated by DNA injury and PARP activation,

PARP also modulates the course of cardiovascularinflammation and injury by regulating the activation ofNF-B

and inducing over-expression of ET (endothelin)-1 and ETreceptors Blocking PARP activity with two differentcompetitive PARP inhibitors provides a magic bulletapproach as it blocks activation of all the major pathwaysthought to mediate tissue damage in diabetesDEMA-CVN.COM

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Congestive heart failure in diabetic patient before and after treating highdoses of vitamin B1 at Hue University Hospital

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Published October 2nd, 2010in General Interest, Health,Health News, Health and Wellness,Heart, Life, Medical News, Nutrition,PopularACS.orgGarlic oilhas significant potentialfor preventing cardiomyopathy,a form of heart disease that is aleading cause of death in people withdiabetes, scientists have concluded ina new study. Their report, which also explains why people with diabetesare 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 heartdisease , garlic oil possesses significant potential for protecting heartsfrom diabetes-induced cardiomyopathy,

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References
http://ihealthbulletin.com/blog/category/general-interest/http://ihealthbulletin.com/blog/category/health/http://ihealthbulletin.com/blog/category/health-news/http://ihealthbulletin.com/blog/category/health-and-wellness/http://ihealthbulletin.com/blog/category/heart/http://ihealthbulletin.com/blog/category/life/http://ihealthbulletin.com/blog/category/medical-news/http://ihealthbulletin.com/blog/category/nutrition/http://ihealthbulletin.com/blog/category/popular/http://ihealthbulletin.com/blog/category/popular/http://ihealthbulletin.com/blog/category/nutrition/http://ihealthbulletin.com/blog/category/medical-news/http://ihealthbulletin.com/blog/category/life/http://ihealthbulletin.com/blog/category/heart/http://ihealthbulletin.com/blog/category/health-and-wellness/http://ihealthbulletin.com/blog/category/health-news/http://ihealthbulletin.com/blog/category/health/http://ihealthbulletin.com/blog/category/general-interest/

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1.Sajad A. HAYAT, Billal PATEL, Rajdeep S. KHATTAR and Rayaz A. MALIKDiabetic 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.TheSearch for a Unifying HypothesisCirculation Research March 17, 2006

4.Ding An and Brian RodriguesRole of changes in cardiac metabolism indevelopment 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 Diabetes2011

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