diabetic cardiomyopathy

DIABETIC CARDIOMYOPATHY

IntroductionObesity and sedentary life style.By 2025 300 million will be

affected by Diabetes Mellitus.Cardiovascular disease accounts

for 80% of death among diabetic patients.

Definition“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.”

First described in 1972.(Ruber et al)On the basis of observations in 4

diabetic patients without evidence of HT, CAD, valvular or congenital heart disease.

Epidemiology

Diabetes affects 180 million people worldwide.

2/3 of patients with established CVD have impaired glucose homeostasis; affects 30% of heart failure patients.

Every 1% increase in HBA1c leads to an 8% increase in heart failure.

In United Kingdom Prospective Diabetes Study(UKPDS), it was found that

For HBA1c <6%, there occurred 2.3 HF events /100 person – years.

For HBA1c >10%, there occurred 11.9 HF events /100 person – years

Prevalence of HF in general population: 1-4%.

Prevalence of HF in diabetic population: 15%.

Pathology

Enhanced thickening of capillary basement membrane.

Myocellular atrophy and hypertrophy.

Myocardial and interstitial fibrosis.

Fat droplet deposition.

Other characteristicsEarly changes in diastolic

function – affects up to 75% asymptomatic diabetic patients.

Collagen deposition. Presence of advanced

glycosylation end products(AGEs).

Late compromise of LV systolic function.

Pathogenesis

1) HYPERGLYCEMIA – Excess AGE and Reactive Oxygen

Species(ROS) formation with deactivation of NO.

Myocardial collagen deposition and fibrosis.

2) FATTY ACIDSImpaired glycolysis, pyruvate

oxidation, lactate uptake results in apoptosis.

Alteration of myocardial bioenergetics and contraction/relaxation coupling.

3) PROTEIN KINASE C Activation of DAG/PKC signal

tranduction pathway

Reduction in tissue blood flow.Increased vascular permeability.Alterations in neovascularization.Enhanced extracellular matrix

deposition.

4) RENIN ANGIOTENSIN SYSTEM(RAS)Activation of stretch receptors in heart

activates RAS and the SNS Cardiomyocyte hypertrophy and apoptosis.

5) ALDOSTERONE INDUCED FIBROSIS Existence of local cardiac renin-angiotensin-aldosterone system have been demonstrated.

Myofibroblast growth with interstitial and focal perivascular accumulation of collagen.

6) HYPOXIA INDUCED FACTOR 1/ VASCULAR ENDOTHELIAL GROWTH FACTOR

HIF - 1α activation via hypoxia/free radicals induces angiopoietin, PGF,PDGF-β and VEGF.

In diabetes, VEGF and its receptors are decreased significantly leading to impaired angiogenesis.

7) ENDOTHELIAL DYSFUNCTION Impaired endothelial NO

production. Increased vasoconstrictor

prostaglandins, glycated proteins, endothelium adhesion molecules ,platelet and vascular growth factors which enhance vasomotor tone and vascular permeability and limit growth and remodelling .

8) AUTONOMIC NEUROPATHYDecreased

sympathetic/parasympathetic myocardial innervation with impaired coronary resistance vessel vasodilator response .

Impaired ventricular diastolic filling.

Stages of diabetic cardiomyopathy

STAGES CHARACTERISTICS FUNCTIONAL FEATURES

STRUCTURAL FEATURES

METHODS

Early stage Depletion of GLUT4Increased FFACarnitine deficiencyCa2 homeostasis changesInsulin resistance

No overt functionalabnormalities or possibleovert diastolic dysfunctionbut normal ejectionfraction

Normal LV size, wallthickness, and mass

Sensitive methods such asstrain, strain rate, andmyocardial tissue velocity

Middle stage

Apoptosis and necrosisIncreased AT IIReduced IGF-IIncreased TGF-1Mild CAN

Abnormal diastolicdysfunction and normal orslightly decreased ejectionfraction

Slightly increased LV mass,wall thickness, or size

Conventionalechocardiography orsensitive methods such asstrain, strain rate, andmyocardial tissue velocity

Late stage Microvascular changesHypertensionCADSevere CAN

Abnormal diastolicdysfunction and ejectionfraction

Significantly increased LVsize, wall thickness, andmass

Conventionalechocardiography

Clinical featuresSymptoms

-Typically pts c/o months of fatigue, weakness, reduced exercise tolerance due to CHF.

-May also present as Arrythmia or Sudden Death.Physical Signs

-Tachycardia -Jugular venous distension-Gallop heart sounds

DiagnosisCXR- Cardiomegaly ECG- Normal or low QRS voltage , abn

axis, non specific ST seg abnormalities, conduction defects.

2D EchoTissue doppler echoIntravenous contrast echoComputed tomographyMagnetic resonance imaging

2D ECHOPreserved LV ejection fraction.Reduced early diastolic filling.Prolongation of isovolumetric

relaxation and increased atrial filling.

Pre – ejection period(PEP) increased.

LV ejection time(LVET)decreased.PEP/LVET increased.

GRADES OF DIASTOLIC DYSFUNCTIONGrade 1- Abnormal Relaxation PatternReversal of E/A ratioDevelop normally with age.Patients will not have any symptoms of

heart failure.E/A ratio- Ratio between early(E) and late

(atrial – A) ventricular filling velocity.E caused by accumulation of blood in the

atria during previous systole.A created by atrial contraction.

GRADE II - Pseudonormal Filling DynamicsModerate diastolic dysfunction. Elevated left atrial filling pressure.Symptoms of heart failure.E/A ratio appears normal.GRADE III – Reversible Restrictive Diastolic

dysfunctionReversal of diastolic abnormalities on echo on

performing Valsalva maneuver.E/A ratio > 2.GRADE IV – Fixed Restrictive Diastolic

DysfunctionNo reversibility of echo abnormalities.E/A ratio > 2

Trans-mitral valve spectral Doppler flow patternin a normal subject (upper panel), in a patient with milddiastolic dysfunction (abnormal relaxation; middle panel),and in a patient with severe (restrictive) diastolicdysfunction (lower panel)

TISSUE DOPPLER ECHOIn standard echo , high velocity low

amplitude filter looks at blood flow through valves .

TDI applies high velocity low amplitude filter to myocardium thus looking at myocardial tissue velocities.

Results independent of pre load.Subtle systolic and diastolic

dysfunction can be defined.

INTRAVENOUS CONTRAST ECHONon invasive means of assessing

integrity of the coronary microcirculation and myocardial perfusion.

Relies on resonance of microbubble contrast agents when excited by diagnostic usg freq. producing increased backscatter from blood.

Contrast echocardiographic sequence with microbubble contrast agent defining myocardial perfusion withindifferent myocardial segmentsFrame i) is immediately following a high power ultrasound flash which destroys the micro-bubbles within the myocardium. Frames ii)–iv) show replenishment ofmicro-bubbles in the septum and lateral walls within 2 heartbeats. A clear apical perfusion defect (A) is demonstrated which persists.

Treatment

GLYCAEMIC CONTROLLIFESTYLE MODIFICATIONβ BLOCKERS Chronic stimulation of SNS inc.

heart rate and altered gene expression cardiac remodelling in both HF and diabetes.

Traditionally β blockers were not used ( insulin resistance and hypoglycemia unawareness).

But with recent advances in understanding of heart failure and importance of SNS, β blockers have become essential in treatment of HF.

COPERNICUS(Carvedilol Prospective Randomized Cumulative Survival) study

67% reduction in morbidity and mortality in HF patients treated with carvedilol.

ACE INHIBITORSHOPE( Heart Outcomes Prevention

Evaluation) studyDecreased cardiovascular morbidity and

mortality in diabetic patients.33% reduction in rate of development

of new HF. ARBs – additive effects on

hemodynamic measurements, neurohormonal activity and LV remodelling with ACE ≠.

Cardiovascular morbidity and mortality in theHOPE study, illustrating a greater benefit in the diabetic patients

ALL PATIENTS DIABETIC PATIENTS

Death from cardiovascular causes

26% 37%

MI 20% 22%

Stroke 32% 33%

All- cause mortality 16% 24%

Revascularisation 15% 17%

STATINSDirect effect on cholesterol

metabolism. Augments collateral blood flow

downstream of activated plaques. Enhances endothelial cell NO

synthase activity.Prevents upregulation of VEGF

mRNA.Prevents AGE related damage.

Newer therapeutic directionsPARP inhibitors[poly(ADP-ribose) polymerase

1]Functions as DNA-nick-sensor enzyme.Hyperglycemia overproduction of

mitochondrial superoxideDNA strand breaksactivation of PARPinhibits GAPDHaccumulation of glycolytic intermediatesactivate major transducers of hyperglycemic damage(AGE formation and PKC pathway).

PARP inhibitors block all those pathways.Trials are going on.

THANKS