pathophysiology of diabetic cardiomyopathy

Pathophysiology of diabetic cardiomyopathy

DR MAHENDRA CARDIOLOGY, JIPMER

Cardiovascular disease is a common complication of diabetes responsible for 80% of the mortality.

1972 for the fist time , the description of 4 patients withdiabetes and heart failure but without arterial hypertension or coronary artery disease appeared.

anatomical dissection of their hearts revealed LV hypertrophy and fibrosis without evidence of coronary artery atheroma or another substrate pathology responsible for these findings.

defined as cardiovascular damage characterized by myocardial dilatation and hypertrophy, decrease systolic and diastolic function of LV independent of IHD or HTN.

Pathogenesis of diabetic cardiomyopathy

1) HYPERGLYCEMIA – Excess AGE and Reactive Oxygen Species(ROS)

formation with deactivation of NO. Myocardial collagen deposition and fibrosis.

2) FATTY ACIDS Impaired 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 transduction

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) ENDOTHELIAL DYSFUNCTION Impaired endothelial NO production. Increased- vasoconstrictor prostaglandins glycated proteins endothelium adhesion molecules platelet and vascular growth factors enhance vasomotor tone and vascular permeability

and limit growth and remodeling.

7) AUTONOMIC NEUROPATHY Decreased sympathetic/parasympathetic

myocardial innervation with impaired coronary resistance vessel vasodilator response .

Impaired ventricular diastolic filling.

Gene expression Enhanced myocardial gene expression for muscle carnitine

palmitoyltransferase 1–8. Significant depression of the Na+/K+ ATPase α1-subunit mRNA. increase in Na+/Ca2+ exchanger mRNA in the ventricular

myocardium. Enhanced arrhythmogenicity, associated with a decrease of

repolarizing K+ currents. down-regulation of αMHC (fast) isoform (contains 3–4 times enzymic

activity of βMHC.

Screening and analysis of early cardiopathology-related gene in type 2 diabetes mellitus. Zhonghua Nei. Ke. Za. Zhi. 41, 530–533

Diabetic cardiomyopathy: mild myocardial interstitial fibrosis stained in blue with Masson trichrome (white arrow) in a patient with long-duration type 1 diabetes mellitus at autopsy, with perivascular fibrosis (A) and mild fibrosis between myocytes (B).

Fibrotic infiltration in the myocardium with Masson's trichrome staining. Area stained blue represent fibrotic infiltration. Magnification at 200×, scale bar is 100 μm. B) Quantitative analysis of fibrosis. The collagen volume fraction was higher in the diabetic group than in the control group

Stages of diabetic cardiomyopathySTAGES CHARACTERISTICS FUNCTIONAL

FEATURESSTRUCTURAL 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

Functional change in heart

Summary belief is widely held that the increase in cardiovascular mortality is

a consequence of accelerated atherosclerosis Studies showing diabetes mellitus increases the risk for cardiac

dysfunction and heart failure independently of other risk factors such as coronary disease and hypertension

down-regulation of SERCA2a, mitochondrial dysfunction, and defects in cytoprotective signaling appear to be leading cause for cardiomyopathy.

Novel therapy is required to counteract above failure mechanism.