Diabetic men and women are 2.4 and 5.1 times more likely to develop cardiac heart failure than their nondiabetic counterparts (Framingham study). As well as predisposing to noncardiac causes of heart failure, such as hypertension and ischemic cardiomyopathy, diabetes is associated with a form of cardiomyopathy in which the coronary arteries are normal and small-vessel disease is absent (no basal lamina abnormalities in the myocardial capillaries, no lactic acid production during atrial pacing, etc). Diabetic cardiomyopathy is typically of the mildly dilated variety, with diastolic preceding systolic dysfunction. It is also more often associated than other forms of dilated cardiomyopathy (DCM) with bradyarrhythmia (presumably due to conduction neuropathy).
The morphology of diabetic DCM is nonspecific. Its pathophysiology remains incompletely elucidated, but is undoubtedly myriad, comprising vascular and metabolic lesions of the coronary microcirculation, endothelium, and autonomic nervous system. The cell biology changes are equally myriad. Cardiac dysfunction is associated with abnormal sarcoplasmic reticulum and calcium transport, and also with depressed myofibril ATPase activity, possibly due to altered expression of the myosin isoenzymes and the proteins regulating myosin phosphorylation. The abnormal calcium metabolism is probably due to membrane accumulation of dysfunctional metabolic lipids. Animal models of diabetic cardiomyopathy have revealed carnitine deficiency (carnitine being essential for myocardial fatty acid metabolism) and associated mitochondrial abnormalities. The myocytes also show calcium and sodium retention and potassium depletion.
The combination of high glucose and low insulin can induce oxidative stress, which impairs cell remodeling, particularly in the absence of normal scavenger levels. Metabolic changes that lower glucose utilization have been documented, together with a trend to (3-oxidation of fatty acids for metabolic energy. The fatty acids originate from the lipolysis of cardiac triglyceride deposits or from blood-borne exogenous sources (eg, fatty acids transported by albumin or lipoprotein). In addition, in insulin deficiency, adipose tissue lipolysis is increased, thereby compounding the circulating fatty acid elevation. The increased utilization of fatty acids for energy purposes has deleterious effects on cardiac muscle due to the increased oxygen required, and also to the intracellular accumulation of toxic intermediate metabolites that inhibit glucose oxidation. Furthermore, fatty acid oxidation generates high citrate levels that inhibit phosphofructokinase, reduce glycolysis, and promote glycogen synthesis. Decreased glucose oxidation causes lactic acid to accumulate and ultimately promotes free fatty acid degradation.
The myocardial accumulation of triglycerides, cholesterol, and glycoprotein promotes perivascular and interstitial fibrosis, which in turn increases myocyte damage (atrophy) and capillary injury (thickening of the basal lamina). Additional causes of fibrosis include hypertrophy in patients with concomitant hypertension and increases in collagen deposition in the left ventricular wall and in the myocardial levels of sorbitol and 1,2-diacylglycerol.
Diabetic autonomic neuropathy decreases vagal tone, thus increasing the heart rate and lowering R-R variability. Parasympathetic precedes sympathetic dysfunction and hastens the development of cardiomy- opathy, with an increase in oxygen consumption and a decrease in perfusion time. In addition, the large areas of adrenergic denervation in the myocardium decrease the contractile reserve: an abnormal response to exercise in the presence of normal basal systolic function is a sign of incipient diabetic cardiomyopathy. The degree of diabetic autonomic neuropathy (in particular, the failure of nocturnal blood pressure to fall by >10% the nondipper phenomenon) has been correlated with the development of nephropathy, and may thus account for hypertension, left ventricular hypertrophy, and increased myocardial oxygen consumption. Endothelial dysfunction, with an associated decrease in vasodilatation reserve causing a decrease in coronary flow capacity, has been observed in the absence of coronary disease in diabetes type 1 or 2. It was recently shown that hyperglycemia actually abolishes endothelium-dependent vasodilation, probably via an increase in free radical production. Endothelial dysfunction may thus play an important role in the development of diabetic cardiomyopathy, in addition to intramyocardial microangiopathy (proliferative arterial thickening, ultrastructural vascular smooth muscle changes, thickening of the basal lamina in small vessels and capillaries, and increased capillary tortuosity and microaneurysms).
Diabetes is also associated with a form of neonatal cardiomyopathy: cardiomegaly or heart failure can present in about half the babies born to diabetic mothers. This type of obstructive hypertrophic cardiomyopathy may be induced by maternal hematological, respiratory, and/or metabolic problems, or by maternal hormones. It is in any event reversible.
diabetes; risk factor; glycated hemoglobin (HbAIc); cardiomyopathy; endothelial dysfunction; prevention