Hypertension (H) is the most common predisposing factor leading to CHF in man. Diabetes mellitus (D) is also an independent risk factor for the development of CHF. As with the experimental studies of H, drug induced D produces reversible cardiac dysfunction. Recent clinical evidence suggests that the combination of H and D is particularly likely to lead to a cardiomyopathy. Initial studies of HD have shown myocardial damage in a substantial proportion of animals. Many exhibit CHF and a high mortality. We have shown a progressive increase in in- vitro myocardial dysfunction in H, D and HD which was paralleled by changes in myosin ATPase and isoenzyme distribution. There was a similar degree of cardiac pathology in surviving H and HD but no pathology in D's. Spontaneously dying HD's had more cardiac damage than did survivors but the amount of LV damage was modest (less than 10% of the LV. Hemodynamic studies of the HD showed marked changes in contraction and relaxation that closely resembled those observed in isolated papillary muscle. A prophylactic effect of the calcium blocker nisoldipine on cardiac structure was shown in HD. The proposed study will explore the possibility that calcium overload mediates myocardial damage in HD using a Vitamin D analogue increased calcium absorption. We will examine the functional significance of the observed degree of myocardial pathology by imposing a diffuse graded loss of cells using the model of catecholamine necrosis in H, D, HD and controls. We will re-examine the problem of functional irreversibility in HD by reversing both H and D after several months of these disorders. We will try to correlate functional irreversibility to changes in myocardial structure. HD will be examined using echocardiography to select the best time for invasive study. The proposed studies will include in-vivo hemodynamics, papillary muscle function techniques, contractile (including regulatory) protein studies, quantitative histology, and measurement of cardiac levels of hydroxyproline, catecholamines and electrolytes. They should expand knowledge of the pathophysiology of CHF in human HD's. We will determine if D sensitizes the heart to the damaging effects of angiotensin II and we will explore the possibility of preventing the increase in connective tissue, with associated improvement in cardiac function, using beta-amino propionitrile to prevent collagen cross linking.
