Hypertension is the most common predisposing factor leading to congestive heart failure (CHF) in man. However, our studies of gradual onset renovascular hypertension in the rat have not shown evidence for irreversible functional changes or structural cardiac damage, although multiple reversible alterations were observed. Recent clinical studies have shown that diabetes mellitus is also an independent risk factor for the development of CHF. As with the experimental studies of hypertension, drug induced diabetes in rats produces a reversible cardiomyopathy but no structural heart disease. Recent clinical evidence suggests that the combination of hypertension and diabetes is particularly likely to lead to a congestive cardiomyopathy. Our initial studies of renovascular hypertensive-diabetic (HD) rats have shown marked structural (including microvascular) damage in a substantial proportion of animals. A fraction of these animals also demonstrated cardiac muscle failure and many exhibit pathological evidence of CHF; a very high spontaneous mortality was observed. The proposed study will carefully examine myocardial function and structure in HD rats. In vitro papillary muscle and in vivo hemodynamic studies will characterize myocardial function. Structural analysis will include a quantitative evaluation of the degree of replacement fibrosis in this model which will be correlated with in vitro functional performance. Microfil perfusion studies of the coronary microvasculature will be correlated with both functional and structual data. Isolated cardiac myocytes will be functionally characterized; and the contributions of excitation-contraction coupling, alterations in the myofibrils, or interstitial and replacement fibrosis, to contractile failure will be analyzed. HD rats will initially be compared to rats with isolated hypertension or diabetes, with respect to function, structure and mortality. The influence of duration of these stresses will then be explored in a longitudinal study of HD rats. The possible ocurrence of arrhythmias and their contribution to the animals' mortality will be examined using Holter monitering techniques. Different modes of antihypertensive therapy will be employed in reversal studies to determine if all methods of blood pressure lowering have equivalent effects on myocardial function, structure (including the microvasculature) and mortality. The sensitivity of HD rats to catecholamine necrosis will be compared to that of controls. Finally, a model of HD rabbits will be developed with evaluation of its consequences with respect to structure and mortality. These studies should expand knowledge of the pathophysiology and treatment of CHF in human hypertensive diabetics.
