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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL033240-01
Application #
3344895
Study Section
Experimental Cardiovascular Sciences Study Section (ECS)
Project Start
1984-12-01
Project End
1987-11-30
Budget Start
1984-12-01
Budget End
1985-11-30
Support Year
1
Fiscal Year
1985
Total Cost
Indirect Cost
Name
Albert Einstein College of Medicine
Department
Type
Schools of Medicine
DUNS #
009095365
City
Bronx
State
NY
Country
United States
Zip Code
10461
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Fein, F S; Miller, B; Flores, M et al. (1991) Myocardial adaptation to chronic propranolol therapy in diabetic rats. J Cardiovasc Pharmacol 17:846-53
Fein, F S; Cho, S; Malhotra, A et al. (1991) Beneficial effects of diltiazem on the natural history of hypertensive diabetic cardiomyopathy in rats. J Am Coll Cardiol 18:1406-17
Fein, F S; Cho, S; Zola, B E et al. (1989) Cardiac pathology in the hypertensive diabetic rat. Biventricular damage with right ventricular predominance. Am J Pathol 134:1159-66
Zola, B E; Miller, B; Stiles, G L et al. (1988) Heart rate control in diabetic rabbits: blunted response to isoproterenol. Am J Physiol 255:E636-41
Jones, J G; Cho, S; Factor, S M (1988) The anatomy and pathophysiology of the microvasculature in different organs: relationship to vasculogenic necrosis and tissue damage. Methods Achiev Exp Pathol 13:114-43
Fein, F S; Zola, B; Miller, B et al. (1987) Myocardial adaptation to chronic propranolol therapy in normal rats. Am J Physiol 253:H444-53