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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL033240-05
Application #
3344901
Study Section
Experimental Cardiovascular Sciences Study Section (ECS)
Project Start
1984-12-01
Project End
1991-07-31
Budget Start
1989-08-15
Budget End
1990-07-31
Support Year
5
Fiscal Year
1989
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