The long-term objective is to understand why patients with chronic hypertension (HTN) have a marked increase in morbidity and mortality when they develop left ventricular hypertrophy (LVH), and to determine whether reversal of HTN and regression of LVH will reduce the associated morbidity and mortality. Patients with chronic HTN also have a high incidence of coronary artery and ischemic heart disease. We hypothesize that LVH makes the heart less tolerant to ischemia. Accordingly, our specific aims are to use hypertensive rats and rabbits to define basic interactions between ischemic and hypertensive heart disease. HTN will be induced in rats by uninephrectomy + deoxycortisone (DOC) + high salt and in rabbits by unilateral renal artery clip and contralateral nephrectomy. Studies will be done 1) Prior to induction of HTN, 2) After HTN but before LVH, 3) After LVH has developed, 4) After reversal of HTN but before regression of LVH, and 5) After regression of LVH. Reversal of HTN will be done by several methods to evaluate potential differences between classes of pharmacologic agents. We hypothesize that, relative to normal hearts, hypertrophied hearts, will have: 1) a decreased tolerance to transient global or regional ischemia. We will measure: a) Contractile and diastolic function before and after transient ischemia; function will be compared in intact animals, isolated perfused hearts, and skinned cardiac fiber preparations. Changes in function will be correlated with the capillary/myocyte ratio, myocardial glycogen, and collagen content. b) Myocardial infarction (MI) size after transient coronary occlusion and reperfusion. c) The effect of lowering BP during the acute MI phase. 2) Impaired post-MI healing and repair. We will measure a) The incidence of post-MI LV rupture and aneurysm formation, b) Mechanical properties of post-MI scar tissue, c) The effect of BP lowering during post-MI healing and repair. 3) Impaired coronary vasomotor function. We will measure: a) Myocardial blood flow, endo/epicardial distribution and the maximum vasodilator response, and b) the critical degree of coronary perfusion pressure decrease required to produce cellular hypoxia, c) The mechanical interrelationship between the coronary circulation and the myocardium. 4) Reversal of HTN and regression of LVH may reverse these LVH associated abnormalities. We postulate that anti-HTN agents which increase or preserve myocardial glycogen content may be particularly beneficial in increasing myocardial tolerance to transient ischemia.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL031807-04
Application #
3343012
Study Section
(SRC)
Project Start
1983-09-30
Project End
1988-09-29
Budget Start
1986-09-30
Budget End
1987-09-29
Support Year
4
Fiscal Year
1986
Total Cost
Indirect Cost
Name
Boston University
Department
Type
Schools of Medicine
DUNS #
604483045
City
Boston
State
MA
Country
United States
Zip Code
02118
Plehn, J F; Foster, E; Grice, W N et al. (1993) Echocardiographic assessment of LV mass in rabbits: models of pressure and volume overload hypertrophy. Am J Physiol 265:H2066-72
Mochizuki, T; Eberli, F R; Apstein, C S et al. (1992) Exacerbation of ischemic dysfunction by angiotensin II in red cell-perfused rabbit hearts. Effects on coronary flow, contractility, and high-energy phosphate metabolism. J Clin Invest 89:490-8
Schunkert, H; Dzau, V J; Tang, S S et al. (1990) Increased rat cardiac angiotensin converting enzyme activity and mRNA expression in pressure overload left ventricular hypertrophy. Effects on coronary resistance, contractility, and relaxation. J Clin Invest 86:1913-20
Cunningham, M J; Apstein, C S; Weinberg, E O et al. (1990) Influence of glucose and insulin on the exaggerated diastolic and systolic dysfunction of hypertrophied rat hearts during hypoxia. Circ Res 66:406-15
Gaasch, W H; Zile, M R; Hoshino, P K et al. (1990) Tolerance of the hypertrophic heart to ischemia. Studies in compensated and failing dog hearts with pressure overload hypertrophy. Circulation 81:1644-53
Cunningham, M J; Apstein, C S; Weinberg, E O et al. (1989) Deleterious effect of ouabain on myocardial function during hypoxia. Am J Physiol 256:H681-7
Gaasch, W H; Zile, M R; Hoshino, P K et al. (1989) Stress-shortening relations and myocardial blood flow in compensated and failing canine hearts with pressure-overload hypertrophy. Circulation 79:872-83
Wexler, L F; Grice, W N; Huntington, M et al. (1989) Coronary hypertension and diastolic compliance in isolated rabbit hearts. Hypertension 13:598-606
Lorell, B H; Isoyama, S; Grice, W N et al. (1988) Effects of ouabain and isoproterenol on left ventricular diastolic function during low-flow ischemia in isolated, blood-perfused rabbit hearts. Circ Res 63:457-67
Wexler, L F; Lorell, B H; Momomura, S et al. (1988) Enhanced sensitivity to hypoxia-induced diastolic dysfunction in pressure-overload left ventricular hypertrophy in the rat: role of high-energy phosphate depletion. Circ Res 62:766-75

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