HYPERTENSION AND HYPERTROPHY IN THE NON-HUMAN PRIMATE

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The major objective of this research proposal is to define the fundamental mechanical, neurohumeral and biochemical properties of left ventricular pressure overload hypertrophy and hypertrophy regression in a unique model of experimentally induced renal hypertension in the nonhuman primate (baboon, papio anubis). Our working hypothesis is that longitudinal studies of systolic function using end systolic stress-volume, stress-length and stress-velocity relations and of diastolic function using quantitation of ventricular chamber and myocardial stiffness will identify which characteristics of left ventricular performance herald the onset of contractile depression. Using this approach, we propose to test the following specific hypotheses: 1) That myocardial contractile depression in pressure overload hypertrophy is manifest by either a rightward parallel shift and/or a depression in the slope of the left ventricular force-length relation. 2) That a decrease in the ratio of left ventricular mass to volume or thickness to dimension will be an early marker for contractile depression. 3) That augmented myocardial stiffness in pressure overload hypertrophy unlike chamber stiffness will not occur in the absence of increased myocardial collagen content. 4) That regression of hypertrophy will be accompanied by unaltered contractile function, reduced chamber stiffness and variable effects upon myocardial stiffness. 5) That heterogeneity in the magnitude of hypertrophy in response to hypertension of similar severity and duration may relate to differences in the modulation of the hypertrophy process by the renin-angiotensin and sympathetic nervous systems. 6) That alterations in primate myosin ATPase activity and/or isoenzyme patterns will be an early and sensitive marker of contractile depression. The following specific studies are designed to answer these hypotheses: chronically hypertensive (2-4 years) baboons with LV hypertrophy and variable systolic function will be studied during the progression of hypertrophy and during hypertrophy regression produced by methyldopa. Serial biplane LV cineangiography/M-mode echocardiography with high fidelity pressure measurement will be used to assess serial alterations in end-systolic circumferential/meridional stress-volume/dimension relations and diastolic properties. Plasma renin, catecholamines and vasopressin levels plus baroreceptor function will be measured in the conscious state. Myocardial tissue hydroxyprolene and myosin ATPase will be assayed at necropsy. It is anticipated this multidisciplinary approach will provide basic insights into the determinants of the evolution and regression of pressure overload hypertrophy in an animal model phylogenetically close to man.