Exercise tolerance in heart failure (CHF) is not well correlated with left ventricular (LV) systolic performance, instead, it varies more closely with the level of left atrial (LA) pressure (P). Observations in applicant's laboratory and in patients indicate that in CHF there is a reversal of the normal exercise induced augmentation of LV relaxation and fall in early diastolic LV P with a resulting increase in LA P. Thus, the diastolic dysfunction present at rest in CHF is exacerbated during exertion and is an important cause of exercise intolerance in CHF. The mechanisms that produce this abnormal exercise response after CHF have not been determined. Factors that might contribute include altered responses of LV relaxation in CHF to the increased systolic load, angiotensin (ANG) II, heart rate and adrenergic stimulation that occur during exercise. Although myocardial ANG II levels have not been determined during CHF exercise, applicant's preliminary observations indicate that circulating ANG II levels increase to very high levels during CHF exercise. Thus, it appears possible that LV relaxation may be slowed and diastolic filling dynamics altered during CHF exercise by both increased sensitivity to ANG II and high ANG II levels. The purpose of this application is to investigate the mechanisms of the abnormal integrated response of LV relaxation and increased early diastolic LV P and LA P during exercise after CHF result from: 1) increased sensitivity of LV relaxation and diastolic filling dynamics to ANG II, which increases to high levels in the myocardium during CHF exercise; 2) increased sensitivity to increased systolic load during exercise; 3) reduction in the augmentation of relaxation produced by the increase in heart rate and adrenergic stimulation during exercise; and 4) endocardial ischemia. Their studies will quantify the relative importance of each of these possible mechanisms of the abnormal response of LV filling dynamics to exercise in dogs chronically instrumented to measure LV P and volume (V) and LA P before and after inducing CHF by rapid ventricular pacing. They will also determine systemic and myocardial activation of the renin-ANG during CHF exercise. They will evaluate the effect of each potential factors alone, before and after CHF, and the effect of blocking the increase in systolic load, heart rate, adrenergic stimulation and ANG II (both with an ACE inhibitor and/or an ANG II receptor blocker) on the response to exercise before and after CHF. This new information on the mechanism of the abnormal response of diastolic filling dynamics during CHF exercise, will help target therapy to improve exercise tolerance in patients with CHF.
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