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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL053541-04
Application #
2750450
Study Section
Special Emphasis Panel (ZRG4-CVB (03))
Project Start
1995-08-01
Project End
2000-07-31
Budget Start
1998-08-01
Budget End
2000-07-31
Support Year
4
Fiscal Year
1998
Total Cost
Indirect Cost
Name
Wake Forest University Health Sciences
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
937727907
City
Winston-Salem
State
NC
Country
United States
Zip Code
27157
Fukuta, Hidekatsu; Little, William C (2008) The cardiac cycle and the physiologic basis of left ventricular contraction, ejection, relaxation, and filling. Heart Fail Clin 4:1-11
Tachibana, Hideo; Cheng, Heng-Jie; Ukai, Tomohiko et al. (2005) Levosimendan improves LV systolic and diastolic performance at rest and during exercise after heart failure. Am J Physiol Heart Circ Physiol 288:H914-22
Zhang, Zhu-Shan; Cheng, Heng-Jie; Onishi, Katsuya et al. (2005) Enhanced inhibition of L-type Ca2+ current by beta3-adrenergic stimulation in failing rat heart. J Pharmacol Exp Ther 315:1203-11
Morimoto, Atsushi; Hasegawa, Hiroshi; Cheng, Heng-Jie et al. (2004) Endogenous beta3-adrenoreceptor activation contributes to left ventricular and cardiomyocyte dysfunction in heart failure. Am J Physiol Heart Circ Physiol 286:H2425-33
Hasegawa, Hiroshi; Little, William C; Ohno, Michiya et al. (2003) Diastolic mitral annular velocity during the development of heart failure. J Am Coll Cardiol 41:1590-7
Ohte, Nobuyuki; Cheng, Che-Ping; Little, William C (2003) Tachycardia exacerbates abnormal left ventricular-arterial coupling in heart failure. Heart Vessels 18:136-41
Ukai, T; Cheng, C P; Tachibana, H et al. (2001) Allopurinol enhances the contractile response to dobutamine and exercise in dogs with pacing-induced heart failure. Circulation 103:750-5
Cheng, C P; Ukai, T; Onishi, K et al. (2001) The role of ANG II and endothelin-1 in exercise-induced diastolic dysfunction in heart failure. Am J Physiol Heart Circ Physiol 280:H1853-60
Cheng, H J; Zhang, Z S; Onishi, K et al. (2001) Upregulation of functional beta(3)-adrenergic receptor in the failing canine myocardium. Circ Res 89:599-606
Little, W C; Kitzman, D W; Cheng, C P (2000) Diastolic dysfunction as a cause of exercise intolerance. Heart Fail Rev 5:301-6

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