Chin Med J (Taipei) 1998;61:S108.

Exercise Intolerance in Congestive Heart Failure: The Role of Diastolic Dysfunction and Neurohormonal Modulation

Che-Ping Cheng, M.D., Ph.D.

Wake Forest University School of Medicine, Winston-Salem, NC, USA

Abstract

Background. A major symptom of patients with congestive heart failure (CHF) is limited exercise (EX) tolerance due to fatigue and dyspnea. In recent years, left ventricular (LV) diastolic dysfunction has been increasingly recognized as an important determinant of EX intolerance in patients with CHF. However, the role and mechanisms of diastolic abnormalities in producing symptoms of CHF and limiting EX tolerance in patients with CHF have not been systematically investigated.

Methods. We assessed the LV filling dynamic response and circulating levels of angiotensin II (AII) and endothelin-1 (ET-1) in a well established chronically instrumented canine model before and after pacing-induced CHF at rest and during EX.

Results. We found that before CHF, at rest, about one-fifth of the stroke volume (SV) normally entered the LV while LV pressure (P) continues to fall. The mitral valve P gradient (LAP-LVP), which was primarily controlled by the rate of LV relaxation and LAP, determined the rate of early LV filling (dV/dtmax). During normal EX, sympathetic stimulation and tachycardia enhanced LV relaxation caused a downward shift of the early diastolic portion of the LV P-volume (V) loop, so that early diastolic LVP was reduced during EX. Although mean LAP did not increase during normal EX, the fall in early diastolic LVP resulted in an increased early diastolic P gradient across the mitral valve, producing an increase in dV/dtmax. This enhanced rate of filling helped to augment the SV despite the reduction in the diastolic period during EX. In contrast, after CHF, although the SV and dV/dtmax still increased, the mechanism of the increased peak mitral flow was different. Instead of a fall in early diastolic LVP, the early diastolic LVP increased during EX. The early diastolic portion of the LV P-V loop shifted upward, and the rate of LV relaxation was prolonged. Thus, the increased early diastolic mitral valve P gradient resulted entirely from an increase in LAP. Therefore, the diastolic dysfunction present at rest in CHF is exacerbated during EX. In this investigation, we further found that before CHF, there was a modest increase in systemic levels of plasma renin activity (PRA), All and ET-1. After CHF, not only were the resting values of PRA, AII, and ET-1 elevated, but further increased to very high levels during EX. Both AT1 receptor blocker (Losartan, 1 mg/kg plus 50 mcg/kg/min, iv) and ET-1 receptor antagonist (L-754,142, 3 mg/kg plus 3 mg/kg/nv, iv) significantly attenuated this abnormal EX response in CHF.

Conclusions. The failure of the normal EX-induced falls in early diastolic LV P and the increase in LAP contribute to the limitation of EX tolerance in patients with CHF. The EX-induced enhanced activation of RAS and ET-l in CHF produces an adverse cardiac functional response to EX and may play an important role in EX intolerance in CHF.

Keywords: LV filling, diastole, exercise, heart failure, angiotensin II, endothelin-1

[Chin Med J (Taipei) 1998;61:S108.]