Coronary endothelial dysfunction precedes heart failure and reduction of coronary reserve in awake dogs

Abstract

Endothelial dysfunction in coronary circulation is well documented in heart failure (HF). However, whether this dysfunction is a consequence of heart failure or precedes the development of HF remains unknown. To determine endothelium-dependent regulation in the remote coronary vasculature in a canine coronary microembolization-induced HF model, seven dogs were chronically instrumented for measurement of systemic hemodynamics, for selective coronary microembolization via an implanted coronary catheter and for measurement of corollary blood flow in the non-embolized coronary artery. Microembolizations were performed daily until hemodynamic and echocardiographic measurements showed HF. The responses of coronary blood flow to acetylcholine (0.25, 0.5, 5, 10 μg/kg), nitroglycerine (0.2, 0.8, 5, 25 μg/kg), adenosine (0.25, 0.5, 2, 5 μmol/kg) and brief coronary occlusions (5, 10, 15, 20, 30 s) were examined. Although no signs of HF developed and the responses of coronary blood flow to nitroglycerine, adenosine and occlusions were not altered, the response to acetylcholine was selectively reduced after 1 week of embolization (275,000 ± 55,000 microspheres). Resting coronary flow increased from 21.3 ± 1.4 ml/min in control state to 27.7 ± 3.5 ml/min (P < 0.001). As HF developed, characterized by an elevated left ventricular end-diastolic pressure (6.4 ± 1.6 v 16 ± 1.6 mmHg, P < 0.001), a decreased area election fraction (54 ± 5 v 36 ± 5% P < 0.05) and a reduced β-adrenergic response to isoproterenol, the responses of coronary blood flow to acetylcholine, nitroglycerine, adenosine and occlusions were consistently depressed. Resting coronary blood flow was decreased to 15.4 ± 2.7 ml/min (P < 0.01). Our results indicate, that there is a selectively impaired endothelium-mediated dilator capacity of the resistance coronary vasculature before the development of HF and a reduction of the coronary flow reserve.