Paracrine coronary endothelial modulation of diastolic left ventricular function in man: implications for diastolic heart failure.

Coordinated release of relaxing and contracting factors from the endothelium modulates arterial distensibility. Recently, a similar release of the same and other factors from the coronary endothelium was shown to modulate myocardial performance in humans. This paracrine modulation of left ventricular (LV) performance by substances released from the coronary endothelium mainly affects diastolic LV function. This was evident from the reduction in end-systolic LV pressure, the earlier onset of LV relaxation and the increased LV diastolic distensibility observed in normal subjects during bi-coronary infusion of substance P. In experimental preparations, substance P elicited similar effects on diastolic LV function, which were attributed to a paracrine myocardial action of nitric oxide (NO) because they were absent after addition of hemoglobin. In normal subjects, the myocardial effects of NO were investigated during bi-coronary infusion of the NO-donor sodium nitroprusside and resembled the effects observed during bi-coronary infusion of substance P. This paracrine control of diastolic LV function by the coronary endothelium is influenced by substrate availability and by many neurohumoral substances, whose plasma levels are raised in heart failure. In transplant recipients, bi-coronary co-infusion of substance P and of L-arginine, the substrate for NO production, potentiated the fall in LV filling pressures. Pretreatment with intravenous dobutamine augmented the drop in LV end-systolic pressures observed during bi-coronary infusion of substance P. In isolated papillary muscles, a higher baseline myocardial c-GMP level, as induced by atrial natriuretic peptide, potentiates the negative inotropic and relaxation hastening effects of NO. In isolated ejecting guinea-pig hearts, an endothelin receptor antagonist improved diastolic LV function and this improvement implies paracrine myocardial action on diastolic LV function not only of NO but also of endothelin. Coronary endothelial control of myocardial function affects LV performance both acutely and chronically. An acute increase in heart rate augments release of NO because of coronary reactive hyperemia, lowers LV filling pressures thereby promoting subendocardial perfusion, and hastens LV relaxation thereby prolonging the diastolic time interval for coronary perfusion. Chronic changes in coronary endothelial function could also influence diastolic LV performance. Enhanced coronary endothelial NO release, as occurs during chronic exercise or pacing, could explain increased LV diastolic distensibility observed in athlete's heart and in tachycardia cardiomyopathy. Reduced endothelial NO release, as occurs with aging or after transplantation, could contribute to reduced LV diastolic distensibility in the elderly or in allograft recipients.