Acute Endothelin A Receptor Blockade Causes Selective Pulmonary Vasodilation in Patients With Chronic Heart Failure

Abstract

Background —Elevated plasma endothelin-1 (ET-1) levels in patients with chronic heart failure correlate with pulmonary artery pressures and pulmonary vascular resistance. ET A receptors on vascular smooth muscle cells mediate pulmonary vascular contraction and hypertrophy. We determined the acute hemodynamic effects of sitaxsentan, a selective ET A receptor antagonist, in patients with chronic stable heart failure receiving conventional therapy. Methods and Results —This multicenter, double-blind, placebo-controlled trial enrolled 48 patients with chronic New York Heart Association functional class III or IV heart failure (mean left ventricular ejection fraction 21±1%) treated with ACE inhibitors and diuretics. Patients with a baseline pulmonary capillary wedge pressure ≥15 mm Hg and a cardiac index ≤2.5 L · min −1 · m −2 were randomized to 1 of 3 doses (1.5, 3.0, or 6.0 mg/kg) of sitaxsentan or placebo as an intravenous infusion over 15 minutes. Hemodynamic responses were assessed by catheterization of the right side of the heart for 6 hours. Sitaxsentan decreased pulmonary artery systolic pressure, pulmonary vascular resistance, mean pulmonary artery pressure, and right atrial pressure ( P ≤0.001, 0.003, 0.017, and 0.031, respectively) but had no effect on heart rate, mean arterial pressure, pulmonary capillary wedge pressure, cardiac index, or systemic vascular resistance. Plasma ET-1 levels were elevated at baseline and decreased with sitaxsentan. Conclusions —In patients with moderate to severe heart failure receiving conventional therapy, acute ET A receptor blockade caused selective pulmonary vasodilation associated with a reduction in plasma ET-1. Sitaxsentan may be of value in the treatment of patients with pulmonary hypertension secondary to chronic heart failure.