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(Circulation. 2000;101:2922.)
© 2000 American Heart Association, Inc.
Clinical Investigation and Reports |
Acute Endothelin A Receptor Blockade Causes Selective Pulmonary Vasodilation in Patients With Chronic Heart Failure
From the Cardiomyopathy Program and Cardiovascular Section, Boston University Medical Center, Boston University School of Medicine, Boston, Mass (M.M.G., W.S.C.); Albert Einstein College of Medicine, Bronx, NY (T.H.L.); University of Maryland, Baltimore, Md (S.S.G.); Johns Hopkins Medical Institutions, Baltimore, Md (J.M.H.); Boston VA Medical Center, Boston, Mass (M.T.S.); Ohio State University, Columbus, Ohio (C.V.L.); University of Pennsylvania, Philadelphia, Pa (E.L.); University of Michigan, Ann Arbor, Mich (J.M.N.); and Loyola University, Maywood, Ill (B.E.L.).
Correspondence to Wilson S. Colucci, MD, Cardiovascular Section, Boston University Medical Center, 88 E Newton St, Boston, MA 02118. E-mail wilson.colucci{at}bmc.org
Background—Elevated plasma endothelin-1 (ET-1) levels in patients with chronic heart failure correlate with pulmonary artery pressures and pulmonary vascular resistance. ETA receptors on vascular smooth muscle cells mediate pulmonary vascular contraction and hypertrophy. We determined the acute hemodynamic effects of sitaxsentan, a selective ETA 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 (P0.001,
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 ETA 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.
Key Words: endothelin • heart failure • hemodynamics
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