Published Online
on November 4, 2002

A more recent version of this article appeared on November 19, 2002

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Submitted on June 17, 2002
Revised on September 4, 2002
Accepted on September 5, 2002

Hemodynamic and Neurohumoral Effects of Selective Endothelin A (ET_A) Receptor Blockade in Chronic Heart Failure. The Heart Failure ET_A Receptor Blockade Trial (HEAT)

Thomas F. Lüscher MD^*, Frank Enseleit MD, Richard Pacher MD, Veselin Mitrovic MD, Matthias R. Schulze MD, Roland Willenbrock MD, Rainer Dietz MD, Valentin Rousson PhD, David Hürlimann MD, Sebastian Philipp MD, Thomas Notter MD, Georg Noll MD, and Frank Ruschitzka MD

From the Cardiovascular Center, Cardiology, University Hospital, Zürich, Switzerland (T.F.L., F.E., D.H., G.N., F.R.); Allgemeines Krankenhaus, Wien, Austria (R.P.); Kerckhoff Clinic, Bad Nauheim, Germany (V.M.); Herz- und Kreislaufzentrum, Department of Cardiology, Dresden, Germany (M.R.S.); Franz Volhard Clinic, Berlin, Germany (R.W., R.D., S.P.); the Department of Biostatistics, University of Zürich, Switzerland (V.R.); Abbott, Ludwigshafen, Germany (T.N.); and the Clinical Research Center, InterCorNet (T.F.L.), Zurich, Switzerland.

^* To whom correspondence should be addressed. E-mail: cardiotfl{at}gmx.ch.

Background—The endothelin (ET-1) system is activated in chronic heart failure (CHF). Whether, what type, and what degree of selective ET blockade is clinically beneficial is unknown. We investigated hemodynamic and neurohumoral effects of 3 weeks of treatment with various dosages of the orally available ET_A antagonist darusentan in addition to modern standard therapy in patients with CHF.

Methods and Results—A total of 157 patients with CHF (present or recent NYHA class III of at least 3 months duration), pulmonary capillary wedge pressure 12 mm Hg, and a cardiac index 2.6 L · min^-1 · m^-2 were randomly assigned to double-blind treatment with placebo or darusentan (30, 100, or 300 mg/d) in addition to standard therapy. Short-term administration of darusentan increased the cardiac index, but this did not reach statistical significance compared with placebo. The increase in cardiac index was significantly more pronounced after 3 weeks of treatment (P<0.0001 versus placebo). Pulmonary capillary wedge pressure, pulmonary arterial pressure, pulmonary vascular resistance, and right atrial pressure remained unchanged. Heart rate, mean artery pressure, and plasma catecholamines remained unaltered, but systemic vascular resistance decreased significantly (P=0.0001). Higher dosages were associated with a trend to more adverse events (including death), particularly early exacerbation of CHF without further benefit on hemodynamics compared with moderate dosages.

Conclusions—This study demonstrates for the first time in a large patient population that 3 weeks of selective ET_A receptor blockade improves cardiac index in patients with CHF. However, long-term studies are needed to determine whether ET_A blockade is beneficial in CHF.

Key words: endothelin • heart failure • hemodynamics

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