Published Online
on June 15, 2009

A more recent version of this article appeared on September 1, 2009

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Original Article

Endothelin-1 Is a Key Mediator of Coronary Vasoconstriction in Patients with Transplant Coronary Arteriosclerosis

Eric Larose¹; Dominik Behrendt²; Scott Kinlay³; Andrew P. Selwyn³; Peter Ganz^4,6 and James C. Fang⁵

¹ Québec Heart and Lung Institute at Laval Hospital; Laval University, Québec, Canada;
² Universitaetsklinikum, Duesseldorf, Germany;
³ Brigham and Women's Hospital; Harvard Medical School, Boston MA;
⁴ University of California, San Francisco, San Francisco CA;
⁵ Case Western Reserve University, Cleveland, OH

⁶ E-mail: pganz{at}aol.com

Background—Transplant coronary arteriosclerosis (TCA) is the principal long-term complication in cardiac transplant recipients. The mediators responsible for vascular proliferation and vasoconstriction typical of TCA remain largely unknown. We tested whether endothelin-1 (ET-1), a potent vasoconstrictor and mitogen, contributes to the pathogenesis and manifestations of TCA.

Methods and Results—BQ-123, an ET-1 receptor-A antagonist, was infused into a coronary artery (40nmol/min for 60min) of 18 subjects, 6±4 years after transplantation. Vasomotor responses were measured in the infused artery and in a non-infused control artery in patients with (n=10) and without (n=8) advanced TCA (108 total coronary segments). Changes in diameters were compared at 15 minute intervals up to 60 minutes. Contribution of ET-1 to coronary constrictor tone was assessed by comparing vasodilation from BQ-123 to that of the maximal vasodilator nitroglycerin (200µg intracoronary bolus). BQ-123 dilated coronary arteries of transplanted patients (8.4% at 60 minutes, vs. -0.4% in non-infused arteries, p<0.001). Dilation was greater for arteries with advanced TCA defined as diameter stenosis 15% (dilation 15.2% with vs. 0.6% without advanced TCA, p=0.004). Judged against the response to nitroglycerin, ET-1 accounted for 53.2% of coronary tone in advanced TCA but only 12.9% without advanced TCA.

Conclusion—This study shows for the first time in humans that ET-1 is an important mediator of coronary vasoconstriction in TCA and accounts for >50% of the increased vasomotor tone. Therapeutic targeting of ET-1 may retard the development of TCA.

Key Words: arteriosclerosis • endothelin • heart transplant