Published online before print June 15, 2009, doi: 10.1161/CIRCHEARTFAILURE.108.836759
Original Articles |
Endothelin-1 Is a Key Mediator of Coronary Vasoconstriction in Patients With Transplant Coronary Arteriosclerosis
From the Multidisciplinary Department of Cardiology (E.L.), Quebec Heart and Lung Institute at Laval Hospital and Laval University, Quebec, Canada; the Klinik fur Kardiologie (D.B.), Pneumologie und Angiologie, Universitaetsklinikum, Duesseldorf, Germany; the Cardiovascular Division (S.K., A.P.S.), Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Mass; the Division of Cardiology (P.G.), San Francisco General Hospital, University of California, San Francisco, Calif; and the Division of Cardiovascular Medicine (J.C.F.), Department of Medicine, University Hospitals and Case Western Reserve School of Medicine, Cleveland, Ohio.
Correspondence to Peter Ganz, MD, San Francisco General Hospital, 1001 Potrero Ave, 5G1, San Francisco, CA 94110. E-mail ganzp{at}medsfgh.ucsf.edu
Received November 17, 2008; accepted May 13, 2009.
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 (40 nmol/min for 60 minutes) of 18 subjects, 6±4 years after transplantation. Vasomotor responses were measured in the infused artery and in a noninfused 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 with that of the maximal vasodilator nitroglycerin (200-µg intracoronary bolus).
BQ-123 dilated coronary arteries of transplanted patients (8.4% at 60 minutes versus –0.4% in noninfused arteries, P<0.001). Dilation was greater for arteries with advanced TCA defined as diameter stenosis 
15% (dilation 15.2% with versus 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.
Conclusions— 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: heart transplant • transplant coronary arteriosclerosis • endothelin