Abstract 2315: Markedly Enhanced Activity of Endothelin-1 in Transplant Coronary Arteriosclerosis
Background: Coronary arteriosclerosis is the principal complication limiting long-term survival after heart transplantation. In humans, the mediators responsible for vascular proliferation and vasoconstriction typical of TCA are unknown. Endothelin-1 (ET-1) is a potent vasoconstrictor and mitogen derived primarily from endothelial and mononuclear cells. We tested the hypothesis that ET-1’s biological activity is increased in TCA and that it may contribute to the pathogenesis and manifestations of TCA. We inhibited the ETA receptor by administering a specific antagonist BQ-123 into the coronary arteries in heart transplant recipients undergoing routine annual cardiac catheterization. We compared the coronary vasomotor responses to BQ-123 in subjects with angiographic evidence of TCA and subjects free of angiographic evidence of TCA.
Methods: BQ-123 was infused into one proximal coronary artery (40nmol/min for 60min) of 18 subjects, age 18 –75, 6 +/− 4 years after transplantation. In each patient 3 coronary segments were studied in both the infused and in a non-infused control coronary artery (Total 108 segments). Changes from baseline in diameters of the infused arterial segments were compared to those of non-infused arterial segments at 15 minute intervals. Contribution of ET-1 to coronary constrictor tone was assessed by comparing vasodilation from BQ-123 infusion to dilation from intracoronary nitroglycerin (200μg bolus).
Results: BQ-123 induced dilation in coronary arteries of transplanted patients (8.4% at 60 minutes, vs. −0.4% in noninfused arteries, p<0.001). Dilation was greater for arteries with TCA defined as angiographic diameter stenosis ≥15% (dilation 15.2% with TCA, n=10, vs. 0.6% without TCA, n=8, p=0.004). As compared to dilation from nitroglycerin indicative of overall vascular tone, ET-1 was responsible for 53.2% of vascular tone in TCA arteries but only 12.9% in arteries without TCA.
Conclusions: The endogenous biological activity of ET-1 is markedly increased in humans with TCA compared to those without evidence of TCA. This supports a role for ET-1 in the pathogenesis of TCA and suggests that therapeutic targeting of ET-1 may slow the development and manifestations of TCA in cardiac transplant recipients.