ENDOTHELIAL DYSFUNCTION IN HEART TRANSPLANTED PATIENTS WITH GRAFT VASCULOPATHY

The pathological mechanism of cardiac transplant vnsculopathy (TVP) is uncertain. We tested the hypothesis that the endothelial function, in terms of the release of endothelium-derived relaxing factor is impair ed in patients with angiographic evidence of transplant vasculopathy. In a pilot study, the effects of the substances used (substance P, ace tylcholine, nitroglycerin) were assessed as regards tone of pre-contra cted human coronary arteries in vitro, obtained from recipient hearts during cardiac transplantation. The study shows that substance P is a 'pure' endothelium-dependent dilator of epicardial human coronary arte ries, whereas acetylcholine has a more complex effect on vascular tone involving both a direct effect on the endothelium and the smooth musc le cells. In a second pilot study, the effects of intracoronary infusi ons of substance P (5-100 pmol.min(-1)) and acetylcholine (2-50 nmol.m in(-1)) on flow velocity were compared in 10 patients undergoing cardi ac catheterization after heart transplantation Flow velocity was deter mined by a 3F Doppler catheter placed into tile proximal segment of th e left anterior descending artery (LAD). Both drugs increased concentr ation-dependent flow velocity; substance P and acetylcholine maximally increased flow velocity by about 85 +/- 24% and 143 +/- 15%, respecti vely (P < 0.05). In a third study, 23 patients undergoing diagnostic c ardiac catheterization were ere included approximately 40 months after heart transplantation. Patients were classified into those with (n = 8) and those without (n = 15) angiographic evidence of TVP Coronary fl ow velocity (by Doppler) and epicardial coronary diameter (by quantita tive angiography) were determined after intracoronary injections of su bstance P (20 pmol), nitroglycerin (0.1 mg), and papaverine (8 mg). Su bstances were injected through the central lumen which was placed into the LAD. Increases inflow velocity in response to substance P were si gnificantly less in patients with TVP than in patients without evidenc e of TVP. Moreover, flow-mediated vasodilation in response to papaveri ne was almost abolished in patients with TVP Vasodilation in response to nitroglycerin and maximal increase in flow velocity in response to papaverine was similar in both groups. These results suggest that TVP is associated with endothelial dysfunction, which may contribute to th e pathogenesis of TVP and its vascular complications.