Endothelial dysfunction in heart transplanted patients with graft vasculopathy.

The pathological mechanism of cardiac transplant vasculopathy (TVP) is uncertain. We tested the hypothesis that the endothelial function, in terms of the release of endothelium-derived relaxing factor, is impaired in patients with angiographic evidence of transplant vasculopathy. In a pilot study, the effects of the substances used (substance P, acetylcholine, nitroglycerin) were assessed as regards tone of pre-contracted 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 arteries, whereas acetylcholine has a more complex effect on vascular tone involving both a direct effect on the endothelium and the smooth muscle cells. In a second pilot study, the effects of intracoronary infusions of substance P (5-100 pmol.min-1) and acetylcholine (2-50 nmol.min-1) on flow velocity were compared in 10 patients undergoing cardiac catherization after heart transplantation. Flow velocity was determined by a 3F Doppler catheter placed into the proximal segment of the left anterior descending artery (LAD). Both drugs increased concentration-dependent flow velocity; substance P and acetylcholine maximally increased flow velocity by about 85 +/- 24% and 143 +/- 15%, respectively (P < 0.05). In a third study, 23 patients undergoing diagnostic cardiac catheterization were 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 flow velocity (by Doppler) and epicardial coronary diameter (by quantitative angiography) were determined after intracoronary injections of substance P (20 pmol), nitroglycerin (0.1 mg), and papaverine (8 mg). Substances were injected through the central lumen which was placed into the LAD. Increases in flow velocity in response to substance P were significantly less in patients with TVP than in patients without evidence of TVP. Moreover, flow-mediated vasodilation in response to papaverine 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 the pathogenesis of TVP and its vascular complications.