Endothelial dysfunction in heart transplanted patients with graft vasculopathy

Abstract

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.

Coronary endothelial dysfunction as a predictor of intimal thickening in the long term after heart transplantation

“…22,23 However, in the human patient neither angiography nor IVUS shows a clear relationship between the existence of an abnormal endothelial function and development of allograft vascular disease. [11][12][13][14][15][16][17][18][19][20] In the present study we found that patients with endothelial dysfunction had a higher degree of intimal thickness than those without. Moreover, the magnitude of the paradoxical vasomotor response to acetylcholine was more intensive the more severe the intimal thickness.…”

“…[10][11][12] Whether the presence of endothelial dysfunction could predispose to the development of intimal thickening is controversial. [13][14][15][16][17][18][19][20] To test the hypothesis that endothelial dysfunction is related to the degree of intimal thickening, we prospectively analyzed the vasomotor response to acetylcholine (vasodilator endothelium dependent) and nitroglycerin (vasodilator endothelium independent), as well as other donor and recipient variables. Findings were correlated with the intimal thickness, which was evaluated with IVUS.…”

Role of nitric oxide following cardiac transplantation

“…53 However, the response of both substance P and acetylcholine is attenuated in the vessels of hearts that are affected by graft vasculopathy. 24,54,55 This inhibition of the effect of nitric oxide is also apparent in angiographically normal coronary segments in hearts with atherosclerotic changes in other regions of the coronary circulation. 54 This dysfunction of the endothelium has also been shown to occur in non-cardiac vessels.…”

“…24,[52][53][54][55][56] The response of the coronary arteries to intra-coronary injection of acetylcholine has been shown to change from dilation in normal coronary vessels to either no response or a vasoconstriction in transplanted hearts. 24 In contrast, the response to substance P in coronary arteries from transplanted hearts that were angiographically normal, is similar to that observed in non-transplanted hearts.…”

Coronary artery vasospasm causing acute myocardial infarction in a heart transplant recipient

“…10,11 In some studies, endothelial dysfunction occurred in 20% to 30% of cases in the first year and 30% to 40% in long-term follow-up; however, no correlation was found between impaired endothelial regulated vasomotion and CAV. 12 Based on this observation, it has been proposed that endothelial dysfunction and CAV associated with neointimal proliferation constitute two distinct entitites of allograft vasculopathy. Furthermore, a reduction in endothelial independent flow reserve in cardiac transplant recipients was correlated with a reduction in left ventricular ejection fraction 2 years later.…”