Peripheral endothelial dysfunction in heart transplant recipients: possible role of proinflammatory cytokines

Endothelium-dependent vasodilation in the peripheral circulation may be imp aired in heart transplant recipients (HTx rec). Conflicting results have be en obtained and the mechanisms involved have not been examined. In the pres ent study, we examined whether long-time survivors of heart transplantation (Tx) show signs of endothelial dysfunction in the peripheral microcirculat ion, and further investigated the possible role of endothelium-related mark ers and proinflammatory cytokines in this process. The vasodilatory respons es to acetylcholine (Ach) (endothelium-dependent) and sodium nitroprusside (SNP) (endothelium-independent) were evaluated by skin laser-Doppler perfus ion measurements in 63 clinically stable HTx rec 6 yr (range 1-13 yr) after Tx, and compared with 20 healthy controls. Ten HTx rec were also followed prospectively with three repeated measurements during the first year after Tx. Plasma von Willebrand factor, big-endothelin (b-ET), and proinflammator y cytokines were measured by enzyme immunoassays. Vascular responses to bot h Ach and SNP were significantly attenuated in the HTx rec compared with co ntrols. In longitudinal testing, there was a significant reduction in endot helium-dependent vasodilation, but not independent vasodilation from 1 to 1 2 months after Tx. Plasma levels of VWF and b-ET, as well as levels of proi nflammatory cytokines, tumor necrosis factor (TNF)-alpha, interleukin (IL)- 6 and IL-1 beta, were all markedly increased in HTx rec. HTx rec responses to Ach were negatively correlated to TNF-alpha levels in plasma (r = - 0.39 , P < 0.01). Moreover, there was also a significant positive correlation be tween plasma b-ET and TNF-alpha (r = 0.3-1, p < 0.01). In the long-term fol low-up of HTx rec, endothelial dysfunction is demonstrated by both regulati on of blood flow in the skin microcirculation and by raised markers of endo thelial activation in plasma. This endothelial dysfunction may be related t o enhanced levels of proinflammatory cytokines in these patients.