Endothelin in coronary endothelial dysfunction early after human heart transplantation

Background: Cytokines and growth factors released as part of the immune res ponse to alloantigenic stimuli are capable of regulating endothelin-l expre ssion in the allograft. Endothelin plays a significant role as a modulator of coronary vascular reactivity in the early stages of atherosclerosis and may be important as a participant in and marker for cardiac allograft vascu lopathy. Methods: We characterized a possible relationship between morphological and functional coronary changes, transcardiac plasma endothelin level and myoc ardial endothelin-mRNA expression in 33 cardiac transplant recipients in th e early, stable phase 5 +/- 3 months after orthotopic heart transplantation . Coronary microvascular function was determined as endothelium-dependent w ith acetylcholine and endothelium-independent with adenosine using intracor onary Doppler-FloWire. The percentage of the epicardial diameter changes wa s measured using quantitative coronary angiography. Intravascular ultrasoun d was performed to quantify intimal hyperplasia. Cardiac endothelin uptake or release was determined by measuring plasma endothelin levels in the coro nary sinus and aorta. Myocardial endothelin-gene expression was determined using semiquantitative RT-PCR. Results: The aortic endothelin levels were significantly increased in trans plant recipients compared to nontransplanted patients (11.8 +/- 2.2 vs 7.2 +/- 0.9 fmol/ml; P < 0.001). Endothelin uptake was noticed in the majority of patients, and the amount of endothelin uptake was correlated to microvas cular (r = 0.37; P < 0.05) and epicardial (r = 0.41; P < 0.03) endothelium- dependent vasodilatation. High mRNA signal intensity was associated with si gnificantly reduced coronary flow response to acetylcholine compared to pat ients with low myocardial gene expression (coronary flow reserve 2.4 +/- 0. 9 vs 3.4 +/- 0.8, respectively; P < 0.005). Morphological coronary changes early after transplantation were not correlated to endothelin plasma levels or myocardial gene expression. Conclusion: Coronary endothelial vasomotor dysfunction after cardiac transp lantation is associated with an increased myocardial endothelin mRNA expres sion and decreased endothelin-uptake by the heart. We postulate that early activation in the endothelin system may have a pivotal role in the accelera tion of the atherosclerotic process in. transplant patients.