Modulation of coronary vasomotor tone by cytokines in cardiac transplant recipients

Background. Upon exposure to cytokines, endothelial cells may undergo profo und alterations of vasomotor function. In this study, we characterized the relationship between coronary epicardial and microvascular vasomotor functi on and expression of specific cytokine patterns in human heart transplant r ecipients, Methods. We studied 49 cardiac transplant recipients, without acute rejecti on or infection at an average of 6+/-3 months after transplantation. Corona ry resistance vessel function was measured in an endothelium-dependent mann er with acetylcholine (5 and 150 mu g/5 min; intracoronary injection) and i n an endothelium-independent manner with adenosine (400 and 800 mu g/5 min; intracoronary injection) using an intracoronary Doppler flow wire. Simulta neous epicardial diameter changes were measured using quantitative coronary angiography. Coronary sinus and aortic serum levels of soluble interleukin (IL)-2 receptor and soluble tumor necrosis factor-alpha receptors (sTNF-R1 and sTNF-R2), TNF-alpha, and IL-6 were determined. Transcardiac cytokine r elease (coronary sinus minus aortic levels) was correlated with coronary va somotor function. Results. The highest amounts of cardiac cytokine release were observed for IL-6 (32+/-14% increase) and sTNF-R1 (26+/-13% increase). A significant inv erse correlation between microvascular endothelial function and cardiac rel ease of soluble IL-2 receptor (P=0.04) and IL-6 (P=0.03) was detected, wher eas a positive correlation was observed to sTNF-R1 (P=0.004). Distal epicar dial endothelial vasomotion was inversely correlated to transcardiac sTNF-R 2 release (P=0.03). Conclusions. Cytokine production and activation, a common phenomenon early after heart transplantation, is related at least in part to endothelial vas omotor dysfunction of the epicardial and microvascular compartment. These r esults support the hypothesis that coronary endothelial dysfunction after c ardiac transplantation is an immunologic phenomenon. Since endothelial dysf unction seems to be a crucial step in the pathogenesis of cardiac allograft vasculopathy, coronary cytokine suppression should be a therapeutic target of improved future immunosuppressive regimens.