Coronary flow reserve and nitric oxide synthases after cardiac transplantation in humans

Objective: Coronary endothelial dysfunction may precede morphological chang es in birth the epicardial conduit and microvascular resistance vessels in heart transplant recipients. Since the development of transplant atheroscle rosis is the major limiting factor for longterm survival, the identificatio n of early mediators of vasomotor dysfunction may be of therapeutic interes t. We therefore investigated the potential relationship between the express ion of nitric oxide synthases (NOS) and coronary endothelial function in hu man cardiac transplant recipients over time. Methods: Forty-two human cardi ac transplant recipients were studied at 1 and 12, months after heart trans plantation (HTx). The microvascular coronary how velocity reserve (CFVR) wa s tested for endothelium-dependent (acetylcholine) and -independent (adenos ine) stimuli by intravascular Doppler flow-wire. Epicardial diameter change s were evaluated by quantitative coronary angiography. Endomyocardial induc ible (iNOS) and endothelial constitutive nitric oxide synthase were determi ned by RT-PCR. Nitric oxide production (nitrite and nitrate (NOx)) and TNF- alpha were measured in plasma samples from the aorta and coronary sinus. Re sults: CFVR was impaired in 26.1% (n = 11) of patients at 1 month and in 31 % (n = 13) 12 months after HTx. iNOS-mRNA levels were significantly higher in patients with impaired endothelium-dependent CFVR. In addition, only in these patients were TNF-alpha levels higher and these correlated with plasm a NOx levels at 1 and 13 months post-HTx (1 month: r = 0.81, P = 0.001; 12 months: r = 0.62, P = 0.04). Conclusions: Coronary microcirculatory dysfunc tion in response to acetylcholine is present in nearly 30% of patients duri ng the first year following transplantation. These patients present with hi gher iNOS-mRNA expression and TNF-a: plasma levels. Selective modulation of the TNF-alpha /iNOS-pathway may be of therapeutic value to improve coronar y endothelial dysfunction in cardiac transplant recipients. (C) 2001 Elsevi er Science B.V. All rights reserved.