Coronary vasomotor dysfunction in the cardiac allograft: Impact of different immunosuppressive regimens

Immunosuppression may have an important impact on early graft coronary endo thelial injury. We investigated functional and morphologic coronary alterat ions, myocardial expression, and cardiac release of possible mediators of a llograft vasculopathy within 6 months after cardiac transplantation with re spect to different immunosuppressive regimens. Epicardial and microvascular endothelium-dependent and endothelium-independent vasomotor function and e picardial intimal thickening were measured in 8 transplant recipients treat ed with cyclosporin A (CyA), azathioprine, and prednisone (group 1), 9 tran splant recipients treated with tacrolimus (TKL), azathioprine, and predniso ne (group 2), and 14 patients treated with TKL, mycophenolate mofetil (MMF) , and prednisone (group 3). The gene expressions of inducible and endotheli al nitric oxide synthase (iNOS and eNOS), endothelin-1, prostacyclinsynthas e, and thromboxansynthase were analyzed in endomyocardial biopsy specimens using semiquantitative reverse transcription polymerase chain reaction. Tra nscardiac cytokine release, endothelin-1, and nitrate-release were determin ed from plasma samples. Epicardial endothelial dysfunction (vasoconstrictio n to acetylcholine > 10%) and microvascular smooth muscle cell dysfunction (flow velocity increase to adenosine and nifedipine < 2.0) were enhanced in heart transplant recipients immunosuppressed with TKL, azathioprine, and p rednisone. The prevalence of epicardial dysfunction was 78% in group 2 vers us 44% and 46% in group 1 and 3 (p < 0.05), respectively. The prevalence of microvascular dysfunction was 56% in group 2 versus 13% and 7% in group 1 and a (p < 0.02), respectively. Coronary vasomotor dysfunction was associat ed with increased myocardial iNOS expression (p < 0.05), decreased eNOS exp ression (p < 0.05), and enhanced cardiac immunoreactive interleukin-6 (p < 0.01). Coronary intimal thickening was not different between the groups. Th e combination of TKL and MMF appears to be superior to TKL and azathioprine (and comparable to CyA and azathioprine) concerning preservation of early coronary vasomotor function, eNOS expression, iNOS suppression as well as c ardiac interleukin-6 release. This may have an important impact on subseque nt development of transplant coronary atherosclerosis.