Coronary Vasomotor Dysfunction in the Cardiac Allograft: Impact of Different Immunosuppressive Regimens

Abstract

Immunosuppression may have an important impact on early graft coronary endothelial injury. We investigated functional and morphologic coronary alterations, myocardial expression, and cardiac release of possible mediators of allograft vasculopathy within 6 months after cardiac transplantation with respect to different immunosuppressive regimens. Epicardial and microvascular endothelium-dependent and endothelium-independent vasomotor function and epicardial intimal thickening were measured in 8 transplant recipients treated with cyclosporin A (CyA), azathioprine, and prednisone (group 1), 9 transplant recipients treated with tacrolimus (TKL), azathioprine, and prednisone (group 2), and 14 patients treated with TKL, mycophenolate mofetil (MMF), and prednisone (group 3). The gene expressions of inducible and endothelial nitric oxide synthase (iNOS and eNOS), endothelin-1, prostacyclinsynthase, and thromboxansynthase were analyzed in endomyocardial biopsy specimens using semiquantitative reverse transcription polymerase chain reaction. Transcardiac cytokine release, endothelin-1, and nitrate-release were determined from plasma samples. Epicardial endothelial dysfunction (vasoconstriction 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 prednisone. The prevalence of epicardial dysfunction was 78% in group 2 versus 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 3 (p < 0.02), respectively. Coronary vasomotor dysfunction was associated with increased myocardial iNOS expression (p < 0.05), decreased eNOS expression (p < 0.05), and enhanced cardiac immunoreactive interleukin-6 (p < 0.01). Coronary intimal thickening was not different between the groups. The 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 cardiac interleukin-6 release. This may have an important impact on subsequent development of transplant coronary atherosclerosis.

Allograft Vasculopathy Versus Atherosclerosis

“…99 In further support, eNOS immunoreactivity is gradually lost after human heart transplantation, 100 and reduced myocardial eNOS gene expression is associated with coronary endothelial dysfunction. 101 In summary, endothelial dysfunction is an early feature of vascular disease that contributes to the pathogenesis of both atherosclerosis and AV.…”

Mycophenolate Acid Inhibits Endothelial NAD(P)H Oxidase Activity and Superoxide Formation by a Rac1-Dependent Mechanism

“…8,9 There are limited data regarding whether different immunosuppressive regimens after heart transplantation may have a significant impact on progression of CAV. 10 It has been shown that the calcineurin inhibitors cyclosporine A (CsA) and tacrolimus (FK506), which cannot prevent CAV, 5,11 can induce endothelial dysfunction and hypertension, 12,13 which has been explained by an increase in vascular reactive oxygen species (ROS) formation. 14, 15 In contrast to this, the inhibitor of inosine monophosphate dehydrogenase (IMPDH), mycophenolate mofetil, or its active metabolite, mycophenolate acid (MPA), have been associated with positive effects on atherosclerosis or hypertension in animal models.…”

A model of prediction system for adverse cardiovascular reactions by calcineurin inhibitors among patients with renal transplants using gene-based single-nucleotide polymorphisms

“…In fact, reversible vasospasm was observed in several CNI-treated patients in the present study (data not shown). Proposed mechanisms by which these drugs cause coronary vasospasm include inhibition of expression of the gene encoding endothelial nitric oxide synthetase (eNOS) and activation of the endothelin (ET) gene (Weis et al 2000). In support of this hypothesis, several groups have demonstrated that administration of CNIs significantly increases concentrations of ET, a potent vasoconstrictive peptide, in plasma from organ-transplant recipients (Haug et al 1995;Slowinski et al 2002).…”