Cardiac Allograft Vasculopathy and Dysregulation of the NO Synthase Pathway

Abstract

Abstract-Cardiac allograft vasculopathy is the most aggressive form of atherosclerosis in humans and is the leading cause of death after the first year of heart transplantation. Endothelial dysfunction is a major contributing factor to the acceleration of coronary vascular disease in these individuals. A reflection of this endothelial dysfunction is the severe impairment in endothelium-dependent vasodilation that occurs early after transplantation. The etiology of this allograft endothelial alteration is multifactorial and may include preexisting atherosclerosis of the graft vessels, reperfusion injury during transplantation, denervation, disruption of the lymphatic system, and acute and chronic immune injury, as well as traditional risk factors for coronary artery disease (hyperlipidemia, diabetes, hypertension, or hyperhomocysteinemia) and pathogens, such as cytomegalovirus. The alteration in endothelial function affects vasomotor tone of the coronary arteries. Evidence indicates that there may be an impairment of endothelial production and/or activity of NO. Because NO is a potent vasodilator, its deficiency would explain the abnormal vasomotor tone in these individuals. In addition, because NO inhibits key processes in vascular inflammation and atherosclerosis, its absence may contribute to the acceleration of transplant vascular disease. Recent studies from our group and others have shed light on the mechanisms of endothelial dysfunction and its importance in cardiac allograft vasculopathy. In addition, the alteration in endothelial function contributes to vascular inflammation and progression of the disease. Key Words: endothelium Ⅲ coronary Ⅲ transplantation Ⅲ heart Ⅲ inflammation A ccelerated graft atherosclerosis is a key feature of most chronic rejection syndromes. 1 Coronary atherosclerosis frequently limits the long-term success of cardiac transplantation, is characterized by intimal proliferation during the early phase of the disease, and ultimately manifests itself as luminal stenosis of epicardial branches, occlusion of smaller vessels, and myocardial infarction. 2 The most salient difference between cardiac allograft vasculopathy (CAV) and typical atherosclerotic coronary artery disease is the diffuse involvement of the coronary vasculature. 3 Whereas the structural changes of atherosclerosis largely affect the proximal epicardial coronary arteries, in CAV, the disease is much more extensive. Cardiac transplant recipients often manifest concentric intimal thickening that affects the distal epicardial vessels, as well as their branches. Intimal thickening and inflammation may extend into the donor aorta up to the suture lines and, in some instances, even into the great veins of the allograft. 4,5 Histopathologic analysis reveals that morphological manifestation of this vasculopathy may range from concentric, diffuse, intimal hyperplasia to fibrofatty plaques indistinguishable from spontaneously occurring atherosclerosis. 3 The clinical detection of CAV is made more difficult by the frequent absenc...

Macrophage Depletion Suppresses Cardiac Allograft Vasculopathy in Mice

“…Injury of this vascular endothelium is hypothesized to be the common insult that underpins all causes of CAV, perhaps through a pathway involving dysregulation of endothelial nitric oxide production (37). Finally, in addition to inducing direct vascular endothelial injury, macrophages may promote an aberrant healing response fostering allograft arteriopathy through the production of a large array of growth factors (such as PDGF, IGF-1 and TGF-b).…”

T cell–mediated vascular dysfunction of human allografts results from IFN-γ dysregulation of NO synthase

“…Various studies in cardiac transplant patients have correlated coronary EC dysfunction to elevated cytokine levels (35,36) and attributed the dysfunction to reduced NO bioavailability (3,37) and loss of eNOS in luminal ECs (38). In an apparent paradox, other studies have described elevated NO production in cardiac allografts associated with iNOS expression (39,40).…”

The Role of Viruses in Cardiac Allograft Vasculopathy

“…There is considerable data indicating that NO deficiency plays a role in CAV, and some evidence that CMV may contribute to this NO deficiency that leads to CAV, reviewed by Weis (56). In allograft transplantation, eNOS expression and activity can be impaired by several factors including pre-existing disease in the graft, ischemia at the time of transplantation, immunosuppressive agents, and conventional risk factors such as hypertension, diabetes hyperlipidemia, and infections.…”