on March 20, 2003
Published online before print March 20, 2003, doi: 10.1161/01.ATV.0000067060.31369.F9
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Submitted on October 23, 2002
Accepted on February 5, 2003
Cardiac Allograft Vasculopathy and Dysregulation of the NO Synthase Pathway
Michael Weis and John P. Cooke *
From the Division of Cardiovascular Medicine (J.P.C.), Stanford University School of Medicine, Stanford, Calif, and Medizinische Klinik I (M.W.), University Medical Center Munich-Grosshadern, Ludwig-Maximilians University of Munich, Munich, Germany.
* To whom correspondence should be addressed. E-mail: john.cooke{at}stanford.edu.
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.
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