Accelerated atherosclerosis in cardiac transplantation

Accelerated coronary atherosclerosis remains a potential rate-limiting problem to longterm survival in cardiac transplantation. In order to gain insight into this problem, we have formulated the hypothesis that chronic immune injury (cytotoxic B-cell antibodies) and/or hypercholesterolemia (increase in total cholesterol/high-density lipoprotein cholesterol) predispose to accelerated coronary atherosclerosis. Fourteen long-term survivors of cardiac transplantation (>6 months) were longitudinally followed for the presence of cytotoxic B-cell antibodies, hyperlipidemia, and the development of coronary atherosclerosis. Three patients who received transplants for treatment of cardiomyopathy remained antibody negative, maintained normal serum lipids, and have no coronary disease. Eleven patients developed hyperlipidemia (one receiving transplant for idiopathic cardiomyopathy, 10 for ischemic cardiomyopathy). Six of these patients developed cytotoxic B-cell antibodies and all six developed severe, diffuse, tubular atherosclerosis and died within 8 to 30 months. The presence of cytotoxic B-cell antibodies combined with hyperlipidemia was a predictor of early myocardial infarction and/or sudden death (<2.5 years; p =.004). Histologically, the disease was characterized by severe atherosclerosis with the presence of lymphocytic and monocytic infiltrates. In the remaining five hyperlipidemic patients who did not develop cytotoxic B-cell antibodies, late graft atherosclerosis developed (>3 years), characterized by more proximal discrete lesions and only one death from myocardial infarction at 6.5 years. We conclude that hypercholesterolemia (increase in total cholesterol/ high-density lipoprotein) and the presence of cytotoxic B-cell antibodies results in the development of graft atherosclerosis, early myocardial infarction, and death. Hypercholesterolemia in the absence of cytotoxic B-cell antibodies is a risk factor for the development of late graft atherosclerosis that is more proximal in nature.