Homocysteine and atherothrombosis.

From the Whitaker Cardiovascular Institute and Evans Department of Medicine, Boston University School of Medicine, 715 Albany St., W-507, Boston, MA 02118, where reprint requests should be addressed to Dr. Loscalzo. ©1998, Massachusetts Medical Society. N 1969, McCully made the clinical observation linking elevated plasma homocyst(e)ine concentrations with vascular disease. 1 He reported autopsy evidence of extensive arterial thrombosis and atherosclerosis in two children with elevated plasma homocyst(e)ine concentrations and homocystinuria. On the basis of this observation, he proposed that elevated plasma homocyst(e)ine (hyperhomocyst(e)inemia) can cause atherosclerotic vascular disease. The term “homocyst(e)ine” is used to define the combined pool of homocysteine, homocystine, mixed disulfides involving homocysteine, and homocysteine thiolactone found in the plasma of patients with hyperhomocyst(e)inemia. Subsequent investigations have confirmed McCully’s hypothesis, and it has recently become clear that hyperhomocyst(e)inemia is an independent risk factor for atherosclerosis and atherothrombosis. Although severe hyperhomocyst(e)inemia is rare, mild hyperhomocyst(e)inemia occurs in approximately 5 to 7 percent of the general population. 2,3 Patients with mild hyperhomocyst(e)inemia have none of the clinical signs of severe hyperhomocyst(e)inemia or homocystinuria and are typically asymptomatic until the third or fourth decade of life when premature coronary artery disease develops, as well as recurrent arterial and venous thrombosis. Abundant epidemiologic evidence has demonstrated that the presence of mild hyperhomocyst(e)inemia is an independent risk factor for atherosclerosis in the coronary, cerebral, and peripheral vasculature (see below). 4,5 Although I the molecular mechanism by which homocyst(e)ine or a related metabolite promotes atherothrombosis is unknown, the epidemiologic evidence of the association of hyperhomocyst(e)inemia with atherothrombotic vascular disease is convincing. In this review, we will evaluate the evidence of a relation between elevated plasma homocyst(e)ine concentrations and vascular disease. Potential mechanisms for this effect are also discussed.