Homocysteine, Folate, Vitamin B₆, and Cardiovascular Disease

The importance of hyperhomocysteinemia in the pathogenesis of arteriosclerosis was first recognized by study of vascular pathology in children with homocystinuria caused by 2 different enzymatic abnormalities of homocysteine metabolism.¹ Homocystinuria caused by deficiency of cystathionine synthase, a pyridoxal phosphate-dependent enzyme, is characterized by vascular abnormalities and frequent arterial and venous thromboses.² In 1968 a 2-month-old boy with a rare form of homocystinuria caused by deficiency of methyltetrahydrofolate homocysteine methyl transferase, a cobalamin-dependent enzyme, was discovered to have rapidly progressive arteriosclerosis.¹ Because of the different metabolic patterns caused by these 2 enzymatic abnormalities, it was suggested that homocysteine causes arteriosclerotic plaques by a direct effect on the cells and tissues of the arteries. A third enzyme abnormality leading to homocystinuria, deficiency of methylenetetrahydrofolate reductase, a folate-dependent enzyme, was found to cause arteriosclerotic plaques,³ also supporting the conclusion that homocysteine is atherogenic. This interpretation explains the origin of arteriosclerosis observed in vitamin B₆–deficient monkeys and choline-deficient rats, 2 important animal models in which hyperhomocysteinemia also leads to atherogenesis. The atherogenic effect of homocysteine was subsequently demonstrated experimentally by parenteral and alimentary administration of the amino acid to rabbits^4- 5 and baboons.⁶