Homocysteine, Vitamin Deficiency and Prevention of Arteriosclerosis

Abstract

The homocysteine theory of arteriosclerosis was discovered by study of children with homocystinuria caused by different enzymatic disorders of homocysteine metabolism. Deficiency of cystathionine synthase, a pyridoxal phosphate dependent enzyme, causes elevated levels of plasma homocysteine. Deficiency of methyl transferase, a folic acid and cobalamin dependent enzyme, causes elevated levels of plasma homocysteine and cystathionine. Arteriosclerosis was discovered to be associated with homocysteinemia in both of these inherited dirorders. Because of different metabolic consequences of these two diseases, it was possible to conclude that homocysteine causes arteriosclerosis by damaging the endothelial cells and producing hyperplasia of smooth muscle cells and other connective tissue changes. Deficiency of a third enzyme, methylenetetrahydrofolate reductase, also causes homocystinuria and arteriosclerotic plaques, providing independent evidence to support this conclusion. Further evidence to support this conclusion came from studies with animals showing that injection of homocysteine causes arteriosclerotic plaques and thrombosis that closely resemble the vascular changes in children with homocystinuria. The homocysteine theory of arteriosclerosis relates the pathogenesis of the disease in the general population to dietary deficiencies of vitamin B6, folic acid, and vitamin B12. Deficiencies of these vitamins are produced by losses incurred during processing and preservation of basic foodstuffs. Population surveys have concluded that elevated levels of plasma homocysteine are an independent risk factor for arteriosclerosis, heart disease, and stroke. Elevated homocysteine levels have in turn been related to widespread deficiencies of folic acid and vitamin B6 within susceptible populations. The decline in mortality from coronary heart disease in the U.S. during the past three decades is attributed to increased vitamin B6 and folic acid that were introduced into the food supply through voluntary fortification and supplementation. A properly designed intervention trial is needed to show a major reduction in cardiovascular disease risk and complications by a diet and supplementary nutrients that reduce levels of homocysteine in the plasma.