An elevated plasma homocysteine level is recognized as a risk factor for atherosclerotic vascular disease, although the strength of the relationship is unknown. Graham and colleagues examined the relationship between total plasma homocysteine level and risk of vascular disease and the possible interaction between homocysteine level and conventional risk factors.

The case-control study included 750 persons with coronary, cerebrovascular or peripheral vascular disease and 800 control subjects, all of whom were under 60 years of age. Patients were excluded if they had nonatherothrombotic vascular disease (such as vasculitis), diabetes mellitus, renal or hepatic disease, or thyroid disorders. Plasma cobalamin, pyridoxal 5'-phosphate, red blood cell folate and serum cholesterol levels were measured in addition to plasma homocysteine levels.

Homocysteine levels in the top one fifth of the distribution were considered elevated. Homocysteine levels were elevated in 241 control subjects (30.1 percent) and in 375 of the persons with vascular disease (50.0 percent). The relative risk of vascular disease in persons with homocysteine levels in the top one fifth of the distribution was 2.2 compared with the risk of vascular disease in those with levels in the lower four fifths of the distribution. The relationship between elevated homocysteine levels and the presence of vascular disease was as strong as the relationship between hypercholesterolemia or smoking and vascular disease. Even when the presence of other risk factors was controlled for, an elevated homocysteine level was still strongly predictive of vascular disease.

For a 5-μmol-per-L increment in the plasma homocysteine level, the relative risk of vascular disease was 1.35 in men and 1.42 in women. Patients who were in the top 10th of the distribution of homocysteine levels had a greater than threefold relative risk of vascular disease, compared with those in the bottom 10th of the distribution.

The authors conclude that an elevated plasma homocysteine level is a strong and independent risk factor for atherosclerotic vascular disease. They believe that measurement of the homocysteine level should be part of the risk assessment for vascular disease. The additive and multiplicative effects of an elevated homocysteine level plus other risk factors suggest that interventions to lower blood pressure and encourage smoking cessation are even more important in patients with elevated homocysteine levels. The authors note that studies of the effects of folic acid and, perhaps, pyridoxine on secondary prevention of cardiovascular disease are needed.