Homocysteine as a Risk Factor for Peripheral Vascular Disease

Summary

Since the observation that patients suffering from homocystinuria had marked and early progression of diffuse atherosclerosis, the association between mildly elevated homocysteine levels and atherosclerosis has been documented. The identification of a large number of people with elevated homocysteine levels due to genetic and/or dietary effects has pushed research to evaluate the question of whether homocysteine is a modifiable risk factor for atherosclerosis. The ability to return elevated homocysteine levels to normal with vitamin therapy has given rise to the possibility of not only secondary prevention, but also primary prevention of atherosclerosis. We will focus on the relationship between homocysteine and peripheral vascular disease.

A clear association between elevated homocysteine and the presence of peripheral vascular disease has been demonstrated by several investigators. In studies excluding patients with standard risk factors (diabetes mellitus, hypertension, elevated lipids) or statistically eliminating these factors, elevated homocysteine has been shown to be an independent risk factor for the presence of peripheral vascular disease. Moreover, the magnitude of the risk appears to be proportional to the elevation in homocysteine and not a threshold effect.

The effect of elevated homocysteine appears to be of a magnitude similar to elevated cholesterol.

With the association established between elevated homocysteine and peripheral vascular disease, the next step was to evaluate whether the elevation of homocysteine could be modified. Several studies have demonstrated that treatment with vitamin B₆, folate, or a combination of these can successfully lower homocysteine levels in patients with peripheral vascular disease. Moreover, while the underlying cause of elevated homocysteine is varied (genetic {cystathionine ßsynthase mutations, thermolabile methylenetetrahydrofolate reductase}, nutritional), the success of vitamin therapy appears applicable across the board.

A link has also been documented between elevated homocysteine and progression of peripheral vascular disease. A key retrospective study has demonstrated greater progression of peripheral vascular disease in patients with elevated homocysteine levels compared to those with normal levels. Homocysteine elevation has also been shown to adversely affect the outcome of surgical interventions for peripheral vascular disease, as well as to contribute to a higher incidence of vein graft stenosis following lower extremity bypass.

The key question looms ahead: Will the treatment of elevated homocysteine levels retard or even halt the progression of peripheral vascular disease? We are currently involved in a prospective study evaluating the natural history of elevated homocysteine as pertains to peripheral vascular disease, as well as the role of treatment with folate on the progression of peripheral vascular disease. Phase one of this trial has recently been completed which evaluated the effect of elevated homocysteine on the progression of peripheral vascular disease. Over a follow-up period of 37 months, elevated homocysteine did appear to have an adverse effect on progression of lower extremity arterial disease, however this effect did not reach statistical significance. The most important results from this observational phase of the study were the marked increase in both progression of cardiac disease as well as death in patients with elevated homocysteine levels. Phase two of this study is ongoing and includes treatment with either folic acid or placebo with an additional 5 years of observation. Data from this study, and other ongoing prospective studies, will offer more definitive information regarding the potential role of nontoxic vitamin therapy in the treatment of peripheral vascular disease.