Synopsis: A case-control comparison demonstrated that the risk for vascular disease in subjects with elevated homocysteine was approximately two-fold greater. The increased risk was independent of other risk factors and positively interacted with smoking and hypertension.
Source: Graham IM, et al. JAMA 1997;277:1775-1781.
Prior case-control and prospective studies have suggested that elevated homocysteine level is a risk factor for the development of vascular disease. However, methodologic issues prevent appropriate relative magnitude of the risk and the interaction with other standard risk factors. Seven hundred fifty (750) cases of recently diagnosed vascular disease (coronary heart disease, cerebrovascular, and peripheral vascular disease) were compared with 800 age- and gender-matched controls free of known vascular disease. Plasma homocysteine levels were measured fasting and after methionine-loading, which stresses the metabolic degradation of homocysteine. Elevated levels were defined as one in the top fifth of levels in controls, and the relative risk was estimated by comparison of this top quintile with the remaining subjects. The independent risk as well as additive risk was compared for lipid levels (total, LDL, triglyceride, and HDL), systolic and diastolic BP, and presence or absence of current smoking. The cases were more likely to have each of the risk factors and had homocysteine levels that were 16% higher than controls. The relative risk for vascular disease was approximately two-fold greater in those with elevated homocysteine levels (top fifth) compared to the remaining four- fifths. The magnitude of the risk was in the same range of that estimated for hypercholesterolemia or smoking. The risk was independent of other risk factors and had strongly additive effects with smoking and hypertension.
COMMENT BY WILLIAM STRAUSS, MD
Over the last 30 years, clinical and epidemiologic evidence has been mounting that homocysteine is an independent risk factor for the development of atherosclerotic vascular disease. The present study confirms other prior epidemiologic data including that derived from the Framingham Heart Study and the Physician’s Health study. The current study confirms both the independence of the risk and the relative magnitude compared with other risk factors such as smoking or hyperlipidemia. In addition, it confirms the "multiplier" effect seen with these same risk factors. If one or two are bad, three is far worse, etc. Yet, what is lacking in consideration of our "newer or sexier" risk factors such as homocysteine, Lp(a), fibrinogen, and even triglycerides, is the second half of the story: Can we modify these risk factors, and, if so, does it reduce the risk for development of vascular disease?
Homocysteine levels are determined by both genetic and nutritional factors. Accumulating data suggest that those receiving supplemental B6, B12, and/or folate may lower homocysteine levels and, in the exceedingly small number of patients taking vitamin supplements in this current study, may even reduce the risk of vascular disease. Yet, as the authors suggest, what we really need is a good clinical trial or two, exploring the effect of such supplementation in appropriate doses on vascular disease. Homocysteine is a readily available laboratory determination, and even the methionine load test, although inconvenient, is not prohibitively expensive. However, I believe, before we rush to measure and treat such risk factors, we must ensure that we and our patients have paid maximal attention to those risk factors for which we have not only the evidence of risk, but the proof of benefit of treatment. I strongly suggest those with interest in such matters obtain a copy of the 27th Bethesda Conference: Matching the intensity of risk factor management with the hazard for coronary disease events.1
Reference
1. 27th Bethesda Conference. J Am Coll Cardiol 1996; 27:957-1047.
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