Homocysteine and Stroke Risk: Role for Folate Therapy
July 1, 2002
Abstracts & Commentary
Sources: Bazzano LA, et al. Stroke. 2002;33:1183-1189; Kasner SE. Stroke. 2002;33:1189; Miller JW, et al. Neurology. 2002;58:1471-1475.
Substantial evidence exists to link homocysteine (Hcy) levels with atherosclerosis and cardiovascular disease. Hcy may damage arteries by promoting endothelial cell proliferation or it may produce oxidative damage to vessel walls. Alternatively, it may increase coagulation and disturb endothelium dependent vasomotor reactivity. Because Hcy metabolism directly depends on other nutrients, such as folate and vitamin B12, intake of these compounds either in the diet or as supplementation is crucial to keep Hcy levels low. An inverse relationship between blood concentrations of folate and cardiovascular disease has been strongly suggested in epidemiological studies. Similar findings occur with stroke. Bazzano and colleagues’ study further strengthens these associations showing that dietary folate intake has a strong influence on subsequent stroke risk.
Bazzano et al studied 9764 subjects from a National Health and Nutrition Examination Survey (NHANES), aged 25-74 years who were healthy at the time of recruitment in 1971-1975. Dietary folate intake was calculated based on a 24-hour food survey. Follow-up through 1992 showed 926 stroke events and 3758 incidents of cardiac disease. Stroke was defined based on ICD-9 codes with data taken from death certificates, hospital, or nursing home records. Individuals who consumed > 300 µg of folate per day were 20% less likely to suffer stroke than those consuming < 136 µg. Higher folate intake reduced cardiovascular disease by 13%. These effects were preserved when adjusting for variables such as gender, blood pressure, cholesterol, tobacco use, diabetes, or physical activity. Benefits were similar whether folate intake was analyzed as a continuous variable or by quartile analysis, suggesting that there was no particular threshold effect.
As observed by Bazzano et al, this study is limited by possible inaccuracies in dietary recall or variability not appreciated with a 1-day survey. Such discrepancies, however, would have skewed the study toward a negative result (Type-II error) rather than bias in favor of a folate benefit. Also, folate supplementation with vitamins was not specifically examined in the 1970s, however, typical vitamins contained only 100 µg of folate and only 12.6% of participants reported regular vitamin use.
In another study worthy of note, Miller and colleagues studied Hcy levels in patients with Alzheimer’s disease (AD) and compared them to controls without AD. There was no increase in plasma Hcy levels in the AD patients. This was in contrast to several other studies that have previously associated elevated Hcy levels with AD risk. Interestingly, however, when patients in Miller’s study were divided based on the presence of concomitant vascular disease, there was a significant association between vascular disease and elevated Hcy. Mean serum Hcy levels among patients with vascular disease was 12.9 compared with 10.1 among those without (P < 0.001). When dichotomized into groups with Hcy above or below 12, elevated Hcy showed an odds ratio of 10.0 (P < 0.03). Vascular disease was not restricted to stroke but, rather, was broadly defined as patients with coronary artery disease, prior TIA, or the presence of cerebral infarction on CT or MRI.
Commentary
As noted by Kasner in an accompanying editorial, studies of high-dose vitamin supplementation such as the Vitamin Intervention for Stroke Prevention (VISP) may provide randomized evidence to support the findings of the observational studies such as that of Bazzano et al. Such studies may be underpowered, however, since over the past few years the FDA has mandated the addition of folate to flour and other food products. The effect of additional supplementation may, therefore, be attenuated by increased background dietary intake.
It is not entirely clear what dose of folate is optimal. Typical multivitamin preparations contain 400 µg of folate which exceeds the quantity found effective in Bazzano et al’s study. Intake of fortified food, for instance, highly supplemented breakfast cereals, could also match these levels. In contrast, studies such as VISP dose folate in a much higher 2.5-3.0 mg range. Folate dosing may be best guided by serum Hcy levels. However, it is equally unclear exactly how low we should go with Hcy. Hcy levels < 12 are likely optimal, but since risk related to Hcy is a continuous rather than dichotomized variable, further decreases into the 8-10 range are probably optimal. —Alan Z. Segal
Dr. Segal, Assistant Professor, Department of Neurology, Weill-Cornell Medical College, Attending Neurologist, New York Presbyterian Hospital, is Assistant Editor of Neurology Alert.
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