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Title: Low Dietary Folate Intake is Associated with an Excess Incidence of Acute Coronary Events. The Kuopio Ischemic Heart Disease Risk Factor Study

Authors: Sari Voutilainen, Tiina H. Rissanen et al

Reference: Circulation. (2001); 103:2674-2680.

Reviewer: Carlos Mendoza Montano, PhD

Problem addressed: In a number of cross-sectional studies, higher concentrations of plasma homocysteine ( Hcy) have been observed in patients with cardiovascular disease than in control subjects, suggesting that elevated plasma Hcy concentration is a risk factor for cardiovascular disease. Defects in intracellular Hcy metabolism lead to the elevation of plasma total Hcy (tHcy) levels. These metabolic defects can have a genetic or a nutritional background, ie, an inadequate intake of folate or vitamin B6 or B12 that serve as cofactors or substrates to the enzymes involved in Hcy metabolism. Although several prospective studies have shown that low folate intake and low circulating folate are associated with increased risk of coronary heart disease (CHD), the findings are inconsistent.

Purpose of study: The purpose of this prospective cohort study was to test the hypothesis that high folate intakes are associated with a decreased risk of acute coronary events in middle-aged Finnish men free of prior coronary heart disease (CHD).

Location of study: Kuopio, Finland.

Study design: The study investigated the associations of dietary intake of folate, vitamin B6, and vitamin B12 with the risk of acute coronary events in a prospective cohort study of 1980 Finnish men 42 to 60 years old examined in 1984 to 1989 in the Kuopio Ischemic Heart Disease Risk Factor Study. Nutrient intakes were assessed by 4-day food record. The subjects were divided into fifths of the mean daily folate intake (<211, 211 to 236, 237 to 261, 262 to 297, and >297 µg).

Results: During an average follow-up time of 10 years, 199 acute coronary events occurred. In a Cox proportional hazards model adjusted for 21 conventional and nutritional CHD risk factors, men in the highest fifth of folate intake had a relative risk of acute coronary events of 0.45 (95% CI 0.25 to 0.81, P=0.008) compared with men in the lowest fifth. This association was stronger in nonsmokers and light alcohol users than in smokers and alcohol users. A high dietary intake of vitamin B6 had no significant association and that of vitamin B12 a weak association with a reduced risk of acute coronary events. The role of folate in secondary prevention of acute coronary events was also studied. Of 660 men with previous CHD, those in the highest folate intake fifth had a relative risk of 0.71 (95% CI 0.35 to 1.44, P=0.34).

Comments: Together with previous findings, the present observations support the theory that folate and possibly vitamin B12 have a role in the prevention of CHD. This study indicates that moderate-to-high daily intake of folate is associated with greatly reduced incidence of acute coronary events. The association is strong, and adjustment for other dietary factors or traditional coronary risk factors did not attenuate the observed association. The risk-lowering effects of folate seem to be restricted mainly to study subjects without previous CHD at the study baseline. Potential mechanisms of folate independent of homocysteine lowering on cardiovascular health include antioxidant actions, effects on cofactor availability, or direct interactions with the enzyme endothelial NO synthase. Results of the ongoing large randomized trials are needed to conclusively verify the effect of folic acid supplementation in cardiovascular health.

Citations:

1.Chasan-Taber L, Selhub J, Rosenberg IH, et al. A prospective study of folate and vitamin B6 and risk of myocardial infarction in US physicians. J Am Coll Nutr. 1996;15:136-143.
2.Rimm EB, Willett WC, Hu FB, et al. Folate and vitamin B6 from diet and supplements in relation to risk of coronary heart disease among women. JAMA. 1998;279:359-364.