Is folic acid the answer?

In 1969 McCully proposed his “homocysteine theory of arteriosclerosis,” ie, that elevated homocysteine concentrations may be a cause of cardiovascular disease (CVD) in the general population (1). The first evidence was reported in 1976, when Wilcken and Wilcken showed a relation between abnormal homocysteine metabolism and coronary artery disease (CAD) (2). Since then, the results of numerous studies have led to the conclusion that the association between total homocysteine (tHcy) and CVD is strong, graded, and independent of the conventional risk factors (3). However, the association seems to be largely confined to populations already at high risk of CVD events (4). Because folate concentrations are an important determinant of tHcy, it is surprising that reports on the relation between folate status and CVD have been slow to catch up. A seminal study in 1996, the Nutrition Canada Survey (5), reported that low serum folate concentrations are associated with an increased risk of fatal CAD events. Other studies have followed, and the overall impression is that there is a modest inverse relation between serum folate concentrations and CVD risk (3). In this issue of the Journal, Voutilainen et al (6) report their data from the Kuopio Ischaemic Heart Disease Risk Factor Study, a population-based study of 810 men aged 46–64 y who had no previous history of CAD. Acute coronary events were observed in 61 of the men during a follow-up of 7.7 y. Compared with the men with serum folate concentrations in the lowest tertile, those with concentrations in the highest tertile had an adjusted relative risk of acute coronary events of 0.35 (95% CI: 0.17, 0.73). In contrast, there was no association between tHcy and the risk of acute coronary events (relative risk: 1.03; 95% CI: 0.57, 1.87). This new report extends the same authors’ findings in 2 previous reports. One was a report of a nested case-control study of the same population in which the baseline was in 1984 and the follow-up was in 1996: tHcy concentrations were almost identical in 163 cases and 163 controls (11.24 compared with 11.20 mol/L, respectively). Logistic regression showed no evidence that elevated tHcy was a risk factor for CAD (7). In the second of their earlier reports (8), the same baseline (ie, 1991–1993) was used as in the new report, but the follow-up time was 5.3 y, and the number of cases with events was only 34. In that earlier study, mean serum folate concentrations in the cases and controls were 9.4 and 10.5 nmol/L, respectively (ie, identical to the concentrations reported in the new study). The value of this new study lies in the longer follow-up time with more cases and in the fact that both folate and tHcy concentrations were measured in the same baseline samples and in the entire cohort. The most surprising finding in this Finnish male population is that low folate concentrations are associated with increased risk of CAD events independently of tHcy concentrations. Most other studies have found that the effect of low folate concentrations is mediated at least in part by tHcy (3). The other main finding, ie, that elevated tHcy is not a risk factor in a population in whom subjects with prior CAD were excluded, is less surprising. In 2002 the Homocysteine Studies Collaboration reported the result of a large meta-analysis, which included a total of 5073 CAD events and 1113 stroke events. They concluded that tHcy is at most a modest CVD risk factor in the general population (9). This finding may be used as an argument against the homocysteine theory. In my opinion, the finding only shows that in a population with a low overall risk of CVD and in whom most subjects have normal tHcy concentrations, tHcy is not a strong risk factor. Indeed, even in high-risk populations (ie, patients with CVD, renal failure, diabetes, etc), for whom tHcy is a consistently strong risk factor, the marked increase in risk is predominantly observed in those with a tHcy concentration 15 mol/L (4). Unfortunately, the Homocysteine Studies Collaboration did not report the risk in subjects with a tHcy concentration 15 mol/L. Nevertheless, the findings from the meta-analysis, as well as those from the Kuopio Ischaemic Heart Disease Risk Factor Study, suggest that homocysteine may be overrated as a potential causal risk factor for CVD. Supplementation with B vitamins, particularly including folic acid, reduces tHcy concentrations. However, whether such treatment prevents CVD events is unknown; this can be determined only by large-scale clinical trials. Unfortunately, current trials cannot distinguish between the risk due to elevated tHcy and that due to low folate status. Nearly all the trials include high doses of folic acid, which influence folate concentrations as well as tHcy concentrations, and most of the trials also include high doses of vitamin B-12 or vitamin B-6 (3). What are missing are trials using agents such as betaine that lower tHcy independently of folate. Some reports from trials using folic acid and vitamins B-12 and B-6 in combination are now available. In healthy siblings of patients with atherothrombotic disease, B vitamins decreased the occurrence of abnormal results on an exercise electrocardiography test but did not improve peripheral arterial abnormalities (10). In renal transplant recipients, the intima-media thickness of