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The homocysteine hypothesis: Still relevant to the prevention and treatment of cardiovascular disease?

Cleveland Clinic Journal of Medicine. 2010 December;77(12):911-918 | 10.3949/ccjm.77a.10036
December 1, 2010|Cleveland Clinic Journal of Medicine
Joellyn M. Abraham, MD;Leslie Cho, MD
Author and Disclosure Information

Joellyn M. Abraham, MD
Cardiovascular Medicine, Cleveland Clinic

Leslie Cho, MD
Section Head, Preventive Cardiology and Rehabilitation, and Director, Women’s Cardiovascular Center, Cleveland Clinic

Address: Leslie Cho, MD, Women’s Cardiovascular Center, JB-1, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195; e-mail chol@ccf.org

ABSTRACTAlthough evidence suggests that the homocysteine hypothesis is still relevant as a predictor of cardiovascular risk, we cannot conclude that measuring the homocysteine level is useful in guiding treatment. Furthermore, studies of primary and secondary prevention show no evidence that taking folic acid or other B vitamins lowers the risk of cardiovascular events.

KEY POINTS

  • Factors that can cause the plasma homocysteine concentration to be high include deficiencies of vitamin B6, vitamin B12, and folic acid; renal insufficiency; and genetic variants in enzymes responsible for homocysteine metabolism.
  • Higher plasma homocysteine levels are associated with a higher risk of cardiovascular, cerebrovascular, and peripheral arterial disease.
  • Supplementation of B vitamins and folic acid can lower plasma homocysteine levels.
  • Randomized controlled trials of supplementation to prevent cardiovascular events and other adverse outcomes have had mostly negative results. However, most patients in these trials had normal baseline plasma homocysteine levels.
  • Needed are randomized trials to see if supplementation improves outcomes in patients with high homocysteine levels.

HOW GREAT IS THE RISK?

Studies over the past 10 to 20 years have shown that elevated homocysteine is a marker of risk of cardiovascular disease. The association was first noted in patients with cystathionine beta-synthase deficiency, who tend to have premature cardiovascular disease.

However, studies of patients with MTHFR 677C>T have yielded mixed results. Although several meta-analyses found up to a 42% higher rate of ischemic heart disease and stroke in patients homozygous for MTHFR 677C>T (the TT genotype) than in those with the CC genotype,17,19,20 two other large meta-analyses did not find an association between this variant and vascular risk.21,22

Nonetheless, in a meta-analysis of the association between homocysteine and cardiovascular disease, Wald et al17 found that for every 5-μmol/L increase in serum homocysteine concentration, the risk of ischemic heart disease increased 20% to 30%.

TRIALS OF HOMOCYSTEINE-LOWERING THERAPY HAVE HAD MIXED RESULTS

Primary prevention of cardiovascular disease

Given the finding that treatment with folic acid lowers homocysteine—initially noted in patients with homocystinuria—researchers hypothesized that treatment with folic acid, vitamin B6, and vitamin B12 would decrease the risk of cardiovascular disease.

Little evidence currently exists to guide recommendations for homocysteine-lowering therapy to prevent first attacks of cardiovascular disease. The few studies published to date have been observational studies of dietary intake (not vitamin supplementation), and many were performed before folic acid fortification was mandated for flour and cereal (Table 2).23–27 Although the studies suggest that higher B-vitamin intake correlates with less vascular disease and its sequelae, there is uncertainty as to whether it is folic acid, vitamin B6, or vitamin B12 that is responsible, and also whether supplements would provide the same protective benefit as the presence of these nutrients in a varied diet.

Thus, in its recent evaluation of novel risk markers of cardiovascular disease, the United States Preventive Services Task Force 28,29 does not recommend measuring the plasma homocysteine level in the evaluation of either low-risk or intermediate-risk populations, finding no evidence that it adds any useful information in predicting major coronary events beyond what one could get from calculating the Framingham Risk Score. The task force also found no evidence that treating people who have elevated homocysteine levels decreases their risk of subsequent cardiovascular events.

In addition, a recent Cochrane Database review of eight randomized controlled trials in patients at low risk did not find a lower risk of myocardial infarction (fatal or nonfatal), stroke, or death from any cause in patients receiving B-complex vitamins.30

Secondary prevention of cardiovascular disease

Results have been mixed with regard to the ability of B vitamins to prevent cardiovascular events in patients with known cardiovascular disease (Table 3).4,5,11,12,31–46

Bazzano et al,47 in a meta-analysis published in 2006, evaluated 12 randomized controlled trials of folic acid supplementation in patients with known cardiovascular disease and did not find that treated patients had better cardiovascular outcomes. The mean homocysteine level was elevated (> 15 μmol/L) at baseline in only 4 of the 12 trials. However, in 1 of these 4 trials, there was no difference in outcomes comparing those with and without elevated homocysteine.31

Albert et al4 more recently evaluated the effect of a combination pill containing folic acid, vitamin B6, and vitamin B12 on cardiovascular events in women at high risk, ie, those with a history of cardiovascular disease or having three or more coronary risk factors. Treatment did not decrease the rate of the composite outcome of cardiovascular disease mortality, stroke, myocardial infarction, or coronary revascularization, although the homocysteine level decreased by a mean of 30% in the treated group. However, only 27.7% of the participants had an elevated homocysteine level. One might not expect patients to benefit from such treatment if they had normal homocysteine levels to begin with.

Ebbing et al,5 in a trial published in 2008, investigated the effect of folic acid, vitamin B12, and vitamin B6 supplements on the risks of death from any cause and of cardiovascular events in patients undergoing coronary angiography. Outcomes were no better in the treatment group than in the control group, despite a mean decrease in homocysteine level of 19%. However, over 90% of the participants had a normal homocysteine level.

Mager et al,32 in a study published in 2009, looked specifically at whether patients with coronary artery disease and elevated homocysteine levels (> 15 μmol/L) would benefit from folate-based vitamin therapy. In this subset, the incidence of death from any cause was lower in the treated group than in the control group (4% vs 32%, P < .001), an association that was not present in patients with normal homocysteine levels.

The SEARCH trial (Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine),33 recently published, was a double-blind, randomized controlled trial of vitamin B12 and folic acid treatment in 12,064 patients who had survived a myocardial infarction. Although those who received the vitamin therapy had a 28% reduction in homocysteine level, no clinical benefit was demonstrated. Of note, 66% of the patients had a homocysteine level lower than 14 μmol/L at baseline.

Restenosis after angioplasty

Results are also mixed regarding whether folic acid supplements modify the risk of restenosis after coronary angioplasty.

Namazi et al48 evaluated the effect of folic acid supplementation on in-stent restenosis in 200 patients and found no difference between the treatment and placebo groups in the rates of either restenosis or target-vessel revascularization.

Schnyder et al49 evaluated the effect of folic acid, vitamin B6, and vitamin B12 treatment on the rate of coronary restenosis (in cases of balloon angioplasty) or in-stent restenosis (if a stent was used). Patients receiving treatment had lower rates of restenosis or instent restenosis (40% vs 48%, P = .01) and of need for target-vessel revascularization (11% vs 22%, P = .047). The mean homocysteine level was not elevated in this study either, and the researchers did not analyze the outcomes according to whether patients had high or normal homocysteine levels.

Lange et al35 also evaluated the effect of folic acid, vitamin B6, and vitamin B12 treatment on coronary in-stent restenosis. Paradoxically, the rate was higher with treatment in the overall group (mean homocysteine level 12.2 μmol/L), leading to a higher incidence of target-vessel revascularization. Patients who had a baseline elevation in homocysteine level had a nonsignificant trend toward a lower rate of in-stent restenosis.

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