Vitamin B12, homocysteine and carotid plaque in the era of folic acid fortification of enriched cereal grain products

Background

Carotid plaque area is a strong predictor of cardiovascular events. High homocysteine levels, which are associated with plaque formation, can result from inadequate intake of folate and vitamin B₁₂. Now that folic acid fortification is widespread in North America, vitamin B₁₂ has become an important determinant of homocysteine levels. We sought to determine the prevalence of low serum levels of vitamin B₁₂, and their relation to homocysteine levels and carotid plaque area among patients referred for treatment of vascular disease since folic acid fortification of enriched grain products.

Methods

We evaluated 421 consecutive new patients with complete data whom we saw in our vascular disease prevention clinics between January 1998 and January 2002. We measured total carotid plaque area by ultrasound and determined homocysteine and serum vitamin B₁₂ levels in all patients.

Results

The patients, 215 men and 206 women, ranged in age from 37 to 90 years (mean 66 years). Most were taking medications for hypertension (67%) and dyslipidemia (62%). Seventy-three patients (17%) had vitamin B₁₂ deficiency (vitamin B₁₂ level < 258 pmol/L with homocysteine level > 14 μmol/L or methylmalonic acid level > 271 nmol/L). The mean area of carotid plaque was significantly larger among the group of patients whose vitamin B₁₂ level was below the median of 253 pmol/L than among those whose vitamin B₁₂ level was above the median: 1.36 (standard deviation SD] 1.27) cm² v. 1.09 (SD 1.0) cm²; p = 0.016.

Conclusions

Vitamin B₁₂ deficiency is surprisingly common among patients with vascular disease, and, in the setting of folic acid fortification, low serum vitamin B₁₂ levels are a major determinant of elevated homocysteine levels and increased carotid plaque area.Elevated plasma total homocysteine levels are a strong, graded independent risk factor for stroke and myocardial infarction.^1,2 Mechanisms by which homocysteine may cause vascular disease include a propensity for thrombosis and impaired thrombolysis, increased production of hydrogen peroxide, endothelial dysfunction and increased oxidation of low-density lipoproteins and Lp(a) lipoproteins.³ Folic acid fortification of enriched cereal grain products began in North America in March 1996 and was made mandatory in 1998. Fortification has reduced the number of neural tube defects by half,⁴ which is clearly a beneficial outcome, but so far it has had little impact on cardiovascular mortality.⁵Carotid plaque area is a strong predictor of cardiovascular events.⁶ High homocysteine levels, which are associated with plaque formation, can result from inadequate intake of folate and vitamin B₁₂. Now that folic acid fortification is widespread, vitamin B₁₂ has become an important determinant of homocysteine levels.⁷ We sought to determine the prevalence of low serum levels of vitamin B₁₂, and their relation to homocysteine levels and carotid plaque area among patients referred for treatment of vascular disease since folic acid fortification of enriched grain products.