Vascular and Blood Pressure Effects of Folic Acid in Older Patients with Cardiovascular Disease

To the Editor: Homocysteine (Hcy) plasma concentrations are positively correlated with cardiovascular risk and increase with advancing age.1 The mechanisms responsible for Hcy deleterious effects include endothelial dysfunction and wall stiffening.1 Hcy levels are inversely related to plasma levels of folic acid (F).1 Despite the fact that F effectively reduces Hcy, it is largely unknown whether the Hcy lowering is associated with a reversal of the vascular abnormalities. We addressed this issue by studying the short-term effects of F supplementation on pulse-wave velocity (PWV), a marker of arterial stiffness, in 10 patients with previous myocardial infarction or stroke. Each subject underwent three visits at −1, 0, and 6 weeks after F supplementation. During visit 1, blood pressure (BP) and heart rate (HR) were measured, a blood sample was taken (lipid profile, creatinine, Hcy, F, vitamin B12 concentrations, and methylenetetrahydrofolate reductase (MTHFR) genotype), and the carotid-radial PWV was measured. During visit 2, BP, HR, and PWV were reassessed and the patients started F supplementation (5 mg/day for 6 weeks). During visit 3, BP, HR, and PWV were measured again and a blood sample, for the reassessment of the parameters apart from MTHFR genotype, was taken. Three subjects were heterozygotes for the C→T677 thermolabile variant of MTHFR. Mean PWV values at weeks −1 and 0 were identical (10.3 ± 0.6 meters/sec at −1 vs. 10.3 ± 0.6 m/sec at 0, Table 1). There were no changes in concomitant medication or dosage or reported adverse events during F supplementation. Body mass index, plasma cholesterol, triglycerides, creatinine, and vitamin B12 before and after F were similar. F induced a significant reduction of both Hcy:creatinine ratio and PWV (Table 1). This was associated with a marked fall in both systolic BP (SBP) and pulse pressure (PP), whereas HR did not change (Table 1). A backward-stepwise multiple regression analysis showed that baseline Hcy:creatinine ratio was an independent predictor of Hcy:creatinine ratio (R2 = 73.2, P = .001), SBP (R2 = 42.4, P = .041), and PP changes (R2: 68.7, P = .027). Our study provides, to our knowledge, the first evidence that short-term F supplementation markedly reduces arterial stiffness within a short period of time. An unexpected observation is represented by the fall in both SBP and PP, which has not been reported thus far. Therefore, a simple, inexpensive, nontoxic vitamin intervention appears to provide potential cardioprotection in high-risk people and might play a major role in the prevention of cardiovascular disease. Hyperhomocysteinemia decreases bioavailable nitric oxide by increasing its susceptibility to oxidative inactivation in vitro.2 Therefore, increased nitric oxide activity secondary to Hcy lowering might contribute to the reduction of arterial stiffness, hence the SBP and PP lowering. Our study may have important clinical implications for several reasons. First, the effects of F have been investigated in selected groups of patients with hyperhomocysteinemia, such as healthy subjects, patients with familial hypercholesterolemia, and healthy siblings of patients with premature cardiovascular disease.3-5 Our data show that F is safe and effective in a group representative of a larger population, namely high-risk subjects with a history of cardiovascular disease, thus broadening the spectrum of its potential applications. Interestingly, five patients had mild hyperhomocysteinemia, whereas the remaining five had values in the upper normal range. Although the definition and classification of hyperhomocysteinemia is still controversial, F supplementation appears to be beneficial not only in patients with severe hyperhomocysteinemia, but also in those with mild hyperhomocysteinemia or even in those with normal Hcy. This is confirmed by the observation that relatively low baseline Hcy:creatinine ratios still account for a significant proportion of the changes in Hcy, SBP, and PP. Interestingly, the effects of F on PWV and blood pressure are additive to those already achieved by conventional pharmacological treatment with cardioactive drugs. Second, PWV is a marker of cardiovascular risk as it relates to the presence and severity of atherosclerosis.6 Therefore, its reduction following F supplementation indicates not only a modification of arterial function, but also probable cardiovascular disease risk reduction. Third, the Hcy lowering is associated with a parallel reduction of both SBP and PP, two established cardiovascular risk factors, thus providing substantial cardioprotection by reducing both arterial impedance and cardiac afterload. Moreover, the Hcy:creatinine ratio is a predictor of the BP changes, thus potentially allowing the identification of the “responders” versus “nonresponders” to F supplementation. The limitations of our study are related to its open design and the limited number of subjects. Therefore, large-based randomized controlled trials are needed to confirm that our findings would result in a reduction of cardiovascular endpoints. We thank Ms. Tracy Dew for her technical support.