See article vol. 23: 681–691
Hyperhomocysteinemia is associated with the risk of atherosclerotic disease. A variety of effects of homocysteine including induction of endothelial dysfunction, lipid peroxidation, decrease in nitric oxide availability and platelet activation are related to the pathophysiology of vascular disease1). However, homocysteine- lowering interventions by supplements of vitamins B6, B9 (folate), and B12 have recently been shown by meta-analyses to have no significant effect on nonfatal or fatal myocardial infarction, stroke or death from any cause2, 3). Thus, the causal relationship between homocysteine levels and atherosclerotic disease remains obscure.
Arterial stiffness is associated with atherosclerotic burden and is a predictor of cardiovascular events, although the nature of the possible link between arterial stiffness and atherosclerosis is not clearly established4). Homocysteine may increase arterial stiffness through stimulation of smooth muscle proliferation, increase in collagen synthesis, induction of endothelial dysfunction and degradation of arterial elastic structures1). Homocysteine levels in blood are known to be associated with arterial stiffness in patients with hypertension. However, it is controversial whether homocysteine levels are associated with arterial stiffness in the general population. In addition, there have been few prospective studies on the relationship between homocysteine level and arterial stiffness in the general population.
Mantjoro et al. investigated the relationships of arterial stiffness with plasma homocysteine level and its related factors including genetic polymorphisms of 5,10-methylenetetrahydrofolate reductase (MTHFR) and methionine synthase (MS) and folate intake5). Arterial stiffness was evaluated at baseline and after a 5-year follow-up by measuring cardio-ankle vascular index (CAVI), which is believed to be a better approach to evaluate arterial stiffness than the conventional method of pulse wave velocity because CAVI is independent of blood pressure. After adjustment for multiple variables including age, hypertension, dyslipidemia, glucose intolerance, current smoking, current drinking, family history of coronary arterial disease, body mass index, and habitual exercise, homocysteine levels were significantly associated with CAVI values after the 5-year follow-up and the difference in CAVI values at the baseline and 5-year follow-up in men, whereas these associations were not found in women. There were no significant associations between CAVI values and homocysteine-related factors including polymorphisms of MTHFR and MS and folate intake both in men and women. The authors carefully reviewed eight related previous studies, and the aforementioned positive association between homocysteine levels and CAVI values is consistent with the results of three cross-sectional studies and one prospective study showing that homocysteine levels were significantly associated with CAVI and aorta-femoral, brachial-ankle, or carotid-femoral pulse wave velocity.
There are two intriguing aspects of this article to be discussed. One is the gender difference in the homocysteine–arterial stiffness relationship5). This finding is consistent with the results of a recent cross-sectional study showing that plasma homocysteine levels were associated with carotid-femoral pulse wave velocity and carotid-ankle pulse wave velocity in men but not in women6). Possible reasons for this gender difference are presence of higher levels of homocysteine and arterial stiffness in men than in women, which may make the association between homocysteine and arterial stiffness more detectable in men than in women. The gender difference in blood homocysteine concentration may be explained by the differences in homocysteine metabolism (Fig. 1): The rate of conversion of homocysteine to cystathionine has been shown to be higher in women than in men7). Activity of the transamination pathway of methionine, which may exist as a minor pathway for methionine metabolism in humans, was also reported to be higher in women than in men8). A recent study suggested that high blood pressure and mild hypertension enhanced the effect of high homocysteine levels on arterial stiffness, which is possibly explained by high blood pressure-induced susceptibility of the endothelium to deleterious effects of homocysteine in the blood9). Therefore, higher blood pressure in men than in women may also be related to the gender difference in the relationship between homocysteine level and arterial stiffness.
Fig. 1.
Homocysteine metabolism and effects of homocysteine on arterial stiffness.
The other issue for discussion regarding this article is that no significant association was found between CAVI values and polymorphisms of MTHFR C677T and MS A2756G or folate intake, although homocysteine levels were significantly associated with MTHFR polymorphism5). Results of previous studies regarding the relationship between blood homocysteine levels and polymorphisms of enzymes involved in the metabolism of homocysteine are conflicting. Further studies are therefore needed to clarify the relationship between homocysteine-related gene polymorphisms and arterial stiffness. Moreover, the detailed mechanisms under-lying the association between homocysteine and arterial stiffness remains to be clarified.
The absence of significant association between folate intake and CAVI values in this article is consistent with the results of meta-analysis for previous intervention studies on intake of B-complex vitamins and the risk of cerebro- and cardiovascular diseases2, 3). However, according to a recent randomized clinical trial (RCT) for primary prevention of stroke, the combined use of enalapril and folate, compared with enalapril alone, significantly reduced the risk of first stroke among 20702 Chinese adults with hypertension10). The advantages of that investigation are a large population size, a low percentage of participants taking antiplatelet agents, and low blood levels of folate at baseline. Further investigations of well-controlled RCTs are warranted to determine whether high homocysteine in blood is a causal risk factor for atherosclerotic disease.
Conflicts of Interest
None.
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