1. Introduction
Cardiovascular disease (CVD) is responsible for a third of all global deaths [
1], and the prevalence of CVD is increasing worldwide [
2] as well as in Korea [
3]. As the rise in the CVD incidence poses an economic burden and leads to increases in the number of disability-adjusted life years, indicating a diminished quality of life, it is important to identify and understand the potential risk factors and protective factors that may alleviate the burden of this disease [
4].
Certain nutrients have long been highlighted as modifiable risk factors for CVD [
5,
6]. Previous studies have investigated the possible biological mechanisms underlying the beneficial effects of vitamin B
6 on CVD prevention, such as the inhibition of lipoperoxide production and decreases in the levels of homocysteine and inflammation which are known risk factors of CVD [
7]. In addition, vitamin B
6 deficiency can cause hyperhomocysteinemia [
8], which may lead to arterial wall damage [
7]. Nevertheless, epidemiological studies investigating the association between vitamin B
6 and CVD have shown inconsistent results [
9,
10,
11]. The Nurses’ Health Study in the United States demonstrated an inverse relationship between plasma vitamin B
6 levels and the risk of myocardial infarction [
9]. Similarly, a Japanese cohort study revealed an inverse association between vitamin B
6 intake and coronary heart disease (CHD) incidence [
10]. In contrast, a study conducted in Finnish men found no significant association between vitamin B
6 intake and CVD risk [
11]. In Korea, few studies have investigated the effect of vitamin B
6 intake on CVD, and no corresponding prospective analyses have been conducted to date. Two previous case-control studies analyzed the association between vitamin B
6 and stroke in the Korean population and yielded conflicting results [
12,
13]. Those case-control studies were limited by their design, which aggravated the analysis of long-term dietary effects on chronic diseases, as it is practically impossible to recall long-term dietary habits prior to disease diagnosis [
14,
15].
Further investigation of the longitudinal association between vitamin B6 and CVD is warranted in a prospective cohort study, as is the assessment of dietary intake prior to disease onset. We, therefore, prospectively examined this association among Korean adults enrolled in the Ansung–Ansan cohort study.
3. Results
During the mean follow-up period of 7.4 years, 278 and 284 CVD cases were documented among men and women, respectively. The general baseline characteristics of the participants are shown in
Table 1. The dietary vitamin B
6 intake ranges were 1.01–6.22 mg/day in men and 0.88–7.51 mg/day in women, and the average age was 51.47 ± 0.13 years in men and 52.52 ± 0.13 years in women. Almost two-thirds of the alcohol drinkers were male, including 70.78%, 73.52%, and 71.54% of men in the lowest, mid, and highest dietary vitamin B
6 intake groups, respectively. In contrast, female alcohol drinkers accounted for only one-fourth of all the women, including 21.86%, 25.56%, and 27.57% of those in the lowest, mid, and highest dietary vitamin B
6 intake groups, respectively. Approximately half the men were current smokers (51.60%, 48.80%, and 50.06% in the lowest, mid, and highest dietary vitamin B
6 intake groups, respectively.), while the proportion of female smokers was very low (3.62%, 2.45%, and 4.19% in the lowest, mid, and highest dietary vitamin B
6 intake groups, respectively).
Table 2 shows the HRs of incident CVD in men and women according to the quintiles of dietary vitamin B
6 intake levels. In the multivariable adjusted model (Model 4), men in the highest quintile of dietary vitamin B
6 intake were less likely to develop CVD than those in the lowest quintile (HR: 0.44; 95% CI: 0.25–0.78). In contrast, the dietary intake of vitamin B
6 was not associated with CVD risk in women.
Figure 1 presents the spline curve for the association between dietary vitamin B
6 intake and CVD incidence among men. An inverse linear association was observed, in that CVD risk decreased with each increment in the dietary levels of vitamin B
6 intake after about 1.9 mg/day (
p for nonlinearity = 0.3).
4. Discussion
In this prospective study, we evaluated the effect of dietary vitamin B6 intake on the risk of CVD among Korean men and women enrolled in the community-based Ansung–Ansan cohort study. As a result, Korean men with a higher dietary intake of vitamin B6 had a lower incidence of CVD. This association was not significant in women. Dose-response analyses confirmed the presence of a linear association between higher dietary vitamin B6 intake and decreased CVD incidence in men.
Pyridoxal 5′-phosphate (PLP), the active coenzyme form of vitamin B
6, is required for more than 140 different enzymatic reactions in carbohydrate, amino acid and lipid metabolism, neurotransmitter synthesis, and steroid hormone receptor modulation [
26]. PLP is also involved in reactions pertaining to antioxidant activity, the inflammatory process, homocysteine catabolism, and phosphorylation-all metabolic processes that are related to CVD prevention [
27]. Oxidative stress, which represents a state of imbalance between oxidants and antioxidants, may occur due to the excessive accumulation of oxidants in the body or due to a lack of antioxidants, and may lead to vascular inflammation and endothelial dysfunction [
28]. Homocysteine, an amino acid synthesized during the conversion of methionine to cysteine in one-carbon metabolism [
29], is known to increase oxidative stress when deposited in the body [
30]. The results of a meta-analysis of prospective cohort studies demonstrated that elevated homocysteine levels are associated with the incidence of CVD, indicating that homocysteine is an independent risk factor for CVD along with oxidative stress [
31]. Vitamin B
6 acts as an antioxidant by scavenging free radicals, reducing lipid peroxidation, and preventing damage to the integrity of the mitochondrial membrane [
32]. It is also linked to inflammatory-related functions, which play a key part in the pathogenesis of atherosclerosis [
33]. PLP regulates inflammatory reactions through involvement in the regulation of cytokine-induced mechanisms of immunocytes for the activation of the inflammatory reaction as well as synthesis of nucleic acids and proteins [
33,
34]. Several epidemiological studies have shown that low plasma PLP levels are inversely associated with the major bio-markers of inflammation [
33,
34,
35]. In addition, vitamin B
6 acts as a cofactor of cystathionine β-synthase and cystathionine γ-cystathionase in the trans-sulfuration of homocysteine to cystathionine and cysteine [
36]. A previous study revealed that a higher vitamin B
6 intake level was associated with a lower plasma total homocysteine level [
37]. In other words, vitamin B
6 may lower the risk of CVD by regulating the homocysteine concentrations in the plasma and indirectly regulating the production of cysteine as a precursor of the antioxidant, glutathione.
Previous epidemiological studies evaluating the association between vitamin B
6 from diet and plasma PLP levels, and the incidence of CVD yielded inconsistent results [
23,
24,
25,
38,
39,
40]. An inverse association between plasma PLP levels and CHD was previously identified in a cohort study in the United States [
40], while a study in the Netherlands reported that plasma PLP concentrations were not associated with CHD risk in women and men [
39]. A study in Chinese men demonstrated that a higher vitamin B
6 intake level was associated with a decreased CVD risk and total mortality [
23]. In addition, a study conducted in Finland revealed a significantly decreased risk of stroke in male smokers with a high dietary vitamin B
6 intake after adjustment for age and dietary supplement intake; however, this association was not significant after adjustment for multiple confounding factors such as alcohol consumption, smoking, and BMI [
38]. Furthermore, the Health Professional Follow-up Study found no association between vitamin B
6 intake and the risk of stroke [
25]. A recent meta-analysis demonstrated an inverse association between vitamin B
6 intake and CHD risk. In addition, a strong inverse association between the intake of vitamin B
6 and CHD incidence was found in a sensitivity analysis after the exclusion of participants with pre-existing CVD [
41]. No such association was observed in women, which is consistent with our results.
In the present study, higher dietary vitamin B
6 intake levels lowered the CVD risk in men but had no significant effect on the CVD risk in women. This may be attributed to the sex-specific difference in plasma homocysteine levels and the complex interactions between vitamin B
6, estrogen, and homocysteine. A sex-related comparison in Europe and the United States showed that men had higher levels of plasma homocysteine than women [
42,
43]. A previous study assessing homocysteine levels in Koreans also demonstrated that the mean homocysteine concentrations and prevalence of hyperhomocysteinemia were significantly higher in men than women [
44]. The effects of the female hormone, estrogen, on the cardiovascular system may also mask the health benefits of vitamin B
6 in women. Estrogen leads to enhanced glutathione levels and prevents peroxynitrite (ONOO-) formation by activating cystathionine β-synthase and regulating enzymes in glutathione synthesis [
45]. Furthermore, estrogen is known to prevent the accumulation of low-density lipoproteins in the blood vessel walls, promote the bio-availability of nitric oxide, and improve vascular endothelium function [
46]. Nevertheless, the mechanism underlying the sex-dependent effect of vitamin B
6 on CVD risk is unclear; hence, further research is needed to investigate this association.
Several limitations of this study should be noted. First, the residual confounding effects of unmeasured or unknown variables may have affected the results, although we did adjust for multiple potential confounding factors. Second, we could not obtain data on dietary supplements and plasma homocysteine levels in our study; thus, the interactions between vitamin B6 intake (food and supplement), homocysteine levels, and CVD incidence could not be evaluated. Third, the incidence of CVD was assessed based on responses to self-reported questionnaires, which may have led to diagnostic misclassification. However, a previous study reported that the validity of the CVD cases in this cohort was acceptable, showing a 93% concordance between self-reported CVD and medical records. Finally, as the participants of this study were all residents of the Gyeonggi area in South Korea, it may be difficult to generalize the results to other populations. Nevertheless, we aimed to minimize errors in measurement by using the average dietary values of two repeats of a validated SQFFQ. To our knowledge, this is the first study to prospectively evaluate the association between dietary vitamin B6 intake and CVD risk in Korean adults.