In recent decades, hypertension has been the major single factor in all causes of death and disability worldwide and is one of the major preventable risk factors for numerous diseases such as cardiovascular disease (CVD), renal insufficiency, and Alzheimer’s disease (1). In the United States, hypertension is the largest contributor to CVD deaths compared to other modifiable risk factors and is second only to smoking in terms of all-cause mortality (2). The progression of disease due to blood pressure (BP) is known to be graded and continuous, and a BP of 115/75 mmHg or less is considered to be within the perfectly normal range (3). The Global Burden of Disease Study shows that 9.4 million deaths and 212 million lost healthy life yearly due to exceeding optimal BP levels. It is worrying that over 3.5 billion people worldwide have systolic BP (SBP) outside the ideal range (i.e., >115/mmHg) and 874 million people have SBP pressure above 140 mmHg, and this data will gradually increase with economic and social development (4). Therefore, controlling BP is an important step in reducing the burden of disease and increasing the life expectancy of the world’s population.

Many factors have been shown to be associated with BP increase, such as socio-demographic factors like gender, age, ethnicity, and environmental and behavioral factors. There are also many changeable exposure elements such as a high sodium diet, low potassium diet, obesity, and a sedentary lifestyle that could increase BP (5). In addition, studies have shown that oxidative stress plays an important role in the development of hypertension (6–8). Oxidative stress increases the generation of endothelium-derived contractile factors and decreases the biological availability of nitric oxide, resulting in impairment of vascular relaxation and endothelial dysfunction in hypertensive patients (9). Vitamin E is an antioxidant, however, its effect on BP has been controversial. Some interventional trials and animal experiments indicated that vitamin E could produce beneficial effects on BP by inhibiting oxidative stress (10–12). Some studies also argue that vitamin E has no effect on BP and may even be harmful (13–16). In addition, it has recently been shown that the effect of vitamin E on BP has a multisegmented effect, with an inverted J-shaped relationship (17). Differences in study design, sample size, ethnic distribution, and control of confounding factors may explain the controversial results among these studies. More importantly, most of these studies did not separately investigate the single active form of vitamin E.

Vitamin E is made up of tocopherols and tocotrienols (α, β, γ, and δ) and has two main dietary forms in the body, α-tocopherol (ATC) and γ-tocopherol (GTC), of which the most studied is ATC, because ATC is most bioactive and abundant in the blood, and vitamin E deficiency can be corrected by taking this supplement (18). More recently, there has been a growing body of research discussing the role of GTC in public health. GTC is the most common form of vitamin E in the diet, and its concentration in tissues is much greater than its concentration in the blood (19, 20). Differences in morphology, biological activity, and tissue distribution lead to different biological effects of ATC and GTC. Because vitamin E may have an impact on the development of hypertension and there are few studies on the role of GTC, we propose to conduct cross-sectional studies in U.S. adults to explore the correlation between GTC serum concentration (GTSC) and BP, including SBP, diastolic BP (DBP), and the prevalence of hypertension.

In this study, we extracted data from a representative National Health and Nutrition Examination Survey (NHANES) database of 4 cycles with GTSC data to investigate the correlation between GTSC and BP, and possible modifiers of this relationship.

In this large sample cross-sectional study, we found that GTSC was positively associated with SBP, DBP, and the prevalence of hypertension, and this relationship remained significant after adjustment for confounders. Furthermore, we noted that alcohol consumption modifies the relationship of GTSC with SBP and DBP, but not the relationship with the incidence of hypertension.

To date, there is still controversy regarding the role of vitamin E in hypertension. Boshtam et al. conducted a randomized triple-blind placebo-controlled trial including 78 patients with mild hypertension in Isfahan and indicated that compared to the placebo group, the oral vitamin E group was able to significantly reduce SBP (−24% in the vitamin E group versus −1.6% in the placebo group) and DBP (−12.5% in the vitamin E versus −6.2% in the placebo group) (p < 0.05) (11). Although this study followed a strict clinical randomized study design, it had significant limitations, such as its small sample size, which added significant bias, and weight (kg), which is known to be an important risk factor for hypertension, was different between the two groups (88.91 ± 20.03 vs 75.92 ± 10.67). In addition, there are some cross-sectional studies, meta-analyses, and animal studies that also suggest that taking vitamin E can lower BP (15, 22, 23). However, other studies hold a different view. Ward and his colleagues also performed a randomized, double-blind, placebo-controlled trial including 58 patients with type 2 diabetes to investigate the effects of vitamin E on hypertension (24). Compared with the placebo group, the α-tocopherol group (500 mg/day for 6 weeks) increased SBP by 7.0 mmHg (β 7, 95% CI 5.2–8.8) and DBP by 5.3 mmHg (β 5.3, 95% CI 4.0–6.5); the mixed tocopherol group (60% γ-, 25% δ- and 15% α-tocopherol, 500 mg /day for 6 weeks) increased SBP by 6.8 mmHg (β 6.8, 95% CI 4.9–8.6) and DBP by 3.6 mmHg (β 3.6, 95% CI 2.3–4.9). Moreover, the prospective cohort study by Lai et al. including 684 pregnant women, and the cross-sectional study by Francis et al. both concluded that vitamin E (in either form) was not significantly associated with BP (13, 25). A recent large sample prospective cohort study showed an inverse J-shaped relationship between dietary vitamin intake and the incidence of new-onset hypertension, with participants in the second to fourth quintiles (Q2-Q4) having the lowest incidence of new-onset hypertension. Compared with Q2-Q4, the incidence of new-onset hypertension increased by 40% in Q1 participants (OR 1.4, 95% CI 1.29–1.52), and by 18% in Q5 (OR 1.18, 95% CI 1.09–1.29) (17). The controversial results in these studies may be explained by differences in study design, sample size, study population, and confounding factors. However, what is more, important is that several different forms of vitamin E are known both in vivo and in dietary supplementation, and most of these studies have not been studied separately.

Based on previous studies, the present study is the first to individually investigate the association of GTSC with BP using cross-sectional data from a large sample, adding more evidence to the field. Our study has several important findings. First, our study found that GTSC was linearly and positively correlated with SBP, DBP, and the prevalence of hypertension, with a trend toward higher BP and hypertension prevalence with higher GTC concentrations. It is not clear the specific mechanism by which GTSC increases SBP, DBP, and the prevalence of hypertension, but the following mechanisms might explain it. Firstly, GTC has a dual role in oxidative stress. GTC is known to have antioxidant and anti-inflammatory effects, but some studies indicated that excess GTC could promote the production of nitric oxide, an inflammatory mediator through its oxidation products, leading to an enhancement of cellular immune response and an increase of lipid peroxidation (26). Studies have proven that endothelial damage, vascular dysfunction, cardiovascular remodeling, renal dysfunction, immune cell activation, and systemic inflammation during oxidative stress underlie the pathophysiology of hypertension (27–30). Another possible mechanism is that GTC could increase the excitability of the sympathetic nervous system. This hypothesis was supported by a randomized clinical trial in which heart rate was significantly increased by either ATC or mixed tocopherol treatment, indicating a central effect of tocopherol (24). However, it contradicts another study, which concluded that the cardiac autonomic nervous system improved after treatment with vitamin E (31).

Second, we noted that alcohol consumption could modify the relationship of GTSC with both SBP and DBP. In participants who consumed alcohol, a potentiation of the GTC-driven increase in SBP and DBP was observed, but not in non-drinking participants. Numerous studies have demonstrated that alcohol consumption is positively associated with BP increase, even in small amounts (32–34). The potential mechanisms responsible for this outcome are complex and varied, including effects on the central nervous system, inhibition of the vagal, excitation of the sympathetic nerve, activation of the renin-angiotensin-aldosterone system, increased cortisol secretion, insulin resistance and impaired glucose tolerance, oxidative stress, and impaired endothelial function (35, 36). Overall, our findings encouraged people with high levels of GTSC to lower their GTSC appropriately to control BP, especially those who consume alcohol. However, it is worth noting that the above results are only hypothesis generation and further investigations need to be conducted to support the findings of our study.

Although our study is based on nationally representative U.S. general population data and has a large sample size that minimizes bias and has good extrapolation, we must also acknowledge several important limitations of this study. First, this study was a retrospective cross-sectional design, and thus no causal inferences could be made about the association of GTSC with SBP, DBP, and the prevalence of hypertension, which is an inherent drawback of all cross-sectional designs. Second, although we adjusted for numerous confounding factors, we still cannot exclude the interference of unknown confounders (e.g., daily lifestyle, medication use) on the study results. In this study, only a single blood test was performed to assess the status of GTC, and repeat sampling may be required to overcome the daily variability of individuals, but this process would become very complex and expensive. Fourth, our study was limited to adults in the United States, so generalization to other countries or age groups requires caution.

In summary, this study investigated the relationship between GTSC and SBP, DBP, and the prevalence of hypertension in the general U.S. population and found that GTSC was linearly and positively associated with SBP, DBP, and the prevalence of hypertension, and found that this correlation of GTSC with SBP and DBP was more significant in those who consumed alcohol.