Vitamin D plays an essential role in bone mineralization and calcium homeostasis. More recently, there has been growing evidence for a role of vitamin D in extraskeletal health, including beneficial effects in the cardiovascular system. Daylight exposure and vitamin D intake in many western populations are insufficient for maintaining an adequate vitamin D status. It is at present unclear whether vitamin D supplementation could improve cardiovascular health. This paper summarizes the evidence from observational studies and randomized–controlled trials on the relation of vitamin D with blood pressure (BP) and risk of cardiovascular diseases (CVDs). Epidemiological data suggest that optimal vitamin D status is important for CVD prevention, but results from different studies are conflicting and confounding cannot be ruled out. Randomized–controlled trials of vitamin D supplementation and BP have yielded inconsistent results, and trials that addressed the effect of vitamin D on CVDs are lacking. It is therefore premature to recommend supplemental vitamin D intake specifically for the prevention of hypertension or CVDs. Data from large, well-controlled clinical trials in this field with vitamin D supplements of sufficiently high doses are awaited to settle this issue.
American Journal of Hypertensionadvance online publication 16 September 2010; doi:10.1038/ajh.2010.199
Vitamin D has long been known for its central role in bone mineralization and maintenance of calcium homeostasis, via regulation of parathyroid hormone (PTH) secretion (Figure 1).1,2 More recently, evidence has accumulated that an adequate vitamin D status is also important for many other health conditions, including cardiovascular health.3,4 Vitamin D deficiency may predispose to hypertension via elevation of PTH and disturbed calcium homeostasis.5–7 Furthermore, it has been linked to insulin resistance, systemic inflammation, and regulation of the renin–angiotensin system.8–10 Many tissues express the vitamin D receptor,11–13 including the myocardium, endothelium, and macrophages, and it has been proposed that vitamin D also influences cardiovascular health via autocrine and paracrine actions (Figure 1).2 At present, however, the role of vitamin D in the prevention of hypertension and cardiovascular diseases (CVDs) in humans is not yet clear. This article aims to provide an unbiased overview of the current evidence on vitamin D intake and status in relation to blood pressure (BP), hypertension and risk of CVD. For this purpose, data are summarized from epidemiological studies and randomized–controlled trials of vitamin D supplementation.
Vitamin D supply and function in the human body. (Modified and reproduced from ref. 2). 1αOHase, 1α –hydroxylase; 25OHase, vitamin D (cholecalciferol) 25-hydroxylase; 25OHD, 25-hydroxy vitamin D; 1,25(OH)2D, 1,25 dihydroxy vitamin D; PTH, parathyroid hormone; UVB, ultraviolet B light; VDR, vitamin D receptor.
Vitamin D: Sources and Requirements
Vitamin D (calciferol) is a generic name for a group of fat-soluble steroids of which the two major forms are vitamin D2 (ergocalciferol) and vitamin D3 (cholecalciferol). Vitamin D3 can be obtained from a limited number of animal foods (e.g. oily fish, egg yolk), fortified products (e.g. milk, margarines), and dietary supplements.4,14,15 Vitamin D2 (ergocalciferol) is formed in plants, fungi, and invertebrates during ultraviolet (UV) light exposure, and is also provided via prescribed supplements. More important to humans than dietary sources, however, is the endogenous production of vitamin D in the skin during exposure to UVB light (wavelengths of 280–315nm).1–4 Upon UVB exposure, 7-dehydrocholesterol in the skin is converted into precholecalciferol, after which spontaneous thermal isomerization occurs and vitamin D3 is formed (Figure 1). Biologically inert vitamin D3 then undergoes hepatic conversion into 25-hydroxyvitamin D (25(OH)D or calcidiol) and further conversion in the kidney by 1-α-hydroxylase, yielding the physiologically active 1,25-dihydroxyvitamin D (1,25(OH)2D or calcitriol).1–4
The amount of vitamin D produced is affected by age, time spent outdoors, degree of latitude, skin color, the amount of skin exposed, and use of sunscreen.15,16 In the winter at northern latitudes, there is insufficient UV radiation at the right wavelength for the skin to produce significant levels of vitamin D. Therefore, maintenance of a good vitamin D status depends for part of the year on vitamin D reserves in the body and on dietary intake.
Serum 25(OH)D, the transport and storage form, has a half-life of 2–3 weeks and is a good indicator of the body's vitamin D status.1,17,18 Most experts now classify 25(OH)D concentrations as follows: ≥30ng/ml (or 75nmol/l), optimal; 21–29ng/ml, insufficient; and ≤20ng/ml, deficient.14,15,19,20 An exploratory dose–response analysis by Cranney et al. based on 16 pooled studies suggested that serum 25(OH)D increases by 2.5–5ng/ml for every 100 international units (IU) (2.5µg) of supplemental vitamin D3.21 In case of deficiency, supplemental intake of 800–1,000IU/day (20–25µg/day) of vitamin D3 would be needed to restore serum 25(OH)D, based on these estimates.3 Others propose intakes as high as 2,000IU/day to achieve serum levels of 30–40ng/ml, which is considered to have no adverse health effects like hypercalcemia.22
Cross-Sectional Studies of Vitamin D and BP or Hypertension
Already in the 1980s, reports were published that showed higher BP in individuals with low circulating 25(OH)D or vitamin D intake.23,24 More recently, the inverse relationship between serum 25(OH)D levels and BP was confirmed in the third National Health and Nutrition Examination Survey.25–27 In contrast, 25(OH)D levels were not associated with BP in Dutch men and women aged >65 years.6 In the Tromsø Study in over 15,000 Norwegian men and women,28 no association of dietary vitamin D intake with BP was found after adjustment of major confounding variables, such as body mass index, smoking, and physical activity. Vitamin D intake, however, was only 240–360IU/day, which may have been too low to detect an association.28 Schmitz et al. examined circulating vitamin D in relation to BP in 1,334 Hispanics and African Americans and found nonsignificant associations of 25(OH)D with BP after adjustment for body mass index and other potential confounders (−0.94mmHg systolic and −0.64mmHg/10ng/ml).29 Richart et al. hypothesized that an increased PTH/25(OH)D ratio promotes an inward calcium flux in target cells that are involved in glucose metabolism and arterial calcification, and that these effects are more pronounced when habitual calcium intake is low. In 542US men and women (mean age: 50 years), they found that BP and other components of the metabolic syndrome increased significantly across quartiles of the PTH/25(OH)D ratio, whereas serum and 24-h urinary calcium decreased.30
In total, around 30 cross-sectional analyses mainly in Caucasians have been published of which many reported a beneficial relation between vitamin D status and BP or hypertension, although this was not consistent across all studies.7 A disadvantage of cross-sectional analyses, however, is that no temporal relationship can be established as the exposure and outcome are measured at the same time. Therefore, one cannot conclude whether low vitamin D intake or status caused elevated BP or whether it was a consequence (e.g. less outdoor activities due to suboptimal health). Also, confounding could play a major role in observational studies. For example in the cross-sectional study by Schmitz et al.,29 both vitamin D deficiency and BP were strongly associated with body mass index and the metabolic syndrome and statistical techniques could not disentangle which situation aggravated the other.31
Prospective Cohort Studies of Vitamin D and Hypertension
Temporal relationships between vitamin D and risk of hypertension have been assessed in prospective epidemiological studies,32 which are summarized in Table 1. Vitamin D intake was assessed by means of a food frequency questionnaire in the Nurses Health Study (NHS) I and II and the Health Professionals Follow-up Study (HPFS) in >200,000 men and women who were free of hypertension at baseline.33 In these subjects, high vitamin D intake (roughly >500IU/day) was not associated with the risk of hypertension during 8 years of follow-up. Blood samples were then analyzed for plasma 25(OH)D in >1,800 participants in NHS I and HPFS.34 During 4 years of follow-up, women with a poor vitamin D status (25(OH)D <15ng/ml) had a significant three times higher risk of incident hypertension compared to women with levels ≥15ng/ml. In men with low 25(OH)D, the risk was even more strongly increased. It should be noted, however, that only 33 subjects were deficient in 25(OH)D, which creates large uncertainty about the observed associations. Moreover, after 8 years of follow-up, relative risks (RRs) for incident hypertension were attenuated and no longer statistically significant (Table 1).
Forman et al. subsequently performed a nested case–control study in NHS II and assessed plasma 25(OH)D in women who developed hypertension during follow-up, and in a matched sample of normotensive controls.35 Plasma 25(OH)D was inversely associated with risk of hypertension, with an odds ratio of 1.66 (95% CI, 1.11–2.48) for levels <21ng/ml compared to >32ng/ml. No dose-response was observed, and the risk of hypertension was already increased for levels 21–32ng/ml. In a prospective cohort analysis by Wang et al. of almost 30,000 participants in the Women's Health Study,36 the risk of hypertension was ~5% lower for higher dietary vitamin D intakes (>243IU/day), whereas it was not related to >400IU/day intake from supplements (Table 1).
In the Tromsø study, serum 25(OH)D assessed in 1994 was examined in relation to change in BP and incident hypertension during 14 years of follow-up.37 There was no significant difference in risk of hypertension (i.e. BP >140/90mmHg and/or initiation of antihypertensive treatment) when comparing extreme quartiles of serum 25(OH)D in 1,268 subjects who were normotensive at baseline. In 1,605 subjects not treated with antihypertensive drugs during follow-up, systolic blood pressure increased by 6.4mmHg and diastolic blood pressure by 1.1mmHg in subjects with serum 25(OH)D >25.1ng/ml compared to those with levels <16.6ng/ml, although this was not statistically significant. The risk of hypertension did not differ between these groups (Table 1).
Prospective Cohort Studies of Vitamin D and CVD
Bostick et al. examined dietary vitamin D intake, assessed by questionnaire, and use of vitamin D supplements in relation to coronary heart disease (CHD) mortality in Iowa women who were followed for 8 years.38 No association was found with dietary intake of vitamin D with RR close to 1 (Table 2). For supplemental vitamin D intake, inverse but nonsignificant associations were found (RR = 0.85 for >400IU/day and RR = 0.86 for 1–400IU/day, compared to nonuse; P = 0.50).
In more recent years, there has been increasing interest in the relation between vitamin D status and cardiovascular events (Table 2). Giovannucci et al. performed a nested case–control study in 1,354 US Health Professionals who were followed for 10 years, and examined 25(OH)D in baseline plasma samples in relation to incident nonfatal myocardial infarction.39 The risk of myocardial infarction was significantly doubled in men with initial 25(OH)D levels ≤15ng/ml compared to men with levels ≥30ng/ml, after adjustment for relevant confounders. For levels between 15 and 30ng/ml, the risk was increased by ~50%.
Wang et al. examined 1,739 men and women from the Framingham Offspring Study and found a 60–80% higher risk for incident CVD in subjects with 25(OH)D levels below 15ng/ml compared to subjects with higher levels.40 After stratification for prevalent hypertension at baseline, this elevated risk appeared to be only significant for hypertensives (RR = 2.43 (95% CI, 1.23–4.80) for 25(OH)D <10 vs. ≥15ng/ml).
In the Ludwigshafen Risk and Cardiovascular Health (LURIC) study, over 3,000 German men and women who had been referred to coronary angiography were followed for 7.7 years for CVD mortality.41–43 In this study, the risk of fatal CVD was doubled for subjects with low baseline 25(OH)D levels, i.e. RR of 2.22 (95% CI, 1.57–3.13) for bottom quartile (median, 7.6ng/ml) and 1.82 (1.29–2.58) for second quartile (median, 13.3ng/ml) compared to top quartiles (median, 28.4ng/ml).41 Further analyses showed that 25(OH)D levels <10ng/ml were related to heart failure mortality, and levels <30ng/ml to sudden cardiac death.42 For fatal stroke, no thresholds for vitamin D status were examined but a significantly lower risk was reported per standard unit increase in 25(OH)D.43
Finally, Bolland et al. examined the risk of cardiovascular events in relation to vitamin D status in US women.44 This observational analysis was conducted within the framework of a 5-year trial of calcium supplementation and fracture incidence in which baseline 25(OH)D was assessed in 1,471 participating women. The risk of myocardial infarction, stroke, or other cardiovascular events did not differ between women with seasonally adjusted serum 25(OH)D levels <20ng/ml and ≥20ng/ml. It should be noted, however, that part of the women were treated with vitamin D supplements at some time during follow-up (30% in the low 25(OH)D group and 20% in the high 25(OH)D group).
Observational Data: A Need for Caution
It should be noted that associations of vitamin D with BP in cross-sectional and prospective cohort studies need not be causal, due to selection bias, information bias, or confounding. Vitamin D intake and status in free-living populations are strongly related to other dietary and lifestyle factors. For dietary intake data, there is a need to properly adjust for other food components that may influence the risk of CVD, e.g. n-3 fatty acids from fish that are ingested along with vitamin D. Furthermore, vitamin D supplement users could be more highly educated and health conscious. Despite extensive adjustment for varying potential confounders in multivariable models (Tables 1 and 2), residual confounding resulting from inaccurate measurement of these factors, unknown confounders, or factors not included in the model cannot be ruled out.
Levels of 25(OH)D in the blood are mainly influenced by UVB exposure, which is turn is strongly determined by being outdoors. In epidemiological studies, it is not possible to disentangle the cardiovascular benefits from outdoor physical activities from benefits related to UVB exposure, which also hampers statistical adjustment for confounding by physical activity. Furthermore, being outdoors and daylight exposure are also determined by behavioral and socioeconomic factors (e.g. type of job). In addition, daylight influences circadian rhythm, sleeping patterns, and the regulation of hormones like serotonin and melatonin, which may be important in BP regulation and possibly also exert other effects in the cardiovascular system.45–47 Causality between 25(OH)D and BP or CVD can therefore not be established on basis of observational data.
Randomized–Controlled Trials of Vitamin D and BP
Problems of confounding that exist in observational epidemiological studies can be overcome by well-conducted randomized–controlled trials. A disadvantage of trials, however, is that only specific doses of vitamin D (mostly via supplements) can be studied and that optimal compliance to treatment is hard to achieve. Trials are of relatively short duration, and if health effects only occur after long-term (or maybe even life-long) exposure, this will likely be missed in randomized–controlled trials. Furthermore, long-term well-controlled trials of endogenously produced 25(OH)D after UVB exposure or vitamin D in its natural food matrix are not feasible.
In a recent meta-analysis, Pittas et al. pooled 10 trials of vitamin D supplementation and BP and found no significant effect on systolic BP (weighted mean difference: −1.9mmHg, 95% CI −4.2 to 0.4) or diastolic BP (−0.1mmHg, −0.7 to 0.5).32 Doses of vitamin D varied largely from 400 to >5,000IU/day. Higher doses of vitamin D had a larger effect on diastolic BP (−1.5 vs. +0.1mmHg for ≥1,000 vs. <1,000IU/day, P = 0.04), but not on systolic BP. BP effects were similar for vitamin D alone and for vitamin D in combination with calcium. In most trials, vitamin D3 (cholecalciferol) was provided. In a trial by Krause et al., however, the effect of endogenously produced vitamin D on BP was examined.48 A total of 18 German subjects were randomized to whole-body UVA (wavelengths of 315-400nm) or UVB radiation (3 times/week) for 6 weeks at the end of the winter season. Plasma 25(OH)D increased by 162% and PTH decreased by 15% during UVB therapy, and UVB had a significant beneficial effect on systolic and diastolic BP (−6 and −8mmHg, respectively, P < 0.001).
Table 3 provides an overview of trials with a duration of at least 6 months, 4 of which49–52 had also been included in the meta-analysis by Pittas et al.32 Only in a 6-month trial by Jorde and Figenschau in diabetic patients,52 there was some evidence for a BP-lowering effect of a high dose of vitamin D3 (two capsules of 20,000IU/week), but this finding was not statistically significant, which may be due to the small sample size. A recently published 1-year trial by the same group showed an elevation rather than decrease in BP with relatively high doses of vitamin D in overweight and obese subjects.53 BP was assessed as an ancillary end point in the Women's Health Initiative (WHI) study in which 36,282 postmenopausal US women were randomly allocated to 400IU of vitamin D3 plus 1g of calcium per day, or placebo.50 No significant effects of this relatively low dose of vitamin D on BP were found after 7 years of follow-up.
Randomized–Controlled Trials of Vitamin D and CVD
Studies on vitamin D and calcium supplementation in the prevention of cardiovascular events have recently been reviewed by Wang et al.54 No trials primarily addressed the effect of vitamin D on CVD. Two randomized, placebo-controlled trials of vitamin D supplementation and fractures or falls also provided data on CVD events during follow-up. Trivedi et al. randomly assigned 2,686 UK men and women aged 65–85 years to a high dose of oral vitamin D (100,000IU) or placebo every 4 months, for a period of 5 years, and found that risks of total CVD, fatal CVD, and nonfatal CHD were nonsignificantly decreased in the vitamin D group by 10, 16, and 6%, respectively.55 In a small trial in 302 Australian women aged 70–90 years with serum 25(OH)D levels ≤24ng/ml, the rate of CHD after 1 year of follow-up was lower in subjects who received 1,000IU/day of supplemental vitamin D, added to calcium supplements, compared to subjects who received calcium supplements only (1.3 and 2.0%, respectively).56 However, there was no difference in the occurrence of stroke (2.0% in both groups).
In the aforementioned WHI study, the effect of calcium and vitamin D treatment on incident CHD, stroke, and other CVD was assessed.57 After vitamin D supplementation (400IU/day) compared to placebo, RRs were 1.04 (95% CI, 0.92–1.18) for incident CHD and 0.95 (0.82–1.10) for incident stroke. Also for other CVD outcomes no association was found.
Sanders et al. randomly assigned 2,256 community-dwelling US women aged ≥70 years to study to a single annual dose of 500,000IU of oral vitamin D3 each autumn to winter, or placebo, for 3–5 years.58 The primary outcome was risk of fractures and falls. Incident CVD was monitored as an adverse event, which did not differ significantly between the vitamin D and placebo groups (1.5% vs. 1.2%).
Prospective epidemiological studies provide little evidence for a link between dietary intake of vitamin D and BP or CVD.33,36,38 Apart from no causal relationship being present, this could be due to residual confounding or the relatively narrow range of vitamin D intake within populations. Alternatively, it could indicate that vitamin D intake via foods, which is generally below 400IU/day, is too low to exert a biologically meaningful effect. In a number of short-term trials, BP was reduced by relatively large doses of vitamin D,32 but long-term trials have not confirmed this antihypertensive effect.49–53
Observational studies in US populations support the hypothesis that a suboptimal vitamin D status (25(OH)D below 15–20ng/ml) increases the risk of hypertension.34,35 It is too early, however, to draw conclusions because the number of prospective studies of vitamin D status and BP is limited and negative findings have also been reported.37 Concerning CVD, however, there is a larger number observational studies showing a significant relation of low 25(OH)D with an increased risk of fatal and nonfatal cardiovascular events.39–43
Because observational data are prone to bias and confounding, evidence for a causal relationship should come from well-controlled trials. However, one should be aware that these may not capture the right time window of exposure for answering questions on vitamin D status and health. Furthermore, it is possible that endogenously produced vitamin D via UVB irradiation acts differently on health than vitamin D supplements. Repeating the trial by Krause et al.48 of UVB vs. UVA exposure in a larger number of subjects with a low vitamin D status is therefore warranted. Also, there is a need for trials with higher doses of supplemental vitamin D in different populations (especially blacks) to establish its potential for the prevention of hypertension and CVD.
More clarity will hopefully come from the recently initiated Vitamin D and Omega-3 Trial (VITAL), a 2 × 2 factorial study of vitamin D and fish oil that is funded by the National Institutes of Health (www.vitalstudy.org; accessed on 1 May 2010). In this study, 20,000 older US men and women will be randomized to daily dietary supplements of vitamin D (about 2,000IU) or placebo and followed for the occurrence of CVD and other diseases.
At present, it is premature to recommend vitamin D supplements for the prevention of hypertension or CVD. However, frequent outdoor physical activity can be advised to all to improve vitamin D status and cardiovascular health.
The authors declared no conflict of interest.