Should We Be Recommending Vitamin D Supplementation for Hypertension and Cardiovascular Disease Prevention?
The Journal of Clinical Hypertension Article first published online: 5 OCT 2012
Debbie L. Cohen, MD; Raymond R. Townsend, MD
Address for correspondence: Debbie L. Cohen, MD, Hospital of University of Pennsylvania, 1 Founders Building, 3400 Spruce St., Philadelphia, PA, 19104 E-mail: debbie.cohen at uphs.upenn.edu
The prevalence of both hypertension and vitamin D deficiency is high.1 Due to the emerging knowledge of protean actions of vitamin D there has been increased interest and research in vitamin D. Vitamin D deficiency has been linked with hypertension, myocardial infarction, stroke, and other cardiovascular (CV)-related diseases including atherosclerosis and endothelial dysfunction.2 There is also increasing evidence that vitamin D plays a role in renin-angiotensin system (RAS) regulation, may directly affect cardiac muscle, and regulates the immune system.2
Vitamin D is a collection of fat-soluble steroids with two dominant forms: vitamin D2 (ergocalciferol) and vitamin D3 (cholecalciferol). Vitamin D2 is made in invertebrates and plants after exposure to sunlight. Vitamin D3 is naturally present in a small number of foods and is derived endogenously in the skin through exposure to sunlight. Vitamin D3 can also be obtained by dietary and pharmacologic supplementation.3 Exogenous-acquired vitamin D (dietary or supplements) is inactive and requires two hydroxylation reactions for activation: the first occurs in the liver in the form of 25 hydroxy vitamin D (25-OHD), which undergoes further hydroxylation in the kidney and is converted to 1,25 hydroxy vitamin D (1,25 OHD). 25-OHD has a long half-life and is the major form of vitamin D circulating in the blood and its measurements are useful clinically.4 Vitamin D deficiency is defined by the current International Osteoporosis Guidelines as vitamin D insufficiency if 25-OHD levels are <50 nmol/L and as vitamin D deficiency if 25-OHD levels are <25 nmol/L.5
Multiple observational and epidemiologic studies link vitamin D deficiency with hypertension; however, prospective randomized trials have shown conflicting results.6-8 There are both in vitro and animal studies demonstrating a proposed link between vitamin D and hypertension due to inhibition of the RAS, highlighting the potential role of the vitamin D receptor complex as a modulator of renin activity particularly in hypertensive patients.9,10 A study by Forman and colleagues 11 examined renal plasma flow responses to angiotensin II infusion in 184 normotensive individuals stratified according to vitamin D status and then assessed them during a high sodium diet. All the African Americans in the study were either vitamin D insufficient or deficient. Response was blunted in participants with vitamin D deficiency. Circulating levels of angiotensin II but not plasma renin activity were higher in insufficient and deficient participants. The resulting up-regulation of RAS may result from low plasma 25-OHD levels. The impact of sodium is also important as has been shown that the renin status has a modifying effect on the relationship between 25-OHD and salt-sensitive hypertension. In a cross-sectional study of 223 Caucasian patients, 25-OHD was inversely associated with plasma renin on both a low and high sodium diet.12 A genetic association study has also shown that the minor allele (T) at the FOK1 polymorphism (coding for the N terminal region of the vitamin D receptor) and 25-D were significantly associated with lower plasma renin levels in hypertensive but not normotensive participants.13
There is also evidence that secondary hyperparathyroidism and hypocalcemia, which are common in patients with vitamin D deficiency, explain some of the association between vitamin D deficiency and hypertension. Prior observational studies have shown an association between parathyroid hormone and hypertension.14,15 The pathogenesis for this association is unclear but it is proposed that parathyroid hormone may increase arterial stiffness and induce atherosclerotic changes by acting on smooth muscle cells in the endothelium.16 A double-blind randomized controlled trial of 148 women found that supplementation with vitamin D and calcium resulted in a significant increase in 25-D levels by 72% and decreased serum PTH levels by 17% along with significant decreases in systolic blood pressure and heart rate compared with calcium supplementation alone.17
Epidemiologic studies have also shown a link between vitamin D and hypertension. One study included 1181 normotensive patients who were followed for 4 years. When compared with 25-OHD levels of >30 nmol/L, levels of 25-OHD <15 nmol/L were associated with a relative risk for developing hypertension to 2.67 (95% confidence interval, 1.05-6.67).6 In the Nurses Health Study II, lower 25-OHD levels were found in the 1484 women who went on to develop hypertension. More recently, 2000 participants had their blood pressure monitored over 14 years. There was a difference in baseline blood pressure seen between the lowest and highest quartiles of 25-OHD levels. However, baseline levels of 25-OHD were not predictive of future hypertension or current hypertension.18 Randomized controlled trials assessing vitamin D supplementation and hypertension have shown inconsistent results, probably due to study issues with sample size, duration and type of vitamin D supplementation used,6-8 or the possibility that epidemiologic associations do not guarantee cause-and-effect relationships.
Prospective studies assessing vitamin D and CV risk have been less convincing. Wang and colleagues 19 performed a meta-analysis of 17 prospective cohort studies and randomized trials and found moderate to high doses of vitamin D supplementation may decrease the risk for CV disease with benefits mainly seen in dialysis patients. Only one study in the general population showed a consistent decrease in CV disease after vitamin D supplementation.20 Another recent meta-analy-sis of 51 trials examining the effects of vitamin D on CV outcomes found that the trial data could not demonstrate a statistically significant reduction in mortality or CV risk in relation to vitamin D status.21
Wang also examined more than 1700 participants from the Framingham Offspring Study who had no history of prior CV disease and measured 25-OHD levels. Participants with a level <37 nmol/L had an increased risk for incident CV events of 1.62 (95% confidence interval) compared with those participants with higher 25-OHD levels.22 However, further analysis revealed that positive findings were found only in patients with hypertension, causing investigators to propose that hypertension may enhance the adverse effects of vitamin D deficiency. A large prospective, case-controlled study of 18,000 men showed a significant correlation between low 25-OHD levels and an increased risk for myocardial infarction after adjustment for traditional risk factors.23 More recently, the effect of paricalcitol (an activated form of 1,25 OHD) on changing the urinary albumin-to-creatinine ratio (UACR) was compared with a placebo in a double-blind, randomized study including patients with type 2 diabetes and albuminuria. After 24 weeks, no difference in the UACR change could be detected between the two groups. However, systolic blood pressure was significantly decreased by 3 mm Hg to 9 mm Hg (but fluctuated over the study) compared with the placebo group.24
Two meta-analyses have looked at the effect of vitamin D on blood pressure levels. Both have included randomized interventional trials, most of which were limited in size. These meta-analyses could not find any effect of vitamin D on blood pressure.25,26 Significant heterogeneity was observed in both meta-analyses. Subgroup analysis suggested that supplementation with 25-OHD produced a greater fall in systolic blood pressure than 1,25 OHD.26
Other studies examined the association between low 25-OHD levels and endothelial dysfunction. Osteoprotegerin may play a role in vascular calcification and promote endothelial dysfunction. Studies suggest that serum osterprotegerin levels are associated with increased calcification of vessels, ischemic heart disease, and stroke.27 Supplementation of vitamin D in patients with low vitamin D levels showed significant improvement in arterial stiffness when compared with placebo. Other studies have also shown an association between vitamin D supplementation and a decrease in pulse wave velocity and arterial stiffness 28 and an inverse association between 25-OHD levels and sub-clinical atherosclerosis as measured by carotid intimal-media thickness.29 Vitamin D may play a protective role on blood vessels. A study assessing brachial artery flow-mediated dilatation (FMD) showed that participants with low 25-OHD levels (<20 nmol/L) had lower baseline FMD than controls.18 After 3 months of vitamin D supplementation FMD had significantly improved. This was again shown in another randomized controlled trial of overweight African Americans who showed improvement in FMD after receiving vitamin D3 supplementation vs the placebo group.30
Animal data have also shown that vitamin D supplementation may play a role in left ventricular hypertrophy regression; however, a recent study in the chronic kidney disease population showed that after 48 weeks of therapy with paricalcitol (a form of 1,25-OHD), left ventricular mass index was unchanged in patients with chronic kidney disease.31
There are observational and epidemiologic data linking vitamin D deficiency to hypertension and CV disease, but in prospective trials, to date, there is no convincing evidence indicating that vitamin D supplementation has a role to play in hypertension or CV protection. There are three large prospective clinical trials being performed at this time that will provide more information, but vitamin D supplementation cannot be recommended for CV prevention at this time.
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13. Vaidya A, Sun B, Forman JP, et al. The Fok1 vitamin D receptor gene polymorphism is associated with plasma renin activity in Caucasians. Clin Endocrinol (Oxf). 2011;74:783-790.
14. Snijder MB, Lips P, Seidell JC, et al. Vitamin D status and parathyroid hormone levels in relation to blood pressure: a population-based study in older men and women. J Intern Med. 2007;261:558-565.
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18. Jorde R, Figenschau Y, Emaus N, et al. Serum 25-hydroxyvitamin D levels are strongly related to systolic blood pressure but do not predict future hypertension. Hypertension. 2010;55:792-798.
19. Wang L, Manson JE, Song Y, Sesso HD. Systematic review: vitamin D and calcium supplementation in prevention of cardiovascular events. Ann Intern Med. 2010;152:315-323.
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21. Elamin MB, Abu Elnour NO, Elamin KB, et al. Vitamin D and cardiovascular outcomes: a systematic review and meta-analysis. J Clin Endocrinol Metab. 2011;96:1931-1942.
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23. Giovannucci E, Liu Y, Hollis BW, Rimm EB. 25-hydroxyvitamin D and risk of myocardial infarction in men: a prospective study. Arch Intern Med. 2008;168:1174-1180.
24. de Zeeuw D, Agarwal R, Amdahl M, et al. Selective vitamin D receptor activation with paricalcitol for reduction of albuminuria in patients with type 2 diabetes (VITAL study): a randomised controlled trial. Lancet. 2010;376:1543-1551.
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31. Thadhani R, Appelbaum E, Pritchett Y, et al. Vitamin D therapy and cardiac structure and function in patients with chronic kidney disease: the PRIMO randomized controlled trial. JAMA. 2012;307:674-684.
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