They add that further clinical and experimental studies may be warranted to validate their findings, to investigate the mechanisms underlying increased cardiovascular risk, and to determine whether correction of vitamin D deficiency could contribute to the prevention of cardiovascular disease.
A common problem
Wang et al explain that vitamin D deficiency is highly prevalent in the US and worldwide, affecting as many as one third to one half of otherwise healthy middle-aged to elderly adults, and that limited cutaneous synthesis due to inadequate sun exposure or pigmented skin and inadequate dietary intake are the principal causes of low vitamin D levels.
They note that although the best-characterized sequelae of vitamin D deficiency involve the musculoskeletal system, a growing body of evidence suggests that low levels of vitamin D may adversely affect the cardiovascular system. Vitamin D receptors have a broad tissue distribution that includes vascular smooth muscle, endothelium, and cardiomyocytes, and there are higher rates of coronary heart disease and hypertension with increasing distance from the equator, a phenomenon that has been attributed to the higher prevalence of vitamin D deficiency in regions with less exposure to sunlight.
But they caution that prospective data are needed because vitamin D deficiency could be a consequence of cardiovascular disease rather than a cause. Thus, they prospectively investigated the relation of vitamin D status to the incidence of cardiovascular events in a large, ambulatory, community-based population from the Framingham Offspring Study who were all free of cardiovascular disease at baseline.
In the 1739 participants (mean age 59 years; 55% women; all white), vitamin D status was assessed by measuring 25-dihydroxyvitamin D (25-OH D) levels. Overall, 28% of individuals had levels below 15 ng/mL, and 9% had levels below 10 ng/mL, thresholds which characterize varying degrees of vitamin D deficiency.
During a mean follow-up of 5.4 years, 120 individuals developed a first cardiovascular event. After adjustment for conventional cardiovascular risk factors, individuals with 25-OH D levels below 15 ng/mL had an increased risk for incident cardiovascular events compared with those with 25-OH D levels above 15 ng/mL. The higher risk associated with vitamin D deficiency was particularly evident among individuals with hypertension, in whom 25-OH D levels below 15 ng/mL were associated with a 2-fold risk of cardiovascular events. But there was no correlation seen in participants without hypertension.
Hazard ratio for heart disease for 25-OH D levels below 15 ng/mL
|Group||Hazard ratio (95% CI)||P value|
|All participants||1.62 (1.11 - 2.36)||0.01|
|Those with hypertension||2.13 (1.30 - 3.48)||0.003|
|Those without hypertension||1.04 (0.55 - 1.96)||Ns|
There was also a graded increase in cardiovascular risk as levels of 25-OH D decreased, and further adjustment for C-reactive protein, physical activity, or vitamin use did not affect the findings.
Hazard ratio for heart disease according to level of 25-OH D
|Level of 25-OH D||Hazard ratio (95% CI)|
|10-15 ng/mL||1.53 (1.00 - 2.36)|
|< 10 ng/mL||1.80 (1.05 - 3.08)|
P for linear trend 0.01.
The authors note that these data indicate that increased cardiovascular risk is present at 25-OH D levels (< 15 ng/mL) compatible with at least moderate vitamin D deficiency. They add that the present findings extend the results of smaller, cross-sectional studies that have examined the association between vitamin D status and cardiovascular risk and have shown 25-OH D levels in individuals with MI, stroke, heart failure, and cardiovascular disease.
On the possible mechanisms, Wang et al point out that 1,25-OH D is involved in the regulation of the renin-angiotensin axis, and putative vascular effects of vitamin D are wide-ranging and include modulation of smooth muscle cell proliferation, inflammation, and thrombosis.
They add that potential interaction between vitamin D deficiency and hypertension suggested in this study fits in with the observation that both hypertension and vitamin D deficiency may influence cardiac and vascular remodeling, and with data suggesting that vitamin D deficiency directly promotes the development of hypertension.
They point out that in small clinical trials, vitamin D supplementation has promoted reductions in blood pressure, left ventricular hypertrophy, and inflammatory cytokines, although vitamin D supplements were not associated with a reduction in cardiovascular events in the Women's Health Initiative. But they add that the Women's Health Initiative was a fracture-prevention trial and was not designed to evaluate cardiovascular risk, the dose of vitamin D used was far below the amount necessary to correct vitamin D deficiency, patients in the placebo arm were also allowed to take vitamin D supplements which could have masked any benefit, and the trial did not address whether vitamin D supplementation benefited individuals with vitamin D deficiency, because enrollment was performed irrespective of vitamin D status. They note however that vitamin D did appear to reduce cardiovascular risk in obese individuals, who are prone to endogenous vitamin D deficiency, and also in those with multiple coronary risk factors.
The National Institutes of Health, the US Department of Agriculture, and the American Heart Association supported this study. One of the study authors has received honoraria from Abbott Laboratories and Genzyme. The other study authors have disclosed no relevant financial relationships.
- Wang TJ, Pencina MJ, Booth SL, et al. Vitamin D deficiency and risk of cardiovascular disease. Circulation. 2008. Published online before print DOI: 10.1161/CIRCULATIONAHA.107.706127.
Vitamin D deficiency may be present in up to one half of older adults, and inadequate sun exposure, skin pigmentation, and dietary deficiency can all contribute to reduced body stores of vitamin D. Although the negative effects of vitamin D deficiency on bone health are well documented, there is emerging evidence that vitamin D is important in cardiovascular health. Vitamin D may decrease renin activity as well as lower blood pressure, and there is evidence that vitamin D helps to regulate the growth and proliferation of vascular smooth muscle cells.
The current study of the Framingham Offspring Cohort examines the relationship between serum levels of 25-OH D, the best marker of vitamin D stores in the body, and cardiovascular events.
- The current study excluded Framingham Offspring participants with preexisting cardiovascular or kidney disease.
- All participants underwent a baseline examination for cardiovascular risk factors. Serum levels of 25-OH D and C-reactive protein were included in these analyses, and researchers calculated Vitamin D intake from diet and supplement sources.
- The main outcome of the study was the relationship between levels of 25-OH D and the risk for a cardiovascular event, which was determined after a review of medical records and included diagnoses of myocardial infarction, coronary insufficiency (prolonged chest pain with documented electrocardiographic changes), angina, stroke, transient ischemic attack, peripheral claudication, and heart failure. This main result was adjusted for multiple possible confounders of cardiovascular risk.
- Data from 1739 participants were included in the study. The mean age of the subjects was 59 years, and 55% of participants were women. The rates of hypertension and diabetes mellitus were 40% and 8%, respectively, at baseline.
- The mean concentration of 25-OH D was 19.7 ng/mL, 28% of subjects were found to have a 25-OH D level less than 15 ng/mL, and 9% had a level lower than 10 ng/mL.
- The mean duration of follow up was 5.4 years. During this period, 120 subjects had a primary cardiovascular event.
- The fully adjusted hazard ratio for a cardiovascular event associated with a 25-OH D level of less than 15 ng/mL vs higher levels was 1.62 (P = .01). Further adjustment for vitamin D supplementation and physical activity failed to alter this main result.
- There was a nonlinear increase in the risk for a cardiovascular event as 25-OH D levels fell. Compared with subjects with a 25-OH D level of 15 ng/mL or more, participants with levels of 10 to 15 ng/mL and less than 10 ng/mL experienced hazard ratios of 1.53 and 1.80, respectively, for an incident cardiovascular event.
- Lower levels of vitamin D increased the risk for cardiovascular events among participants with hypertension but not among subjects without hypertension.
Pearls for Practice
- Up to one half of older adults may have vitamin D deficiency, and multiple factors can account for this deficiency. Vitamin D deficiency has been associated with increasing risk factors for cardiovascular disease.
- The current study suggests that vitamin D deficiency can independently increase the risk for cardiovascular disease in a nonlinear fashion