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© 2008 Lippincott Williams & Wilkins, Inc.

Volume 11(1), January 2008, p 7–12

Vitamin D and cardiovascular disease risk
[Ageing: biology and nutrition: Edited by Ronni Chernoff and Paolo M. Suter] Michos, Erin Da; Melamed, Michal Lb
Department of Medicine, Division of Cardiology, Johns Hopkins School of Medicine, Baltimore, Maryland Department of Medicine, Division of Nephrology, and Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, New York, USA Correspondence to Erin D. Michos, MD, MHS, Division of Cardiology, Johns Hopkins School of Medicine, Carnegie 568A, 600 N. Wolfe Street, Baltimore, MD 21287, USA Tel: +1 410 502 6813; fax: +1 410 955 3478; e-mail: edonnell@jhmi.edu
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Abstract
Purpose of review: Despite our understanding of how to prevent and treat traditional cardiovascular risk factors, cardiovascular disease remains the leading cause of death of both men and women in the US. Thus, there is widespread interest in a number of emerging nontraditional risk factors for the detection of early cardiovascular disease in order to implement aggressive preventive therapies. 25-Hydroxyvitamin D deficiency has been identified as a potential novel cardiovascular disease risk factor. This review outlines what is known about the association of 25-hydroxyvitamin D levels and cardiovascular disease risk. Recent findings: Low 25-hydroxyvitamin D levels have been associated with the cardiovascular disease risk factors of hypertension, obesity, diabetes mellitus and the metabolic syndrome, as well as cardiovascular disease events including stroke and congestive heart failure. Studies suggest vitamin D deficiency may be a contributor to the development of cardiovascular disease potentially through associations with diabetes or hypertension. Summary: Vitamin D deficiency is easy to screen for and easy to treat with supplementation. Further larger observational studies and randomized clinical trials are, however, needed to determine whether vitamin D supplementation could have any potential benefit in reducing future cardiovascular disease events and mortality risk.

Introduction
Atherosclerosis and osteoporosis are common diseases among the elderly, and it has been postulated that the two are related. Age is a major risk factor for both conditions; however, many studies [1,2] (but not all [3,4]) have indicated that after age adjustment, arterial calcification and atherosclerosis are associated with low bone density. Vitamin D deficiency is common in the elderly and is associated with osteoporosis; however, the association of serum vitamin D levels with cardiovascular risk (CVD) events is debated in the literature, with smaller case–control studies suggesting both increased and decreased risk [5–7]. Serum 25-hydroxyvitamin D [25(OH)D] levels vary with geography, seasonality, latitude and altitude, presumably as a result of sunlight exposure [8]. Interestingly, the risk of CVD is noted to be highest in areas of increased geographic latitude and during winter months, which parallels the trends where 25(OH)D levels are the lowest [8]; however, a direct causal relationship between 25(OH)D deficiency and CVD has not been established.

Vitamin D metabolism
Vitamin D has long been known to be vital to bone health. More recently, vitamin D has been shown to play a role in the risk of malignancy [9], infections [10], immune function and cardiovascular health. The major source of vitamin D is endogenous production via the action of the sun's ultraviolet light on skin 7-dehydrocholesterol precursors, converting them to vitamin D3. Vitamin D3 undergoes 25-hydroxylation in the liver, to form 25(OH)D, the metabolite that reflects vitamin D stores. The active metabolite, 1,25-dihydroxyvitamin D [1,25(OH) D] is primarily 2 formed after 1[alpha]-hydroxylation in the kidneys; however, many other tissues, including breast, colon and vascular smooth muscle cells, also express 1[alpha]-hydroxylase where the locally formed 1,25(OH)2D serves as a cell-differentiating factor. Although 1,25(OH)2D is the active metabolite, its serum level does not correlate well with 25(OH)D deficiency. The optimal level of 25(OH)D has been suggested to be 30 ng/ml or above [11], a level associated with maximal suppression of parathyroid hormone and reduced fracture rates. Using 28 ng/ml as a cut-off, it was estimated that approximately 41% of men and 53% of women in the US have insufficient levels of 25(OH)D [12]. Ethnic differences in vitamin D deficiency have been also described, with African-Americans being at higher risk of 25(OH)D deficiency than whites despite paradoxically having increased bone mass and lower fracture rates [12,13].

Vitamin D and cardiovascular disease risk factors

Vitamin D deficiency is associated with obesity [14–16], glucose intolerance [17], the metabolic syndrome, hypertension and dyslipidemia, which are all well-established CVD risk factors [18]. For example, in the Third National Health and Nutrition Examination Survey (NHANES-III), a cross-sectional representative sample of the US population, the prevalences of hypertension [odds ratio (OR) 1.30], diabetes mellitus (OR 1.98), obesity (OR 2.29) and high serum triglyceride levels (OR 1.47) were all significantly higher in the lowest compared to the highest quartiles of serum 25(OH)D ( < 0.001 for all) [19••]. P

Diabetes
Many studies have shown an association between glucose intolerance/insulin resistance and low serum levels of 25(OH)D or vitamin D intake [21]. A recent meta-analysis found a consistent inverse association across observational studies between

[17,20]

serum 25(OH)D levels and prevalent type 2 diabetes mellitus (i.e. OR 0.36) [95% confidence interval (CI) 0.16–0.80] among nonblacks for highest vs. lowest 25(OH)D levels [22•]. The risk of incident diabetes was also inversely associated with both combined calcium/vitamin D intake [OR 0.82 (0.72–0.93) for highest vs. lowest intake] and for dairy intake [OR 0.86 (0.79–0.93)]
[22•].

Evidence from clinical trials also suggests that combined vitamin D/calcium supplementation may have a role in the prevention of type 2 diabetes, but only in high-risk populations. Among those with impaired fasting glucose at baseline, intake of combined calcium/vitamin D supplements conferred a lower increase in fasting glucose at 3 years compared with placebo [0.02 (0.4) vs. 0.34 mmol/l (6.1 mg/dl), respectively, P = 0.042] and a lower increase in insulin resistance evaluated by the method of glucose homeostasis (0.05 vs. 0.91, P = 0.031), but there was no difference in the change in glucose or insulin resistance levels among those normoglycemic at baseline [23•]. While promising, the overall evidence from clinical trials regarding vitamin D supplementation for diabetes prevention is still limited by short study durations, few subjects, varying formulations and doses of the vitamin D/calcium supplements or by post-hoc analyses.

Hypertension
Cross-sectional analyses of data from NHANES-III also shows that lower 25(OH)D levels are associated with higher blood pressures [24•]. In contrast, another cross-sectional analysis showed higher blood pressures were associated with high parathyroid hormone levels, but not with low 25(OH)D levels [25]. Similarly, conflicting evidence exists regarding vitamin D and the risk of incident hypertension. Results from three large prospective cohort studies did not find that higher intake of vitamin D reduced risk of incident hypertension over more than 8 years of follow-up, even in the highest quintile of intake (494–3519 IU/day) [26]. On the other hand, a study evaluating four large prospective cohorts found that serum 25(OH)D levels were indeed inversely associated with the risk of incident hypertension [27•]. During 4 years of follow-up, the multivariable-adjusted relative risk of incident hypertension for serum 25(OH)D levels below 15 ng/ml (i.e. vitamin D deficiency) compared with levels of 30 ng/ml or above was 6.13 (95% CI 1.00–37.8) among men and 2.67 (95% CI 1.05–6.79) among women [27•]. One reason for the difference in the findings of the two studies is potentially poor correlation between vitamin D intake and 25(OH)D levels. Two small clinical trials that suggest that vitamin D supplementation, one with ultraviolet B radiation ( = 20) [28], and another n with 1200 mg of calcium and 800 IU of vitamin D (n = 145) [29], reduced systolic blood pressure by approximately 6 mmHg.

Preeclampsia
Vitamin D deficiency may also be a risk factor for maternal preeclampsia (new-onset gestational hypertension and proteinuria for the first time after 20 weeks gestation). In a recent study, a 20 ng/ml lower 25(OH)D concentration early in pregnancy doubled the risk of preeclampsia [adjusted OR 2.4 (95% CI 1.1–5.4)] [30]. The beneficial effects of vitamin D on the elastic wall of blood vessels may be one explanation [31]. Furthermore, activated vitamin D promotes angiogenesis by increasing vascular smooth muscle cell proliferation through growth factor expression [32]. These beneficial effects of activated vitamin D on the vasculature may have relevance to nonpregnant older adults as well.

The metabolic syndrome
Since the individual components of glucose intolerance, triglycerides, obesity and hypertension are associated with low 25(OH)D levels, not too surprisingly, 25(OH)D deficiency is also associated with the metabolic syndrome in several studies. Again in NHANES-III, the multivariable-adjusted odds of having the metabolic syndrome decreased progressively across increasing quintiles of serum 25(OH)D (P < 0.001 for the trend) [33]. Among women participating in the Women's Health Study, dietary vitamin D intake was inversely associated with the prevalence of the metabolic syndrome [age and calorie adjusted relative risk (RR) 0.77, 95% CI 0.65–0.91] when comparing the highest to the lowest quintile of vitamin D intake [34], although this relationship went away when adjusting additionally for calcium intake (RR 1.01, 95% CI 0.82–1.24). Another recent study, however, found an increased risk of metabolic syndrome with elevated parathyroid hormone levels only in older men and no association of 25(OH)D levels with the metabolic syndrome in either sex, which may in part be due to the higher levels of 25(OH)D in this cohort [35].

In the Women's Health Initiative, calcium plus vitamin D supplementation had a small but significant effect on prevention of weight gain (mean difference, -0.13 kg; 95% CI -0.21 to -0.05), which was observed primarily in women who reported inadequate calcium intakes [36•].

Vitamin D and inflammation
In addition to vitamin D's central role in calcium and bone metabolism, vitamin D also has intriguing immunoregulatory properties [37,38] that have potential therapeutic benefit in several autoimmune diseases and allograft rejection [39,40], and perhaps potentially in the treatment of CVD. In other noncardiac disorders of inflammation such as multiple sclerosis and ankylosing spondylitis, vitamin D may modulate disease severity with reduced levels of C-reactive protein, erythrocyte sedimentation rate and cytokines seen with higher serum 25(OH)D levels or after supplementation [41–43]. In two small clinical trials, vitamin D supplementation lowered C-reactive protein levels [44,45]. In congestive heart failure, vitamin D supplementation may reduce production of inflammatory cytokines as well [46]. Albeit small, these trials are of interest given the well-documented association of C-reactive protein with CVD risk as either a marker of inflammation or possibly even in the causal pathway [47,48]. The benefits of statin therapies are thought to extend beyond their lipid-lowering effects, perhaps with antiinflammatory and endothelial protective effects. Statins interestingly have been also shown to be associated with improved bone mass [49] and reduced fractures [50,51]. Vitamin D, similarly, also increases bone mass, reduces hip fracture [52] and has antiinflammatory properties. The similarities between the benefits of vitamin D and the benefits of statins on the cardiovascular system have been noted, and it has been hypothesized that statins may even activate vitamin D receptors (VDRs) [53]. Additionally, a recent study revealed that treatment with atorvastatin raised serum 25(OH)D levels among patients with a recent acute coronary syndrome event [54•].

Vitamin D receptor polymorphisms
Perhaps some of the discrepancy in results of studies associating 25(OH)D levels with CVD risk may be explained by VDR gene polymorphisms within the population. Many polymorphisms of the VDR are known to exist, with three adjacent restriction fragment length polymorphisms for BsmI, ApaI and TaqI at the 3'-end of the VDR gene being the most frequently studied [55]. The relationship between VDR polymorphisms and atherosclerosis is controversial, however, particularly with conflicting findings regarding the VDR BsmI (B/b) polymorphism. The B allele of the VDR (an allele which seems to predispose gene carriers to blunted calcium absorption, more rapid bone loss and reduced bone mineral density) is associated with increased calcific aortic stenosis [56], type 2 diabetes mellitus [57] and higher intimal medial thickness on carotid ultrasound [58] compared to the b allele. In another study, however, the b allele was also found to be associated with the severity of coronary heart disease (CHD) [59], and a large study of 3441 patients referred for coronary angiography found no association of VDR BsmI polymorphisms (neither the B nor the b allele) in the prevalence and severity of CHD seen at angiography [60].

Vitamin D and subclinical vascular disease
The association of serum levels of vitamin D metabolites with subclinical disease is also controversial. Animal models suggest that animals fed a vitamin D and cholesterol-rich diet have accelerated atherosclerosis [61–64]. In a group of 173 patients at moderately high risk for CHD who underwent electron beam computed tomography scanning of their coronary arteries, however, serum 1,25(OH)2 D levels were inversely correlated with the extent of coronary artery calcification [65]. This finding might be explained by 1,25(OH)2D's differentiating effect on cells and antiinflammatory properties. The authors hypothesized that vitamin D deficiency may be the factor that explains the potential association between osteoporosis and vascular calcification. Another study, however, found no correlation between serum 1,25(OH)2D levels and coronary calcification in 50 patients undergoing coronary angiography [66]. Vitamin D levels may have beneficial effects on the vascular system by improving vessel compliance. In a cohort of patients with end-stage renal disease, serum 25(OH)D and 1,25(OH)2D were negatively correlated with aortic pulse wave velocity (P < 0.001), and positively correlated with brachial artery distensibility (P < 0.01) and flow-mediated dilation (P < 0.001) after adjustment for blood pressure and age [67].

Vitamin D and cardiovascular disease events
Low 25(OH)D levels have been associated with CHD [6], stroke [7] and congestive heart failure [68], although a causal mechanism through incident diabetes or hypertension is plausible, this has not been confirmed. The association of both 25(OH)D and 1,25(OH)2D levels with CVD events is, however, widely debated in the literature. A case–control study by Rajasree et al. [5] found in 143 patients with CHD that elevated 25(OH)D levels (above 89 ng/ml) conferred a multivariate-adjusted OR of 3.18 (95% CI 1.31–7.73) for CHD. In contrast, another case–control study [6] of 179 patients who presented with acute myocardial infarction

suggested that increased 25(OH)D levels above the median are protective against CHD (OR 0.43, 95% CI 0.27–0.69). In this study, cases with myocardial infarction had significantly lower mean 25(OH)D levels than controls (12.8 vs. 14.2 ng/ml, P = 0.017), of which both levels are notably lower than the 25(OH)D levels compared by Rajasree et al. [5]. A recent study that compared 44 elderly patients admitted with a first acute stroke with 96 elderly controls found that 25(OH)D levels were significantly lower in cases than controls (P < 0.0001) with the majority (77%) of stroke patients having vitamin D deficiency which likely preceded the stroke [7]. Observational data in several different end-stage renal disease populations shows that supplementation with activated vitamin D in dialysis patients is associated with decreased mortality [69–72] as well as decreased hospital admissions [73]. In mice, vitamin D has also been shown to be an inhibitor of the renin–angiotensin system [74]. Other inhibitors of the renin–angiotensin system, such as angiotensin-converting enzyme inhibitors, have been shown to reduce mortality and morbidity in multiple disease states
[75].

In generally healthy postmenopausal women participants of the Women's Health Initiative randomized clinical trial, however, vitamin D supplementation (200 IU twice daily) did not reduce CVD risk over 7-year average follow-up [76••], although it is widely agreed that the supplementation dose was inadequate for the normal adult requirement of at least 800 IU daily of vitamin D [77]. Furthermore, 25(OH)D levels were not measured in that trial; thus, whether vitamin D supplementation at higher doses can reduce CVD risk among those with documented vitamin D deficiency is unknown. A more recent meta-analysis of 18 randomized clinical trials, including the Women's Health Initiative, did show that participants randomized to vitamin D supplementation experienced fewer deaths compared to those randomized to placebo [78••].

Conclusion
Vitamin D deficiency is easy to screen for, although not yet widely accepted in clinical practice. Furthermore, vitamin D deficiency is easy to treat with supplementation. Thus, if an association of vitamin D deficiency and CVD is confirmed in further studies, this could have important implications for health policy and patient care. Randomized clinical trials using adequate dosages (at least 800 IU to achieve serum levels above 30 ng/ml) are needed to determine whether vitamin D supplementation therapy could have any potential benefit in reducing future CVD events and mortality risk.

Acknowledgements
E.D.M. is supported by the P.J. Schafer Preventive Cardiology Research Award. M.L.M. is supported by grant DK078774 from the National Institute of Diabetes, Digestive and Kidney Diseases of the National Institutes of Health.

References and recommended reading Papers of particular interest, published within the annual period of review, have been highlighted as: • of special interest •• of outstanding interest Additional references related to this topic can also be found in the Current World Literature section in this issue (pp. 62–63).
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