Journal 54.pmd

JIACM 2013; 14(3-4): 247-52
Vitamin D deficiency: A new risk factor for cardiovascular disease
Biswajit Das*, Trinath Kumar Mishra**, Satya Narayan Routray**, Chhabi Satpathy*, Hrudananda Mishra***
Vitamin D deficiency is emerging as a new risk factor for various cardio-vascular diseases (CVDs), specifically atherosclerotic vascular
disease. A number of epidemiological studies have shown that vitamin D deficiency is prevalent among many populations cutting
across all ethnicities and among all age groups. With the growing menace of the epidemic of CAD, emergence of another commonly
prevalent risk factor for the same is a matter of concern. Although the link between vitamin D deficiency and CAD has been
consistently proven, interventional trials with supplementation of vitamin D or calcium have been disappointing in terms of risk
reduction. Further research in this direction is underway and is likely to improve our understanding, and open up newer avenues
for reducing the risk of CAD.
Key words: Vitamin D, calcium supplementation, coronay artery disease.
in many populations worldwide. It has been reported inhealthy children, young adults, especially African Vitamin D deficiency is emerging as a new risk factor for Americans, and middle-aged and elderly adults. Typically, various cardiovascular diseases (CVDs), especially the prevalence of low 25 (OH) D levels (< 20 ng/mL [50 atherosclerotic vascular diseases. With growing nmol/L]) is approximately 36% in otherwise healthy urbanisation and adoption of a westernised lifestyle, the young adults aged 18 to 29 years, 49.42% in black prevalence of both CVD and Vitamin D deficiency are women aged 15 to 49 years, 50.41% in outpatients aged increasing. Apart from its direct role in CVD, vitamin D has 49 to 83 years, up to 57% in general medicine inpatients also been attributed to other metabolic diseases which in the United States, and even higher in Europe (28% - also affect CV health. Although vitamin D has been linked 100% of healthy and 70% - 100% of hospitalised adults).
to a wide variety of diseases starting from cancer to Vitamin D inadequacy is particularly common among immunological conditions, the focus here will be on CVD.
patients with osteoporosis7. A recent systematic review Emergence of this particular association has a special by Gaugris et al concluded that the prevalence of importance in the Indian context. With a billion plus inadequate 25 (OH) D levels appears to be high in post- population and the burgeoning number of patients with menopausal women and especially those with CVD, emergence of another risk factor – vitamin D osteoporosis and a history of fracture8. The results of a deficiency – which is commonly prevalent, should raise recent cross-sectional, observational study conducted at 61 sites across North America showed that 52% of post-menopausal women receiving therapy for osteoporosis Prevalence of vitamin D insufficiency
had 25 (OH) D levels of less than 30 ng/mL (75 nmol/L)9.
Vitamin D deficiency is prevalent in India and worldwide.
The high prevalence of vitamin D inadequacy in that Several studies have demonstrated low serum vitamin study was consistent across all age groups and North 25 (OH) D levels in populations across India1. In North American geographic regions studied. The prevalence India, 96% of neonates2, 91% of healthy school girls3, 78% of very low serum 25 (OH) D levels (<12 ng/mL [30 nmol/ of healthy hospital staff4, and 84% of pregnant women2 L]) was 76% among patients with osteoporosis in another were found to have hypovitaminosis D. In South India, study. A global study of vitamin D status in post- hypovitaminosis D is equally prevalent among different menopausal women with osteoporosis showed that 24% population groups5. Hypovitaminosis D is equally had 25 (OH) D levels less than 10 ng/mL (25 nmol/L), with prevalent among rural and urban subjects but in some the highest prevalence reported in central and southern studies urban subjects are found to be more deficient.
Europe10. A study of Asian adults in the United Kingdom In one report by Malhotra et al, vitamin D deficiency was showed that 82% had 25 (OH) D levels less than 12 ng/ reported to be found among diverse population groups mL (30 nmol/L) during the summer season, with the in different countries of South Asia6. Vitamin D proportion increasing to 94% during the winter inadequacy constitutes a largely unrecognised epidemic months11. A study of 1,546 African American women in * Assistant Professor, ** Associate Professor, *** Professor and Head, Department of Cardiology, Shri Ramachandra
Bhanj (SCB) Medical College, Cuttack - 753 007, Orissa.
the United States, ranging in agefrom 15 to 49 years, (25 [OH] D) are low, calcium absorption is insufficient to showed that more than 40% had serum25 (OH) D levels satisfy the calcium requirements not only for bone health less than 15 ng/mL (37 nmol/L)12.
but also for most metabolic functions andneuromuscular activity. The body responds by increasing Vitamin D photobiochemistry, metabolism,
the production and release of PTH into the circulation(Figure 1). The increase in PTH restores calcium homoeostasis by increasing tubular reabsorption of UV-B irradiation of skin triggers photolysis of 7- calcium in the kidneys, increasing bone calcium dehydrocholesterol (provitamin D3) to previtamin D3 in mobilisation from the bone, and enhancing the the plasma membrane of human skin keratinocytes.
production of 1, 25 (OH) 2D13.
Once formed in the skin, cell plasma membraneprevitamin D3 is rapidly converted to vitamin D3 by the Assessment of vitamin D status
skin's temperature. Vitamin D3 from the skin and vitamin Serum 25 (OH) D is the major circulating metabolite of D from the diet undergo 2 sequential hydroxylations, first vitamin D and reflects vitamin D inputs from cutaneous in the liver to 25 (OH) D and then in the kidney to its synthesis and dietary intake. The serum 25 (OH) D level biologically active form, i.e., 1, 25- dihydroxyvitamin D is the standard clinical measure of vitamin D status.
(1, 25 [OH] 2D) (Figure 1). Excessive solar UV-B irradiation Although 1, 25 (OH) 2D is the active form of vitamin D, it will not cause vitamin D intoxication because excess should not be measured to determine vitamin D status.
vitamin D3 and previtamin D3 are photolysed to It usually is normal or even elevated in patients with biologically inactive photoproducts. Melanin skin vitamin D deficiency. Testing of serum 25 (OH) D is most pigmentation is an effective natural sunscreen, and useful in patients who are at risk of vitamin D deficiency, increased skin pigment can greatly reduce UVB- including elderly patients, infirm patients, children and mediated cutaneous synthesis of vitamin D3 by as much adults with increased skin pigmentation, patients with as 99%, similar to applying a sunscreen with a sun fat malabsorption syndromes, and patients with protection factor of 15. Keratinocytes are also capable osteoporosis. This measurement is also useful for of hydroxylating 25 (OH) D to produce 1, 25 (OH) 2D. The purposes of planning or monitoring vitamin D therapy.
1, 25 (OH) 2D (from keratinocyte or renal sources) may Clinical assays of 25 (OH) D include the Nichols regulate keratinocyte differentiation, melanocyte Advantage Assay (chemilu-minescence protein-binding apoptosis, and melanin production, and this may be assay, the DiaSorin radioimmunoassay, and the another mechanism for regulating the cutaneous benchmark high-performance liquid chromatography synthesis of vitamin D3 by negative feedback. The 1, 25 assays and liquid chromatography mass spectroscopy (OH) 2D ligand binds with high affinity to the vitamin D assays. The chemiluminescence protein-binding assay receptor (VDR) and triggers an increase in intestinal and the radioimmunoassay are most commonly used to absorption of both calcium and phosphorus. In addition, determine patient vitamin D status. Recent reports have vitamin D is involved in bone formation, resorption, and raised concerns about the degree of variability between mineralisation, and in maintaining neuromuscular assays and between laboratories, even when using the function (Figure 1). Circulating 1, 25 (OH) 2D reduces same assay. Although reliable and consistent evaluation serum parathyroid hormone (PTH) levels directly by of serum 25 (OH) D levels remains an issue, reliable decreasing parathyroid gland activity and indirectly by laboratories currently exist, and efforts are in progress increasing serum calcium. The 1, 25 (OH) 2D regulates to improve and standardise assays to enhance accuracy bone metabolism in part by interacting with the VDR in and reproducibility at other laboratories. As noted osteoblasts to release biochemical signals, leading to previously, vitamin D plays a central role in calcium and formation of mature osteoclasts. The osteoclasts release phosphorus homoeostasis and skeletal health. Since collagenases and hydrochloric acid to dissolve the matrix impaired calcium metabolism due to low serum 25 (OH) and mineral, releasing calcium into the blood.When D levels triggers secondary hyperparathyroidism, vitamin D levels are inadequate, calcium and phosphorus increased bone turnover, and progressive bone loss, the homoeostasis becomes impaired. Vitamin D is primarily optimal range of circulating 25 (OH) D for skeletal health responsible for regulating the efficiency of intestinal has been proposed as the range that reduces PTH levels calcium absorption. In a low vitamin D state, the small to a minimum and calcium absorption is maximal.
intestine can absorb approximately 10% - 15% of dietary Several studies have shown that PTH levels plateau to a calcium. When vitamin D levels are adequate, intestinal minimum steady-state level as serum 25 (OH) D levels absorption of dietary calcium more than doubles, rising approach and rise above approximately 30 ng/mL (75 to approximately 30% - 40%. Thus, when vitamin D levels Journal, Indian Academy of Clinical Medicine l Vol. 14, No. 3-4 l July-December, 2013
Nonskeletal consequences of vitamin D
all been successfully prevented in models using mice that were prone to these diseases if they received 1, 25 (OH)2D3 early in life. In a recent observation by Hypponen et It has long been recognised that people who live at higher al found that children receiving 2,000 IU vitamin from age latitudes face an increased risk of many chronic diseases, 1 year on was decreased their risk of getting type 1 including common cancers, multiple sclerosis, and diabetes by 80%20. Krause et al reported that hypertensive hypertension15. As early as 1941, Apperly observed that patients exposed to UVB radiation for 3 months had a people living at higher latitudes, e.g., Massachusetts and 180% increase in circulating concentrations of 25 (OH) D New Hampshire, had a higher risk of dying of the most and a 6 mm Hg decrease in their diastolic and systolic common cancers than did people living in the South, e.g., blood pressures – results similar to those expected if the Georgia and South Carolina16. In 1979, Rostand reported patients had received a blood pressure medication21. A that people living at higher latitudes in both the United similar group of patients who were exposed to ultraviolet States and Europe were at higher risk of hypertension17.
A radiation and whose circulating concentrations of 25 In the late 1980s and early 1990s, several investigators (OH) D did not increase continued to be hypertensive reported increased risks of dying of colon, prostate, and throughout the 3-month study. The exact mechanism by breast cancer in people living at higher latitudes in both which UVB radiation returned the blood pressure to the United States and Europe. Grant reported that 25% of normal [presumably due to increased blood the deaths due to breast cancer in women in Europe could concentrations of 25 (OH) D] in these hypertensive adults be attributed to the women's lack of UVB from exposure is not well understood, but the observation by Li et al22 to sunlight18. Both men and women are at higher risk of sheds some light on the question. They observed in a dying of cancer if they have minimum exposure to mouse model that 1, 25 (OH) 2D is effective in down- sunlight. In a retrospective study, Ahonen et al reported regulating renin and angiotensin and thereby decreasing that men on average begin to develop prostate cancer blood pressure.
by the age of 52 years, whereas men exposed to moresunlight throughout their lives did not begin developing Vitamin D and cardiovascular health
prostate cancer until 3 - 5 years later19.
Although the best-characterised sequelae of vitamin D Vitamin D metabolism and noncalcaemic
deficiency involve the musculoskeletal system, a growingbody of evidence suggests that low levels of vitamin D may adversely affect the cardiovascular system. Vitamin It has been known since long that vitamin D3 made in D receptors have a broad tissue distribution that includes the skin or coming from the diet requires 2 obligate vascular smooth muscle, endothelium, and hydroxylations, first in the liver and then in the kidney, to cardiomyocytes. In vitro, activated 1, 25-dihydroxyvitamin create the active form of vitamin D, 1, 25 (OH) 2D (Figure D (1, 25-OH D) directly suppresses renin gene expression, 1). 1, 25 (OH) 2D interacts with its nuclear receptor in the regulates the growth and proliferation of vascular smooth intestine, bone, and kidney to regulate calcium and bone muscle cells and cardiomyocytes, and inhibits cytokine metabolism. Most tissues and cells in the body, including release from lymphocytes. Studies in knockout mice heart, stomach, pancreas, brain, skin, gonads, and activated confirm that the absence of vitamin D receptor activation T and B lymphocytes, have nuclear receptors for 1, 25 (OH) leads to tonic upregulation of the renin-angiotensin 2D, called vitamin D receptors. Thus, it is natural that 1, 25 system, with the development of hypertension and left (OH) 2D has a multitude of biologic effects that are ventricular hypertrophy. Clinical studies have reported noncalcaemic in nature. One of the most intriguing, cross-sectional associations between lower vitamin D important and unappreciated biologic functions of 1, 25 levels and plasma renin activity, blood pressure, coronary (OH) 2D is its ability to down-regulate hyperproliferative artery calcification, and prevalent cardiovascular disease.
cell growth. Normal and cancer cells that have a vitamin Additionally, ecological studies have reported higher rates D receptor often respond to 1, 25 (OH) 2D by decreasing of coronary heart disease and hypertension with their proliferation and enhancing their maturation. This increasing distance from the equator, a phenomenon that was the rationale for using 1, 25 (OH) 2D3 and its analogs has been attributed to the higher prevalence of vitamin to treat the common hyperproliferative skin disorder D deficiency in regions with less exposure to sunlight. The psoriasis. Vitamin D receptors are present in activated T possibility of a causal link between vitamin D and B lymphocytes and in activated macrophages. The deficiencyand cardiovascular disease is supported by most common autoimmune diseases, including type 1 biological plausibility, the demonstration of a temporal diabetes, rheumatoid arthritis, and multiple sclerosis, have association, and the finding of a dose response between Journal, Indian Academy of Clinical Medicine l Vol. 14, No. 3-4 l July-December, 2013
25-OH D deficiency and risk. These data raise the vitamin D and have the ability to convert circulating 25 possibility that treatment of vitamin D deficiency, via (OH) D to 1, 25 (OH) D. Putative vascular effects of vitamin supplementation or lifestyle measures, could reduce D are wide-ranging and include modulation of smooth cardiovascular risk. However, treatment strategies muscle cell proliferation, inflammation, and thrombosis.
suggested by observational data are not always borne out Interestingly, transgenic rats constitutively expressing by randomised trials, as evidenced by studies of hormone vitamin D-24-hydroxlyase, the enzyme that catalyzes the replacement therapy and B vitamins for homocysteine breakdown of 1 to 25 (OH) D, develop substantial lowering. Problems related to the use of observational atherosclerosis. Third, vitamin D deficiency triggers data include indication bias, confounding, and reverse secondary hyperparathyroidism. Parathyroid hormone causation. In a large observational study by Wang et al (PTH) promotes myocyte hypertrophy and vascular sponsored by the NIH, where they employed direct remodelling. Other studies suggest that PTH has a pro- measurement of 25 hydroxy vitamin D, they concluded inflammatory effect, stimulating the release of cytokines that moderate-to-severe vitamin D deficiency is a risk by vascular smooth muscle cells. Hypertension plays a factor for developing cardiovascular disease.
key role in the development of left ventricularhypertrophy and vascular remodelling. Because vitamin Among different spectrum of cardiovascular diseases D deficiency may also influence cardiac and vascular linked to vitamin D deficiency, CAD is the most extensively remodelling, hypertension could magnify the adverse studied. A Danish study examined 25-hydroxyvitamin D effects of vitamin D deficiency on the cardiovascular (25 [OH] D) levels measured in 128 patients admitted to system. Also, experimental and clinical data suggest that the hospital with ischaemic heart disease (75 with angina vitamin D deficiency directly promotes the development pectoris and 53 with acute MI) and 409 control subjects of hypertension, which provides another potential and found that 25 (OH) D levels were significantly lower mechanism linking vitamin D deficiency, hypertension, in those with angina (23.5 ng/ or MI (24.0 ng/mL) than in and cardiovascular risk. Calcification is a common feature controls (28.8 ng/mL)(23). In a New Zealand case control of atherosclerosis, and nearly all angiographically study, 3 of 179 patients with MI, cases had a lower mean significant lesions are calcified. Calcification of coronary 25 (OH) D level (P = .02), which was more pronounced in arteries has been associated with increased risk of MI and the winter-spring period than in the summer-autumn poorer 5-year survival. Atherosclerotic calcification is a period. The relative risk (RR) of MI decreased across process regulated in ways similar to skeletal osteogenesis.
increasing quartiles of 25 (OH) D24. Multivariate analyses A significant association exists between osteoporosis and of major CVD risk factors did not appreciably alter the vascular calcification, suggesting that osteoregulatory results. A small, nested, case control study of MI based in mechanisms related to bone development may affect the Tromso Heart Study (northern Norway) with only 30 calcification in the vasculature. Levels of 1, 25- cases and 60 matched controls found a slightly dihydroxyvitamin D have been shown to be inversely nonsignificant lower 25 (OH) D level in cases (23.6 ng/mL) associated with vascular calcification, suggesting that compared with controls (25.4 ng/mL)25. Another vitamin D may affect MI risk through its effects on vascular prospective study by Giovannucci, funded by the National calcification. Other mechanisms could account for or Cancer Institute and the National Heart, Lung, and Blood contribute to the association between 25 (OH) D and MI Institute, vitamin D deficiency was found to be an risk. Vitamin D deficiency, possibly combined with low independent risk factor for development of AMI after calcium intake, has been associated with impaired fasting adjusting for all known CAD risk factors. In this cohort glucose and possibly risk of type 2 diabetes mellitus, risk study, men with circulating 25 (OH) D levels of at least 30 factors for CVD.
ng/mL had approximately half the risk of AMI,independent of other CVD factors26.
In an excellent review published in the Annals of InternalMedicine by Pittas et al, the authors analysed different studies conducted on the role of vitamin D on differentcardiometabolic outcomes and the effect vitamin D Several mechanisms may explain the link between vitamin supplementation on them. They identified seven D deficiency and cardiovascular disease. First, longitudinal studies, analysing vitamin D status and experimental studies indicate that 1, 25 (OH) D participates cardiovascular end-points including 43,527 participants in the regulation of renin-angiotensin axis by directly who were followed from 5 to 27 years for incident suppressing renin gene expression. Renin over-expression cardiovascular disease. Cardiovascular end-points can be produced in wild-type mice by pharmacological included myocardial infarction, cardiovascular related inhibition of vitamin D synthesis. Second, vascular smooth death, a composite cardiovascular end-point, and stroke.
muscle cells and endothelial cells express receptors for All studies measured 25 (OH) D concentration, and all Journal, Indian Academy of Clinical Medicine l Vol. 14, No. 3-4 l July-December, 2013
reported multivariate adjusted results. Overall, 5 of the 9 reference group included individuals with "mild" analyses found that lower 25 (OH) D concentration was deficiency was observed.
associated with increased risk for incident cardiovasculardisease.The Framingham Offspring Study found the Role of vitamin D and calcium
association between lower 25 (OH) D concentration and increased risk for overall cardiovascular events to benonlinear and the association was statistically significant With a growing evidence base implicating the role of only among participants with hypertension at baseline.
vitamin D deficiency in cardiovascular diseases, correction The authors concluded that although cross-sectional of hypovitaminosis D and calcium supplementation studies have reported consistent associations between should be the next logical step, because they attempt to lower 25 (OH) D concentration or vitamin D intake and address the pathophysiological anomaly involved in prevalent cardiometabolic outcomes in the longitudinal causation cardiovascular diseases. Unfortunately, data observational studies, lower 25 (OH) D concentration or regarding the effect of these measures to prevent vitamin D intake was associated with increased risk for cardiovascular diseases have not been as consistent.
incident hypertension and possibly cardiovascular disease, In a sytematic review of the role of vitamin D and calcium but the strengths of these associations were attenuated supplementation in prevention of cardiovascular events compared with those from cross-sectional studies27.
by Lu Wang et al published in the Annals of Internal Among the studies that evaluated fatal cardiovascular Medicine28, prospective studies of dialysis patients and a events, 2 of 3 found statistically significant associations single cohort study involving a general population that favoured higher vitamin D concentration for all fatal showed consistent reductions in CVD mortality among cardiovascular events (cardiac or stroke), 2 found similar those who received vitamin D supplements. Randomised significant associations with fatal stroke, and 1 found no trials reported a slight but statistically nonsignificant significant association with fatal cardiac events. Of the 2 reduction in CVD risk with vitamin D supplementation at studies that evaluated myocardial infarction, only the moderate-to-high doses. In contrast, both prospective analysis in the men-only Health Professionals Follow-up studies and randomised trials showed no apparent effect Study found a significant association between lower 25 of calcium supplementation, with or without vitamin D, (OH) D concentration and increased risk. The authors did on the risk for CVD. A consistently strong inverse not perform a meta-analysis because of the heterogeneity association between active vitamin D use and CVD of outcomes27.
mortality among patients receiving dialysis suggests apotential cardioprotective effect of vitamin D. However, Although data linking vitamin D deficiency and the generalisation and applicability of such findings to cardiovascular disease is consistent, the exact threshold broader populations warrants more study. Women's at which risk for cardiovascular disease may increase is Health Initiative is the largest trial of vitamin D unclear. Relatively high levels of 25 (OH) D (> 30ng/mL) supplementation to date and has shown no effect of are required to maintain normal PTH levels, but optimal vitamin D plus calcium supplementation on CVD event levels for cardiovascular protection may differ from those risk. Notably, the vitamin D dosage of 400 IU/d used in for bone metabolism or normal PTH physiology. Many the Women's Health Initiative increased median plasma studies report increased cardiovascular risk at 25 (OH) D 25-hydroxyvitamin D levels from 42.3 nmol/L to only 54.1 levels well below 30 ng/mL. In the Framingham Offspring nmol/L. Extrapolating these data to achieve 25- Study the mean 25 (OH) D concentration was 19.7 ng/ hydroxyvitamin D levels above 75 nmol/L, the mL. The overall prevalence of 25 (OH) D 15 ng/mL was recommended level for several health outcomes, would 28%, with 9% having 25 (OH) D 10 ng/mL. The age- and require supplementation of at least 1,000 IU/d to sex-adjusted 5-year rate of cardiovascular disease was determine whether improvements in vitamin D status may approximately twice as high in those with 25 (OH) D 15 prevent CVD. These findings indicate that a protective ng/mL as in those with 25 (OH) D 15 ng/mL. The highest effect of vitamin D supplementation on CVD is possible, rate of cardiovascular disease was observed in those with but that a moderate-to-high dosage may be needed. Null hypertension and vitamin D deficiency. Although the findings in 4 large-scale prospective studies of initially study was reported to have inadequate statistical power healthy participants suggest that calcium supplements are to evaluate the effect of milder degrees of vitamin D unlikely to confer a major effect on CVD risk. Secondary deficiency (15 to 30 ng/mL), given the low proportion of analyses in 4 randomised trials also have not individuals in the cohort with levels < 30 ng/mL (10%), demonstrated a clear effect of calcium supplementation an increased cardiovascular risk associated with on CVD risk. A recent study by Bolland and co-workers decreased 25-OH D levels in analyses in which the raised concerns about a possible adverse effect of calcium Journal, Indian Academy of Clinical Medicine l Vol. 14, No. 3-4 l July-December, 2013
supplements on the risk for MI. In conclusion, evidence Clin Nutr 2005; 81: 1060-4.
from prospective observational studies and randomised, Puri S, Marwaha RK, Agarwal N et al. Vitamin D status of apparently healthyschool-girls from two different socioeconomic strata in Delhi: relation to controlled trials suggests that vitamin D supplementation nutrition and lifestyle. Br J Nutr 2008; 99: 876-82.
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Journal, Indian Academy of Clinical Medicine l Vol. 14, No. 3-4 l July-December, 2013

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