US Pharm. 2016;41(2):43-45,
Cardiovascular disease (CVD) is a major cause of morbidity and mortality in the United States. It is also the number-one cause of death globally. People with CVD, or those who are at high CVD risk, need early detection and management of their condition, through either counseling or medication.1
Vitamin D is a fat-soluble vitamin and has long been known to play a classic hormonal role in skeletal health by regulating calcium and phosphate metabolism. In recent years, vitamin D deficiency has been identified as a potential risk factor for several diseases not traditionally associated with vitamin D, such as CVD and cancer. Many researchers have reported the evidence suggesting an association between low 25-hydroxyvitamin D levels and CVD and the possible mechanisms involved in these conditions.2
Vitamin D deficiency has also been associated with clinical atherosclerosis in coronary calcification as well as with cardiovascular events such as myocardial infarction, stroke, and congestive heart failure. Several clinical studies have generally demonstrated an independent association between vitamin D deficiency and various manifestations of degenerative CVD such as vascular calcification.3 While the deficiency of vitamin D has now been proven to have a connection with CVD, the role of vitamin D supplementation in the management or treatment of this disease remains to be established.3
In this article, we take a closer look at the new findings on vitamin D deficiency and the reported association between its deficiency and CVD.
Vitamin D Deficiency
Vitamin D is primarily produced in the skin through exposure to sunlight. Several forms of vitamin D exist. Cholecalciferol (or vitamin D3) is synthesized in response to ultraviolet (UV) irradiation of the skin, resulting in the photochemical cleavage of 7-dehydrocholesterol, a precursor of cholesterol in the skin. A second form of vitamin D, ergocalciferol (or vitamin D2) is produced by irradiation of ergosterol, a membrane sterol found in the ergot fungus.4
Vitamin D deficiency is prevalent in 30% to 50% of adults in developed countries. This is largely due to its inadequate production in the skin and, to a lesser degree, to low dietary intake of vitamin D. A growing number of studies point to vitamin D deficiency as a risk factor for heart attacks, congestive heart failure, peripheral arterial disease, strokes, and other conditions associated with CVD, such as high blood pressure and diabetes. The connection between vitamin D deficiency and CVD, therefore, could be through its association with the above risk factors.5
Experimental studies have demonstrated physiological functions of vitamin D metabolites on cardiomyocytes and endothelial and vascular smooth muscle cells. Low 25-hydroxyvitamin D levels are associated with left ventricular hypertrophy, vascular dysfunction, and renin-angiotensin system (RAS) activation.5 Mechanisms by which vitamin D deficiency may confer increased cardiovascular risk include the development of electrolyte imbalance, pancreatic beta-cell dysfunction, and RAS activation.6
However, despite a large body of experimental, cross-sectional, and prospective evidence implicating vitamin D deficiency in the pathogenesis of CVD, a causal relationship remains to be established. More randomized clinical trials of vitamin D replacement in CVD are needed to determine its role in cardiovascular protection.6
Obesity is an important risk factor in CVD because fat cells absorb vitamin D and keep it from circulating throughout the bloodstream. People with darker skin pigmentation have a built-in natural sunscreen called melanin, which keeps the skin from synthesizing vitamin D.4 Women tend to have more body fat than men. Women who spend less time outdoors or use more sunscreen when they are outdoors have a tendency toward vitamin D deficiency. Several studies have connected low vitamin D levels with CVD in women.1
Age also plays a role in vitamin D deficiency, because as people get older, they absorb less vitamin D from their diets and produce less vitamin D in their skin. In addition, their reduced activity affords them less opportunity to be outdoors. People who live farther away from the equator are not exposed to enough UV light, so their bodies are unable to make meaningful amounts of vitamin D between November and February.2
There is limited documentation that certain indoor tanning lamps effectively produce vitamin D, but the diversity of such devices has not been extensively surveyed. As a result, indoor tanning is not an advisable source of vitamin D3. The reason lies in the characteristics of UV light rays and how they affect the body. The use of indoor tanning sources for vitamin D benefits requires caution.4
Mechanism of Action
A key concept in understanding vitamin D metabolism and vitamin D deficiency is to recognize that this compound is misnamed—it is not a vitamin, but rather a fat-soluble secosteroid produced in the skin from the action of UV light on 7-dehydrocholesterol. Vitamin D acts as a hormone, regulating more than 200 genes throughout the body. The active metabolite of vitamin D, 1, 25-dihydroxyvitamin D [1,25 (OH)2D], binds to vitamin D receptors (VDRs) that regulate numerous genes involved in fundamental processes of potential relevance to CVD.7
Vitamin D does an impressive amount of work and plays a classic hormonal role in skeletal health by regulating calcium and phosphorus metabolism. While the endocrine functions of vitamin D related to bone metabolism and mineral ion homoeostasis have been extensively studied, epidemiological evidence also suggests a close association between vitamin D deficiency and cardiovascular morbidity and mortality. In addition, vitamin D keeps abnormal cells from multiplying in breast and colon tissues, and helps regulate blood pressure in the kidneys and blood glucose levels in the pancreas.7
VDRs have been found in all the major cardiovascular cell types, including cardiomyocytes, arterial wall cells, and immune cells. The ezyme 1-alfa-hydroxlase, which converts vitamin D into the hormonal 1,25-(OH)2D (calcitriol) form, is also actively expressed in cardiovascular tissues. Experimental studies have established a role for vitamin D metabolites in pathways that are integral to cardiovascular function and disease, including inflammation, thrombosis, and the RAS.7
Vitamin D Metabolism
Following its synthesis or ingestion, vitamin D and its metabolites circulate bound to vitamin D–binding protein, which is produced in the liver. Low protein conditions are thus associated with reduced total vitamin D levels, although free levels may be normal. Two hydroxylation steps in the liver and kidneys are required for vitamin D activation. The vitamin D is not biologically active until it undergoes 25-hydroxylation in the liver to form 25-hydroxyvitamin D (25[OH]D), which is the principal circulating form of vitamin D.7
The second hydroxylation step in the kidney is regulated by parathyroid hormone, calcium, phosphate, calcitonin, and growth hormone. This second hydroxylation produces 1,25(OH)2D, which has a 1,000-fold greater affinity for the VDRs than 25(OH)D. Both 25(OH)D and 1,25(OH)2D are catabolized by 24-hydroxylation to inactive metabolites. The enzyme 1,25(OH)2D also increases intestinal phosphate absorption, stimulates bone turnover through receptors in the osteoblast, and regulates its own production and degradation in the kidney. There is a growing amount of literature suggesting that it also acts on a variety of other tissues.7
Dosage and Healthy Vitamin D Levels
A simple blood test of 25(OH)D can reveal the blood levels of vitamin D in ng/mL. Serum levels of 25(OH)D <20 ng/mL indicate vitamin D deficiency, and levels >30 ng/mL are considered optimal.8
It is suggested that to maintain healthy levels of vitamin D, most adults on average need 1,000 to 2,000 international units (IU) a day. People who spend a fair amount of time in the sun might have healthy levels and not need supplements at all. Conversely, women with levels well below 30 ng/mL might need a carefully monitored prescription of up to 50,000 IU per week for several weeks, followed by a lower OTC dosage when vitamin levels are back to normal.
While vitamin D can be obtained from the diet (in fish oils, egg yolks, milk, butter, liver, and fortified foods), endogenous production is quantitatively much more important in most individuals. It is believed that getting about 10 minutes of moderate summer sun exposure can supply between 3,000 to 5,000 IU of vitamin D in normal people. One would need to drink approximately 30 glasses of milk to match that amount.8
Production of vitamin D3 in the skin is related to the intensity of UV B irradiation, so production is diminished with increasing latitude. It is also diminished by skin pigmentation and by advancing age. When exposure to sunlight is sustained, there is increased production of inactive vitamin D metabolites, thus preventing vitamin D intoxication. In plants, similar chemical processes result in the production of vitamin D2, frequently used in supplements. Pharmacologic supplementation with vitamin D2 and D3 is often required, particularly in areas where few foods are fortified with vitamin D or in individuals with heightened risk factors.
While a direct link has yet to be found between higher vitamin D levels and lower CVD risk, it is important not to overlook other possible benefits. Therefore, screening and treating for vitamin D deficiency, particularly in women who tend to have more fractures and osteoporosis than men, is very important.9
To determine vitamin D levels, it seems logical to measure serum 25(OH)D and then treat with calciferol if necessary. This can be followed with annual blood tests. However, measuring 25(OH)D can be difficult and expensive. There is substantial variation in results between assays and between laboratories, with some immunoassays giving results differing by up to 40% from the correct value. Furthermore, in some countries, a single measurement can cost substantially more than the annual cost of vitamin D supplements for an individual. These considerations have caused many clinicians dealing with high-risk groups (the elderly, veiled women, and individuals with dark skins living in temperate climates) to treat without undertaking a 25(OH)D measurement. Routine measurement of 25(OH)D greatly increases the cost of managing vitamin D status, adversely impacting its cost-effectiveness.10
If treatment is required, regimens involving 500 to 1,000 IU per day, or 50,000 IU per month, will usually achieve serum levels of 25(OH) D greater than 50 ng/ml. Advocates of higher 25(OH)D levels encourage daily doses of 2,000 or more IU. However, pushing levels to more than 100 ng/mL has been questioned by many authorities.10
Despite the effectiveness of vitamin D supplementation in improving serum levels, there is insufficient evidence to support vitamin D supplementation as a way of improving cardiovascular outcomes. However, many cardiovascular patients are frail and immobile and are at risk of markedly reduced vitamin D levels and osteoporosis. Supplementation of such patients is justified to prevent very low levels of 25(OH)D, with their signs of musculoskeletal pain, myopathy, and accelerated bone loss.1
Emerging studies show that vitamin D deficiency is a highly prevalent condition and is independently associated with most CVD risk factors and to CVD morbidity and mortality.
New findings reinforce that vitamin D deficiency is an important public health problem. Future studies are still required to establish clinical guidelines for vitamin D supplementation required to achieve adequate vitamin D levels in people who are at risk for CVD, both in the absence and presence of chronic kidney disease. However, although vitamin D deficiency is now linked to CVD, the role of vitamin D supplementation in the management or treatment of CVD requires additional evidence.
Future studies are also needed to better understand the role of 25(OH)D and local 25(OH)D-1-alpha-hydroxylase on vascular and cardiac function as well as the role of 25(OH)D in selected organs.
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3. Reid IR, Bolland MJ. Role of vitamin D deficiency in cardiovascular disease. Heart. 2012;98(8):609-614.
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5. Lindqvist PG. On the possible link between vitamin D deficiency and cardiovascular disease. Circulation. 2014;129:e413-e414.
6. Bergman P, Norlin AC, Hansen S, et al. Vitamin D3 supplementation in patients with frequent respiratory tract infections: a randomised and double-blind intervention study. BMJ Open. 2012;2:e001663.
7. Bikle DD. Vitamin D metabolism, mechanism of action, and clinical applications. Chem Biol. 2014;
8. Institute of Medicine. Food and Nutrition Board. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: National Academy Press, 2010.
9. National Institutes of Health. Office of Dietary Supplements. Vitamin D fact sheets for health professionals. https://ods.od.nih.gov/factsheets/VitaminD-HealthProfessional. Accessed October 15, 2015.
10. Taylor CL, Patterson KY, Roseland JM, et al. Including food 25-hydroxyvitamin D in intake estimates may reduce the discrepancy between dietary and serum measures of vitamin D status. J Nutr. 2014;144:654-659.
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