Treatment of Vitamin D Deficiency as a Primary Prevention for Cardiovascular Disease

Monica Raharjo

Faculty of Medicine Universitas Trisakti Jakarta 2012

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Table of Contents 1. Abstract………………………………………………………………………..5 2. Introduction……………………………………………………………...….....5 3. Defining Vitamin D Deficiency……………………………………………5-10 3.1. Vitamin D Metabolism…………………………………………………6-7 3.2. Measure of Vitamin D Status……………………………..........................8 3.3. Prevalence of Hypovitaminosis D in Indonesia…………………….......8-9 3.4. Risk Factors for Hypovitaminosis D………………………………….9-10 4. Vitamin D and Cardiovascular Disease…………………………………..10-16 4.1. Studies Linking Vitamin D Deficiency with Cardiovascular Risk…..11-14 4.2. Vitamin D and Hypertension……………………………………………14 4.3. Vitamin D and Coronary Heart Disease……………………………..14-15 4.4. Vitamin D and Heart Failure………………………………………...15-16 5. Treatment of Vitamin D Deficiency………………………………….......16-21 5.1. Screening for Vitamin D Deficiency………………………………...18-19 5.2. Vitamin D Supplementation…………………………………………20-21 6. Conclusion………………………………………………………………..21-22 7. References………………………………………………………………...22-24

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Abstract Vitamin D refers to a collection of fat-soluble steroid responsible for calcium regulation and musculoskeletal health. Recent studies have shown that vitamin D also plays a role in maintaining cardiovascular health. Low vitamin D levels, reflected by measurements of 25-hydroxyvitamin D, have been related with a higher risk of cardiovascular disease and cardiovascular mortality. Low vitamin D levels are also risk factors for coronary heart disease and heart failure, because of its role in the development of hypertension, atherosclerosis, endothelial dysfunction, and vascular calcification. With the relatively high prevalence of hypovitaminosis D found in Indonesia, treatment of vitamin D deficiency, including use of vitamin D supplementations, may be proposed as a primary prevention method for cardiovascular disease. Key Words: cardiovascular disease, vitamin D, hypovitaminosis D, primary prevention, vitamin D supplementation Introduction A growing body of evidence has found that low vitamin D levels are related to an increase in the risk of cardiovascular disease (CVD). CVD linked with low vitamin D levels includes peripheral vascular disease, coronary artery disease, heart failure, and stroke.1 Evidence also suggests that vitamin D deficiency also plays a role in the development of atherosclerosis, endothelial dysfunction, and vascular calcification.2 All these data suggest that vitamin D plays a role in maintaining cardiovascular health. Therefore, the issue of whether correcting vitamin D levels in individuals with vitamin D deficiency may lead to a reduction in CVD risk should be explored. The objectives of this paper is to define vitamin D deficiency, discuss the relationship between low vitamin D levels and CVD, and elaborate on treatment of vitamin D deficient individuals, which includes the use of vitamin D supplements, as a possible means of primary prevention for CVD, all based on available evidences and data. All data were collected by searching PubMed for recent English-language articles related to vitamin D and CVD. The goal of this paper is to propose a possible primary prevention method of CVD that may hopefully benefit the public and those in the medical field in fighting CVD.

Defining Vitamin D Deficiency Vitamin D refers to a collection of fat-soluble steroid which comes in five different forms vitamin D1-D5 (Table-1), vitamin D2 (ergocalciferol) and vitamin 5

D3 (cholecalciferol) being the most studied forms of vitamin D.1 Vitamin D2 is made by invertebrates and plants after being exposed to ultraviolet radiation and can be found in certain mushrooms. Vitamin D3 is made endogenously in the skin after being exposed to ultraviolet B (UVB) light that comes from the sunlight. UVB light converts cutaneous 7-dehydrocholesterol to vitamin D3. Vitamin D3 produced by the skin is variable depending on skin pigmentation, latitude, season, clothing, age, sunscreen use, and local weather conditions. Vitamin D3 can also be derived from food such as cod liver oil, salmon, mackerel, tuna, and also fortified foods. Dietary intakes of vitamin D only comprise 10-20% of circulating vitamin D levels. Both vitamin D2 and vitamin D3 can be found in multivitamins and supplements and have the same ability to increase circulating vitamin D levels.2-4

Table-1. Five Different Forms of Vitamin D 1

Vitamin D Metabolism Vitamin D is biologically inactive and must be converted into its active form, 1,25(OH)2D or calcitriol (Figure-1). Vitamin D, produced in the skin or

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ingested in food, multivitamins, or supplements, is either stored in adipose tissue or brought to the liver where it is converted to 25-hydroxyvitamin D or 25(OH)D by the enzyme D-25-hydroxylase.4 25(OH)D is the standard measure of a person’s vitamin D status. 25(OH)D is used as a measurement because it is the form of vitamin D that circulates in blood in the highest concentration (1000x higher in circulation compared to calcitriol), because it reflects total vitamin D from solar and dietary exposure as well as conversion from adipose stores, and because of its long half-life (3 weeks as compared to short 8 hours half-life of calcitriol).5 25(OH)D is then converted into its active form calcitriol in the proximal tubule of the kidney by the enzyme 25(OH)D-1α-hydroxylase. Calcitriol levels are regulated primarily by the parathyroid hormone (PTH), which will stimulate calcitriol synthesis when there is a decrease in calcitriol levels. Therefore, calcitriol levels are a poor measure of a person’s vitamin D status because it may be normal in deficient states due to the regulatory control of calcitriol levels by PTH.2-4, 6

Figure-1. Process of vitamin D activation 2

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Measure of Vitamin D Status As stated above, 25(OH)D is the standard measure of a person’s vitamin D status and therefore an important parameter in defining vitamin D deficiency. The World Health Organization (WHO) and current International Osteoporosis Foundation guidelines defined vitamin D deficiency as 25(OH)D serum levels below 10 ng/mL and vitamin D insufficiency as 25(OH)D serum levels below 20 ng/mL. This differs with normal laboratory reference range which is 30-76 ng/mL. Reasons for setting the low end of 25(OH)D serum normal range at 30 ng/mL are as follows. Firstly, several studies suggest that levels of PTH rise when levels of 25(OH)D fall below 30 ng/mL. Secondly, several studies suggest that active calcium absorption is optimal when levels of 25(OH)D is 30 ng/mL. However, these two reasons are now being questioned as it is found that there is no absolute threshold level of serum 25(OH)D at which PTH levels rise. Also, peak absorption of calcium occurs at levels of 25(OH)D between 20 and 30 ng/mL. Osteoporosis Canada also issued a report defining vitamin D insufficiency as 25(OH)D levels between 10 and 29 ng/mL and suggests that 25(OH)D levels should be at least 30 ng/mL. Even though definitions of vitamin D insufficiency/ deficiency and interpretation of 25(OH)D levels still varies, it is agreed that serum 25(OH)D levels below 20 ng/mL are considered inadequate.2, 4

Prevalence of Hypovitaminosis D in Indonesia Hypovitaminosis D can be found in developing countries in East Asia and the Pacific, including Indonesia (Table-2), despite the fact that most developing countries lie in the zones that have sufficient sunlight for vitamin D synthesis. The distance that sunlight travels to the earth’s atmosphere is the least in regions nearest the equator, like Indonesia. UVB rays in regions near the equator are most intense and thus vitamin D synthesis is possible all year long. In developing countries, hypovitaminosis D is found to be one of the most prevalent childhood disorders, in addition to infectious disease and malnutrition. Hypovitaminosis D has also been reported in women of all age groups living in the Philippines, Malaysia, and Indonesia. A study done in postmenopausal women living in Jakarta, Indonesia showed that 73% of study participants had a serum 25(OH)D

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level < 50 nmol/l (equivalent to 20 ng/mL). Another study found that over 60% of 504 women 18-40 year old living in Kuala Lumpur or Jakarta, Indonesia were reported in 2008 to have serum 25(OH)D levels below 50 nmol/l or 20 ng/mL. A study also done in 2008 reported that 35% of 74 Indonesian elderly women living in institutionalized care units in Jakarta or Bekasi, Indonesia had serum 25(OH)D levels below 75 nmol/l (equivalent to 30 ng/mL).7 More studies to assess prevalence of hypovitaminosis D in Indonesia should be done.

Table-2. Prevalence of Hypovitaminosis D in Developing Countries in East Asian and the Pacific 7

Risk Factors for Hypovitaminosis D Risk factors associated with hypovitaminosis D includes age, female sex, obesity, dark skin pigmentation, clothing style, socioeconomic status, nutritional status, pollution in the atmosphere, and various medical conditions especially malabsorption syndromes. These risk factors are similar to risk factors for hypovitaminosis D in Western countries and are therefore not unique to developing countries. Individuals at the extremes of age (elderly persons, preschool children, and neonates) are prone to hypovitaminosis D. Aging has been shown to reduce by half the capacity of the skin to produce cutaneous 7dehydrocholesterol that will be converted to vitamin D3. This occurs because of structural changes in the dermis when a person ages. Furthermore, people of older age usually spend less time outdoors and have a relatively lower dietary intake. Obesity also increases a person’s susceptibility to hypovitaminosis D. Vitamin D levels negatively correlates with BMI and fat because vitamin D is stored in excess adipose tissue. Vitamin D deficiency is twice as likely to be found among

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individuals with obesity compared to non-obese individuals. Skin pigmentation greatly affects vitamin D synthesis, in which it acts as a natural sunscreen. The use of sunscreen with a sun protection factor (SPF) greater than 15 also affects vitamin D synthesis, reducing it by 99%. Clothing style which conceals skin exposure will also reduce vitamin D synthesis. Socioeconomic status and nutritional status also affect vitamin D levels. Individuals of low socioeconomic status are usually malnourished in protein. This may cause a decrease in vitamin D binding protein in blood, thus diminishing the body’s ability to conserve 25(OH)D. Air or atmospheric pollution has also been associated with lower vitamin D synthesis. High atmospheric pollution diminishes the amount of UVB light reaching ground level thus reducing cutaneous vitamin D synthesis.2, 6-7

Vitamin D and Cardiovascular Disease It has been long known that vitamin D in its active form is responsible for regulating calcium metabolism and thus affects bone health if insufficient. Recently, it has been found that hypovitaminosis D not only affects bone health but also cardiovascular health. Vitamin D receptors have been found on most tissues in the body including cardiomyocytes, endothelium, and vascular smooth muscle cells. Circulating calcitriol enters target cell (in its free form or facilitated by megalin) and binds to vitamin D receptor in the cytoplasm causing transcription of vitamin D-regulated genes which includes genes important for innate immunity, muscle function, and endothelial cell proliferation.5-6 Furthermore, extra-renal 25(OH)D-1α-hydroxylase (the enzyme that converts 25(OH)D to calcitriol) has also been found in vascular smooth muscle cells.3 Locally produced calcitriol is thought to have an important paracrine or autocrine function in regulating the cardiovascular system.5 First, calcitriol inhibits proliferation of vascular smooth muscle cells, a process which contributes to vascular proliferation. Calcitriol also increases synthesis of matrix G1A protein, a substance which inhibits vascular calcification. Next, calcitriol suppresses levels of proinflammatory cytokines tumor necrosis factor-α and interleukin-6 and upregulates the level of interleukin-10, an anti-inflammatory cytokine.3 Lastly, in mice, calcitriol is found to be a negative regulator of the renin-angiotensin system

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(by suppressing renin gene expression) thus affecting an individual’s blood pressure.8 As mentioned previously, in individuals with inadequate vitamin D, serum 25(OH)D will fall below normal levels but calcitriol levels will remain normal as it is regulated by PTH. This statement is only true for calcitriol produced by renal 25(OH)D-1α-hydroxylase, but does not apply to locally produced calcitriol by extra-renal 25(OH)D-1α-hydroxylase. Locally produced calcitriol level is dependent on serum levels of 25(OH)D. Thus, a person with low levels of serum 25(OH)D will also have low levels of locally produced calcitriol, and is more prone to CVD.3 Decreased 25(OH)D levels also correlates with elevated PTH serum levels. Elevated PTH levels may contribute to CVD because PTH promotes myocyte hypertrophy and vascular remodeling and also stimulates secretion of proinflammatory cytokines by vascular smooth muscle cells. High levels of PTH are known to induce the synthesis of interleukin-6. Hyperparathyroidism is also found to be associated with left ventricular hypertrophy, cardiomyopathy, and increased mortality.1, 3, 9-10

Studies Linking Vitamin D Deficiency with Cardiovascular Risk Various studies have been done linking vitamin D deficiency with a risk of CVD and cardiovascular death. A cohort study was done by Kilkkinen et al on 6,219 Finnish men and women who participated in the Mini-Finland Health Survey (2,817 men and 3,402 women, mean age 49.4 years old) without history or findings of CVD at baseline. Blood samples were taken at baseline and levels of 25(OH)D determined by radioimmunoassay. Follow-up was done until death by CVD or other causes (640 coronary heart disease deaths and 293 cerebrovascular disease deaths) were identified through linkage with Statistics Finland or until end of follow-up (maximum 28.9 years, median 27.1 years). Results show that there was an inverse association between serum 25(OH)D levels and total CVD mortality. Age-and-sex-adjusted hazard ratio for total CVD death was 0.71 (95% confidence interval [CI], 0.58 to 0.87, P for trend <0.001) for the highest quintile of 25(OH)D serum levels compared to the lowest quintile. After adjustment for potential confounders which includes marital status, educational level, body mass

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index, alcohol consumption, smoking, physical activity, and season, hazard ratio for total CVD death was 0.76 (95% CI, 0.61 to 0.95, P=0.005). An inverse association was also found between serum 25(OH)D levels and the risk of coronary heart disease in which hazard ratio was 0.83 (95% CI, 0.65-1.06, P=0.037) for the highest quintile of 25(OH)D serum levels versus the lowest. This study concludes that a low circulating level of vitamin D may predict a higher risk of CVD death.11 Another cohort study was conducted by Wang et al on 1,739 Framingham Offspring Study participants (mean age 59 years old, 947 women, all white) without previous CVD. Measurement of 25(OH)D serum was done on all 1,739 participants by radioimmunoassay. Only 10% of total participants had 25(OH)D levels above 30 ng/mL, 28% had 25(OH)D levels below 15 ng/mL, and 9% had 25(OH)D levels below 10 ng/mL. In this study, vitamin D deficiency was defined as 25(OH)D levels below 15 ng/mL. During the follow up of participants (maximum 7.6 years, mean 5.4 years), 120 participants among them 57 women developed a first cardiovascular event (65 coronary heart disease events, 28 cerebrovascular events, 8 occurrences of claudication, and 19 occurrences of heart failure). Cardiovascular disease was approximately twice as high in participants with 25(OH)D levels < 15 ng/mL compared to participants with 25(OH)D levels ≥ 15 ng/mL. The highest rate of CVD was observed in participants with hypertension and vitamin D deficiency. Levels of 25(OH)D < 15 ng/mL were associated with an age-and-sex-adjusted hazard ratio of 2.04 (95% CI, 1.42 to 2.94, P < 0.001) for cardiovascular events compared to levels of 25(OH)D ≥15 ng/mL. After adjustment for conventional cardiovascular risk factors and renal function, levels of 25(OH)D < 15 ng/mL were associated with a multivariableadjusted hazard ratio 1.62 (95% CI, 1.11 to 2.63, P=0.01) for cardiovascular events compared to levels of 25(OH)D ≥15 ng/mL. This shows that there is a significant association between low 25(OH)D levels and risk of cardiovascular events. Participants with hypertension and low 25(OH)D levels had a greater risk of cardiovascular events, in which levels of 25(OH)D < 15 ng/mL in hypertensive participants were associated with a multivariable-adjusted hazard ratio of 2.13 (95% CI, 1.30 to 3.48, P=0.003) for cardiovascular events. This study concludes

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that moderate to severe vitamin D deficiency is associated with an increased cardiovascular risk, with higher risk in individuals with hypertension.9 Analysis of an electronic medical record database of the integrated Intermountain Healthcare system identified 41,497 subjects with vitamin D measurements (mean age 55 years, 74.8% women). Vitamin D levels were divided into three categories: normal > 30 ng/mL found in 36% of patients, low 16-30 ng/mL found in 47% of patients, and very low ≤ 15 ng/mL found in 17% of patients. Follow-up of patients after vitamin D determination was done for an average of 1.3 years (maximum 9.3 years). Results of this study showed an increased prevalence of hypertension (30% relative and 12% absolute) in very low versus normal categories. There was also an increase in incident hypertension by 62% (P < 0.0001) in low versus normal categories. Increases in prevalence of heart failure (90% relative and 9% absolute), myocardial infarction (MI) (81% relative and 2.6% absolute), and stroke (51% relative and 2% absolute) were also observed in very low versus normal vitamin D categories in subjects ≥50 years old (P < 0.0001). Greater hazard ratio for CVD was found in those with very low to low levels as compared to normal levels.12 Findings from a study presented at the American Heart Association’s scientific conference in 2009 held in Orlando, Florida also reported that low vitamin D levels is associated with a higher mortality and CVD risk. Patients with very low levels of serum 25(OH)D were 77% more likely to die, 45% more likely to develop coronary artery disease, and 78% more likely to suffer from stroke than patients with normal levels of serum 25(OH)D. Patients with low levels of 25(OH)D were also twice as likely to develop heart failure compared with those having normal values of 25(OH)D.13 Examination of 8,351 adult patients with CVDs using data from the National Health and Nutrition Examination Survey (NHANES) shows that hypovitaminosis D was highly prevalent in these patients. The CVDs examined were coronary heart disease (CHD) which includes angina and MI, heart failure, stroke, and peripheral arterial disease. Results show that hypovitaminosis D was especially more common in patients with CHD and heart failure. It is still uncertain whether hypovitaminosis D precedes CVDs in these patients or

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hypovitaminosis D is due to limited physical activity and sunlight exposure as a result of CVDs.14

Vitamin D and Hypertension Vitamin D deficiency has been linked with hypertension, a major risk factor for CVD. The Framingheart Offspring Study found that CVD risk was greater in participants with hypertension and vitamin D deficiency as compared to vitamin D deficiency alone.9 Vitamin D is related to blood pressure control because of the effect it has on the renin-angiotensin system, in which vitamin D in its active form (calcitriol) suppresses renin gene expression.3,
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Suppression of

renin activities may be due to increased intracellular calcium levels. Vitamin D also alters the sensitivity of vascular smooth muscle cells, causing vasodilatation and thus improved blood flow and lower blood pressure. Serum levels of 25(OH)D inversely correlates with blood pressure.1 A study has been done to examine the associations of serum 25(OH)D with heart rate, systolic blood pressure, and rate-pressure product (heart rate times systolic blood pressure). Analysis was done on 27,153 participants ≥ 20 years with measured 25(OH)D determined by radioimmunoassay, heart rate, and systolic blood pressure in the NHANES. Results of the study showed that pulse rate and systolic blood pressure increased with decreasing vitamin D levels. Consequently, rate-pressure product also increased as vitamin D decreased. Participants with 25(OH)D levels < 10 ng/mL had consistently higher ratepressure product than those with 25(OH)D levels ≥ 35 ng/mL. This suggests that vitamin D deficiency may increase cardiac work and cardiac oxygen demand, and also may affect myocardial blood flow.15

Vitamin D and Coronary Heart Disease In addition to its effect on the renin-angiotensin system, vitamin D also affects endothelial function, vascular compliance, and lipid profile. Low levels of 25(OH)D is associated with endothelial dysfunction (change in endothelium properties toward decreased vasodilatation and proinflammatory state),2 vascular

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calcification, and higher levels of very low density lipoprotein and triglyceride,1 all contributing to atherosclerosis and may cause CHD. A nested case-control study was done by Giovannucci et al to assess whether plasma 25(OH)D levels are associated with risk of CHD. Participants included 18,225 men health care professionals in the Health Professionals Followup Study (aged 40 to 75 years) who were free of diagnosed CVD at blood collection. Blood samples were collected at baseline and plasma 25(OH)D levels were determined by using the radioimmunoassay technique. Plasma 25(OH)D levels were divided into 4 categories: deficient defined as 25(OH)D levels ≤ 15 ng/mL; insufficient defined as 25(OH)D levels between 15.1 to 29.9 ng/mL, further divided into two different categories at its midpoint; and sufficient defined as 25(OH)D levels ≥30 ng/mL. During 10 years of follow-up, 454 participants were identified with incident non-fatal MI or fatal CHD (352 participants had non-fatal MI and 102 had fatal CHD). Nine hundred men were randomly selected as controls. Results of the study showed that plasma 25(OH)D levels were lower in cases than in controls. Men with lower 25(OH)D concentrations were more likely to be smokers, less physically active, weigh heavier, and have a parental history of MI. Risk of MI was significantly elevated in men with deficient levels of 25(OH)D (relative risk [RR] was 2.42 after adjustment for matching factors, 95% CI, 1.53-3.84, P<0.001). After further adjustment for plasma lipids, the RR was 2.09 (95% CI, 1.24-3.54, P=0.02). Men with circulating 25(OH)D levels of at least 30 ng/mL had approximately half the risk of MI, independent of other CVD factors.16

Vitamin D and Heart Failure Vitamin D has a direct protective effect against heart failure. This includes effects on myocardial contractile function (myocardium is found to be an important target tissue for vitamin D-mediated effects), regulation of natriuretic hormone secretion, effects on extracellular matrix remodeling, reduced left ventricular hypertrophy, and regulation of inflammatory cytokines.1, 17 A cross-sectional study of patients referred for coronary angiography was done to find out whether insufficient vitamin D status is associated with heart

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failure and sudden cardiac death. Participants of this study were 3,299 patients of the Ludwigshafen Risk and Cardiovascular Health (LURIC) study referred to coronary angiography at a single tertiary care center in southwest Germany. Serum 25(OH)D concentrations of these patients were determined at baseline. Vitamin D status was classified into four categories based on 25(OH)D concentrations: severe vitamin D deficiency for 25(OH)D concentrations less than 10 ng/mL, moderate vitamin D deficiency for 25(OH)D concentrations between 10 to 19.99 ng/mL, vitamin D insufficiency for 25(OH)D concentrations between 20 to 29.99 ng/mL, and vitamin D of optimal range for 25(OH)D concentrations more than 30 ng/mL. Results of this study are as follows. Patients with lower 25(OH)D concentrations were observed to have arterial hypertension, higher New York Heart Association (NYHA) classes, and impaired left ventricle function. Levels of N-terminal pro-B-type natriuretic peptide was inversely associated with 25(OH)D concentrations (R= -0.253, P < 0.001). After a median follow-up time of 7.7 years, 188 patients died from sudden cardiac death and 116 patients died of heart failure. The hazard ratio for death due to heart failure and sudden cardiac death was 2.84 (95% CI, 1.20 to 6.74) for patients with severe vitamin D deficiency compared to 5.05 (95% CI, 2.13 to 11.97) for patients with 25(OH)D levels in the optimal range. These results showed that low levels of 25(OH)D are associated with myocardial dysfunction, and deaths due to heart failure and sudden cardiac death.17

Treatment of Vitamin D Deficiency All these data, presented above, seem to suggest that vitamin D deficiency is an important risk factor of CVD apart from known conventional risk factors of CVD. The clinical implication is that vitamin D deficiency should be identified and corrected to prevent cardiovascular events. Correction of vitamin D deficiency can be achieved by two different means: first, by increasing endogenous synthesis of vitamin D; and second, by increasing dietary intakes of vitamin D (exogenous source of vitamin D). Endogenous synthesis of vitamin D is related to sunlight exposure and risk factors for hypovitaminosis D, whereby increasing sunlight exposure and

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eliminating risk factors will lead to an increase in cutaneous vitamin D synthesis. However, this cannot always be done for every individual. For example, in elderly persons with changes in the dermis and in individuals living in places with air pollution which reduces UVB light exposure, risk factors (aging and pollution, in this case) cannot be eliminated. Hence, individuals with vitamin D deficiency whose risk factors cannot be eliminated can correct their vitamin D status by increasing dietary intakes of vitamin D. Individuals with vitamin D deficiency should first attempt to increase sunlight exposure and modify risk factors because 95% of the body’s vitamin D requirement comes from the synthesis of vitamin D in the epidermis. Further, excessive sunlight exposure cannot cause vitamin D toxicity because UVB will convert excess vitamin D3 into inert isomers, in contrast to excessive oral vitamin D intake which can cause vitamin D toxicity if taken at very high doses.18 Increasing dietary intakes of vitamin D may come from three sources which are: natural foods containing vitamin D such as oily fish (Table-3), fortified foods, and last vitamin D supplementation. For adults, every 100 IU vitamin ingested daily increases serum 25(OH)D levels by about 1 ng/mL.4, 18-19

Table-3. Food Sources of Vitamin D 18

Treatment recommendation by Lee at al (Figure-2) for vitamin D deficiency starts with initiation of 50,000 IU vitamin D2 or D3 weekly for a period of 8 to 12 weeks (initial repletion phase). Initial repletion phase is followed by maintenance therapy that can be done in 3 different ways: 1.administration of 50,000 IU vitamin D2 or D3 every two weeks, 2.administration of 1,000 to 2,000 IU vitamin D3 daily, and 3.sunlight exposure for 5 to 10 minutes in Caucasians

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(individuals with darker skin should be exposed to sunlight at longer times) between 10 in the morning to 3 o’clock in the evening. Serum levels of 25(OH)D should be assessed after 3 to 6 months of treatment.18 Schwalfenberg recommends the use of vitamin D3 over vitamin D2 because vitamin D2 is associated with higher risk of toxicity. If prescribed, vitamin D2 therapy should be monitored well to prevent overdose.20 A maintenance or prevention daily dose of 800-2000 IU or more will be needed to avoid recurrent deficiency.21

Figure-2. Treatment Recommendation for Vitamin D Deficiency 18

Treatment of vitamin D deficiency is expected to prevent CVDs related with low levels of vitamin D including CHD and heart failure, taking into considerations the role of vitamin D in maintaining cardiovascular health. This includes slowing down atherosclerosis, endothelial dysfunction, and vascular calcification. Treatment of vitamin D deficiency is also related with a reduction of hypertension, a major risk factor of CVD, by suppressing the renin-angiotensin system. Thus, treating vitamin D deficiency in otherwise healthy individuals should be explored further as a primary prevention method for CVD.

Screening for Vitamin D Deficiency Although vitamin D deficiency is prevalent even in people living in regions exposed to the sun (like Indonesia), measurement of serum 25(OH)D levels is expensive and is therefore not supported as a universal screening method. Measurement of serum 25(OH)D is generally recommended for those at risk for 18

severe deficiency of vitamin D, that is people with decreased intake of vitamin D, malabsorption of vitamin D due to gastrointestinal problems, or alterations in renal function (Table-4).21 Measurement of 25(OH)D serum levels should also be done in patients with musculoskeletal symptoms, such as bone pain, myalgias, and generalized weakness because these symptoms are often the first sign of hypovitaminosis D.18, 21

Table-4. Individuals to be Screened for Vitamin D Deficiency 21

Holick argued that with the recognition of widespread vitamin D deficiency or insufficiency, there is no need to measure everybody’s blood 25(OH)D levels. He added that it will be much more cost-effective to implement a vitamin D supplementation program until there is higher fortification of vitamin D in more foods. Patients who should be screened for hypovitaminosis D includes patients with inflammatory bowel disease, cystic fibrosis, liver and kidney disease, gastric-bypass patients, patients taking antiseizure/ glucocorticoids/ AIDS medication, patients with primary hyperparathyroidism, and patients with chronic granulomatous disorders. These patients are at high-risk for vitamin D deficiency.19 However, these recommendations are made for hypovitaminosis D in general and it is still unclear who to screen for vitamin D deficiency in relation to primary prevention of CVD.

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Vitamin D Supplementation In light of vitamin D’s protective effects on cardiovascular health, several studies have been done to evaluate the effects of vitamin D supplementations on risk of CVD. Apart from consistent results of studies confirming a link between vitamin D and CVDs, results of studies on vitamin D supplementation were not consistent. A meta-analysis of 18 randomized controlled trials was done to examine effect of vitamin D supplementation on any health condition and mortality. Outcome of analysis was total mortality and the supplementation evaluated was vitamin D2 and vitamin D3, excluding calcitriol and other vitamin D analogues. Data related to groups receiving vitamin D were considered from the intervention group, while data related to groups not receiving vitamin D were considered from the control group. Mean daily dose of vitamin D used in the trials varied from 300 IU to 2000 IU, but most of the daily doses were between 400 IU and 833 IU. Difference in serum 25(OH)D levels between intervention groups and control groups was 1.4 to 5.2-fold greater in intervention groups. The summary RR (= 0.93) of the 18 trials shows a significant decrease in the risk of all-cause mortality with the use of vitamin D supplementation (95% CI, 0.87-0.99). Results of this meta-analysis suggest that intake of vitamin D supplements may decease total mortality, independent of the dose of vitamin D supplements.22 The result of this meta-analysis is consistent with the result of a cohort study done on 3,285 patients scheduled for coronary angiography at a single tertiary center which found that low 25(OH)D and calcitriol levels are independently associated with all-cause and cardiovascular mortality.23 Johnson et al studied 36,282 postmenopausal women who joined the Women’s Health Initiative (WHI) 50 to 79 year old at 40 clinical sites, evaluating the risk of coronary and cerebrovascular events in women given supplementation of calcium carbonate 500 mg with vitamin D 200 IU twice daily as compared to women who received placebo. A follow-up of 7 years was done in which 499 women assigned to active calcium/vitamin D and 475 women assigned to placebo died of MI or CHD. 362 women assigned to calcium/vitamin D and 377 assigned

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to placebo were diagnosed with stroke. Risks of coronary revascularization, angina, heart failure, transient ischemic attack, and outcomes were similar in women who received calcium/vitamin D and in women who received placebo. The study concludes that calcium/vitamin D supplementation neither increased nor decreased the risk for CHD or stroke in participants of the 7-year randomized trial.24 Several explanations as to why the WHI study was inconsistent with previous results were because the dose of vitamin D used in the trial was inadequate and placebo-treated women were allowed to take calcium or vitamin D supplementation. Experts argue that current recommended daily allowance recommendations (which is 200 IU for adults 20-50 years old, 400 IU for adults 51-70 year old, and 600 IU for adults >70 years old) are inadequate. The average older adult needs at least 800 IU vitamin D daily to achieve serum 25(OH)D concentration sufficient to suppress PTH levels maximally. Further, older adults with dark skin and limited sun exposure may require ≥ 2000 IU daily because full body sun exposure provides 10,000 IU of vitamin D in a day. The prevalence of vitamin D deficiency in WHI patients is unknown because measurements of serum 25(OH)D were not done at baseline. This explains why benefits from vitamin D supplementation were not found because only patients with vitamin D deficiency would benefit from vitamin D supplementation.25 Inconsistency found in studies done to assess effectiveness of vitamin D supplementation warrants that large clinical trials be conducted. The vitamin D and omega-3 trial (VITAL), the first large-scale randomized clinical trial studying vitamin D and omega-3 for the primary prevention of cancer and CVD should resolve the issue of whether vitamin D supplementation is effective for primary prevention of CVD.3, 9

Conclusion As discussed above, various studies and reviews have shown that vitamin D plays a role in maintaining cardiovascular health. Low levels of vitamin D (reflected by circulating levels of 25(OH)D) are associated with an increased risk of CVD and also an increased cardiovascular mortality. It is also associated with

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an increase in the prevalence of hypertension, a major risk factor for CVD, and CVDs like CHD and heart failure. Treatment of vitamin D deficiency either by increasing endogenous or exogenous source of vitamin D in otherwise healthy individuals may be a primary prevention method for CVD that can be implemented in various countries with prevalent vitamin D deficiency. However, who to screen for vitamin D deficiency and effectiveness of vitamin D supplementation in regards to cardiovascular health are still unclear. The use of supplementation in treatment of vitamin D deficiency for cardiovascular health has been studied but results are inconsistent. Ongoing clinical trials studying vitamin D for the primary prevention of CVD should be able to provide more answers.

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10. Straughan JL. Vitamin D – The Forgotten Vitamin and The Cardiovascular Physician. Cardiovasc J Afr 2007; 18(3): 182-4. 11. Kilkkinen A, Knekt P, Aro A, Rissanen H, Marniemi J, Heliovaara M, et al. Vitamin D Status and the Risk of Cardiovascular Disease Death. Am J Epidemiol 2009; 170: 1032-9. 12. Anderson JL, May HT, Horne BD, Bair TL, Hall NL, Carlquist JF, et al. Relation of Vitamin D Deficiency to Cardiovascular Risk Factors, Disease Status, and Incident Events in a General Healthcare Population. Am J Cardiol 2010; 106: 963-8. 13. Straughan JL. Sunshine and The Cardiovascular Benefits – A Dose of Sunshine! Cardiovasc J Afr 2010; 21(3): 168-70. 14. Kim DH, Sabour S, Sagar UN, Adams S, Whellan DJ. Prevalence of Hypovitaminosis D in Cardiovascular Diseases (from the National Health and Nutrition Examination Survey 2001 to 2004). Am J Cardiol 2008; 102: 1540-4. 15. Scragg RK, Camargo CA, Simpson RU. Relation of Serum 25Hydroxyvitamin D to Heart Rate and Cardiac Work (from the National Health and Nutrition Examination Surveys). Am J Cardiol 2010; 105: 1228. 16. Giovannucci E, Liu Y, Hollis BW, Rimm EB. 25-Hydroxyvitamin D and Risk of Myocardial Infarction in Men. Arch Intern Med 2008; 168(11): 1174-80. 17. Pilz S, Marz W, Wellnitz B, Seelhorst U, Fahrleitner-Pammer A, Dimai HP. Association of Vitamin D Deficiency with Heart Failure and Sudden Cardiac Death in a Large Cross-Sectional Study of Patients Referred for Coronary Angiography. J Clin Endocrinol Metab 2008; 93: 3927-35. 18. Lee JH, O’Keefe JH, Bell D, Hensrud DD, Holick MF. Vitamin D Deficiency – An Important, Common, and Easily Treatable Cardiovascular Risk Factor? J Am Coll Cardiol 2008; 52: 1949-56. 19. Holick MF. The D-lemma: To Screen or Not to Screen for 25Hydroxyvitamin D Concentrations. Clinical Chemistry 2010; 56(5): 72931.

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Curriculum Vitae

Name Student Number Place/ Date of Birth Gender Address Nationality Phone Number E-mail Address Education Background

: Monica Raharjo : 030.09.157 : Jakarta/ 04 March 1992 : Female : Green Garden Blok D3/11-12, Jakarta Barat 11520 : Indonesian : 0818777019 : monica_raharjo@hotmail.com :

 1995-1998: TK Kristen XI PBK KPS, Jakarta, Indonesia  1998-2003: Telok Kurau Primary School, Singapore  2003-2009: Morning Star Academy, Jakarta, Indonesia  2009-now: Faculty of Medicine Universitas Trisakti, Jakarta, Indonesia

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