Vitamin D in Cardiovascular Health and Disease

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Abstract

The most frequent cause of morbidity and mortality is cardiovascular disease (CV). While there are clearly established risk factors, new ones are emerging from the results of various epidemiological studies. Recent research indicates that vitamin D deficiency would be associated with increased risk of cardiovascular disease, for its association with hypertension, peripheral artery disease, diabetes, metabolic syndrome, coronary heart disease and heart failure. Vitamin D deficiency is highly prevalent and is observed significantly in children and adolescents. The prevalence of vitamin D deficiency in the general population varies between 30% and 50%. Although the data indicate the importance of vitamin D in health CV, little is known about the effects of supplementation in cases of deficiency.

Experimental evidence suggests that the cardiovascular system is adversely affected by its deficiency, and observational and epidemiological studies demonstrate the existence of a clear link between vitamin D deficiency and cardiovascular disease. It would be unfair to mention here that, given the nature of most of the studies conducted, the findings represent only associations do not imply causality. There is also the possibility that patients with cardiovascular disease are weakest, present less exposure to sunlight and consequently have lower concentrations of vitamin D. A limited number of studies suggest that the increased levels of vitamin D may be associated with clinical benefit in patients with heart failure and hypertension. The future prospective studies should determine whether the supplementation of vitamin D can help prevent cardiovascular disease.

Chapter One: Introduction

Traditionally, vitamin D has been linked to health of bones, and it is well known that its deficiency can cause rickets in children and osteomalacia in adults. However, at present it has recognized the need for adequate levels of vitamin D for optimum functioning of different organs of the body, such as the cardiovascular system (CVS) [2]. The receptors of vitamin D are present in different cell lines, among which include myocytes, cardiomyocytes, pancreatic beta cells, , brain cells, immune cells, endothelial cells and osteoblasts. In this context it must be mentioned that the deficiency or insufficiency of vitamin D is a highly prevalent situation in the population, including children and young adults one , so it is easy to understand that this situation usually pass unnoticed and, Consequently, unless treated [1].

The current research paper will focus on the relationship between two major health problems: deficiency of vitamin D and cardiovascular disease, a link between these two prevalent diseases has been suggested in recent years. To this must be addressed first, it is suggested by the recent evidence that vitamin D deficiency plays a role in the genesis of coronary risk of cardiovascular disease [2]. In this sense, vitamin D deficiency seems to affect to the development of hypertension (HTN), metabolic syndrome, congestive heart failure, left ventricular hypertrophy, diabetes mellitus and chronic vascular inflammation [1].

Brief Introduction of metabolism of vitamin D

Vitamin D comes in two forms: vitamin D 2, or ergocalciferol, and vitamin D 3 or cholecalciferol. Vitamin D 2can be found in plants and is produced by the ultraviolet B (UVB) (290-315mm) on ergosterol. It can be consumed in the form of supplement or fortified foods. Vitamin D 3, resulting from 7-dehydrocholesterol UVB irradiation, is synthesized in human skin or ingested by eating fatty fish, fortified foods or supplements. Sustained exposure to sunlight cannot cause vitamin D toxicity as excess vitamin D 3 is converted by UVB in a biologically inert isomer; however, toxicity can be caused due to oral intake of vitamin D in excess at very high doses [2].

Vitamin D is converted to 25-hydroxyvitamin D (25 [OH] D) in the liver that is the main circulating metabolite of vitamin D. Both exogenous and endogenous production is reflected by Serum 25 (OH) D, so its quantification serves to know the situation regarding the status of vitamin D [5, 9]. In the kidney, the 1α-hydroxylase transforms 25 (OH) D to its active form, dihydroxyvitamin D (1, 25 [OH] 2 D) [6], which plays a fundamental role in maintaining the bone and muscle health by regulating calcium metabolism. While the active form of vitamin D is 1, 25 (OH) 2 D, its serum concentration does not correlate with the overall status of vitamin D and, therefore, is not clinically useful determination [1, 10].

Vitamin D is a hormone in the form of 1, 25 (OH) 2 D, since it is produced mainly in kidney, and is then circulated throughout the body and produces a variety of effects. The vitamin D receptor is present in many tissues, such as endothelium, vascular smooth muscle and myocardium [14]. Furthermore, endothelial cells have the ability to convert the 25 (OH) D 1, 25 (OH) 2 D as smooth muscle cells. 1, 25 (OH) 2 D circulating through the cell membrane and cytoplasm, and binds to the vitamin D receptor complex by reaching the nucleus, receptor-vitamin D-1,25 (OH) 2 D, heterodimerizes the receiver retinoic acid and acts as nuclear transcription factor with consequent change in function of gene and induction of synthesis of protein [6]. Directly or indirectly, genes are regulated by 1,25 (OH) 2 D 200, among which include those involved in the production of renin by the kidney, insulin by the pancreas, cytokines secretions by lymphocytes, cathelicidin production by macrophages, cardiomyocytes growth and proliferation and smooth muscle cells [5].

Definition and prevalence of vitamin D deficiency

Although no consensus has established yet for  the optimal level of 25 (OH) D, most experts believe insufficiency of vitamin D to concentrations of 25 (OH) D below 20 ng / ml (50 nmol / l), and insufficiency of vitamin D between 21-29ng / ml. In the following table the link between 25 (OH) D serum and different states of health or disease occurs. In almost all studies related to the subject at hand, 25 (OH) D at 30 ng / ml optimum concentration as the lower limit number [1].

Table 1: Classification of serum vitamin D

Serum 25-hydroxyvitamin D Situation
ng / mlto nmol / lto
≤10 ≤25 Links with vitamin D insufficiency and rickets in children
<10-15 <25 to 37.5 Insufficient for bone and overall health in healthy individuals
≥30 ≥75 Proposed by some experts as optimal for global health and prevention
> 200 > 500 Considered toxic, it behaves hypercalcemia and hyperphosphatemia, although data are limited. In animals, concentrations ≤400ng / ml (≤1.000nmol / l), models are not toxic

1ng / ml = 2,5nmol / l [9]

It is noteworthy that vitamin D insufficiency is more widespread than a priori was identified, being present in about 50% of adolescents and children apparently healthy. The occurrence of vitamin D deficiency increases as there is distance from Ecuador due to an increase in atmospheric filter UVB radiation as a result of the incident at oblique angles from sunlight at high latitudes [14]. In addition, ethnic groups with cutaneous hyperpigmentation require comparably more sun exposure for the production of equivalent amounts of vitamin D with white individuals. Skin production of vitamin D is lower in part due to the existence of protective strategies to minimize sun exposure.

Also, vitamin D deficiency is also associated with obesity, probably due to decrease in bioavailability. So, after UVB radiation exposure equivalent or administration of a bolus of vitamin D 2, experimental studies show that obese subjects had lower serum vitamin D 3 and D 2 compared to non-obese subjects for kidnapping of 25 (OH) D fat in individuals with excess adipose tissue [32]. The ability of cutaneous vitamin D synthesis induced by UVB rays also decreases with age; well, an adult of 70 years can only produce 75% less vitamin D than a person of 20 years. Certain drugs such as phenytoin, phenobarbital and corticosteroids, can accelerate the metabolism of 1, 25 (OH) 2 D [9].

Aim of the Research:

The aim of the current research is to discuss in depth the association between Vitamin D and cardiovascular health in the light of the experimental studies and observational and epidemiological studies. The purpose is to identify the potential benefits that vitamin D can bring to cardiovascular health through the review of research studies as well as to recognize the significant limitations in the studies conducted to date.

Objectives of the Research:

The objectives of the research are to

  • Identify the potential benefits of vitamin D on Cardiovascular health
  • Determine the causes of Vitamin D deficiency
  • Discuss whether supplementation of Vitamin D can bring benefits to the patients suffering from cardiovascular diseases.
  • To evaluate the direct and indirect effects of vitamin D on cardiovascular health.
  • To analyze the limitations in the interpretation of existing data

Rationale of the Research:

According to recent studies, the cardiovascular system can be regulated by vitamin D. These results raised hopes that v cardiovascular health can be cured or protected by the supplementation of vitamin D. However, current data are insufficient to recommend vitamin D supplement those showing deficiencies in the interests of cardiovascular prevention or reduction of cardiovascular risk. Therefore the existing studies have significant limitations. Majority of the studies have shown that patients suffering from cardiovascular diseases have low level of vitamin D [14]; however, direct link between the consumption of vitamin D and the protection against cardiovascular disease needs to be studied more to conclude whether the increased levels of vitamin D may cause clinical benefit in patients with heart failure and hypertension [40]. The current research will therefore serve as a basis for future studies to determine whether the supplementation of vitamin D can help prevent cardiovascular disease

Chapter Two: Literature Review

In recent literature there have been many articles highlighting the possible link between vitamin D insufficiency and increased cardiovascular risk. In adults, decreased vitamin D levels have been linked with the metabolic syndrome, insulin resistance, cardiovascular disease, type 2 diabetes, and increased risk of myocardial infarction [27].

Vitamin D would have a direct role in endothelial function, as both endothelial cells and smooth muscle express 1-alpha hydroxylase, so that the locally synthesized calcitriol may have autocrine and paracrine functions [19]. Calcitriol may modulate the renin-angiotensin system, since it is a negative regulator of renin and blood pressure [20]. Moreover, calcitriol affect lipid metabolism maintaining low levels of apolipoprotein A1, replacement or indirectly affecting HDL cholesterol, or through protective immune mechanisms of the vasculature [12].

It has been established that participants who had serum 25 OH vitamin D below 25 ng / mL exhibited a higher occurrence of diabetes mellitus (OR 1.98), hypertriglyceridemia (OR 1.47), obesity (OR 2.29), and hypertension (OR 1.30) compared to those who had higher levels of 37 ng / mL [20]. The myocardial infarction RR was 57% lower in patients with levels of 25 OH vitamin D above 12 ng / mL (23). In the UK, a study showed that 77% of stroke patients had insufficient levels of 25 OH vitamin D (less than 20 ng / mL) [36].

The progression of cardiovascular disease includes an inflammatory component [23]. The 25 OH vitamin D has been recognized as an important immune function modulator with numerous effects on especially on the constituents of the inflammatory cascade which include B cells, T cells, interleukin 1, 4 and 10; TNF alpha, interferon gamma and nuclear factor kappa B [32].

 

It has been extensively studied in relation to hypertension with vitamin D. This body includes in its pathogenesis the impairment of endothelial function, propagation of vascular smooth muscle cells and the renin axis, all related to vitamin D [39].

613 men and 1,198 women (Nurses Study) were evaluated by relating pressure and levels of 25 OH vitamin D was found that levels below 15 ng / ml compared to 30 ng / ml, exhibited an RR of hypertension 6, 13 men (95% CI 1.00 to 37.8) and 2.67 in women (95% CI: 1.05 to 6.79) [24].

The pregnancy-induced hypertension (PIH) is one of the most serious diseases in pregnancy and one of the major reasons of morbidity and maternal and perinatal mortality. A case-control study showed that women who ran in early pregnancy levels below 15 ng / mL of 25 OH vitamin D were 5 times more likely to develop HIE in late pregnancy (95% CI). The children of mothers with infants HIE were 2 times more likely to manage levels of 25 OH vitamin D lower than 15 ng / mL that children of mothers without HIE [35]. Another recent case-control study that included 78 women with BP above 140/90 near the end of pregnancy, and 109 controls, found that people with low levels of 25 (OH) D are at more risk of hypertension [32]. It is likely that vitamin D plays its role in Congestive Heart Failure. A study in men with this disease, showed levels of 25 (OH) vitamin D 14% lower [38].

In the early 20th century, Vitamin D was identified as a fat soluble pro-hormones group, after the detection of the anti-rachitic effect of cod-liver oil.  Following the finding of Vitamin A, B and C, the newly discovered vitamin type was referred as ‘’D’’. Ergocarciferol (Vitamin D2) and Cholecalciferol (Vitamin D3) are the two chief indolent originators of Vitamin D. On exposure to solar ultraviolet B (UVB 290-320 nm), the 7-dehydrocholestrol in skin forms Vitamin D3 is converted to previtamin D3. Vitamin D formation instantaneously takes place in a heart-dependent process. Various mechanisms and steroids, lumisterol and tachysterol, the inactive biological metabolites and the excessive UVB rays, take part to transform vitamin D into vitamin D3 [29].

Radiation of ergosterol produces the plant derived Vitamin D2, which through diet becomes part of the dissemination. Through sunlight contact and dietary consumption, humans obtain Vitamin D.  Vitamin D is found in very few naturally occurring foods [33]. The various food sources enrich in Vitamin D supply include orange juice, milk, cereals, and oily fish. Eggs are also source of Vitamin D, but the high cholesterol that they have made them a poor Vitamin D source. For the mineralization of the bone, Vitamin D is an important pro-hormone. It has several associated functions in diseases [19].

The likeliness of metabolic syndrome involving hypertension results in from lower absorption of 25(OH) D. The cardiovascular risk can be reduced by lowering the systolic blood pressure which can be attained by restoring the Vitamin D level in the body [29].

Several substantial prospective studies have underlined Vitamin D insufficiency as autonomous risk aspect for cardiovascular cases, and all the death resulting diseases [28].

Vitamin deficiency is a causative factor for several diseases, such as dental caries, rickets, oestoroprosis, oestomalacia, while decreased muscle strength and increased fracture risks in adults is a common health problem that often remains disguised and untreated. Indoor lifestyles promote the Vitamin D deficiency causing problems, such as diabetes mellitus, obesity, older age, darker skin, renal and liver diseases and many others [32].

Avels of vitamin D could lessen by 43% the probability of causing heart diseases or diabetes. A researcher team from Warwick Medical School conducted a systematic literature review of various studies on the subject matter of vitamin D and cardiometabolic disorders. Cardiovascular disease, type 2 diabetes mellitus and metabolic syndrome are some of the cardiometabolic disorders. The researchers found 28 studies involving 99,745 people of various racial groups participated, including both genders. The studies showed a significant link between abundance of vitamin D and reduced danger of cardiovascular disease (33% compared with the lowest levels of vitamin D), type 2 diabetes (55%) and metabolic syndrome (51%).

Insufficient Vitamin D status, according to the research, is found to have contributing effect in the major non-skeletal chronic diseases specifically cardiovascular diseases [36].  The experimental and epidemiological research and laboratory studies suggest Vitamin D supplementation to have risks reducing associating characteristics. Numerous researches are presently being conducted by combining the omega-3 fatty acids and cholecalciferol with sufficient dosing [33]. Despite the unconvincing results obtained pertaining to the Vitamin D supplementation on having effects on the mortality rate, the poor vitamin D level was found to have linkage with the cardiovascular disease and the overall mortality rate [5].

Epidemiological studies have detailed the rates of coronary heart disease, hypertension and diabetes, as well as the deficiency of vitamin D increase proportionately as people move from Ecuador. They have found lower concentrations of 25 (OH) D in myocardial infarction patients, stroke, diabetes with cardiovascular disease, heart failure and peripheral vascular disease (22). Recently, the association between risk factors of cardiovascular diseases and serum 25 (OH) D has been analyzed in 15,088 subjects in American cohort Third National Health and Nutrition Examination Survey. In that study, the levels of 25 (OH) D showed a counter link with hypertension, hypertriglyceridemia, diabetes and obesity [18, 29].

Other observational studies have established the relationship between hypertension and diabetes with insufficiency of vitamin D. In addition, vitamin D deficiency inclines insulin resistance, dysfunctions pancreatic beta cell and develops the metabolic syndrome. Pittas et al reported that the daily consumption of 800 IU of vitamin D leads to a decreased risk of type 2 diabetes of 33% as compared to a contribution lower than 400 IU of vitamin D (32). Also, a Finnish study included 10,366 children who had received vitamin D dose of 2,000 IU per day during the first year and showed a 78% reduction of type 1 diabetes risk. These findings have been established by a meta-analysis conducted recently of observational studies [19, 20, and 30].

The Framingham Offspring Study noted a relationship between vitamin D deficiency and the occurrence of serious cardiovascular events in 1,739 participants in primary prevention. In this study, 25 (OH) D concentrations were determined at its inclusion time with a mean of 5.4 years. The rate of cardiovascular endpoint composed of myocardial fatal and nonfatal myocardial infarction, stroke, ischemia or heart failure, was higher for about 53-80% in subjects with hipoavitaminosis D [28, 22].

In addition, the increased cardiovascular risk was magnified hypertensives in this cohort. So coeval, a study conducted by male health professionals presented a doubled risk of myocardial infarction in patients with vitamin D deficiency comparably to those in the desirable range. Similarly, a recent German study of vitamin D levels in 3,258 adults suffering elective cardiac catheterization was determined [33]. Individuals located in the baseline serum 25 (OH) D bottom quartile were observed during a mean follow up of 7.7 years, had an adjusted risk of death twice, mainly coronary death, compared to those located in the quartile top [10].

Vitamin D deficiency inclines the renin-angiotensin-aldosterone system regulation, as well as left ventricular hypertrophy and vascular smooth muscle cells. In animals deficient in vitamin D testing it has documented an increased occurrence of hypertension, left ventricular hypertrophy and atherosclerosis [34]. Studies in humans show that 1, 25 (OH) 2 D hinders the production of renin, resulting in a decrease in blood pressure. A study conducted by Krause et al indicated that improved exposure to UVB radiation in a solarium three times a week for three months is accompanied by an increase of 180% in 25 (OH) D levels with decreased pressure 6mmHg systolic and diastolic blood [32].

In a small randomized placebo-controlled study in type 2 diabetic patients with low basal levels of 25 (OH) D, it was found that administration of a single dose of 100,000 IU of vitamin D 2 decreased blood pressure by 14 mmHg average and considerably enhanced endothelial function. To record the Third National Health and Nutrition Examination Survey, the average systolic blood pressure was found to be 3 mmHg lower in people with in the highest quintile of 25 (OH) D as compared to the lowest quintile [11].

The activation of the renin-angiotensin-aldosterone system and the immune system with vitamin D deficiency may cause harmful effects in heart patients. The association between vitamin D deficiency and heart failure rate and severity has been examined in several studies demonstrating that heart failure patients have low vitamin D. A randomized clinical trial evaluated the effect of vitamin D supplementation (cholecalciferol [2,000 IU / day]) compared with placebo in 123 outpatients with heart failure grade II or higher and lower than 2 mg / dl, it showed that vitamin D supplements can certainly change the heart patients’ cytokine profile [11, 34]. However, after 15 months of follow up there was no change in survival curves in markers of severity of heart failure, such as the left ventricle ejection fraction, or in the concentrations of CRP or NT pro- BNP comparably to the placebo group. The sample size of the study population, clinical follow-up time or the dose of vitamin D used may be partly linked to the lack of clinical benefits obtained in this study, which should be taken into account in future approaches [24, 13].

Parker et al (2010) states that through food supplementation, Vitamin D deficiency could be lowered, on establishing the potential link between cardiovascular pathology and low vitamin status. Most of the experts define calcidiol <20 ng/mL and 21–29 ng/mL as vitamin insufficiency.

Range >30 ng/mL is considered as adequate Vitamin D and >150 ng/mL reflects Vitamin D intoxication (13). 600 IU/ day doses of vitamin D is favorable for the bones, but it is not evident if higher amount could lessen the chronic diseases risk, including cardiovascular pathology and cancer, states one of the Institute of Medicine (IOM) reports [32].

Kunadian, et al. (2014) suggested edge between Vitamin D level and cardiovascular risk. 30-35 ng/mL Vitamin D level was identified as the paramount range for risk reduction in cardiovascular mortality.

Atherosclerosis and Vitamin D Deficiency

Vitamin D deficiency has immensely been highlighted as cardiovascular risk indicators in several epidemiological studies stimulating augmented atherosclerosis [38, 33].

Vascular stiffness, a known prognosticator of cardiovascular death and illness and subclinical atherosclerosis indicator was related with Vitamin D deficiency [23].

Renin-Angiotensin-Aldosterone (RAA) System and Vitamin D

Renin-angiotensin-aldosterone (RAA) system as a result of Vitamin D insufficiency suppresses the renin gene expression (38). Left ventricular hypertrophy and hypertension develop due to restriction of vascular arteries which occur due to an elevated angiotensin II production [20].

Hypertension and Vitamin D Deficiency

Increased diastolic blood pressure or increased hypertension is one of the effects of Vitamin D deficiency [26, 27, 28].  Ultraviolet light exposure has contrary effect on Vitamin D synthesis and the blood pressure levels.  The blood pressure levels in hypertension patients are effectively treated through Vitamin D3 supplementation [21].

Vitamin deficient, hypertensive patients are found to have twofold risk of cardiovascular events, including angina, prolonged chest pain and myocardial infarction with recorded stroke, ECG changes, heart failure, transient ischemic attack and peripheral claudication [7].

However, not all studies showed the Vitamin D insufficiency effects yielded the same results. Orthostatic hypotension patients have been originated to have low Vitamin D levels, however, no certain reason could be established for the impairment. In elderly patients, vitamin D deficiency could be involved in orthostatic hypotension development [33].

Vitamin D induces direct effects on calcium metabolism and endothelial cells, inhibiting growth of vascular smooth muscle cells, preventing hyperparathyroidism, suppressing Reno protective effects and suppressing the RAA systems and thus its hypersensitive properties produce beneficial effects on common cardiovascular risk factors [28, 31]. Vitamin D insufficiency is found to have link with high blood pressure according to the observational studies, however, the arbitrary trails did not support the association [33].

Metabolic Syndrome and Vitamin D Deficiency

An individual is often a target of various cardiovascular factors such as diabetes, hypertension, hyperlipidemia and abdominal obesity. Vitamin D metabolites were found to have association with serum urate, lipid and glucose metabolism, a small cross-sectional study including the middle-aged men, revealed.  And serum calcitriol was found to have a reversing effect on blood pressure [9, 10].

Favorable influences relating to lowering bone metabolism, diabetes, cholesterol level and inflammatory conditions, likely associated with Vitamin D are governed by Statins. Due to the shared metabolic pathway of Vitamin D and cholesterol, the cholesterol and levels of Vitamin D reversely changed in the acute coronary syndrome affected patients, treated with atorvastatin [33].

Obese people are at excessive risk of diabetes, hypertension, hypercholesterolemia, vitamin D insufficiency and cardiovascular mortality. The sedentary lifestyles, less outdoor activities and the clothing habits can impair the skin formation of Vitamin D [5, 13].

Vitamin D has a significant function in glycemic regulation, which may stimulate cardiovascular results [17]. Several components of metabolic syndrome, particularly, hyperlipidemia, hyperglycemia, hypertension and insulin resistance may be influenced by Vitamin D [37].

Vitamin D, Heart Failure, Coronary Heart Disease

At coronary angiography, patients with regular or near-regular coronary arteries are found to have strong association between endothelial function, subclinical atherosclerosis and slow coronary flow and Vitamin D deficiency [37]. The plasma of young age myocardial infarction survivors were found to have Vitamin D reduced levels tie protein demographically associated with the number of affected coronary arteries [7]. Augmented vascular stiffness, inflammation, increased coronary artery calcium scores, higher average platelet volume have been linked to low vitamin D levels [23]. The vitamin D deficient patients with increased release of proinflammatory cytokines experience higher average platelet volume, oxidative stress and discharge of rudimentary and triggered platelets [37].

Vitamin D insufficiency has observed to be associated with myocardial infarction and coronary heart disease [7, 22]. Vitamin D status is analytical for chief post infarction events, such as death, periodic critical myocardial infarction and heart failure hospitalizations [37], or restenosis after percutaneous coronary intervention. Risks of all-cause deaths, particularly, mortalities due to coronary disease were found to occur due to momentous association with vitamin D circulation.

ST-segment elevation myocardial infarction was not found to have any association with the coronary lesions with low vitamin D level [22]. Contrarily, the Gensini score ratified the angiographic severity of coronary heart diseases to have association with vitamin D deficiency [37].

After an acute myocardial function, the vascular cell adhesion molecules shrunk in size, interleukin-6 and C-reactive protein, observe for the short-term vitamin-D supplementation effects on inflammatory cytokines [40].

The calcium uptake in cardiac myocytes, and stimulated calcium-ATPase activity are the biological effects that vitamin-D exerts on cardiac myocytes [23]. Vitamin D deficient individuals were prone to diastolic dysfunction, Hoorn study suggested [31]. A demonstrative observational study established no mark of association between left ventricular diastolic performance and vitamin D deficiency [31].

Due to numerous factors such as the reduced sunlight exposure, confined outdoor activity, difficult mobilization, obesity, hepatic and renal failure, comorbidities, intestinal edema in severe right heart failure and various nutritional factors, the massive congestive patients with heart failure have deficient vitamin D [39]. Secondary hyperparathyroidism and hypocalcaemia are caused due to vitamin D deprivation. The congestive heart failure individuals should be studied for fracture, osteoporosis and osteomalacia rates [25]. Despite the provocative causal relationship between heart failure and vitamin D deficiency, the occurrence of osteopenia, osteomalacia or hypocalcaemia could substantiate vitamin D supplementation. Besides the vitamin D endocrine system, independent of PTH level, a paracrine vitamin D system exists [3].

The correct vitamin D and lacking levels of the myocardial infarction afflicted patients is hence important to be determined. However further study needs to be conducted to observe vitamin D satiation to counteract cardiac transformation [3]. Through antiapoptotic, antifibrotic and anti-inflammatory mechanisms, vitamin D indicates a significant cardio protective function after myocardial infarction [22].

Despite reduction of PTH level and inflammatory markers and the numerous studies uncovering vitamin inadequacy in congestive heart failure patients, no well-defined information on advancement of result with vitamin D supplementation occur [40]. It was however visible from the controlled trial that vitamin D supplementation was ineffective against stroke or myocardial dysfunction but in the elderly people, it could guard against cardiac failure [22].

Through translocation of vitamin D receptors and increased expression, vitamin D cutbacks fibrosis in mesenchymal multipotent cells; thus reducing numerous collagen reforms and probiotic factors and raising antifibrotic factors expressions (plasminogen activator inhibitor and transforming growth factor B1) [4].

Taking into consideration the cardiac alteration, marred coronary perfusion, profibrotic and proatherogenic, vitamin D insufficiency is linked with an amplified occurrence of coronary heart disorder with injurious effects [39].

Left Ventricular Hypertrophy and Vitamin D

Weakened electromechanical coupling and ventricular dilatation occur due to enlarged ventricular mass, impaired homeostasis of fibroblasts and metalloproteinase and complex atrial natriuretic peptides as an effect due to the deficiency of vitamin D receptor [35]. Since hypertension is linked with low levels of vitamin D, left ventricular hypertrophy could be an outcome.

The probability of cardioprotective effect of vitamin D was observable in hemodialysis patients who were treated with intravenous calcitriol, causing reduction of QT interval dispersion and regression of myocardial hypertrophy [21]. Cell dissemination lacking apoptosis with the addition of calcitriol to cardiomycocytes, promotes cardiac differentiation.

AKT, the cardiac hypertrophy developing protein kinase and cellular proliferation are obtained through calcium [39]. Vitamin D supplementation could increase calcium amount and also facilitate cardiac hypertrophy [35].

However, the vitamin D effect on left ventricular hypertrophy, as reported, are not  encouraging, they range from useful stimulations to detrimental consequences [4]. Still it remains unclear that whether the vitamin D supplementation is required in the occurrence on vitamin D insufficiency or to exercise its cardioprotective impacts. Another question that demands answer is the type of effective vitamin D. Higher mortality rates were the result of low vitamin D2 doses in supplementation and less intercession phases. At the moment, the question about the vitamin D supplementation benefits for cardiovascular consequences cannot be answered certainly, however; further studies can provide further details to the analysis [35].

Vitamin D and Omega 3 trial (VITAL) which is one of the important inhibition trial and ‘’Role of vitamin D in secondary prevention of cardiovascular events’’ the other test would provide the cardiovascular consequences of supplementation of vitamin D [26].

Chapter Three: Methodology

The aim of this section is to highlight and certify the methodology used in the research paper. The current research paper is based on secondary data.

Secondary Data Sources:

A comprehensive literature search was conducted for secondary data including online published journal articles. Internet search engine Google scholar has been the best source for collecting secondary data. The review of the literature enables to further analyze the key concepts and issues under study based on the existing research studies done in the past and to associate the current study with the existing ones.

The literature review has been conducted to analyze the link between vitamin D and cardiovascular health. The current research holds great importance as to whether the supplementation of vitamin D is valuable in preventing the occurrence of cardiovascular diseases is a subject of ongoing debate. Despite of a significant number of studies conducted on this subject, there are some major limitations that emphasize on the need to carry out further research in the field.

Search Strategy:

To conduct, a significant number of English Language studies, published between 2007 to current, were selected using the following databases: PubMed and MEDLINE. The choice of indices displays the terms present in the different indices: descriptor (MeSH), author, title or abstract word, magazine etc. But I directly chose to consult the descriptor clicking the MeSH Database menu to view a journal in Journal Database.

By choosing the ‘MeSH database’ I did not have to input the search terminology each time that saved time for searches. Index gave me access to a list of terms within the specific field: MeSH Terms, Author Name, etc and to select terms to develop a search strategy using the Boolean or logical operators: AND, OR, NOT. For example, to see the MeSH terms beginning with “Vitamin D” I selected MeSH Terms of drop-down menu, entered the term and pressed Index.

The terms I used to search these databases were “Vitamin D Deficiency”, “Vitamin D in Cardiovascular health”, “vitamin D deficiency and health”, “adequate vitamin D prevents cardiovascular diseases”, etc. Moreover, I used truncation and Boolean operators to join together my search terms to narrow the scope of my research. The inclusion criteria adopted in this research is as follows:

  • The published study must be in English Language
  • The studies included must be published in a peer reviewed journal (reviews, magazine articles and books must be excluded)
  • The study must be published no earlier than 2007.
  • The target population in the studies must not be confined to specific age or gender
  • The study must relate to the link between vitamin D and cardiovascular health.
  • The significant content of the published article must be related to the effects of vitamin D deficiency or adequacy on the cardiovascular health.

The above criteria has been used in selecting the studies to make sure only the most related, suitable, up-to-date and consistent studies have been involved as part of the literature review.

Data Analysis:

The final selected studies for the review were repetitively read and analyzed in full in order to certify acquaintance with the data and for this it was essential to abstract and synthesize the results of the reviewed studies. In studies related to such kind of subject in which the purpose is to identify association between two factors, often thematic analysis has been used as a variant for extraction and synthesis of the findings. However, for the current review, a form of directed content analysis was selected to be the most appropriate method for extracting relevant subject matter from the studies. The decision of using the directed content analysis was made when it became clear, after reading the studies repeatedly, that only this analysis form would be the most appropriate in extracting the findings according to impact of vitamin D deficiency on cardiovascular health. This form of analysis focuses on the research objectives using the existing concepts and proceeds as the basis for categorizing initial coding.

For analysis, the studies are categorized depending on the main findings and nature of the study in the findings section. Almost all major studies end up declaring vitamin D insufficiency leads to cardiovascular diseases. Methodologically, the selected studies were composed of mixed research designs: both qualitative and quantitative. Taking into account the heterogeneous nature of the methods and the methods of reporting findings used in the studies, a narrative synthesis was selected to be used to conduct review [16]. The narrative synthesis is method that creates a textual summary to explain in depth the results of the multiple studies through an interpretive or integrative process. In other words, a narrative synthesis summarizes the outcomes obtained by directed content analysis [15].

Chapter Four: Findings and Discussion

Is there a connection between vitamin d deficiency and cardiovascular disease risk? This has always been a matter of debate and studies reviewed have produced astonishingly different results. However, after the most recent meeting of the American Heart Association in Chicago, two things now seem certain: on the one hand, vitamin D serum levels play a major role in the functioning of several organ systems, and not only in the skeleton and central nervous system; on the other hand, further, quality studies are needed to lend support to solid conclusions. And this is particularly important as vitamin D deficiency is extremely widespread, especially among adults and the elderly.

Secondary hyperparathyroidism is caused by chronic vitamin D insufficiency and this may facilitate many of the deleterious cardiovascular effects caused by inadequate levels of vitamin D. The threshold value for the increase of parathyroid hormone (PTH) is 25 (OH) D concentration lower to 30ng / ml. higher decreases in the concentration of 25 (OH) D behave proportionally higher PTH levels in order to maintain serum calcium in the body [8, 9, 10]. Intestinal absorption of calcium is reduced by Vitamin D deficiency by more than 50%. The decrease in calcium serum concentration behaves PTH secretion to quickly correct the blood calcium from bone calcium mobilization, increasing the calcium reabsorption of renal tubular and increased manufacture of renal 1,25 (OH) 2 D [4, 25].

The impact of hyperparathyroidism in cardiovascular disease was evident in the study of Vestergaard et al, who reported a near 40% decrease in relative risk of myocardial infarction, stroke and mortality in patients with primary hyperparathyroidism who had undergone surgical parathyroidectomy compared to those who had followed a conservative strategy. These results were confirmed in a study in individuals with renal insufficiency and secondary hyperparathyroidism (triggered by lower conversion of 25 [OH] D to 1, 25 [OH] 2 D). In this study, patients with more than or equal to 250pg / ml PTH showed a coronary risk twice that of patients with PTH less than 250pg / ml. In a recent observational study it has shown that the elderly individuals with elevated levels of PTH have mortality rate twice as high as those with normal levels of PTH [5, 25].

The increase in PTH is linked with increased blood pressure 47 and myocardial contractility, which can cause hypertrophy, apoptosis and left ventricular fibrosis and vascular smooth muscle cell. Deficiency of vitamin D and / or elevated PTH also inclines heart valves calcification, the mitral annulus and the myocardium, especially in individuals with reasonable to severe chronic renal failure [22].

Chronic kidney disease is linked with a marked increase in cardiovascular risk, mediated at least in part by insufficient levels of vitamin D. Vitamin D lack is linked with increased death in CKD and replenishing vitamin D in these patients improves clinical objectives. Observational studies in chronic kidney disease patients and hyperparathyroidism have originated that oral administration of 1, 25 (OH) 2 D 3 or calcitriol was linked with a substantial increase in existence [6]. In a study a placebo-controlled trial was conducted in 30 patients with renal insufficiency in predialysis study, left ventricular diastolic function is improved by 1, 25 (OH) 2 D 3 treatment. Analogues of vitamin D used in dialysis patients have presented a clear increase in survival [5].

The diminished and augmented levels of 25 (OH) D of PTH are linked with increased inflammation and the risk of cardiovascular events. Here, vitamin D deficiency is connected with increased systemic inflammation documented by a rise in C-reactive protein and interleukin [27]. Furthermore, management of 1, 25 (OH) 2 D deficient subjects Vitamin D is accompanied by down regulation of markers of inflammation and confers an anti-proliferative effect. Extra renal production of 1, 25 (OH) 2 D is produced by cytokine stimulation and is important paracrine growth directive, diversity and cell function. This fact explains why vitamin D insufficiency has been related with cancer, type 1 diabetes and multiple sclerosis [4].

A meta-analysis conducted recently that included 57,000 individuals from 18 randomized clinical trials concluded that a higher consumption of vitamin D 500UI daily improved overall mortality, partly due to the decrease in cardiovascular mortality. Furthermore, the efficacy data for cardiovascular safety and vitamin D are superior with respect to calcium supplements [26]. In fact, calcium supplements have been concerned in an increased risk of cardiovascular events, particularly in chronic kidney disease patients [6]. Serum calcium levels are quickly increased by calcium supplements, a fact that can accelerate artery calcification. By contrast, vitamin D concentrations showed an inverse relationship with coronary calcium [17, 27].

Typically, 95% of the vitamin D requirements are from production in the epidermis by sun contact and the rest comes from the diet. American recommendation of daily oral consumption of vitamin D is 200UI for individuals under 50 years of 400 IU for individuals aged 50-70 years and 600 IU for individuals over 70 years. It has been estimated that an average adult takes a 230UI of vitamin D a day. However, it has been estimated 1.000-2.000 UI that are essential to meet the body’s needs for individuals 7. Many specialists suggest increasing vitamin D recommendations at least 800-2.000UI daily dose problematic to attain without supplements, mostly at high opportunities and extreme winter weather areas. In a recent review it has been concluded that the upper limit for vitamin D intake 10.000UI day is safe, because the risk of formation of kidney stones is increased by higher doses, especially in absorptive hypercalciuria patients and patients with renal insufficiency dialysis terminal [35].

The most effective sources of vitamin D are daylight or prescription 50.000UI oral supplements of vitamin D 2 or D 3 every two weeks. Among the major sources of foods, fatty fish is one that has a higher content of vitamin D, while milk or supplemented orange juice contains about 100 IU of vitamin D. In general, for every 100 IU of vitamin D consumed daily, the concentration of 25 (OH) D in 1 ng / ml increases [35].

In the absence of studies based on prospective, controlled and randomized to analyze the effectiveness of vitamin D in the inhibition and treatment of cardiovascular disease clinical evidence, vitamin D role and its metabolites in coronary heart disease administration remains unclear. Screening and supplementation should not be done across the board, but may be useful in some people. For example, in patients who have several risk factors for vitamin D insufficiency and having hypertension difficult to control, or heart failure, or who remain symptomatic despite receiving the most appropriate treatment strategy should be assessed reasonable way their situation with regard to vitamin D, and those with a serum 25 (OH) D below 20 ng / ml should be measured for supplementation [9].

The advantages on bone mineral health, together with an acceptable safety profile, easy availability and low cost, make vitamin D supplementation a sound option for selected patients, especially in those where the traditional drug therapy is insufficient. In patients who have a higher risk of osteoporosis, the option of starting treatment with vitamin D (and calcium) for the prevention of cardiovascular disease is much easier.

Cando is indicated, treatment should begin with 50.000UI vitamin D 2 or D 3 on weekly basis for a time period of 8-12 weeks. Maintenance therapy should continue once the initial phase is complete with one of the following three guidelines: 50.000UI vitamin D 2 or D 3 every two weeks; 1.000-2.000UI of vitamin D 3 daily, and sunlight exposure for 5-10min between 10-15h for the white population. Vitamin D may affect the CVD risk by its indirect effects on CV risk factors such as hypertension, kidney and sdiabetes but also by its direct effects on the heart and vascular system failure [35].

Indirect effects

The associations between vitamin D, hypertension, myocardial infarction and stroke have been discussed recently, 11including a recent article in the Medical Journal Switzerland. The relationship between vitamin D and diabetes on the one hand, and vitamin D and renal insufficiency (RI) of the other part, is presented here as an illustration of possible indirect effects of vitamin D on CVD risk factors [28, 22].

One area that is also receiving growing attention is the impact of vitamin D on renal function. Hypovitaminosis may naturally arise in the context of IR. This hypovitaminose is then generally attributed to the reduction of sun exposure, the hypoproteinemia and a reduction in the activity of the 1-α-hydroxylase. The latter explanation is, however, revisited and it seems to be mostly increased inactivation of 1, 25 (OH) D2 by 24-hydroxylase that is at the origin of hypovitaminosis at IR. But can a vitamin D insufficiency be a risk factor for renal dysfunction? Vitamin D has reno-protective effects through its inhibition of renin transcription by the corresponding gene and through its inhibitory action of the factors promoting tubulointerstitial fibrosis and glomerulosclerosis (e.g. NF-kB). The effect antiproteinuric vitamin D has been shown in patients with chronic IR and vitamin D low levels were associated with a higher risk of chronic IR progression [35].

Direct effects

The importance of the VDR and vitamin D in maintaining cardiac function and vascular system is suggested by several animal models. For example, the mouse, the VDR gene has been blocked, develop cardiac hypertrophy. Links between vitamin D and endothelial function, atherosclerosis and vascular calcification have been reported. A counter link between vitamin D levels and the thickness of the carotid has been identified in a cross sectional studies in apparently healthy adults [20].

Clinical trials and observational studies

There is no proof from RCTs yet that evaluated primary objective effectiveness of vitamin D supplementation in reducing CV disease. Secondary analyzes of ERC, led in the field of bone fracture risk, comparing vitamin D supplementation alone to placebo showed no reduction in CV mortality or the number of CV events [35]. Trials evaluating combinations Vitamin D + calcium are difficult to interpret, since recent data suggest an increased CV risk when calcium supplementation. Two Meta-analyses of observational studies have revealed an increased CV risk events and overall mortality low levels of 25 (OH) D [40].

It may be nothing new but it is still worth remembering that our heart too needs vitamin D. Erin Michos (Johns Hopkins School of Medicine, Baltimore) and Matthew Good (Kansas University Hospital, Kansas City) are agreed about one thing: vitamin D deficiency may be directly linked to an increase in cardiovascular risk. Both researchers worked with large study cohorts – around 8,000 and 11,000 individuals respectively – but diverge regarding the extent of the risks involved cited by [37].

Dr Michos, for example, believes that vitamin D deficiency is connected to an increase in cerebrovascular accidents (CVAs or stroke) and only in the white population. African Americans, among whom vitamin D insufficiency is widely predominant, also have a CVA mortality level that is higher than their fellow citizens of Caucasian origin. However, Dr Michos believes that the two are not connected [28].

A systematic review for the Institute of Medicine by the Tufts Evidence-based Practice Center conducted in 2009 in preparation for the revision of the Dietary Reference Intakes for vitamin D and calcium determined the following about vitamin D and cardiovascular disease cited by [12]:

  • The link between serum 25 (OH) D and the cardiovascular events risk have been studied by a randomized and four cohort studies [12];
  • The authors of the randomized study comparing the intake of vitamin D 3 (100 000 IU per 4 months) to that of placebo in aged people for 5 years, have no major difference in Event occurrence for several cardiovascular types, including total occasions and mortalities due to cardiovascular diseases [11];
  • In two cohort studies, major links were established between concentrations of 25 (OH) D progressively weaker and higher cardiovascular events risks. The two other cohort studies have not demonstrated significant association between serum 25 (OH) D levels and death due to cardiovascular disease, heart attack or stroke [9, 10]
  • Another systematic review examined the burden linked to diseases caused by vitamin D insufficiency in Canada and how the increase in mean serum 25 (OH) D of Canadians from 67 to 105 nmol / l could change the situation, a value that would guarantee that the frequency of more than half of the population would be in the optimum range. This evaluation showed the following regarding vitamin D and cardiovascular disease [2]:
  • An increase in serum 25 (OH) D of about 62.5 to 105 nmol / L lowers cardiovascular disease risks by up to 25% (15-35%) [19];
  • Increased levels of vitamin D produced an improvement of insulin sensitivity up to 60%, which could have a significant impact on the prevention of type 2 diabetes [3].

Requiring further investigation

Dr. Good’s team came to the conclusion that vitamin D insufficiency is a significant risk factor exposing people to several types of cardiovascular disorder: hypertension, diabetes, metabolic syndrome, coronary disease and cardiac insufficiency. Nothing less! They also believe that a vitamin D supplement programme could substantially improve the situation and even the survival of the populations concerned [37].

Charles B. Eaton of Brown University, Pawtucket, Rhode Island (between New York and Boston) takes a more qualified view of research results. With his co-authors, Dr Eaton conducted a study on 1,829 menopausal women who had undergone cardiovascular monitoring for more than 10 years. They noted a definite correlation between their subjects’ vitamin status and their cardiovascular risk. However, this was modified after correction of other risk factors. Their conclusion was – unsurprisingly – that abdominal girth was a very predominant cardiovascular risk factor [19].

At the University of West Virginia, Dr Charumathi Sabanayagam and her colleagues established a positive association between persistent vitamin D deficiency and the risk of arterial hypertension among adults. Working with a cohort of 9,215 people, they concluded that this relationship exists regardless of age, sex, ethnic origin, alcohol and/or tobacco consumption, body mass index or sedentary lifestyle and many other risk markers. According to these researchers, “randomised intervention studies must be arranged to determine any possible benefits of supplementation (dietary or in medication) to prevent the development of arterial hypertension [35].

Limitations in the interpretation of existing data

The different definitions of vitamin D standards complicate data interpretation. Table 1 shows the definitions being proposed by different groups. These definitions are not the same as developed on the basis of different criteria (e.g. vitamin D values for which an increase of parathyroid hormone is observed fracture risk, the risk of CV events, mortality by cancers, overall mortality) [35]. It is in fact unlikely that same vitamin D threshold may agree to an increase in the risk of events so different. Given these definitions, Pitz et al. suggest that the ideal 25 (OH) D concentration is somewhere between 40 nmol / L and 120 nmol / L (rather 50 nmol / l by European companies and 75 nmol / l according to the North American companies). 21 L ideal gap seems to be rather between 40 and 80 nmol / l a recent study suggesting a J curve between vitamin D and overall mortality. The debate on the ideal vitamin D level has also been revived in 2011 in the report published by the Institute of Medicine (government agency of the United States) that offers a lower threshold to describe the deficiency of vitamin D [34].

In addition to the potential biases of measurements and classifications, the possibility of reverse causation and confounding effects limit the validity of the associations reported in observational studies. The studies show different interpretations that can make associations between vitamin D levels and risk factors for CV disease [35]. The relationships reported in observational studies can be enlightened by the fact that the level of vitamin D is only a “simple” indicator more or less general good health. Numerous observational links between vitamin D levels and a variety of medical conditions (CV diseases, infections, cancer, dementia etc) are compatible with the wide distribution of VDR in body tissues. But this diversity may also suggest that the associations are confounded by a common factor in these conditions as involuntarily reduced exposure to UV-B. This especially since the wide distribution of VDR in body tissues has been questioned recently.

 Chapter Five: Conclusion

Vitamin D insufficiency is highly widespread and is present in 50% of young adults and children worldwide. Experimental evidence suggests that deficiency exerts adversarial effects on the cardiovascular system, and observational and epidemiological studies demonstrate the existence of a clear connection between vitamin D insufficiency and cardiovascular disease. The results of these studies are fundamental for generating hypotheses. The data should also help establish a definitive definition of vitamin D deficiency in the context of the risk of CV disease.

It would be unfair to mention here that, given the nature of most of the studies conducted, the findings only show associations do not imply causality i.e. observational studies are subject to bias, they do not determine whether the associations vitamin D-CV disease are causal. There is also the possibility that patients with cardiovascular disease are weakest, present less exposure to sunlight and consequently have lower concentrations of vitamin D. A limited number of studies propose that the increased levels of 25 (OH) D may be linked with clinical benefit in patients with heart failure and hypertension. Vitamin D supplementation at the doses used is safe and well tolerated. Currently, the determination of vitamin D and its supplementation is not performed widely in clinical practice, but may be useful in patients where the therapeutic intervention is insufficient. Therefore, future prospective studies should determine whether the correction of this situation can help prevent cardiovascular disease.

Vitamin D may influence the cardiovascular disease risk by its indirect effects on risk factors for cardiovascular disease such as hypertension, diabetes and kidney failure, as well as its direct effects on the heart and vascular system. The ideal interval of the blood concentration of 25 (OH) D appears to be between 40 and 80 nmol /l. In addition to the potential biases of measurements and classifications, the possibility of reverse causation and confounding effects limit the validity of the associations reported in observational studies. The statistics from RCTs estimating the effect of vitamin D on cardiovascular events have become available from this year.

References

[1]. Anderson, J. L., May, H. T., Horne, B. D., Bair, T. L., Hall, N. L., Carlquist, J. F., … & Group, I. H. C. I. S. (2010). Relation of vitamin D deficiency to cardiovascular risk factors, disease status, and incident events in a general healthcare population. The American journal of cardiology106(7), 963-968.

[2]. Anderson, J. L., Vanwoerkom, R. C., Horne, B. D., Bair, T. L., May, H. T., Lappé, D. L., & Muhlestein, J. B. (2011). Parathyroid hormone, vitamin D, renal dysfunction, and cardiovascular disease: dependent or independent risk factors?. American heart journal162(2), 331-339.

[3]. Anderson, T. J., Grégoire, J., Hegele, R. A., Couture, P., Mancini, G. J., McPherson, R., … & Ur, E. (2013). 2012 update of the Canadian Cardiovascular Society guidelines for the diagnosis and treatment of dyslipidemia for the prevention of cardiovascular disease in the adult. Canadian Journal of Cardiology29(2), 151-167.

[4]. Artaza, J. N., Mehrotra, R., & Norris, K. C. (2009). Vitamin D and the cardiovascular system. Clinical Journal of the American Society of Nephrology,4(9), 1515-1522.

[5]. Barnard, K., & Colón-Emeric, C. (2010). Extraskeletal effects of vitamin D in older adults: cardiovascular disease, mortality, mood, and cognition. The American journal of geriatric pharmacotherapy8(1), 4-33.

[6]. Barreto, D. V., Barreto, F. C., Liabeuf, S., Temmar, M., Boitte, F., Choukroun, G., … & Massy, Z. A. (2009). Vitamin D affects survival independently of vascular calcification in chronic kidney disease. Clinical Journal of the American Society of Nephrology4(6), 1128-1135.

[7]. Bolland, M. J., Avenell, A., Baron, J. A., Grey, A., MacLennan, G. S., Gamble, G. D., & Reid, I. R. (2010). Effect of calcium supplements on risk of myocardial infarction and cardiovascular events: meta-analysis. Bmj341, c3691.

[8]. Bolland, M. J., Grey, A., Avenell, A., Gamble, G. D., & Reid, I. R. (2011). Calcium supplements with or without vitamin D and risk of cardiovascular events: reanalysis of the Women’s Health Initiative limited access dataset and meta-analysis. Bmj342.

[9]. Dhingra, R., Sullivan, L. M., Fox, C. S., Wang, T. J., D’Agostino, R. B., Gaziano, J. M., & Vasan, R. S. (2007). Relations of serum phosphorus and calcium levels to the incidence of cardiovascular disease in the community.Archives of internal medicine167(9), 879-885.

[10]. Dobnig, H., Pilz, S., Scharnagl, H., Renner, W., Seelhorst, U., Wellnitz, B., … & Maerz, W. (2008). Independent association of low serum 25-hydroxyvitamin D and 1, 25-dihydroxyvitamin D levels with all-cause and cardiovascular mortality. Archives of internal medicine168(12), 1340-1349.

[11]. Gepner, A. D., Ramamurthy, R., Krueger, D. C., Korcarz, C. E., Binkley, N., & Stein, J. H. (2012). A prospective randomized controlled trial of the effects of vitamin D supplementation on cardiovascular disease risk. PLoS One7(5), e36617.

[12]. Grandi, N. C., Breitling, L. P., & Brenner, H. (2010). Vitamin D and cardiovascular disease: systematic review and meta-analysis of prospective studies. Preventive medicine51(3), 228-233.

[13]. Holick, M. F. (2007). Vitamin D deficiency. New England Journal of Medicine,357(3), 266-281.

[14]. Hsia, J., Heiss, G., Ren, H., Allison, M., Dolan, N. C., Greenland, P., … & Trevisan, M. (2007). Calcium/vitamin D supplementation and cardiovascular events. Circulation115(7), 846-854.

[15]. Hsieh, H.-F., & Shannon, S. (2005). Three approaches to qualitative content analysis. Qualitative Health Research, 15, 1277e1288.

[16]. Jackson, N., & Waters, E. (2005). Criteria for the systematic review of health promotion and public health interventions. Health Promotion International, 20, 367e374.

[17]. Judd, S. E., & Tangpricha, V. (2009). Vitamin D deficiency and risk for cardiovascular disease. The American journal of the medical sciences338(1), 40.

[18]. Kendrick, J., Targher, G., Smits, G., & Chonchol, M. (2009). 25-Hydroxyvitamin D deficiency is independently associated with cardiovascular disease in the Third National Health and Nutrition Examination Survey.Atherosclerosis205(1), 255-260.

[19]. Kestenbaum, B., Katz, R., de Boer, I., Hoofnagle, A., Sarnak, M. J., Shlipak, M. G., … & Siscovick, D. S. (2011). Vitamin D, parathyroid hormone, and cardiovascular events among older adults. Journal of the American College of Cardiology58(14), 1433-1441.

[20]. Kilkkinen, A., Knekt, P., Aro, A., Rissanen, H., Marniemi, J., Heliövaara, M., … & Reunanen, A. (2009). Vitamin D status and the risk of cardiovascular disease death. American journal of epidemiology170(8), 1032-1039.

[21]. Kim, D. H., Sabour, S., Sagar, U. N., Adams, S., & Whellan, D. J. (2008). Prevalence of hypovitaminosis D in cardiovascular diseases (from the National Health and Nutrition Examination Survey 2001 to 2004). The American journal of cardiology102(11), 1540-1544.

[22]. Kromhout, D., Giltay, E. J., & Geleijnse, J. M. (2010). n–3 Fatty acids and cardiovascular events after myocardial infarction. New England Journal of Medicine363(21), 2015-2026.

[23]. Kunadian, V., Ford, G. A., Bawamia, B., Qiu, W., & Manson, J. E. (2014). Vitamin D deficiency and coronary artery disease: A review of the evidence.American heart journal167(3), 283-291.

[24]. Lee, J. H., O’Keefe, J. H., Bell, D., Hensrud, D. D., & Holick, M. F. (2008). Vitamin D deficiency: an important, common, and easily treatable cardiovascular risk factor?. Journal of the American College of Cardiology,52(24), 1949-1956.

[25]. Levin, A., Bakris, G. L., Molitch, M., Smulders, M., Tian, J., Williams, L. A., & Andress, D. L. (2007). Prevalence of abnormal serum vitamin D, PTH, calcium, and phosphorus in patients with chronic kidney disease: results of the study to evaluate early kidney disease. Kidney international71(1), 31-38.

[26]. Manson, J. E., Bassuk, S. S., Lee, I. M., Cook, N. R., Albert, M. A., Gordon, D., … & Buring, J. E. (2012). The VITamin D and OmegA-3 TriaL (VITAL): rationale and design of a large randomized controlled trial of vitamin D and marine omega-3 fatty acid supplements for the primary prevention of cancer and cardiovascular disease. Contemporary clinical trials33(1), 159-171.

[27]. Martins, D., Wolf, M., Pan, D., Zadshir, A., Tareen, N., Thadhani, R., … & Norris, K. (2007). Prevalence of cardiovascular risk factors and the serum levels of 25-hydroxyvitamin D in the United States: data from the Third National Health and Nutrition Examination Survey. Archives of internal medicine,167(11), 1159-1165.

[28]. Michos, E. D., & Melamed, M. L. (2008). Vitamin D and cardiovascular disease risk. Current Opinion in Clinical Nutrition & Metabolic Care11(1), 7-12.

[29]. Nemerovski, C. W., Dorsch, M. P., Simpson, R. U., Bone, H. G., Aaronson, K. D., & Bleske, B. E. (2009). Vitamin D and cardiovascular disease.Pharmacotherapy: The Journal of Human Pharmacology and Drug Therapy,29(6), 691-708.

[30]. Parker, J., Hashmi, O., Dutton, D., Mavrodaris, A., Stranges, S., Kandala, N. B., … & Franco, O. H. (2010). Levels of vitamin D and cardiometabolic disorders: systematic review and meta-analysis. Maturitas65(3), 225-236.

[31]. Pilz, S., Tomaschitz, A., März, W., Drechsler, C., Ritz, E., Zittermann, A., … & Dekker, J. M. (2011). Vitamin D, cardiovascular disease and mortality. Clinical endocrinology75(5), 575-584.

[32]. Pludowski, P., Holick, M. F., Pilz, S., Wagner, C. L., Hollis, B. W., Grant, W. B., … & Soni, M. (2013). Vitamin D effects on musculoskeletal health, immunity, autoimmunity, cardiovascular disease, cancer, fertility, pregnancy, dementia and mortality—a review of recent evidence. Autoimmunity reviews,12(10), 976-989.

[33]. Souberbielle, J. C., Body, J. J., Lappe, J. M., Plebani, M., Shoenfeld, Y., Wang, T. J., … & Zittermann, A. (2010). Vitamin D and musculoskeletal health, cardiovascular disease, autoimmunity and cancer: Recommendations for clinical practice. Autoimmunity reviews9(11), 709-715.

[34]. Thadhani, R., Appelbaum, E., Pritchett, Y., Chang, Y., Wenger, J., Tamez, H., … & Solomon, S. D. (2012). Vitamin D therapy and cardiac structure and function in patients with chronic kidney disease: the PRIMO randomized controlled trial. Jama307(7), 674-684.

[35]. Vacek, J. L., Vanga, S. R., Good, M., Lai, S. M., Lakkireddy, D., & Howard, P. A. (2012). Vitamin D deficiency and supplementation and relation to cardiovascular health. The American journal of cardiology109(3), 359-363.

[36]. Wang, L., Manson, J. E., Song, Y., & Sesso, H. D. (2010). Systematic review: vitamin D and calcium supplementation in prevention of cardiovascular events.Annals of internal medicine152(5), 315-323.

[37]. Wang, L., Song, Y., Manson, J. E., Pilz, S., März, W., Michaëlsson, K., … & Sesso, H. D. (2012). Circulating 25-hydroxy-vitamin D and risk of cardiovascular disease a meta-analysis of prospective studies. Circulation: Cardiovascular Quality and Outcomes5(6), 819-829.

[38]. Wang, T. J., Pencina, M. J., Booth, S. L., Jacques, P. F., Ingelsson, E., Lanier, K., … & Vasan, R. S. (2008). Vitamin D deficiency and risk of cardiovascular disease. Circulation117(4), 503-511.

[39]. Xiao, Q., Murphy, R. A., Houston, D. K., Harris, T. B., Chow, W. H., & Park, Y. (2013). Dietary and supplemental calcium intake and cardiovascular disease mortality: the National Institutes of Health–AARP Diet and Health Study. JAMA internal medicine173(8), 639-646.

[40]. Zittermann, A., Frisch, S., Berthold, H. K., Götting, C., Kuhn, J., Kleesiek, K., … & Koerfer, R. (2009). Vitamin D supplementation enhances the beneficial effects of weight loss on cardiovascular disease risk markers. The American journal of clinical nutrition89(5), 1321-1327

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