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Literature Review: Vitamin D and Cardiovascular Health

Mishka Bartholow FSCN 4612 12/5/12

1 This paper aims to explore the connections between vitamin D and cardiovascular health. Vitamin D is a fat-soluble vitamin whose best understood functions are involved in bone formation and calcium and phosphorus homeostasis.1 While vitamin Ds link to skeletal formation is well established, it is clear that there are many other functions that have yet to be fully explained. Vitamin D receptors (VDRs) are present in many diverse biological tissues including lymphocytes, hepatocytes and cardiac myocytes, and are involved in the expression of almost 3000 human genes.2 This widespread distribution of VDRs indicates that there are likely many functions of vitamin D that have yet to be understood. An emerging trend is the association between vitamin D deficiency and various cardiovascular concerns. Correlations between vitamin D deficiency and an array of diseases have been demonstrated including: hypertension, peripheral vascular disease, diabetes mellitus, metabolic syndrome, coronary artery disease and heart failure.2,3 It is therefore of great concern that vitamin D deficiency is widespread in the general population.4,5 It is the contention of the author that though the connections between vitamin D deficiency and various cardiovascular concerns are sound, evidence regarding the benefits, if any, of supplementation is lacking. This text will first overview the metabolism of vitamin D, deficiency trends, and vitamin Ds effects on the cardiovascular system in animal models. A summary of clinical studies on the links between cardiovascular health and vitamin D status in humans will follow, before finally exploring data on the effects of supplementation. Vitamin D can be acquired by three different ways: manufactured by the body when exposed to sunlight, acquired through the diet, or obtained via supplementation. The majority of vitamin D in the body is acquired via the first method of extraction from

2 sunlight.6 The term vitamin D in fact refers to an array of various metabolites. Dietary sources of vitamin D include vitamin D2 (ergocalciferol) and vitamin D3 (cholecalciferol). These are converted mainly in the liver to 25-hydroxy vitamin D (25(OH)D).6 Serum measurement of 25(OH)D concentration provides the best measurement of an individuals vitamin D status.6,7,8 25(OH)D is processed by kidneys into the biologically active form of vitamin D1,25(OH)2D, which travels via chylomicrons in the blood, regulating blood calcium and phosphate levels among other functions.6 As stated previously, the majority of vitamin D is provided via sun exposure, which leaves populations in high latitudes susceptible to deficiency if dietary sources are not provided.5,6 Other risk factors include: old age, darker skin tone, obesity, and liver or kidney dysfunction.6 Vitamin D deficiencies are most commonly associated with the disease rickets in children, characterized by bone deformation and growth problems.5,9 It is also of note that children with rickets commonly have cardiomyopathy, a weakening of heart muscle function.9 This points to the cardiovascular implications of sub-optimal vitamin D status. As to the threshold of vitamin D deficiency and optimal status, there is some disagreement among the medical community.6 Measurement of serum concentrations of 25(OH)D is agreed upon as the best method of assessing vitamin-D status. 6,7,8 Typically, 25(OH)D serum levels below 20ng/ml are considered deficient and levels above 30ng/ml are considered optimal.3,6 Critics argue that levels above 35ng/ml may be needed to prevent increased risk of fractures.6 Most studies focus on bone health in their assessment of vitamin D status, with no agreed upon parameter focusing on cardiovascular health.6 It is clear, however, that regardless of the threshold, vitamin D

3 deficiency is widespread. It is estimated that between 30-50% of the US and European populations are vitamin D deficient.5 Many studies have since demonstrated an inverse relationship between vitamin D status and cardiovascular risk factors, yet animal studies have most dramatically illustrated the importance of vitamin D on cardiac function through removing vitamin D receptors (VDR) in mice.10,11 The results of studies comparing normal and VDR knockout mice demonstrated hypertrophy of cardiac cells among knockout mice. This increased the heart: body weight ratio by 41% in the VDR knockout mice.10 Further consequences included the accumulation of collagen, the abnormal thickening of heart valves (cardiac fibrosis), as well as instances of left ventricular dilation and heart failure.10,11 These studies are commonly cited as concretely establishing the effects of D vitamins on cardiac tissue.1,2,6,9 Further studies have expanded on this research by examining the effects of supplementation in preventing cardiac hypertrophy in rodents.9 Rats were fed a high sodium diet resulting in cardiac hypertrophy. Once this was achieved four distinct treatments were prescribed while continuing the high-salt diet. The two treatments containing a vitamin D2 analogue (paricalcitol at 200ng, 3x/week) were effective in preventing progression of pre-existing cardiac hypertrophy and heart failure despite the continuation of the high-salt diet.9 These studies provide sound data that effectively demonstrates a significant role of vitamin D in the maintenance of cardiac function. The affected rodents in the VDR knockout study also produced elevated levels of the hormone renin (a discussion of the Renin-angiotensin system appears below). The authors of the studies on VDR knockout mice pointed out that this hormone system did not specifically elicit the changes seen in cardiac function.10,11 However, this piqued

4 interest that has stimulated further research on the relationship between the Reninangiotensin system and vitamin D. The renin-angiotensin system (RAS) is primarily associated with the regulation of blood pressure. Stimulation of the RAS, and the effects of angiotensin in particular, are associated with increased vasoconstriction. The association of vitamin D in regulating the RAS increased interest in the effects of vitamin D on blood pressure. The largest study on this issue was part of the third National Health and Nutrition Examination Survey (NHANES III), which analyzed the correlation between blood pressure and vitamin D status among 12,644 US civilians.12 A fault of this survey was that its data was based on a solitary measurement of each individuals blood pressure and serum vitamin D (25(OH)D. However, a significant inverse correlation was found between blood pressure and vitamin D status, even after adjusting for age, sex, ethnicity, physical activity and BMI.12 It is hypothesized that vitamin D affects the renin-angiotensin system (RAS), by suppressing the production of renin.3 Renin is needed to free angiotensin from angiotensinogen, thus increased plasma vitamin D limits the vasoconstrictive effects of the RAS.3 This explains in part why such a strong correlation exists between vitamin D deficiency and hypertension. Further studies also portray an inverse correlation of vitamin D stores and blood pressure. A case-control study of women in late-pregnancy demonstrated a marked correlation between low circulating vitamin D and hypertension, though this study had a small sample size (less than 200) and focused on an isolated population in northern Canada, among whom vitamin D deficiency was common.7 A study on angiotensin and its vasoconstriction effects demonstrated increased sensitivity to angiotensin II in obese individuals as compared to non-obese individuals with similar

5 25(OH)D levels.13 However, obese individuals with lower 25(OH)D stores exhibited higher sensitivity to angiotensin II, indicating some level of association between vitamin D and vascular sensitivity, at least in the obese.13 This study contained a control and a mix-gender population, although the data can again be questioned because of the small sample size (N=97). Other studies have called into the question the relationship between vitamin D status and blood pressure. A controlled study of 274 Thai males found a significant correlation between BMI and hypertension as would be expected, but a relatively weak correlation (.55) when solely comparing Vitamin D status and hypertension.14 All in all, most studies exploring the links between hypertension and vitamin D status seem to confirm that vitamin D deficiency is associated with hypertension. Besides hypertension, several studies have demonstrated a link between reduced 25(OH)D and increased risks associated with cardiovascular disease.3,15 25(OH) D levels were measured in a study of 701 adolescent boys and girls to assess cardiometabolic risk factors. The results adjusted for age, sex, race, physical activity, and percent body fat demonstrated links between low 25(OH)D serum levels and various cardiometabloic risk factors including: hypertension, high fasting glucose levels and high cholesterol levels.15 This study neglected to measure the amount of sun exposure in adolescents, relying on activity level to infer the amount of sun exposure. However, this was the first study to assess adolescents and strongly demonstrates the association of vitamin D deficiency with a host of cardiovascular problems. Other studies have eliminated associations of vitamin D deficiency with particular symptoms or conditions. A cohort study of 625 middle-aged participants found no

6 significant correlation between 25(OH)D levels and arterial plaques or thickness.16 This study varied in its definition of deficiency however, terming those with 25(OH)D stores <10ng/ml as deficient. This is a very low threshold to set for deficiency and explains the low prevalence of deficient patients at 19%. However this only reinforces their data ruling out a correlation between vitamin D deficiency and arterial plaques. Further clinical experiments have demonstrated that heart failure patients have poor vitamin D status. A four year study of 1108 diabetic haemodialysis patients found that patients with severe vitamin D deficiency (measured again as 25(OH)D 20ng/ml) were three times more likely to suffer sudden cardiac death compared to those with sufficient 25(OH)D levels (>30ng/ml).17 A further cohort study of over 1800 patients with metabolic syndrome (combination of medical disorders that increase the risk of cardiovascular disease and type 2 diabetes) found that optimal 25(OH)D levels substantially lowered risk of heart failure and mortality in general compared to vitamin D deficient individuals.4 Despite this correlation it has not been established whether vitamin D deficiency actively contributes to heart failure or is a consequence of poor heart health.3,4 In most cases there has simply been an observed correlation of poor vitamin D status and adverse effects on the cardiovascular system, many citing the need for study on the affects of supplementation.2,3,9,13,15,17 One such study released this year followed 92 Type 2 Diabetes patients for 18 months, supplementing them daily with 200IU of vitamin D. The goal was to determine any change in metabolic profile related to the supplement. Several favorable outcomes from vitamin D supplementation were found, including improved HDL/LDL cholesterol ratio and insulin resistance.18 However, these effects were first observed after six months

7 of supplementation, and some patients remained vitamin D deficient even after 18 months of treatment.18 This indicates that prolonged use of supplements may be necessary to achieve significant metabolic effects. A flaw of this study was the lack of a control group, however these initial results show that positive effects on the cardiovascular system can be attained through the use of a vitamin D supplement. Recent research in fields of endocrinology and cardiology are exposing the varied and complex effects of D vitamins, and more functions are bound to emerge. Many varied effects of vitamin D have been observed; more often than not these have studied the results of deficiency. Vitamin D deficiency is widespread throughout the world and there is strong data associate this deficiency with an increased risk of hypertension and heart failure.3,4,5,12,17 While it can be claimed with some authority that there are relationships between low vitamin D stores and a variety of cardiovascular and metabolic ailments, the positive effects of supplementation are yet to be fully explored and merit further research.2,3,9,13,15,17

8 Works Cited: 1. McDermott MM, Liu K, Ferrucci L, Tian L, Guralnik J, Kopp P..., Criqui MH. Vitamin D status and functional performance in peripheral artery disease. Vascular Medicine. 2012;17(5):294-302. 2. Vacek JL, Vanga SR, Good M, Lai SM, Lakkireddy D, Howard PA. Vitamin D Deficiency and Supplementation and Relation to Cardiovascular Health. American Journal Of Cardiology. 2012;109(3):359-363. 3. Pilz S, Tomaschitz A, Marz W, et al. Vitamin D, cardiovascular disease and mortality. Clinical Endocrinology. 2011;75(5):575-584. 4. Bohm BO, Bosch JA, Fischer JE, Grammer TB, Hartaigh BO, Kleber ME,Thomas GN. Vitamin D levels predict all-cause and cardiovascular disease mortality in subjects with the metabolic syndrome: the Ludwigshafen Risk and Cardiovascular Health (LURIC) study. Diabetes Care. 2012;35(5):1158-1164. 5. Holick MF. Vitamin D status: measurement, interpretation, and clinical application. Annals of Epidemiology. 2009;19(2):7378. 6. Brandenburg VM, Vervloet MG, Marx N. The role of vitamin D in cardiovascular disease: From present evidence to future perspectives. Atherosclerosis. 2012; 225(2):253-261. 7. Ringrose JS, PausJenssen AM, Wilson M, Blanco L, Ward H, Wilson TW. Vitamin D and hypertension in pregnancy. Clinical & Investigative Medicine. 2011; 34(3):E147E154. 8. Martini LA, Wood RJ. Vitamin D and blood pressure connection: update on epidemiologic, clinical, and mechanistic evidence. Nutrition Reviews. 2008;66(5):291-297. 9. Bae S, Yalamarti B, Ke Q, Choudhury S, Yu H, Karumanchi S..., Kang PM. Preventing progression of cardiac hypertrophy and development of heart failure by paricalcitol therapy in rats. Cardiovascular Research. 2011;91(4): 632-639. 10. Rahman A, Hershey S, Ahmed S, Nibbelink K, Simpson RU. Heart extracellular matrix gene expression profile in the vitamin D receptor knockout mice. Journal of Steroid Biochemistry and Molecular Biology. 2007;103:41619. 11. Simpson RU, Hershey SH, Nibbelink KA. Characterization of heart size and blood pressure in the vitamin D receptor knockout mouse. Journal of Steroid Biochemistry and Molecular Biology. 2007;103:521-524. 12. Scragg R, Sowers MF, Bell C. Serum 25-hydroxyvitamin D, ethnicity, and blood pressure in the third national health and nutrition examination survey. Am J Hypertens. 2007;20:713-719. 13. Vaidya A, Forman JP, Williams JS. Vitamin D and the vascular sensitivity to angiotensin II in obese Caucasians with hypertension. Journal Of Human Hypertension. 2011;25(11):672-678. 14. Sumriddetchkajorn K, Chailurkit L, Thakkinstian A, Sritara P. Hypertension is statistically associated with higher body mass index but not with vitamin D level in a Thai population. European Journal Of Clinical Nutrition. 2012;66(3): 405407. 15. Bhagatwala J, Dong Y, Guo D, Gutin B, Houk C, Parikh S, Petty K, Pollock NK, Zhu H. Circulating 25-hydroxyvitamin D concentrations are correlated with

9 cardiometabolic risk among American Black and White adolescents living in a yearround sunny climate. Diabetes Care. 2012;35(5):1133-1138. 16. Knox S, Welsh P, Bezlyak V, McConnachie A, Boulton E, Deans KA, Sattar N. 25-Hydroxyvitamin D is lower in deprived groups, but is not associated with carotid intima media thickness or plaques: Results from pSoBid. Atherosclerosis. 2012;223(2): 437-441. 17. Al-Daghri NM, Al-Othman A, Al-Saleh Y, Alkharfy KM, Alokali MS, Chrousos GP. Vitamin D supplementation as an adjuvant therapy for patients with T2DM: an 18month prospective interventional study. Cardiovascular Diabetology. 2012;11:85-91.