WORLD JOURNAL OF PHARMACY AND PHARMACEUTICAL SCIENCES Jaganathan et al.

World Journal of Pharmacy and Pharmaceutical SJIFSciences Impact Factor 6.041

Volume 5, Issue 11, 405-418

Review Article

ISSN 2278 – 4357

VITAMIN D AND HEART HEALTH Neema Johnson, Sudha M., Jaganathan K.* and Sambathkumar R. Department of Pharmacy Practice, J.K.K. Nattraja College of Pharmacy, Kumarapalayam, Tamil Nadu, India- 638 183.

Article Received on 10 Sept. 2016,

ABSTRACT Vitamin D deficiency, as well as cardiovascular diseases (CVD) like

Revised on 30 Sept. 2016, Accepted on 20 October 2016

arrhythmia, angina, heart attack, congestive heart failure, stroke and

DOI: 10.20959/wjpps201611-7951

related risk factors such as diabetes, hypertension, obesity and atherosclerosisare highly prevalent worldwide and frequently co-occur.

*Corresponding Author

Vitamin D has long been known to be an essential part of bone

Jaganathan K.

metabolism, although recent studies suggests that vitamin D plays a

Department of Pharmacy

key role in the pathophysiology of other life threatening diseases,

Practice, J.K.K. Nattraja

including CVD, as well. In this review, we aim to summarize the most

College of Pharmacy, Kumarapalayam, Tamil Nadu, India- 638 183.

recent data on the involvement of vitamin D deficiency in the development of major cardiovascular diseases and its risk factors.

KEYWORDS: Vitamin D, Cardiovascular disease, Parathyroid hormone. INTRODUCTION The discovery about the critical roles of Vitamin D for overall health was a fascinating story in the history of medicine. First were its osseous effects and the association to rickets. Then they came with the discovery of its anti-infectious role, from the breakthrough by Niels Finson, earning him a Nobelprize in 1903 for the use of a form of ‘concentrated light radiation’ to treat tuberculosis skin lesions, until the discovery of cathelicidin, regulated by vitamin D, that serves a critical role in immune defense against invasive bacterial infection.[1] Over the last two decades, understanding of vitamin D synthesis and its function has changed remarkably. With its plethora of biological effects on diverse tissues, vitamin D sustains health throughout the body. It is now believed that low levels of vitamin D have been shown to be associated with increased risks of atherosclerosis, obesity, hypertension, glucose intolerance, type 2 diabetes mellitus and cardiovascular disease. [2]

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Vitamin D Vitamin D is a collection of fat-soluble steroids, the two dominant forms of which are vitamins D2 (ergocalciferol) and D3 (cholecalciferol). Vitamin D2 is synthesized by invertebrates and in plants after exposure to ultraviolet(UV)radiation and Vitamin D3 is naturally present in some dietary sources and is also made endogenously in the skin when7dehydrocholesterol is exposed to UV-B light.[3] Exogenously acquired vitamin D is biologically inactive and requires two hydroxylation reactions forits activation.[4] The first one is occurs in the liver, where 25- hydroxyvitamin D ([OH]D) is produced; this is the main circulating vitamin D in the blood. The second one takes place in the kidneys, where it is converted to 1, 25-[OH]D. Because of its long half-life, 25-[OH]D measurements are clinically effectivein assessing vitamin D status in patients.[5] Its potential cardiovascular benefits are related with its ability to inhibit Parathyroid hormone (PTH), which is associated with the pathogenesis of several disease conditions that increase the risk for CVD; and with its effects on the vasculature, including improved calcium uptake, regulation of RAAS (Renin Angiotensin Aldosterone System), inhibition of platelet aggregation, enhanced production of nitric oxidesynthase, inhibition of abnormal and unwanted thrombotic activity, and, possibly, the regulation of vasomotor activity to neural input.[6-10] Defining vitamin D deficiency Considerable controversies surround the definition ofvitamin D deficiency. According to Current International Osteoporosis Foundation guidelines define vitamin D insufficiency as 25-(OH)D levels less than 50 nmol/L and deficiency as levels less than 25 nmol/L. No universal consensus has been reached on which level of serum 25-(OH)D reflects optimum vitamin D status. A recent position statement from the International Osteoporosis Foundation recommended a target level of 75 nmol/L, which is associated with maximal suppression of parathyroid hormone.[11] Prevalence of vitamin D deficiency Vitamin D deficiency is prevalent in most parts of world; this is very well reflected by the fact that more than half of the world population has levels below 30 ng/mL.[3,12] Different factors, such as increased age, female sex, cultural dresses, reduced sun exposure, malabsorption

syndrome,

hyperpigmentation,

seasonal variation,

changes

in

lifestyles,

latitude, air pollution are risk factors for decreased levels of vitamin D and must be considered.[13]

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Vitamin D: Effects on heart Vitamin D has a key role in maintaining cardiovascular health through both direct action of the vitamin D on cardiomyocytes and indirect actions on circulating hormone and intracellular calcium levels.[14] The vitamin D receptor (VDR) is seen in several types of tissues throughout the body, such as hepatocytes, lymphocytes and cardiac myocytes.[15,16] Vitamin D is associated with elevated plasma renin activity, coronary artery calcification, high BP and most of the associated CVD.17-20 In vitamin D deficiencies, secondary hyperparathyroidism develops resulting increased parathyroid hormone action in blood and the increased levels of parathyroid hormone have been associated with increases in BP and acute increase in cardiac contractility. The sustained stress on myocardial tissue leads to cardiac hypertrophy, myocardial fibrosis and heart failure.[21,22] Administration of activated forms of vitamin D (1,25[OH]2D or analogs) to patients with secondary hyperparathyroidism has resulted in decreased left ventricular hypertrophy, along with a decrease in cardiovascular mortality.[23-25]

Hypertension Increased parathyroid hormone (PTH) levels are a hallmark of low vitamin levels in circulation and are known to be linked with myocardial hypertrophy and increased blood pressure levels.[26] The pathogenesis for this correlation is unclear, even though available

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evidence suggests that secondary hyperparathyroidism and hypocalcemia, may be an alternative explanation for the association between vitamin D deficiency and hypertension. Previous observational studies are also seen a relation between increased parathyroid hormone and hypertension.[26,27] Recent studiessuggests that parathyroid hormone may causes arterial stiffness and induce atherosclerotic changes by acting on smooth muscle cells in the endothelium.[28] Increasing evidence suggests that the relationship between parathyroid hormone, vitamin D and aldosterone mediates cardiovascular damage independent of the RAAS.[29,30]

Endothelial Dysfunction and Atherosclerosis The Vitamin D receptor(VDR) is expressed in the vasculature, and vitamin D might protect against diseases, including atherosclerosis and other endothelial dysfunction.31Endothelial dysfunction is expressed by a change in the properties of the endothelium toward decreased vasodilation and the initiation of a proinflammatory reactions and prothrombotic state. Vitamin D plays a main role in the pathogenic mechanism of atherosclerosis and which is contributes to plaque formation and progression. According toexperimental works, putative vasculoprotective actions of vitamin D may be potentiated by increasing production of vasodilatornitric oxide (NO), inhibiting formation of foam cell from macrophages or reducing the expression of adhesion molecules in vascularendothelial cells.[32-34] Atherosclerosis is a chronic immuno-inflammatory response within the arterial vessel wall resulting from the influx of lipids, extracellular matrix and cellsthat cause several adverse

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vascular events like coronary artery disease, stroke, and peripheral arterial disease.[35] The inflammatory process involved in development of atherosclerosisis mediated by both proinflammatory and anti-inflammatory cytokines, which are responsible forinitiating events of plaque rupture and thrombosis. Vitamin D deficiency is considered as an important risk factor for atherosclerosis. Vitamin D may inhibit cholesterol uptake by macrophages and foam cell formation.[33] In addition to this, VDR activation may also regulate theatherosclerotic process through modulation of inflammatory cytokines. It is known that atherosclerosis is promoted by The T helper 1 cells, interleukin-1 b (IL-1 β), interleukin-6 (IL-6) and tumor TNF- α and inhibited by T-helper 2 cells, mainly interleukin-4 (IL-4), and interleukin-10 (IL-10).[36] Several

studies

suggest

vitamin

D

supplementation

demonstrates

anti-atherogenetic

properties through its inhibition of serum TNF- α levels and promotion of IL-10 levels.[37] Glucose metabolism and Diabetes Mellitus Type II (DM II) Low vitamin D levels have largely been associated with disturbances in glucose metabolism, as well as increased risk of developing DM in the future. Several possible mechanisms that could explain the association of vitamin D deficiency and the increased incidence of diabetes mellitus are available. The presence of VDR, as well as 1-α-hydroxylase in pancreatic beta cells, indicating a crucial role of vitamin D on beta cell function.[38,39] It has also been hypothesized that calcium, which is crucial for insulin synthesis and secretion, could play a main role in diabetes development, since it is mainly maintained by vitamin D levels.[40] Another possible explanation for this association may be

the vitamin D-induced stimulation

of osteocalcin, which may increase insulin sensitivity.[41] Hyperlipedemia Vitamin D has a main role in reduction of triglycerides (TG) level and associated cardiovascular risks. Two mechanisms might be involved in the vitamin D mediated decrease in serum TG levels. One is by increasing intestinal calcium absorption which in turn leads to increase absorbed calcium levels. Increased calcium levels can reduce serum TG levelsby reducing hepatic TG formation and secretion into blood.[42] Other one is via a suppression of serum PTH levels by vitamin D. Since elevated PTH levels may cause reduction in plasma post-heparin lipolytic activity and reduction in serum PTH by vitamin D may decrease serum TGs via increased peripheral removal.[43] A third mechanism may also be involved, in which vitamin D induces the expression of VLDL-cholesterol receptors in some types of cell.[44] A fourth possible mechanism to explain the link between vitamin D and TGs is related to

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insulin resistance: when vitamin D deficiency levels decreased, the risk of insulin resistance increases and this situation is associated with an elevation of the levels of VLDL and TGs.[45] Obesity Obesity is closely related with low vitamin levels. Obesity leads to vitamin D deposition in adipose tissue, resulting in lower circulating levels of vitamin D in the blood.[46] Obesity can be considered as a important risk factor for low vitamin D levels, on the other hand, genetically determined vitamin D levels were not significantly associated with BMI.[47] These suggest that the association between obesity and vitamin D deficiency is only driven by the fact that a increased BMI lowers vitamin D in circulation. Cardiac hypertrophy There is evidence that vitamin D3 (cholecalciferol), reduces the risk of cardiac hypertrophy and related cardiac events. The VDR acts with retinoic acid receptors on cardiomyocytes and vascular smooth muscle cells to decrease the size of cell and the vitamin D3inhibits the maturation of cardiomyocytes.[48,49] Vitamin D3 deficiency may lead to cardiac hypertrophy, which is

characterized by a significant increase in collagen-filled extracellular space and an

increase in myofibrillar area.[50] Cell size is also affected by the action of protein kinase C (PKC), which can be activated by various mediators like norepinephrine (NE), angiotensin II (Ang II), or PTH to contribute to enlargement of cell and increased PKC activity may leads to left ventricular hypertrophy.[51] Adequate vitamin D levels may limit this hypertrophic response by inhibiting PTH action, thereby preventing it from activating PKC. Heart muscle contractility Vitamin D has a great role in supporting normal heart muscle contractility and normal functioning.

Adequate vitamin Dlevel needs to be maintained to achieve maximum

contractility of cardiac muscles.[52] Regulation of calcium homeostasis by vitamin D may be the second mechanism its support of cardiac contractility. By inhibiting PTH induced reabsorption of calcium from bone, vitamin D reduces the risk of calcification of valves of heart and coronary artery vessel walls.[53] Cardiac arrhythmia Vitamin D’s ability to maintain calcium homeostasisenable it to prevent cardiac arrhythmias. Intracellular calcium regulates the activity of sodium channels which transmit action potentials throughout the myocardial tissue to keep the heart function and rate under control.

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If calcium homeostasis is disrupted in any situations, mechanical dysfunction or an arrhythmia may develop, which, if left untreated, may result in cell injury or death of myocardial tissue.[54] Heart failure Heart failure (HF) is featured byaltered heart structure and disorganized function that interferes with normal filling or ejection of blood from heart through valves.[55] Evidence of vitamin D’s influence on the size, character and contractility of myocardial tissue suggests that it may have a beneficial effect in HF. Ischemic heart disease (IHD Decreased vitamin D levels may increases the incidence of ischemic heart diseases in patients with high risk factors. Carotid artery intimal medial thickness is common in vitamin D deficiency patients than those with adequate vitamin D levels and PTH also contributes to changes in the structure and function of vascular endothelium that increase the risk of most fatal atherosclerosis.[56] By suppressing PTH activity, vitamin Dmay reduce the risk of coronary vessel calcification and stenosis in people with adequate vitamin D levels and thereby decreasing the risk of ischemic heart diseases and other complications.[57] Chronic kidney diseases (CKD) Vitamin D deficiency is linked with albuminuria and progression in renal disease. In most of the patients with CKD have vitamin D level lees than 20ng/ml. The therapeutic effect of vitamin D in lowering PTH is used in CKD patients because secondary hyperparathyroidism is common in most of the kidney failure patients.[58,59] Peripheral artery diseases Occurrence of peripheral artery diseases is more prevalent in people with vitamin D deficiency. This association may be due to the increased carotid artery intimal medial thickness in patients with vitamin D deficiency than those with adequate vitamin D stores.[60] Vitamin D and the treatment of heart disease Although strong evidence is currently not sufficient to make general recommendations for vitamin D supplementation for the treatment and prevention of systemic hypertension and cardiovascular disease, it must be underlined that low vitamin D level is definitely common among patients with cardiovascular and related events. In most of the drugs commonly used

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in the treatment of cardiovascular diseases appear to increase the action of vitamin D on bone by

improving osteoblast differentiation (e.g., calcium channel blockers like verapamil and

dilitiazem), inhibiting substances that block osteoblast activity, such as Angiotensin II (e.g., ACE inhibitors like ramipril and enalapril), preventing the loss of calcium in the urine (thiazide diuretics like chlorthiazide) and by inhibiting the production of prostaglandins by platelet cyclooxygenases (COX, especially COX-2) to prevent bone loss (e.g., aspirin).[61,64] Prescription with vitamin D for CVD Evidence of benefits of vitamin D on heart health is still in preliminary stages. So it is best you can do that is to advise the patient with heart disease is to follow current guidelines for an adequate intake of vitamin D- 400 IU daily is usually recommended, although 1000 IU/d of vitamin D may be necessaryto achieve the highest serum levels possible. [65] Other best thing you can do are to add sun exposure in your patient’s prescription. Elders with cardiovascular disease are often avoiding the sun because of physical limitations that keep them indoors or a fear of developing skin cancer. So we want to teach them about the safe sun exposure 5 to 10 minutes of sunscreen-free exposure between the hours of 10am and 3pm 2 to 3 times a week in a temperate climate to achieve maximal vitamin Dproduction with minimal skin cancer risk. What happens if vitamin D in excess When levels of vitamin D in the blood become too high,toxicity signs which include nausea, vomiting, constipation, weakness, poor appetite and weight loss may starts to occur. Too much of vitamin D can increase calcium levels in blood and can cause confusion, disorientation and problems with heart rhythm. The excess calcium can be deposited in kidney and cause damage to it. Excessive intakes of vitamin D can also cause calcium to be reabsorbedfrom bones, which can weaken them and lead to many musculoskeletal disorders. The upper limit for vitamin D is 1,000 to 1,500 IU/day for infants, 2,500 to 3,000 IU/day for children 1-8 years and 4,000 IU/day for children 9 years and older, adults and pregnant and lactating teens and women. The most common reason for Vitamin D toxicity is always the overuse of vitamin D supplements. Excessive sun exposure doesn't cause vitamin D poisoning because the body limits the amount of this vitamin it produces. FUTURE OUTLOOK Based on currently available observational studies, RCTs and Meta analyses it can be concluded that vitamin D deficient patients are at anincreased risk for CVD and other related www.wjpps.com

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events. However, it is largely unclear that whether these associations are of causal nature. Number of RCTs in the past failed to provide a strong relationship between raised risk of cardiovascular events and vitamin D deficiency. This may be dueto less sample sizes or inappropriate study designs, since most trials were initially designed for clinical endpoints other than cardiovascular events. While available data are not sufficient to make final conclusions on the role of vitamin D on cardiovascular outcomes, several large RCTs are needed to evaluate the effect of vitamin D supplementation on different cardiovascular disease as primary endpoints in ill patients, as well as general populations. The question whether vitamin Dcan treat or prevent cardiovascular and related diseases will be answered only after the completion of these types of large randomized controlled trials. CONCLUSION Emerging evidence indicates that vitamin D play an main role in regulating normal cardiovascular activity through its ability to regulate BP, prevent heart wall and blood vessels calcification, support normal cardiovascular contractility and reduce the risk of formation of thrombosis. Cholecalciferol in particular has a main role in maintaining normal cardiac contractility and prevents cardiac hypertrophy, and thus may be helpful in preventing or managing CVD and related events. There is no clear evidence that support vitamin D supplementation has a key role to play in the management and prevention and of CVD. Sowe can still encourage patients with cardiovascular disease or patents under risk to consume suitable amounts of vitamin D-rich foods, to take a supplement in proper dosage and to increase their sun exposure by following current guidelines for doing so without increasing risk of skin cancer. REFERENCE 1. Pinhas HO, Carel JC, Hochberg Z. Type 2 Diabetes Mellitus, Metabolic Syndrome, Lipids. Yearbook of Pediatric Endocrinology 2010: Carel JC: Basel: Karger, 2010; 155–170. 2. Johnson

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