FOCUS ON CARDIOVASCULAR DISEASE

The Consequences of Vitamin D Deficiency: FOCUS ON CARDIOVASCULAR DISEASE Vitamin D deficiency is a global health problem. With all the medical advances of the century, vitamin D deficiency is still epidemic. Over a billion people worldwide are suffering from vitamin D deficient (<20ng/mL) or insufficient (<30ng/mL). 1 Once rickets appeared to have been conquered, many health care professionals thought the major health problems resulting from vitamin D deficiency had been resolved. 2 But the discovery that most tissues and cells in the body have a vitamin D receptor (VDR) and that several possess the enzymatic machinery to convert the primary circulating form of vitamin D, 25-hydroxyvitamin D, to the active form, 1,25-dihydroxyvitamin D, has provided new insights into the function of this vitamin. 2 With the finding of the VDR in nearly every tissue and the more recent discovery of thousands of VDR binding sites throughout the genome controlling thousands of genes, the interest in vitamin D and its impact on multiple biologic processes has accelerated tremendously as evidenced by the thousands of publications each year for the past several years. 3 Low vitamin D status has been associated with an increased risk of type 1 diabetes mellitus, cardiovascular disease, certain cancers, cognitive decline, depression, pregnancy complications, autoimmunity, allergy, and even frailty. Low prenatal and neonatal vitamin D status may also increase susceptibility to schizophrenia, type 1 diabetes, and multiple sclerosis in later life via specific target organ effects, including the immune system, or through epigenetic modification. 4 So, focusing on different therapeutic group, we are currently introducing an article series on consequences of vitamin D deficiency. In this issue effect of vitamin D deficiency on cardiovascular disease (CVD) is focused. Role of Vitamin D on Disease Over the last few decades, there has been a recurring trend in cardiac nutritional science. Observational data shows a strong association between a nutritional deficiency and worse CVD outcomes, generating a hype for supplementation. Numerous epidemiological and observational studies and meta-analyses have investigated the effect of vitamin D on cardiovascular disease outcomes. Almost all the studies found that there is a close link between vitamin D deficiency and cardio vascular diseases. Vitamin D receptors are present on a large variety of cell types, including myocytes, cardiomyocytes etc. Evolving data indicate that vitamin D deficiency is playing an important role in the genesis of coronary risk factors and CVD. Deficient or insufficient serum 25(OH)D levels have been documented in patients with myocardial infarction, stroke, heart failure, diabetic CVD, peripheral arterial disease & many more. 5 Vitamin D & Hypertension: Research shows that there is a link between vitamin D and hypertension. People with higher vitamin D levels tend to have lower blood pressure and are less likely to develop hypertension. Some studies show that taking a vitamin D medical newsletter I as a service to the medical profession I 17

1,25(OH)2D Endothelial Cell Smooth Muscle Cell VDR Cardiomyocyte Dendritic Cell T Cell Macrophage Flow-mrdiated Dilation Tissue Factor Thrombospondin *PAI-1 Modulation of Proliferation, Migration, Differentiation, Matrix Turnover Regulation of Ca 2+ Flux and Sarcomere Function T H1/ T H2 Modulated Cytokine Production Cholesterol Uptake *RAS Activation Optimal Endothelial Function and Vascular Tone Modulation of Osteoblastic Gene Expression Optimal Myocardial Contractility Physiological Balance Between Fibrinolysis and Thrombogenicity Adaptive (Physiological) Arterial and Cardiac Remodelling Maintains Immune and Inflammatory Response in Vascular Tissue Limits *PAI-1 indicates plasminogen activator inhibitor-1; and *RAS, renin angiotensin system. Figure 4.1 : Overview of vitamin D receptor (VDR) mediated endocrine actions of 1,25(OH)2D on arterial wall and cardiac cells supplement may help people lower their blood pressure. One large study found that people with higher levels of vitamin D had lower blood pressures and a lower risk of developing hypertension. 6 A review in 2013 looked at many studies involving people with hypertension. 7 They found that, risk of developing hypertension reduces 12% for each 10 ng/ml increase of vitamin D level. The people with the highest vitamin D levels had a 30% lower risk of developing hypertension compared to the people with the lowest levels. An experiment in 2012 in Denmark 8 looked at the effects of vitamin D supplements on lowering blood pressure in people with hypertension. For 20 weeks, people either took 3,000 IU per day of vitamin D or a placebo pill. The researchers measured blood pressure and found that, the people in the vitamin D supplementation group lowered their blood pressure more than the people getting the placebo. People in the vitamin D group who had low levels of vitamin D at the beginning of the study had a bigger reduction in their blood pressures. A double-blind study, Nasri et al. showed that supplementary therapy with cholecalciferol based on 50,000 units weekly for 12 weeks, reduced blood pressure significantly (P<0.01) in diabetic patients. 9 Vitamin D and Myocardial Infraction: Multiple studies evaluated the relation of vitamin D prospectively with long term cardiovascular outcomes in subjects with no histories of cardiovascular disease. In healthy male health professionals aged 40 to 75 years with no histories of coronary artery disease, vitamin D deficiency (vitamin D<15 ng/ml) was associated with a twofold increased rate of myocardial infarction over a 10-year period. In the Framingham Offspring Study, subjects with no histories of cardiovascular disease and severe vitamin D deficiency (25[OH] vitamin D < 10 ng/ml) had increased risk for developing a first cardiovascular event after 5 years of follow-up compared with subjects with of 25(OH) vitamin D levels 15 ng/ml (hazard ratio 1.80, 95% confidence interval 1.05 to 3.08). 10 Vitamin D and Heart Failure: The major potential mechanisms that may explain a direct protective effect of vitamin D against heart failure include effects on myocardial contractile function, regulation of 18 I medical newsletter I as a service to the medical profession

Vitamin D Deficiency Insulin Resistance Pancreatic Beta Cell Dysfunction Parathyroid hormone Inflamation Renin-angiotensinaldosterone system Diabetes and Metabolic Syndrome Atherosclerosis Hypertension and Hypertrophy Adverse Events Figure 4.2: Possible mechanisms of increased cardiovascular risk from vitamin D deficiency natriuretic hormone secretion, effects on extracellular matrix remodeling, reduced left ventricular hypertrophy, and the regulation of inflammatory cytokines. Observational studies have shown that osteoporosis, osteopenia, and low serum 25(OH) vitamin D levels are common in patients with congestive heart failure. In a study involving African American patients with left ventricular ejection fraction <35%, vitamin D deficiency ( 30 ng/ml) was associated with decompensated heart failure and prolonged hospital stays. Low vitamin D levels were associated with poor outcomes in patients with end-stage heart failure awaiting heart transplantation. One study showed patients with heart failure who had low baseline levels of vitamin D were almost 3 times more likely to die over the five years of the study. A randomized, double-blind placebo controlled trial of 80 children with congestive heart failure and dilated cardiomyopathy recently published in Pediatric Cardiology showed a high daily dose of vitamin D3 significantly improved heart failure. Ejection fraction went from 37% to 52% in just 12 weeks of high dose vitamin D3 treatment. 5 An even more recent 2013 prospective study of 100 adult patients showed high dose vitamin D significantly improved New York Heart Association classifications (P<.001), ejection fraction (P<0.001), high sensivity C-reactive protein (P<0.001) and Brain-derive neurotrophic factor (P=<0.001). 11 Vitamin D and Arrhythmia: Vitamin D deficiency can cause an irregular heartbeat. Vitamin D levels affect the amount of calcium that our body absorbs. Calcium helps generate electronic impulses and muscle contractions that help regulate our heartbeat. Vitamin D deficiency can lead to calcium deficiency which can cause an irregular heartbeat. In a recent report, the correction of vitamin D deficiency and hypocalcemia resulted in control of incessant ventricular tachycardia and cardiomyopathy. 5 Vitamin D and Left Ventricular Hypertrophy: Considering hypertension associated with low vitamin D levels, left ventricular hypertrophy could also be a consequence. O Connell et al. demonstrated that vitamin D increases myocytes protein levels and cell size, suggesting medical newsletter I as a service to the medical profession I 19

Table 4.1 : Potential Mechanisms Through which Vitamin D Deficiency Affects Disease 5 Pathology Hypertensive vascular disease Peripheral vascular disease Diabetes mellitus Lipid metabolism Coronary artery disease Heart failure Arrhythmia Mechanism of Action* Increased Intracellular calcium leading to decreased renin activity Calcitriol suppression of renin promoter gene Alteration of the sensitivity of vascular smooth muscle cells Increased calcification Immunomodulatory effects by reducing tumor necrosis factor- α, parathyroid hormone & interleukin-10 Decreased insulin receptor expression, leading to peripheral resistance of insulin Effect on intracellular calcium levels leading to decreased insulin secretion Increase peripheral insulin resistance, contributing to high lipid profile Statins may increase vitamin D levels by increasing 7-dehydrocholesterol Increased vessel free radicals lead to oxidation of low density lipoprotein & increased engulfment by macrophages, an early sign of atherosclerosis Indirect effect through risk factor modification Altering endothelial function Increased coronary artery calcification Direct effect on myocardial contractility Regulation of brain natriuretic peptide secretion Reduction of left ventricular hypertrophy with effects on extracellular remodeling Regulation of inflammatory cytokines Secondary hyperparathyroidism, which leads to vasodilatation & positive inotropic stimulation Direct myocardial substrate modification Indirectly via calcium levels & metabolism at a cellular level *Proposed that its deficiency induces cardiac myocytes hypertrophy. Blocking the synthesis phase of the cell cycle is the mechanism by which 1,25(OH)2D3 regulates myocytes proliferation. 12 Vitamin D and Lipid Metabolism: Serum levels of 1,25(OH)2 vitamin D are inversely correlated with very low density lipoprotein and triglyceride levels. Vitamin D deficiency may cause an abnormal lipid profile by increasing peripheral insulin resistance and contributing to metabolic syndrome. 5 A new study published in the journal Cell Chemical Biology found vitamin D may inhibit the activation of a type of protein responsible for lipid production. This protein is crucial for maintaining lipid balance in the body. 3 A recent 5-year study published by the journal Nutrition found low vitamin D status was associated with an increased risk of high lipid levels. The researchers found that those who were vitamin D deficient (<20 ng/ml) experienced a significantly increased risk of developing dyslipidemia compared to higher levels (>30 ng/ml) [RR 1.19 (1.02-1.39)]. Studies have suggested that statin therapy may increase vitamin D levels, a finding that may account for some of the non-lipid pleiotropic actions of statins. 5 Vitamin D and Coronary Artery Disease: Vitamin D has been shown to affect endothelial function and decrease vascular calcification. Calcification of coronary arteries was inversely correlated with vitamin D levels. The initial suggestion of vitamin D as a protective factor came from a study in the United Kingdom showing that mortality from ischemic heart disease was inversely proportional to the hours of sunlight. Larger cross-sectional observations using the National Health and Nutrition 20 I medical newsletter I as a service to the medical profession

Examination Survey (NHANES) databases found that in a sample of 16,603 men and women aged 18 years, those with ischemic heart disease and stroke had a greater frequency of 25(OH) vitamin D deficiency (P< 0.0001). This was confirmed by a more recent analysis involving 8,351 adults in which the prevalence of vitamin D deficiency was 74% in patients with coronary artery disease and heart failure. In the general population, the lowest quartile of 25(OH) vitamin D level was independently associated with all-cause of mortality. Together, the findings of these epidemiologic studies suggest that poor vitamin D status is associated with poor cardiovascular outcomes. 5 Vitamin D and Hyperparathyroidism: Chronic vitamin D deficiency causes secondary hyperparathyroidism, which in turn may mediate many of the detrimental cardio vascular effects. Some studies found that elevated Parathyroid hormone (PTH) levels in elderly individuals was associated with a doubling of mortality during follow-up compared with those with normal PTH levels. An increased PTH level is associated with increases in both blood pressure and myocardial contractility, which eventually lead to hypertrophy, apoptosis, and fibrosis of both the left ventricle and vascular medial smooth muscle. Vitamin D deficiency and/or increased PTH also predispose to calcification of heart valves, mitral annulus, and myocardium, especially in patients with moderate or severe chronic kidney disease. 13 Vitamin D and Peripheral Vascular Disease: Vitamin D levels have been inversely correlated with calf vascular resistance and positively correlated with calf blood flow. Similar associations were identified in the NHANES III study. After multivariate adjustment for demographics, co-morbidities, physical activity level, and laboratory measures, low 25(OH) vitamin D levels were associated with a higher prevalence of peripheral arterial disease. Vitamin D deficiency is also strongly associated with increased thickness of the intima media in carotid arteries. One third of the excess risk for peripheral arterial disease in an African American population was attributed to racial differences in vitamin D status. Similarly, a high prevalence of vitamin D deficiency with secondary hyperparathyroidism was observed in a non-diabetic population with peripheral vascular disease. (5) Vitamin- D & Mortality Vitamin D deficiency was linked to increased risk of death and cardiovascular death in multiple studies. Follow-up of the 3258 participants in the Ludwigshafen Risk and Health (LURIC) study over a median period of 7.7 years showed that patients with severe and moderate vitamin D deficiency (median levels of 25(OH) D of 19.0 and 33.3 nmol/l) had higher incidence of death [HR = 2.08, (1.60 2.70) and HR = 1.53 (1.17 2.01), respectively, and cardiovascular death [HR = 2.22; (1.57 3.13) and HR = 1.82 (1.29 2.58), respectively, when compared to patients with normal levels (median levels of 71.0 nmol/l). Similar results were obtained for patients in the lowest calcitriol quartile. The follow-up of 1739 Framingham Offspring Study participants without prior cardiovascular disease with vitamin D deficiency over a mean of 5.4 years showed an increased risk of and a considerably high cardiovascular event (composite of death, myocardial infarction, stroke and congestive heart failure rate of 6.9%. Lower levels of 25(OH) D of 15 ng/ ml were associated with higher risk of cardiovascular events [HR = 2.04 (1.42 2.940; P< 0.001) compared to the rest of the cohort. Similarly, the University of Utah study showed an increased risk of cardiac events including death (HR = 1.77, P< 0.0001), coronary artery disease (HR = 1.45, P< 0.0001), heart failure (HR = 2.01, P< 0.0001), and stroke (HR = 1.78, P= 0.004) in vitamin D deficient individuals. The Heart and Soul Study followed 946 participants with stable cardiovascular disease in San Francisco, California for a median of eight years and recently reported that levels less than 20 ng/ml remained independently associated with cardiovascular events (HR=1.30 [1.01 1.67]) even after adjustment for socio-demographic factors, season of blood measurement, health behaviors, and co-morbid conditions. 14 Renal Implications of Vitamin D Deficiency Related to Pathology The kidneys are involved in the synthesis of the metabolically active form of vitamin D, since the second hydroxylation, stimulated by the PTH, occurs in the kidneys. diseases are more prevalent in patients with chronic kidney disease compared to patients with normal kidney function, and several links between vitamin D deficiency and poor cardiovascular outcomes were described in patients with renal disease. Vitamin D deficient patients with chronic renal failure had enhanced atherosclerotic lesions with arterial stiffening. 12 Recommended Dose of Vitamin-D It has been estimated that for every 100 IU of vitamin D ingested, the blood level of 25(OH) vitamin D increases only by 1 ng/ml (2.5 nmol/l). For many individuals, the present medical newsletter I as a service to the medical profession I 21