Ibhar Al Mheid, Riyaz S. Patel, Vin Tangpricha, Arshed A. Quyyumi; Vitamin D and cardiovascular disease: While the endocrine functions of vitamin D related to bone metabolism and mineral ion homoeostasis have been extensively studied, vitamin d and cardiovascular disease, robust epidemiological evidence also suggests a close association between vitamin D deficiency and cardiovascular morbidity and mortality.
Experimental studies have demonstrated novel actions of vitamin D metabolites on cardiomyocytes, and endothelial and vascular smooth muscle cells.
Low OH D levels are associated with left ventricular hypertrophy, vascular dysfunction, and renin—angiotensin system activation. Despite a large body of experimental, cross-sectional, and prospective evidence implicating vitamin D deficiency in the pathogenesis of cardiovascular disease, a causal relationship remains to be established.
Moreover, the cardiovascular benefits of normalizing OH D levels in those without renal disease or hyperparathyroidism have not been established, and questions of an epiphenomenon where vitamin D status merely reflects a classic risk burden have been raised.
Randomized trials of vitamin D replacement employing cardiovascular endpoints will provide much needed evidence for determining its role in cardiovascular protection. Identification of essential dietary nutrients that humans cannot synthesize vitamin d and cardiovascular disease in the eighteenth century and led to the discovery of common diseases such as scurvy, beriberi, and rickets that were subsequently successfully treated by altering dietary intake.
While vitamin D is found in foods, its name is a misnomer given that vitamin d and cardiovascular disease skin can synthesize sufficient amounts with adequate exposure to sunlight. Several forms of vitamin D exist; cholecalciferol or vitamin D3 is synthesized in response to ultraviolet UV irradiation of the skin resulting in the photochemical cleavage of 7-dehydrocholesterol, a precursor of cholesterol in the skin.
A second form of vitamin D, ergocalciferol or vitamin D2 is produced by irradiation of ergosterol, a membrane sterol found in the Ergot fungus. Dietary sources of vitamin D include fish oils D3vitamin d and cardiovascular disease, egg yolks D3and mushrooms D2 as well as artificially fortified cereals and dairy products D2 or D3. Vitamin D synthesis and metabolism. Vitamin D is photosynthesized in the skin and is also acquired by dietary intake.
Two hydroxylation steps in the liver and the kidney are required for vitamin D activation, forming 1, dihydroxyvitamin D. UVB, ultraviolet radiation in B-wavelength region — nm. Energy received from the sun at UV wavelengths is most efficient rheumatoid arthritis and the skin producing skin erythaema and hence cleavage of 7-dehydrocholesterol.
The ability to convert 7-dehydrocholesterol into vitamin D in the skin also decreases with age and with increasing skin pigmentation or sunscreen use. Whether it is derived from the diet or vitamin d and cardiovascular disease cutaneously, vitamin D undergoes two successive hydroxylation steps. The first step occurs in the liver by mitochondrial and microsomal enzymes yielding hydroxyvitamin D OH Dthe major circulating form of vitamin D.
This is in contrast to OH D which has a longer half-life weeks vs. Nevertheless, calcitriol levels are measured in hypocalcaemic or hyperparathyroid patients and in those with a decreased renal mass i.
Biologic effects of vitamin D result largely from its binding to the nuclear steroid hormone vitamin D receptor VDRwhich is found in virtually all tissues and is also closely related to the thyroid, retinoid, and peroxisome proliferator-activator receptors. Although all vitamin D metabolites bind the VDR, most biological effects are likely mediated by calcitriol because of its greater receptor affinity.
This in turn binds to specific promoter regions referred to as vitamin D response elements VDREsmodulating the expression of a multitude of genes. Nevertheless, these activities appear to be vitamin d and cardiovascular disease by nuclear VDR activation and include controlling cation traffic across the cell membrane and regulating voltage-gated calcium channels. Mechanisms by which vitamin D deficiency may confer cardiovascular risk. Potential effects of vitamin D metabolism on the cardiovascular system are divergent, but share common initial steps of nuclear and plasma membrane VDR activation.
Classically, clinical effects of vitamin D deficiency are considered to be the result of reduced intestinal absorption of calcium that in turn raises parathyroid hormone levels, and is accompanied by accelerated bone de-mineralization to maintain serum rheumatica and cipro concentration.
Following chronic, severe vitamin D deficiency, frank hypocalcaemia ensues, but patients rarely present with acute symptoms e. Rather, the most common presenting symptoms of vitamin D deficiency include vague, local, or diffuse musculoskeletal aches and pains. Increased prevalence of several metabolic, autoimmune, and malignant disorders has been long noted in geographic locales with increasing latitude from the vitamin d and cardiovascular disease. In ventricular myocytes isolated from neonatal rat hearts, calcitriol regulated the number of cells entering the synthesis phase of the cell cycle, therefore affecting subsequent maturation and differentiation.
These changes eventually lead to ventricular dilation and impaired electromechanical coupling. All these effects are readily corrected by vitamin D analogues. Endothelial cells express VDR and its activation affects the development of immature cells, partly by modulating response elements in the vascular endothelial growth factor VEGF promoter, vitamin d and cardiovascular disease.
Renin expression was shown to be highly deregulated in VDR knockout murine models, despite maintenance of a normal electrolyte balance. Tonic scission of angiotensinogen sharply increased angiotensin II levels and resulted in hypertensive heart disease. Vitamin d and cardiovascular disease abnormalities were observed with defective calcitriol synthesis in a wild-type model, independent of calcium metabolism, which were normalized following calcitriol administration.
Although evidence confirms a robust association between vitamin D status and several cardiovascular disorders, a causal relationship remains to be fully elucidated. Serum OH D levels are also lower in women, in obesity, and in those with decreased physical activity. Key population study findings that relate vitamin D deficiency with cardiovascular disease and its risk factors. The association between vitamin D deficiency and elevated blood pressure perhaps offers the most convincing evidence for the involvement of vitamin D metabolism in the pathogenesis of cardiovascular disease.
For example, andrew lessman vitamin coupon in normotensive and hypertensive subjects reveal an inverse relationship between vitamin D metabolites and plasma renin activity, regardless of baseline renin levels or salt intake. Moreover, infusion of angiotensin II following cholecalciferol therapy resulted in a greater RPF decline and higher aldosterone secretion when compared with pre-treatment infusions.
RAS activation and subsequent synthesis of angiotensin II are known to increase vascular tone and arterial stiffness, which precede and contribute to the development of hypertension and are also strong predictors of overall CVD risk. Furthermore, vitamin d and cardiovascular disease, those with a normalized vitamin D status after 6 vitamin d and cardiovascular disease exhibited significant improvements in vascular function measurements.
Relationship between OH D levels, arterial stiffness, and vascular function. Error bars represent mean and standard error of predicted values adjusted for age, gender, race, body mass index, total cholesterol, low-density lipoprotein, triglycerides, C-reactive protein, and medication use.
In the same way, measures of arterial stiffness inversely correlated with vitamin D status in the Baltimore Longitudinal Study of Aging and in a British multiethnic study, as well as in studies looking specifically at patients with diabetes, rheumatological conditions, peripheral arterial disease, and renal insufficiency.
After multivariable adjustment, those with OH D levels in the lowest quartile had a significantly higher prevalence of hypertension compared with those in the highest quartile, and sufficient levels attenuated the expected age-related increases in blood pressure, vitamin d and cardiovascular disease. The cardiovascular benefits of vitamin D therapy in those with chronic kidney disease and hyperparathyroidism have been long recognized, including blood pressure reduction, improved electrolyte balance, and an overall reduced cardiovascular mortality in haemodialysis patients.
It is less clear if vitamin D therapy in essential hypertension, without overt kidney disease or electrolyte disturbances, will provide similar benefits. Trials reporting these measurements have either shown no blood pressure changes or small reductions in BP; however, these were limited by small and heterogeneous study samples, widely variable dosing strategies, and a short duration of follow-up.
Another complication in determining effects of vitamin D on blood pressure skin cancer and bleeding that exposure to UV light also causes reductions in blood pressure, independent of vitamin D photosynthesis. Significant, immediate hypotensive effects of erythaemal and pre-erythaemal doses of UV irradiation have been demonstrated in both normotensive and hypertensive subjects.
Vitamin D deficiency is associated with disorders of insulin synthesis, secretion, and sensitivity. Furthermore, vitamin D deficiency results in aberrant immune responses that precipitate an inflammatory milieu and subsequent insulin resistance. However, discrepancies in experimental and clinical evidence underscore knowledge gaps in determining the relationship between vitamin D metabolism and glycaemic control.
Further, models heterozygous for VDR show a similar, albeit less severe phenotype. Many retrospective, cross-sectional, case—control, and prospective studies demonstrate a higher incidence and prevalence of type I diabetes mellitus with depressed vitamin D status. Similarly, low serum OH D correlates with insulin resistance, obesity, aberrant phasing of insulin responses to glucose loading, glucose intolerance, fasting hyperglycaemia, and frank type II diabetes mellitus.
Observational, case—control, and prospective evidence strongly suggests that supplementing infants with vitamin D may significantly reduce the future incidence of type I diabetes.
Dosage and timing of therapy appear to modulate this protective effect. While several smaller and non-randomized clinical trials show promising improvements in glycaemic control with vitamin D therapy, a recent Endocrine Society statement emphasized the lack of solid evidence supporting benefits of vitamin D therapy in diabetes mellitus.
Other potential consequences of vitamin D metabolism on human vasculature derive from several lines of experimental investigation and include exacerbation of atherogenesis and acceleration of arterial calcification. Vitamin D deficiency has been implicated as an independent risk factor for incident cardiovascular events and all-cause mortality in several large prospective studies.
After 7 years of follow-up, rates of incident myocardial infarction and coronary disease related death, revascularization, confirmed angina, strokes, and transient vitamin d and cardiovascular disease attacks did not differ between the treatment and placebo groups. Significant favourable changes in lipoprotein composition were noted in treated individuals, but were deemed to be clinically unimportant by study investigators. A recent meta-analysis of prospective studies that assessed the relationship between vitamin D status and CVD risk from torevealed an inverse relationship between levels of OH D and future risk of CVD endpoints, including coronary heart disease, stroke, and total CVD mortality.
The investigators examined over incident events that occurred in over 65 subjects who participated in independent studies. Baseline OH D levels will be measured in the majority of subjects at baseline, allowing for subgroup analysis in deficient subjects, and repeat measurements will be performed in participants on follow-up.
The independent association between vitamin D deficiency and incident cardiovascular disease, while implying a cause—effect relationship, is complicated by the fact that low OH D levels may be a result of cardiovascular disorders rather than the cause of disease, vitamin d and cardiovascular disease.
Ambient sunlight exposure maintains physiological vitamin D levels and ambulatory subjects with normal outdoor exercise activities are likely to have higher OH D levels and lower likelihood of cardiovascular disease, thus raising the concern that the link between CVD and vitamin D is an epiphenomenon. Indeed, vitamin d and cardiovascular disease, we previously demonstrated an independent correlation between vitamin D status and cardiovascular fitness, measured by cardiopulmonary exercise testing in healthy adults.
Additionally, though pharmacological preparations of cholecalciferol or ergocalciferol raise serum OH D levels as effectively as sunlight exposure, other undefined physiological sequelae of either approach may vary.
For example, cutaneous synthesis of cholecalciferol requires the cholesterol precursor 7-dehydrocholesterol and may produce other photoproducts which may affect lipid levels. This is supported by the observed seasonal variation in plasma lipid levels and lipoprotein composition, whereby higher total cholesterol and low-density lipoprotein are observed in the winter, and reach their nadir during the summer, vitamin d and cardiovascular disease.
These cyclical changes remain pronounced despite adjusting for dietary or physical activity changes. While vitamin D deficiency is prevalent, non-institutionalized individuals that maintain moderate sun exposure will probably not benefit from additional supplementation.
This is especially true in areas of lower latitude and in younger individuals who are physically vitamin d and cardiovascular disease, with a normal body mass index and fairer skin complexions for which casual exposure of the face, arms and legs as little as 10—15 min, thrice weekly results in cutaneous production of sufficient amounts of vitamin D. In contrast, excessive intake of pharmacological preparations can cause severe OH D elevation.
However, this condition is exceedingly rare and is usually the result of exposure to mega doses of pharmacological preparation of vitamin D. Although UV irradiation causes direct DNA damage and is now an established skin carcinogen, the incidence of non-melanoma skin cancer heavily depends on skin tone blacks have 1 of 80 the lifetime risk compared with Caucasians.
Even in sunny locations, expanding urbanization and concomitant air pollution, together with increasing concerns of skin malignancies and resultant sun avoidant behaviour all adversely contribute to the high prevalence of vitamin D deficiency.
Supplementation of food materials vitamin D is now an established public health strategy in preventing deficiency worldwide. As most vitamin d and cardiovascular disease generally provide less than the recommended daily allowance of vitamin D, pharmacological supplementation with vitamin D2 or D3 is, therefore, often required, particularly in locations where few foods are fortified with vitamin D or in individuals with increasing risk factors.
Thus, whereas vitamin D sufficiency confers a protective CVD effect compared with deficiency, further increases in OH D by means of pharmacological supplementation may have no effects on CVD. For treatment of documented vitamin D deficiency, a recent practice guideline statement by the The Endocrine Society recommends oral administration of 50 IU per week of either vitamin D2 or D3 for 8 weeks, vitamin d and cardiovascular disease, followed by daily maintenance doses between and IU.
Both loading and maintenance doses may be folds higher to in those with increasing risks for the development or recurrence of vitamin D deficiency.
Concurrent calcium supplementation is a key component of effective therapy, and a preventative strategy should always address underlying causes, if possible. Therefore, careful monitoring of vitamin D status, serum, and urinary calcium is necessary in these patients.
Vitamin D deficiency is a highly prevalent condition and is independently associated with most CVD risk factors and to CVD morbidity and mortality. Despite a large body of experimental, cross-sectional, and prospective evidence that implicate vitamin D deficiency in the pathogenesis of CVD, the causality of this relationship remains to be established.
Most importantly, randomized trials of vitamin D reduced cholesterol and 20 points with CVD endpoint are needed to support a role vitamin d and cardiovascular disease vitamin D therapy in cardiovascular protection. Oxford University Press is a department of the University of Oxford. Sign In or Create an Account.