Future directions in vitamin D and cardiovascular research

AimsEvidence is accumulating that vitamin D status may influence the risk of cardiovascular disease (CVD). Final confirmation for a causal relationship between vitamin D and CVD is however still lacking. The present viewpoint article outlines several future research directions to close this gap.Data synthesisFuture directions include the need of performing large randomised controlled supplementation trials with vitamin D in specific risk groups. In addition, large register sets of data on vitamin D supplementation can be used, provided that adequate statistical methods such as propensity score modelled analysis are applied. To better understand vitamin D-mediated effects on CVD risk, the routine measurement of circulating levels of the hormonal vitamin D form, 1,25-dihydroxyvitamin D, is also necessary, in addition to the determination of its precursor 25-hydroxyvitamin D. Further, genetic association studies may help in clarifying the contribution of vitamin D to the development of CVD. Finally, the interrelationship of vitamin D with physical activity should be considered when studying CVD risk.ConclusionsOverall, it can be expected that the next 10–15 years will provide an increased clarity concerning the role of vitamin D in CVD.     

Hypovitaminosis D and peripheral arterial disease: Emerging link beyond cardiovascular risk factors

Vitamin D has received increasing interest for its beneficial effect on health. Beyond its conventional role in bone metabolism, emerging evidence suggests a possible link between low vitamin D levels and cardiovascular disease (CVD), including peripheral arterial disease (PAD), and cardiovascular risk factors. Vitamin D interacts either directly with the vascular tree or indirectly through its association with cardiovascular risk factors, but the exact mechanism remains controversial. This review outlines the association between hypovitaminosis D and PAD. Both entities are quite prevalent in the general population and, therefore, their potential association might have important clinical implications. Whether vitamin D deficiency represents a novel risk factor for PAD/CVD, and whether vitamin D supplementation would reduce the burden of CVD still remains to be answered. Until then, vitamin D intake is not recommended for PAD/CVD prevention. Outdoor physical activity, coupled with adequate but safe sun exposure, is a healthy lifestyle practice suggested for the prevention of both PAD and hypovitaminosis D.     

Vitamin D, cardiovascular disease and mortality

A poor vitamin D status, i.e. low serum levels of 25-hydroxyvitamin D [25(OH)D], is common in the general population. This finding is of concern not only because of the classic vitamin D effects on musculoskeletal outcomes, but also because expression of the vitamin D receptor (VDR) and vitamin D metabolizing enzymes in the heart and blood vessels suggests a role of vitamin D in the cardiovascular system. VDR-knockout mice suffer from cardiovascular disease (CVD), and various experimental studies suggest cardiovascular protection by vitamin D, including antiatherosclerotic, anti-inflammatory and direct cardio-protective actions, beneficial effects on classic cardiovascular risk factors as well as suppression of parathyroid hormone (PTH) levels. In epidemiological studies, low levels of 25(OH)D are associated with increased risk of CVD and mortality. Data from randomized controlled trials (RCTs) are sparse and have partially, but not consistently, shown some beneficial effects of vitamin D supplementation on cardiovascular risk factors (e.g. arterial hypertension). We have insufficient data on vitamin D effects on cardiovascular events, but meta-analyses of RCTs indicate that vitamin D may modestly reduce all-cause mortality. Despite accumulating data suggesting that a sufficient vitamin D status may protect against CVD, we still must wait for results of large-scale RCTs before raising general recommendations for vitamin D in the prevention and treatment of CVD. In current clinical practice, the overall risks and costs of vitamin D supplementation should be weighed against the potential adverse consequences of untreated vitamin D deficiency.     

Vitamin D, thrombosis, and hemostasis: more than skin deep

Vitamin D(3) deficiency is a highly prevalent condition worldwide. Clinically, vitamin D(3) has a key role in calcium homeostasis and bone mineralization and has recently been implicated in the pathogenesis and/or progression of several acute and chronic illnesses, including cardiovascular disease (CVD). Accumulating evidence from observational, prospective studies suggests that low levels of serum 25-hydroxyvitamin D(3) are independently associated with an increased risk of CVD events and death. The molecular mechanisms of this association remain incompletely understood. A variety of biologically plausible mechanisms may mediate a cardiovascular role for the active metabolite of vitamin D(3). 1-α,25-dihydroxyvitamin D(3) regulates the renin-angiotensin system, suppresses proliferation of vascular cell smooth muscle, improves insulin resistance and endothelial cell-dependent vasodilation, inhibits myocardial cell hypertrophy, exerts anticoagulant and antifibrotic activity, and modulates macrophage activity and cytokine generation. Overall, the high prevalence of vitamin D(3) deficiency and the plausible biological mechanisms linking this to CVD risk suggest that the treatment of vitamin D(3) deficiency to prevent CVD is a promising field to explore. Large placebo-controlled randomized clinical trials are urgently needed to determine whether vitamin D supplementation could have any potential benefit in reducing future CVD events and mortality risk.     

Vitamin D and Cardiovascular Disease: Is There Evidence to Support the Bandwagon?

In the last 3?years, more evidence accumulated that vitamin D (vitD)deficiency associates with cardiovascular disease (CVD) and risk factors. The association with higher cardiovascular (CV) mortality was stronger than with nonfatal CVD events. A higher incidence of type 2 diabetes was also shown. Many factors related to lifestyle (physical activity in particular) influence both vitD levels and CVD, and may contribute to explain these observational data. Whether the association between vitD and CVD is causal can only be established through randomized controlled trials (RCTs), and to date the results of the randomized trials, which were not designed for investigating CV outcomes, do not support the association data. Answers on the effects of vitD supplementation on primary and secondary prevention of CV may be found in the specifically designed ongoing RCTs. In the mean time, low vitamin D levels should be regarded as a marker of unhealthy lifestyle, requiring a more aggressive attempt at modifying individual lifestyle.     

Vitamin D and Cardiovascular Disease

OPINION STATEMENT: Vitamin D has received widespread attention for its potential role in preventing cardiovascular disease (CVD) and type 2 diabetes mellitus. Several epidemiological studies have suggested that individuals with low blood levels of vitamin D have increased risks of heart disease, stroke, hypertension, and diabetes. Yet, the revised 2011 Institute of Medicine report for intake of calcium and vitamin D, which was guided by skeletal health alone, concluded that the evidence that vitamin D prevents CVD, diabetes, or other cardiometabolic outcomes was inconsistent and inconclusive and did not meet criteria for establishing a cause and effect relationship [1?, 2]. This finding was consistent with an earlier systematic review conducted by the Agency for Healthcare Research and Quality (AHRQ) in 2009 [3?]. Ongoing clinical trials seek to address the effects of vitamin D supplementation on CVD and other nonskeletal outcomes.     

Can vitamin D deficiency cause diabetes and cardiovascular diseases? Present evidence and future perspectives

Several studies have shown that vitamin D may play a role in many biochemical mechanisms in addition to bone and calcium metabolism. Recently, vitamin D has sparked widespread interest because of its involvement in the homeostasis of the cardiovascular system. Hypovitaminosis D has been associated with obesity, related to trapping in adipose tissue due to its lipophilic structure. In addition, vitamin D deficiency is associated with increased risk of cardiovascular disease (CVD) and this may be due to the relationship between low vitamin D levels and obesity, diabetes mellitus, dyslipidaemia, endothelial dysfunction and hypertension. However, although vitamin D has been identified as a potentially important marker of CVD, the mechanisms through which it might modulate cardiovascular risk are not fully understood. Given this background, in this work we summarise clinical retrospective and prospective observational studies linking vitamin D levels with cardio-metabolic risk factors and vascular outcome. Moreover, we review various randomised controlled trials (RCTs) investigating the effects of vitamin D supplementation on surrogate markers of cardiovascular risk. Considering the high prevalence of hypovitaminosis D among patients with high cardiovascular risk, vitamin D replacement therapy in this population may be warranted; however, further RCTs are urgently needed to establish when to begin vitamin D therapy, as well as to determine the dose and route and duration of administration.     

Role of vitamin D deficiency in cardiovascular disease

Vitamin D is a fat-soluble secosteroid produced in the skin as a result of sunlight exposure, and its circulating levels are reduced in a wide variety of chronic illnesses and obesity. Observational studies clearly demonstrate a higher incidence of cardiovascular events in individuals with low circulating 25-hydroxyvitamin D [25(OH)D]. This relationship can potentially be explained by confounding, because individuals with low 25(OH)D are generally older, frailer, heavier, and have more comorbidities and higher estimated cardiovascular risk than individuals with higher 25(OH)D. The vitamin D receptor appears to be widely distributed, including in cardiovascular tissue, although this has recently been contested. Despite these epidemiological and laboratory findings, meta-analyses of clinical trials have not shown evidence of beneficial effects of vitamin D supplementation on cardiovascular endpoints. Trials are underway to assess these possibilities further. At present, there is insufficient evidence to support vitamin D supplementation for improving cardiovascular outcomes.     

Who should receive calcium and vitamin D supplementation?

Combined calcium and vitamin D supplementation is recommended in the prevention and treatment of osteoporosis. Until recently, supplementation was perceived as harmless without adverse effects. However, recent meta-analyses have provided evidence suggesting that calcium supplements, whether or not in combination with vitamin D, may be associated with cardiovascular risks. Although this finding constitutes a safety signal that has to be taken seriously, these data have to be interpreted with some caution. Current data do not allow definite conclusions to be drawn, but require further independent confirmation, since in numerous large studies, combined calcium and vitamin D supplementation did not increase cardiovascular events, even in the most frail and elderly populations. Nevertheless, it seems appropriate to correct calcium deficiency preferably by enhancing dietary intake and to target supplementation on individuals at high risk of fracture or in whom calcium and vitamin D deficiency is highly prevalent. Other trials have shown an increased risk of falls and fractures with annual oral administration of high dose of vitamin D. Therefore, supplementation with more frequent, lower doses is preferred. Yet, the optimal dosing schedule is unknown and needs further study. In order to correct age-associated secondary hyperparathyroidism and to prevent osteoporotic fractures, a daily dose of 1,000-1,200?mg calcium and 800?IU vitamin D is recommended in elderly or institutionalised people, patients with established osteoporosis and individuals on glucocorticoids.     

Vitamin D in the aetiology and management of polycystic ovary syndrome

Vitamin D deficiency is common in women with polycystic ovary syndrome (PCOS), with the 67–85% of women with PCOS having serum concentrations of 25‐hydroxy vitamin D (25OHD) <20 ng/ml. Vitamin D deficiency may exacerbate symptoms of PCOS, with observational studies showing lower 25OHD levels were associated with insulin resistance, ovulatory and menstrual irregularities, lower pregnancy success, hirsutism, hyperandrogenism, obesity and elevated cardiovascular disease risk factors. There is some, but limited, evidence for beneficial effects of vitamin D supplementation on menstrual dysfunction and insulin resistance in women with PCOS. Vitamin D deficiency may play a role in exacerbating PCOS, and there may be a place for vitamin D supplementation in the management of this syndrome, but current evidence is limited and additional randomized controlled trials are required to confirm the potential benefits of vitamin D supplementation in this population.     

Vitamin D and cardiovascular disease will it live up to its hype?

Substantial evidence suggests that a large portion of the population have suboptimal levels of vitamin D, which may adversely affect the cardiovascular (CV) system, including increasing levels of parathyroid hormone, activating the renin-angiotensin-aldosterone system, and increasing insulin resistance, thus leading to hypertension and left ventricular hypertrophy, metabolic syndrome/diabetes mellitus, systemic inflammation, and increased risk of atherosclerosis and CV disease events. We review the evidence that vitamin D deficiency is associated with incident CV disease events, as well as evidence that vitamin D supplementation is associated with reduction in CV diseases. Although the current evidence has created substantial hype, randomized controlled trials are needed to determine whether routine vitamin D assessment and supplementation will improve CV outcomes.     

Circulating vitamin C and the risk of cardiovascular diseases: A Mendelian randomization study

Background and aimsThe impact of vitamin C supplementation on the risk of cardiovascular diseases (CVDs) remains uncertain with inconsistent evidence obtained from observational studies and randomized clinical trials (RCTs). We aimed to assess possible causal associations of vitamin C with major CVD events as well as their risk factors using Mendelian randomization (MR) design.Methods and resultsNine genetic variants associated with vitamin C at genome-wide significance (p < 5 × 10^?8) were used as instrumental variables to predict plasma vitamin C levels. The primary outcomes were coronary artery disease (Ncase = 122,733 and Ncontrol = 424,528), atrial fibrillation (Ncase = 60,620 and Ncontrol = 970,216), heart failure (Ncase = 47,309 and Ncontrol = 930,014), and ischemic stroke (Ncase = 40,585 and Ncontrol = 406,111). Several CVD risk factors were also evaluated in secondary analyses. Two-sample MR analyses were performed using the inverse variance weighted method, with several sensitivity analyses. Genetically determined higher levels of plasma vitamin C were not significantly associated with any of the four examined CVD events. Likewise, there is no convincing evidence for the associations between genetically determined vitamin C and CVD risk factors, including higher blood lipids, higher blood pressure, and abnormal body composition. Sensitivity analyses using different analytical approaches yielded consistent results. Additionally, MR assumptions did not seem to be violated.ConclusionThis MR study does not support a causal protective role to circulate vitamin C levels on various types of CVD events. In combination with previous RCT results, our findings suggest that vitamin C supplementation to increase circulating vitamin C levels may not help in CVD prevention.     

New insights about vitamin D and cardiovascular disease: a narrative review

The worsening worldwide trend toward nutritional insufficiency and the emerging knowledge of the nonhormonal actions of vitamin D and its metabolites have increased interest in the synthesis, metabolism, and action of vitamin D. Vitamin D deficiency has been linked with hypertension, myocardial infarction, and stroke, as well as other cardiovascular-related diseases, such as diabetes, congestive heart failure, peripheral vascular disease, atherosclerosis, and endothelial dysfunction. This review discusses the physiology and definition of vitamin D deficiency, evaluates the worldwide prevalence of vitamin D deficiency, and discusses recent evidence for the association between hypovitaminosis D and cardiovascular disease. Few randomized, controlled trials have evaluated the effect of vitamin D replacement on cardiovascular outcomes, and the results have been inconclusive or contradictory. Carefully designed randomized, controlled trials are essential to evaluate the role of vitamin D supplementation in reducing cardiovascular disease.     

Vitamin supplement use in a low-risk population of US male physicians and subsequent cardiovascular mortality

BACKGROUND: Although basic research suggests that vitamins may have an important role in the prevention of cardiovascular diseases (CVD), the data from cohort studies and clinical trials are inconclusive. METHODS: This prospective cohort study was conducted among 83 639 male physicians residing in the United States who had no history of CVD or cancer. At baseline, data on use of vitamin E, ascorbic acid (vitamin C), and multivitamin supplements were provided by a self-administered questionnaire. Mortality from CVD and coronary heart disease (CHD) was assessed by death certificate review. RESULTS: Use of supplements was reported by 29% of the participants. During a mean follow-up of 5.5 years, 1037 CVD deaths occurred, including 608 CHD deaths. After adjustment for several cardiovascular risk factors, supplement use was not significantly associated with total CVD or CHD mortality. For vitamin E use, the relative risks (RRs) were 0.92 (95% confidence interval [CI], 0.70-1.21) for total CVD mortality and 0.88 (95% CI, 0.61-1.27) for CHD mortality; for use of vitamin C, the RRs were 0.88 (95% CI, 0.70-1.12) for total CVD mortality and 0.86 (95% CI, 0.63-1.18) for CHD mortality; and for use of multivitamin supplements, the RRs were 1.07 (95% CI, 0.91-1.25) for total CVD mortality and 1.02 (95% CI, 0.83-1.25) for CHD mortality. CONCLUSIONS: In this large cohort of apparently healthy US male physicians, self-selected supplementation with vitamin E, vitamin C, or multivitamins was not associated with a significant decrease in total CVD or CHD mortality. Data from ongoing large randomized trials will be necessary to definitely establish small potential benefits of vitamin supplements on subsequent cardiovascular risk.     

Relationship between vitamin D deficiency and cardiovascular disease

Epidemiological studies have found that low 25-hydroxyvitamin D levels may be associated with coronary risk factors and adverse cardiovascular outcomes.Additionally,vitamin D deficiency causes an increase in parathyroid hormone,which increases insulin resistance and is associated with diabetes,hypertension,inflammation,and increased cardiovascular risk.In this review,we analyze the association between vitamin D supplementation and the reduction in cardiovascular disease.The role of vitamin D deficiency in cardiovascular morbidity and mortality is still controversial,and larger scale,randomized placebo controlled trials are needed to investigate whether oral vitamin D supplementation can reduce cardiovascular risk.Given the low cost,safety,and demonstrated benefit of higher 25-hydroxyvitamin D levels,vitamin D supplementation should become a public health priority for combating common and costly chronic cardiovascular diseases.     

Vitamin D,Calcium Supplements,and Implications for Cardiovascular Health: JACC Focus Seminar

Vitamin D and calcium supplements are commonly used, often together, to optimize bone health. Multiple observational studies have linked low serum 25-hydroxyvitamin D concentrations with increased cardiovascular risk. However, subsequent randomized controlled trials (RCTs) failed to demonstrate cardiovascular benefit with vitamin D supplementation. Although vitamin D supplements do not appear to be harmful for cardiovascular health, the lack of benefit in RCTs should discourage their use for this purpose, favoring optimizing vitamin D status through healthy lifestyles such as specific foods and modest sunlight exposure. Furthermore, some (but not all) observational and RCT studies of calcium supplementation have suggested potential for cardiovascular harm. Therefore, calcium supplementation should be used cautiously, striving for recommended intake of calcium predominantly from food sources. In this review, the authors examine the currently available evidence investigating whether vitamin D and calcium supplements are helpful, harmful, or neutral for cardiovascular health.     

Vitamin D in Heart Failure

Evidence linking vitamin D to cardiovascular (CV) health has accumulated in recent years: numerous epidemiologic studies report deficiency as a significant CV risk factor, and rodent models suggest that active vitamin D can modulate critical remodeling processes, including cardiac hypertrophy and extracellular matrix remodeling. The presence of vitamin D signaling machinery within the human heart implies a direct role for this hormone in cardiac physiology and may explain associations between vitamin D status and CV outcomes. Heart failure (HF) represents a growing social and economic burden worldwide. Myocardial remodeling is central to HF development, and in the context of emerging evidence supporting mechanistic involvement of vitamin D, this review provides critical appraisal of scientific literature related to the role of vitamin D in CV disease, including data from epidemiologic and supplementation studies, as well as novel findings from animal models and in vitro work. Although associative data linking vitamin D and CV outcomes and evidence supporting a role for vitamin D in relevant pathogenic processes are both substantial, there are limited mechanistic data to indicate vitamin D supplementation as a viable therapeutic adjunct for the prevention of HF development following myocardial injury.     

The Role of Calcium in the Prevention of Cardiovascular Disease—A Review of Observational Studies and Randomized Clinical Trials

Calcium is a mineral that is important for bone health and has also been suggested to play a role in the prevention of cardiovascular disease (CVD). Lately, the potential effects of both inadequate and excessive calcium intake have received growing attention. In this review, we summarize the evidence from experimental, epidemiologic, and clinical studies investigating the role of calcium intake, either from the diet or from supplements, as well as blood concentrations, in relation to the risk of CVD in adults. In vitro and in vivo laboratory studies suggest that calcium may be involved in CVD development through multiple pathways, including blood cholesterol, insulin secretion and sensitivity, vasodilation, inflammatory profile, thrombosis, obesity, and vascular calcification. Several prospective epidemiologic studies have examined how dietary or supplemental calcium intake is associated with CVD incidence or mortality in middle-aged and older adults, and the results are inconsistent. Prospective studies investigating blood concentrations of calcium have also reported mixed results. However, changes in blood calcium concentrations may reflect a disturbed calcium phosphate balance, which is associated with increased risk of CVD. To date there is no randomized clinical trial that has been designed specifically to test the effect of calcium supplementation on the risk of CVD as the primary end point. Existing trials have performed secondary analyses, and most of them have been conducted among postmenopausal women. These trials suggest that calcium supplementation has no effect on CVD development; however, they do not allow a definitive conclusion to be drawn. The average daily intake of calcium is low in many populations; however, the evidence for a potential role of dietary or supplemental calcium in the prevention of CVD remains insufficient and inconclusive. Only large-scale randomized trials designed to investigate the effects of calcium supplementation on CVD events as the primary end point, as well as short-term trials investigating the effect on coronary biomarkers, can provide a definitive answer.     

Vitamin D and cardiometabolic disorders: a review of current evidence,genetic determinants and pathomechanisms

Vitamin D deficiency has been implicated in the pathophysiology of cardiometabolic disorders including obesity, type 2 diabetes mellitus, cardiovascular diseases and polycystic ovary syndrome. Despite a large number of experimental and observational studies supporting a role for vitamin D in these pathologies, randomized controlled trials have reported little to no effect of vitamin D supplementation in the prevention or treatment of these disorders, although some results remain ambiguous. Polymorphisms in genes related to vitamin D metabolism, particularly in the vitamin D receptor and binding protein and the metabolizing enzyme 1‐α‐hydroxylase, have emerged as potential contributors to these divergent results. It is now becoming increasingly recognized that the effects and potential benefits of vitamin D supplementation may vary by several factors including vitamin D deficiency status, ethnicity and/or the presence of genetic variants, which affect individual responses to supplementation. However, these factors have seldom been explored in the available literature. Future trials should consider inter‐individual differences and, in particular, should aim to clarify whether certain subgroups of individuals may benefit from vitamin D supplementation in the context of cardiometabolic health.