Vitamin D Deficiency and Its Implications on Cardiovascular Disease

Vitamin D is widely known for its important role in bone health. More recent evidence suggests that vitamin D may also play a protective role in many chronic conditions, including cancer, autoimmune, kidney, and cardiovascular diseases (CVDs). Observational studies have associated low vitamin D levels with CVD risk factors, including hypertension, hyperlipidemia, diabetes, and metabolic syndrome, as well as with cardiovascular events, including stroke, myocardial infarction, and congestive heart failure. Much less evidence is available from clinical trials of vitamin D supplementation. It remains to be determined whether the vitamin D–CVD relationship is causal, and what dosing of vitamin D supplementation would be adequate for prevention. Large-scale randomized controlled trials with adequate vitamin D dosing are needed before treatment strategies can be implemented. The purpose of this article is to review the scientific evidence linking vitamin D deficiency with CVD, including explanations of potential biologic mechanisms.     

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.     

Vitamin D and acute myocardial infarction

Vitamin D deficiency is a prevalent condition,cutting across all ethnicities and among all age groups,and occurring in about 30%-50% of the population. Besides vitamin D established role in calcium homeostasis,its deficiency is emerging as a new risk factor for coronary artery disease. Notably,clinical investigations have suggested that there is an association between hypovitaminosis D and acute myocardial infarction(AMI). Not only has it been linked to incident AMI,but also to increased morbidity and mortality in this clinical setting. Moreover,vitamin D deficiency seems to predispose to recurrent adverse cardiovascular events,as it is associated with post-infarction complications and cardiac remodeling in patients with AMI. Several mechanisms underlying the association between vitamin D and AMI risk can be involved. Despite these observational and mechanistic data,interventional trials with supplementation of vitamin D are controversial. In this review,we will discuss the evidence on the association between vitamin D deficiency and AMI,in terms of prevalence and prognostic impact,and the possible mechanisms mediating it. Further research in this direction is warranted and it is likely to open up new avenues for reducing the risk of AMI.     

The prevalence of peripheral arterial disease in high risk subjects and coronary or cerebrovascular patients

Atherosclerosis is a generalized disease with considerable overlap of its coronary, carotid, and peripheral manifestations. As an indicator of multifocal atherosclerosis, peripheral arterial disease (PAD) is emerging as an important aid in risk stratification of patients with coronary artery (CAD) or cerebrovascular disease (CVD). Therefore, the aim of the study was to assess the prevalence of PAD in high risk subjects and its ability to identify coronary or cerebrovascular patients. A total of 952 (63.3% male; age 63.7 +/-10.7 years) patients at high cardiovascular risk (>or=2 risk factors), or with evidence of CAD or CVD were screened for PAD by means of ankle-brachial index (ABI) assessment; 226 patients were at high risk (>or=2 risk factors), 575 had CAD, and 151 had CVD. A total of 42% of patients with CAD and 36% of patients with CVD had PAD. In patients with CAD one half of cases of PAD were asymptomatic. Asymptomatic PAD (pathological ABI) was strongly associated with CAD and CVD, even after adjustment for age, gender, and other risk factors. No significant differences between CAD, PAD, and CVD patients were observed in terms of risk profiles. In conclusion, our findings confirm a high prevalence of both symptomatic and asymptomatic PAD in patients at high cardiovascular risk and its association with both CAD and CVD.     

Serum and dietary vitamin D and cardiovascular disease risk in elderly men: a prospective cohort study

Background and aimRecent research suggests that low vitamin D may be associated with cardiovascular disease (CVD).Methods and resultsWe prospectively evaluated the association of dietary plus supplemental vitamin D intake and serum 25(OH) vitamin D with CVD incidence in the Osteoporotic Fractures in Men (MrOS) Study. Vitamin D intake was measured using a food frequency questionnaire and self-reported supplemental intake in 3094 men (mean age 76.4 years). From a subset of this population, we measured 25(OH) vitamin D in 813 men. Median 25(OH) vitamin D was 25.3 ng/mL. During a median follow-up of 4.4 years, there were 472 CVD cases, including 371 from coronary heart disease (CHD) and 101 from cerebrovascular attack (CVA). In the 25(OH) vitamin D sub-cohort, there were 140 cases of CVD including 115 from CHD and 25 from CVA. We used a Cox proportional hazards regression to calculate hazard ratios (HR) for CVD by vitamin D quartile. After adjusting for age, season, and standard CVD risk factors, the lowest quartile of 25(OH) vitamin D (HR, 1.18; 95% CI, 0.69–2.03) and vitamin D intake (HR, 0.76; 95% CI, 0.56–1.04) were not significantly associated with CVD incidence, compared to the highest vitamin D quartiles. When 25(OH) vitamin D was further analyzed by sufficiency (≥30 ng/mL), insufficiency (≥15–29.9 ng/mL), and deficiency (<15 ng/mL), vitamin D deficiency was not significantly associated with CVD incidence compared to sufficiency (HR 1.34; 95% CI 0.65–2.77).ConclusionVitamin D intake and serum 25(OH) vitamin D were not associated with CVD risk.     

Vitamin D and neurological diseases

We provide an overview of the association between vitamin D and some neurological diseases where the correlation has repeatedly been described. The majority of literature refers to cerebrovascular diseases, followed by multiple sclerosis and cognitive disorders. Vitamin D hypovitaminosis might be associated with the diseases directly or it might contribute to the disease risk factors (typically in cerebrovascular events). Vitamin D hypovitaminosis may also play a role in patients with residual functional involvement due to a neurological disorder (movement disorders, lack of self-sufficiency) and worsen functional status owing to muscle weakness, instability and falls.     

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 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.     

Cardiovascular disease and Alzheimer's disease: common links

Growing evidence supports a strong and likely causal association between cardiovascular disease (CVD), and its risk factors, with incidence of cognitive decline and Alzheimer's disease. Individuals with subclinical CVD are at higher risk for dementia and Alzheimer's. Several cardiovascular risk factors are also risk factors for dementia, including hypertension, high LDL cholesterol, low HDL cholesterol and especially diabetes. Moderate alcohol appears to be protective for both CVD and dementia. In contrast, inflammatory markers predict cardiovascular risk, but not dementia, despite biological plausibility for such a link. The substantial overlap in risk factors points to new avenues for research and prevention.     

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.     

Evidence-Experience Gap and Future Perspective on the Treatment of Peripheral Artery Disease

Peripheral artery disease (PAD) is a systemic disease associated with impaired limb function, poor quality of life, and increased cardiovascular morbidity. Its incidence has been dramatically increasing over years because of the emergence of an aging society and the increase in the number of patients with atherosclerotic risk factors. The clustering of these risk factors promotes disease development, reportedly leading to the differential location of atherosclerotic lesions in lower extremity arteries. The clinical presentations of PAD include intermittent claudication and chronic limb-threatening ischemia (CLTI). PAD is associated with a high risk of mortality and morbidity from both cardiovascular and limb events. The therapeutic goals for patients with PAD include 1) relief from PAD-related limb symptoms, 2) the prevention of new-onset and the development and recurrence of PAD, and 3) the prevention of concomitant adverse events due to coronary artery disease (CAD) and cerebrovascular disease (CVD). There are several types of antithrombotic agents, and their main role in patients with PAD is to reduce systemic events mainly including cardiovascular and lower extremity-related events. Currently, the efficacy of direct oral anticoagulant (DOAC) is also suggested by recent clinical trials. Although endovascular therapy (EVT) has been a first-line revascularization strategy for symptomatic PAD, whether clinical outcomes after EVT are comparable to those after surgical bypass therapy remains inconclusive.     

Relation of borderline peripheral arterial disease to cardiovascular disease risk

Peripheral arterial disease (PAD) is a well-established risk factor for clinical cardiovascular disease (CVD). The impact of a low ankle-brachial index (ABI), higher than the generally recognized 0.9 cutpoint for PAD, on CVD risk is not well characterized. We analyzed data from the 1999 to 2002 National Health and Nutrition Examination Survey (n = 4,895), a nationally representative sample of United States adults, to determine the prevalence of PAD (ABI <0.90), borderline PAD (ABI 0.90 to 0.99), a low-normal ABI (1.00 to 1.09), and a normal ABI (1.10 to 1.29), and the association of these ABI levels with CVD. The prevalence of PAD, borderline PAD, a low-normal ABI, and a normal ABI was 5.0%, 8.7%, 27.8%, and 54.8%, respectively. After age, race/ethnicity, and gender adjustment, the odds ratios of a 10-year coronary heart disease (CHD) risk of >or=20%, CHD, stroke, and CVD were higher at lower ABI levels (each p trend <0.01). After additional adjustment for potential confounders, the odds ratios associated with a low-normal ABI, borderline PAD, and PAD, compared with those with a normal ABI, were 1.24 (95% confidence interval [CI] 0.91 to 1.70), 1.34 (95% CI 0.99 to 1.83), and 1.87 (95% CI 1.29 to 2.73), respectively (p trend <0.001) for CVD and 1.20 (95% CI 0.82 to 1.77), 1.45 (95% CI 0.80 to 2.63), and 2.02 (95% CI 1.20 to 3.39), respectively (p trend = 0.015) for a 10-year risk of CHD of >or=20%. In contrast, a trend was not present for CHD and stroke after multivariate adjustment. In conclusion, subjects with a low-normal ABI or with borderline PAD need screening for CVD risk factors, and interventions may be appropriate to prevent cardiovascular events.     

Vitamin D deficiency: A global perspective

Vitamin D is essential for the maintenance of good health. Its sources can be skin production and diet intake. Most humans depend on sunlight exposure (UVB 290-315 nm) to satisfy their requirements for vitamin D. Solar ultraviolet B photons are absorbed by the skin, leading to transformation of 7-dehydrocholesterol into vitamin D3 (cholecalciferol). Season, latitude, time of day, skin pigmentation, aging, sunscreen use, all influence the cutaneous production of vitamin D3. Vitamin D deficiency not only causes rickets among children but also precipitates and exacerbates osteoporosis among adults and causes the painful bone disease osteomalacia. Vitamin D deficiency has been associated with increased risk for other morbidities such as cardiovascular disease, type 1 and type 2 diabetes mellitus and cancer, especially of the colon and prostate. The prevalence of hypovitaminosis D is considerable even in low latitudes and should be taken into account in the evaluation of postmenopausal and male osteoporosis. Although severe vitamin D deficiency leading to rickets or osteomalacia is rare in Brazil, there is accumulating evidence of the frequent occurrence of subclinical vitamin D deficiency, especially in elderly people.     

Association of vitamin D with cardiometabolic risk factors in rheumatoid arthritis

Objective

Individuals with rheumatoid arthritis (RA) are at a greater risk for cardiovascular disease (CVD). Vitamin D deficiency is a potential risk factor for CVD and metabolic syndrome. Since patients with RA have a high prevalence of vitamin D deficiency, we investigated the association of vitamin D levels with cardiometabolic risk factors in a cohort of RA patients with no prior history of CVD.

Methods

Serum 25‐hydroxyvitamin D (25[OH]D) levels were measured among RA patients enrolled in a cohort study of subclinical CVD. The cross‐sectional associations of 25(OH)D levels with traditional CVD risk factors such as insulin resistance (IR; estimated using the homeostatic model assessment [HOMA]), adipokines, markers of systemic inflammation, and endothelial activation were explored, adjusting for pertinent sociodemographic, lifestyle, and RA characteristics.

Results

Among 179 RA patients, 73 (41%) had a 25(OH)D level <30 ng/ml. Only 23 patients (13%) had a 25(OH)D level ≥45 ng/ml. After adjusting for demographics and body mass index (BMI), 25(OH)D remained significantly associated with high‐density lipoprotein (HDL) cholesterol and inversely associated with HOMA‐IR, fibrinogen, E‐selectin, and soluble intercellular adhesion molecule 1 (sICAM‐1). Significant associations with HDL cholesterol, E‐selectin, and sICAM‐1 were maintained after adjusting for the Disease Activity Score in 28 joints (DAS28) and autoantibody status. These associations were similar between the groups subdivided by sex, ethnicity, BMI, DAS28 level, and autoantibody status.

Conclusion

These data suggest that vitamin D deficiency is common in RA and may be independently associated with several cardiometabolic intermediates in this population.     

The association of serum vitamin D levels with several cardiometabolic risk and aortic pulse wave velocity in elderly persons

Recent studies have shown that vitamin D, an important factor for bone health, can also play a role in reducing the risk for several other diseases. Its deficiency seems to be associated with cardiovascular disease. Arterial stiffness, a well-known predictor of hypertension, morbidity and mortality, increases with advancing age. We evaluated the relationship between serum 25-hydroxyvitamin D levels and arterial pulse wave velocity (aPWV) in an aging population. In randomly selected 876 subjects we studied the association between the vitamin D level and arterial stiffness. We used a Sphygmocor device to measure the aortic pulse velocity (PWV) to evaluate the arterial stiffness. There was a clearly negative trend in aortic PWV among 25-OH-D tertiles. The association between 25-0H-D and aortic PWV remained significant after adjustment for age, gender and other potential confounders; subjects in the first 25-OH-D tertile had adjusted odds ratio 1.9 (1.2–3.0) for having aortic PWV top tertile in multiple regression. Vitamin D levels are inversely associated with increased arterial stiffness in a normative aging population, irrespective of traditional risk factors burden. Further research is needed to clarify the role of vitamin D on arterial stiffness and whether supplemental vitamin D may play a role in prevention of cardiovascular disease or not.     

Vitamin D deficiency in hospitalized patients

Vitamin D deficiency is one of the important risk factors for the development of osteoporosis and fractures. The high prevalence of hypovitaminosis in elderly people in old age pnesioners homes was proved in several investigations, similarly as the favourable effect of vitamin D (800 IU/day) and calcium supplementation on a decline of fracture risk. Risk factors of hypovitaminosis such as an inadequately varied diet; low exposure to sunlight, chronic liver and kidney disease and treatment affecting the metabolism and clearance of vitamin D are very frequent in elderly patients hospitalized in medical departments. In the submitted trial the authors assessed in a group of 38 patients, mean age 70 years, hospitalized at the medical department at the end of the winter period the vitamin D3 serum level. They found a significant reduction of the concentration of 1.25 hydroxyvitamin D3 (p < 0.01) in the investigated group. The results of the trial, along with data in the literature on the high prevalence of hypovitaminosis D in the European population, indicate the need to introduce this simple cheap and safe therapeutic modality into routine practice.     

Peripheral arterial disease and isolated systolic hypertension: the ATTEST study

Hypertension is a risk factor for cardiovascular (CV) diseases, either coronary artery disease (CAD), peripheral artery disease (PAD) or cerebrovascular disease (CVD). The relationships between those different localizations of CV disease and the haemodynamic features of hypertension have been poorly evaluated in the past. In the ATTEST study, a geographically representative panel of 3020 general practitioners recruited 8316 consecutive patients with CV diseases (PAD, CAD or CVD, alone or in association). Blood pressure, which was not an inclusion criterion, was then measured and related to the different forms of CV diseases. Blood pressure classification involved 20% normotensive subjects, 24% subjects with controlled hypertension, 42% subjects with isolated systolic hypertension and 14% subjects with systolic-diastolic hypertension, all hypertensives with or without antihypertensive therapy. From multiple regression analysis, it appeared that subjects with systolic hypertension were characterized by the presence of PAD, with little or no presence of CAD and/or CVD. Subjects with systolic-diastolic hypertension were characterized by the presence of CAD and/or CVD, but without PAD. Although the former was only influenced by age, dyslipidaemia and diabetes mellitus influenced the latter. This study confirms the high prevalence of hypertension (80%) in a large population of patients with CV diseases selected in primary care. Analysis of different features of hypertension revealed that isolated systolic hypertension was the most prevalent form of hypertension in this treated population. Finally, one of the predominant goals of secondary prevention in subjects with PAD should be the treatment of isolated systolic hypertension.     

A narrative review on effects of vitamin D on main risk factors and severity of Non-Alcoholic Fatty Liver Disease

The global prevalence of Non-alcoholic fatty liver disease (NAFLD) is increasing rapidly. Many studies have been conducted on the treatment of NAFLD; nevertheless, there is still no approved drug treatment for this disease. Although the pathogenesis of NAFLD is not fully understood, but inflammation, insulin resistance, oxidative stress, obesity and dyslipidemia are among the main causes. Epidemiological studies have shown that hypovitaminosis D is associated with these factors causing NAFLD. In addition, rate of Vitamin D deficiency has been shown to be directly related to the severity of NAFLD. Accordingly, it is believed that vitamin D may help to treatment of NAFLD by improving the above-mentioned risk factors. The purpose of this review is to survey the recent advances in the field of Vitamin D efficacy on risk factors and the severity of NAFLD based on existing evidence, especially the clinical efficiency of vitamin D supplementation in patients with NAFLD.     

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.