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.     

Prospective Study of Serum 25-Hydroxyvitamin D Level, Cardiovascular Disease Mortality, and All-Cause Mortality in Older U.S. Adults

OBJECTIVES: To evaluate the association between serum 25‐hydroxyvitamin D (25(OH)D) levels and mortality in a representative U.S. sample of older adults. DESIGN: Prospective cohort from the Third National Health and Nutrition Examination Survey (NHANES III) and linked mortality files. SETTING: Noninstitutionalized U.S. civilian population. PARTICIPANTS: Three thousand four hundred eight NHANES III participants aged 65 and older enrolled from 1988 to 1994 and followed for mortality through 2000. MEASUREMENTS: Primary exposure was serum 25(OH)D level at enrollment. Primary and secondary outcomes were all‐cause and cardiovascular disease (CVD) mortality, respectively. RESULTS: During the median 7.3 years of follow‐up, there were 1,493 (44%) deaths, including 767 CVD‐related deaths. Median 25(OH)D level was 66 nmol/L. Adjusting for demographics, season, and cardiovascular risk factors, baseline 25(OH)D levels were inversely associated with all‐cause mortality risk (adjusted hazard ratio (HR)=0.95, 95% confidence interval (CI)=0.92–0.98, per 10 nmol/L 25[OH]D). Compared with subjects with 25(OH)D levels of 100 nmol/L or higher, the adjusted HR for subjects with levels less than 25.0 nmol/L was 1.83 (95% CI=1.14–2.94) and for levels of 25.0 to 49.9 nmol/L was 1.47 (95% CI=1.09–1.97). The association appeared stronger for CVD mortality (adjusted HR=2.36, 95% CI=1.17–4.75, for subjects with 25[OH]D levels<25.0 nmol/L vs those ≥100.0 nmol/L) than for non‐CVD mortality (adjusted HR=1.42, 95% CI=0.73–2.79, for subjects with 25[OH]D levels<25.0 nmol/L vs those ≥100.0 nmol/L). CONCLUSION: In noninstitutionalized older adults, a group at high risk for all‐cause mortality, serum 25(OH)D levels had an independent, inverse association with CVD and all‐cause mortality. Randomized controlled trials of vitamin D supplementation in older adults are warranted to determine whether this association is causal and reversible.     

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.     

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: epidemiology of cardiovascular risks and events

Vitamin D may influence blood pressure through the renin-angiotensin system, parathyroid hormone levels, myocardial function, inflammation, and vascular calcification. In the past several years, a number of high-quality prospective studies have examined 25(OH)vitamin D (25(OH)D) levels in relation to risk of cardiovascular disease (CVD). Studies consistently show that levels of 25(OH)D below 20-25 ng/mL are associated with an increased risk of CVD incidence or mortality. Risk appears especially elevated at 25(OH)D levels below 10 or 15 ng/mL. It is unclear if levels higher that 25 ng/mL provide further benefits for CVD disease. Currently, results from randomized clinical trials are sparse and do not allow a definitive conclusion. Given other potential benefits of vitamin D, and low potential for toxicity, deficient levels below 25-30 ng/mL should be avoided and treated when identified. Further observational and randomized clinical trial data are important to better characterize the optimal range for 25(OH)D.     

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.     

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, sunlight and longevity

Humans acquire vitamin D through skin photosynthesis and digestive intake. Two hydroxylations are needed to obtain the bioactive compound, the first produces 25-hydroxyvitamin D [25(OH)D], and the second 1,25-dihydroxyvitamin D [1,25(OH)2D]. There is no consensus regarding the appropriate cut-off level to define the normal serum 25(OH)D range. Experimental, epidemiological and clinical studies have related low vitamin D status with longevity. Although some results are controversial, low serum 25(OH)D levels have been linked to all-cause, cardiovascular, cancer and infectious related mortality. Throughout life span a significant proportion of human beings display insufficient (20-30 ng/mL) or deficient (<20 ng/mL) serum 25(OH)D levels. Appropriate lifestyle changes, such as regular short exposures to sunlight (15 min a day), and an adequate diet that includes vitamin D rich components, are not always easily accomplished. Studies relating to vitamin D supplementation have methodological limitations or are based on relatively low doses. Therefore, dosages used for vitamin D supplementation should be higher than those traditionally suggested. In this sense, there is an urgent need for prospective controlled studies using high daily vitamin D doses (2,000 IU or higher) including cardiovascular, cancer, infectious and other endpoints. Relationship between vitamin D and health outcomes is not linear, and there are probably various optimal vitamin D levels influencing different endpoints.     

The effect of vitamin D supplementation on cardiovascular risk in patients with prediabetes: A secondary analysis of the D2d study

AimsLow blood 25(OH)D level is associated with increased cardiovascular disease (CVD) risk. Additionally, individuals with prediabetes are at higher risk for CVD than individuals with normoglycemia. We investigated the effects of vitamin D supplementation on CVD outcomes in the vitamin D and type 2 diabetes (D2d) study, a large trial among adults with prediabetes.Methods2423 participants were randomized to 4000 IU/day of vitamin D₃ or placebo and followed for median 3.0 years for new-onset diabetes. In pre-specified secondary analyses, we examined the effect of vitamin D supplementation on composite Major Adverse Cardiovascular Events (MACE); expanded MACE (MACE + revascularization); atherosclerotic CVD (ASCVD) risk score; and individual CVD risk factors (blood pressure, lipids, high-sensitivity C-reactive protein). Cox models compared hazard ratios (HR) between the two groups on MACE and expanded MACE.ResultsMean age was 60 years, 45 % were women, 13 % had history of CVD. Twenty-one participants assigned to vitamin D and 12 participants assigned to placebo met the MACE outcome (HR 1.81, 95%CI 0.89 to 3.69). There were 27 expanded MACE outcomes in each group (HR 1.02, 95%CI, 0.59 to 1.76). There were no significant differences between vitamin D and placebo in individual CVD risk factors, but change in ASCVD risk score favored the vitamin D group (?0.45 %, 95%CI -0.75 to ?0.15).ConclusionsIn people with prediabetes not selected for vitamin D insufficiency and with intermediate CVD risk, vitamin D supplementation did not decrease MACE but had a small favorable effect on ASCVD risk score.Trial registration: D2d ClinicalTrials.gov number, NCT01942694, prospectively registered September 16, 2013.     

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, 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.     

The effect of physical activity on dose-relationship between serum 25-hydroxyvitamin D and cardiovascular health events in older adults

Background and aimsReverse J- or U-shaped associations between serum 25-hydroxyvitamin D (25[OH]D) concentrations and cardiovascular outcomes have been reported, which need clarifications in older adults. Physical activity, correlating with both serum 25[OH]D concentration and cardiovascular health, may have an effect on the dose-relationships.Methods and ResultsAt baseline, 2790 participants aged 65 years and over, free of vitamin D supplementation use, had assays for serum 25[OH]D concentrations and health related characteristics and measurements, were followed up for cardiovascular events and death by up to 7 and 15 years, respectively. The dose–response associations of serum 25[OH]D concentrations with cardiovascular events and mortality risk were examined using Cox regression models.After adjusting for physical activity and other covariates, serum 25[OH]D concentration was non-linearly associated with cardiovascular mortality risk (U-shaped, P = 0.009). According to the Institute of Medicine categories, the HR(95% CI) of cardiovascular mortality risk separately in deficient (<25 nmol/L), inadequate (25 to < 50 nmol/L) and potentially harmful (≥125 nmol/L) level was 1.67 (0.23, 12.01), 1.66 (1.25, 2.20) and 2.21 (0.30, 16.37), respectively. The risk of 25[OH]D inadequacy for cardiovascular mortality was significantly attenuated by increased physical activity, especially leisure activity (P for trend = 0.008 and 0.021, respectively). No significant finding was observed for incident cardiovascular events.ConclusionBoth lower and higher serum 25[OH]D concentrations were associated with risk of cardiovascular mortality in Chinese community-dwelling older adults. Physical activity may attenuate the cardiovascular mortality risk of vitamin D inadequacy, but its role in individuals with higher 25[OH]D concentrations remains unclear.     

Vitamin D and mortality in older men and women

Objective Vitamin D deficiency is common among the elderly and may contribute to cardiovascular disease. The aim of our study was to elucidate whether low serum levels of 25‐hydroxyvitamin D [25(OH)D] are associated with an increased risk of all‐cause and cardiovascular mortality. Design and patients The Hoorn Study is a prospective population‐based study among older men and women. Measurements Fasting serum 25(OH)D was determined in 614 study participants at the follow‐up visit in 2000–2001, the baseline for the present analysis. To account for sex differences and seasonal variations of 25(OH)D levels we formed sex‐specific quartiles, which were calculated from the 25(OH)D values of each season. Results After a mean follow‐up period of 6·2 years, 51 study participants died including 20 deaths due to cardiovascular causes. Unadjusted Cox proportional hazard ratios (HRs; with 95% confidence intervals) for all‐cause and cardiovascular mortality in the first when compared with the upper three 25(OH)D quartiles were 2·24 (1·28–3·92; P = 0·005) and 4·78 (1·95–11·69; P = 0·001), respectively. After adjustment for age, sex, diabetes mellitus, smoking status, arterial hypertension, high‐density lipoprotein‐cholesterol, glomerular filtration rate and waist‐to‐hip ratio, the HRs remained significant for all‐cause [1·97 (1·08–3·58; P = 0·027)] and for cardiovascular mortality [5·38 (2·02–14·34; P = 0·001)]. Conclusions Low 25(OH)D levels are associated with all‐cause mortality and even more pronounced with cardiovascular mortality, but it remains unclear whether vitamin D deficiency is a cause or a consequence of a poor health status. Therefore, intervention studies are warranted to evaluate whether vitamin D supplementation reduces mortality and cardiovascular diseases.     

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.     

Effect of one-anastomosis gastric bypass on cardiovascular risk factors in patients with vitamin D deficiency and morbid obesity: A secondary analysis

Background and aimsBariatric patients often suffer from vitamin D (VD) deficiency, and both, morbid obesity and VD deficiency, are related to an adverse effect on cardiovascular disease (CVD) risk. Therefore, we assessed the change of known CVD risk factors and its associations during the first 12 months following one-anastomosis gastric bypass (OAGB).Methods and resultsIn this secondary analysis, CVD risk factors, medical history and anthropometric data were assessed in fifty VD deficient (25-hydroxy-vitamin D (25(OH)D) <75 nmol/l) patients, recruited for a randomized controlled trial of VD supplementation. Based on previous results regarding bone-mass loss and the association between VD and CVD risk, the study population was divided into patients with 25(OH)D ≥50 nmol/l (adequate VD group; AVD) and into those <50 nmol/l (inadequate VD group; IVD) at 6 and 12 months (T6/12) postoperatively. In the whole cohort, substantial remission rates for hypertension (38%), diabetes (30%), and dyslipidaemia (41%) and a significant reduction in CVD risk factors were observed at T12. Changes of insulin resistance markers were associated with changes of total body fat mass (TBF%), 25(OH)D, and ferritin. Moreover, significant differences in insulin resistance markers between AVD and IVD became evident at T12.ConclusionThese findings show that OAGB leads to a significant reduction in CVD risk factors and amelioration of insulin resistance markers, which might be connected to reduced TBF%, change in 25(OH)D and ferritin levels, as an indicator for subclinical inflammation, and an adequate VD status.Registered at clinicaltrials.gov(Identifier: NCT02092376) and EudraCT (Identifier: 2013-003546-16).     

The Epidemiology of Vitamin D and Cancer Risk

The relation between vitamin D status and cancer risk has been investigated in a number of epidemiologic studies, while data from interventional studies remain scarce. The approaches to estimate vitamin D status have been varied, and include direct measures of circulating 25(OH)vitamin D (25(OH)D) levels, surrogates, or determinants of 25(OH)D, including region of residence, intake, and sun exposure estimates. In terms of cancer sites, the body of evidence is the most extensive for colorectal cancer, for which support comes from studies of 25(OH)D, vitamin D intake, multiple predictors of 25(OH)D, and region of residence in a sunny climate. The evidence for breast cancer is also intriguing, but prospective studies of 25(OH)D are sparse and somewhat conflicting. In one case–control study, retrospectively reported sun exposure during ages 10–19 was most strongly associated with reduced risk of breast cancer. For prostate cancer, the data on circulating 25(OH)D have been equivocal, suggesting no association or a weak inverse association, but studies tend to support a benefit of sun exposure on prostate cancer risk. It is plausible that for prostate cancer, exposure to vitamin D level much longer before the time of diagnosis is the most relevant. Most of the epidemiologic studies to date have examined vitamin D status in relation to risk of cancer, but emerging evidence suggests that vitamin D may be an important factor for cancer progression and mortality, independently of any effects on incidence. Further study is needed to establish the precise role of vitamin D on carcinogenesis, especially in terms of when in the lifespan and on what stages of carcinogenesis vitamin D is relevant, the precise intakes and levels required, the magnitude of the association, and which cancer sites are most affected.     

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 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.     

Relation between serum 25-hydroxyvitamin D and C-reactive protein in asymptomatic adults (from the continuous National Health and Nutrition Examination Survey 2001 to 2006)

The inverse relation between vitamin D supplementation and inflammatory biomarkers among asymptomatic adults is not settled. We hypothesized that the inverse relation is present only at lower levels and disappears at higher serum levels of vitamin D. We examined the relation between 25-hydroxyvitamin D [25(OH)D] and C-reactive protein (CRP) using the continuous National Health and Nutrition Examination Survey data from 2001 to 2006. Linear spline [single knot at median serum levels of 25(OH)D] regression models were used. The median serum 25(OH)D and CRP level was 21 ng/ml (interquartile range 15 to 27) and 0.21 mg/dl (interquartile range 0.08 to 0.5), respectively. On univariate linear regression analysis, CRP decreased [geometric mean CRP change 0.285 mg/dl for each 10-ng/ml change in 25(OH)D, 95% confidence interval [CI] -0.33 to -0.23] as 25(OH)D increased ≤21 ng/ml. However, an increase in 25(OH)D to >21 ng/ml was not associated with any significant decrease [geometric mean CRP change 0.05 mg/dl for each 10-ng/ml change in 25(OH)D, 95% CI -0.11 to 0.005) in CRP. The inverse relation between 25(OH)D below its median and CRP remained significant [geometric mean CRP change 0.11 mg/dl for each 10-ng/ml change in 25(OH)D, 95% CI 0.16 to -0.04] on multivariate linear regression analysis. Additionally, we observed a positive relation between 25(OH)D above its median and CRP [geometric mean CRP change 0.06 mg/dl for each 10-ng/ml change in 25(OH)D, 95% CI 0.02 to 0.11) after adjusting for traditional cardiovascular risk factors. In conclusion, from this cohort of asymptomatic adults, independent of traditional cardiovascular risk factors, we observed a statistically significant inverse relation between 25(OH)D at levels <21 ng/ml and CRP. We found that 25(OH)D at a level ≥21 ng/ml is associated with an increase in serum CRP. It is possible that the role of vitamin D supplementation to reduce inflammation is beneficial only among those with a lower serum 25(OH)D.     

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.