Curriculum in Cardiology
Vitamin D deficiency and coronary artery disease: A review of the evidence

https://doi.org/10.1016/j.ahj.2013.11.012Get rights and content

Coronary artery disease remains the leading cause of death in developed countries despite significant progress in primary prevention and treatment strategies. Older patients are at particularly high risk of poor outcomes following acute coronary syndrome and impaired nutrition, including low vitamin D levels, may play a role. The extraskeletal effects of vitamin D, in particular, its role in maintaining a healthy cardiovascular system are receiving increased attention. Longitudinal studies have demonstrated increased cardiovascular mortality and morbidity associated with vitamin D deficiency. Low vitamin D levels have been linked to inflammation, higher coronary artery calcium scores, impaired endothelial function and increased vascular stiffness. However, so far, few randomized controlled trials have investigated the potential benefits of vitamin D supplementation in preventing cardiovascular events, and most available trials have tested low doses of supplementation in relatively low-risk populations. Whether vitamin D supplementation will be beneficial among patients with coronary artery disease, including high risk older patients presenting with acute coronary syndrome, is unknown and warrants further investigation.

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Search strategy

The literature review was conducted on PubMed and Medline using the following search terms: ‘acute coronary syndrome’, ‘percutaneous coronary intervention’, ‘coronary artery disease’, ‘cardiovascular disease’, ‘mortality’, ‘myocardial infarction’, ‘major adverse cardiac events’, ‘vitamin D’, ‘25OHD’, ‘frailty’, ‘older patients’. Studies assessing the relationship between vitamin D and the more general outcome of cardiovascular disease were included. For such studies, we delineated the outcomes

Vitamin D: a prohormone

Vitamin D is a prohormone obtained both endogenously and exogenously. With exposure to ultraviolet B light, 7-dehydrocholesterol in the skin converts to cholecalciferol (vitamin D3) which is also obtained through diet or supplements. 25-hydroxylation of vitamin D occurs in the liver and subsequently, 1-alphahydroxylase converts the 25-hydroxyvitamin D (25-OHD) to 1, 25-dihydroxyvitamin D [1,25(OH)2D] primarily in the kidney. This activated form of vitamin D exerts its biological effects by

Vitamin D deficiency: Definition and Prevalence

Serum 25-OHD levels most accurately reflect vitamin D status. However, there are variations among professional bodies regarding the cut-offs considered to represent insufficient and deficient 25-OHD. The US Endocrine Society guideline defines vitamin D deficiency as 25-OHD levels less than 20 ng/mL (50 nmol/L) and vitamin D insufficiency as 25-OHD levels between 21 and 29 ng/mL (52.5-72.5 nmol/L).8 The serum level of 25-OHD corresponding to the Institute of Medicine (IOM) recommended dietary

Vitamin D, endothelial function and vascular stiffness

Vitamin D deficiency has been associated with impaired endothelial function and vascular stiffness, which are known predictors of long-term cardiovascular morbidity and mortality.12, 13 Furthermore, endothelial dysfunction has been shown to promote atherosclerosis via several processes including vasoconstriction, increased endothelial permeability, platelet aggregation, leukocyte adhesion and cytokine generation.14 In an observational study of 554 healthy subjects with mean age 47 years, 25-OHD

Vitamin D and Platelet Function

In addition to the potential but unproven beneficial effects of vitamin D on vascular function, vitamin D might also be beneficial in the setting of CAD because of its effect on platelets, which are in a highly reactive state especially in the setting of ACS. Preincubation with 1-alpha-25OH-D3 significantly attenuated the increased expression of vascular cell adhesion molecule 1 and membrane type 1 matrix metalloproteinase in endothelial cells by proinflammatory stimulation with

Vitamin D and Inflammation

There is strong evidence to support the role of inflammation in the pathogenesis of CAD.19 Laboratory studies have demonstrated that vitamin D suppresses inflammation via several pathways, including the inhibition of prostaglandin and cyclooxygenase 2 pathways, reduction of matrix metalloproteinase-9 and up-regulation of the anti-inflammatory cytokine interleukin (IL)-10.20 Among 3316 patients (age 62 ± 10 years [mean ± SD]) referred for elective coronary angiography, low 25-OHD levels were

Vitamin D and other cardiovascular effects

Vitamin D, through its active metabolite, 1,25(OH)2D, exerts its biological actions in target tissues including cardiac myocytes, vascular smooth muscle cells and aortic endothelial cells.7 It has been demonstrated that 1,25(OH)2D may stimulate Ca2+-ATPase activity and Ca2+ uptake in cardiac myocytes and vascular smooth muscle cells.7 Vitamin D is also linked to optimal intravascular volume homeostasis and blood pressure control as it decreases renin gene expression and the synthesis of renin.

Vitamin D deficiency and cardiovascular events in population studies

In addition to mechanistic studies supporting the role of vitamin D in modulating CAD risk, many longitudinal studies support the association between low vitamin D levels and increased cardiovascular adverse events. In a retrospective analysis of 10,899 patients followed up in a cardiovascular practice at a large academic medical centre in the United States, 7665 (70.3%) had vitamin D levels of <30 ng/mL (75 nmol/L) defined as vitamin D deficiency in the study.24 Vitamin D deficiency was

Vitamin D deficiency and acute myocardial infarction

A recent cross-sectional population multicentre study demonstrated that vitamin D levels <30 ng/mL (75 nmol/mL) were present in almost all patients with AMI. Of the 239 enrolled patients (mean age 57.6 years), 179 (75%) had low 25-OHD levels (≤20 ng/mL) and 50 (21%) had 25-OHD levels in the range of 20 to <30 ng/mL.33 In a prospective study of 139 patients, vitamin D deficiency defined by 25-OHD levels of <14 ng/mL (35 nmol/L) was present in 72.7% of the patients who presented with AMI.21

Vitamin D and coronary artery disease burden

There is growing evidence that vitamin D deficiency is associated with worse CAD. Among 101 patients undergoing elective coronary angiography in a single center in Israel, low 25-OHD (serum 25-OHD levels <20 ng/mL or 50 nmol/L) was associated with significant CAD after adjusting for sex, age, BMI, ethnicity and smoking status (OR 2.44, 95% CI 1.05-5.68, P = .038).36 In another single center study of 100 Indian patients undergoing coronary angiography, the mean 25-OHD level was 14.8 ± 9.1 ng/mL

Vitamin D and coronary artery calcium

The presence of coronary artery calcium (CAC), a strong marker of cardiovascular risk has also been linked to vitamin D deficiency. In a cross-sectional study from Denmark involving 200 type 2 diabetic patients without a history of CAD but with elevated urinary albumin excretion (>30 mg/24 h), the prevalence of severe vitamin D deficiency (<5 ng/mL or <12.5 nmol/L) was 9.5%. In this cohort, severe vitamin D deficiency (<5 ng/mL or <12.5 nmol/L) compared to levels ≥12.5 nmol/L was associated

Vitamin D and coronary artery restenosis

Vitamin D receptor gene polymorphisms have been demonstrated to be associated with restenosis following PCI. In a study evaluating genetic determinants of restenosis (GENDER) following PCI, polymorphisms from haplotype block 2, 3 and 4 of the VDR gene showed a significant association with clinical restenosis (P = .01, .04, and .02, respectively). The polymorphisms in block 2 showed an additive effect in the haplotype analysis for the risk of clinical restenosis (HR 0.73; 95% CI 0.57-0.94)

Therapeutic vitamin D levels and their role in risk reduction

A recent meta-analysis demonstrated a dose response association between vitamin D and CVD risk over a broad range of 25-OHD levels. Wang et al undertook a meta-analysis of 19 independent prospective studies totaling 65994 participants and 6123 CVD cases to assess 25-OHD and its association with CVD risk.45 The study reaffirmed the association between low vitamin D levels and increased CVD risk but supported a “threshold” effect. Pooled relative risks were 1.52 (95% CI 1.30-1.77) for total CVD

Randomized trials of Vitamin D supplementation and cardiovascular outcomes

Only a few RCTs have so far investigated the impact of vitamin D supplementation on cardiovascular events or surrogate markers of CAD as primary endpoints (Table). Recently, a RCT of vitamin D supplementation on blood pressure in blacks yielded promising results demonstrating that 3 months of oral vitamin D3 supplementation significantly decreased systolic blood pressure (−1.4 mmHg for each additional 1000 IU/day of vitamin D, P = .04).48 There was also a significant reduction of 0.2 mmHg in

Future directions

So far, only a few RCTs have investigated the impact of vitamin D on cardiovascular-specific endpoints. These are limited by the generally low-risk cohorts, small sample sizes and lack of hard clinical endpoints. Furthermore, there are no RCTs that have evaluated the benefit of vitamin D supplementation among older patients presenting with ACS and undergoing PCI. No study has specifically evaluated whether vitamin D administration is associated with improvements in cardiovascular parameters

Conclusion

CAD remains the leading cause of death despite advanced treatment strategies. Vitamin D is often deficient in older patients and among those with AMI. Vitamin D deficiency may contribute to atherosclerosis and thrombus formation through several mechanisms. Vitamin D deficiency has been linked to CAD, increased calcium score, increased arterial stiffness and endothelial dysfunction in the conductance and resistance blood vessels irrespective of traditional risk factors. Whether vitamin D

Disclosures

This work was supported by the National Institute for Health Research (NIHR) Newcastle Biomedical Research Centre based at Newcastle-upon-Tyne Hospitals National Health Service (NHS) Foundation Trust and Newcastle University. The authors are solely responsible for the design, drafting and editing of the paper and its final contents. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health.

Conflict of interest: None of the authors

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