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New Insights About Vitamin D and Cardiovascular Disease: A Narrative Review

Cora McGreevy, MB, BCh, BAO; and David Williams, MB, BAO, BCh, PhD
[+] Article and Author Information

From Royal College of Surgeons in Ireland, Beaumont Hospital, Dublin, Ireland.


Potential Conflicts of Interest: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M11-1745.

Requests for Single Reprints: Cora McGreevy, MB, BCh, BAO, Royal College of Surgeons in Ireland, Beaumont Hospital, Dublin 9, Ireland; e-mail, coramcgreevy@rcsi.ie.

Current Author Addresses: Drs. McGreevy and Williams: Royal College of Surgeons in Ireland, Beaumont Hospital, Dublin 9, Ireland.

Author Contributions: Conception and design: C. McGreevy, D. Williams.

Analysis and interpretation of the data: D. Williams.

Drafting of the article: C. McGreevy, D. Williams.

Critical revision of the article for important intellectual content: C. McGreevy, D. Williams.

Final approval of the article: C. McGreevy, D. Williams.

Administrative, technical, or logistic support: C. McGreevy.

Collection and assembly of data: C. McGreevy.


Ann Intern Med. 2011;155(12):820-826. doi:10.7326/0003-4819-155-12-201112200-00004
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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.

Figures

Grahic Jump Location
Figure.
Process of vitamin D activation in the body.

UV = ultraviolet.

Grahic Jump Location

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Strong evidence exists for a beneficial role of vitamin D in reducing risk of cardiovascular disease
Posted on December 23, 2011
William B., Grant, Director, Epidemiologist
Sunlight, Nutrition and Health Research Center
Conflict of Interest: None Declared

The recent review by McGreevy and Williams (1) found strong evidence for a beneficial role of vitamin D in reducing risk of cardiovascular disease (CVD) from clinical studies but stated that until confirmed by randomized controlled trials (RCTs), the evidence was insufficient to conclude that vitamin D reduced the risk of CVD. There are several problems with RCTs: they often use too little vitamin D to produce a large increase in serum 25-hydroxyvitamin D [25(OH)D] concentration; other sources of vitamin D are not always controlled; serum 25(OH)D is generally not measured after supplementation, which is a problem since there is not a consistent relation between oral vitamin D intake and serum 25(OH)D change; and many of the participants have sufficiently high serum 25(OH)D concentrations that vitamin D supplementation may not increase serum 25(OH)D sufficiently to produce a significant result.

The review by Pittas et al. [Ref. 42 in (1)] found that five of nine observational studies reported lower risk of CVD incidence or death with higher serum 25(OH)D concentrations. No meta-analysis was conducted of the nine studies. However, another paper reported a meta-analysis of cohort and cross-sectional studies of risk of CVD with a summary odds ratio of 0.67 (95% confidence interval, 0.56, 0.81) for high vs. low 25(OH)D concentration (2). My meta-analysis of CVD relative hazard ratio based on eight studies in (2) plus an additional one found that the hazard ratio dropped rapidly from 7 ng/ml to 15 ng/ml, then more slowly, reaching a plateau around 40 ng/ml (3).

An observational study published after (1) was submitted found vitamin D deficiency (<30 ng/ml) significantly associated with coronary artery disease, myocardial infarction, heart failure, stroke, heart failure as well as subsequent death from these diseases in a review of 41,497 subjects in Utah with at least one 25(OH)D measurement between 2000 and 2009 (4). Another observational study published after (1) reported vitamin D deficiency significantly associated with several CVD diseases and CVD mortality rate (5).

As to the comment in (1) that it is unlikely that a single hormone could play such an important role, one should consider that skin pigmentation has adapted to solar ultraviolet doses in a manner to ensure adequate vitamin D production but reduce the risk of adverse effects. Also, that every cell in the body has vitamin D receptors, and when activated by 1,25-dihydroxyvitamin D, can affect the expression of about 1000 different genes.

References

1. McGreevy C, Williams D. New insights about vitamin d and cardiovascular disease: a narrative review. Ann Intern Med. 2011;155:820-6.

2. Parker J, Hashmi O, Dutton D, Mavrodaris A, Stranges S, Kandala NB, et al. Levels of vitamin D and cardiometabolic disorders: systematic review and meta-analysis. Maturitas. 2010;65:225-36.

3. Grant WB. An estimate of the global reduction in mortality rates through doubling vitamin D levels. Eur J Clin Nutr. 2011;65:1016-26.

4. Anderson JL, May HT, Horne BD, Bair TL, Hall NL, Carlquist JF, et al. Relation of vitamin D deficiency to cardiovascular risk factors, disease status, and incident events in a general healthcare population. Am J Cardiol. 2010;106:963-8.

5. Vacek JL, Vanga SR, Good M, Lai SM, Lakkireddy D, Howard PA. Vitamin D deficiency and supplementation and relation to cardiovascular health. Am J Cardiol. 2011 Nov 7. [Epub ahead of print]

Conflict of Interest:

I receive funding from the UV Foundation (McLean, VA), Bio-Tech-Pharmacal (Fayetteville, AR), the Vitamin D Council (San Luis Obispo, CA), and the Vitamin D Society (Canada).

Regulation of the Metabolic Steps in this Pathway are Fairly Complex
Posted on December 27, 2011
Arthur B., Chausmer, MD, PhD, FACP, FACE, FACN, CNS
Johns Hopkins University School of Medicine, Endocrinology, Diabates, and Metabolism
Conflict of Interest: None Declared

In the December 20th issue of the Annals there were two articles regarding vitamin D. The actual information was about the 25 hydroxycalciferol (25 OHD) intermediate metabolite and there are some other important points to consider when reading and assessing these articles. Among them is to remember that the regulation of the metabolic steps in this pathway are fairly complex involving at least phosphorus, calcium, PTH as well as hepatic and renal functionality. These, and other limitations, must all be considered when assessing any discussion of the vitamin D pathways and intermediates. Since the total body load of any of the D metabolites has yet to be quantitatively assessed, there is no way of knowing if there is a deficiency state or not; what relationship, if any, exists between blood levels and the total body stores; or what the relationship between the active and inactive metabolites might be. These are key points. The other key point to at least be remembered is that no matter how strong a statistical correlation may be, it in no way infers causality.

The popular, and wrong, interpretation of low serum 25 hydroxycholecalciferol (25 OHD) is that this reflects a vitamin D deficiency state. No one has any idea what the actual total body stores of 25 OHD or 1,25 dihydroxycholecalciferol (1,25 OHD) are. Therefore one cannot say the stores of either metabolite are low or anything about the relationship of the 25 OHD to 1,25 OHD, which is the active metabolite. 25 OHD is inactive for all practical purposes and measurements of this metabolite are of questionable physiologic significance. The extrapolations of indirect data on which some of the basic assumptions have been made are, at best, supposition and cannot be considered proof on which clinical decisions should be made.

25 OHD is an intermediate which is the result of 25 hydroxylation of calciferol in the liver. It is no more an index of whole body D status, or even 25 OHD status, than a low serum Na reflects total body Na stores in edema or low

serum K reflects intracellular K stores until there is profound depletion. The total body stores of D can be high, as it is a fat soluble vitamin, and the serum level low if the 25 hydroxylase is relatively inactive. The stores can be low and the circulating 250HD high if the 25 hydroxylase has been stimulated. These are but one set of examples. There are, of course, several other scenarios in which there is a less than acceptable correlation.

While there may be some suggestive evidence of non calcium activity for 25 OHD, it must still be considered physiologically inactive for all practical purposes. There has been no evidence other than suggestive correlations for these, and even those studies are arguable.

These points suggest a critical, and even skeptical, approach to the studies presented before any clinical actions are taken based on these data.

These, of course, represent my own views and not necessarily of any organization with which I am affiliated.

Conflict of Interest:

None declared

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