ReviewVitamin D and cardiovascular disease: Systematic review and meta-analysis of prospective studies
Introduction
Vitamin D, primarily known for its essential role in bone metabolism, has recently been linked to various diseases including cancer, autoimmune or infectious diseases (Holick, 2007, Maalouf, 2008). Furthermore, cross-sectional and case–control studies have suggested a potential role of 25-hydroxyvitamin D (25-OH-D), the major circulating form of vitamin D, in risk reduction of cardiovascular diseases (CVD) (Hintzpeter et al., 2008, Kendrick et al., 2009, Scragg et al., 1990). Although the underlying biological causes are not fully understood, the association of 25-OH-D with cardiovascular pathology is speculated to be driven by various mechanisms: apart from a potential direct impact on cardiomyocytes and myocardial diseases (Pilz et al., in press), it has been suggested that 25-OH-D indirectly modifies CVD risk (Michos and Melamed, 2008) by its association with cardiovascular risk factors like diabetes (Martins et al., 2007, Mattila et al., 2007), obesity (Aasheim et al., 2008, Martins et al., 2007), hypertension (Forman et al., 2007, Kim et al., in press), smoking (Brot et al., 1999, Hill et al., 2006), or cholesterol level (Auwerx et al., 1992, Scragg et al., 1995).
Although calcitriol (1,25-(OH)2-D) is the active form of vitamin D, in the investigation of associations of vitamin D with incident cardiovascular events, serum-25-OH-D is generally used. Not only is the latter the substrate for 1-alpha-hydroxylase which produces intracellular calcitriol and is expressed in relevant tissues like cardiomyocytes (Pilz et al., in press) and the vessel wall (Somjen et al., 2005), it also is the major form circulating in serum and has been shown to be a better marker of vitamin D status (Holick, 1990, Maalouf, 2008). Longitudinal data on these relationships remain scarce.
Since cardiovascular diseases account for more deaths worldwide than any other disease (Lopez et al., 2006) while at the same time hypovitaminosis D is widespread in many populations (Ginde et al., 2009a, Prentice, 2008) and established risk factors insufficiently explain CVD occurrence (Greenland et al., 2003, Ridker, 1999, Wang et al., 2006), it would be desirable to elucidate possible associations of 25-OH-D with CVD and prognosis in order to explore further potential for CVD prevention. We therefore conducted a systematic review of prospective studies reporting on the association of serum 25-OH-D with cardiovascular disease risk.
Section snippets
Methods
A systematic literature search was performed by the first author (NCG) in the EMBASE (up to 13 November 2009) and Pubmed-Medline (up to 17 November 2009) databases, using the keywords vitamin D, cholecalciferol, calcidiol, calcitriol, 25-hydroxyvitamin D or 25-OH-D, connected by “AND” with the keywords cardiovascular diseases, cardiovascular, cardiovascular risk, cardiovascular system, coronary risk, ischemic heart disease, myocardial infarction, CHD, CAD, coronary heart disease, coronary
Literature search
The database search initially yielded 5019 results of which 695 duplicates were deleted (Fig. 1). From the remaining 4324 publications, 3949 were excluded because they were classified as not relevant to the topic after title and abstract review and another 63 because they were not published in English language. The remaining 312 references were full text reviewed, identifying 122 original articles. Of these, 3 animal studies were excluded. Other reasons for final exclusion were assessment of
Discussion
Five out of nine studies prospectively assessing the association between 25-OH-D and risk of incident CVD or mortality reported a significant increase in risk in subjects with lower 25-OH-D levels. The small number of studies fulfilling the rigorous inclusion criteria of our systematic review highlights the dearth of high-level evidence for the relationship examined.
Some inconsistencies in results were observed among both incidence and mortality studies which might, at least in part, be based
Conclusion
Prospective studies evaluating the prognostic value of 25-OH-D on cardiovascular disease outcomes in the general population or in populations with preexisting cardiovascular disease remain very rare. Overall, the published data seem to be in favor of an inverse association between 25-OH-D and cardiovascular risk. However, given the heterogeneity of eligible studies in terms of study population, outcome and exposure level definitions, there remains an urgent need for additional large-scale
Grant support
This work was supported in part by a grant from the Baden Württemberg Ministry of Research, Science and Arts. The funding source was not involved in any step of the analysis or the preparation or submission of the manuscript.
Conflict of interest statement
The authors declare that there are no conflicts of interest.
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