Expanding roles of vitamin D.

The traditional role of vitamin D involves calcium absorption and skeletal health. Two articles published recently in the Journal address two nontraditional roles of vitamin D. Pilz et al. (1) showed that vitamin D deficiency is associated with death from heart failure and sudden cardiac death in 3299 patients referred to coronary angiography in Germany. Circulating levels of 25-hydroxyvitamin D [25(OH)D] were measured at baseline, andtheindividualswerefollowedforupto7.7yr. Atbaseline, lower 25(OH)D level was associated with higher N-terminal pro-B-type natriuretic peptide levels and impaired left ventricular function, but not with angiographic coronary artery disease (CAD). After adjustment for cardiac risk factors, the individuals with low vitamin D levels [ 25 nmol/liter (10 ng/ml)] were about three times more likely to die of heart failure and five times more likely to die of sudden cardiac death, compared with individuals with 25(OH)D levels of at least 75 nmol/liter (30 ng/ml). The risk for the combined endpointofdeathdue toheart failureandsuddencardiacdeathwas higher in patients without CAD than those with CAD, suggesting a closer relationship between vitamin D deficiency and nonischemic diseases than with ischemic heart disease. Nonetheless, other studies suggest that vitamin D deficiency may increase risk of CAD, possibly by increasing calcification of coronary arteries (2). The other study published in the Journal focused on vitamin D and skeletal muscle in 99 postmenarchal 12to 14-yr-old girls in the United Kingdom (3). This study was cross-sectional and examined 25(OH)D concentrations in relation to results from jumping mechanography, a method that measures muscle force and power based on measurements from an individual’s ground reaction forces. The proximal muscles required for jumping (quadriceps, gastrocnemius, soleus) appear to be the ones most affected by vitamin D deficiency, at least in older adults (4). This study found that 25(OH)D level was positively related to muscle power, force, velocity, and jump height, suggesting that muscle contractility may be affected by a girl’s vitamin D status. The findings of both studies, relating vitamin D status to cardiac and skeletal muscle, are provocative and potentially clinically important if confirmed as causal associations in interventional studies. The designs of both studies require us to consider the possibility of reverse causation; that is, the outcomes of the study may have influenced vitamin D status, rather than vice versa. In the study by Pilz et al. (1), whereas the assessment of vitamin D was prospective in relation to the main endpoints of death from cardiac failure or sudden cardiac death, an inverse correlation existed at baseline between 25(OH)D level and measures of heart failure. Thus, it is possible that individuals with some degree of heart failure avoided outdoor activities, which could have limited their sun exposure and hence reduced their vitamin D status. The authors collected data on physical activity, and the reported associations remained after adjustment for physical activity. Although residual confounding from imperfectly measured physical activity might still have occurred, the fact that the associations for death due to heart failure or sudden cardiac death with low 25(OH)D were essentially unchanged after adjustment for physical activity, and remained strong, indicated that limited mobility leading to low 25(OH)D was unlikely to account entirely for the association. In the study of 25(OH)D and skeletal muscle contractility in girls, the potential influence of physical activity was not assessed. Both findings can be placed in the context of a rapidly expanding literature that vitamin D level influences both cardiac and skeletal muscle function. Cardiac myocytes express the vitamin D receptor (VDR) and 1-hydroxylase and 24-hydroxylase, the enzymes required for the conversion of 1,25-dihydroxyvitamin D [1,25(OH)2D] from 25(OH)D and its subsequent breakdown. Treatment with 1,25(OH)2D leads to increased expression and nuclear localization of the VDR, increased expression of myotrophin, and decreased expression of atrial natriuretic peptide, c-myc (5) and human B-type natriuretic peptide (6). The induction of myocyte hypertrophy either in vitro or in vivo leads to an increase in VDR mRNA and protein levels, suggesting that the vitamin D system may act as an antihypertrophic system in cardiac muscle. In addition, animal studies