Vitamin D status: to be considered in heart failure patients!

Recent data on the worldwide high prevalence of vitamin D deficiency and identification of vitamin D receptor (VDR) expression in almost all human cells has raised public health interest in vitamin D. Vitamin D is well known as a major regulator of calcium and bone metabolism, and its supplementation is an established treatment for patients suffering from musculoskeletal diseases. Furthermore, it is increasingly recognized that vitamin D and its related mineral metabolism may also play a crucial role in overall and cardiovascular health. –7 In this issue of the European Journal of Heart Failure two prospective studies report that poor vitamin D status is highly prevalent among heart failure patients and indicate an increased risk of mortality. Liu et al. examined 548 heart failure patients and found that after a mean follow-up of 18-month lower baseline 25-hydroxyvitamin D [25(OH)D] plasma concentrations were associated with significantly increased risk of all-cause mortality, even after adjustment for various confounders. Hazard ratio (HR) for mortality per 25 nmol/L (10 ng/mL) decreases in 25(OH)D was 1.10 [95% confidence interval (CI): 1.00–1.22; P 1⁄4 0.049]. In line with this, Schirbeck et al. reported similar results among 148 heart failure outpatients who were followed up for 3.5 years. Compared with patients with higher 25(OH)D levels, the multivariate adjusted HR for all-cause mortality was 1.9 (95% CI: 1.1–3.4) for vitamin-D-deficient patients [25(OH)D , 50 nmol/L (20 ng/mL)]. In line with these two publications, several further studies have shown associations of low 25(OH)D concentrations with heart failure, cardiovascular events including sudden cardiac death and mortality. It should be acknowledged that sunlight (ultraviolet-B)-induced vitamin D production in the skin is the main source of vitamin D. Morbidity-associated limitations in the ability to undertake outdoor activities might therefore underlie the relationship of vitamin D deficiency with cardiovascular diseases and mortality. Many observational studies that support a link between vitamin D deficiency and heart failure or fatal events have, however, considered this possible source of confounding. For clinicians, the burning question is whether vitamin D deficiency is a marker or a player in the context of heart failure and thus associated with increased mortality. Expressions of VDR and key enzymes of vitamin D metabolism in both the heart and the arterial vessels argue for an important role of vitamin D in the cardiovascular system. This is supported by observations in VDR knockout mice that suffer from arterial hypertension and myocardial hypertrophy with increased activity of the renin–angiotensin aldosterone system. Molecular pathways for vitamin-D-induced renin suppression have already been clarified and this is in line with the negative association between 25(OH)D and plasma renin activity observed by Liu et al. In the same work, C-reactive protein was significantly increased in patients with a poor vitamin D status. This may reflect antiinflammatory actions of vitamin D which have been observed in previous studies including a randomized controlled trial (RCT) of heart failure patients. In addition, vitamin D metabolites have been shown to exert various direct effects on cardiomyocytes including anti-hypertrophic actions, regulation of extracellular matrix turnover, and modulation of contractility. This latter effect seems to be mainly driven by regulation of cardiac calcium flux. Deleterious consequences of vitamin D deficiency on the cardiovascular system may also be mediated by parathyroid hormone (PTH). Vitamin D deficiency contributes to low serum calcium levels which in turn stimulate PTH secretion in order to maintain serum calcium within physiological ranges. This PTH elevation is known to occur at 25(OH)D levels below 75 nmol/L (30 ng/mL). It is therefore of concern that almost all of the patients included in the studies by Liu et al. and Schierbeck et al. had 25(OH)D concentrations below this threshold. Importantly, Schierbeck et al. reported that PTH serum concentrations above the median are an independent predictor of mortality. This supports previous studies documenting associations of PTH with