Vitamin D supplementation in heart failure: case closed?

Vitamin D deficiency is one of the most common nutritional deficiencies, affecting hundreds of millions of people in western societies, but also in Africa, the Middle East, and Asia. Although mostly denoted as a vitamin, vitamin D in fact is a pleiotropic hormone that acts as a transcription factor, with global effects on gene transcription; it has been suggested that up to 3% of the entire humane genome is regulated by vitamin D. Transcriptional activity is regulated by the vitamin D–vitamin D receptor (VDR) complex which, in concert with a complex set of co-repressors and co-activators, switches on or off downstream genes. As a result, vitamin D deficiency has been associated with multiple conditions and diseases, in almost all organ systems. More specifically, a low vitamin D concentration appeared to be associated with a poor prognosis in patients with heart failure. Mechanistic studies have provided potential mechanisms that may explain this relationship: vitamin D directly inhibits renin transcription, and regulates genes and pro-inflammatory cytokines involved in tissue fibrosis. Other, indirect, effects may also define why vitamin D deficiency is associated with increased cardiovascular morbidity and mortality: low vitamin D levels directly increase parathyroid hormone (PTH) levels, inducing deleterious effects on cardiac function and structure. Additionally, vitamin D deficiency in parents has been associated with hypertension in (vitamin D-sufficient) offspring via epigenetic modifications. The effects of vitamin D on the cardiovascular system are thus multifold and strongly suggest that restoration of vitamin D levels may improve cardiac function and outcome. Associative studies, however, cannot prove causality. In order to prove causality, it is essential to embark on interventional studies. In the current issue of the journal, Zittermann and colleagues have examined the effects of long-term vitamin D supplementation on hard cardiovascular outcomes in a moderately large sized randomized placebo controlled trial in patients with heart failure. This trial is important since it shows that vitamin D supplementation does not improve such outcomes, and, more importantly, suggests that safety may potentially be an issue. The study by Zittermann et al. is methodologically sound: it has a relatively large sample size and adequate long-term follow up of 3 years. Therefore, in our opinion, these findings should carry substantial weight as they allow evaluation of hard outcomes such as death and hospitalizations. Vitamin D supplementation boosted vitamin D levels quite readily, and patients on supplementation remained vitamin D sufficient for the entire study period. Patient recruitment, however, was an issue: although the study initially was powered to recruit 934 patients, recruitment had to be stopped after 31 months at a total of 400 patients because too many patients were already using vitamin D supplements, vitamin D levels were >75 nmol/L (which was the cut-off point for inclusion), or patients declined to participate in the study. Besides all-cause mortality, this study also considered mechanical circulatory support (MCS) as an (secondary) outcome parameter, since heart transplantation remains scarce because of lack of donors. Interestingly, it was observed that vitamin D supplementation may be associated with more frequent need for MCS. Although this additional analysis provides potentially important and valuable information, we question the importance of this relatively rare event; EVITA was not powered for this secondary outcome analysis, and the result may very well be a chance finding. The overall numbers of MCS systems were low (28/199 in the vitamin D group vs. 15/201 in the placebo group), with a reported P-value of 0.031. Given the number of endpoints evaluated, we would have corrected for multiple testing, resulting in a P-value exceeding 0.05. We nevertheless agree with the authors that this finding certainly warrants caution; supplementing vitamin D either chronically or in mega dosages, as done in some countries, has (again) not been proven to be efficacious, while safety issues cannot be accepted in this light. Furthermore, a recent intervention trial in the general population also did not provide any