Systematic Vitamin D Supplementation And Monitoring: Improving Outcomes in Heart Failure?

Vitamin D insufficiency is a global burden that also affects heart failure (HF) patients.1, 2 However, in contrast to iron metabolism, vitamin D and biomarkers of the bone and mineral metabolism as well as a potential need for vitamin D supplementation are not mentioned in the recent update of the ESC guidelines for HF.3 Heart failure patients present usually severe vitamin D deficiency illustrated by very low levels of 25-hydroxyvitamin D [25(OH)D], referred to as the best indicator of vitamin D status of an individual.1, 2 The levels of 25(OH)D in HF patients are clearly lower than 20 ng/mL, and only a limited percentage of patients had levels higher than the commonly recommended 30 ng/mL.1, 4 The 25(OH)D is documented as an inactive prohormone in contrast to the biologically active 1,25 dihydroxyvitamin D [1,25(OH)2D] also known as calcitriol. Recent reports have also shown that 1,25(OH)2D levels are markedly decreased in HF patients.2 The available data also suggest that low concentrations of 25(OH)D and 1,25(OH)2D are associated with poor outcomes and are independent predictors of mortality in HF patients.2, 4 The association persisted after adjusting for several potential confounders, including cardiovascular risk factors, and calcium, phosphate, kidney function, and parathyroid hormone (PTH) levels. Different explanations can support the association of low vitamin D and adverse outcomes in HF patients. Vitamin D has pleiotropic effects through its interaction with the vitamin D receptor and regulation of multiple genes.5 The myocardium is considered to be an important target organ for 25(OH)D, 1,25(OH)2D, and PTH, and vitamin D status could influence LV geometry and function.6 Data obtained in a community-based study suggest that higher circulating vitamin D concentrations are associated cross-sectionally with better LV systolic function and smaller LV end-systolic diameters.7 Recent evidence suggests that suboptimal levels of vitamin D may adversely affect the cardiovascular system and could be associated with the activation of several pathways contributing to adverse cardiac remodelling, inflammation, and worsening of HF. First, low vitamin D levels stimulate renin expression, activating the renin–angiotensin–aldosterone system.8 Secondly, decreased vitamin D concentrations are a well-established risk for secondary hyperparathyroidism, a feature also frequently observed in HF patients and related to cardiovascular and all-cause mortality.1 This relationship was independent of established risk factors such as NT-proBNP, estimated glomerular filtration rate, age, and LVEF. Thirdly, vitamin D could participate in a cross-talk with fibroblast growth factor 23 (FGF-23),9 which is a potent phosphaturic hormone regulating bone and mineral metabolism.9 FGF-23 is produced by osteocytes and binds to renal and parathyroid FGF–Klotho receptor heterodimers resulting in phosphate excretion, decreased 1-α-hydroxylation of 25(OH)D, and decreased PTH secretion.9 Markedly elevated levels of FGF-23 were observed in patients with cardiovascular disorders and HF, and have been related to adverse cardiovascular events.9 A recent study also demonstrated in community-dwelling elderly individuals where vitamin D deficiency was highly prevalent, that FGF-23 levels were associated with LV hypertrophy and were an independent predictor of mortality.10 Additionally, vitamin D suppresses the pro-inflammatory state by down-regulating nuclear factor-κB activity and decreasing interleukin (IL)-6, IL-12, interferon-c, and tumour necrosis factor-α production.11 These aspects should be considered in both HF patients with reduced EF and HF patients with preserved EF. Considering the potential deleterious effects of low vitamin D concentrations and adverse outcomes in HF patients, the supplementation of vitamin D could represent a real benefit for HF patients. Several studies have documented that vitamin D supplementation was independently associated with reduced mortality in HF patients, and recently the data from the VINDICATE trial showed that vitamin D3 supplementation had a favourable effect on LVEF and a reversal of LV remodelling.6 However, if a systematic vitamin D supplementation is considered to improve outcomes in HF patients, several practical aspects must be considered: a minimum dose of 4000 IU per day seems to be required to obtain beneficial effects and, as in patients with chronic kidney disease, a monitoring of vitamin D levels will be required to maintain the concentrations in a therapeutic interval between 30 and 50 ng/mL to avoid the consequences of excess vitamin D and therefore calcium levels in more sensitive patients.4 Considering the requirement of a cost-effectiveness analysis and based on the prices of different vitamin D supplements available on the European market, the monthly cost of vitamin D supplementation in HF patients should be less than €15. Nevertheless, additional evidence needs to be generated through robust clinical trials to demonstrate the benefits of vitamin D supplementation on different hard endpoints such as functional capacity, hospitalizations, prognosis, and mortality. In conclusion, the systematic supplementation and monitoring of vitamin D in HF patients could appear as a potential cost-effective way of optimizing outcomes in HF patients. Conflict of interest: none declared. Damien Gruson Pôle de Recherche en Endocrinologie, Diabète et Nutrition, Institut de Recherche Expérimentale et Clinique Cliniques Universitaires St-Luc and Université Catholique de Louvain Brussels Belgium Email: [email protected] Department of Laboratory Medicine Cliniques Universitaires St-Luc and Université Catholique de Louvain Brussels Belgium Anne-Catherine Pouleur Division of Cardiology, Cliniques Universitaires St-Luc and Pôle de Recherche Cardiovasculaire, Institut de Recherche Expérimentale et Clinique Université Catholique de Louvain Brussels Belgium Konstantinos Makris Clinical Biochemistry Department KAT General Hospital Kifissia Greece Christina Chrysohoou First Cardiology Clinic, Hippokration Hospital, School of Medicine National and Kapodistrian University of Athens Athens Greece