PTH, vitamin D, and the FGF-23–klotho axis and heart: Going beyond the confines of nephrology

Background: Profound disturbances in mineral metabolism are closely linked to the progression of chronic kidney disease. However, increasing clinical and experimental evidence indicates that alterations in phosphate homoeostasis could have an even stronger impact on the heart. Aim: The aim of this review is to provide the reader with an update of how alterations in mineral metabolism are related to direct and indirect cardiotoxic effects beyond the nephrology setting. Results: Evidence exists that alterations in mineral metabolism that are related to changes in parathyroid hormone (PTH), vitamin D, and the FGF-23–klotho axis have direct pathological consequences for the heart. Alterations in plasma PTH levels are associated with cardiac dysfunction and detrimental cardiac remodelling. Several clinical studies have associated vitamin D deficiency with the prevalence of cardiovascular disease (CV) and its risk factors. Recent evidences support deleterious direct and nonphosphaturic effects of FGF-23 on the heart as hypertrophy development. In contrast, reduced systemic klotho levels are related to CV damage, at least when advanced age is present. In addition, we discuss how these mineral metabolism molecules can counteract each other in some situations, in the context of failed clinical trials on cardiac protection as is the case of vitamin D supplementation. Conclusions: Among all mineral components, an increase in systemic FGF-23 levels is considered to have the greatest CV impact and risk. However, it is quite possible that many intracellular mechanisms mediated by FGF-23, especially those related to cardiomyocyte function, remain to be discovered.