Pathophysiological and clinical significance of mineral homeostasis disorders in the development of cardiovascular disease

Abstract

A growing incidence, prevalence, morbidity and mortality from cardiovascular disease dictate an urgent need in identification of its risk factors and their pathogenetic links with coronary artery disease and stroke. Aging of the population is inevitably associated with an increasing prevalence of comorbid conditions. Among them are disorders of mineral homeostasis which, often being neglected, are clearly associated with major adverse cardiovascular events and cardiovascular death. Maintenance of mineral homeostasis in the human body is largely dependent on the formation of calciprotein particles (CPPs) which arise in the blood upon the binding of a mineral chaperone fetuin-A to nascent calcium phosphate crystals, thereby aggregating excessive calcium (Ca2+) and phosphate (PO4 3-), removing them from the bloodstream and preventing extraskeletal calcification. During the circulation, CPPs are internalised by arterial endothelial cells and provoke endothelial dysfunction through endothelial activation, endothelialto-mesenchymal transition and impairment of endothelial mechanotransduction. Animal studies demonstrated that regular intravenous injections of CPPs lead to intimal hyperplasia and adventitial/perivascular inflammation in the absence of any other cardiovascular risk factors, indicating pathophysiological importance of CPPs for cardiovascular disease. Further, a number of clinical studies suggested an association of an augmented serum calcification propensity or elevated CPP count with arterial hypertension, myocardial infarction, chronic brain ischemia, ischemic stroke and cardiovascular death in patients with chronic kidney disease (including those with end-stage renal disease as well as kidney transplant recipients) and individuals with a preserved renal function. Here, we critically discuss the pathophysiological consequences of CPP formation, mechanisms of their pathogenic effects, and potential therapeutic interventions.