Iron and stable ischemic heart disease - lessons from heart failure

Abstract

Iron is an essential element for cardiomyocyte viability and contractility. Systemic iron deficiency, even without anemia, is reflected by iron deficiency in cardiomyocytes. As in other cells, there is here a complex, local and autonomous regulation of iron metabolism, based on two molecular systems: the hepcidin/ferroportin/transferrin receptor-1 axis; and the iron regulatory proteins-1,2 system. These molecular pathways allow cardiomyocytes to react to changes in serum iron availability. In mice, dietary manipulations of serum iron availability or cardio-specific deletions and mutations of regulatory genes for intracellular iron metabolism have clarified some aspects of the causal relationship between cardiomyocyte iron deficiency and the development of severe heart failure, prevented by intravenous iron treatment even without the occurrence of iron deficiency (sideropenic) anemia. The deleterious effects of iron deficiency and hypoxia on gene expression of the main regulators of intracellular iron and oxygen metabolism and on cardiac function are very similar in heart failure and in chronic stable ischemic heart disease, and conjure towards cardiomyocyte injury. We here hypothesize that in non-anemic patients with stable ischemic heart disease a chronic or acute serum iron deficiency can amplify the chronic activation of the cardiomyocyte hypoxia-inducible factor-1α. As a consequence, cardiac adaptative responses to chronic hypoxia/ischemia are significantly impaired, and cardiac dysfunction exacerbated. We hypothesize that, in such patients, iron replacement through forced iron supplementation may replete cardiomyocyte iron deficiency and improve ischemic heart disease. This hypothesis requires further experimental studies, but also, and already now, specific clinical trials.