THE FAILING HEART SHOWS A PATTERN OF IRON ACCUMULATION IN FIBROTIC AREAS

Christina MERTENS1,2,3, Markus A WEIGAND8, Dania FISCHER8, Johannes BACKS3,4,7, Martina U MUCKENTHALER1,2,3,7, Alireza SAADATMAND3,4, Matthias DEWENTER3,4, Ana ANTONOVICI8, Judith SCHENZ8, Andreas WEIGERT5, Andreas MÖBIUS6, Matthias KARCK6, Gregor WARNECKE6

1Department of Pediatric Hematology, Oncology and Immunology, Heidelberg University Hospital, Heidelberg, Germany
2Center for Translational Biomedical Iron Research, Heidelberg, Germany
3German Centre for Cardiovascular Research (DZHK), partner site Heidelberg/Mannheim, Germany
4Institute of Experimental Cardiology, Heidelberg, Germany
5Institute of Biochemistry I, Faculty of Medicine, Goethe-University , Frankfurt am Main, Germany
6Department of Cardiothoracic Surgery, Heidelberg University Hospital, , Heidelberg, Germany
7Molecular Medicine Partnership Unit, EMBL , Heidelberg, Germany
8Department of Anesthesiology, Heidelberg University Hospital, Heidelberg, Germany

Both iron-overload and iron-deficiency negatively impact cardiac health. We aim to understand how changes in cardiac iron-availability affect cardiac iron distribution and cardiac function in steady-state and conditions of heart-failure. As a murine disease model of heart-failure, we apply the O-ring-aortic-banding (ORAB) in twelve-week-old C57BL6/N wildtype mice maintained on diets with low- or high-iron content. As expected, a decreased dietary iron content causes iron-deficiency with a mild anemic phenotype, while dietary iron supplementation led to iron accumulation in the liver, and increased serum ferritin values. Interestingly, cardiac iron levels only showed mild responses to the dietary iron manipulations. Furthermore, we show that independent of the systemic iron content, ORAB mice develop heart-failure as shown by a comparable reduction in ejection-fraction and a similar increase in left-ventricular mass. Our data suggest that alterations in steady-state iron-availability before the ORAB-surgery do not significantly influence heart-failure outcome and that rather iron redistribution in the heart may affect cardiac damage and regeneration. To understand whether iron accumulation in macrophages induces phenotypic changes, we applied multiplex-immunohistochemistry. Indeed, we found in wildtype mice after the ORAB-surgery iron accumulation in the vicinity of fibrotic areas. Importantly, the same pattern of iron accumulation was observed in human cardiac biopsies from patients undergoing open-heart-aortic-valve replacement. Our findings highlight the need for an improved understanding how cardiac iron distribution affects cardiomyocyte function. This knowledge will be fundamental to improve our understanding of the iron metabolism in the heart and aid the development of novel therapeutics maintaining iron homeostasis during heart-failure.