Cardiac and skeletal muscle iron deficiency in acute heart failure and dilated cardiomyopathy: Pathomechanisms and therapy

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Systemic iron deficiency (ID) is a frequent comorbidity in acute and (pre-)terminal heart failure (HF). Systemic iron deficiency is associated with reduced exercise tolerance, increased symptom severity, and higher mortality rates. Iron is an essential cofactor in haeme and iron-sulphur cluster-containing proteins required for oxygen transport (hemoglobin) and storage (myoglobin) as well as cellular energy metabolism (e.g. components of the mitochondrial electron transport chain). We have recently shown that the cardiac iron concentration in end-stage HF is ~30% lower than in non-transplanted donor hearts. Cardiac ID (as measured by inductively-coupled plasma optical emission spectroscopy in left ventricular (LV)-endomyocardial biopsies) in patients with dilated cardiomyopathy and symptomatic HF is associated with increased disease severity (DETECT-ID registry). Cardiac ID was not related to the systemic iron status or anemia. We identified an inactivation of the central cellular iron-regulators (IRPs) and/or a local cardiac hepcidin-ferroportin interaction as possible mechanisms for cardiac ID. Using gene-targeted mice with cardiomyocyte-selective ID, we have recently observed that a 30% decrease in cardiac iron concentration impairs cardiac contractile reserve and promotes adverse left ventricular remodeling after myocardial infarction. In a mouse model with skeletal muscle-selective ID, we observed that these mice develop skeletal muscle atrophy and cachexia. The mice exhibited early LV-dysfunction (day 2) and increased mortality after transverse aortic constriction (TAC). We postulate that the cardiac and skeletal muscle iron concentration affects disease progression and outcome in patients with acute and advanced heart failure. Targeting organ-specific ID could become a therapeutic option to improve the poor prognosis of these patients. In the 2nd funding period we will investigate the regulation of cardiac iron homeostasis in the LV-endomyocardial biopsies from the DETECT-ID registry by high-sensitivity proteome analyses (mass spectrometry). In addition, we aim to identify a plasma signature (liquid biopsy) of the ID heart by proteome analyses. We will characterize the function of isolated human cardiomyocytes from hearts with dilated cardiomyopathy with and without ID. In a new mouse model of cardiogenic shock we will investigate how cardiac iron deficiency affects the cardiac response to acute stress and if iron therapy is effective in the acute situation. We will investigate a novel treatment with a small molecule drug to prevent cardiomyocyte iron loss/deficiency due to an impaired ferroportin degradation in the failing heart. In the skeletal muscle-selective ID mice we want to explore how ID leads to the early functional impairment of the heart upon chronic stress (TAC).