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

全身性铁缺乏(ID)是急性和(前期)终末性心力衰竭(HF)的常见共病。全身性铁缺乏与运动耐力降低、症状严重程度增加和死亡率升高有关。铁是血红素和含铁硫簇的蛋白质中必不可少的辅因子，是氧气运输(血红蛋白)和储存(肌红蛋白)以及细胞能量代谢(例如线粒体电子传输链的组成部分)所必需的。我们最近的研究表明，终末期心力衰竭患者的心脏铁浓度比非移植供者心脏低约30%。扩张型心肌病和症状性心衰患者的心脏ID(通过左心室(LV)-心内膜活检中的电感耦合等离子体光学发射光谱测量)与疾病严重程度的增加相关(DETECT-ID登记)。心脏ID与全身铁状态及贫血无关。我们发现中心细胞铁调节蛋白(IRPS)的失活和/或心脏局部的海普西丁-铁蛋白相互作用是心脏ID的可能机制。最近，我们利用心肌细胞选择性ID的基因靶向小鼠，最近观察到心肌铁浓度降低30%会损害心肌收缩储备并促进心肌梗死后不利的左室重构。在骨骼肌选择性ID的小鼠模型中，我们观察到这些小鼠出现骨骼肌萎缩和恶病质。小鼠表现出早期的左心功能障碍(第2天)和增加的死亡率后横向主动脉缩窄(TAC)。我们推测，心肌和骨骼肌铁浓度影响急性和晚期心力衰竭患者的疾病进展和预后。靶向器官特异性ID可能成为改善这些患者不良预后的一种治疗选择。在第二个资助期，我们将通过高灵敏度蛋白质组分析(质谱学)研究DETECT-ID登记的左室心内膜心肌活检组织中心脏铁稳态的调节。此外，我们的目标是通过蛋白质组分析确定ID心脏的血浆特征(液体活检)。在一种新的心源性休克小鼠模型中，我们将研究心脏缺铁如何影响心脏对急性应激的反应，以及铁疗法在急性情况下是否有效。我们将研究一种新的治疗方法，使用一种小分子药物来预防因衰竭心脏铁蛋白降解受损而导致的心肌细胞铁丢失/缺乏。在骨骼肌选择性ID小鼠中，我们想要探索ID如何导致慢性应激(TAC)时心脏的早期功能损害。

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).