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

急性心力衰竭和扩张型心肌病中心脏和骨骼肌缺铁：病理机制和治疗

• 批准号: 317781716
• 负责人: Professor Dr. Tibor Kempf
• 金额: --
• 依托单位: Klinik für Kardiologie und Angiologie
• 依托单位国家: 德国
• 项目类别: Clinical Research Units
• 财政年份: 2016
• 资助国家: 德国
• 起止时间: 2015-12-31 至 2023-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/317781716?language=en
• 关键词: Cardiac; skeletal; muscle; iron; deficiency

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).

全身性铁缺乏是急性和终末期心力衰竭（HF）的常见合并症。全身性缺铁与运动耐量降低、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的一种重要辅因子，这些蛋白质是氧气运输（血红蛋白）和储存（肌红蛋白）以及细胞能量代谢（例如线粒体电子传递链的组成部分）所需的。我们最近发现，终末期HF的心脏铁浓度比非移植供体心脏低约30%。扩张型心肌病和症状性HF患者的心脏ID（通过左心室（LV）-心肌内膜活检中的电感耦合等离子体发射光谱测量）与疾病严重程度增加相关（DETECT-ID登记研究）。心脏ID与全身铁状态或贫血无关。我们确定了一个失活的中央细胞铁调节（IRP）和/或局部心脏hepcidin-ferroportin相互作用的心脏ID的可能机制。使用基因靶向小鼠心肌细胞选择性ID，我们最近观察到，心脏铁浓度降低30%损害心脏收缩储备，促进心肌梗死后不利的左心室重构。在骨骼肌选择性ID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LV功能障碍（第2天），并在横向主动脉缩窄（TAC）后死亡率增加。我们推测心脏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结局。靶向器官特异性ID可能成为改善这些患者不良预后的治疗选择。在第二个资助期，我们将通过高灵敏度蛋白质组分析（质谱法）研究来自DETECT-ID登记处的LV-肌内膜活检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来识别ID心脏的血浆特征（液体活检）。我们将描述分离的人心肌细胞的功能与扩张型心肌病和不ID。在一个新的小鼠模型的心源性休克，我们将研究心脏缺铁如何影响心脏对急性应激的反应，如果铁治疗是有效的急性情况。我们将研究一种新的小分子药物治疗方法，以防止由于衰竭心脏中铁转运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，我们想探索ID如何导致慢性应激（TAC）后心脏的早期功能损害。