Current understanding of iron-deficient heart failure is based on blood tests that are thought to reflect systemic iron stores, but the available evidence suggests greater complexity. The entry and egress of circulating iron is controlled by erythroblasts, which (in severe iron deficiency) will sacrifice erythropoiesis to supply iron to other organs, e.g. the heart. Marked hypoferraemia (typically with anaemia) can drive the depletion of cardiomyocyte iron, impairing contractile performance and explaining why a transferrin saturation < ≈15%–16% predicts the ability of intravenous iron to reduce the risk of major heart failure events in long-term trials (Type 1 iron-deficient heart failure). However, heart failure may be accompanied by intracellular iron depletion within skeletal muscle and cardiomyocytes, which is disproportionate to the findings of systemic iron biomarkers. Inflammation- and deconditioning-mediated skeletal muscle dysfunction—a primary cause of dyspnoea and exercise intolerance in patients with heart failure—is accompanied by intracellular skeletal myocyte iron depletion, which can be exacerbated by even mild hypoferraemia, explaining why symptoms and functional capacity improve following intravenous iron, regardless of baseline haemoglobin or changes in haemoglobin (Type 2 iron-deficient heart failure). Additionally, patients with advanced heart failure show myocardial iron depletion due to both diminished entry into and enhanced egress of iron from the myocardium; the changes in iron proteins in the cardiomyocytes of these patients are opposite to those expected from systemic iron deficiency. Nevertheless, iron supplementation can prevent ventricular remodelling and cardiomyopathy produced by experimental injury in the absence of systemic iron deficiency (Type 3 iron-deficient heart failure). These observations, taken collectively, support the possibility of three different mechanistic pathways for the development of iron-deficient heart failure: one that is driven through systemic iron depletion and impaired erythropoiesis and two that are characterized by disproportionate depletion of intracellular iron in skeletal and cardiac muscle. These mechanisms are not mutually exclusive, and all pathways may be operative at the same time or may occur sequentially in the same patients.

中文翻译：

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确定缺铁性心力衰竭的三种机制途径

目前对缺铁性心力衰竭的理解是基于血液测试，血液测试被认为反映了全身铁储备，但现有证据表明更加复杂。循环铁的进出是由成红细胞控制的，成红细胞（在严重缺铁的情况下）将牺牲红细胞生成来向其他器官（例如心脏）提供铁。明显的低铁血症（通常伴有贫血）会导致心肌细胞铁的消耗，损害收缩性能，并解释了为什么转铁蛋白饱和度<1。 ≈15%–16% 预测长期试验中静脉补铁降低主要心力衰竭事件风险的能力（1 型缺铁性心力衰竭）。然而，心力衰竭可能伴有骨骼肌和心肌细胞内的细胞内铁耗竭，这与全身铁生物标志物的发现不成比例。炎症和去适应介导的骨骼肌功能障碍（心力衰竭患者呼吸困难和运动不耐受的主要原因）伴随着细胞内骨骼肌细胞铁耗竭，即使是轻微的低铁血症也会加剧这种情况，这解释了为什么症状和功能能力在以下情况下得到改善静脉补铁，无论基线血红蛋白或血红蛋白变化如何（2 型缺铁性心力衰竭）。此外，晚期心力衰竭患者由于铁进入心肌的减少和铁从心肌排出的增加而表现出心肌铁耗竭。这些患者心肌细胞中铁蛋白的变化与全身性缺铁所预期的变化相反。尽管如此，补充铁剂可以预防在没有全身缺铁的情况下实验性损伤引起的心室重构和心肌病（3型缺铁性心力衰竭）。这些观察结果共同支持了缺铁性心力衰竭发展的三种不同机制途径的可能性：一种是通过全身性铁耗竭和红细胞生成受损驱动的，另一种是以骨骼和心脏中细胞内铁不成比例的耗竭为特征的。肌肉。这些机制并不相互排斥，所有途径可能同时起作用，也可能在同一患者中依次发生。