Aksentijevic Dunja, Sedej Simon, Fauconnier Jeremy, Paillard Melanie, Abdellatif Mahmoud, Streckfuss-Bömeke Katrin, Ventura-Clapier Renée, van der Velden Jolanda, de Boer Rudolf A, Bertero Edoardo, Dudek Jan, Sequeira Vasco, Maack Christoph
William Harvey Research Institute, Bart's Faculty of Medicine and Dentistry, Queen Mary University of London, London, UK.
Department of Cardiology, Medical University of Graz, Graz, Austria.
Nat Rev Cardiol. 2025 Jun 22. doi: 10.1038/s41569-025-01167-6.
Heart failure (HF) is a major global and life-threatening disease. Despite advances in therapies, the prevalence of HF is increasing owing to an ageing population and the pervasive pandemic of obesity and metabolic disorders, which have transformed the pathophysiology of HF. Changes in cardiac energy metabolism and the related energy deficit crucially contribute to the severity and type of HF. Furthermore, perturbations in excitation-contraction coupling, mitochondrial function and oxidative stress are characteristic features of HF. In this Review, we focus on the close interaction between cardiac mechanics and mitochondrial energetics, and decipher how this mechano-energetic coupling is disturbed in various acquired and hereditary forms of HF. In HF with reduced ejection fraction, defects in excitation-contraction coupling are key drivers of mechano-energetic uncoupling, whereas in HF with preserved ejection fraction, increased preload and afterload imposed by obesity, hypertension and age-dependent vascular stiffness increase mechanical workload, which is insufficiently matched by mitochondrial tricarboxylic acid cycle activity and ATP supply. In both scenarios, oxidative stress results from depletion of the antioxidative capacity and contributes to maladaptive cardiac remodelling and dysfunction. Several established and emerging treatments for HF target this mechano-energetic uncoupling, and a greater understanding of the underlying mechanisms will open new therapeutic opportunities to alleviate the burden of HF.
心力衰竭（HF）是一种严重的全球性威胁生命的疾病。尽管治疗方法有所进步，但由于人口老龄化以及肥胖和代谢紊乱的普遍流行，HF的患病率仍在上升，这些因素改变了HF的病理生理学。心脏能量代谢的变化和相关的能量缺乏对HF的严重程度和类型起着关键作用。此外，兴奋-收缩偶联、线粒体功能和氧化应激的紊乱是HF的特征性表现。在本综述中，我们重点关注心脏力学与线粒体能量学之间的密切相互作用，并解读在各种获得性和遗传性HF形式中这种机械-能量偶联是如何被破坏的。在射血分数降低的HF中，兴奋-收缩偶联缺陷是机械-能量解偶联的关键驱动因素，而在射血分数保留的HF中，肥胖、高血压和年龄相关的血管僵硬度导致的前负荷和后负荷增加会增加机械负荷，而线粒体三羧酸循环活性和ATP供应无法充分匹配这种负荷。在这两种情况下，氧化应激都源于抗氧化能力的耗尽，并导致适应性不良的心脏重塑和功能障碍。几种已确立和新出现的HF治疗方法都针对这种机械-能量解偶联，对其潜在机制的更深入了解将为减轻HF负担带来新的治疗机会。
