Mericskay Mathias, Zuurbier Coert J, Heather Lisa C, Karlstaedt Anja, Inserte Javier, Bertrand Luc, Kararigas Georgios, Ruiz-Meana Marisol, Maack Christoph, Schiattarella Gabriele G
Université Paris-Saclay, INSERM CARPAT Unit, Signalling and Cardiovascular Pathophysiolgy, Orsay, France.
Laboratory of Experimental Intensive Care and Anaesthesiology (L.E.I.C.A.), Amsterdam Cardiovascular Sciences, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands.
Nat Rev Cardiol. 2025 Jun 22. doi: 10.1038/s41569-025-01166-7.
The number of patients with heart failure is expected to rise sharply owing to ageing populations, poor dietary habits, unhealthy lifestyles and improved survival rates from conditions such as hypertension and myocardial infarction. Heart failure is classified into two main types: heart failure with reduced ejection fraction (HFrEF) and heart failure with preserved ejection fraction (HFpEF). These forms fundamentally differ, especially in how metabolism is regulated, but they also have shared features such as mitochondrial dysfunction. HFrEF is typically driven by neuroendocrine activation and mechanical strain, which demands a higher ATP production to sustain cardiac contraction. However, the primary energy source in a healthy heart (fatty acid β-oxidation) is often suppressed in HFrEF. Although glucose uptake increases in HFrEF, mitochondrial dysfunction disrupts glucose oxidation, and glycolysis and ketone oxidation only partially compensate for this imbalance. Conversely, HFpEF, particularly in individuals with metabolic diseases, such as obesity or type 2 diabetes mellitus, results from both mechanical and metabolic overload. Elevated glucose and lipid levels overwhelm normal metabolic pathways, leading to an accumulation of harmful metabolic byproducts that impair mitochondrial and cellular function. In this Review, we explore how disruptions in cardiac metabolism are not only markers of heart failure but also key drivers of disease progression. We also examine how metabolic intermediates influence signalling pathways that modify proteins and regulate gene expression in the heart. The growing recognition of the role of metabolic alterations in heart failure has led to groundbreaking treatments that target these metabolic disruptions, offering new hope for these patients.
由于人口老龄化、不良饮食习惯、不健康的生活方式以及高血压和心肌梗死等疾病存活率的提高，心力衰竭患者的数量预计将急剧上升。心力衰竭主要分为两种类型：射血分数降低的心力衰竭（HFrEF）和射血分数保留的心力衰竭（HFpEF）。这些类型在根本上存在差异，尤其是在代谢调节方式上，但它们也有一些共同特征，如线粒体功能障碍。HFrEF通常由神经内分泌激活和机械应变驱动，这需要更高的ATP生成来维持心脏收缩。然而，健康心脏中的主要能量来源（脂肪酸β-氧化）在HFrEF中常常受到抑制。尽管HFrEF中葡萄糖摄取增加，但线粒体功能障碍会破坏葡萄糖氧化，糖酵解和酮体氧化只能部分补偿这种失衡。相反，HFpEF，特别是在患有肥胖症或2型糖尿病等代谢疾病的个体中，是由机械和代谢过载共同导致的。升高的葡萄糖和脂质水平使正常代谢途径不堪重负，导致有害代谢副产物积累，从而损害线粒体和细胞功能。在本综述中，我们探讨了心脏代谢紊乱如何不仅是心力衰竭的标志物，而且是疾病进展的关键驱动因素。我们还研究了代谢中间体如何影响信号通路，这些信号通路可修饰蛋白质并调节心脏中的基因表达。对代谢改变在心力衰竭中作用的认识不断提高，已催生出针对这些代谢紊乱的突破性治疗方法，为这些患者带来了新的希望。
