Prolonged tachycardia—a risk factor for cardiovascular morbidity and mortality—can induce cardiomyopathy in the absence of structural disease in the heart. Here, by leveraging human patient data, a canine model of tachycardia and engineered heart tissue generated from human induced pluripotent stem cells, we show that metabolic rewiring during tachycardia drives contractile dysfunction by promoting tissue hypoxia, elevated glucose utilization and the suppression of oxidative phosphorylation. Mechanistically, a metabolic shift towards anaerobic glycolysis disrupts the redox balance of nicotinamide adenine dinucleotide (NAD), resulting in increased global protein acetylation (and in particular the acetylation of sarcoplasmic/endoplasmic reticulum Ca²⁺-ATPase), a molecular signature of heart failure. Restoration of NAD redox by NAD⁺ supplementation reduced sarcoplasmic/endoplasmic reticulum Ca²⁺-ATPase acetylation and accelerated the functional recovery of the engineered heart tissue after tachycardia. Understanding how metabolic rewiring drives tachycardia-induced cardiomyopathy opens up opportunities for therapeutic intervention.

长期心动过速是心血管发病和死亡的危险因素，在心脏没有结构性疾病的情况下，可能会诱发心肌病。在这里，通过利用人类患者数据、心动过速犬模型和由人类诱导多能干细胞产生的工程心脏组织，我们发现心动过速期间的代谢重新布线通过促进组织缺氧、提高葡萄糖利用率和抑制氧化磷酸化来驱动收缩功能障碍。从机制上讲，向无氧糖酵解的代谢转变破坏了烟酰胺腺嘌呤二核苷酸 (NAD) 的氧化还原平衡，导致整体蛋白质乙酰化增加（特别是肌浆/内质网 Ca ²⁺ -ATP 酶的乙酰化），这是心力衰竭的分子特征。通过补充 NAD ⁺恢复 NAD 氧化还原可减少肌浆/内质网 Ca ²⁺ -ATP 酶乙酰化，并加速心动过速后工程化心脏组织的功能恢复。了解代谢重新布线如何驱动心动过速诱发的心肌病为治疗干预提供了机会。