Hypoplastic left heart syndrome (HLHS) is a severe congenital heart disease with 30% mortality from heart failure (HF) in the first year of life, but the cause of early HF remains unknown. Induced pluripotent stem-cell-derived cardiomyocytes (iPSC-CM) from patients with HLHS showed that early HF is associated with increased apoptosis, mitochondrial respiration defects, and redox stress from abnormal mitochondrial permeability transition pore (mPTP) opening and failed antioxidant response. In contrast, iPSC-CM from patients without early HF showed normal respiration with elevated antioxidant response. Single-cell transcriptomics confirmed that early HF is associated with mitochondrial dysfunction accompanied with endoplasmic reticulum (ER) stress. These findings indicate that uncompensated oxidative stress underlies early HF in HLHS. Importantly, mitochondrial respiration defects, oxidative stress, and apoptosis were rescued by treatment with sildenafil to inhibit mPTP opening or TUDCA to suppress ER stress. Together these findings point to the potential use of patient iPSC-CM for modeling clinical heart failure and the development of therapeutics.

左心发育不全综合征 (HLHS) 是一种严重的先天性心脏病，30% 的人在出生后第一年死于心力衰竭 (HF)，但早期 HF 的病因尚不清楚。来自 HLHS 患者的诱导多能干细胞衍生心肌细胞 (iPSC-CM) 表明，早期 HF 与细胞凋亡增加、线粒体呼吸缺陷和线粒体通透性转换孔 (mPTP) 异常开放引起的氧化还原应激和抗氧化反应失败有关。相比之下，没有早期 HF 的患者的 iPSC-CM 显示正常呼吸，但抗氧化反应升高。单细胞转录组学证实，早期 HF 与伴随内质网 (ER) 应激的线粒体功能障碍有关。这些发现表明，未代偿的氧化应激是 HLHS 早期 HF 的基础。重要的，通过西地那非治疗抑制 mPTP 开放或 TUDCA 抑制 ER 应激，线粒体呼吸缺陷、氧化应激和细胞凋亡得以挽救。这些发现共同指出了患者 iPSC-CM 在模拟临床心力衰竭和治疗学发展方面的潜在用途。