Cardiac hypertrophy can develop to end-stage heart failure (HF), which inevitably leading to heart transplantation or death. Preserving cardiac function in cardiomyocytes (CMs) is essential for improving prognosis in hypertrophic cardiomyopathy (HCM) patients. Therefore, understanding transcriptomic heterogeneity of CMs in HCM would be indispensable to aid potential therapeutic targets investigation. We isolated primary CM from HCM patients who had extended septal myectomy, and obtained transcriptomes in 338 human primary CM with single-cell tagged reverse transcription (STRT-seq) approach. Our results revealed that CMs could be categorized into three subsets in nonfailing HCM heart: high energy synthesis cluster, high cellular metabolism cluster and intermediate cluster. The expression of electron transport chain (ETC) was up-regulated in larger-sized CMs from high energy synthesis cluster. Of note, we found the expression of Cytochrome c oxidase subunit 7B (COX7B), a subunit of Complex IV in ETC had trends of positively correlation with CMs size. Further, by assessing COX7B expression in HCM patients, we speculated that COX7B was compensatory up-regulated at early-stage but down-regulated in failing HCM heart. To test the hypothesis that COX7B might participate both in hypertrophy and HF progression, we used adeno associated virus 9 (AAV9) to mediate the expression of Cox7b in pressure overload-induced mice. Mice in vivo data supported that knockdown of Cox7b would accelerate HF and Cox7b overexpression could restore partial cardiac function in hypertrophy. Our result highlights targeting COX7B and preserving energy synthesis in hypertrophic CMs could be a promising translational direction for HF therapeutic strategy.

心脏肥大可发展为终末期心力衰竭（HF），这不可避免地导致心脏移植或死亡。保护心肌细胞（CM）的心脏功能对于改善肥厚型心肌病（HCM）患者的预后至关重要。因此，了解转录组异质性对于帮助潜在的治疗靶点研究是必不可少的。我们从进行了扩大间隔肌切除术的 HCM 患者中分离出原发性 CM，并通过单细胞标记逆转录 (STRT-seq) 方法获得了 338 例人类原发性 CM 的转录组。我们的结果表明，非衰竭 HCM 心脏中的 CM 可分为三个子集：高能量合成簇、高细胞代谢簇和中间簇。来自高能合成簇的较大尺寸的CM中电子传递链（ETC）的表达上调。值得注意的是，我们发现ETC中复杂IV亚基细胞色素c氧化酶亚基7B（ COX7B）的表达与CM大小呈正相关趋势。此外，通过评估COX7B 的表达，我们推测COX7B在早期代偿性上调，但在衰竭的 HCM 心脏中下调。为了检验COX7B的假设压力超负荷诱导的小鼠中Cox7b的表达小鼠体内数据支持Cox7b会加速心力衰竭，而Cox7b 的过度表达可以恢复肥厚的部分心脏功能。我们的结果强调，靶向COX7B并保持肥厚 CM 中的能量合成可能是 HF 治疗策略的一个有前途的转化方向。