Department of Physiology, Amsterdam UMC, Location VUmc, O2 Science building-11W53, De Boelelaan 1108, 1081HZ Amsterdam, The Netherlands.
Amsterdam Cardiovascular Sciences, Heart failure & Arrhythmias, Amsterdam UMC, Location VUmc, O2 Science building, De Boelelaan 1108, 1081 HZ Amsterdam, The Netherlands.
Eur Heart J. 2023 Apr 1;44(13):1170-1185. doi: 10.1093/eurheartj/ehad028.
Genetic hypertrophic cardiomyopathy (HCM) is caused by mutations in sarcomere protein-encoding genes (i.e. genotype-positive HCM). In an increasing number of patients, HCM occurs in the absence of a mutation (i.e. genotype-negative HCM). Mitochondrial dysfunction is thought to be a key driver of pathological remodelling in HCM. Reports of mitochondrial respiratory function and specific disease-modifying treatment options in patients with HCM are scarce.
Respirometry was performed on septal myectomy tissue from patients with HCM (n = 59) to evaluate oxidative phosphorylation and fatty acid oxidation. Mitochondrial dysfunction was most notably reflected by impaired NADH-linked respiration. In genotype-negative patients, but not genotype-positive patients, NADH-linked respiration was markedly depressed in patients with an indexed septal thickness ≥10 compared with <10. Mitochondrial dysfunction was not explained by reduced abundance or fragmentation of mitochondria, as evaluated by transmission electron microscopy. Rather, improper organization of mitochondria relative to myofibrils (expressed as a percentage of disorganized mitochondria) was strongly associated with mitochondrial dysfunction. Pre-incubation with the cardiolipin-stabilizing drug elamipretide and raising mitochondrial NAD+ levels both boosted NADH-linked respiration.
Mitochondrial dysfunction is explained by cardiomyocyte architecture disruption and is linked to septal hypertrophy in genotype-negative HCM. Despite severe myocardial remodelling mitochondria were responsive to treatments aimed at restoring respiratory function, eliciting the mitochondria as a drug target to prevent and ameliorate cardiac disease in HCM. Mitochondria-targeting therapy may particularly benefit genotype-negative patients with HCM, given the tight link between mitochondrial impairment and septal thickening in this subpopulation.
遗传性肥厚型心肌病（HCM）是由肌节蛋白编码基因突变引起的（即基因型阳性 HCM）。在越来越多的患者中，HCM 在没有突变的情况下发生（即基因型阴性 HCM）。线粒体功能障碍被认为是 HCM 病理性重塑的关键驱动因素。关于 HCM 患者线粒体呼吸功能和特定疾病修正治疗选择的报告很少。
对 HCM 患者（n=59）的间隔心肌切除术组织进行呼吸测定，以评估氧化磷酸化和脂肪酸氧化。NADH 连接呼吸的受损最明显地反映了线粒体功能障碍。在基因型阴性患者中，但在基因型阳性患者中，NADH 连接呼吸在间隔厚度指数≥10 的患者中明显低于<10 的患者。通过透射电子显微镜评估，线粒体功能障碍不能用线粒体丰度或碎片化减少来解释。相反，相对于肌原纤维的线粒体不当组织（表示为紊乱线粒体的百分比）与线粒体功能障碍强烈相关。用心脏磷脂稳定药物埃拉米普雷特预先孵育并提高线粒体 NAD+水平均能增强 NADH 连接呼吸。
线粒体功能障碍是由心肌细胞结构破坏引起的，并与基因型阴性 HCM 的间隔肥大有关。尽管心肌严重重塑，但线粒体对旨在恢复呼吸功能的治疗有反应，将线粒体作为药物靶点，以预防和改善 HCM 中的心脏疾病。鉴于在该亚群中线粒体损伤与间隔增厚之间的紧密联系，针对线粒体的治疗可能特别有益于基因型阴性的 HCM 患者。
