Background:Hypertrophic cardiomyopathy (HCM) is a complex disease partly explained by the effects of individual gene variants on sarcomeric protein biomechanics. At the cellular level, HCM mutations most commonly enhance force production, leading to higher energy demands. Despite significant advances in elucidating sarcomeric structure–function relationships, there is still much to be learned about the mechanisms that link altered cardiac energetics to HCM phenotypes. In this work, we test the hypothesis that changes in cardiac energetics represent a common pathophysiologic pathway in HCM.Methods:We performed a comprehensive multiomics profile of the molecular (transcripts, metabolites, and complex lipids), ultrastructural, and functional components of HCM energetics using myocardial samples from 27 HCM patients and 13 normal controls (donor hearts).Results:Integrated omics analysis revealed alterations in a wide array of biochemical pathways with major dysregulation in fatty acid metabolism, reduction of acylcarnitines, and accumulation of free fatty acids. HCM hearts showed evidence of global energetic decompensation manifested by a decrease in high energy phosphate metabolites (ATP, ADP, and phosphocreatine) and a reduction in mitochondrial genes involved in creatine kinase and ATP synthesis. Accompanying these metabolic derangements, electron microscopy showed an increased fraction of severely damaged mitochondria with reduced cristae density, coinciding with reduced citrate synthase activity and mitochondrial oxidative respiration. These mitochondrial abnormalities were associated with elevated reactive oxygen species and reduced antioxidant defenses. However, despite significant mitochondrial injury, HCM hearts failed to upregulate mitophagic clearance.Conclusions:Overall, our findings suggest that perturbed metabolic signaling and mitochondrial dysfunction are common pathogenic mechanisms in patients with HCM. These results highlight potential new drug targets for attenuation of the clinical disease through improving metabolic function and reducing mitochondrial injury.

中文翻译：

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肥厚型心肌病的心脏能量学改变和线粒体功能障碍


背景：肥厚型心肌病（HCM）是一种复杂的疾病，部分原因是个体基因变异对肌节蛋白生物力学的影响。在细胞水平上，HCM 突变最常见的是增强力的产生，从而导致更高的能量需求。尽管在阐明肌节结构与功能关系方面取得了重大进展，但关于心脏能量改变与 HCM 表型之间的联系机制，仍有很多东西有待了解。在这项工作中，我们测试了这样的假设：心脏能量学的变化代表了 HCM 中常见的病理生理学途径。方法：我们对 HCM 能量学的分子（转录本、代谢物和复杂脂质）、超微结构和功能成分进行了全面的多组学分析。使用来自 27 名 HCM 患者和 13 名正常对照（供体心脏）的心肌样本。结果：综合组学分析揭示了多种生化途径的改变，其中包括脂肪酸代谢的严重失调、酰基肉碱的减少和游离脂肪酸的积累。 HCM 心脏显示出整体能量失代偿的证据，表现为高能磷酸代谢物（ATP、ADP 和磷酸肌酸）的减少以及参与肌酸激酶和 ATP 合成的线粒体基因的减少。伴随这些代谢紊乱，电子显微镜显示严重受损的线粒体比例增加，嵴密度降低，与柠檬酸合酶活性和线粒体氧化呼吸降低相一致。这些线粒体异常与活性氧升高和抗氧化防御能力降低有关。然而，尽管存在严重的线粒体损伤，HCM 心脏未能上调线粒体自噬清除率。结论：总体而言，我们的研究结果表明，代谢信号紊乱和线粒体功能障碍是 HCM 患者常见的致病机制。这些结果突出了通过改善代谢功能和减少线粒体损伤来减轻临床疾病的潜在新药物靶点。