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Altered Cardiac Energetics and Mitochondrial Dysfunction in Hypertrophic Cardiomyopathy

Circulation (New York, N.Y.), 2021-11, Vol.144 (21), p.1714-1731 [Peer Reviewed Journal]

ISSN: 0009-7322 ;EISSN: 1524-4539 ;DOI: 10.1161/circulationaha.121.053575 ;PMID: 34672721

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Title:
Altered Cardiac Energetics and Mitochondrial Dysfunction in Hypertrophic Cardiomyopathy
Author: Ranjbarvaziri, Sara ; Kooiker, Kristina B ; Ellenberger, Mathew ; Fajardo, Giovanni ; Zhao, Mingming ; Vander Roest, Alison Schroer ; Woldeyes, Rahel A ; Koyano, Tiffany T ; Fong, Robyn ; Ma, Ning ; Tian, Lei ; Traber, Gavin M ; Chan, Frandics ; Perrino, John ; Reddy, Sushma ; Chiu, Wah ; Wu, Joseph C ; Woo, Joseph Y ; Ruppel, Kathleen M ; Spudich, James A ; Snyder, Michael P ; Contrepois, Kévin ; Bernstein, Daniel
Subjects: 60 APPLIED LIFE SCIENCES ; Adult ; Aged ; cardiomyopathy ; Cardiomyopathy, Hypertrophic - diagnosis ; Cardiomyopathy, Hypertrophic - etiology ; Cardiomyopathy, Hypertrophic - metabolism ; Cardiomyopathy, Hypertrophic - therapy ; Cell Respiration - genetics ; Computational Biology - methods ; Disease Management ; Disease Susceptibility ; Energy Metabolism ; Female ; Gene Expression Profiling ; Heart Function Tests ; Humans ; hypertrophic ; Lipidomics ; Male ; metabolism ; Metabolome ; Metabolomics - methods ; Middle Aged ; mitochondria ; Mitochondria - genetics ; Mitochondria - metabolism ; Mitochondria - ultrastructure ; mitophagy ; Mutation ; Oxidative Stress ; Reactive Oxygen Species ; Transcriptome
Is Part Of: Circulation (New York, N.Y.), 2021-11, Vol.144 (21), p.1714-1731
Description: 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. 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). 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. 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.
Publisher: United States: American Heart Association, Inc
Language: English
Identifier: ISSN: 0009-7322
EISSN: 1524-4539
DOI: 10.1161/circulationaha.121.053575
PMID: 34672721
Source: Geneva Foundation Free Medical Journals
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Altered Cardiac Energetics and Mitochondrial Dysfunction in Hypertrophic Cardiomyopathy

ISSN: 0009-7322 ;EISSN: 1524-4539 ;DOI: 10.1161/circulationaha.121.053575 ;PMID: 34672721

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