Altered Cardiac Energetics and Mitochondrial Dysfunction in Hypertrophic Cardiomyopathy

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

doi:10.1161/circulationaha.121.053575

Title: Altered Cardiac Energetics and Mitochondrial Dysfunction in Hypertrophic Cardiomyopathy

Journal Article · Thu Oct 21 00:00:00 EDT 2021 · Circulation

DOI:https://doi.org/10.1161/circulationaha.121.053575· OSTI ID:1872400

Ranjbarvaziri, Sara ^[1]; Kooiker, Kristina B. ^[2];

^[1]; Fajardo, Giovanni ^[1]; Zhao, Mingming ^[1];

^[1];

^[3]; Koyano, Tiffany T. ^[3]; Fong, Robyn ^[3];

^[1]; Tian, Lei ^[1];

^[1]; Chan, Frandics ^[3];

^[3];

^[1]; Chiu, Wah ^[3]; Wu, Joseph C. ^[1]; Woo, Joseph Y. ^[3]; Ruppel, Kathleen M. ^[1]; Spudich, James A. ^[3] more »

Stanford Univ., CA (United States). School of Medicine
Univ. of Washington, Seattle, WA (United States)
Stanford Univ., CA (United States)

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. Here, 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.

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Research Organization:: SLAC National Accelerator Lab., Menlo Park, CA (United States)

Sponsoring Organization:: USDOE Office of Science (SC), Basic Energy Sciences (BES); American Recovery and Reinvestment Act; National Institutes of Health (NIH); National Institute of Diabetes and Digestive Kidney Diseases; National Institute of General Medical Sciences; American Heart Association; National Institute of Biomedical Imaging and Bioengineering

Grant/Contract Number:: AC02-76SF00515; 1S10RR026780-01; P30DK079626; DK056336; RM1GM131981; 17CSA33590101; 2RM1HG00773506; 2T32EB009035

OSTI ID:: 1872400

Journal Information:: Circulation, Vol. 144, Issue 21; ISSN 0009-7322

Publisher:: American Heart Association, Inc.Copyright Statement

Country of Publication:: United States

Language:: English

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Clinical Relevance of Biomarkers of Oxidative Stress Frijhoff, Jeroen; Winyard, Paul G.; Zarkovic, Neven Antioxidants & Redox Signaling, Vol. 23, Issue 14 https://doi.org/10.1089/ars.2015.6317	journal	November 2015
Impaired Mitochondrial Biogenesis Precedes Heart Failure in Right Ventricular Hypertrophy in Congenital Heart Disease Karamanlidis, Georgios; Bautista-Hernandez, Victor; Fynn-Thompson, Francis Circulation: Heart Failure, Vol. 4, Issue 6 https://doi.org/10.1161/circheartfailure.111.961474	journal	November 2011
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