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PMID: 34672721 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Altered Cardiac Energetics and Mitochondrial Dysfunction in Hypertrophic Cardiomyopathy.

Circulation ·Vol. 144 ·No. 21 ·2021-00-23 ·Pages 1714-1731

Ranjbarvaziri S, Kooiker KB, Ellenberger M, Fajardo G, Zhao M, Vander Roest AS, Woldeyes RA, Koyano TT, Fong R, Ma N, Tian L, Traber GM, Chan F, Perrino J, Reddy S, Chiu W, Wu JC, Woo JY, Ruppel KM, Spudich JA, Snyder MP, Contrepois K, Bernstein D

Abstract

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.

Keywords
cardiomyopathy hypertrophic metabolism mitochondria mitophagy reactive oxygen species
MeSH Terms
Adult Aged Cardiomyopathy, Hypertrophic/diagnosis,etiology,metabolism,therapy Cell Respiration/genetics Computational Biology/methods Disease Management Disease Susceptibility Energy Metabolism Female Gene Expression Profiling Heart Function Tests Humans Lipidomics Male Metabolome Metabolomics/methods Middle Aged Mitochondria/genetics,metabolism,ultrastructure Mutation Oxidative Stress Reactive Oxygen Species Transcriptome
Chemicals
Reactive Oxygen Species
Authors & Affiliations
23 authors, click to expand affiliations / ORCID
Ranjbarvaziri Sara
Department of Pediatrics (S.Ranjbarvaziri, G.F., M.Z., A.S.V.R., S.Reddy, K.M.R., D.B.), Stanford University School of Medicine, CA. | Cardiovascular Research Institute (S.Ranjbarvaziri, G.F., M.Z., A.S.V.R., N.M., L.T., S.Reddy, J.C.W., D.B.), Stanford University School of Medicine, CA.
Kooiker Kristina B
Department of Medicine, Division of Cardiology, University of Washington, Seattle (K.B.K.).
Ellenberger Mathew ORCID
Department of Genetics (M.E., G.M.T., M.P.S., K.C.), Stanford University School of Medicine, CA.
Fajardo Giovanni
Department of Pediatrics (S.Ranjbarvaziri, G.F., M.Z., A.S.V.R., S.Reddy, K.M.R., D.B.), Stanford University School of Medicine, CA. | Cardiovascular Research Institute (S.Ranjbarvaziri, G.F., M.Z., A.S.V.R., N.M., L.T., S.Reddy, J.C.W., D.B.), Stanford University School of Medicine, CA.
Zhao Mingming
Department of Pediatrics (S.Ranjbarvaziri, G.F., M.Z., A.S.V.R., S.Reddy, K.M.R., D.B.), Stanford University School of Medicine, CA. | Cardiovascular Research Institute (S.Ranjbarvaziri, G.F., M.Z., A.S.V.R., N.M., L.T., S.Reddy, J.C.W., D.B.), Stanford University School of Medicine, CA.
Vander Roest Alison Schroer ORCID
Department of Pediatrics (S.Ranjbarvaziri, G.F., M.Z., A.S.V.R., S.Reddy, K.M.R., D.B.), Stanford University School of Medicine, CA. | Cardiovascular Research Institute (S.Ranjbarvaziri, G.F., M.Z., A.S.V.R., N.M., L.T., S.Reddy, J.C.W., D.B.), Stanford University School of Medicine, CA.
Woldeyes Rahel A ORCID
Department of Bioengineering (R.A.W., W.C.), Stanford University, CA.
Koyano Tiffany T
Department of Cardiothoracic Surgery (T.T.K., R.F., J.Y.W.), Stanford University, CA.
Fong Robyn
Department of Cardiothoracic Surgery (T.T.K., R.F., J.Y.W.), Stanford University, CA.
Ma Ning ORCID
Cardiovascular Research Institute (S.Ranjbarvaziri, G.F., M.Z., A.S.V.R., N.M., L.T., S.Reddy, J.C.W., D.B.), Stanford University School of Medicine, CA. | Department of Medicine, Division of Cardiology (N.M., L.T., J.C.W.), Stanford University, CA.
Tian Lei
Cardiovascular Research Institute (S.Ranjbarvaziri, G.F., M.Z., A.S.V.R., N.M., L.T., S.Reddy, J.C.W., D.B.), Stanford University School of Medicine, CA. | Department of Medicine, Division of Cardiology (N.M., L.T., J.C.W.), Stanford University, CA.
Traber Gavin M ORCID
Department of Genetics (M.E., G.M.T., M.P.S., K.C.), Stanford University School of Medicine, CA.
Chan Frandics
Department of Radiology (F.C.), Stanford University, CA.
Perrino John ORCID
Cell Sciences Imaging Facility (J.P.), Stanford University, CA.
Reddy Sushma ORCID
Department of Pediatrics (S.Ranjbarvaziri, G.F., M.Z., A.S.V.R., S.Reddy, K.M.R., D.B.), Stanford University School of Medicine, CA. | Cardiovascular Research Institute (S.Ranjbarvaziri, G.F., M.Z., A.S.V.R., N.M., L.T., S.Reddy, J.C.W., D.B.), Stanford University School of Medicine, CA.
Chiu Wah
Department of Bioengineering (R.A.W., W.C.), Stanford University, CA. | Division of Cryo-Electron Microscopy and Bioimaging, SLAC National Accelerator Laboratory (W.C.), Stanford University, CA.
Wu Joseph C
Cardiovascular Research Institute (S.Ranjbarvaziri, G.F., M.Z., A.S.V.R., N.M., L.T., S.Reddy, J.C.W., D.B.), Stanford University School of Medicine, CA. | Department of Medicine, Division of Cardiology (N.M., L.T., J.C.W.), Stanford University, CA.
Woo Joseph Y
Department of Cardiothoracic Surgery (T.T.K., R.F., J.Y.W.), Stanford University, CA.
Ruppel Kathleen M
Department of Pediatrics (S.Ranjbarvaziri, G.F., M.Z., A.S.V.R., S.Reddy, K.M.R., D.B.), Stanford University School of Medicine, CA. | Department of Biochemistry (K.M.R.), Stanford University School of Medicine, CA.
Spudich James A
Snyder Michael P
Department of Genetics (M.E., G.M.T., M.P.S., K.C.), Stanford University School of Medicine, CA.
Contrepois Kévin
Department of Genetics (M.E., G.M.T., M.P.S., K.C.), Stanford University School of Medicine, CA.
Bernstein Daniel
Department of Pediatrics (S.Ranjbarvaziri, G.F., M.Z., A.S.V.R., S.Reddy, K.M.R., D.B.), Stanford University School of Medicine, CA. | Cardiovascular Research Institute (S.Ranjbarvaziri, G.F., M.Z., A.S.V.R., N.M., L.T., S.Reddy, J.C.W., D.B.), Stanford University School of Medicine, CA.
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Article Info
Journal
Circulation
Abbr.
Circulation
ISSN
1524-4539
DOI
10.1161/CIRCULATIONAHA.121.053575
Published
2021-00-23
Epub
2021-00-21
Pages
1714-1731
Language
English
Region
United States
NLM ID
0147763
PMCID
PMC8608736
Subset
IM
Grants
NIBIB NIH HHS · T32 EB009035 · United States
NHLBI NIH HHS · K99 HL153679 · United States
NIGMS NIH HHS · RM1 GM131981 · United States
NIH HHS · S10 OD028536 · United States
NIGMS NIH HHS · R01 GM033289 · United States
NIDDK NIH HHS · P30 DK079626 · United States
NHLBI NIH HHS · T32 HL094274 · United States
NIDDK NIH HHS · P30 DK056336 · United States
NIGMS NIH HHS · T32 GM099608 · United States
NCRR NIH HHS · S10 RR026780 · United States
External Links
PubMed source DOI: 10.1161/CIRCULATIONAHA.121.053575 PMC Full Text View journal details
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