학술논문
Altered Cardiac Energetics and Mitochondrial Dysfunction in Hypertrophic Cardiomyopathy.
Document Type
Academic Journal
Author
Ranjbarvaziri S; 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 KB; Department of Medicine, Division of Cardiology, University of Washington, Seattle (K.B.K.).; Ellenberger M; Department of Genetics (M.E., G.M.T., M.P.S., K.C.), Stanford University School of Medicine, CA.; Fajardo G; 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 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.; 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 AS; 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 RA; Department of Bioengineering (R.A.W., W.C.), Stanford University, CA.; Koyano TT; Department of Cardiothoracic Surgery (T.T.K., R.F., J.Y.W.), Stanford University, CA.; Fong R; Department of Cardiothoracic Surgery (T.T.K., R.F., J.Y.W.), Stanford University, CA.; Ma N; 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 L; 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 GM; Department of Genetics (M.E., G.M.T., M.P.S., K.C.), Stanford University School of Medicine, CA.; Chan F; Department of Radiology (F.C.), Stanford University, CA.; Perrino J; Cell Sciences Imaging Facility (J.P.), Stanford University, CA.; Reddy S; 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 W; 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 JC; 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 JY; Department of Cardiothoracic Surgery (T.T.K., R.F., J.Y.W.), Stanford University, CA.; Ruppel KM; 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 JA; Snyder MP; Department of Genetics (M.E., G.M.T., M.P.S., K.C.), Stanford University School of Medicine, CA.; Contrepois K; Department of Genetics (M.E., G.M.T., M.P.S., K.C.), Stanford University School of Medicine, CA.; Bernstein D; 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.
Source
Publisher: Lippincott Williams & Wilkins Country of Publication: United States NLM ID: 0147763 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1524-4539 (Electronic) Linking ISSN: 00097322 NLM ISO Abbreviation: Circulation Subsets: MEDLINE
Subject
Language
English
Abstract
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.
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.