title: Decreased mitochondrial oxidative phosphorylation capacity in the human heart with left ventricular systolic dysfunction.
abstract: OBJECTIVE
  Heart failure (HF) with left ventricular systolic dysfunction (LVSD) is associated with a shift in substrate utilization and a compromised energetic state. Whether these changes are connected with mitochondrial dysfunction is not known. We hypothesized that the cardiac phenotype in LVSD could be caused by reduced mitochondrial oxidative phosphorylation (OXPHOS) capacity and reduced mitochondrial creatine kinase (miCK) capacity. The study aim was to test mitochondrial OXPHOS capacity in LVSD myocardium compared with OXPHOS capacity in a comparable patient group without LVSD.
  
  
  RESULTS
  Myocardial biopsies were obtained from the left ventricle during cardiac valve or left ventricular assist device (LVAD) surgery. Patients were stratified according to left ventricular ejection fraction (LVEF) into LVSD (LVEF <45%, n = 14) or CONTROL (LVEF >45%, n = 15). Mitochondrial respiration was measured in muscle fibres with addition of non-fatty acid substrates or octanoyl-l-carnitine, a medium chain fatty acid (MCFA). The in situ enzyme capacity of miCK was determined from APD titrations in the presence or absence of creatine. Maximal OXPHOS capacity with non-fatty acid substrates was lower in the LVSD group compared with the CONTROL group (P ≤ 0.05). ADP sensitivity always increased significantly (P ≤ 0.05) with the addition of creatine, after which the sensitivity was highest (P ≤ 0.05) in LVSD compared with CONTROL. The stimulation of OXPHOS from octanoyl-l-carnitine titrations elicited ∼40% lower respiration in LVSD compared with CONTROL (P ≤ 0.05).
  
  
  CONCLUSIONS
  Human LVSD is associated with markedly diminished OXPHOS capacity, particularly in MCFA oxidation. This offers a candidate mechanism for a compromised energetic state and decreased reliance on fatty acid utilization in HF.
authors.affiliation: Xlab, Center for Healthy Aging, Department of Biomedical Sciences, Faculty of Health Sciences, University of Copenhagen, Blegdamsvej 3b, DK-2200 Copenhagen, Denmark. nis.stride@gmail.com
authors.forename: Nis
authors.initials: N
authors.lastname: Stride
authors.forename: Steen
authors.initials: S
authors.lastname: Larsen
authors.forename: Martin
authors.initials: M
authors.lastname: Hey-Mogensen
authors.forename: Kåre
authors.initials: K
authors.lastname: Sander
authors.forename: Jens T
authors.initials: JT
authors.lastname: Lund
authors.forename: Finn
authors.initials: F
authors.lastname: Gustafsson
authors.forename: Lars
authors.initials: L
authors.lastname: Køber
authors.forename: Flemming
authors.initials: F
authors.lastname: Dela
mesh_terms: D000368:Aged; D001706:Biopsy; D002331:Carnitine / Q000031:analogs & derivatives / Q000378:metabolism; D003401:Creatine / Q000378:metabolism; D052281:Creatine Kinase, Mitochondrial Form / Q000502:physiology; D004734:Energy Metabolism / Q000502:physiology; D005227:Fatty Acids / Q000378:metabolism; D005260:Female; D054143:Heart Failure, Systolic / Q000503:physiopathology* / Q000601:surgery; D019918:Heart Valve Prosthesis Implantation; D006353:Heart-Assist Devices; D006801:Humans; D008297:Male; D008875:Middle Aged; D008929:Mitochondria, Heart / Q000502:physiology*; D028361:Mitochondrial Diseases / Q000503:physiopathology; D009206:Myocardium / Q000473:pathology; D010085:Oxidative Phosphorylation; D012016:Reference Values; D013318:Stroke Volume / Q000502:physiology; D018487:Ventricular Dysfunction, Left / Q000503:physiopathology* / Q000601:surgery
chemical_list: D005227:Fatty Acids; D052281:Creatine Kinase, Mitochondrial Form; D003401:Creatine; C008698:octanoylcarnitine; D002331:Carnitine