title: Mitochondrial function in heart failure: The impact of ischemic and non-ischemic etiology.
abstract: BACKGROUND
  Although cardiac mitochondrial dysfunction is associated with heart failure (HF), this is a complex syndrome with two predominant etiologies, ischemic HF (iHF) and non-ischemic HF (niHF), and the exact impact of mitochondrial dysfunction in these two distinct forms of HF is unknown.
  
  
  RESULTS
  To determine the impact of HF etiology on mitochondrial function, respiration was measured in permeabilized cardiac muscle fibers from patients with iHF (n=17), niHF (n=18), and healthy donor hearts (HdH). Oxidative phosphorylation capacity (OXPHOS), assessed as state 3 respiration, fell progressively from HdH to niHF, to iHF (Complex I+II: 54±1; 34±4; 27±3pmol·s(-1)·mg(-1)) as did citrate synthase activity (CSA: 206±18; 129±6; 82±6nmol·mg(-1)·min(-1)). Although still significantly lower than HdH, normalization of OXPHOS by CSA negated the difference in mass specific OXPHOS between iHF and niHF. Interestingly, Complex I state 2 respiration increased progressively from HdH, to niHF, to iHF, whether or not normalized for CSA (0.6±0.2; 1.1±0.3; 2.3±0.3; pmol·mg(-1)·CSA), such that the respiratory control ratio (RCR), fell in the same manner across groups. Finally, both the total free radical levels (60±6; 46±4AU) and level of mitochondrial derived superoxide (1.0±0.2; 0.7±0.1AU) were greater in iHF compared to niHF, respectively.
  
  
  CONCLUSIONS
  Thus, the HF-related attenuation in OXPHOS actually appears to be independent of etiology when the lower mitochondrial content of iHF is taken into account. However, these findings provide evidence of deleterious intrinsic mitochondrial changes in iHF, compared to niHF, including greater proton leak, attenuated OXPHOS efficiency, and augmented free radical levels.
authors.affiliation: Geriatric Research, Education, and Clinical Center, George E. Whalen VA Medical Center, Salt Lake City, UT, USA; Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, MA, USA.
authors.forename: Song-Young
authors.initials: SY
authors.lastname: Park
authors.affiliation: Geriatric Research, Education, and Clinical Center, George E. Whalen VA Medical Center, Salt Lake City, UT, USA; Department of Internal Medicine, Division of Cardiovascular Medicine, University of Utah, Salt Lake City, UT, USA.
authors.forename: Joel D
authors.initials: JD
authors.lastname: Trinity
authors.affiliation: Geriatric Research, Education, and Clinical Center, George E. Whalen VA Medical Center, Salt Lake City, UT, USA; Department of Internal Medicine, Division of Cardiovascular Medicine, University of Utah, Salt Lake City, UT, USA.
authors.forename: Jayson R
authors.initials: JR
authors.lastname: Gifford
authors.affiliation: Department of Internal Medicine, Division of Cardiovascular Medicine, University of Utah, Salt Lake City, UT, USA.
authors.forename: Nikolaos A
authors.initials: NA
authors.lastname: Diakos
authors.affiliation: Department of Internal Medicine, Division of Cardiovascular Medicine, University of Utah, Salt Lake City, UT, USA.
authors.forename: Lauren
authors.initials: L
authors.lastname: McCreath
authors.affiliation: Department of Internal Medicine, Division of Cardiovascular Medicine, University of Utah, Salt Lake City, UT, USA.
authors.forename: Stavros
authors.initials: S
authors.lastname: Drakos
authors.affiliation: Geriatric Research, Education, and Clinical Center, George E. Whalen VA Medical Center, Salt Lake City, UT, USA; Department of Nutrition and Integrative Physiology, University of Utah, Salt Lake City, UT, USA; Department of Internal Medicine, Division of Cardiovascular Medicine, University of Utah, Salt Lake City, UT, USA. Electronic address: r.richardson@hsc.utah.edu.
authors.forename: Russell S
authors.initials: RS
authors.lastname: Richardson
mesh_terms: D005260:Female; D005609:Free Radicals / Q000378:metabolism; D006333:Heart Failure / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D008297:Male; D008875:Middle Aged; D008929:Mitochondria, Heart / Q000502:physiology*; D017202:Myocardial Ischemia / Q000378:metabolism* / Q000473:pathology; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology
chemical_list: D005609:Free Radicals
keywords: Free radicals; Ischemic heart failure; Mitochondrial function; Non-ischemic heart failure