title: Impaired mitochondrial biogenesis precedes heart failure in right ventricular hypertrophy in congenital heart disease.
abstract: BACKGROUND
  The outcome of the surgical repair in congenital heart disease correlates with the degree of myocardial damage. In this study, we determined whether mitochondrial DNA depletion is a sensitive marker of right ventricular (RV) damage and whether impaired mitochondrial DNA (mtDNA) replication contributes to the transition from compensated hypertrophy to failure.
  
  
  RESULTS
  RV samples obtained from 31 patients undergoing cardiac surgery were compared with 5 RV samples from nonfailing hearts (control). Patients were divided into compensated hypertrophy and failure groups, based on preoperative echocardiography, catheterization, and/or MRI data. Mitochondrial enzyme activities (citrate synthase and succinate dehydrogenase) were maintained during hypertrophy and decreased by ≈40% (P<0.05 versus control) at the stage of failure. In contrast, mtDNA content was progressively decreased in the hypertrophied RV through failure (by 28±8% and 67±11%, respectively, P<0.05 for both), whereas mtDNA-encoded gene expression was sustained by increased transcriptional activity during compensated hypertrophy but not in failure. Mitochondrial DNA depletion was attributed to reduced mtDNA replication in both hypertrophied and failing RV, and it was independent of PGC-1 downregulation but was accompanied by reduced expression of proteins constituting the mtDNA replication fork. Decreased mtDNA content in compensated hypertrophy was also associated with pathological changes of mitochondria ultrastructure.
  
  
  CONCLUSIONS
  Impaired mtDNA replication causes early and progressive depletion of mtDNA in the RV of the patients with congenital heart disease during the transition from hypertrophy to failure. Decreased mtDNA content probably is a sensitive marker of mitochondrial injury in this patient population.
authors.affiliation: Mitochondria and Metabolism Center, Department of Anesthesiology and Pain Medicine, University of Washington, Seattle, WA 98109, USA.
authors.forename: Georgios
authors.initials: G
authors.lastname: Karamanlidis
authors.forename: Victor
authors.initials: V
authors.lastname: Bautista-Hernandez
authors.forename: Francis
authors.initials: F
authors.lastname: Fynn-Thompson
authors.forename: Pedro
authors.initials: P
authors.lastname: Del Nido
authors.forename: Rong
authors.initials: R
authors.lastname: Tian
mesh_terms: D000293:Adolescent; D015415:Biomarkers; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D002950:Citrate (si)-Synthase / Q000378:metabolism; D004261:DNA Replication / Q000235:genetics; D004272:DNA, Mitochondrial / Q000235:genetics; D018450:Disease Progression; D005260:Female; D006331:Heart Diseases / Q000150:complications* / Q000151:congenital* / Q000473:pathology; D006333:Heart Failure / Q000175:diagnosis / Q000209:etiology* / Q000473:pathology; D006801:Humans; D017380:Hypertrophy, Right Ventricular / Q000175:diagnosis / Q000209:etiology* / Q000473:pathology; D007223:Infant; D008297:Male; D008929:Mitochondria, Heart / Q000201:enzymology / Q000473:pathology* / Q000648:ultrastructure; D011379:Prognosis; D013385:Succinate Dehydrogenase / Q000378:metabolism; D055815:Young Adult
chemical_list: D015415:Biomarkers; D004272:DNA, Mitochondrial; D013385:Succinate Dehydrogenase; D002950:Citrate (si)-Synthase