Impaired mitochondrial biogenesis precedes heart failure in right ventricular hypertrophy in congenital heart disease

Circ Heart Fail. 2011 Nov;4(6):707-13. doi: 10.1161/CIRCHEARTFAILURE.111.961474. Epub 2011 Aug 12.


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.

Methods and 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Biomarkers
  • Case-Control Studies
  • Child
  • Child, Preschool
  • Citrate (si)-Synthase / metabolism
  • DNA Replication / genetics
  • DNA, Mitochondrial / genetics
  • Disease Progression*
  • Female
  • Heart Diseases / complications*
  • Heart Diseases / congenital*
  • Heart Diseases / pathology
  • Heart Failure / diagnosis
  • Heart Failure / etiology*
  • Heart Failure / pathology
  • Humans
  • Hypertrophy, Right Ventricular / diagnosis
  • Hypertrophy, Right Ventricular / etiology*
  • Hypertrophy, Right Ventricular / pathology
  • Infant
  • Male
  • Mitochondria, Heart / enzymology
  • Mitochondria, Heart / pathology*
  • Mitochondria, Heart / ultrastructure
  • Prognosis
  • Succinate Dehydrogenase / metabolism
  • Young Adult


  • Biomarkers
  • DNA, Mitochondrial
  • Succinate Dehydrogenase
  • Citrate (si)-Synthase