title: Normalization of cardiac substrate utilization and left ventricular hypertrophy precede functional recovery in heart failure regression.
abstract: OBJECTIVE
  Impaired cardiac substrate metabolism plays an important role in heart failure (HF) pathogenesis. Since many of these metabolic changes occur at the transcriptional level of metabolic enzymes, it is possible that this loss of metabolic flexibility is permanent and thus contributes to worsening cardiac function and/or prevents the full regression of HF upon treatment. However, despite the importance of cardiac energetics in HF, it remains unclear whether these metabolic changes can be normalized. In the current study, we investigated whether a reversal of an elevated aortic afterload in mice with severe HF would result in the recovery of cardiac function, substrate metabolism, and transcriptional reprogramming as well as determined the temporal relationship of these changes.
  
  
  RESULTS
  Male C57Bl/6 mice were subjected to either Sham or transverse aortic constriction (TAC) surgery to induce HF. After HF development, mice with severe HF (% ejection fraction < 30) underwent a second surgery to remove the aortic constriction (debanding, DB). Three weeks following DB, there was a near complete recovery of systolic and diastolic function, and gene expression of several markers for hypertrophy/HF were returned to values observed in healthy controls. Interestingly, pressure-overload-induced left ventricular hypertrophy (LVH) and cardiac substrate metabolism were restored at 1-week post-DB, which preceded functional recovery.
  
  
  CONCLUSIONS
  The regression of severe HF is associated with early and dramatic improvements in cardiac energy metabolism and LVH normalization that precede restored cardiac function, suggesting that metabolic and structural improvements may be critical determinants for functional recovery.
authors.affiliation: Cardiovascular Research Centre, Department of Pediatrics, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada.
authors.forename: Nikole J
authors.initials: NJ
authors.lastname: Byrne
authors.affiliation: Cardiovascular Research Centre, Department of Pediatrics, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada.
authors.forename: Jody
authors.initials: J
authors.lastname: Levasseur
authors.affiliation: Cardiovascular Research Centre, Department of Pediatrics, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada.
authors.forename: Miranda M
authors.initials: MM
authors.lastname: Sung
authors.affiliation: Cardiovascular Research Centre, Department of Pediatrics, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada.
authors.forename: Grant
authors.initials: G
authors.lastname: Masson
authors.affiliation: Cardiovascular Research Centre, Department of Pediatrics, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada.
authors.forename: Jamie
authors.initials: J
authors.lastname: Boisvenue
authors.affiliation: Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: Martin E
authors.initials: ME
authors.lastname: Young
authors.affiliation: Cardiovascular Research Centre, Department of Pediatrics, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada jason.dyck@ualberta.ca.
authors.forename: Jason R B
authors.initials: JR
authors.lastname: Dyck
mesh_terms: D000818:Animals; D001011:Aorta / Q000601:surgery; D004734:Energy Metabolism / Q000502:physiology; D006333:Heart Failure / Q000503:physiopathology*; D017379:Hypertrophy, Left Ventricular / Q000503:physiopathology*; D008297:Male; D008810:Mice, Inbred C57BL; D023421:Models, Animal; D016277:Ventricular Function, Left / Q000502:physiology*; D020257:Ventricular Remodeling
keywords: Cardiac hypertrophy; Heart failure regression; Metabolism; Remodelling