title: Reversal of cardiac dysfunction after long-term expression of SERCA2a by gene transfer in a pre-clinical model of heart failure.
abstract: OBJECTIVE
  The aim of this study was to examine the effects of sarcoplasmic reticulum Ca(2+) ATPase (SERCA2a) gene transfer in a swine heart failure (HF) model.
  
  
  BACKGROUND
  Reduced expression and activity of SERCA2a have been documented in HF. Prior studies have reported the beneficial effects of short-term SERCA2a overexpression in rodent models. However, the effects of long-term expression of SERCA2a in pre-clinical large animal models are not known.
  
  
  METHODS
  Yorkshire-Landrace pigs were used (n = 16) to create volume overload by percutaneously severing chordae tendinae of the mitral apparatus with a bioptome to induce mitral regurgitation. At 2 months, pigs underwent intracoronary delivery of either recombinant adeno-associated virus type 1 (rAAV1) carrying SERCA2a under a cytomegalovirus promoter (rAAV1.SERCA2a) (n = 10; group 1) or saline (n = 6; group 2).
  
  
  RESULTS
  At 2 months, study animals were found to be in a compensated state of volume-overload HF (increased left ventricular internal diastolic and systolic diameters [LVIDd and LVIDs]). At 4 months, gene transfer resulted in: 1) positive left ventricular (LV) inotropic effects (adjusted peak left ventricular pressure rate of rise (dP/dt)max/P, 21.2 +/- 3.2 s(-1) group 1 vs. 15.5 +/- 3.0 s(-1) group 2; p < 0.01); 2) improvement in LV remodeling (% change in LVIDs -3.0 +/- 10% vs. +15 +/- 11%, respectively; p < 0.01). At follow-up, brain natriuretic peptide levels remained stable in group 1 after gene transfer, in contrast to rising levels in group 2. Further, cardiac SERCA2a expression was significantly decreased in group 2 whereas in group 1 it was restored to normal levels. There was no histopathological evidence of acute myocardial inflammation or necrosis.
  
  
  CONCLUSIONS
  Using a large-animal, volume-overload model of HF, we report that long-term overexpression of SERCA2a by in vivo rAAV1-mediated intracoronary gene transfer preserved systolic function, potentially prevented diastolic dysfunction, and improved ventricular remodeling.
authors.affiliation: Mount Sinai School of Medicine, New York, New York 10029, USA.
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Kawase
authors.forename: Hung Q
authors.initials: HQ
authors.lastname: Ly
authors.forename: Fabrice
authors.initials: F
authors.lastname: Prunier
authors.forename: Djamel
authors.initials: D
authors.lastname: Lebeche
authors.forename: Yanfen
authors.initials: Y
authors.lastname: Shi
authors.forename: Hongwei
authors.initials: H
authors.lastname: Jin
authors.forename: Lahouaria
authors.initials: L
authors.lastname: Hadri
authors.forename: Ryuichi
authors.initials: R
authors.lastname: Yoneyama
authors.forename: Kozo
authors.initials: K
authors.lastname: Hoshino
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Takewa
authors.forename: Susumu
authors.initials: S
authors.lastname: Sakata
authors.forename: Richard
authors.initials: R
authors.lastname: Peluso
authors.forename: Krisztina
authors.initials: K
authors.lastname: Zsebo
authors.forename: Judith K
authors.initials: JK
authors.lastname: Gwathmey
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Tardif
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Tanguay
authors.forename: Roger J
authors.initials: RJ
authors.lastname: Hajjar
mesh_terms: D000818:Animals; D003587:Cytomegalovirus / Q000235:genetics; D004195:Disease Models, Animal; D015870:Gene Expression; D015971:Gene Expression Regulation, Enzymologic; D018014:Gene Transfer Techniques; D006333:Heart Failure / Q000235:genetics / Q000503:physiopathology / Q000628:therapy*; D054144:Heart Failure, Diastolic / Q000628:therapy; D054143:Heart Failure, Systolic / Q000628:therapy; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000235:genetics* / Q000378:metabolism; D013552:Swine; D018487:Ventricular Dysfunction, Left / Q000628:therapy*; D020257:Ventricular Remodeling
chemical_list: D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases