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J Am Coll Cardiol, 2008; 51:1112-1119, doi:10.1016/j.jacc.2007.12.014
© 2008 by the American College of Cardiology Foundation
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PRECLINICAL RESEARCH: HEART FAILURE

Reversal of Cardiac Dysfunction After Long-Term Expression of SERCA2a by Gene Transfer in a Pre-Clinical Model of Heart Failure

Yoshiaki Kawase, MD*, Hung Q. Ly, MD, MSc*,{dagger}, Fabrice Prunier, MD, PhD{ddagger}, Djamel Lebeche, PhD*, Yanfen Shi, MD{dagger}, Hongwei Jin, PhD*, Lahouaria Hadri, PhD*, Ryuichi Yoneyama, MD, PhD§, Kozo Hoshino, MD||, Yoshiaki Takewa, MD, PhD*, Susumu Sakata, PhD, Richard Peluso, PhD#, Krisztina Zsebo, PhD**, Judith K. Gwathmey, VMD, PhD{dagger}{dagger}, Jean-Claude Tardif, MD{dagger}, Jean-François Tanguay, MD{dagger} and Roger J. Hajjar, MD*,*

* Mount Sinai School of Medicine, New York, New York
{dagger} Montreal Heart Institute, University of Montreal School of Medicine, Montreal, Quebec, Canada
{ddagger} Université d’Angers, Angers, France
§ Department of Radiology, University of Tokyo School of Medicine, Tokyo, Japan
|| Department of Cardiovascular Medicine, Kyoto University, Kyoto, Japan
Department of Physiology II, Nara Medical University, Nara, Japan
# Targeted Genetics, Seattle, Washington
** Celladon, Inc., La Jolla, California
{dagger}{dagger} Boston Medical Center, Boston, Massachusetts.

Manuscript received October 12, 2007; revised manuscript received December 5, 2007, accepted December 10, 2007.

* Reprint requests and correspondence: Dr. Roger J. Hajjar, Mount Sinai School of Medicine, Cardiovascular Research Center, One Gustave Levy Place, Box 1030, New York, New York 10029. (Email: roger.hajjar{at}mssm.edu).

Objectives: The aim of this study was to examine the effects of sarcoplasmic reticulum Ca2+ 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.

Abbreviations and Acronyms
  BNP = brain natriuretic peptide
  CK = creatine kinase
  dP/dt = peak left ventricular pressure rate
  HF = heart failure
  LV = left ventricle/ventricular
  LVEF = left ventricular ejection fraction
  LVIDd = left ventricular internal diastolic diameter
  LVIDs = left ventricular internal systolic diameter
  MR = mitral valve regurgitation
  rAAV1 = recombinant adeno-associated virus type 1
  RT-PCR = reverse transcription polymerase chain reaction
  SERCA2a = sarcoplasmic reticulum Ca2+ ATPase
  Tau = time constant of isovolumic relaxation




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