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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^_*,, Fabrice Prunier, MD, PhD, Djamel Lebeche, PhD^_*, Yanfen Shi, MD, 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, Jean-Claude Tardif, MD, Jean-François Tanguay, MD and Roger J. Hajjar, MD^_*,_*

^_* Mount Sinai School of Medicine, New York, New York
Montreal Heart Institute, University of Montreal School of Medicine, Montreal, Quebec, Canada
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
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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