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
Cited by (0)
This study was supported in part by grants from the National Institutes of Health: R01 HL078691, HL071763, HL080498, HL083156, and a Leducq Transatlantic Network (Dr. Hajjar); HL075934 (Dr. Gwathmey); and K01 HL076659 (Dr. Lebeche); and a grant from Celladon, Inc. (Dr. Hajjar). Dr. Hajjar is cofounder of Celladon, Inc., a biotechnology company commercializing rAAV1.SERCA2a for the treatment of heart failure; Dr. Zsebo is chief executive officer of Celladon; and Dr. Peluso is a staff scientist at Targeted Genetics, which manufactures rAAV1.SERCA2a for Celladon. Drs. Kawase and Ly contributed equally to this work.
