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.
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Figure 1 Differences in Adjusted Peak LV Pressure Rate of Rise
Relative to the saline group, study animals that underwent gene transfer with recombinant adeno-associated virus type 1 (rAAV1) sarcoplasmic reticulum Ca2+ ATPase (SERCA2a) had: 1) comparable peak left ventricular pressure rate (dP/dt)max/P at the 2-month time point (state of compensated volume-overload heart failure); and 2) significant improvement in (dP/dt)max/P. This confirms a positive effect on left ventricular (LV) inotropy of SERCA2a overexpression.
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Figure 2 Differences in Time Constant of Isovolumic Relaxation
Both study groups had no discernable difference in diastolic function at the time of gene transfer. Over the course of the next 2 months after gene transfer, there was a clear trend favoring the SERCA2a group for lack of deterioration of diastolic function. This confirms a potential positive effect on LV lusitropy of SERCA2a overexpression. Tau = time constant of isovolumic relaxation; other abbreviations as in Figure 1.
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Figure 3 LV Internal Systolic Diameters at 4 Months
Despite comparable diameters at baseline and at the time of gene transfer, the saline group showed evidence of progression of their LV internal systolic diameters at the term of the study. Conversely, animals that underwent rAAV1.SERCA2a gene transfer were documented with persistent, stable LV internal systolic diameters. This confirms a positive effect on LV remodeling of SERCA2a overexpression. Abbreviations as in Figure 1.
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Figure 4 SERCA2a Overexpression After Gene Transfer With rAAV1 Vector
After gene transfer with the cardiotropic viral vector, rAAV1, both protein expression levels (A) as well as mRNA levels (B) of SERCA2a were found to be significantly elevated when compared with SERCA2a tissue expression in the saline group. This confirms the ability of this viral vector to promote the persistent overexpression (2 months after gene transfer) of the calcium cycling protein, SERCA2a. Control = normal heart group; GAPDH = glyceraldehyde 3-phosphate dehydrogenase; HF = heart failure; other abbreviations as in Figure 1.
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Figure 5 PLB Expression After Gene Transfer With rAAV1 Vector
After gene transfer with the cardiotropic viral vector, recombinant adeno-associated virus serotype 1 (rAAV1), protein expression levels of phospholamban were found to be unchanged between groups. PLB = phospholamban; other abbreviations as in Figures 1 and 4.
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Figure 6 Differences in BNP Levels Between Study Groups
At the time of rAAV1.SERCA2a gene transfer, all study animals had comparable levels of brain natriuretic peptide (BNP) levels. The latter were significantly elevated relative to baseline, evidence of a compensated state of volume-overload heart failure. At the term of the study, 2 months after gene transfer, the progressive rise in BNP levels seen in the saline group was not seen in the SERCA2a group. This confirms that SERCA2a overexpression could favor the stabilization of the physiological effects resulting from volume-overload heart failure. Abbreviations as in Figure 1.
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