Circulation. 2001;104:1424-1429
doi: 10.1161/hc3601.095574
doi: 10.1161/hc3601.095574
(Circulation. 2001;104:1424.)
© 2001 American Heart Association, Inc.
Basic Science Reports |
Improvement in Survival and Cardiac Metabolism After Gene Transfer of Sarcoplasmic Reticulum Ca2+-ATPase in a Rat Model of Heart Failure
From the Cardiovascular Research Center and the Cardiology Division, Massachusetts General Hospital (F.D., E.W., D.L., U.S., A.R., R.J.H.), and Harvard Medical School (J.K.G.), Boston, Mass; and the Department of Physiology and Biophysics, College of Medicine, University of Illinois at Chicago (E.D.L.).
Correspondence to Roger J. Hajjar, MD, Cardiovascular Research Center, Massachusetts General Hospital, 149 13th St, CNY-4, Charlestown, MA 02129. E-mail hajjar{at}cvrc.mgh.harvard.edu
Background—— In heart failure, sarcoplasmic reticulum (SR) Ca2+-ATPase (SERCA2a) activity is decreased, resulting in abnormal calcium handling and contractile dysfunction. We have previously shown that increasing SERCA2a expression by gene transfer improves ventricular function in a rat model of heart failure created by ascending aortic constriction.
Methods and Results—— In this study, we tested the effects of gene transfer of SERCA2a on survival, left ventricular (LV) volumes, and metabolism. By 26 to 27 weeks after aortic banding, all animals developed heart failure (as documented by >25% decrease in fractional shortening) and were randomized to receive either an adenovirus carrying the SERCA2a gene (Ad.SERCA2a) or control virus (Ad.ßgal-GFP) by use of a catheter-based technique. Sham-operated rats, uninfected or infected with either Ad.ßgal-GFP or Ad.SERCA2a, served as controls. Four weeks after gene transfer, survival in rats with heart failure treated with Ad.ßgal-GFP was 9%, compared with 63% in rats receiving Ad.SERCA2a. LV volumes were significantly increased in heart failure (0.64±0.05 versus 0.35±0.03 mL, P<0.02). Overexpression of SERCA2a normalized LV volumes (0.46±0.07 mL) in the failing hearts. 31P NMR analysis showed a reduced ratio of phosphocreatine to ATP content in failing+Ad.ßgal-GFP compared with sham+Ad.ßgal-GFP (0.82±0.13 versus 1.38±0.14, P<0.01). Overexpression of SERCA2a in failing hearts improved the phosphocreatine/ATP ratio (1.23±0.28).
Conclusions—— In this study, we show that unlike inotropic agents that improve contractile function at the expense of increased mortality and worsening metabolism, gene transfer of SERCA2a improves survival and the energy potential in failing hearts.
Key Words: gene therapy • heart failure • calcium • excitation • contractility
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|
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|
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|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
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|
|
|
|
 |
|
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|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
 |
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
 |
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
 |
|
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|
|
|
|
|
|
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|
|
|
|
 |
|
 R. Ventura-Clapier, A. Garnier, and V. Veksler Energy metabolism in heart failure J. Physiol., February 15, 2004; 555(1): 1 - 13. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. W. Dorn II and J. D. Molkentin Manipulating Cardiac Contractility in Heart Failure: Data From Mice and Men Circulation, January 20, 2004; 109(2): 150 - 158. [Full Text] [PDF]
|
|
|
|
|
|
M. J. Lohse, S. Engelhardt, and T. Eschenhagen What Is the Role of {beta}-Adrenergic Signaling in Heart Failure? Circ. Res., November 14, 2003; 93(10): 896 - 906. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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|
|
|
|
 |
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
S. R. Houser and K. B. Margulies Is Depressed Myocyte Contractility Centrally Involved in Heart Failure? Circ. Res., March 7, 2003; 92(4): 350 - 358. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. G. Angeja and W. Grossman Evaluation and Management of Diastolic Heart Failure Circulation, February 11, 2003; 107(5): 659 - 663. [Full Text] [PDF]
|
|
|
|
|
|
K. F Frank, B. Bolck, E. Erdmann, and R. H.G Schwinger Sarcoplasmic reticulum Ca2+-ATPase modulates cardiac contraction and relaxation Cardiovasc Res, January 1, 2003; 57(1): 20 - 27. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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|
|
|
|
|
|
R. Beeri, J. L. Guerrero, G. Supple, S. Sullivan, R. A. Levine, and R. J. Hajjar New Efficient Catheter-Based System for Myocardial Gene Delivery Circulation, October 1, 2002; 106(14): 1756 - 1759. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Ohga, S. Sakata, C. Takenaka, T. Abe, T. Tsuji, S. Taniguchi, and M. Takaki Cardiac dysfunction in terms of left ventricular mechanical work and energetics in hypothyroid rats Am J Physiol Heart Circ Physiol, August 1, 2002; 283(2): H631 - H641. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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|
|
|
|
 |
|
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|
|
|
|
|
|
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|
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|
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