Improvement in survival and cardiac metabolism after gene transfer of sarcoplasmic reticulum Ca2+-ATPase in a rat model of heart failure

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.beta gal-GFP) by use of a catheter-based technique. Sham-operated rats, uninfected or infected with either Ad.beta gal-GFP or Ad.SERCA2a, served as controls. Four weeks after gene transfer, survival in rats with heart failure treated with Ad.beta gal-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. P-31 NMR analysis showed a reduced ratio of phosphocreatine to ATP content in failing+ Ad.beta gal-GFP compared with sham+Ad.beta gal-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.