Overwhelming Evidence of the Beneficial Effects of SERCA Gene Transfer in Heart Failure

To the Editor:We read with great interest the work by O'Donnell et al 1 on the possible toxic effect of the sarcoplasmic reticulum Ca 2ϩ ATPase pump in neonatal cardiac myocytes.Because gene transfer of SERCA2a is being currently considered as a modality for the treatment of heart failure, 2 the work by O'Donnell et al has the potential of raising concern about such a strategy.However, a number of limitations in this study preclude any definitive conclusions regarding the toxicity of overexpressing SERCA.The authors demonstrated the expression of the noncardiac isoform SERCA1 in embryonic and neonatal cardiac myocytes in their studies.These cardiomyocytes have a poorly developed sarcoplasmic reticulum and do not represent functionally the adult heart.In addition, the expression of the SERCA1 isoform may result in abnormal intracellular trafficking, which results in irregular calcium signaling.Although the authors state that cytotoxic effects observed with SERCA1 overexpression are "slightly" higher than with the empty or reporter viruses, no statistical significance is shown.The apoptosis index, which is unusually high in this study compared with other published studies, 3 is not reportedly different between SERCA1 overexpression or GFP overexpression.The conclusions drawn in this study are in direct contrast to those validated by numerous experimental results showing that overexpression of the cardiac isoform, SERCA2a, improves contractility both in vivo and in vitro without detrimental effects.4 -6 Most importantly, a recent study by Davia et al 7 showed that overexpression of SERCA2a in adult rabbit cardiac myocytes has protective effects in contrast to ␤-agonism and prolongs survival in these adult cardiomyocytes.In addition, the exogenous expression of SERCA2a by either transgenesis or adenovirus has ranged from 1.13-to 2-fold, 4,8,9 pointing toward an endogenous regulation of SERCA2a levels in cardiac cells.Although the study by O'Donnell et al 1 describes cytotoxic effects of recombinant adenoviruses in embryonic and neonatal cardiac myocytes, there is very little evidence that exogenously increasing SR ATPase activity has detrimental effects.On the contrary, there is ample evidence that expression of the cardiac isoform, SERCA2a, not only rescues contractile function in failing hearts but has protective effects.