Dual gene therapy with SERCA1 and Kir2.1 abbreviates excitation without suppressing contractility

vious studies have demonstrated the utility of SERCA gene delivery in boosting cardiac contractility by increasing calcium loading of the sarcoplasmic reticulum; here, we chose to use the SERCA1 isoform given its usual absence in the heart and its unique antigenicity (properties which facilitate the unambiguous documentation of transgene expression), as well as its high turnover rate relative to SERCA2 (2, 3). For the K channel, we selected Kir2.1, which encodes a cardiac inward rectifier channel. Kir2.1 is expected to abbreviate excitability by accelerating terminal repolarization (4). By itself, such an effect might prove deleterious for pump function, but we hypothesized that the addition of SERCA1 would offset the loss of contractility due to abbreviation of the action potential. The ideas were tested by expression of the dual gene therapy vector in the ventricle, measuring endpoints both in isolated cells (action potentials, membrane current, and calcium transients) and in vivo (electrocardiograms and echocardiograms).