Abstract 3491: A Combined Gene and Cell Therapy Approach for Conduction System Repair
Abnormalities in myocardial conduction may underlie both bradyarrhythmias and reentrant tachyarrhythmias. Here, we present a novel strategy for conduction repair utilizing genetically engineered cells designed to form biological “conductive cables”. An in vitro model of conduction block was established using spatially-separated, non-synchronized, beating human ES-derived cardiomyocyte clusters. We next examined the hypothesis that HEK293 cells transfected with the Nav1.5 voltage-gated sodium channel can couple with the cultured myocytes and synchronize their electrical activity. Cx43 immunostaining and Calcein-dye transfer experiments confirmed the formation of functional gap junctions between the engineered cells and neighboring myocytes. A microelectrode array mapping system was used to assess the ability of the engineered cells to synchronize contractions of these spatially separated clusters (activation maps in Fig. 1⇓). Synchronization was defined by the establishment of fixed local activation time differences between the two clusters and convergence of their spontaneous activation cycle lengths. Nontransfected control cells were able to induce synchronization between myocyte clusters separated by distances up to 300 μm (n=21). In contrast, the engineered cells synchronized contractions between clusters separated by up to 900 μm, the longest distance studied (n=23). In conclusion, genetically engineered cells, transfected to express Na+ channels, can form biological conduits bridging and coupling excitable cells. This novel cell therapy approach may be used for the development of therapeutic strategies for both brady- and tachyarrhythmias.