Abstract
Modern treatment of cardiac arrhythmias is limited to pharmacotherapy, radiofrequency ablation, or implantable devices. Antiarrhythmic medications suppress arrhythmias, but their systemic effects are often poorly tolerated and their proarrhythmic tendencies increase mortality1,2,3. Radiofrequency ablation can cure only a limited number of arrhythmias. Implantable devices can be curative for bradyarrhythmias and lifesaving for tachyarrhythmias, but require a lifetime commitment to repeated procedures, are a significant expense, and may lead to severe complications. One possibility is the use of gene therapy as an antiarrhythmic strategy. As an initial attempt to explore this option, we focused on genetic modification of the atrioventricular node. First, we developed an intracoronary perfusion model for gene delivery, building on our previous work in isolated cardiac myocytes and hearts perfused ex vivo4,5. Using this method, we infected porcine hearts with Adβgal (recombinant adenovirus expressing Escherichia coli β-galactosidase) or with AdGi (adenovirus encoding the Gαi2 subunit). We hypothesized that excess Gαi2 would mimic the effects of β-adreneric antagonists, in effect creating a localized β-blockade. Gαi2 overexpression suppressed baseline atrioventricular conduction and slowed the heart rate during atrial fibrillation without producing complete heart block. In contrast, expression of the reporter gene β-galactosidase had no electrophysiological effects. Our results demonstrate the feasibility of using myocardial gene transfer strategies to treat common arrhythmias.
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Acknowledgements
This work was supported by the Richard S. Ross Clinician-Scientist Award, Johns Hopkins University (J.K.D.), the NIH (P50 HL52307, J.K.D. and E.M.), and by a fellowship from the Alberta Heritage Foundation for Medical Research (H.F.). E.M. holds the Michel Mirowski, M.D. Professorship of Cardiology at the Johns Hopkins University. AdGi was constructed by T.E. with the assistance of U. Remmers, K. Peppel and W.J. Koch.
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Kevin Donahue, J., Heldman, A., Fraser, H. et al. Focal modification of electrical conduction in the heart by viral gene transfer. Nat Med 6, 1395–1398 (2000). https://doi.org/10.1038/82214
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DOI: https://doi.org/10.1038/82214
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