In the United States, several hundred thousand people experience cardiac arrest each year, with the vast majority dying from this condition. Approximately two-thirds of cardiac arrest victims have previously suffered a myocardial infarction, and the dominant cause of death is a ventricular tachyarrhythmia (VT) originating in the border zone around the infarct scar. Several etiological studies have shown that the changes exhibited by border zone cells are related to cellular electrophysiological function and transcellular communication. These abnormalities slow conduction of the cardiac impulse through this region, creating a substrate for ventricular arrhythmias. This proposal seeks to develop an understanding of the mechanism, efficacy and safety of gene therapy strategies for elimination of post-infarction VT. To achieve this, we will focus on 3 aims: (1) To disrupt reentrant VT circuits by focal and targeted prolongation cellular refractory period with KCNH2-G628S gene transfer to the infarct border zone, (2) to eliminate reentry through the infarct border zone by increasing regional conduction velocity with connexin 43 gene transfer, (3) to assess proarrhythmic risk of KCNH2-G628S or connexin 43 gene therapy for post-infarct VT. Successful completion of these aims will further our understanding of the mechanism responsible for infarct-related VT and possibly allow translation of these findings into novel therapies.
| Finet, J Emanuel; Wan, Xiaoping; Donahue, J Kevin (2018) Fusion of Anthopleurin-B to AAV2 increases specificity of cardiac gene transfer. Virology 513:43-51 |
| Donahue, J Kevin (2016) Biological Therapies for Atrial Fibrillation: Ready for Prime Time? J Cardiovasc Pharmacol 67:19-25 |
| Nassal, Michelle M J; Werdich, Andreas A; Wan, Xiaoping et al. (2016) Phosphorylation at Connexin43 Serine-368 Is Necessary for Myocardial Conduction During Metabolic Stress. J Cardiovasc Electrophysiol 27:110-9 |
| Panda, Nikhil C; Zuckerman, Sean T; Mesubi, Olurotimi O et al. (2014) Improved conduction and increased cell retention in healed MI using mesenchymal stem cells suspended in alginate hydrogel. J Interv Card Electrophysiol 41:117-27 |
| Wolfram, Julie A; Donahue, J Kevin (2013) Gene therapy to treat cardiovascular disease. J Am Heart Assoc 2:e000119 |
| Donahue, J K (2012) Gene therapy for ventricular tachyarrhythmias. Gene Ther 19:600-5 |
| Greener, Ian D; Sasano, Tetsuo; Wan, Xiaoping et al. (2012) Connexin43 gene transfer reduces ventricular tachycardia susceptibility after myocardial infarction. J Am Coll Cardiol 60:1103-10 |
| Igarashi, Tomonori; Finet, J Emanuel; Takeuchi, Ayano et al. (2012) Connexin gene transfer preserves conduction velocity and prevents atrial fibrillation. Circulation 125:216-25 |
| Greener, Ian; Donahue, J Kevin (2011) Gene therapy strategies for cardiac electrical dysfunction. J Mol Cell Cardiol 50:759-65 |
| Amit, Guy; Kikuchi, Kan; Greener, Ian D et al. (2010) Selective molecular potassium channel blockade prevents atrial fibrillation. Circulation 121:2263-70 |
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