Connexin43 Gene Transfer Reduces Ventricular Tachycardia Susceptibility After Myocardial Infarction

Abstract

Objectives The aim of this study was to evaluate the links between connexin43 (Cx43) expression, myocardial conduction velocity, and ventricular tachycardia in a model of healed myocardial infarction. Background Post-infarction ventricular arrhythmias frequently cause sudden death. Impaired myocardial conduction has previously been linked to ventricular arrhythmias. Altered connexin expression is a potential source of conduction slowing identified in healed scar border tissues. The functional effect of increasing border-zone Cx43 has not been previously evaluated. Methods Twenty-five Yorkshire pigs underwent anterior infarction by transient left anterior descending coronary artery occlusion, followed by weekly testing for arrhythmia inducibility. Twenty animals with reproducibly inducible sustained monomorphic ventricular tachycardia were randomized 2:1:1 to receive AdCx43, Adβgal, or no gene transfer. One week later, animals underwent follow-up electrophysiologic study and tissue assessment for several functional and molecular measures. Results Animals receiving AdCx43 had less electrogram fractionation and faster conduction velocity in the anterior-septal border zone. Only 40% of AdCx43 animals remained inducible for ventricular tachycardia, while 100% of controls were inducible after gene transfer. AdCx43 animals had 2-fold higher Cx43 protein levels in the anterior-septal infarct border, with similar percents of phosphorylated and intercalated disk-localized Cx43 compared with controls. Conclusions These data mechanistically link Cx43 expression to slow conduction and arrhythmia susceptibility in the healed scar border zone. Targeted manipulation of Cx43 levels improved conduction velocity and reduced ventricular tachycardia susceptibility. Cx43 gene transfer represents a novel treatment strategy for post-infarction arrhythmias.

Gap Junctions, Slow Conduction, and Ventricular Tachycardia After Myocardial Infarction

“…The diminished electrical fractionation suggests that enhanced expression of Cx43 partially reversed microscopic heterogeneity in excitation, producing a more uniform propagation pattern that, at the scale of mapping used in this study, would be manifest as an increase in velocity. Greener et al (23) conclude that increased expression of Cx43 in healed infarct border zones is sufficient to reduce arrhythmia susceptibility, and they suggest further that targeted Cx43 gene transfer might be a viable future therapy in patients with post-infarction VT. A skeptic might ask where the significant advance in this work lies. Although the investigators have pioneered the development of gene transfer methods, they used an existing approach in the present study (24).…”

“…Now, in this issue of the Journal, Greener et al(23) report the use of a state-of-the-art targeted gene transfer approach in a large animal model to provide an important new demonstration of the critical role of Cx43 expression and, by inference, cell-cell coupling, in the development of fractionated electrograms, slow conduction, and VT inducibility in the healed infarct border zone. Greener et al(23) subjected Yorkshire pigs to transient left anterior descending coronary artery occlusion to produce infarction and then monitored arrhythmia inducibility as the infarcts healed.…”

“…Greener et al(23) subjected Yorkshire pigs to transient left anterior descending coronary artery occlusion to produce infarction and then monitored arrhythmia inducibility as the infarcts healed. *Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology.…”

The Current and Future Landscape of SERCA Gene Therapy for Heart Failure: A Clinical Perspective

“…There is laboratory evidence supporting its potential utility in the treatment of coronary ischemia and cardiac arrhythmias and as a means to induce cardiac cell repair. [1][2][3][4][5][6][7] It is, however, the application of gene therapy to heart failure that has generated excitement recently with the publication of the first two clinical trials using this novel approach. [8][9][10] In addition, there are several other clinical trials of gene therapy in heart failure now underway.…”

Simvastatin-induced up-regulation of gap junctions composed of connexin 43 sensitize Leydig tumor cells to etoposide: An involvement of PKC pathway

“…It was showed that deterioration or remodeling of myocardiac gap junction correlated to higher vulnerability to ventricular fibrillation or atrial fibrillation (Sato et al, 2008). Nevertheless, an increase of gap junctional conductance by some compounds or methods can protect heart from life-threatening arrhythmia (Greener et al, 2012). Non-antiarrhythmic drugs simvastatin, coming as a surprise, exhibit antiarrhythmic ability in human by some unclear mechanism (Naji et al, 2009;Van Gelder, 2007).…”