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.

• Authors: Ian D Greener, Tetsuo Sasano, Xiaoping Wan, Tomonori Igarashi, Maria Strom, David S Rosenbaum, J Kevin Donahue
• Journal: Journal of the American College of Cardiology (J Am Coll Cardiol) Vol. 60 Issue 12 Pg. 1103-10 (Sep 18 2012) ISSN: 1558-3597 [Electronic] United States
• PMID: 22883636 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2012 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

Chemical References

• Connexin 43

Topics

• Animals
• Connexin 43 (administration & dosage, genetics)
• Disease Susceptibility (metabolism, physiopathology, therapy)
• Gene Transfer Techniques
• Genetic Therapy (methods)
• Heart Conduction System (metabolism, physiopathology)
• Myocardial Infarction (complications, genetics, therapy)
• Random Allocation
• Swine
• Tachycardia, Ventricular (etiology, genetics, therapy)