Abstract 15082: The Effects of Connexin45 Over-Expression on Cardiac Physiology in the Intact Animal
Introduction: Gap junction remodelling occurs in heart disease and likely contributes to the pathophysiology of cardiac arrhythmias. The most abundant cardiac gap junction proteins (connexins) are connexin (Cx) 43, 40 and 45. Limited information is available on the role of Cx45 expression in cardiac electrophysiology. Our aim was to phenotype the rat heart following overexpression of Cx45 by somatic gene transfer.
Methods: Adult Sprague-Dawley rats were tail vein (TV) injected with 2x1012 vector genomes of recombinant adeno-associated virus (rAAV2/9) encoding either eGFP or rat Cx45 cDNA. Electrophysiological studies (EPS) were carried out on anaesthetised rats on Days 0 and 28 following injection. EPS consisted of surface and transoesophageal ECGs.
Results: Twelve rats were injected with rAAV2/9 eGFP and 20 with rAAV2/9 Cx45. Immunofluorescence imaging revealed a transduction efficiency of >90% with TV injection. Surface ECG revealed PR prolongation 56.5±13.0ms at Day 28 vs 46.2±6.0ms at baseline (P=0.003)) in Cx45 treated rats. Heart block was seen in five Cx45 treated rats and in none of the eGFP treated rats. The QRS duration in the Cx45 group was significantly prolonged at day 28 compared to baseline (16.2±1.8ms vs 14.8±1.9ms (P=0.02)) while the eGFP group had no significant change (14.7±1.5ms vs 15.4±1.5ms (P=0.35)). Importantly more Cx45 transduced rats had ventricular tachyarrhythmia (VT/VF) induced by pacing protocols. At day 28, twelve Cx45 transduced rats had VT/VF versus none of the eGFP treated rats (P=0.001).
Conclusion:Cardiac over-expression of Cx45 slowed conduction as evidenced by PR prolongation, heart block and QRS widening at Day 28 ECG recordings. In addition, Cx45 over-expression modified ventricular myocardium increasing the propensity for inducible ventricular arrhythmia.
- © 2012 by American Heart Association, Inc.