The role of Connexin45 in the pathogenesis of ventricular tachyarrhythmia

Abstract

Gap junction remodelling occurs in heart disease and likely contributes to the pathophysiology of cardiac arrhythmias. The most abundant cardiac gap junction proteins are Connexin (Cx) 43, 40 and 45. Cx45 expression in cardiac physiology is the least studied and has been associated with cardiac tachyarrhythmia. This thesis phenotyped the rat heart following over-expression of Cx45 by somatic gene transfer and was able to show slowing of conduction as evidenced by prolongation of both PR and QRS intervals seen on the ECG’s of rodent hearts. In addition there was increased ventricular arrhythmia (VA) as compared to control, GFP transduced rats. This is likely due to co-localisation of Cx45 and Cx43 in gap junctions as found in our protein-protein interaction studies. Furthermore knockdown of Cx45 by gene therapy in a disease model of post-myocardial infarction VA, where increased Cx45 was noted, led to reduced VA and sudden cardiac death. In summary this thesis has shown that Cx45 has a role in the pathophysiology of ventricular arrhythmias where an increase in expression leads to increased VA and targeted reduction of Cx45 in a disease model leads to a reduction in VA.