Selective Molecular Potassium Channel Blockade Prevents Atrial Fibrillation

Abstract

Background-Safety and efficacy limit currently available atrial fibrillation (AF) therapies. We hypothesized that atrial gene transfer would allow focal manipulation of atrial electrophysiology and, by eliminating reentry, would prevent AF. Methods and Results-In a porcine AF model, we compared control animals to animals receiving adenovirus that encoded KCNH2-G628S, a dominant negative mutant of the I Kr potassium channel ␣-subunit (G628S animals). After epicardial atrial gene transfer and pacemaker implantation for burst atrial pacing, animals were evaluated daily for cardiac rhythm. Electrophysiological and molecular studies were performed at baseline and when animals were euthanized on either postoperative day 7 or 21. By day 10, none of the control animals and all of the G628S animals were in sinus rhythm. After day 10, the percentage of G628S animals in sinus rhythm gradually declined until all animals were in AF by day 21. The relative risk of AF throughout the study was 0.44 (95% confidence interval 0.33 to 0.59, PϽ0.01) among the G628S group versus controls. Atrial monophasic action potential was considerably longer in G628S animals than in controls at day 7, and KCNH2 protein levels were 61% higher in the G628S group than in control animals (PϽ0.01). Loss of gene expression at day 21 correlated with loss of action potential prolongation and therapeutic efficacy. Conclusions-Gene therapy with KCNH2-G628S eliminated AF by prolonging atrial action potential duration. The effect duration correlated with transgene expression. (Circulation.

Recent advances in the molecular pathophysiology of atrial fibrillation

“…A selective small-conductance I KCa channel inhibitor suppresses AF in a range of animal models (144). Still another approach is to use gene transfer to deliver dominant-negative K + channel subunits to selectively prolong atrial APD, which suppresses AF in a porcine model (145).…”

Cardiac gene therapy in large animals: bridge from bench to bedside

“…KCNH2-G628S successfully delayed the onset of atrial fibrillation. 85 Recently, Bauer et al 77 reported intra-atrial delivery of three different genes employing epicardial electroporation: dominant-negative canine ether-a-go-go-related gene channel mutant CERG-G627S, 86 small interfering RNA caspase3 (ref. 87) and connexin 43.…”

“…98 Another pericardial approach employs a camel hair paintbrush to paint the virus on epicardial surface with trypsin and poloxamer gel. 85 This method was reported to achieve transmural gene transfer to the atrium, without negatively affecting the ventricular myocardium.…”

Analysis of Genes Involved in Persistent Atrial Fibrillation: Comparisons of ‘Trigger’ and ‘Substrate’ Differences

“…That study underscores the fact that the pathogenesis of AF and its underlying molecular mechanisms are not completely understood. Recently, a series of preclinical studies suggested that genebased approaches could be used for the diagnosis and treatment of AF [9,10]. Most studies have had encouraging results that indicate the potential of gene-based therapies to combat AF.…”

“…Most studies have had encouraging results that indicate the potential of gene-based therapies to combat AF. Amit's group utilized an adenoviral-mediated delivery of KCNH2 (negative mutant of the IKr potassium channel) into a porcine AF model to enable epicardial atrial gene transfer and pacemaker implantation, as well as electrophysiological and molecular studies [9]. The authors found that KCNH2 transfer prolonged atrial action potential duration and prevented AF [9].…”