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 alpha-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, P<0.01) 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 (P<0.01). 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.

Conflict of interest statement

Disclosure. The authors declare no competing financial or conflicting interests.

Figures

Figure 1

Rhythm on daily telemetry as a function of time since gene transfer. The left panel shows that control animals (N=10) continually progress toward persistent AF after initiation of burst atrial pacing, whereas the G628S animals (N=7) show an abrupt increase in percent with sinus rhythm 3 days after gene transfer, correlating with onset of gene expression. G628S animals maintained sinus rhythm until days 11-18, correlating with the time that gene expression is lost. The right panel shows examples of telemetry recordings from animals 8 days after gene transfer.

Figure 2

Change in MAPD90 at the termination study relative to the baseline study. a. The left panel shows changes in atrial MAPD90 for the indicated groups, and the right panel shows changes in ventricular MAPD90, measured from the basal left and right ventricles in close proximity to the atria. The bars represent the median change and the lines represent the corresponding inter-quartile range. For 1-week data: N=5 for both the controls and HERG-G628S groups. For the 3 week data: N=10 for the controls and N-7 for HERG-G628S groups, respectively. (* p ≤ 0.01, † p = 0.06, ‡ p =NS) b. Representative MAPD90 tracings from individual animals in the indicated groups for the indicated heart chamber. G is the KCNH2-G628S group, C is the control group,.

Figure 3

KCNH2 protein expression measured with Western blot. The left panel shows the level of KCNH2 expression in the KCNH2-G628S group relative to the control group at the indicated time point. Individual bands were normalized to GAPDH prior to analysis. The right panel shows the actual western blot bands. (* p