Preclinical efficacy and safety of KCNH2-G628S gene therapy for postoperative atrial fibrillation

Abstract

Background: Postoperative atrial fibrillation (POAF) is the most common complication occurring after cardiac surgery. Multiple studies have shown significantly increased risks of stroke, myocardial infarction, and death associated with POAF. Current prophylaxis strategies are inadequate to eliminate this problem. We examined the preclinical efficacy and safety of KCNH2-G628S gene transfer to prevent POAF.

Methods: Domestic pigs received AdKCNH2-G628S by epicardial atrial gene painting and atrial pacemaker implantation for continuous-burst pacing to induce atrial fibrillation. In an initial dose-ranging evaluation, 3 pigs received 5 × 1010 to 5 × 1011 virus particles. In the formal study, 16 pigs were randomized to 3 groups: 5 × 1011 virus particles of AdKCNH2-G628S with 20% Pluronic P407 in saline, 20% Pluronic P407 in saline with no virus, and saline alone. Animals were followed with daily efficacy and safety evaluations through the period of peak adenovirus-mediated transgene expression. After 14 days, pacing was discontinued, and the animals were followed in sinus rhythm for an additional 14 days to assess any longer-term toxicity.

Results: In the primary efficacy analysis, the G628S animals exhibited a significant increase in the average time in sinus rhythm compared with the Pluronic control group (59 ± 7% vs 14 ± 6%; P = .009). There was no significant difference between the Pluronic and saline controls (14 ± 6% vs 32 ± 12%; P = .16). Safety assessment showed improved left ventricular function in the G628S animals; otherwise there were no significant differences among the groups in any safety measure.

Conclusions: These data indicate that KCNH2-G628S gene therapy can successfully and safely reduce the risk of AF.

Keywords: atrial fibrillation; gene therapy; operative complications; potassium channel.

Published by Elsevier Inc.

Figures

Figure 1:

Study design.

Figure 2:

Percentage of time in sinus rhythm per day after gene painting. Compared to pluronic controls, animals exposed to G628S had a significant decrease in AF even with the continued stress of aggressive burst atrial pacing (p = 0.0006). Saline and pluronic controls were not statistically different. Figure 2 is designated as the central figure. Abbreviated legend: KCNH2-G628S gene transfer decreases atrial fibrillation risk.

Figure 3:

Clinical observations: daily assessment of (A) overall clinical status, (B) activity, (C) appetite, (D) thirst, (E) urine and (F) stool output was recorded using a 2–5 point numerical scale with guidance from the descriptors shown on the graphs. The investigator evaluating the animals was masked to study group identity of each animal. The G628S group is the black square. The pluronic group is the red circle. The saline group is the blue triangle. There were no statistically significant differences between groups.

Figure 4:

Clinical measurements: daily measurement of (A) ventricular rate from ECG, (B) respiratory rate (C) body temperature and (D) QTc from ECG were performed. The animals were weighed weekly. The shaded box indicates the period of time after burst pacing was discontinued. There were no statistically significant between group differences for any measurement.

Figure 5:

Example microsections from hearts of animals receiving AdG628S (left) and pluronic/saline (right). There were no differences between groups when comparing pathological findings in right atria (a,e), right ventricles (b,f), left atria (c,g) or left ventricles (d,h). Pathological findings of hypertrophy and myolysis in all chambers from all animals were consistent with structural remodeling from AF and heart failure. No treatment-specific pathological findings were observed.