Knockdown Of Nox2 Reduces Rotational Drivers In Af - A New Gene Therapy Approach For Atrial Fibrillation?

Introduction: Oxidative Stress (OS) is thought to be a mediator of atrial fibrillation (AF). However, the precise role of OS in electrical remodeling in AF is unknown. We assessed the effect of a novel gene-based strategy by performing knockdown of NOX2 in a clinically relevant large animal on the maintenance of rotational drivers in AF. Hypothesis: We hypothesized that the gene-based strategy by performing knockdown of NOX2 reduces rotational activities in AF. Methods: 1 week after pacemaker implantation, open-chest sub-epicardial gene injection of NOX2 shRNA was performed in the LA (PLA, LAFW, LAA), to significantly knockdown NOX2 in 6 dogs and 10 controls were also used. Epicardial high-density mapping was performed (117 electrodes, inter-elec.-distance 2.5mm) at day1 (gene injection) and at terminal day (up to 12weeks RAP) in 6 atrial regions. Number and stability of rotational activities were detected based on activation maps and CL was analyzed. Results: AF developed in controls (>30 min) in 4-9 days, compared to >21 days in NOX2 shRNA animals (p<0.01). The stability of observed rotational drivers decreased (baseline gene delivery vs terminal day) in all left atrial regions: in the LAA (315.88±123.53ms, median 300.00ms vs 282.55±175.04ms, median 270ms), PLA (462.46±477.04ms, median 360ms vs 280.39±101.55ms, median 240ms), LAFW (416.67±162.50ms, median 405ms vs 241.67±92.63ms, median 195ms) (Figure A). Number of rotational activities reduced by 36.58% (P=0.14) after gene delivery. CL increased in the PLA from (93.74±30.11ms, median 85.00ms to 102.15±33.07ms, median 92.00ms after gene delivery (Figure C). Conclusions: Gene injection by NOX2 shRNA reduced the stability of rotational activities in AF. OS may be an important, dynamic mechanism underlying the formation and maintenance of the AF disease state. Targeted disruption of NOX2-dependent oxidative injury with a new gene therapy approach prevents onset as well as the perpetuation of AF.