2160Continuous shock-free termination of atrial fibrillation by local optogenetic therapy and arrhythmia-triggered activation of an implanted light source

Abstract

Abstract Background Maintenance of sinus rhythm is the primary therapeutic goal for symptomatic atrial fibrillation (AF) patients but remains difficult to achieve because of suboptimal treatment options. While being effective in detecting and terminating AF, the widespread use of implantable atrial defibrillators is limited due to patients intolerance to repeated shocks. The negative adverse effects of electroshock therapy can hypothetically be overcome by allowing the heart itself to produce the electric current required for arrhythmia termination. As a result, the effector function of an electrical defibrillator would be provided by the heart itself, and therefore no longer rely on electronics, but on bioelectricity instead. Purpose To develop a hybrid bio-electronic system for automated and acute shock-free AF treatment. Methods To equip the heart with the effector function of the envisioned AF termination system, adeno-associated virus (AAV) vectors encoding red-activatable channelrhodopsin (ReaChR) (n=12) or citrine (n=4) were delivered locally to the right atrium (RA) of adult Wistar rats by gene painting. Four to 8 weeks later, AF was induced in vivo by atrial burst pacing after carbachol administration, followed by programmed local illumination of the RA by an implanted intrathoracic LED device whose activation was automatically regulated by an electrocardiogram (ECG)-based cardiac rhythm monitor. Results Gene painting of the RA resulted in transmural transduction of right atrial myocytes (78±6%) with minimum transgene expression of the left atrium and ventricles (6±2% and <0.5%, respectively). Electrophysiological assessments revealed no significant differences in ECG characteristics, atrial action potential duration and conduction velocity when compared to baseline or citrine control animals. Feasibility of optical AF termination was first assessed in an open-chest rat model, showing that a single 470-nm light pulse (3.5 mW/mm2, 1000 ms) efficiently terminated AF in all ReaChR-expressing rats with an average termination efficacy of 94±3% (n=12) vs. 3±3% (n=4) in citrine-expressing control animals (p<0.01). AF termination efficacy remained superb following automated detection and termination of AF by ECG-triggered activation of the implanted intra-thoracic LED in closed-chest ReaChR-expressing rats (96±4%), n=4), whereas none of the AF episodes were terminated in control rats (0%, n=4) (p<0.01). No bradycardias or other arrhythmias were observed following optical AF termination. Conclusions By using a hybrid bio-electronic approach to modulate cardiac excitability, our study delivers proof that AF can be detected and terminated automatically in a safe, effective and repetitive, yet shock-free manner. These findings may create the basis for the development of pain-free device therapy for cardiac arrhythmias, thereby paving the way for ambulatory AF treatment with the perspective to improve patients' prognosis and quality of life. Acknowledgement/Funding NWO Vidi grant (1714336) and ERC Starting Grant (716509) both to D.A.P.