Abstract 4142818: Odorgenetics-based noninvasive and precise neuromodulation of cardiac ganglia plexus prevents myocardial ischemia-induced ventricular arrhythmia

Background: Autonomic imbalance exacerbates arrhythmia after myocardial infarction. Previous studies have utilized optogenetics and other techniques to modulate cardiac autonomic rebalance and significantly suppressed arrhythmia. However, electrical or optogenetic modulation requires implantation of device with electrodes or opto-electrodes, which is invasive and has a limited battery life. Research Questions: Odorgenetics technology is based on the binding of volatile odor molecules to specific G-protein coupled olfactory receptors to rapidly activate neurons. This study aimed to utilize odorgenetics to noninvasively and precisely modulate cardiac ganglia plexus (GPs) to prevent myocardial ischemia-induced ventricular arrhythmias (VAs). Methods: Canines were divided into the control group (n=6) and the odorgenetics group (n=6). pAAV-CMV-Or35a-Or83b-EGFP-tWPA was microinjected into GPs to specifically express olfactory receptors Or35a-Or83b in the odorgenetics group. Four weeks after injection, the volatile odorant molecule 2-pentanone was delivered via inhalation to activate Or35a-Or83b for GP modulation. Myocardial ischemia was induced by 1h left anterior descending occlusion followed with 1h reperfusion. GP odorgenetic stimulation was performed for 2h simutaneously. GP function and neural activity, effective refractory period (ERP), and VAs were measured. Results: Neurons in the GPs were transfected EGFP + in the odorgenetics group. Compared to the control group, inhalation of the odorant molecule 2-pentanone significantly activated GP function and neural activity in the odorgenetics group. Moreover, odorgenetic modulation showed a fast on-off effects on GP neural activity, that is, it can rapidly and reversibly modulate GP neural function and activity. In the control group, myocardial ischemia shortened ERP and increased spatial dispersion, which was improved by GP odorgenetic stimulation. In addition, myocardial ischemia induced VAs were significantly decreased by GP odorgenetic modulation (number of VT/VF: 3.5±4.5 vs. 14.8±7.7, P<0.05 vs. control group). Conclusion: Odorgenetics technology enables noninvasive and fast on-off neuromodulation of cardiac GP, and thus prevents myocardial ischemia-induced VAs.