Abstract 4136181: Automated Personalized Modulation of the Sympathetic “fight-or-flight” Reflex In Vivo Using Implantable Microdevices for Enhancing Neurocardiac Function and Reducing Mortality Risk.

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Background: The sympathetic nervous system (SNS) is a critical regulator of cardiovascular function. Whereas acute SNS activation elicits positive inotropy and confers survival advantage, persistent SNS hyperactivity is maladaptive and can lead to arrhythmias, cardiac arrest and heart failure. Hypothesis: Automated optogenetic modulation of the sympathetic stress response in vivo enhances neurocardiac function while avoiding sympathetic hyperactivity-mediated pathological effects. Methods: In normal guinea pigs, we virally transduced excitatory and/or inhibitory channelrhodopsins to the stellate ganglia (SG), the primary sympathetic input to the heart. We studied in situ effects of graded activation of SG opsins (e.g., phasic vs tonic) on cardiac function (e.g., ECG, heart rate) with and without perfusing agents (e.g., β-blockers, antioxidants). In vivo studies used novel implanted µLED devices for wireless body signal streaming (e.g., ECG) and neurophotonic SG opsin modulation closed-loop to dynamic analyses of physiological demand versus ECG-based cardiac risk prediction. Results: Compared to baseline heart rate (218±16 bpm), pulsed activation of inhibitory opsins reduced heart rate by ~25% (156±12; delta=67±14 bpm; p<0.0003; N=5). Pulsed activation of excitatory opsins increased heart rate by ~30% (285±28; delta=65±19 bpm; p<0.0002; N=5). Interestingly, prolonged (>20 min) tonic excitation of the SG caused desensitization, possibly as an intrinsic safety mechanism. Whereas graded SG excitation or inhibition at different LED intensities elicited prompt changes in heart rate, repeated activation of excitatory opsins led to quick desensitization. Our ongoing studies are aimed at understanding how and when SG modulation can enhance cardiac function, trigger intrinsic cardioprotective mechanisms, or cause pathological effects. Conclusion: Automated neurophotonic optogenetic excitation or inhibition of the SG is a robust personalized strategy for modulating cardiovascular function. The ability to rapidly and accurately modulate the sympathetic stress reflex in a graded manner can lead to more timely, effective, and appropriate physiological responses while avoiding undesired pathophysiological responses.

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