Sonogenetic control of cardiomyocytes and cardiac pacing using exogenous Transient Receptor Potential A1 channels

Electronic cardiac pacemakers are the standard of care for treating arrhythmias but, even for wireless pacemakers, they require an intracardiac implant procedure and are invasive. Lead-related complications, including life-threatening infections, and limited suitability in pediatric patients restrict pacemaker use. Biological pacing has emerged as a hardware-free alternative, leveraging cell reprogramming approaches to generate pacemaker-like cardiomyocytes. Despite progress, biological strategies face challenges related to complex signaling pathways, intercellular coupling, durability of effect, efficacy, and safety. In addition, once ion channels or cells are implanted, biological pacemakers offer limited real-time programmability, whereas electronic pacemakers enable continuous adjustment of pacing output based on cardiac performance. Here we propose a hybrid approach that combines genetic sensitization with external control by exploring the feasibility of sonogenetic cardiac pacing. We express the ultrasound-sensitive ion channel hsTRPA1 in cardiomyocytes and use noninvasive ultrasound to modulate channel activity and cardiac function. Using calcium imaging, we show that hsTRPA1 potentiates ultrasound-evoked responses in cardiomyocytes. Furthermore, cardiac expression of hsTRPA1 in mice increases heart rate in response to ultrasound delivered noninvasively through the intact chest, without evidence of a thermal mechanism under the conditions tested. Together, these results establish a proof of concept for sonogenetic cardiac pacing and define an initial acoustic and genetic parameter space compatible with preserving baseline cardiac function. More broadly, this work positions sonogenetics as a minimally invasive, wireless strategy for cardiac rhythm control and motivates future optimization and safety studies toward translation.