Sonogenetic neuromodulation prevents post-myocardial infarction malignant arrhythmia and cardiac remodeling through the brain-heart circuit.

Abstract

Sympathetic hyperactivation within the paraventricular nucleus (PVN) exacerbates post-myocardial infarction (MI) malignant ventricular arrhythmias (VAs) and cardiac remodeling. Sonogenetics is an emerging reversible neuromodulation, which might achieve precise spatio-temporal controllability over targeted neurons. However, the current sonogenetic neuromodulation (SGN) strategies are mainly designed to facilitate neuronal activation, and experimental evidence supporting neuronal inhibition remains elusive. In the current study, we conducted the first inhibitory sonogenetic neuromodulation system by the mechanosensitive ion channel named TWIK-related arachidonic acid-activated K+ channel (TRAAK). rAAV2/9-hsyn-TRAAK-P2A-EGFP was microinjected into the PVN to overexpression TRAAK. Transcranial ultrasound stimulation (TUS) (1.0 MHz, 2.0 W/cm2) was employed to activate the TRAAK channels to facilitate sympathetic hyperpolarization. Electrocardiogram recordings, cardiac electrophysiological experiments, and histopathological staining were performed to assess the protective role of sonogenetic neuromodulation in the acute and chronic phases of MI. The results indicated that sonogenetic neuromodulation reverses the excessive sympathetic activation and autonomic imbalance induced by MI. Furthermore, sonogenetic neuromodulation prevents acute MI-induced malignant VAs and improves the myocardial inflammatory microenvironment through the PVN-left stellate ganglion (LSG)-heart circuit. In the chronic phase of MI, long-term sonogenetic neuromodulation has been demonstrated to alleviate cardiac dysfunction, inhibit ventricular remodeling, and improve cardiac electrophysiological stability. Collectively, TRAAK-mediated sonogenetic modulation of the PVN inhibits sympathetic hyperactivation, thereby preventing MI-induced malignant arrhythmias and adverse cardiac remodeling.