Auricular Vagus nerve stimulation alleviates cardiac dysfunction in Takotsubo syndrome by inhibiting excessive activation of the sympathetic nerve system and inflammation.

Abstract

BACKGROUND: Takotsubo syndrome (TTS) is a stress-induced cardiac disorder that closely resembles acute coronary syndrome but lacks effective and safe therapeutic interventions. This study aimed to investigate the cardioprotective effects of transcutaneous auricular vagus nerve stimulation (taVNS), a noninvasive neuromodulation technique, in a rat model of TTS-like cardiomyopathy. METHODS: Sprague-Dawley rats were randomly assigned to three groups: sham, TTS, and TTS + taVNS. TTS was induced by intraperitoneal injection of isoprenaline, while taVNS was applied for 1 hour. Cardiac function was assessed using electrocardiography, heart rate variability, and ventricular electrophysiological recordings. Histopathological changes, inflammatory responses, and autonomic nervous system activity were analyzed. RNA sequencing was performed to explore underlying molecular mechanisms, with key findings validated by RT-qPCR and Western blotting. RESULTS: Noninvasive taVNS significantly improved left ventricular dysfunction in TTS rats, reducing arrhythmia susceptibility, myocardial injury, and collagen reaction. The treatment significantly suppressed sympathetic overactivation and systemic inflammation. Transcriptomic analysis identified the TLR2/MAPK pathway as a key mediator of inflammation in taVNS-induced protection. Moreover, taVNS significantly downregulated expression of TLR2/MAPK pathway and proinflammatory cytokines confirmed at both mRNA and protein levels compared to the TTS group. CONCLUSIONS: Noninvasive taVNS offers broad cardioprotection in TTS through inhibiting the sympathetic nerve and inflammation. This approach holds promise as an adjunct therapy for TTS, offering benefits in inflammation control, structural preservation, and electrical stability of the heart.