Piezo2 expressed in ganglionated plexi: Potential therapeutic target of atrial fibrillation.

Summary

Piezo2 is upregulated in cardiac ganglionated plexi in AF and with higher left atrial pressure; targeted knockdown of Piezo2 in GP reduces neural activity and AF susceptibility in a large-animal model. Transcriptomics implicated Notch pathway downregulation, supporting a mechanistic link between mechanosensation and autonomic modulation in AF.

Key Findings

• Piezo2 expression in cardiac ganglionated plexi is increased in AF and with higher left atrial pressure.
• AAV-mediated Piezo2 knockdown in GP reduces neural activity and lowers AF inducibility in a large-animal rapid pacing model.
• RNA-seq implicates downregulation of the Notch signaling pathway following Piezo2 knockdown, suggesting mechanistic links.

Clinical Implications

Piezo2 in GP could be targeted pharmacologically or via gene modulation to reduce AF susceptibility, informing future device- or bio-therapies and potentially refining patient selection for GP ablation.

Limitations

• Translational gap remains; no first-in-human interventional targeting of Piezo2.
• Long-term safety and specificity of GP-targeted gene modulation are unknown.

Future Directions

Develop selective Piezo2 modulators or neuromodulation strategies; evaluate efficacy/safety in chronic large-animal models and design early-phase human trials integrating autonomic and electrophysiologic endpoints.