Reversal of Stress-Induced PIEZO1 Elevation with Mechanically Adapted Epicardial Patch for Myocardial Infarction Treatment.

Abstract

Elevated expression of the mechanosensitive ion channel PIEZO1 in response to abnormal mechanical stimuli is implicated in many diseases, including myocardial infarction (MI). However, no effective strategy is currently available to normalize PIEZO1 expression for disease management. This study investigates the therapeutic potential of mechanically adapted cardiac patches in reversing PIEZO1 elevation and treating MI. Increased mechanical stress and PIEZO1 upregulation are observed in ischemic cardiomyopathy myocardium. Using finite element analysis, elastomeric patches are designed and applied on MI rats to reduce left ventricular (LV) wall stress and mitigate LV remodeling. Molecular analysis reveals that patch treatment suppresses stress-induced chromatin opening of the Piezo1 promoter, reversing PIEZO1 elevation and restoring heart contraction gene expression. The patch's therapeutic benefits correlate with the reversal of PIEZO1 elevation is further validated in a porcine model. Notably, constant high expression of endogenous PIEZO1 partially blocks the patch's therapeutic effects, confirming that the mechanism of patch treatment involves reversing PIEZO1 expression, in addition to providing physical support. In conclusion, cardiac patches reduce LV wall stress, preserving cardiac function and geometry by both physically supporting and biologically reversing PIEZO1 expression, highlighting the potential of medical devices in normalizing PIEZO1 expression and treating related diseases.