Using a conditional, cardiomyocyte-specific Piezo1 KO mouse model, we showed that deletion of Piezo1 completely prevented activation of the CaMKII-HDAC4-MEF2 hypertrophic signaling pathway after TAC, and this was associated with significant inhibition of the hypertrophic response to pressure overload. Here, PIEZO1 is linked to persistent truncus arteriosus.