Mechanosensitive Channel Piezo1 in R403Q Hypertrophic Cardiomyopathy: A Computational Study.

Piezo1 is a tension-gated cation channel with a voltage-dependent inactivation and Ca ²⁺ -permeability. In mice, cardiac Piezo1 shows maladaptive dynamics and evokes a hypertrophic response to pressure overload. Mutation-specific hypertrophic feedback to Piezo1 has not been addressed before. Here, we present a novel mechanistic model of Piezo1 current and add it to our in silico whole-cell model of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) to study the mechanotransduction in the presence of MYH7 ^R403Q/+ condition. Our biophysical model of Piezo1 has a tension-dependent activation and a novel voltage-dependent inactivation gate. We modeled MYH7 ^R403Q/+ hypertrophic cardiomyopathy (HCM) following our previous model by altering DRX/SRX myosin ratio and elevating myofilament MgADP and inorganic phosphate. Normalized current-tension relationships of Piezo1 showed a 27.9% increase in Boltzmann slope due to MYH7 ^R403Q/+ HCM. However, the half-maximal activation (P50) elevated 16.7%. This work contributes to investigations on the capacity of mechanotransduction, particularly cardiac Piezo1 channel, as a potential drug target for mutation-specific HCM.