Taken together, these data suggested that Piezo1 perturbed calcium homeostasis by mediating the intracellular Ca2+ overload and increased the activation of Ca2+-modulated signaling, CaMKII, and calpain, leading to the enhancement of phosphorylation of RyR2 and further increment of Ca2+ leaking, which finally provoked cardiac arrhythmias. This evidence concerns the gene RYR2 and cardiac arrhythmia.