PIEZO1 and cardiac hypertrophy: The high-amplitude Ca2+ stimulus occurring during systolic cardiomyocyte contraction, which stretches T-tubules of cardiomyocytes where Piezo1 is localized, activates calmodulin through the lower-affinity Ca2+ binding sites at its N-lobe, followed by activation of the CaMKII-HDAC4-MEF2 pathway, which leads to cardiac hypertrophy (Figure 4).