In summary, this study first establishes the association between the TPM1-p.E181K mutation and sporadic RCM, demonstrating that its pathogenesis is mediated through a cascade of events: calcium dyshomeostasis leads to suppression of CaMKII/HDAC4 phosphorylation, which subsequently causes sarcomeric disruption, and ultimately results in myocardial hypercontractility. Here, HDAC4 is linked to cardiomyopathy, familial restrictive, 1.