Role of CaMKII and PKA in early afterdepolarization of human ventricular myocardium cell: a computational model study (Q2013943)

Summary: Early afterdepolarization (EAD) plays an important role in arrhythmogenesis. Many experimental studies have reported that Ca\(^{2+}\)/calmodulin-dependent protein kinase II (CaMKII) and \(\beta\)-adrenergic signaling pathway are two important regulators. In this study, we developed a modified computational model of human ventricular myocyte to investigate the combined role of CaMKII and \(\beta\)-adrenergic signaling pathway on the occurrence of EADs. Our simulation results showed that (1) CaMKII overexpression facilitates EADs through the prolongation of late sodium current's (\(I_{\mathrm{NaL}}\)) deactivation progress; (2) the combined effect of CaMKII overexpression and activation of \(\beta\)-adrenergic signaling pathway further increases the risk of EADs, where EADs could occur at shorter cycle length (2000\ ms versus 4000\ ms) and lower rapid delayed rectifier K\(^+\) current (\(I_{\mathrm{Kr}}\)) blockage (77\% versus 85\%). In summary, this study computationally demonstrated the combined role of CaMKII and \(\beta\)-adrenergic signaling pathway on the occurrence of EADs, which could be useful for searching for therapy strategies to treat EADs related arrhythmogenesis.