Key result
In a computational model of human ventricular myocytes, the combined effect of CaMKII overexpression and β-adrenergic signaling activation increased the risk of early afterdepolarizations.
Computational modeling demonstrates that combined CaMKII overexpression and beta-adrenergic activation increases the risk of early afterdepolarizations in human ventricular myocytes.
Highlights synergistic EAD risk in computational models; leaves open in vivo validation and therapeutic targeting.
Early afterdepolarization (EAD) plays an important role in arrhythmogenesis. Many experimental studies have reported that Ca 2+ /calmodulin-dependent protein kinase II (CaMKII) and β -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 β -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 (INaL) deactivation progress; (2) the combined effect of CaMKII overexpression and activation of β -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 (IKr) blockage (77% versus 85%). In summary, this study computationally demonstrated the combined role of CaMKII and β -adrenergic signaling pathway on the occurrence of EADs, which could be useful for searching for therapy strategies to treat EADs related arrhythmogenesis.
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Dai et al. (2016) studied Early afterdepolarization and arrhythmogenesis. CaMKII overexpression and activation of β-adrenergic signaling pathway vs. Baseline conditions was evaluated on Occurrence of early afterdepolarizations (EADs). In a computational model of human ventricular myocytes, the combined effect of CaMKII overexpression and β-adrenergic signaling activation increased the risk of early afterdepolarizations.
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