CaMKII-dependent activation of late INa contributes to cellular arrhythmia in a model of the cardiac myocyte

Cardiac voltage-gated Na⁺ channels underlie membrane depolarization during the upstroke of the action potential (AP). These channels also exhibit a late, slowly-inactivating component of current (late I_Na) that may be enhanced under pathological conditions such as heart failure, and may therefore promote AP prolongation and increase the likelihood of arrhythmia. Ca²⁺/calmodulin-dependent protein kinase II (CaMKII) functionally modifies Na⁺ channels, however it remains unclear if the CaMKII-dependent changes in late I_Na are a major contributor to cellular arrhythmias such as early after depolarizations (EADs). In this study we develop a model of I_Na, including CaMKII-dependent effects, based on experimental measurements. The Na⁺ channel model is incorporated into a computational model of the whole myocyte which describes excitation-contraction coupling via stochastic simulation of individual Ca²⁺ release sites. Simulations suggest that relatively small augmentation of late I_Na is sufficient to significantly prolong APs and lead to the appearance of EADs.