Integrative Cardiovascular Physiology and Pathophysiology: Ca2+/calmodulin-dependent kinase II-dependent regulation of atrial myocyte late Na+ current Ca2+ cycling and excitability: a mathematical modeling study

摘要

Atrial fibrillation (AF) affects more than three million people per year in the United States and is associated with high morbidity and mortality. Both electrical and structural remodeling contribute to AF, but the molecular pathways underlying AF pathogenesis are not well understood. Recently, a role for Ca²⁺/calmodulin-dependent protein kinase II (CaMKII) in the regulation of persistent “late” Na⁺ current (INa,L) has been identified. Although INa,L inhibition is emerging as a potential antiarrhythmic strategy in patients with AF, little is known about the mechanism linking INa,L to atrial arrhythmogenesis. A computational approach was used to test the hypothesis that increased CaMKII-activated INa,L in atrial myocytes disrupts Ca²⁺ homeostasis, promoting arrhythmogenic afterdepolarizations. Dynamic CaMKII activity and regulation of multiple downstream targets [INa,L, L-type Ca²⁺ current, phospholamban, and the ryanodine receptor sarcoplasmic reticulum Ca²⁺-release channel (RyR2)] were incorporated into an existing well-validated computational model of the human atrial action potential. Model simulations showed that constitutive CaMKII-dependent phosphorylation of Nav1.5 and the subsequent increase in INa,L effectively disrupt intracellular atrial myocyte ion homeostasis and CaMKII signaling. Specifically, increased INa,L promotes intracellular Ca²⁺ overload via forward-mode Na⁺/Ca²⁺ exchange activity, which greatly increases RyR2 open probability beyond that observed for CaMKII-dependent phosphorylation of RyR2 alone. Increased INa,L promotes atrial myocyte repolarization defects (afterdepolarizations and alternans) in the setting of acute β-adrenergic stimulation. We anticipate that our modeling efforts will help identify new mechanisms for atrial NaV1.5 regulation with direct relevance for human AF.>NEW & NOTEWORTHY Here, we present a novel computational model to study the effects of late Na⁺ current (INa,L) in human atrial myocytes. Simulations predict that INa,L promotes intracellular accumulation of Ca²⁺, with subsequent dysregulation of Ca²⁺/calmodulin-dependent protein kinase II (CaMKII) signaling and ryanodine receptor 2-mediated Ca²⁺ release. Although INa,L plays a small role in regulating atrial myocyte excitability at baseline, CaMKII-dependent enhancement of the current promoted arrhythmogenic dynamics.Listen to this article’s corresponding podcast at .