A Novel Computational Model of Mouse Myocyte Electrophysiology to Assess the Synergy Between Na Loading and CaMKII

Abstract

Ca/Calmodulin-dependent protein kinase II (CaMKII) hyperactivity in heart failure causes intracellular Na ([Na]i) loading (at least in part by enhancing the late Na current (INaL)). This [Na]i gain promotes intracellular Ca ([Ca]i) overload by altering the equilibrium of the Na/Ca exchanger to impair forward-mode (Ca extrusion), and favor reverse-mode (Ca influx) exchange. In turn, this Ca overload is expected to further activate CaMKII thereby forming a pathologic positive feedback loop of ever-increasing CaMKII activity, [Na]i, and [Ca]i. We developed a computational framework to interrogate this potentially arrhythmogenic positive feedback in the mouse ventricular myocyte in both control conditions and when CaMKIIδC is overexpressed as in transgenic mice. In control conditions, simulation of an increase in [Na]i causes the expected increases in [Ca]i, CaMKII activity, and target phosphorylation, which degenerate into unstable Ca handling and and electrophysiology at high [Na]i gain. Notably, clamping CaMKII to basal levels ameliorates but does not completely offset this outcome, suggesting that the increase in [Ca]i per se plays an important role. The effect of this CaMKII-Na-Ca-CaMKII feedback is more striking in CaMKIIδC overexpression, where high but not low [Na]i causes delayed afterdepolarizations, which can be prevented by clamping CaMKII phosphorylation of L-type Ca channels, ryanodine receptors and phospholamban to basal levels. In this setting, Na loading fuels a vicious loop whereby increased CaMKII activation perturbs Ca and membrane potential homeostasis. High [Na]i is also required to produce instability when CaMKII is further activated by increased Ca loading due to β-adrenergic activation. Our results support recent experimental findings of a synergistic interaction between perturbed Na fluxes and CaMKII, and suggest that pharmacological inhibition of intracellular Na loading can contribute to normalizing Ca and membrane potential dynamics in heart failure.