A novel computational model of mouse myocyte electrophysiology to assess the synergy between Na⁺ loading and CaMKII

Ca²⁺-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). This [Na⁺]_i gain promotes intracellular Ca²⁺ ([Ca²⁺]_i) overload by altering the equilibrium of the Na⁺-Ca²⁺ exchanger to impair forward-mode (Ca²⁺ extrusion), and favour reverse-mode (Ca²⁺ influx) exchange. In turn, this Ca²⁺ overload would be expected to further activate CaMKII and thereby form a pathological positive feedback loop of ever-increasing CaMKII activity, [Na⁺]_i, and [Ca²⁺]_i. We developed an ionic model of the mouse ventricular myocyte to interrogate this potentially arrhythmogenic positive feedback in both control conditions and when CaMKIIδC is overexpressed as in genetically engineered mice. In control conditions, simulation of increased [Na⁺]_i causes the expected increases in [Ca²⁺]_i, CaMKII activity, and target phosphorylation, which degenerate into unstable Ca²⁺ handling and electrophysiology at high [Na⁺]_i gain. Notably, clamping CaMKII activity to basal levels ameliorates but does not completely offset this outcome, suggesting that the increase in [Ca²⁺]_i per se plays an important role. The effect of this CaMKII-Na⁺-Ca²⁺-CaMKII feedback is more striking in CaMKIIδC overexpression, where high [Na⁺]_i causes delayed afterdepolarizations, which can be prevented by imposing low [Na⁺]_i, or clamping CaMKII phosphorylation of L-type Ca²⁺ channels, ryanodine receptors and phospholamban to basal levels. In this setting, Na⁺ loading fuels a vicious loop whereby increased CaMKII activation perturbs Ca²⁺ and membrane potential homeostasis. High [Na⁺]_i is also required to produce instability when CaMKII is further activated by increased Ca²⁺ 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 Ca²⁺ and membrane potential dynamics in heart failure.