Enhanced CaMKII-Dependent Late INa Induces Atrial Pro-Arrhythmic Activity in Patients with Sleep-Disordered Breathing.

Rationale: Sleep-disordered breathing (SDB) is frequently associated with atrial arrhythmias. Increased Ca/calmodulin-dependent protein kinase II (CaMKII) activity has been previously implicated in atrial arrhythmogenesis. Objective: We hypothesized that CaMKII-dependent dysregulation of Na current (I_Na) may contribute to atrial pro-arrhythmic activity in SDB patients. Methods and Results: We prospectively enrolled 113 patients undergoing elective coronary artery bypass grafting for cross-sectional study and collected right atrial appendage biopsies. The presence of SDB (defined as apnea-hypopnea index, AHI {greater than or equal to}15/h) was assessed with a portable SDB monitor the night before surgery. Compared to 56 patients without SDB, patients with SDB (57) showed a significantly increased level of activated CaMKII. Patch clamp was used to measure I_Na. There was a significantly enhanced late I_Na but reduced peak I_Na due to enhanced steady-state inactivation in atrial myocytes of patients with SDB consistent with significantly increased CaMKII-dependent cardiac Na channel phosphorylation (Na_V1.5, at serine 571, Western blotting). These gating changes could be fully reversed by acute CaMKII inhibition (AIP). As a consequence, we observed significantly more cellular afterdepolarizations and more severe premature atrial contractions (PACs) in atrial trabeculae of SDB patients, which could be blocked by either AIP or KN93. In multivariable linear regression models incorporating age, gender, body mass index, existing AF, existing heart failure, diabetes and creatinine levels, AHI was independently associated with increased CaMKII activity, enhanced late I_Na and correlated with PAC severity. Conclusions: In atrial myocardium of SDB patients, increased CaMKII-dependent phosphorylation of Na_V1.5 results in dysregulation of I_Na with pro-arrhythmic activity that was independent from pre-existing co-morbidities. Inhibition of CaMKII may be useful for prevention or treatment of arrhythmias in SDB.