Key result
In 113 patients undergoing CABG, sleep-disordered breathing was independently associated with increased CaMKII activity, enhanced late INa, and premature atrial contraction severity.
Why the study?
Sleep-disordered breathing is frequently associated with atrial arrhythmias, and researchers hypothesized that CaMKII-dependent dysregulation of late INa contributes to atrial proarrhythmic activity in these patients.
Does sleep-disordered breathing increase CaMKII-dependent late INa and atrial proarrhythmic activity in patients undergoing coronary artery bypass grafting?
Cross-Sectional (n=113)
Does sleep-disordered breathing increase CaMKII-dependent late INa and atrial proarrhythmic activity in patients undergoing coronary artery bypass grafting?
In patients with sleep-disordered breathing, increased CaMKII-dependent phosphorylation of NaV1.5 dysregulates INa, leading to atrial proarrhythmic activity that can be reversed by CaMKII inhibition.
Supports mechanistic link between sleep-disordered breathing and atrial ectopy via CaMKII in CABG patients; hypothesis-generating pending prospective trials.
Rationale: Sleep-disordered breathing (SDB) is frequently associated with atrial arrhythmias. Increased CaMKII (Ca/calmodulin-dependent protein kinase II) activity has been previously implicated in atrial arrhythmogenesis. Objective: We hypothesized that CaMKII-dependent dysregulation of Na current (I Na ) may contribute to atrial proarrhythmic activity in patients with SDB. 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 ≥15/h) was assessed with a portable SDB monitor the night before surgery. Compared with 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 V 1.5, at serine 571, Western blotting). These gating changes could be fully reversed by acute CaMKII inhibition (AIP [autocamtide-2 related inhibitory peptide]). As a consequence, we observed significantly more cellular afterdepolarizations and more severe premature atrial contractions in atrial trabeculae of patients with SDB, which could be blocked by either AIP or KN93 (N-[2-[[[(E)-3-(4-chlorophenyl)prop-2-enyl]-methylamino]methyl]phenyl]-N-(2-hydroxyethyl)-4-methoxybenzenesulfonamide). In multivariable linear regression models incorporating age, sex, body mass index, existing atrial fibrillation, existing heart failure, diabetes mellitus, and creatinine levels, apnea-hypopnea index was independently associated with increased CaMKII activity, enhanced late I Na and correlated with premature atrial contraction severity. Conclusions: In atrial myocardium of patients with SDB, increased CaMKII-dependent phosphorylation of Na V 1.5 results in dysregulation of I Na with proarrhythmic activity that was independent from preexisting comorbidities. Inhibition of CaMKII may be useful for prevention or treatment of arrhythmias in SDB. Clinical Trial Registration: URL: http://www.clinicaltrials.gov . Unique identifier: NCT02877745. Visual Overview: An online visual overview is available for this article.
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Lebek et al. (2020) conducted a cross-sectional in Sleep-disordered breathing (n=113). Sleep-disordered breathing vs. No sleep-disordered breathing was evaluated on CaMKII activity, late INa, and premature atrial contraction severity. In 113 patients undergoing CABG, sleep-disordered breathing was independently associated with increased CaMKII activity, enhanced late INa, and premature atrial contraction severity.
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