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.
Answers are grounded in this paper and cite their sources.
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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