Enhanced CaMKII-Dependent Late I _Na Induces Atrial Proarrhythmic Activity in Patients With Sleep-Disordered Breathing

Abstract

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.

Interaktionen schlafbezogener Atmungsstörungen mit Vorhofflimmern

“…2 wird der Zusammenhang von apnoeassoziierten Arrhythmien und progressivem strukturellen Remodeling veranschaulicht [52]. [54]. Durch diese entsteht ein signifikanter Repolarisationsgradient, welcher frühe und verspätete Depolarisationen begünstigt und somit kardiale Arrhythmien entstehen lässt [53,54].…”

“…[54]. Durch diese entsteht ein signifikanter Repolarisationsgradient, welcher frühe und verspätete Depolarisationen begünstigt und somit kardiale Arrhythmien entstehen lässt [53,54]. In einem Tiermodell der OSA führt negativer Trachealdruck zu einer ausgeprägten Verkürzung der atrialen effektiven Refraktärzeit (ERP) und einer erhöhten Induzierbarkeit von VHF, die durch sympathische α-und β-Wege, vagale Aktivierung und ganglionäre Plexus vermittelt werden [55].…”

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“…Increased CaMKII expression has been shown in multiple studies to be implemented in the pathogenesis of heart failure, hypertrophy, and arrhythmias [8,9,31], and has also been found in patients with sleep-disordered breathing [4]. Therefore, we analyzed CaMKII expression in ventricular homogenates of PTFE-treated (N = 6) and control mice (N = 9) at 8-week follow up by Western blotting (Fig 6).…”

“…Obstructive sleep apnea (OSA) is a very common disease with high global socio-economic impact, since almost one billion people are affected worldwide [1]. It is frequently associated with heart failure, cardiac hypertrophy or atrial and ventricular arrhythmias [2][3][4]. Patients with OSA have been shown to develop worse outcome after myocardial infarction [5].…”

“…We have shown that the activity of Ca/Calmodulin-dependent protein kinase II (CaMKII), a key player in heart failure development [8,9], was increased in the hearts of patients with sleep-disordered breathing, leading to contractile dysfunction and arrythmias [4]. Proposed mechanisms of CaMKII activation in OSA include increased transmural pressure gradients with increased atrial wall stress, increased sympathetic and parasympathetic activation, and reactive oxygen species (ROS) [3,4,10,11]. Unfortunately, patient studies are not always suited to discriminate between different pathophysiological factors.…”