Enhanced Cardiac CaMKII Oxidation and CaMKII-Dependent SR Ca Leak in Patients with Sleep-Disordered Breathing

Abstract

Background: Sleep-disordered breathing (SDB) is associated with increased oxidant generation. Oxidized Ca/calmodulin kinase II (CaMKII) can contribute to atrial arrhythmias by the stimulation of sarcoplasmic reticulum Ca release events, i.e., Ca sparks. Methods: We prospectively enrolled 39 patients undergoing cardiac surgery to screen for SDB and collected right atrial appendage biopsies. Results: SDB was diagnosed in 14 patients (36%). SDB patients had significantly increased levels of oxidized and activated CaMKII (assessed by Western blotting/specific pulldown). Moreover, SDB patients showed a significant increase in Ca spark frequency (CaSpF measured by confocal microscopy) compared with control subjects. CaSpF was 3.58 ± 0.75 (SDB) vs. 2.49 ± 0.84 (no SDB) 1/100 µm−1s−1 (p < 0.05). In linear multivariable regression models, SDB severity was independently associated with increased CaSpF (B [95%CI]: 0.05 [0.03; 0.07], p < 0.001) after adjusting for important comorbidities. Interestingly, 30 min exposure to the CaMKII inhibitor autocamtide-2 related autoinhibitory peptide normalized the increased CaSpF and eliminated the association between SDB and CaSpF (B [95%CI]: 0.01 [−0.1; 0.03], p = 0.387). Conclusions: Patients with SDB have increased CaMKII oxidation/activation and increased CaMKII-dependent CaSpF in the atrial myocardium, independent of major clinical confounders, which may be a novel target for treatment of atrial arrhythmias in SDB.

CaMKIIδ-dependent dysregulation of atrial Na+ homeostasis promotes pro-arrhythmic activity in an obstructive sleep apnea mouse model

“…Previously, we demonstrated increased ROS production in the myocardium of patients with SDB ( Arzt et al, 2022 ). Additionally, we were able to show increased ROS production in the ventricular cardiomyocytes of the PTFE-treated mice ( Hegner et al, 2023 ).…”

“…Our group previously established that cardiac CaMKIIδ activity is pathologically increased in SDB patients and also in SDB mice in the model used in this study (Lebek et al, 2020a;Lebek et al, 2020b;Arzt et al, 2022;Hegner et al, 2023). In the present study, we present data from isolated atrial cardiomyocytes, but the limited amount of tissue precluded further protein target analysis, which is a potential limitation of this study.…”

“…There are several important downstream targets of CaMKIIδ, including voltage-gated Na + channels Na V 1.5 and Na V 1.8, RyR2, phospholamban, L-type Ca 2+ channels, and Na + /Ca 2+ exchangers, which have been shown to be involved in arrhythmogenesis ( Bers, 2002 ; Fischer et al, 2013 ; Bengel et al, 2021 ). CaMKIIδ overactivation in SDB can lead to disturbed Ca 2+ homeostasis, including increased sarcoplasmic reticulum Ca 2+ leakage, pro-arrhythmic non-stimulated events in humans and mice, and multicellular arrhythmias in the patient trabeculae ( Lebek et al, 2020b ; Arzt et al, 2022 ; Hegner et al, 2023 ). These pro-arrhythmic events could serve as triggers of atrial fibrillation ( Nattel et al, 2020 ).…”