Oxidative activation of CaMKII mediates arrhythmias and contractile dysfunction in an obstructive sleep apnea mouse model

Abstract Background/Introduction Atrial arrhythmias frequently occur in patients with obstructive sleep apnea (OSA), but the underlying mechanisms remain insufficiently understood. We recently demonstrated that CaMKII-dependent pro-arrhythmic activity is increased OSA, of CaMKII activation unknown. Interestingly, OSA can lead to reactive oxygen species production, which may facilitate by oxidation at methionine residues 281/282. Purpose tested if involved development and contractile dysfunction vitro vivo a mouse model tongue enlargement. Methods Experiments were performed using 41 wild-type (WT) 25 genetically modified mice lacking oxidative due mutation 281/282 valine (MMVV mice). Polytetrafluorethylene (PTFE, 100 μl) was injected into 23 WT 12 MMVV induce sustained enlargement as previously established. Whole body plethysmography confirm success intervention. Echocardiography baseline after 8 weeks assess left-ventricular function. After weeks, isolated atrial ventricular cardiomyocytes incubated Ca-sensitive dye FURA-2 AM (5 μM, 15 min) analyzed epifluorescence microscopy under regular electrical field stimulation (1 Hz). Results PTFE injection resulted an frequency inspiratory flow limitations (IFLs/h) from 27.4±5.95 59.6±6.22 (p<0.001, fig. 1A). mice, left ejection fraction (LVEF, %) reduced post procedure 57.0±1.36 51.5±1.85 (p=0.001, 1B). Importantly, protected such decline function, LVEF higher vs. Congruent deterioration contractility vivo, Ca transient amplitude 30s pause (normalized steady-state before pause) decreased indicating SR leak (p for interaction genotype x = 0.014, 1C). In contrast WT, post-pause ratio (p=0.018, addition cellular arrhythmic events non-stimulated (NSEs) during 1 Hz (fig. 1D, red arrows). NSE 0.050±0.005 compared 0.018±0.003 s–1 CTRL 1D). Intriguingly, NSEs treatment (0.020±0.004, p<0.001 PTFE, Fig. Conclusion apnea, are modulated activation, have therapeutic implications. Funding Acknowledgement Type funding sources: Public grant(s) – National budget only. Main source(s): Deutsche Forschungsgemeinschaft; Medical Faculty University Regensburg