DOI DOI https://doi.org/10.1007/s00392-021-01843-w
Atrial fibrillation (AF) is a common comorbidity of sleep-disordered breathing (SDB), but the mechanisms are only partly understood. Interestingly, enhanced activity of Ca/Calmodulin-dependent protein kinase II (CaMKII) and increased CaMKII-dependent diastolic sarcoplasmic reticulum Ca leak have been shown to be hallmarks of human AF and have also been found in patients with SDB. However, the relevance of these findings was limited by potentially confounding comorbidities.
Purpose:
By using a novel mouse model of obstructive sleep apnea, we investigated CaMKII-dependent Ca handling and pro-arrhythmic activity independent from confounding by comorbidities.
Methods and Results:
We injected polytetrafluorethylene (PTFE) into the tongue of wild-type (WT) and CaMKIIδ knock-out (CKO) mice. Sonographic measurements confirmed a significant increase in tongue diameters from (values in mm±SEM) 3.7±0.18 to 5.2±0.18 after PTFE injection (n=15, p<0.05, fig 1A). Apneas were detected by whole-body plethysmography (Buxco Setup) two weeks after PTFE injection during murine sleep time (fig. 1B). Linear regression analysis revealed a significant positive correlation between magnitude of tongue diameter and the frequency of apneas (p<0.05, R²=0.3345, fig. 1C). Eight weeks after PTFE injection, Ca transients were measured in isolated atrial cardiomyocytes using epifluorescence microscopy. After cells were loaded with the Ca-sensitive dye FURA-2 AM for 15 minutes, regular Ca transients were elicited by electric field stimulation at 1 Hz (20 V for 4 ms). The propensity for non-stimulated Ca release (NSE) was increased by superfusion (37° C) with 10 nmol/L isoprenaline at [Ca]o of 2 mmol/L. Delayed NSEs - defined as a deviation from diastolic Ca baseline between two stimulated transients (fig. 1D) - were acquired as a measure of pro-arrhythmic activity. Interestingly, we found a significantly increased frequency of delayed NSEs in WT mice treated with PTFE compared to control mice. NSE frequency (in events/s) increased from 0.025±0.005 (n=7) to 0.04±0.0049 (n=12, p<0.05, fig. 1E). Most intriguingly, the NSE frequency was significantly reduced in PTFE-treated mice lacking CaMKIIδ expression and comparable to WT control. Compared to WT-PTFE, NSE frequency was decreased to 0.028±0.0048 in PTFE-CKO mice (n=7, p<0.05, fig. 1E).
Conclusion:
CaMKII-dependent delayed non-stimulated Ca release events are increased in a novel mouse model of obstructive sleep apnea, which may have therapeutic implications.
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