Clin Res Cardiol (2022). https://doi.org/10.1007/s00392-022-02002-5

Na levels are increased in atrial cardiomyocytes of mice with obstructive sleep apnea
F. Ofner1, S. Lebek1, P. Hegner1, B. Schaner1, L. S. Maier1, M. Arzt1, S. Wagner1
1Klinik und Poliklinik für Innere Med. II, Kardiologie, Universitätsklinikum Regensburg, Regensburg;

Background:

Obstructive sleep apnea (OSA) is a widespread disease that is frequently associated with atrial arrhythmias. Interestingly, we have shown that patients with sleep-disordered breathing exhibit increased Ca/calmodulin-dependent protein kinase II (CaMKII) activity leading to enhanced late Na current. However, the contribution of neuronal NaV1.8 in contrast to cardiac NaV1.5, which has recently been identified in myocardium, and the consequences for intracellular Na levels are currently unclear.

Purpose:

We tested if NaV1.8 contributes to intracellular Na overload in obstructive sleep apnea by using a novel mouse model of OSA.

Methods:

Polytetrafluorethylene (PTFE, 100 µl) was injected into the tongue of mice to induce sustained enlargement. Two weeks after the injection, inspiratory flow limitations were monitored during the murine sleep phases for 8 h by whole-body plethysmography. After eight weeks, isolated atrial cardiomyocytes were incubated with the Na-sensitive dye SBFI-AM for 90 minutes to measure the cellular sodium concentration by using epifluorescence microscopy (1 Hz, 20 V for 4 ms). Some experiments were performed in the presence of the selective NaV1.8 inhibitor PF-01247324 (PF, 1µM) to investigate the role of the neuronal sodium channel in OSA.

Results:

Sonographic measurements of the tongue revealed a significant increase in mean diameter from (in mm) 3.7±0.1 to 5.1±0.1 after PTFE injection (n=23 mice, p<0.001). Interestingly, compared to untreated littermates, PTFE-treatment resulted in a significant increase in intracellular Na concentration (SBFI ratio 340/380nm) from 1.17±0.01 to 1.26±0.01 (n=10 vs. 5, p<0.001, fig. A+B). Accordingly, we found a significant correlation between the Na concentration and the frequency of inspiratory flow limitations, a measure of intermittent airflow obstruction (n=13, p=0.021, r2=0.40, fig. C) that was completely abolished upon selective NaV1.8 inhibition with PF (n=13). Treatment with PF resulted in a significantly decreased Na concentration (1.20±0.01, p<0.001, fig. B, n=10). Interestingly, transgenic knockout of CaMKIIdelta (CKO) resulted in a similar protection from Na dysregulation. After PTFE treatment, the SBFI ratio was 1.18±0.01 in CKO mice (p<0.001, n=11, fig. B) and the positive correlation with the frequency of inspiratory flow limitations was completely absent (fig. C).

Conclusion:

Mice with obstructive sleep apnea exhibit disturbed intracellular Na handling. The increase in intracellular Na after PTFE treatment was abolished either by selective NaV1.8 inhibition or genetic knock-out of CaMKII, which may have therapeutic implications.

 

https://dgk.org/kongress_programme/jt2022/aP1551.html