Abstract 515 Nav1.8 knockout rescues the arrhythmogenic phenotype of CaMKIIδC overexpressingheart failure mice

Clin Res Cardiol (2021) DOI DOI https://doi.org/10.1007/s00392-021-01843-w
Nav1.8 knockout rescues the arrhythmogenic phenotype of CaMKIIδC overexpressingheart failure mice
P. Bengel¹, C. Krekeler¹, B. A. Mohamed¹, N. Hartmann¹, N. Dybkova¹, S. Ahmad¹, P. Tirilomis¹, K. Toischer¹, G. Hasenfuß¹, L. S. Maier², K. Streckfuß-Bömeke¹, S. T. Sossalla²
¹Herzzentrum, Klinik für Kardiologie und Pneumologie, Universitätsmedizin Göttingen, Göttingen; ²Klinik und Poliklinik für Innere Med. II, Kardiologie, Universitätsklinikum Regensburg, Regensburg;
Background: As antiarrhythmic drug therapy is limited in patients with heart failure (HF), a better understanding of the electrical remodeling in HF is necessary. It is known that both, an increased activity of Ca²⁺/Calmodulin-dependent kinase II (CaMKII) and an augmented late sodium current (I_NaL) maintain a vicious cycle amplifying each other and contributing to cellular proarrhythmia. We recently reported that Nav1.8 a non-cardiac sodium channel isoform is overexpressed in human HF and contributes to I_NaL generation. We here tested effects of Nav1.8 inhibition and deletion in a proarrhythmogenic HF mouse model with transgenic CaMKIIC overexpression. Methods/Results: CaMKIIC overexpressing mice (CaMKII^+/T) were crossbred with Nav1.8 knock-out mice (SCN10^-/-). A significant survival benefit in SCN10^-/-/CaMKII^+/T compared to CaMKII^+/T could be observed (98.5 vs 72 days median survival, HR 0.58). SCN10^-/-/CaMKII^+/T and CaMKII^+/T similarly developed cardiac hypertrophy measured as heart-weight tibia-length ratio and cardiomyocyte cross-sectional area compared to Wild-Type (WT) and SCN10^-/- alone, but with no differences between SCN10^-/-/CaMKII^+/T and CaMKII^+/T. Further, serial echocardiography demonstrated a severe HF phenotype with in CaMKII^+/T with increased left-ventricular end-diastolic diameter and reduced ejection fraction. However, results in SCN10^-/-/CaMKII^+/T did not significantly differ from CaMKII^+/T so that effects on HF progression do not explain the improved survival. Patch-clamp experiments showed a significant increase in INaL, as well as the occurrence of proarrhythmic early- (EADs) and delayed afterdepolarizations (DADs) in CaMKKII^+/T compared to Wild-Type (WT) and SCN10^-/-. Interestingly, SCN10^-/- in CaMKII^+/T significantly reduced INaL and the occurrence of EADs and DADs. Similarly, diastolic Ca²⁺-release events from the sarcoplasmic reticulum measured by confocal microscopy using the dye Fluo-4AM were significantly less frequent in SCN10^-/-/CaMKII^+/T compared to CaMKII^+/T. To test whether the reduction of cellular proarrhythmogenic triggers in SCN10^-/-/CaMKII^+/T can be translated in-vivo we implanted telemetric monitors in SCN10^-/-/CaMKII^+/T and CaMKII^+/T. Mice were monitored twice a week for 24 hours over a period of 2 weeks. Matching with our observations on HF progression activity levels did not differ between SCN10^-/-/CaMKII^+/T and CaMKII^+/T. However, SCN10^-/-/CaMKII^+/T showed less premature ventricular contractions, as well as non-sustained and sustained ventricular tachycardia compared to CaMKII^+/T. Conclusion: In our study we demonstrate that knock-out of Nav1.8 reduces cellular proarrhythmogenic triggers in CaMKII overexpressing mice by reducing INaL. Further, these antiarrhythmic effects are translatable to in-vivo conditions and the reduction of arrhythmias is potent enough to generate a survival benefit in this HF mouse model. Future studies with Nav1.8 specific blockers are needed to investigate this novel antiarrhythmic approach for a possible clinical use.
https://dgk.org/kongress_programme/jt2021/aV454.html