Clin Res Cardiol (2023). https://doi.org/10.1007/s00392-023-02180-w
Atrial arrhythmopathy of the RBM20-cardiomyopathy – mutation in splicing factor RBM20 causes severe changes in cellular electrophysiology
L. Weirauch1, M. Grosch2, F. Wiedmann3, A. Paasche3, M. van den Hoogenhof4, N. Frey3, L. Steinmetz2, C. Schmidt3
1Universitätsklinikum Heidelberg, Heidelberg; 2Genome Biology Unit, European Molecular Biology Laboratory (EMBL), Heidelberg; 3Klinik für Innere Med. III, Kardiologie, Angiologie u. Pneumologie, Universitätsklinikum Heidelberg, Heidelberg; 4Innere Medizin VIII, Institut für Experimentelle Kardiologie, Universitätsklinikum Heidelberg, Heidelberg;
Background

One of the main reasons for developing heart failure lies in the dilated cardiomyopathy (DCM), where 30–50 % of these cases are caused by familial inheritance. 3–5 % of these patients carry a mutation in the splicing factor RNA-binding motive protein 20 (Rbm20). This aggressive type of DCM is known for progressive cardiac dysfunction, an increased risk for ventricular arrhythmia and a high prevalence of atrial fibrillation (AF). The molecular remodelling processes which lead to the atrial arrhythmopathy causing the AF are mostly unknown. The treatment options for this kind of arrhythmia in context of the RBM20-cardiomyopathy are an important but unmet need in today’s therapy options. The SGLT-inhibitors (SGLTi) showed huge potential treating patients with heart failure. The effect on patients carrying an RBM20-mutation is also not described.

Purpose

The systematic study of molecular changes in context of the atrial arrhythmopathy helps us to learn more about the role RBM20 as a splicing factor and its involvement in cellular electrophysiology. These findings will lay the foundation for looking deeper in fitting treatment options.

Methods

For comprehensive analysis of molecular changes in context of a mutation in RBM20 we characterised the electrophysiological properties RBM20-mutatant mice performing patch clamp measurement on isolated murine atrial cardiomyocytes. The mice carry a mutation in the RS-Domain of the Rbm20-Gen (R636Q) which causes a severe phenotype. Using echocardiography and ECG we confirmed the severe left ventricular dysfunction respectively atrial fibrillation which is involved in the aggressive manifestation.

 

Results

Patch clamp measurements performed on isolated atrial cardiomyocytes revealed several changes in action potential (AP) morphology, like an AP shortening about 21 ± 1 % and a about 11 ± 1 % decreased AP amplitude. AP shortening is the hallmark for the development of AF and is the cellular correlate for an earlier repolarisation which leads to re-entry mechanism causing arrhythmia. After looking deeper into the different currents forming the AP we discovered a significant increased fast inward sodium current, TASK‑1-current, ACh-activated current and inward-rectifier potassium current. The inward-transient potassium current was significantly decreased.  
Consulting the discovered electrophysiological changes, we thoroughly investigated the cellular effects of SGLTi, recently discovered to treat heart failure. Applying dapa-, empa- and sotagliflozin during patch clamp measurements we observed class-I-antiarrhythmic effect, a reduced AP inducibility and a reduced AP amplitude.

Conclusion
A mutation in the Rbm20 splicing factor causes several changes in cellular electrophysiology and the use of SGLTi as antiarrhythmic treatment seems encouraging. Combined with the positive results of several cardiovascular endpoint studies, these findings lead to the conclusion that the SGLTi could be potent treatment options of the patients suffering on Rbm20-cardiomyopathy. 
https://dgk.org/kongress_programme/jt2023/aV711.html