Rbm20-R636Q mutations in mice induced atrial remodeling and shortened action potential duration leading to atrial fibrillation, an effect partially restored by SGLT inhibitors.
Do SGLT inhibitors improve atrial electrophysiological disturbances in mice with RBM20-R636Q mutations?
Rbm20-R636Q mutations cause atrial electrical remodeling and AF susceptibility in mice, which can be partially mitigated by SGLT inhibitors.
Abstract Background Dilated cardiomyopathy (DCM) is a leading cause of heart failure, with 30–50 % of cases attributed to familial inheritance. Among these, 3–5 % involve mutations in the RNA-binding motif protein 20 (RBM20), a splicing factor associated with a more severe form of DCM. This variant is characterized by progressive cardiac dysfunction. However, their contribution to atrial cardiomyopathy (AtCM) and atrial fibrillation (AF) remains underexplored. Purpose This study aims to investigate the effects of RBM20-R636Q mutations on atrial electrophysiology and evaluate the potential therapeutic benefits of SGLT inhibitors in this context. Methods To determine the electrophysiological significance of a mutation in the Rbm20 gene we characterized the cardiac and cellular phenotype of mice carrying a homozygous point-mutation (R636Q) in the RS domain of the protein which was identified to cause a severe cardiomyopathy phenotype in DCM patients. Rbm20 R636Q mice were compared to Rbm20-KO mice and a Laminopathy model. The phenotype of all models was investigated using in vivo techniques, including echocardiography, non-invasive ECG and functional cellular experiments such as patch-clamp measurements Results Rbm20-R636Q knock-in mice exhibited significant atrial remodeling, including cardiomyocyte hypertrophy, increased left atrial size, and altered action potential morphology, with a notable shortening of action potential (AP) duration (APD), measured at 90 % of repolarization (APD90) resulting in the onset of atrial tachycardia and AF. Comparison with Rbm20-knockout mice and the Laminopathy model revealed that all models shared a reduction in APD90 levels, but with distinct cellular electrophysiological phenotypes. The extent of the alteration in those models was not severe enough to induce atrial arrhythmias. Only in the Rbm20-R636Q mice the ionic current analyses showed a reduction in IK,Peak and no significant changes in IK,sus, or IK,tail currents, but all models displayed upregulation of atrial TASK-1 potassium currents. SGLT inhibitors, including sotagliflozin, empagliflozin, and dapagliflozin, reduced AP inducibility and partially restored the shortened APD90 in Rbm20-R636Q cardiomyocytes. The observed effects were comparable to those achieved with lidocaine, a sodium channel blocker, suggesting that peak sodium current inhibition may contribute to the antiarrhythmic effects in this model. Conclusions These findings demonstrate that Rbm20 mutations play a significant role in atrial electrical remodeling and contribute to both, the development of AtCM and the increased susceptibility to AF. Some of those remodeling pattern seem to be unique for the Rbm20 R636Q mutation. The results also highlight the therapeutic potential of SGLT inhibitors for modulation on atrial electrophysiology in RBM20-related AtCM, offering a promising strategy to mitigate arrhythmogenesis.
Weirauch et al. (2025) studied Atrial cardiomyopathy and atrial fibrillation associated with RBM20 mutations. SGLT inhibitors (sotagliflozin, empagliflozin, dapagliflozin) vs. Untreated models and lidocaine was evaluated on Atrial electrophysiology, action potential duration, and arrhythmia inducibility. Rbm20-R636Q mutations in mice induced atrial remodeling and shortened action potential duration leading to atrial fibrillation, an effect partially restored by SGLT inhibitors.