Kir2.1 mutations differentially increase the risk of flecainide proarrhythmia in Andersen Tawil Syndrome
Authors: Cruz Francisco M. , Moreno-Manuel Ana I. , Pérez Patricia Sánchez , Ruiz-Robles Juan Manuel , Socuellamos Paula García , Gutiérrez Lilian K. , Vera-Pedrosa María Linarejos , Gutierrez Amaia Talavera , Mondéjar Parreño Gema , Macías Álvaro , Martínez-Carrascoso Isabel , Bermúdez-Jiménez Francisco J , Arias Santiago Salvador , Martínez de Benito Fernando , Braza-Boils Aitana , Valenzuela Carmen , Morillo CA , Zorio Esther , Jiménez-Jaimez Juan , Jalife José 
Published: December 2024

AbstractBackgroundFlecainide and other class-Ic antiarrhythmic drugs (AADs) are widely used in Andersen-Tawil syndrome type 1 (ATS1) patients. However, class-Ic drugs might be proarrhythmic in some cases. We investigated the molecular mechanisms of class-I AADs proarrhythmia and whether they might increase the risk of death in ATS1 patients with structurally normal hearts.Methods and ResultsOf 53 ATS1 patients reviewed from the literature, 54% responded partially to flecainide, with ventricular arrhythmia (VA) reduction in only 23%. Of the latter patients, VA persisted in 20-50%. Flecainide was ineffective in 23%, and surprisingly, 13.5% suffered a non-fatal cardiac arrest. In five cardiac-specific ATS1 mouse models (Kir2.1Δ314–315, Kir2.1C122Y, Kir2.1G215Dand Kir2.1R67Wand Kir2.1S136F), flecainide or propafenone (40 mg/Kg i.p.) differentially prolonged the P wave, and the PR, QRS and QTc intervals compared to Kir2.1WT; Kir2.1S136Fhad milder effects. Flecainide increased VA inducibility in all mutant mice except Kir2.1S136F, which exhibited significant VA reduction. At baseline, Kir2.1G215Dcardiomyocytes had the lowest inward rectifier K+ channel (IK1) reduction, followed by Kir2.1C122Y, Kir2.1R67Wand Kir2.1S136F. Kir2.1C122Ycardiomyocytes had a significant decrease in sodium inward current (INa). Flecainide (10 µM) slightly increased IK1density in Kir2.1WTand Kir2.1S136F, while it decreased both IK1and INain Kir2.1C122Yand Kir2.1R67W, despite normal trafficking of mutant channels. Optical mapping in ATS1 patient-specific iPSC-CM monolayers expressing Kir2.1C122Y, Kir2.1G215Dand Kir2.1R67Wshowed an increase in rotor incidence at baseline and under flecainide, confirming the druǵs proarrhythmic effect. Lastly, in-silico molecular docking predicts that the Kir2.1-Cys311pharmacophore-binding site is altered in Kir2.1C122Yheterotetramers, reducing flecainide accessibility and leading to channel closure and arrhythmias.ConclusionsClass-Ic AADs are only partially effective and might be proarrhythmic in some ATS1 patients. Kir2.1 mutations impacting the resting membrane potential and cellular excitability create a substrate for life-threatening arrhythmias, raising significant concern about using these drugs in some ATS1 patients.CLINICAL PERSPECTIVE NOVELTY AND SIGNIFICANCEWhat is known?Andersen-Tawil syndrome type 1 (ATS1) is a rare autosomal dominant disease caused by loss-of-function mutations in theKCNJ2gene, which encodes the Kir2.1 channel responsible for the repolarizing, strong inwardly rectifying current IK1.ATS1 treatment is empirical and subject to clinical judgment. It includes the use of class-Ic antiarrhythmic drugs (AADs), mainly flecainide, alone or in combination with β-adrenergic blocking drugs. However, pharmacological treatment is partial and might fail, leading to life-threatening ventricular arrhythmias (VA) and sudden cardiac death (SCD) in some ATS1 patients.Some ATS1 mutations are known to disrupt the Kir2.1-Nav1.5 channelosome in mice and human iPSC-CMs, with consequent reductions in cardiac excitability and conduction velocity (CV), leading to VA, which may be exacerbated by flecainide.What new information does this article contribute?In our analysis of 53 ATS1 patients, flecainide showed partial effectiveness. While a few patients experienced complete disappearance of VA, others had persistent arrhythmias and even suffered non-fatal cardiac arrest while on medication.In murine models expressing five relevant ATS1 mutations, flecainide or propafenone produced differential alteration in the P wave, PR, QRS and QTc intervals, and increased VA inducibility compared with Kir2.1WTmice. Additionally, flecainide differentially affected IK1and the Na+inward current (INa) current densities despite normal trafficking of mutant channels.In patient-specific induced pluripotent stem cell derived cardiomyocyte (iPSC-CM) monolayers flecainide reduced CV and increased rotor incidence, confirming the drugś proarrhythmic effect.In-silicomolecular docking studies predicted that the Cys311pharmacophore binding site and flecainide accessibility are altered in mutated Kir2.1 channels, leading to premature channel closure and arrhythmias.We conclude that class-Ic AADs are only partially effective and might be proarrhythmic in some ATS1 patients.These findings raise concern about the use of class-Ic AADs in ATS1 patients and highlight the need for further studies to guide personalized therapy.