Kir2.1 mutations differentially increase the risk of flecainide proarrhythmia in Andersen Tawil Syndrome

Flecainide 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.

Of 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 (Kir2.1^Δ314-315, Kir2.1^C122Y, Kir2.1^G215D and Kir2.1^R67W and Kir2.1^S136F), flecainide or propafenone (40 mg/Kg i.p.) differentially prolonged the P wave, and the PR, QRS and QTc intervals compared to Kir2.1^WT; Kir2.1^S136F had milder effects. Flecainide increased VA inducibility in all mutant mice except Kir2.1^S136F, which exhibited significant VA reduction. At baseline, Kir2.1^G215D cardiomyocytes had the lowest inward rectifier K+ channel (I_K1) reduction, followed by Kir2.1^C122Y, Kir2.1^R67W and Kir2.1^S136F. Kir2.1^C122Y cardiomyocytes had a significant decrease in sodium inward current (I_Na). Flecainide (10 μM) slightly increased I_K1 density in Kir2.1^WT and Kir2.1^S136F, while it decreased both I_K1 and I_Na in Kir2.1^C122Y and Kir2.1^R67W, despite normal trafficking of mutant channels. Optical mapping in ATS1 patient-specific iPSC-CM monolayers expressing Kir2.1^C122Y, Kir2.1^G215D and Kir2.1^R67W showed an increase in rotor incidence at baseline and under flecainide, confirming the drugś proarrhythmic effect. Lastly, in-silico molecular docking predicts that the Kir2.1-Cys₃₁₁ pharmacophore-binding site is altered in Kir2.1^C122Y heterotetramers, reducing flecainide accessibility and leading to channel closure and arrhythmias.

Class-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.