PO-01-242 COMMON GENETIC VARIANTS OF THE CARDIAC SODIUM CHANNEL ALTER PATIENT RESPONSE TO CLASS 1B ANTIARRHYTHMICS

Abstract

Several common variants have been identified in SCN5A, which encodes the cardiac Na+ channel α-subunit Nav1.5 and is targeted by class I antiarrhythmics. Lidocaine and its analog mexiletine both have a primary amine that blocks Na+ current. While lidocaine is highly effective in terminating ventricular tachycardia after acute myocardial infarction, mexiletine has been shown to prevent arrhythmia induction in only ∼20% of patients. We aim to test the hypothesis that common SCN5A polymorphisms exhibit an altered pharmacological response to class 1b antiarrhythmics. We investigate four common polymorphisms: R34C, S524Y, H558R, and S1103Y. Recombinant DNA, where the regulatory β1-subunit is connected to Nav1.5 (WT or variant) through a pIRES sequence to ensure co-expression of both proteins, is transfected into HEK293 cells. Automated planar patch clamp is used to record peak Na+ current and measure tonic and use-dependent mexiletine and lidocaine block. The mexiletine dose-response curves for S1103Y (IC50 = 57.2 ± 14.3μM; 13.4 ± 2.7μM; 7.8 ± 1.3μM at 0, 10 and 20Hz) show a substantial left shift compared to WT (IC50 = 148.6 ± 27.8μM; 31.7 ± 4.4μM; 16. 8 ± 2μM). The other variants show a slight right shift. These results imply enhanced mexiletine interaction with S1103Y, while R34C, S524Y and H558R do not significantly affect drug binding. The lidocaine dose-response curves for H558R (IC50 = 75.6 ± 16.6μM) exhibit a substantial left shift compared to WT (IC50 = 136.1 ± 33.9μM) at 0Hz. The difference is not observed at 10 and 20 Hz, suggesting a predominant effect on tonic block for H558R. Other variants do not show a significantly altered response. Lidocaine is lipid-soluble and can interact with the Nav1.5 pore via a hydrophobic pathway block of the channel. The more hydrophilic mexiletine displays a drug-receptor interaction that depends on the state of the channel. Thus, as Na+ current kinetics are altered in different variants, so is the drug interaction with the channel. The S1103Y polymorphism is found almost exclusively in Afro-descendent populations and is present in 13% of black patients, traditionally underrepresented in clinical trials. H558R is present in nearly 20% of the general population, across all ethnicities. A stronger tonic or use-dependent response to each drug would imply that these patients would respond differently to its prescription.