Abstract 443: l-cis- Diltiazem Ameliorates Impaired Calcium Channel Inactivation in a Patient-specific Stem Cell Model of Long-QT Syndrome with a Calmodulin Mutation

Abstract

Background: Calmodulin is a ubiquitous Ca 2+ sensor molecule encoded by three distinct calmodulin genes, CALM1-3 . Recently, mutations in CALM1-3 have been reported to be associated with severe early-onset long-QT syndrome (LQT) due to impaired Ca 2+ dependent inactivation of L-type Ca 2+ channel (LTCC). However, pharmacotherapeutic agents for the treatment of CALM-related LQT have not been established. Objective: We aimed to assess new pharmacotherapies for the treatment of CALM-related LQT using human induced pluripotent stem cell (hiPSC) model. Methods and Results: We used CALM-LQT-hiPSC derived cardiomyocytes (CMs) with a CALM2- N98S mutation which exhibited prolonged action potential durations. First, we confirmed impaired LTCC inactivation in the CALM-LQT-hiPSC-CMs: the ratio of current remaining after 100 ms depolarization (r100) of LTCC currents was significantly larger in CALM-LQT-hiPSC-CMs (r100; CALM-LQT: 0.333 ± 0.016, control: 0.181 ± 0.025 at 0 mV; P < 0.05). Next, we assessed candidate drugs, l-cis- Diltiazem (the stereoisomer of clinically used d-cis -Diltiazem) and Cyclosoprin A, which were reported to enhance voltage-dependent inactivation of LTCC for the treatment of impaired LTCC inactivation. We found that 10 μM l-cis -Diltiazem attenuated impaired LTCC inactivation in CALM-LQT-iPSC-CMs (r100; baseline: 0.333 ± 0.016, with l-cis: 0.294 ± 0.013 at 0 mV; P < 0.05; Figure A and B). On the other hand, Cyclosporine A had less effect compared to l-cis- Diltiazem (Figure A). Conclusion: Using patient-derived hiPSC model, we identified that l-cis -Diltiazem is a promising candidate drug for treating CALM-LQT resulting from impaired LTCC inactivation.