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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


 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.
 
 
 
