In:
Circulation Research, Ovid Technologies (Wolters Kluwer Health), Vol. 121, No. suppl_1 ( 2017-07-21)
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.
Type of Medium:
Online Resource
ISSN:
0009-7330
,
1524-4571
DOI:
10.1161/res.121.suppl_1.443
Language:
English
Publisher:
Ovid Technologies (Wolters Kluwer Health)
Publication Date:
2017
detail.hit.zdb_id:
1467838-X
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