Abstract 17926: CALM2-D134H Mutation Associated With Long-QT Syndrome Delayed Inactivation of L-type Ca2+ Currents in Human iPS Cells Derived Cardiomyocytes

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Background: Recently, CALM mutations were reported to exert arrhythmias including severe early-onset long-QT syndrome (LQTS). Calmodulin (CaM) is a ubiquitous Ca2+-sensor molecule, and an identical CaM protein is encoded by the 3 unique genes, CALM1-3. During the regulation of L-type Ca2+ channel (LTCC) in cardiomyocytes, the complex of Ca2+-CaM promotes inactivation of LTCC current (ICaL). Several CALM mutations were reported to impair the inactivation of LTCC, however, the pathophysiological mechanisms of CALM-related LQTS (CALM-LQT) caused by CALM2-D134H mutation remains unknown. Objectives: The present study aimed to establish the in-vitro CALM-LQT disease model using human induced pluripotent stem cells (hiPSCs) and elucidate the pathophysiological mechanisms.

Methods: The hiPSC clones were generated from a LQTS patient carrying a missense CALM2-D134H mutation (LQT-hiPSC), and differentiated into cardiomyocytes (CMs). Action potentials (APs) and ICaL of LQT-hiPSC-CMs were analyzed using a patch-clamp technique, and compared with those of hiPSC-CMs derived from healthy control.

Results: In AP recordings, AP durations at 50% and 90% repolarization (APD50 and APD90) of LQT-hiPSC-CMs were significantly prolonged compared with those of control-hiPSC-CMs (APD90: LQT, 579.8 ± 147.0 ms vs Control, 235.7 ± 22.1 ms, P < 0.05). As a result of LTCC analysis, the time constants of LTCC inactivation tau slow of LQT-hiPSC-CMs were significantly larger than those of control. There were no significant differences between control and LQT-hiPSC-CMs in the current-voltage relationship.

Conclusion: Our CALM-LQT hiPSC model recapitulated the disease phenotype, i.e. prolonged APD, consistent with clinical phenotype of index patient. In addition, this study revealed that D134H-mutant CaM delayed the inactivation of LTCC. This hiPSC model may be useful to elucidate the pathophysiological mechanism of CALM-LQT in detail and develop the treatment for CALM-LQT.

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