In:
Circulation, Ovid Technologies (Wolters Kluwer Health), Vol. 132, No. suppl_3 ( 2015-11-10)
Abstract:
Background: Calmodulin ( CALM ) is a ubiquitous Ca2+-sensor molecule, and it modulates various proteins including several ion channels, ryanodine receptor 2, and Ca 2+ /calmodulin-dependent protein kinase. Recently, several studies reported that CALM mutations are associated with severe early-onset long-QT syndrome (LQTS). However, the underlying mechanism remains unknown. Purpose: The present study aims to establish the in-vitro disease model of CALM -related LQTS and elucidate the pathophysiological mechanism using human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). Methods: The hiPSC clones were generated from a 12-year-old boy with LQTS carrying a missense CALM2 mutation (c.293A 〉 G, p.N98S), and differentiated into cardiomyocytes via embryoid body (EB) formation. The electrophysiological characteristics of CALM2 -N98S hiPSC-CMs, including action potential (AP) and L-type Ca 2+ channel (LTCC) currents, were analyzed by patch-clamp technique, and compared with those of hiPSC-CMs derived from healthy control. Results: The beating rate of CALM2 -N98S EBs was significantly lower than that of control (23.8 ± 1.6 bpm vs 47.3 ± 1.7 bpm, p 〈 0.01). The corrected AP duration at 90% repolarization (cAPD90) of CALM2 -N98S hiPSC-CMs was significantly prolonged compared to that of control (480.9 ± 59.4 ms vs 201.5 ± 19.5 ms, p 〈 0.01, Figure). At 1 Hz pacing, CALM2 -N98S hiPSC-CMs exhibited significantly longer APD90 than control (495.5 ± 47.7 ms vs 227.8 ± 21.6 ms, p 〈 0.01). The time constants of LTCC inactivation tau fast of CALM2 -N98S hiPSC-CMs were significantly larger than those of control at 0, +10, and +20 mV test potentials (Figure). Conclusion: The hiPSC-CMs model of CALM2 -related LQTS successfully recapitulated the disease phenotypes, and elucidated the pathophysiological mechanism: impaired inactivation of LTCC currents. This model might be useful for drug discovery in CALM2 -related LQTS.
Type of Medium:
Online Resource
ISSN:
0009-7322
,
1524-4539
DOI:
10.1161/circ.132.suppl_3.17739
Language:
English
Publisher:
Ovid Technologies (Wolters Kluwer Health)
Publication Date:
2015
detail.hit.zdb_id:
1466401-X
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