Elucidating arrhythmogenic mechanisms of long-QT syndrome CALM1-F142L mutation in patient-specific induced pluripotent stem cell-derived cardiomyocytes

复极 背景(考古学) 突变 内科学 诱导多能干细胞 内分泌学 长QT综合征 生物 兰尼碱受体2 细胞生物学 遗传学 细胞内 医学 电生理学 基因 兰尼定受体 QT间期 胚胎干细胞 古生物学
作者
Marcella Rocchetti,Luca Sala,Lisa Dreizehnter,Lia Crotti,Daniel Sinnecker,Manuela Mura,Luna Simona Pane,Claudia Altomare,Eleonora Torre,Gaspare Mostacciuolo,Stefano Severi,Alberto Porta,Gaetano Maria De Ferrari,Alfred L. George,Peter J. Schwartz,Massimiliano Gnecchi,Alessandra Moretti,Antonio Zaza
出处
期刊:Cardiovascular Research [Oxford University Press]
卷期号:113 (5): 531-541 被引量:113
标识
DOI:10.1093/cvr/cvx006
摘要

Calmodulin (CaM) is a small protein, encoded by three genes (CALM1-3), exerting multiple Ca2+-dependent modulatory roles. A mutation (F142L) affecting only one of the six CALM alleles is associated with long QT syndrome (LQTS) characterized by recurrent cardiac arrests. This phenotypic severity is unexpected from the predicted allelic balance. In this work, the effects of heterozygous CALM1-F142L have been investigated in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) obtained from a LQTS patient carrying the F142L mutation, i.e. in the context of native allelic ratio and potential gene modifiers.Skin fibroblasts of the mutation carrier and two unrelated healthy subjects (controls) were reprogrammed to hiPSC and differentiated into hiPSC-CMs. Scanty IK1 expression, an hiPSC-CMs feature potentially biasing repolarization, was corrected by addition of simulated IK1 (Dynamic-Clamp). Abnormalities in repolarization rate-dependency (in single cells and cell aggregates), membrane currents and intracellular Ca2+ dynamics were evaluated as putative arrhythmogenic factors. CALM1-F142L prolonged repolarization, altered its rate-dependency and its response to isoproterenol. This was associated with severe impairment of Ca2+-dependent inactivation (CDI) of ICaL, resulting in augmented inward current during the plateau phase. As a result, the repolarization of mutant cells failed to adapt to high pacing rates, a finding well reproduced by using a recent hiPSC-CM action potential model. The mutation failed to affect IKs and INaL and changed If only marginally. Intracellular Ca2+ dynamics and Ca2+ store stability were not significantly modified. Mutation-induced repolarization abnormalities were reversed by verapamil.The main functional derangement in CALM1-F142L was prolonged repolarization with altered rate-dependency and sensitivity to β-adrenergic stimulation. Impaired CDI of ICaL underlined the electrical abnormality, which was sensitive to ICaL blockade. High mutation penetrance was confirmed in the presence of the native genotype, implying strong dominance of effects.
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