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Identification of an I_Na-dependent and I_to-mediated proarrhythmic mechanism in cardiomyocytes derived from pluripotent stem cells of a Brugada syndrome patient.

ABSTRACT: Brugada syndrome (BrS) is an inherited cardiac arrhythmia commonly associated with SCN5A mutations, yet its ionic mechanisms remain unclear due to a lack of cellular models. Here, we used human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) from a BrS patient (BrS1) to evaluate the roles of Na⁺ currents (I_Na) and transient outward K⁺ currents (I_to) in BrS induced action potential (AP) changes. To understand the role of these current changes in repolarization we employed dynamic clamp to "electronically express" I_K1 and restore normal resting membrane potentials and allow normal recovery of the inactivating currents, I_Na, I_Ca and I_to. HiPSC-CMs were generated from BrS1 with a compound SCN5A mutation (p. A226V & p. R1629X) and a healthy sibling control (CON1). Genome edited hiPSC-CMs (BrS2) with a milder p. T1620M mutation and a commercial control (CON2) were also studied. CON1, CON2 and BrS2, had unaltered peak I_Na amplitudes, and normal APs whereas BrS1, with over 75% loss of I_Na, displayed a loss-of-I_Na basal AP morphology (at 1.0?Hz) manifested by a reduced maximum upstroke velocity (by ~80%, p?to densities of BrS1 and CON1 were comparable and increased from 1.0?Hz to 0.1?Hz by ~ 100%. These data indicate that a repolarization deficit could be a mechanism underlying BrS.

SUBMITTER: Ma D

PROVIDER: S-EPMC6062539 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature

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Publications

Identification of an INa-dependent and Ito-mediated proarrhythmic mechanism in cardiomyocytes derived from pluripotent stem cells of a Brugada syndrome patient.

Ma Dongrui D Liu Zhenfeng Z Loh Li Jun LJ Zhao Yongxing Y Li Guang G Liew Reginald R Islam Omedul O Wu Jianjun J Chung Ying Ying YY Teo Wee Siong WS Ching Chi Keong CK Tan Boon Yew BY Chong Daniel D Ho Kah Leng KL Lim Paul P Yong Rita Yu Yin RYY Panama Brian K BK Kaplan Aaron D AD Bett Glenna C L GCL Ware James J Bezzina Connie R CR Verkerk Arie O AO Cook Stuart A SA Rasmusson Randall L RL Wei Heming H

Scientific reports 20180726 1

Brugada syndrome (BrS) is an inherited cardiac arrhythmia commonly associated with SCN5A mutations, yet its ionic mechanisms remain unclear due to a lack of cellular models. Here, we used human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) from a BrS patient (BrS1) to evaluate the roles of Na+ currents (INa) and transient outward K+ currents (Ito) in BrS induced action potential (AP) changes. To understand the role of these current c ...[more]

PMID: 30050137

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Project description:Hundreds of thousands of people die each year as a result of sudden cardiac death, and many are due to heart rhythm disorders. One of the major causes of these arrhythmic events is Brugada syndrome, a cardiac channelopathy that results in abnormal cardiac conduction, severe life-threatening arrhythmias, and, on many occasions, death. This disorder has been associated with mutations and dysfunction of about two dozen genes; however, the majority of the patients do not have a definite cause for the diagnosis of Brugada Syndrome. The protein-coding genes represent only a very small fraction of the mammalian genome, and the majority of the noncoding regions of the genome are actively transcribed. Studies have shown that most of the loci associated with electrophysiological traits are located in noncoding regulatory regions and are expected to affect gene expression dosage and cardiac ion channel function. Noncoding RNAs serve an expanding number of regulatory and other functional roles within the cells, including but not limited to transcriptional, post-transcriptional, and epigenetic regulation. The major noncoding RNAs found in Brugada Syndrome include microRNAs; however, others such as long noncoding RNAs are also identified. They contribute to pathogenesis by interacting with ion channels and/or are detectable as clinical biomarkers. Stem cells have received significant attention in the recent past, and can be differentiated into many different cell types including those in the heart. In addition to contractile and relaxational properties, BrS-relevant electrophysiological phenotypes are also demonstrated in cardiomyocytes differentiated from stem cells induced from adult human cells. In this review, we discuss the current understanding of noncoding regions of the genome and their RNA biology in Brugada Syndrome. We also delve into the role of stem cells, especially human induced pluripotent stem cell-derived cardiac differentiated cells, in the investigation of Brugada syndrome in preclinical and clinical studies.

Dataset Information

Identification of an I_Na-dependent and I_to-mediated proarrhythmic mechanism in cardiomyocytes derived from pluripotent stem cells of a Brugada syndrome patient.

Publications

Identification of an I<sub>Na</sub>-dependent and I<sub>to</sub>-mediated proarrhythmic mechanism in cardiomyocytes derived from pluripotent stem cells of a Brugada syndrome patient.

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