Reduced connexin-43 expression, slow conduction and repolarisation dispersion in a model of hypertrophic cardiomyopathy.

IF 4 3区 医学 Q2 CELL BIOLOGY
Disease Models & Mechanisms Pub Date : 2024-08-01 Epub Date: 2024-08-27 DOI:10.1242/dmm.050407
Seakcheng Lim, Melissa M Mangala, Mira Holliday, Henrietta Cserne Szappanos, Samantha Barratt-Ross, Serena Li, Jordan Thorpe, Whitney Liang, Ginell N Ranpura, Jamie I Vandenberg, Christopher Semsarian, Adam P Hill, Livia C Hool
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引用次数: 0

Abstract

Hypertrophic cardiomyopathy (HCM) is an inherited heart muscle disease that is characterised by left ventricular wall thickening, cardiomyocyte disarray and fibrosis, and is associated with arrhythmias, heart failure and sudden death. However, it is unclear to what extent the electrophysiological disturbances that lead to sudden death occur secondary to structural changes in the myocardium or as a result of HCM cardiomyocyte electrophysiology. In this study, we used an induced pluripotent stem cell model of the R403Q variant in myosin heavy chain 7 (MYH7) to study the electrophysiology of HCM cardiomyocytes in electrically coupled syncytia, revealing significant conduction slowing and increased spatial dispersion of repolarisation - both well-established substrates for arrhythmia. Analysis of rhythmonome protein expression in MYH7 R403Q cardiomyocytes showed reduced expression of connexin-43 (also known as GJA1), sodium channels and inward rectifier potassium channels - a three-way hit that reduces electrotonic coupling and slows cardiac conduction. Our data represent a previously unreported, biophysical basis for arrhythmia in HCM that is intrinsic to cardiomyocyte electrophysiology. Later in the progression of the disease, these proarrhythmic phenotypes may be accentuated by myocyte disarray and fibrosis to contribute to sudden death.

肥厚型心肌病模型中连接蛋白-43表达减少、传导缓慢和再极化弥散。
肥厚型心肌病(HCM)是一种遗传性心肌病,其特征是左心室壁增厚、心肌细胞混乱和纤维化,并与心律失常、心力衰竭和猝死有关。然而,目前还不清楚导致猝死的电生理紊乱在多大程度上是继发于心肌结构变化,或者是 HCM 心肌细胞电生理学的结果。在这项研究中,我们利用肌球蛋白重链 7(MYH7)R403Q 变异的诱导多能干细胞模型,研究了电耦合合胞体中 HCM 心肌细胞的电生理学,发现了明显的传导减慢和复极化空间弥散增加--两者都是心律失常的既定基质。对 MYH7 R403Q 心肌细胞中节律组蛋白表达的分析表明,Connexin-43(又称 GJA1)、钠通道和内向整流钾通道的表达减少--这三者的结合降低了电偶联性并减慢了心脏传导。我们的数据代表了以前未报道过的 HCM 心律失常的生物物理基础,这是心肌细胞电生理学的内在因素。在疾病发展的后期,这些促心律失常表型可能会因心肌细胞混乱和纤维化而加剧,从而导致猝死。
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来源期刊
Disease Models & Mechanisms
Disease Models & Mechanisms 医学-病理学
CiteScore
6.60
自引率
7.00%
发文量
203
审稿时长
6-12 weeks
期刊介绍: Disease Models & Mechanisms (DMM) is an online Open Access journal focusing on the use of model systems to better understand, diagnose and treat human disease.
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