Related Experiment Video
Updated: Jun 29, 2026
Isolation, Culture, and Functional Characterization of Adult Mouse Cardiomyoctyes
Published on: September 24, 2013
Reduced connexin-43 expression, slow conduction and repolarisation dispersion in a model of hypertrophic
Seakcheng Lim1,2, Melissa M Mangala3,4, Mira Holliday1,2
1Agnes Ginges Centre for Molecular Cardiology at Centenary Institute, The University of Sydney, Sydney 2050, Australia.
Insights
Hypertrophic cardiomyopathy (HCM) involves abnormal heart muscle structure. This study reveals intrinsic cardiomyocyte electrophysiology defects, including conduction slowing and repolarization changes, contribute to HCM arrhythmias.
Area of Science:
- Cardiology
- Molecular Biology
- Genetics
Background:
- Hypertrophic cardiomyopathy (HCM) is an inherited heart muscle disease.
- HCM is characterized by left ventricular wall thickening, cardiomyocyte disarray, and fibrosis.
- HCM is associated with arrhythmias, heart failure, and sudden cardiac death.
Purpose of the Study:
- To investigate the electrophysiological disturbances in HCM cardiomyocytes.
- To determine if electrophysiological abnormalities are intrinsic to HCM cardiomyocytes or secondary to structural changes.
- To explore the molecular basis of these electrophysiological changes.
Main Methods:
- Utilized an induced pluripotent stem cell (iPSC) model of the MYH7 R403Q variant associated with HCM.
- Studied electrophysiology of HCM cardiomyocytes in electrically coupled syncytia.
- Analyzed rhythmonome protein expression in MYH7 R403Q cardiomyocytes.
Main Results:
- Demonstrated significant conduction slowing and increased spatial dispersion of repolarization in HCM cardiomyocytes.
- Identified reduced expression of connexin-43 (GJA1), sodium channels, and inward rectifier potassium channels.
- These molecular changes reduce electrotonic coupling and slow cardiac conduction, creating a proarrhythmic substrate.
Conclusions:
- Established a novel, biophysical basis for arrhythmia in HCM intrinsic to cardiomyocyte electrophysiology.
- These intrinsic electrophysiological defects contribute to the arrhythmogenic risk in HCM.
- Myocyte disarray and fibrosis may accentuate these proarrhythmic phenotypes later in disease progression.
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.
