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Updated: Feb 27, 2026
Ambulatory ECG Recording in Mice
Published on: May 27, 2010
Remodeling of repolarization and arrhythmia susceptibility in a myosin-binding protein C knockout mouse model
Amir Toib1,2, Chen Zhang2, Giulia Borghetti2
1Section of Pediatric Cardiology, St. Christopher's Hospital for Children and Department of Pediatrics, Drexel University College of Medicine, Philadelphia, Pennsylvania; and.
Insights
Genetic hypertrophic cardiomyopathy (HCM) increases sudden cardiac death risk. This study shows reduced repolarizing K+ currents in HCM mice cause action potential prolongation and arrhythmias, identifying a key cellular mechanism.
Area of Science:
- Cardiovascular Physiology
- Cardiac Electrophysiology
- Genetic Cardiology
Background:
- Hypertrophic cardiomyopathy (HCM) is a common genetic heart disease linked to sudden cardiac death (SCD) in young individuals.
- The precise cellular mechanisms underlying SCD in HCM remain incompletely understood.
- Action potential duration (APD) prolongation is a known risk factor for arrhythmias in hypertrophied hearts, but the role of K+ currents is unclear.
Purpose of the Study:
- To investigate the arrhythmogenic phenotype and electrophysiological properties of ventricular myocytes in a mouse model of HCM induced by myosin-binding protein C (MyBPC) knockout (KO).
- To test the hypothesis that altered repolarizing K+ currents contribute to APD prolongation in MyBPC KO myocytes.
Main Methods:
- Myosin-binding protein C (MyBPC) knockout (KO) mouse model of hypertrophic cardiomyopathy (HCM).
- Telemetric electrocardiography (ECG) to assess cardiac function and arrhythmias in vivo.
- Whole-cell patch-clamp electrophysiology and quantitative RT-PCR to analyze myocyte properties and gene expression.
Main Results:
- MyBPC KO mice exhibited significant cardiac hypertrophy, dysfunction, and prolonged corrected QT interval compared to wild-type (WT) controls.
- Ventricular myocytes from MyBPC KO mice showed hypertrophy, prolonged action potential duration (APD), and significantly reduced repolarizing K+ currents.
- Quantitative RT-PCR revealed decreased mRNA levels for critical K+ channel subunits in KO myocytes.
Conclusions:
- Reduced repolarizing K+ currents in ventricular myocytes of MyBPC KO mice contribute to APD and corrected QT interval prolongation.
- These cellular repolarization abnormalities are strongly linked to the observed arrhythmia susceptibility in this HCM model.
- The findings implicate impaired K+ current function as a critical factor in the pathogenesis of sudden cardiac death in hypertrophic cardiomyopathy.
Abstract:
Hypertrophic cardiomyopathy (HCM) is one of the most common genetic cardiac diseases and among the leading causes of sudden cardiac death (SCD) in the young. The cellular mechanisms leading to SCD in HCM are not well known. Prolongation of the action potential (AP) duration (APD) is a common feature predisposing hypertrophied hearts to SCD. Previous studies have explored the roles of inward Na+ and Ca2+ in the development of HCM, but the role of repolarizing K+ currents has not been defined. The objective of this study was to characterize the arrhythmogenic phenotype and cellular electrophysiological properties of mice with HCM, induced by myosin-binding protein C (MyBPC) knockout (KO), and to test the hypothesis that remodeling of repolarizing K+ currents causes APD prolongation in MyBPC KO myocytes. We demonstrated that MyBPC KO mice developed severe hypertrophy and cardiac dysfunction compared with wild-type (WT) control mice. Telemetric electrocardiographic recordings of awake mice revealed prolongation of the corrected QT interval in the KO compared with WT control mice, with overt ventricular arrhythmias. Whole cell current- and voltage-clamp experiments comparing KO with WT mice demonstrated ventricular myocyte hypertrophy, AP prolongation, and decreased repolarizing K+ currents. Quantitative RT-PCR analysis revealed decreased mRNA levels of several key K+ channel subunits. In conclusion, decrease in repolarizing K+ currents in MyBPC KO ventricular myocytes contributes to AP and corrected QT interval prolongation and could account for the arrhythmia susceptibility.NEW & NOTEWORTHY Ventricular myocytes isolated from the myosin-binding protein C knockout hypertrophic cardiomyopathy mouse model demonstrate decreased repolarizing K+ currents and action potential and QT interval prolongation, linking cellular repolarization abnormalities with arrhythmia susceptibility and the risk for sudden cardiac death in hypertrophic cardiomyopathy.
