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SHR Neuro Cancer Cardio Lipid Metab Microb

Toib, A; Zhang, C; Borghetti, G; Zhang, X; Wallner, M; Yang, Y; Troupes, CD; Kubo, H; Sharp, TE; Feldsott, E; Berretta, RM; Zalavadia, N; Trappanese, DM; Harper, S; Gross, P; Chen, X; Mohsin, S; Houser, SR.
Remodeling of repolarization and arrhythmia susceptibility in a myosin-binding protein C knockout mouse model.
Am J Physiol Heart Circ Physiol. 2017; 313(3):H620-H630 Doi: 10.1152/ajpheart.00167.2017 [OPEN ACCESS]
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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 Ca(2+) 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. Copyright © 2017 the American Physiological Society.
Find related publications in this database (using NLM MeSH Indexing)
Action Potentials -
Animals -
Cardiomegaly - genetics
Cardiomegaly - metabolism
Cardiomegaly - pathology
Carrier Proteins - genetics
Carrier Proteins - metabolism
Disease Models, Animal -
Electrocardiography, Ambulatory -
Fibrosis -
Genetic Predisposition to Disease -
Heart Rate -
Kinetics -
Male -
Mice, 129 Strain -
Mice, Knockout -
Myocardial Contraction -
Myocytes, Cardiac - metabolism
Myocytes, Cardiac - pathology
Patch-Clamp Techniques -
Phenotype -
Potassium - metabolism
Potassium Channels - genetics
Potassium Channels - metabolism
RNA, Messenger - genetics
RNA, Messenger - metabolism
Tachycardia, Ventricular - genetics
Tachycardia, Ventricular - metabolism
Tachycardia, Ventricular - pathology
Tachycardia, Ventricular - physiopathology
Telemetry -
Ventricular Premature Complexes - genetics
Ventricular Premature Complexes - metabolism
Ventricular Premature Complexes - pathology
Ventricular Premature Complexes - physiopathology

Find related publications in this database (Keywords)
myosin-binding protein C
cardiomyopathy
arrhythmia
repolarization
K+ channels
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