Calcium dysregulation increases right ventricular outflow tract arrhythmogenesis in rabbit model of chronic kidney disease

Chronic kidney disease (CKD) increases the risk of arrhythmia. The right ventricular outflow tract (RVOT) is a crucial site of ventricular tachycardia (VT) origination. We hypothesize that CKD increases RVOT arrhythmogenesis through its effects on calcium dysregulation. We analysed measurements obta...

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Bibliographic Details
Published in:Journal of cellular and molecular medicine 2021-12, Vol.25 (24), p.11264-11277
Main Authors: Huang, Shih‐Yu, Chen, Yao‐Chang, Kao, Yu‐Hsun, Lu, Yen‐Yu, Lin, Yung‐Kuo, Higa, Satoshi, Chen, Shih‐Ann, Chen, Yi‐Jen
Format: Article
Language:English
Subjects:
Action potential
Action Potentials
Animals
Antibodies
Arrhythmia
Arrhythmias, Cardiac - diagnosis
Arrhythmias, Cardiac - etiology
Arrhythmias, Cardiac - metabolism
Autonomic nervous system
Biomarkers
Ca2+-transporting ATPase
Ca2+/calmodulin-dependent protein kinase II
Calcium - metabolism
Calcium currents
calcium homeostasis
Cardiac arrhythmia
Cardiomyocytes
Cefazolin
chronic kidney disease
Confocal microscopy
Disease Models, Animal
Disease Susceptibility
Electrocardiography
Enzymes
Experiments
Heart
Heart Function Tests - methods
Heart Ventricles - metabolism
Heart Ventricles - physiopathology
Hemodialysis
Humans
Hydroxylase
Hyperactivity
Immunohistochemistry
Isoproterenol
Kidney diseases
Kinases
Laboratory animals
Leak channels
Lipid peroxidation
Malondialdehyde
Microelectrodes
Mortality
Myocytes
Myocytes, Cardiac - metabolism
Na+/Ca2+ exchanger
Neomycin
Original
Oxidative Stress
Patch-Clamp Techniques
Potassium
Proteins
Pulmonary arteries
Rabbits
Renal Insufficiency, Chronic - complications
right ventricular outflow tract
Sarcoplasmic Reticulum - metabolism
Sodium
Stains & staining
Tachycardia
Ventricle
ventricular tachycardia
Western blotting
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Summary:Chronic kidney disease (CKD) increases the risk of arrhythmia. The right ventricular outflow tract (RVOT) is a crucial site of ventricular tachycardia (VT) origination. We hypothesize that CKD increases RVOT arrhythmogenesis through its effects on calcium dysregulation. We analysed measurements obtained using conventional microelectrodes, patch clamp, confocal microscopy, western blotting, immunohistochemical examination and lipid peroxidation for both control and CKD (induced by 150 mg/kg neomycin and 500 mg/kg cefazolin daily) rabbit RVOT tissues or cardiomyocytes. The RVOT of CKD rabbits exhibited a short action potential duration, high incidence of tachypacing (20 Hz)‐induced sustained VT, and long duration of isoproterenol and tachypacing‐induced sustained and non‐sustained VT. Tachypacing‐induced sustained and non‐sustained VT in isoproterenol‐treated CKD RVOT tissues were attenuated by KB‐R7943 and partially inhibited by KN93 and H89. The CKD RVOT myocytes had high levels of phosphorylated CaMKII and PKA, and an increased expression of tyrosine hydroxylase‐positive neural density. The CKD RVOT myocytes exhibited large levels of Ito, IKr, NCX and L‐type calcium currents, calcium leak and malondialdehyde but low sodium current, SERCA2a activity and SR calcium content. The RVOT in CKD with oxidative stress and autonomic neuron hyperactivity exhibited calcium handling abnormalities, which contributed to the induction of VT.
ISSN:1582-1838
1582-4934
DOI:10.1111/jcmm.17052