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

Shih Yu Huang, Yao Chang Chen, Yu Hsun Kao, Yen Yu Lu, Yung Kuo Lin, Satoshi Higa, Shih Ann Chen, Yi Jen Chen

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
Pages (from-to)11264-11277
Number of pages14
JournalJournal of Cellular and Molecular Medicine
Volume25
Issue number24
DOIs
Publication statusPublished - Dec 2021

Keywords

  • calcium homeostasis
  • chronic kidney disease
  • right ventricular outflow tract
  • ventricular tachycardia

ASJC Scopus subject areas

  • Molecular Medicine
  • Cell Biology

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