Trastuzumab increases pulmonary vein arrhythmogenesis through modulating pulmonary vein electrical and conduction properties via phosphatidylinositol 3-kinase signaling

Jun Hei Chang, Chen Chuan Cheng, Yen Yu Lu, Yao Chang Chen, Shih Ann Chen, Yi Jen Chen

Research output: Contribution to journalArticlepeer-review

Abstract

Objective(s): Drug-induced atrial fibrillation (AF) is considered an adverse effect of chemotherapeutic drugs. AF is a crucial risk factor for stroke, heart failure, myocardial infarction, and mortality. Pulmonary veins (PVs) are considered triggers inducing AF, and the sinoatrial node (SAN) may modulate PV activity and participate in AF genesis. AF was associated with early discontinuation of trastuzumab in patients with breast cancer. However, whether trastuzumab directly modulates the electrophysiological characteristics of PV and SAN remains unclear. Materials and Methods: ECG and conventional microelectrode system were used to record rabbit heart rhythm in vivo and electrical activities in vitro from isolated SAN, PV, and SAN-PV preparations. Results: Trastuzumab reduced the beating rate in isolated PV and SAN preparations at 1, 10, and 30 μM (particularly in isolated SAN preparations) and induced burst firings in isolated PV preparations at 10 μΜ. In addition, trastuzumab (10 μM) induced SAN-PV conduction block and burst firings, which were blocked by wortmannin (a PI3K inhibitor, 100 nM). Similarly, ECG recordings showed that acute intravenous administration of trastuzumab (10 mg/kg) reduced rabbit heart rates. Conclusion: Trastuzumab increased PV arrhythmogenesis through interfering with PI3K signaling, which may contribute to the genesis of AF.

Original languageEnglish
Pages (from-to)865-870
Number of pages6
JournalIranian Journal of Basic Medical Sciences
Volume23
Issue number7
DOIs
Publication statusPublished - Jul 2020

Keywords

  • Atrial fibrillation
  • Electrophysiology
  • Kinase
  • PI3
  • Pulmonary vein
  • Trastuzumab

ASJC Scopus subject areas

  • Biophysics
  • Biochemistry
  • Immunology and Microbiology(all)
  • Drug Discovery
  • Clinical Biochemistry

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