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

Document Type: Original Article

Authors

1 Department of Medical, Tri-Service General Hospital Songshan Branch, National Defense Medical Center, Taipei, Taiwan

2 Department of Biomedical Engineering, National Defense Medical Center, Taipei, Taiwan

3 Department of Cardiology, Chi-Mei Medical Center, Tainan, Taiwan

4 Division of Cardiology, Department of Internal Medicine, Sijhih Cathay General Hospital, New Taipei City, Taiwan

5 School of Medicine, College of Medicine, Fu-Jen Catholic University, New Taipei City, Taiwan

6 Heart Rhythm Center and Division of Cardiology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan

7 Cardiovascular Research Center, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan

8 Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan

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.

Keywords


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