Mirabegron, a β3‑adrenoreceptor agonist, regulates right and left atrial arrhythmogenesis differently

Chao-Shun Chan; Fong-Jhih Lin; Chih-Min Liu; Yung-Kuo Lin; Yao-Chang Chen; Chun-Chun Hsu; Satoshi Higa; Shih-Ann Chen; Yi-Jen Chen

doi:10.3892/etm.2022.11656

Mirabegron, a β3‑adrenoreceptor agonist, regulates right and left atrial arrhythmogenesis differently

Exp Ther Med. 2022 Oct 18;24(6):720. doi: 10.3892/etm.2022.11656. eCollection 2022 Dec.

Authors

Chao-Shun Chan^{1

2}, Fong-Jhih Lin^{3

4}, Chih-Min Liu^{5

6}, Yung-Kuo Lin^{2

7}, Yao-Chang Chen⁴, Chun-Chun Hsu^{8

9}, Satoshi Higa¹⁰, Shih-Ann Chen^{5

11

12}, Yi-Jen Chen^{7

13

14}

Affiliations

¹ Department of Internal Medicine, Division of Cardiology, Taipei Medical University Hospital, Taipei 11031, Taiwan, R.O.C.
² Department of Internal Medicine, Division of Cardiology, School of Medicine, Taipei Medical University, Taipei 11031, Taiwan, R.O.C.
³ Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan, R.O.C.
⁴ Department of Biomedical Engineering, National Defense Medical Center, Taipei 11490, Taiwan, R.O.C.
⁵ Department of Medicine, Division of Cardiology, Heart Rhythm Center, Taipei Veterans General Hospital, Taipei 11217, Taiwan, R.O.C.
⁶ Institute of Clinical Medicine and Faculty of Medicine, National Yang Ming Chiao Tung University, Taipei 11217, Taiwan, R.O.C.
⁷ Department of Internal Medicine, Division of Cardiology, Wan-Fang Hospital, Taipei Medical University, Taipei 11696, Taiwan, R.O.C.
⁸ School of Respiratory Therapy, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan, R.O.C.
⁹ Department of Internal Medicine, Division of Pulmonary Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan, R.O.C.
¹⁰ Cardiac Electrophysiology and Pacing Laboratory, Division of Cardiovascular Medicine, Makiminato Central Hospital, Okinawa 9012131, Japan.
¹¹ Cardiovascular Center, Taichung Veterans General Hospital, Taichung 40705, Taiwan, R.O.C.
¹² Department of Post-Baccalaureate Medicine, College of Medicine, National Chung Hsing University, Taichung 40227, Taiwan, R.O.C.
¹³ Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan, R.O.C.
¹⁴ Cardiovascular Research Center, Wan-Fang Hospital, Taipei Medical University, Taipei 11696, Taiwan, R.O.C.

Abstract

Mirabegron increases atrial fibrillation (AF) risk. The left atrium (LA) is the most critical 'substrate' for AF and has higher arrhythmogenesis compared with the right atrium (RA). The present study aimed to investigate the electrophysiological and arrhythmogenic effects of mirabegron on the LA and RA and clarify the potential underlying mechanisms. Conventional microelectrodes, a whole-cell patch clamp and a confocal microscope were used in rabbit LA and RA preparations or single LA and RA myocytes before and after mirabegron administration with or without cotreatment with KT5823 [a cyclic adenosine monophosphate (cAMP)-dependent protein kinase inhibitor]. The baseline action potential duration at repolarization extents of 20 and 50% (but not 90%) were shorter in the LA than in the RA. Mirabegron at 0.1 and 1 µM (but not 0.01 µM) reduced the action potential duration at repolarization extents of 20 and 50% in the LA and RA. Mirabegron (0.1 µM) increased the occurrence of tachypacing-induced burst firing in the LA but not in the RA, where it was suppressed by KT5823 (1 µM). Mirabegron (0.1 µM) increased the L-type Ca²⁺ current (I_Ca-L), ultrarapid component of delayed rectifier K⁺ current (I_Kur), Ca²⁺ transients and sarcoplasmic reticulum Ca²⁺ content but reduced transient outward K⁺ current (I_to) in the LA myocytes. However, mirabegron did not change the Na⁺ current and delayed rectifier K⁺ current in the LA myocytes. Moreover, pretreatment with KT5823 (1 µM) inhibited the effects of mirabegron on I_Ca-L, I_to and I_Kur in the LA myocytes. Furthermore, in the RA myocytes, mirabegron reduced I_Ca-L but did not change I_to. In conclusion, mirabegron differentially regulates electrophysiological characteristics in the LA and RA. Through the activation of the cAMP-dependent protein kinase pathway and induction of Ca²⁺ dysregulation, mirabegron may increase LA arrhythmogenesis, leading to increased AF risk.

Keywords: atrial fibrillation; left atrium; mirabegron; right atrium; β3-Adrenoreceptors.

Grants and funding

Funding: This work was supported by the Ministry of Science and Technology of Taiwan (grant no. MOST 110-2314-B-038-126-MY2), Taipei Medical University-Taipei Medical University Hospital (grant no. 108TMU-TMUH-25), Taipei Medical University (grant no. TMU109-AE1-B29) and the Foundation for the Development of Internal Medicine in Okinawa (grant no. 03-009).