Levosimendan attenuates electrical alternans and prevents ventricular arrhythmia during therapeutic hypothermia in isolated rabbit hearts

Yu-Shan Chien; Chi-Jen Weng; Shang-Ju Wu; Cheng-Hung Li; Jiunn-Cherng Lin; Jin-Long Huang; Shien-Fong Lin; Yenn-Jiang Lin; Yu-Cheng Hsieh; Shih-Ann Chen

doi:10.1016/j.hrthm.2023.02.014

Levosimendan attenuates electrical alternans and prevents ventricular arrhythmia during therapeutic hypothermia in isolated rabbit hearts

Heart Rhythm. 2023 May;20(5):744-753. doi: 10.1016/j.hrthm.2023.02.014. Epub 2023 Feb 18.

Authors

Affiliations

¹ Cardiovascular Center, Taichung Veterans General Hospital and Chiayi Branch, Taichung and Chiayi, Taiwan; Department of Internal Medicine, Faculty of Medicine, Institute of Clinical Medicine, Institute of Biomedical Engineering, National Yang Ming Chiao Tung University School of Medicine, Taipei and Hsinchu, Taiwan; Department of Data Science and Big Data Analytics, and Department of Financial Engineering, Providence University, Taichung, Taiwan.
² Cardiovascular Center, Taichung Veterans General Hospital and Chiayi Branch, Taichung and Chiayi, Taiwan; Department of Internal Medicine, Faculty of Medicine, Institute of Clinical Medicine, Institute of Biomedical Engineering, National Yang Ming Chiao Tung University School of Medicine, Taipei and Hsinchu, Taiwan; College of Medicine, National Chung Hsing University, Taichung, Taiwan.
³ Department of Internal Medicine, Faculty of Medicine, Institute of Clinical Medicine, Institute of Biomedical Engineering, National Yang Ming Chiao Tung University School of Medicine, Taipei and Hsinchu, Taiwan.
⁴ Department of Internal Medicine, Faculty of Medicine, Institute of Clinical Medicine, Institute of Biomedical Engineering, National Yang Ming Chiao Tung University School of Medicine, Taipei and Hsinchu, Taiwan; Heart Rhythm Center and Division of Cardiology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.
⁵ Cardiovascular Center, Taichung Veterans General Hospital and Chiayi Branch, Taichung and Chiayi, Taiwan; Department of Internal Medicine, Faculty of Medicine, Institute of Clinical Medicine, Institute of Biomedical Engineering, National Yang Ming Chiao Tung University School of Medicine, Taipei and Hsinchu, Taiwan; Department of Data Science and Big Data Analytics, and Department of Financial Engineering, Providence University, Taichung, Taiwan; College of Medicine, National Chung Hsing University, Taichung, Taiwan. Electronic address: ychsieh@vghtc.gov.tw.
⁶ Cardiovascular Center, Taichung Veterans General Hospital and Chiayi Branch, Taichung and Chiayi, Taiwan; Department of Internal Medicine, Faculty of Medicine, Institute of Clinical Medicine, Institute of Biomedical Engineering, National Yang Ming Chiao Tung University School of Medicine, Taipei and Hsinchu, Taiwan; Heart Rhythm Center and Division of Cardiology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan. Electronic address: epsachen@ms41.hinet.net.

PMID: 36804540
DOI: 10.1016/j.hrthm.2023.02.014

Abstract

Background: Therapeutic hypothermia (TH) increases the susceptibility to ventricular arrhythmias (VAs) by prolonging action potential duration (APD) and facilitating arrhythmogenic spatially discordant alternans (SDA). Levosimendan, a calcium sensitizer, has been reported to shorten APD by enhancing the adenosine triphosphate (ATP)-sensitive K current.

Objective: The purpose of this study was to test the hypothesis that, during TH, levosimendan shortens the already prolonged APD, attenuates SDA, and prevents VA.

Methods: Langendorff-perfused isolated rabbit hearts were subjected to TH (30°C) for 15 minutes, followed by treatment with either levosimendan 0.5 μM (n = 9) or vehicle (n = 8) for an additional 30 minutes under TH. Using an optical mapping system, epicardial APD was evaluated by S1 pacing. SDA threshold was defined as the longest pacing cycle length (PCL) that induces the phenomenon of SDA. Ventricular fibrillation (VF) inducibility was evaluated by burst pacing for 30 seconds at the shortest PCL that achieved 1:1 ventricular capture.

Results: During TH, levosimendan shortened ventricular APD (PCL 400 ms; from 259 ± 8 ms to 241 ± 18 ms; P = .036) and decreased SDA threshold (from 327 ± 88 ms to 311 ± 68 ms; P = .011). VF inducibility was lowered from 39% ± 30% to 14% ± 12% with levosimendan (P = .018), whereas APD at PCL 400 ms (P = .161), SDA threshold (P = 1), and VF inducibility (P = .173) were not changed by vehicle.

Conclusion: During TH, levosimendan could protect hearts against VA by shortening APD and decreasing SDA threshold. Enhancing ATP-sensitive K current with levosimendan might be a novel approach to preventing VA during TH.

Keywords: Action potential duration; Alternans; Hypothermia; Levosimendan; Optical mapping.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Action Potentials / physiology
Animals
Arrhythmias, Cardiac*
Heart
Hypothermia, Induced*
Rabbits
Simendan
Ventricular Fibrillation / etiology
Ventricular Fibrillation / prevention & control

Substances

Simendan