Proinflammatory Cytokine Modulates Intracellular Calcium Handling and Enhances Ventricular Arrhythmia Susceptibility

Yung-Nan Tsai; Ya-Wen Hsiao; Shien-Fong Lin; Yi-Hsin Chan; Yu-Cheng Hsieh; Wei-Hua Tang; An-Sheng Lee; Yu-Ting Huang; Hsing-Yuan Li; Tze-Fan Chao; Satoshi Higa; Tsu-Juey Wu; Shih-Lin Chang; Shih-Ann Chen

doi:10.3389/fcvm.2021.623510

Proinflammatory Cytokine Modulates Intracellular Calcium Handling and Enhances Ventricular Arrhythmia Susceptibility

Front Cardiovasc Med. 2021 Mar 16:8:623510. doi: 10.3389/fcvm.2021.623510. eCollection 2021.

Authors

Yung-Nan Tsai^{1

2}, Ya-Wen Hsiao², Shien-Fong Lin³, Yi-Hsin Chan⁴, Yu-Cheng Hsieh^{1

5}, Wei-Hua Tang^{2

6}, An-Sheng Lee⁷, Yu-Ting Huang², Hsing-Yuan Li⁸, Tze-Fan Chao^{2

9}, Satoshi Higa¹⁰, Tsu-Juey Wu^{1

5}, Shih-Lin Chang^{2

9}, Shih-Ann Chen^{1

2

5

9}

Affiliations

¹ Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan.
² Division of Cardiology, Department of Medicine, Heart Rhythm Center, Taipei Veterans General Hospital, Taipei, Taiwan.
³ Institute of Biomedical Engineering, National Chiao-Tung University, Hsin-Chu, Taiwan.
⁴ Division of Cardiology, Chang Gung Memorial Hospital, Taoyuan, Taiwan.
⁵ Department of Internal Medicine, Cardiovascular Center, Taichung Veterans General Hospital, Taichung, Taiwan.
⁶ Division of Cardiology, Department of Internal Medicine, National Yang-Ming University Hospital, Yilan, Taiwan.
⁷ Department of Medicine, Mackay Medical College, New Taipei, Taiwan.
⁸ Division of Cardiology, Department of Pediatrics, Taipei Veterans General Hospital, Taipei, Taiwan.
⁹ Faculty of Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan.
¹⁰ Cardiac Electrophysiology and Pacing Laboratory, Division of Cardiovascular Medicine, Makiminato Central Hospital, Urasoe, Japan.

Abstract

Background: The mechanism of Interleukin-17 (IL-17) induced ventricular arrhythmia (VA) remains unclear. This study aimed to investigate the effect of intracellular calcium (Ca_i) handling and VA susceptibility by IL-17. Methods: The electrophysiological properties of isolated perfused rabbit hearts under IL-17 (20 ng/ml, N = 6) and the IL-17 with neutralizer (0.4 μg/ml, N = 6) were evaluated using an optical mapping system. The action potential duration (APD) and Ca_i transient duration (Ca_iTD) were examined, and semiquantitative reverse transcriptase-polymerase chain reaction analysis of ion channels was performed. Results: There were longer APD₈₀, Ca_iTD₈₀ and increased thresholds of APD and Ca_iTD alternans, the maximum slope of APD restitution and induction of VA threshold in IL-17 group compared with those in IL-17 neutralizer and baseline groups. During ventricular fibrillation, the number of phase singularities and dominant frequency were both significantly greater in IL-17 group than in baseline group. The mRNA expressions of the Na⁺/Ca²⁺ exchanger, phospholamban, and ryanodine receptor Ca²⁺ release channel were upregulated, and the subunit of L-type Ca²⁺ current and sarcoplasmic reticulum Ca²⁺-ATPase 2a were significantly reduced in IL-17 group compared to baseline and IL-17 neutralizer group. Conclusions: IL-17 enhanced Ca_iTD and APD alternans through disturbances in calcium handling, which may increase VA susceptibility.

Keywords: IL-17; IL-17 neutralizer; alternans; the maximum calcium transient; ventricular arrhythmias.