Evolocumab prevents atrial fibrillation in rheumatoid arthritis rats through restraint of PCSK9 induced atrial remodeling

Xuejie Han; Yunlong Gao; Meijiao He; Yingchun Luo; Ying Wei; Yu Duan; Song Zhang; Hui Yu; Jiuxu Kan; Te Hou; Yun Zhang; Yue Li

doi:10.1016/j.jare.2023.09.007

Evolocumab prevents atrial fibrillation in rheumatoid arthritis rats through restraint of PCSK9 induced atrial remodeling

J Adv Res. 2023 Sep 12:S2090-1232(23)00256-4. doi: 10.1016/j.jare.2023.09.007. Online ahead of print.

Authors

Xuejie Han¹, Yunlong Gao¹, Meijiao He¹, Yingchun Luo¹, Ying Wei¹, Yu Duan¹, Song Zhang¹, Hui Yu¹, Jiuxu Kan¹, Te Hou¹, Yun Zhang², Yue Li³

Affiliations

¹ Department of Cardiology, the First Affiliated Hospital, Harbin Medical University, Harbin 150001, China.
² Department of Cardiology, the First Affiliated Hospital, Harbin Medical University, Harbin 150001, China. Electronic address: 263727@163.com.
³ Department of Cardiology, the First Affiliated Hospital, Harbin Medical University, Harbin 150001, China; NHC Key Laboratory of Cell Translation, Harbin Medical University, Heilongjiang 150001, China; Key Laboratory of Hepatosplenic Surgery, Harbin Medical University, Ministry of Education, Harbin 150001, China; Key Laboratory of Cardiac Diseases and Heart Failure, Harbin Medical University, Harbin 150001, China; Heilongjiang Key Laboratory for Metabolic Disorder & Cancer Related Cardiovascular Diseases, Harbin 150081, China; Institute of Metabolic Disease, Heilongjiang Academy of Medical Science, Harbin, China. Electronic address: ly99ly@hrbmu.edu.cn.

PMID: 37709197
DOI: 10.1016/j.jare.2023.09.007

Abstract

Introduction: Proprotein convertase subtilisin/kexin type 9 (PCSK9) is implicated in the pathogenesis and progression of autoimmune disease. Patients with rheumatoid arthritis (RA) are at high risk of developing atrial fibrillation (AF), while whether PCSK9 is involved in the onset of AF among RA patients remains unclear.

Objectives: To explore the role of PCSK9 in the occurrence of AF in RA patients and decipher the underlying mechanism.

Methods: We established a rat model of collagen-induced arthritis (CIA) by immunization with type II collagen in Freund's incomplete adjuvant. Atrial electrophysiological test was used to evaluate AF susceptibility. We performed a clinical study to examine the correlation between PCSK9 level and AF, which recruited healthy control, RA patients and RA patients complicated with AF. Evolocumab (a monoclonal antibody of PCSK9) is administered via intraperitoneal injection in CIA rats to assess the role of PCSK9 in RA-related AF. LPS-RS (LPS inhibitor), clodronate liposomes (depletion of macrophages), and cell co-culture model were used to dissect the mechanism underlying PCSK9 promotes AF.

Results: AF inducibility and duration were higher in CIA rats, accompanied by elevated plasma and atrial PCSK9. Interestingly, compared with healthy control subjects, patients with RA showed an increase in PCSK9, and the PCSK9 is much higher in RA patients complicated with AF. The level of PCSK9 was independently associated with AF risk in RA patients. In the in vivo experiment, evolocumab reduced AF susceptibility, and ameliorated atrial structural remodeling of CIA rats. Mechanistically, augmented LPS in CIA rats led to an increase in PCSK9, which exacerbated fibrosis of cardiac fibroblasts and apoptosis of cardiac myocytes by enhancement of M1 macrophages polarization and inflammation, thereby contributing to AF.

Conclusion: This study suggests that elevated PCSK9 causes atrial structural remodeling by enhancement of M1 macrophages polarization in atria, and evolocumab can effectively protects CIA rats from AF.

Keywords: Atrial fibrillation; Evolocumab; PCSK9; Rheumatoid arthritis.