Deciphering mechanisms of cardiomyocytes and non-cardiomyocyte transformation in myocardial remodeling of permanent atrial fibrillation

Yixuan Sheng; Yin-Ying Wang; Yuan Chang; Dongting Ye; Liying Wu; Hongen Kang; Xiong Zhang; Xiao Chen; Bin Li; Daliang Zhu; Ningning Zhang; Haisen Zhao; Aijun Chen; Haisheng Chen; Peilin Jia; Jiangping Song

Journal of Advanced Research (Jul 2024)

Deciphering mechanisms of cardiomyocytes and non-cardiomyocyte transformation in myocardial remodeling of permanent atrial fibrillation

Yixuan Sheng,
Yin-Ying Wang,
Yuan Chang,
Dongting Ye,
Liying Wu,
Hongen Kang,
Xiong Zhang,
Xiao Chen,
Bin Li,
Daliang Zhu,
Ningning Zhang,
Haisen Zhao,
Aijun Chen,
Haisheng Chen,
Peilin Jia,
Jiangping Song

Affiliations

Yixuan Sheng: Department of Cardiovascular Surgery, Guangzhou First People’s Hospital, School of Medicine, South China University of Technology, Guangzhou, China; State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences, Peking Union Medical College, 167A Beilishi Road, Xi Cheng District, Beijing 100037, China
Yin-Ying Wang: CAS Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences and China National Center for Bioinformation, Beijing, China
Yuan Chang: Beijing Key Laboratory of Preclinical Research and Evaluation for Cardiovascular Implant Materials, Animal Experimental Centre, Fuwai Hospital, National Centre for Cardiovascular Disease, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100037, China; State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences, Peking Union Medical College, 167A Beilishi Road, Xi Cheng District, Beijing 100037, China
Dongting Ye: Department of Cardiovascular Surgery, Guangzhou First People’s Hospital, School of Medicine, South China University of Technology, Guangzhou, China
Liying Wu: Department of Cardiovascular Surgery, Guangzhou First People’s Hospital, School of Medicine, South China University of Technology, Guangzhou, China
Hongen Kang: CAS Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences and China National Center for Bioinformation, Beijing, China; University of Chinese Academy of Sciences, Beijing, China
Xiong Zhang: Department of Cardiovascular Surgery, Guangzhou First People’s Hospital, School of Medicine, South China University of Technology, Guangzhou, China
Xiao Chen: Beijing Key Laboratory of Preclinical Research and Evaluation for Cardiovascular Implant Materials, Animal Experimental Centre, Fuwai Hospital, National Centre for Cardiovascular Disease, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100037, China; State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences, Peking Union Medical College, 167A Beilishi Road, Xi Cheng District, Beijing 100037, China
Bin Li: Department of Cardiovascular Surgery, Guangzhou First People’s Hospital, School of Medicine, South China University of Technology, Guangzhou, China
Daliang Zhu: Department of Cardiovascular Surgery, Guangzhou First People’s Hospital, School of Medicine, South China University of Technology, Guangzhou, China
Ningning Zhang: Beijing Key Laboratory of Preclinical Research and Evaluation for Cardiovascular Implant Materials, Animal Experimental Centre, Fuwai Hospital, National Centre for Cardiovascular Disease, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100037, China; Beijing Key Laboratory of Preclinical Research and Evaluation for Cardiovascular Implant Materials, Animal Experimental Centre, Fuwai Hospital, National Centre for Cardiovascular Disease, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100037, China
Haisen Zhao: Department of Cardiovascular Surgery, Guangzhou First People’s Hospital, School of Medicine, South China University of Technology, Guangzhou, China
Aijun Chen: Department of Cardiovascular Surgery, Guangzhou First People’s Hospital, School of Medicine, South China University of Technology, Guangzhou, China
Haisheng Chen: Department of Cardiovascular Surgery, Guangzhou First People’s Hospital, School of Medicine, South China University of Technology, Guangzhou, China; Corresponding authors at: Shenzhen Key Laboratory of Cardiovascular Disease, Fuwai Hospital Chinese Academy of Medical Sciences, Shenzhen 518057, China (J. Song).
Peilin Jia: CAS Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences and China National Center for Bioinformation, Beijing, China; Corresponding authors at: Shenzhen Key Laboratory of Cardiovascular Disease, Fuwai Hospital Chinese Academy of Medical Sciences, Shenzhen 518057, China (J. Song).
Jiangping Song: Shenzhen Key Laboratory of Cardiovascular Disease, Fuwai Hospital Chinese Academy of Medical Sciences, Shenzhen 518057, China; Beijing Key Laboratory of Preclinical Research and Evaluation for Cardiovascular Implant Materials, Animal Experimental Centre, Fuwai Hospital, National Centre for Cardiovascular Disease, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100037, China; State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences, Peking Union Medical College, 167A Beilishi Road, Xi Cheng District, Beijing 100037, China; Corresponding authors at: Shenzhen Key Laboratory of Cardiovascular Disease, Fuwai Hospital Chinese Academy of Medical Sciences, Shenzhen 518057, China (J. Song).

Journal volume & issue: Vol. 61
pp. 101 – 117

Abstract

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Introduction: Atrial fibrillation (AF) is the most prevalent cardiac arrhythmia, and it significantly increases the risk of cardiovascular complications and morbidity, even with appropriate treatment. Tissue remodeling has been a significant topic, while its systematic transcriptional signature remains unclear in AF. Objectives: Our study aims to systematically investigate the molecular characteristics of AF at the cellular-level. Methods: We conducted single-nuclei RNA-sequencig (snRNA-seq) analysis using nuclei isolated from the left atrial appendage (LAA) of AF patients and sinus rhythm. Pathological staining was performed to validate the key findings of snRNA-seq. Results: A total of 30 cell subtypes were identified among 80, 592 nuclei. Within the LAA of AF, we observed a specific subtype of dedifferentiated cardiomyocytes (CMs) characterized by reduced expression of cardiac contractile proteins (TTN and TRDN) and heightened expression of extracellular-matrix related genes (COL1A2 and FBN1). Transcription factor prediction analysis revealed that gene expression patterns in dedifferentiated CMs were primarily regulated by CEBPG and GISLI. Additionally, we identified a distinct subtype of endothelial progenitor cells (EPCs) demonstrating elevated expression of PROM1 and KDR, a population decreased within the LAA of AF. Epicardial adipocytes disclosed a reduced release of the anti-inflammatory and anti-fibrotic factor PRG4, and an augmented secretion of VEGF signals targeting CMs. Additionally, we noted accumulation of M2-like macrophages and CD8+ T cells with high pro-inflammatory score in LAA of AF. Furthermore, the analysis of intercellular communication revealed specific pathways related to AF, such as inflammation, extracellular matrix, and vascular remodeling signals. Conclusions: This study has discovered the presence of dedifferentiated CMs, a decrease in endothelial progenitor cells, a shift in the secretion profile of adipocytes, and an amplified inflammatory response in AF. These findings could offer crucial insights for future research on AF and serve as valuable references for investigating novel therapeutic approaches for AF.

Published in Journal of Advanced Research

ISSN: 2090-1232 (Print); 2090-1224 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Medicine: Medicine (General); Science: Science (General)
Website: http://www.journals.elsevier.com/journal-of-advanced-research/

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