Volume overload impedes the maturation of sarcomeres and T-tubules in the right atria: a potential cause of atrial arrhythmia following delayed atrial septal defect closure

Frontiers in Physiology

Physiology

Yuqing Hu¹  Zhuoya Dong²  Haifa Hong³  Sijuan Sun⁴  Yingying Xiao⁵  Sixie Zheng⁶  Zheng Wang⁶  Debao Li⁶  Lisheng Qiu⁶  Dian Chen⁶  Lincai Ye⁷ 

[1] Department of Cardiology, Shanghai Children’s Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai, China;Department of Pediatric Intensive Care Unit, Ningbo Women and Children’s Hospital, Ningbo, Zhejiang, China;Department of Pediatric Intensive Care Unit, Ningbo Women and Children’s Hospital, Ningbo, Zhejiang, China;Department of Thoracic and Cardiovascular Surgery, Shanghai Children’s Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China;Department of Pediatric Intensive Care Unit, Shanghai Children’s Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai, China;Department of Thoracic and Cardiovascular Surgery, Shanghai Children’s Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China;Department of Thoracic and Cardiovascular Surgery, Shanghai Children’s Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai, China;Department of Thoracic and Cardiovascular Surgery, Shanghai Children’s Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai, China;Institute of Pediatric Translational Medicine, Shanghai Children’s Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai, China;Shanghai Institute for Pediatric Congenital Heart Disease, Shanghai Children’s Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai, China;

关键词: volume overload;    atrial septal defects;    atrium;    maturation;    sarcomere;    transverse tubules;   

DOI  :  10.3389/fphys.2023.1237187

 received in 2023-06-09, accepted in 2023-09-28,  发布年份 2023

来源: Frontiers

【 摘 要 】

Introduction: Adult patients with atrial septal defects (ASD), the most common form of adult congenital heart disease, often die of arrhythmias, and the immaturity of cardiomyocytes contributes significantly to arrhythmias. ASD typically induces a left-to-right shunt, which then leads to the right atrium (RA) volume overload (VO). Whether or not VO contributes to RA cardiomyocyte immaturity and thereby causes arrhythmias in adult patients with ASD remains unclear.Methods: Here, we developed the first neonatal RA VO mouse model by creating a fistula between the inferior vena cava and abdominal aorta on postnatal day 7. RA VO was confirmed by increases in the mean flow velocity, mean pressure gradient, and velocity time integral across the tricuspid valve, and an increase in the RA diameter and RA area middle section.Results: We found that VO decreased the regularity and length of sarcomeres, and decreased the T-element density, regularity, and index of integrity of T-tubules in RA cardiomyocytes, suggesting that the two most important maturation hallmarks (sarcomere and T-tubules) of RA cardiomyocytes were impaired by VO. Accordingly, the calcium handling capacity of cardiomyocytes from postnatal day 21 (P21) RA was decreased by VO. VO caused a significant elongation of the PR interval. The expression of connexin 43 (Cx43) was decreased in RA VO. Moreover, gene ontology (GO) analysis of the downregulated genes in RA demonstrated that there was an abundance of enriched terms associated with sarcomeres and T-tubules exposed to VO. The results were further verified by qRT-PCR.Conclusions: In conclusion, the first neonatal RA VO mouse model was developed; furthermore, using this neonatal RA VO mouse model, we revealed that VO impeded RA sarcomere and T-tubule maturation, which may be the underlying causes of atrial arrhythmias in adult patients with ASD.

【 授权许可】

Unknown   
Copyright © 2023 Dong, Chen, Zheng, Wang, Li, Xiao, Sun, Ye, Qiu, Hu and Hong.