Hu Yuqing, Li Debao, Zhou Chunxia, Xiao Yingying, Sun Sijuan, Jiang Chuan, Chen Lijun, Liu Jinfen, Zhang Hao, Li Fen, Hong Haifa, Ye Lincai
Department of Cardiology, 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.
Front Cardiovasc Med. 2022 Apr 12;9:850248. doi: 10.3389/fcvm.2022.850248. eCollection 2022.
Left ventricular (LV) volume overload (VO), commonly found in patients with chronic aortic regurgitation (AR), leads to a series of left ventricular (LV) pathological responses and eventually irreversible LV dysfunction. Recently, questions about the applicability of the guideline for the optimal timing of valvular surgery to correct chronic AR have been raised in regard to both adult and pediatric patients. Understanding how VO regulates postnatal LV development may shed light on the best timing of surgical or drug intervention.
Prepubertal LV VO was induced by aortocaval fistula (ACF) on postnatal day 7 (P7) in mice. LV free walls were analyzed on P14 and P21. RNA-sequencing analysis demonstrated that normal (P21_Sham vs.P14_Sham) and VO-influenced (P21_VO vs. P14_VO) LV development shared common terms of Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) in the downregulation of cell cycle activities and the upregulation of metabolic and sarcomere maturation. The enriched GO terms associated with cardiac condition were only observed in normal LV development, while the enriched GO terms associated with immune responses were only observed in VO-influenced LV development. These results were further validated by the examination of the markers of cell cycle, maturation, and immune responses. When normal and VO-influenced LVs of P21 were compared, they were different in terms of immune responses, angiogenesis, percentage of Ki67-positive cardiomyocytes, mitochondria number, T-tubule regularity, and sarcomere regularity and length.
A prepubertal LV VO mouse model was first established. VO has an important influence on LV maturation and development, especially in cardiac conduction, suggesting the requirement of an early correction of AR in pediatric patients. The underlying mechanism may be associated with the activation of immune responses.
左心室（LV）容量超负荷（VO）常见于慢性主动脉瓣反流（AR）患者，会引发一系列左心室（LV）病理反应，最终导致不可逆的左心室功能障碍。最近，关于瓣膜手术纠正慢性AR的最佳时机指南在成人和儿科患者中的适用性问题引发了关注。了解VO如何调节出生后左心室发育可能有助于明确手术或药物干预的最佳时机。
在出生后第7天（P7）通过主动脉腔静脉瘘（ACF）诱导青春期前小鼠发生左心室VO。在P14和P21对左心室游离壁进行分析。RNA测序分析表明，正常（P21_假手术组与P14_假手术组）和VO影响（P21_VO组与P14_VO组）的左心室发育在细胞周期活动下调以及代谢和肌节成熟上调方面具有共同的基因本体论（GO）和京都基因与基因组百科全书（KEGG）术语。与心脏状况相关的富集GO术语仅在正常左心室发育中观察到，而与免疫反应相关的富集GO术语仅在VO影响的左心室发育中观察到。这些结果通过对细胞周期、成熟和免疫反应标志物的检测得到进一步验证。当比较P21正常和VO影响的左心室时，它们在免疫反应、血管生成、Ki67阳性心肌细胞百分比、线粒体数量、T小管规则性以及肌节规则性和长度方面存在差异。
首次建立了青春期前左心室VO小鼠模型。VO对左心室成熟和发育有重要影响，尤其是在心脏传导方面，提示儿科患者需要早期纠正AR。潜在机制可能与免疫反应的激活有关。
