Jia Hao, Cui Hao, Zhao Zijie, Mo Han, Zhang Ningning, Zhang Yu, Huang Siyuan, Zhang Yue, Xu Mengda, Han Lei, Chen Yulin, Chang Yuan, Hua Xiumeng, Shentu Zhibo, Xia Tie, Chen Xiao, Song Jiangping
Beijing Key Laboratory of Preclinical Research and Evaluation for Cardiovascular Implant Materials, Animal Experimental Centre, National Centre for Cardiovascular Disease, Department of Cardiac Surgery, Fuwai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 167A Beilishi Road, Beijing 100037, China.
Department of General Surgery, Yanan Hospital, Kunming Medical University, Yunnan, China.
Cardiovasc Res. 2024 Dec 31;120(17):2261-2277. doi: 10.1093/cvr/cvae212.
Dilated cardiomyopathy (DCM) has etiological and pathophysiological heterogeneity. Abnormal circadian rhythm (ACR) is related to the development of DCM in animal models, but exploration based on clinical samples is lacking. Sleep apnea (SA) is the most common disease related to ACR, and we chose SA as the study object to explore ACR-DCM.
We included a derivation cohort (n = 105) and a validation cohort (n = 65). DCM patients were divided into SA and without SA group. RT-qPCR was used to determine the change of rhythm gene expression pattern of heart samples from different timepoints. We used single-nucleus RNA sequencing (snRNA-seq) to explore the abnormal transcriptional patterns in the ACR group, and we verified the findings by pathological staining, atomic force microscopy (AFM), and Rev-erbα/β knockout (KO) mice analysis. DCM patients with SA showed decreased amplitude of rhythm gene expression. SA group showed more severe dilation of left heart chambers. From snRNA-seq, ACR-DCM lost the morning transcriptional patterns, detailly, actin cytoskeleton organization of cardiomyocytes (CMs) disrupted and hypertrophy aggravated, and the proportion of activated fibroblasts (Fibs) decreased with the reduction of fibrotic area ratio. The results of pathological staining, mechanical experiments, and transcriptional feature of Rev-erbα/β KO mice supported the above findings.
Compared with the non-SA group, left ventricular (LV) wall dilation was more severe and the structural strength was lower in DCM patients with SA, and phenotypic changes in CM and Fib were involved in this process. ACR-DCM was histopathologically characterized by a structurally weak ventricular wall.
扩张型心肌病（DCM）具有病因和病理生理异质性。昼夜节律异常（ACR）与动物模型中DCM的发生发展有关，但缺乏基于临床样本的探索。睡眠呼吸暂停（SA）是与ACR相关的最常见疾病，我们选择SA作为研究对象来探索ACR-DCM。
我们纳入了一个推导队列（n = 105）和一个验证队列（n = 65）。DCM患者被分为SA组和非SA组。采用RT-qPCR确定不同时间点心脏样本节律基因表达模式的变化。我们使用单核RNA测序（snRNA-seq）来探索ACR组中的异常转录模式，并通过病理染色、原子力显微镜（AFM）和Rev-erbα/β基因敲除（KO）小鼠分析来验证这些发现。伴有SA的DCM患者节律基因表达幅度降低。SA组左心腔扩张更严重。从snRNA-seq结果来看，ACR-DCM失去了早晨的转录模式，具体而言，心肌细胞（CMs）的肌动蛋白细胞骨架组织被破坏且肥大加剧，随着纤维化面积比例的降低，活化成纤维细胞（Fibs）的比例也降低。病理染色、力学实验以及Rev-erbα/β KO小鼠的转录特征结果支持了上述发现。
与非SA组相比，伴有SA的DCM患者左心室（LV）壁扩张更严重且结构强度更低，CM和Fib的表型变化参与了这一过程。ACR-DCM在组织病理学上的特征是心室壁结构薄弱。
