Aims 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. Methods and results 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. Conclusion 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.

中文翻译：

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昼夜节律异常会降低心室机械强度，从而加剧扩张型心肌病


目的 扩张型心肌病 (DCM) 具有病因学和病理生理学的异质性。昼夜节律异常（ACR）与动物模型中 DCM 的发生有关，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作为研究对象来探讨ACR-DCM。方法和结果 我们纳入了衍生队列 (n = 105) 和验证队列 (n = 65)。 DCM患者分为SA组和无SA组。 RT-qPCR用于测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敲除（KO）小鼠验证了结果分析。伴有 SA 的 DCM 患者节律基因表达幅度降低。 SA组左心室扩张更严重。从snRNA-seq来看，ACR-DCM丢失了早晨的转录模式，具体而言，心肌细胞（CM）的肌动蛋白细胞骨架组织被破坏且肥大加剧，并且活化的成纤维细胞（Fib）的比例随着纤维化面积比的减少而减少。 Rev-erbα/β KO小鼠的病理染色、力学实验和转录特征结果支持了上述发现。结论 与非SA组相比，SA组DCM患者左室壁扩张更严重，结构强度更低，CM和Fib的表型变化参与了这一过程。 ACR-DCM 的组织病理学特征是心室壁结构薄弱。