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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异常的昼夜节律通过降低心室机械强度而加剧扩张型心肌病


目的 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。方法和结果我们包括一个派生队列 （n = 105） 和一个验证队列 （n = 65）。将 DCM 患者分为 SA 组和无 SA 组。采用 RT-qPCR 检测不同时间点心脏标本节律基因表达模式的变化。我们使用单核 RNA 测序 （snRNA-seq） 探讨 ACR 组的异常转录模式，并通过病理染色、原子力显微镜 （AFM） 和 Rev-erbα/β 敲除 （KO） 小鼠分析验证了结果。SA 的 DCM 患者表现节律基因表达幅度降低。SA 组显示左心腔扩张更严重。从 snRNA-seq 中，ACR-DCM 丢失了早晨转录模式，详细地表明，心肌细胞 （CMs） 的肌动蛋白细胞骨架组织被破坏，肥大加剧，活化成纤维细胞 （Fibs） 的比例随着纤维化面积比的降低而降低。Rev-erbα/β KO 小鼠的病理染色、机械实验和转录特征结果支持上述发现。结论 与非 SA 组相比，DCM 合并 SA 患者左心室 （LV） 壁扩张更严重，结构强度更低，CM 和 Fib 的表型变化参与这一过程。ACR-DCM 的组织病理学特征是结构薄弱的脑室壁。