Abnormal circadian rhythms exacerbate dilated cardiomyopathy by reducing the ventricular mechanical strength

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 DCM cohort and divided it into SA (n=76) and without SA group (n=29). RT-qPCR was used to determine the change of rhythm gene expression pattern. 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. The severe dilation of the left ventricular (LV) wall in DCM patients with SA was associated with a decrease in structural strength, and phenotypic changes of CMs and Fibs were involved in this process. ACR-DCM was histopathologically characterized by a fluffy ventricular wall. Heart tissue samples from 16 patients were included in the snRNA-seq. The 16 patients were divided into 4 groups: Group A (n=4, ACR, local time in the morning (6 am-10 am)), group B (n=4, ACR, local time in the afternoon (2 pm-6 pm)), group C (n=4, normal circadian rhythm (NCR), morning (6 am-10 am)), and group D (n=4, NCR, afternoon (2 pm-6 pm)). The criteria for the ACR group (groups A and B) were: (1) Diagnosed with SA; (2) Abnormal expression of circadian rhythm genes (based on Log2 (Rev-erbα/Bmal1)) 7; (3) Met the inclusion and exclusion criteria for the DCM cohort. The criteria for the NCR group (groups C and D) were: (1) Without SA history and not diagnosed with SA; (2) Normal expression of circadian rhythm genes (based on Log2 (Rev-erbα/Bmal1)) 7; (3) Met the inclusion and exclusion criteria for the DCM cohort. The local time (China standard time) of the heart sample was defined as the time of the aortic cross-clamp.