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

Abstract

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.