SRP436111 PRJNA967656 GSE231766 single-cell RNA-seq of healthy (ctrl) and heart diseased (TAC) SCGs Disruption of the physiologic sleep-wake cycle and low melatonin levels frequently accompany cardiac disease, yet the underlying mechanism has remained enigmatic. Immunostaining of sympathetic axons in optically cleared pineal glands from humans and mice with cardiac disease revealed their substantial denervation compared to controls. Spatial, single-cell, nuclear, and bulk RNA sequencing traced this defect back to the superior cervical ganglia (SCG), which responded to cardiac disease with accumulation of inflammatory macrophages, fibrosis, and the selective loss of pineal gland-innervating neurons. Depletion of macrophages in the SCG prevented disease-associated denervation of the pineal gland and restored physiological melatonin secretion. Our data identify the mechanism underlying the disturbance of diurnal rhythmicity in cardiac disease and suggest means for therapeutic intervention. Overall design: SCGs from heart healthy and heart diseased mice were subjected to single-cell RNA-seq (10x Genomics). GSE231766 pubmed 37471539 parent_bioproject PRJNA967648