Background: The sympathetic nervous system tightly controls cardiac function. Hereby, heart function is under precise control of extracardiac ganglia. Sympathetic dysfunction has been shown in various cardiac diseases and may serve as a prognostic marker. While remodeling processes in the myocardium have been investigated intensively, it remains poorly understood how myocardial disease involves the innervating extracardiac ganglia and vice versa.

Methods: We collected superior cervical ganglia (SCGs) from mice at early stages of pressure overload induced by transverse aortic constriction (TAC) and from human cadavers with and without cardiovascular disease. We then performed RNA sequencing of murine and human SCGs together with high content imaging-based quantitative cell morphometry and 3-dimensional reconstruction after optical clearing.

Results: Morphometric analyses of murine and human SCGs revealed increased immune cell infiltration (human control vs diseased 1.51 % vs 4.04 %, p < 0.0001; mouse basal vs TAC 2.64 % vs 10.02 %, p < 0.01) and fibrosis (human control vs diseased 59.74 % vs 75.01 %, p < 0.001; mouse basal vs TAC 64.22 % vs 77.42 %, p < 0.05) upon cardiac disease. Additionally, postmortem analysis of SCGs from individuals with cardiovascular disease showed enlargement and a significant increase of SCG organ mass compared to individuals without cardiovascular disease (control vs diseased 0.421 g vs 0.695 g, p < 0.05). On the cellular level, neurons were sparse and displayed cellular hypertrophy (neuronal size control vs diseased 2090 μm² vs 3622 μm², p < 0.0001). Genetic deconvolution of RNA bulk sequencing libraries from the SCGs confirmed these findings with a relative increment of immune cells and loss of sympathetic neurons. 

Conclusion: Our data establishes profound remodeling of cardiac innervating sympathetic ganglia in early stages of pressure overload-induced myocardial disease in mice and in humans with cardiac disease.