Sympathetic ganglion inflammation in Takotsubo syndrome

Takotsubo syndrome (TTS) is a rare form of acute cardiac decompensation triggered by emotional or physical stress that presents with symptoms of acute myocardial infarction in the absence of coronary artery occlusion. Despite the growing recognition of TTS and the implementation of standardized diagnostic criteria, there is little evidence regarding its clinical management, and TTS continues to exhibit a poor prognosis. The pathogenesis of TTS has yet to be fully elucidated; however, the role of sympathetic dysfunction in TTS disease has been implicated in several studies. In particular, excessive catecholamine release has been proposed as a key factor in the pathogenesis of transient myocardial stunning observed in TTS. In light of the pivotal function of the sympathetic ganglia in cardiac (patho-)physiology (Ziegler et al., Science 2023), a detailed examination was conducted with regard to their involvement in TTS.

 Using histomorphological analysis and single-nucleus RNA sequencing, we found macrophage-driven inflammation of sympathetic heart-innervating ganglia in a 50-year-old female diagnosed with TTS compared to a heart-healthy control subject. A comprehensive analysis of the gene expression profile indicated an active recruitment of circulating monocytes into the ganglia, as evidenced by a 93.04% increase in CCR2 mRNA expression in TTS. Similar results were observed in mice shortly after intraperitoneal administration of 2.5 mg/kg epinephrine. Analogous to human TTS, decreased LV function (drop in ejection fraction after 30 min: mean ± SEM 28 ± 3.8 %, p-value < 0.0001, n=11) and characteristic apical ballooning (increase in endsystolic volume after 30 min: mean ± SEM 28.18 ± 4.57 µl, p-value = 0.002, n=11) could be detected. Sympathetic heart-innervating ganglia were again found to exhibit a marked accumulation of macrophages (control 1.7 % vs TTS 9.2 %, p-value = 0.0169, n=4-5 per group). Agnostic gene ontology analysis revealed that, in both human and mouse TTS, there is a marked increase in pro-inflammatory processes driven by ganglionic macrophages.

 Given the emerging data suggesting a link between ganglionic inflammation and cardiac disease, along with the evidence indicating a crucial role exerted by pathologically activated macrophages, these data call for further investigation of these observations as a potential mechanism contributing to the pathophysiology of TTS. Ultimately, the exploration of the therapeutic potential of targeted, intraganglionic anti-inflammatory interventions may provide new avenues for the treatment of patients suffering from TTS.