Phase dependent sympathetic dysinnervation in Takotsubo syndrome revealed with transparent heart

Takotsubo syndrome (TTS) is an acute cardiac syndrome characterized by transient left ventricular dysfunction. Although the wall motion abnormality resolves completely, the prognosis is poor. Defect of ¹²³I-metaiodobenzylguanidine uptake, interpreted as sympathetic impairment, persisted in TTS patients, but the mechanism is not fully understood. We aimed to elucidate morphological sympathetic nerve change in a TTS model mouse using three-dimensional imaging techniques, with a particular focus on the role of factors in these alterations. The TTS model was induced by a single intraperitoneal injection of 2.0 mg/kg adrenaline to C57BL/6 mice, resulting in transient akinesis localized to the inferior apical region of the heart. Three-dimensional morphological assessment revealed that sympathetic nerve length within the inferior apical area of TTS mice reduced during the chronic phase compared with the sham mice. Notably, the study observed a pattern of denervation during the acute phase, followed by re-innervation and subsequent denervation in the chronic phase. The neurotrophic factors expressions changed in a time-dependent manner, corresponding to the phase-specific damage both to cardiomyocytes and sympathetic neurons. The bimodal change in sympathetic nerves and altered neurotrophic factors in TTS mice provide novel insights into the pathophysiological mechanism of TTS to establish therapeutic strategies for TTS.