Neutrophil-driven inflammation in takotsubo syndrome: insights from patient data and a translational murine model

Abstract Background Takotsubo syndrome (TTS) is a stress-induced cardiomyopathy characterized by transient left ventricular dysfunction in the absence of acute coronary artery obstruction. Despite its clinical significance, the underlying mechanisms of TTS and its recovery remain insufficiently understood, resulting in a lack of targeted therapies and reliable diagnostic markers. Emerging evidence suggests that inflammatory processes may have a pivotal role in the pathophysiology of TTS. Purpose To characterize inflammatory responses in TTS patients and evaluate targeted anti-inflammatory interventions in vivo. Methods Myocardial tissue (n=8) and blood samples from TTS patients (n=30) were collected on days 1 and 4 following diagnosis and compared with control subjects (n=10). Immunophenotyping was performed by flow cytometry. In the murine model, epinephrine (2.5 mg/kg) was administered intraperitoneally to induce TTS-like myocardial dysfunction. Repetitive cardiac MRI with a fluorine-based tracer for neutrophils was performed to assess spatial and temporal resolution of immune cell infiltration in TTS allowing correlation with left ventricular function. To further investigate the role of neutrophil mediated inflammation in TTS, mice underwent neutrophil depletion via anti-Ly6G antibody or anti-inflammatory colchicine treatment. Results On day 1, TTS patients exhibited a significant increase in neutrophil count and activation in peripheral blood. By day 4, circulating reverse-migrated neutrophils were markedly elevated, indicating significant prior tissue infiltration. Indeed, neutrophils extracted from affected myocardial tissue displayed increased activation (Fig.1). In the murine model similar pattern of neutrophil activation and migration has been found. Cardiac MRI revealed a strong correlation between regions of wall motion abnormalities and neutrophil accumulation, which occurs within minutes following TTS induction (Fig. 2). Neutrophil depletion improved LV-EF (51.4 ± 4.1%, p=0.0048) compared to the epinephrine-only group (36.4 ± 7.3%), which was also reached by anti-inflammatory colchicine treatment (59.9 ± 6.4%, p=0.0001). Conclusion These findings highlight the role of neutrophil-driven inflammation in TTS pathophysiology. Increased neutrophil activation, reverse migration, and early myocardial infiltration suggest a mechanistic link to ventricular dysfunction. In the murine model, neutrophil depletion, and colchicine treatment improved LV function, supporting inflammation as a potential therapeutic target for TTS. Further studies are warranted to evaluate anti-inflammatory strategies in clinical settings.Fig. 1 Human Data Fig. 2 Murine Data