Background: Takotsubo syndrome (TTS) features transient left ventricular dysfunction triggered by catecholamine surges. While neurohumoral stress responses are known, the role of innate immune cells, particularly neutrophils, in TTS-related myocardial injury remains unclear.
Methods: To assess the clinical relevance of neutrophil activation in TTS, we analyzed the TriNetX global electronic health record database. Propensity score–matched cohorts of TTS and NSTEMI patients (n = 59,625 per group) were matched for age, sex, and acute infections. Absolute neutrophil counts, left ventricular ejection fraction (LVEF), and one-year mortality were compared. In parallel, a murine TTS model was induced by high-dose systemic epinephrine injection. Neutrophil recruitment, endothelial activation, and cardiac function were evaluated by flow cytometry and echocardiography. Coronary endothelial P- and E-selectin expression was quantified, and selective (P- or E-selectin) or dual pharmacologic blockade was applied.
Results: In TriNetX, TTS patients showed higher neutrophil counts at admission (6.12 ± 0.87 × 10⁹/L) than NSTEMI (4.76 ± 0.68 × 10⁹/L; p = 0.045). Within TTS, neutrophilia was independently associated with severe LV dysfunction (LVEF < 30%) and higher one-year mortality (66.3% vs. 86.8%; HR 3.14, 95% CI 2.20–4.48; p < 0.0001), even after excluding bacterial infections (procalcitonin < 0.05 ng/mL).
In the murine TTS model, epinephrine-induced dysfunction was accompanied by myocardial neutrophil infiltration and endothelial P- and E-selectin upregulation. Pharmacologic inhibition of either selectin reduced neutrophil accumulation and improved function, while dual blockade further enhanced left ventricular ejection fraction within 24 hours. Bone marrow analysis 24 hours after epinephrine injection showed reduced granulocyte–monocyte progenitors (GMPs), indicating increased differentiation pressure or consumption, while intermediate precursors were unchanged and mature granulocytes accumulated in bone marrow, blood, and myocardium. Catecholaminergic stress rapidly mobilizes mature neutrophils from marrow reserves, which are then recruited to the myocardium via selectin-mediated adhesion, linking systemic stress to local inflammation.
Conclusions:
Our findings reveal that neutrophil recruitment through selectin-dependent endothelial activation critically contributes to cardiac dysfunction in Takotsubo syndrome. The integration of large-scale human data and mechanistic animal studies provides compelling evidence for inflammation-driven myocardial injury in TTS and highlights selectin blockade as a potential therapeutic strategy.
