BACKGROUND: Takotsubo syndrome has long been deemed a benign condition following sudden emotional stress. While current mechanisms explaining the acute cardiac dysfunction are not fully understood, current evidence suggests certain takotsubo populations are at higher risk of adverse course. Acute neurologic emergencies commonly precede the takotsubo syndrome and new insights into the role of the brain-heart axis and central autonomic regions driving excess sympathetic activation have come about. METHODS AND RESULTS: This multicenter analysis included 595 patients admitted between January 2013 and December 2024 with takotsubo syndrome across 13 German tertiary care centers. The aim of this study was to (I) assess whether acute brain pathology influences severity of cardiac dysfunction differently in comparison to other nonneurologic forms of physical or emotional stress, (II) investigate short-term recovery of cardiac function, and (III) improve identification of vulnerable patients susceptible to critical in-hospital course. Marginal odds ratios were estimated for cardiac complications of takotsubo syndrome across trigger groups using generalized estimating equations. Multivariable mixed-effects logistic regression models were fit to analyze the association between prespecified variables for short-term recovery of wall motion and systolic abnormalities as well as critical in-hospital course. Acute neurologic emergencies (47.5%) and common physical triggers (37.9%) were associated with higher risk of cardiac complications in takotsubo syndrome compared to emotional triggers (12.5%). Nonapical forms of takotsubo syndrome showed improved recovery of wall motion abnormalities (OR 2.70, 95% CI 1.34-5.45), while older patients had worse recovery of systolic function to discharge (OR 0.67, 95% CI 0.48-0.93). Conversely, younger male patients in which disease was triggered by neurologic emergencies or physical triggers presented with higher odds of critical in-hospital course. CONCLUSION: Results of this study challenge the assumption of uniform reversibility of cardiac dysfunction and emphasize the need for early risk stratification and awareness of high-risk features as well as varying clinical presentations.