PROJECT SUMMARY/ABSTRACT Takotsubo syndrome (TS) is an increasingly recognized condition characterized by acute, reversible systolic heart failure which affects post-menopausal women in over 90% of cases. Although most patients recover after an acute episode, survivors have a high risk of long-term major cerebrovascular events (MACCE) and of chronic impairment of the left ventricular (LV) function. While there is a general consensus that an exaggerated sympathetic nervous system (SNS) response underlies the onset of TS, the physiopathology of this underappreciated condition is still incompletely understood, First, exposure to an emotional trigger was thought to be a defining precipitant of TS, but recent registry data indicate instead that emotional triggers are present only in 1/3 of cases, with physical triggers (1/3) and no triggers (1/3) accounting for the remaining cases. Second, the mechanistic pathway linking the precipitating trigger to the onset of TS remains to be articulated. Third, it is unclear why only certain individuals develop an exaggerated SNS response when exposed to emotional triggers which affect all individuals throughout the lifespan with no health consequences. Finally, no study has rigorously tested the contribution of triggering event and mental stress responsiveness to the long- term prognosis of these patients. To address these gaps, we will enroll 106 patients admitted with a new validated diagnosis of TS from 3 large medical centers in the Providence, RI area. Participants will be screened for eligibility within 4 weeks since hospital discharge. After providing informed consent, they will undergo a comprehensive interview to identify the events proximal to the onset of TS, complete a battery of psychosocial questionnaires and undergo a laboratory mental stress protocol. Baseline and reactive changes in measures of autonomic nervous system activity (circulating catecholamines and cardiac vagal control), LV function (ejection fraction, Global Longitudinal Strain evaluated by speckle tracking echocardiography (STE)) will be assessed. LV function will be assessed again 12 months later and at that time information about MACCE will be collected. The proposed study will address the noted evidence gaps by a) Rigorously assessing the full range of circumstances proximal to TS onset, b) Assessing the constellation of physiological elements that define TS (i.e., autonomic nervous system activity and LV function) under controlled conditions, and c) Link the type of trigger and response to stress to prognosis. Notably, by using STE, we will be able to capture both reactive and long-term subtle anomalies of LV function in these patients. This will be the first study to rigorously investigate the heterogeneity in clinical presentation, physiopathology, and prognosis in TS. The identification of distinct sub-groups in TS will provide the rationale for the development of properly targeted interventions to improve the prognosis of th...