Background: Takotsubo syndrome is an increasingly recognized cause of chest pain and occasionally of cardiogenic shock. Despite rapid improvement of the Left Ventricular Ejection Fraction (LV EF), recent registry data raises concerns about long term prognosis. We hypothesized that restoration of normal EF after acute tako-tsubo is not equivalent to full functional recovery. Methods: We prospectively recruited 52 takotsubo patients [according to the Mayo criteria plus cardiac magnetic resonance imaging (CMR) to exclude myocardial infarction] and 44 healthy controls of the same age, gender and cardiovascular co-morbidity distribution. We focused the investigation on takotsubo patients presenting with ST-elevation type ECG or malignant arrhythmias and with LV apical ballooning variant and examined a 4 months recovery end-point. Patients underwent Echocardiography assessment of LV myocardial deformation (Global longitudinal, radial and circumferential strain, LV twist, torsion, untwist, time to peak twist and untwist) and assessment of LV myocardial structure by pre and post contrast-enhanced CMR by T1 mapping acutely and at 4 months follow-up. Controls had a single time-point investigation. Data were analyzed using paired or unpaired tests, as appropriate for their distribution and corrected for multiple comparisons. Results: The patients' mean age was 66 years (range 28-87) and 92% were women. All abnormal echocardiographic indices observed acutely in takotsubo patients improved (but not necessarily normalized) at followup. Significant mechano-temporal alterations characterizing both systole (global longitudinal strain, apical circumferential strain, both p<0.01; left ventricular twist, twist rate and torsion, all p<0.0001) and diastole (untwist rate and time to peak untwisting, all p<0.001) persisted at 4 months follow-up when compared with controls, despite normalization of LV ejection fraction and volumes. Whilst native T1 (which demonstrates edema) normalized at 4 months follow-up only in segments contracting normally during the acute phase [T1=1180± 40.6ms (normally contracting, p=0.2 vs control values of 1189±16 ms) and 1208± 60.3 ms (dysfunctional segments, p<0.05 vs control)], the extracellular volume fraction (ECV, which demonstrates diffuse fibrosis) remained significantly abnormal in all LV segments (whether normally contracting, 0.328±0.043, p<0.001 or ballooning during acute presentation, 0.320±0.044, p<0.001, both vs control values of 0.273±0.045). Conclusion: In patients with the most clinically severe spectrum of takotsubo cardiomyopathy, regional LV systolic and diastolic deformation abnormalities persist beyond the acute event, despite normalization of global LV EF and size. In addition, although myocardial edema partly subsides, a process of global microscopic fibrosis develops in its place, detected as early as 4 months.Suggested Reviewers:Opposed Reviewers: 1 24 th March, 2017 Dear Dr Pearlman, Thank you once again for your comments and those of the associate editors. I think it i...