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Background: Ethnic disparities have been reported in cardiovascular disease. However, ethnic disparities in takotsubo syndrome (TTS) remain elusive. This study assessed differences in clinical characteristics between Japanese and European TTS patients and determined the impact of ethnicity on in-hospital outcomes., Methods: TTS patients in Japan were enrolled from 10 hospitals and TTS patients in Europe were enrolled from 32 hospitals participating in the International Takotsubo Registry. Clinical characteristics and in-hospital outcomes were compared between Japanese and European patients., Results: A total of 503 Japanese and 1670 European patients were included. Japanese patients were older (72.6 ± 11.4 years vs. 68.0 ± 12.0 years; p < 0.001) and more likely to be male (18.5 vs. 8.4%; p < 0.001) than European TTS patients. Physical triggering factors were more common (45.5 vs. 32.0%; p < 0.001), and emotional triggers less common (17.5 vs. 31.5%; p < 0.001), in Japanese patients than in European patients. Japanese patients were more likely to experience cardiogenic shock during the acute phase (15.5 vs. 9.0%; p < 0.001) and had a higher in-hospital mortality (8.2 vs. 3.2%; p < 0.001). However, ethnicity itself did not appear to have an impact on in-hospital mortality. Machine learning approach revealed that the presence of physical stressors was the most important prognostic factor in both Japanese and European TTS patients., Conclusion: Differences in clinical characteristics and in-hospital outcomes between Japanese and European TTS patients exist. Ethnicity does not impact the outcome in TTS patients. The worse in-hospital outcome in Japanese patients, is mainly driven by the higher prevalence of physical triggers., Trial Registration: URL: https://www.clinicaltrials.gov ; Unique Identifier: NCT01947621., (© 2021. The Author(s).)

Background Atrial fibrillation (AF) is a major risk factor for mortality. The prevalence, clinical correlates, and prognostic impact of AF in Takotsubo syndrome (TTS) have not yet been investigated in a large patient cohort. This study aimed to investigate the prevalence, clinical correlates, and prognostic impact of AF in patients with TTS. Methods and Results Patients with TTS were enrolled from the International Takotsubo Registry, which is a multinational network with 26 participating centers in Europe and the United States. Patients were dichotomized according to the presence or absence of AF at the time of admission. Of 1584 patients with TTS, 112 (7.1%) had AF. The mean age was higher ( P <0.001), and there were fewer women ( P =0.046) in the AF than in the non-AF group. Left ventricular ejection fraction was significantly lower ( P =0.001), and cardiogenic shock was more often observed ( P <0.001) in the AF group. Both in-hospital ( P <0.001) and long-term mortality ( P <0.001) were higher in the AF group. Multivariable Cox regression analysis revealed that AF was independently associated with higher long-term mortality (hazard ratio, 2.31; 95% CI, 1.50-3.55; P <0.001). Among patients with AF on admission, 42% had no known history of AF before the acute TTS event, and such patients had comparable in-hospital and long-term outcomes compared with those with a history of AF. Conclusions In patients presenting with TTS, AF on admission is significantly associated with increased in-hospital and long-term mortality rates. Whether antiarrhythmics and/or cardioversion are beneficial in TTS with AF should thus be tested in a future trial. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT01947621.

Aims: Acute pulmonary disorders are known physical triggers of takotsubo syndrome (TTS). This study aimed to investigate prevalence of acute pulmonary triggers in patients with TTS and their impact on outcomes., Methods and Results: Patients with TTS were enrolled from the International Takotsubo Registry and screened for triggering factors and comorbidities. Patients were categorized into three groups (acute pulmonary trigger, chronic lung disease, and no lung disease) to compare clinical characteristics and outcomes. Of the 1670 included patients with TTS, 123 (7%) were identified with an acute pulmonary trigger, and 194 (12%) had a known history of chronic lung disease. The incidence of cardiogenic shock was highest in patients with an acute pulmonary trigger compared with those with chronic lung disease or without lung disease (17% vs. 10% vs. 9%, P = 0.017). In-hospital mortality was also higher in patients with an acute pulmonary trigger than in the other two groups, although not significantly (5.7% vs. 1.5% vs. 4.2%, P = 0.13). Survival analysis demonstrated that patients with an acute pulmonary trigger had the worst long-term outcome (P = 0.002). The presence of an acute pulmonary trigger was independently associated with worse long-term mortality (hazard ratio 2.12, 95% confidence interval 1.33-3.38; P = 0.002)., Conclusions: The present study demonstrates that TTS is related to acute pulmonary triggers in 7% of all TTS patients, which accounts for 21% of patients with physical triggers. The presence of acute pulmonary trigger is associated with a severe in-hospital course and a worse long-term outcome., (© 2021 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Background: Several reports have described Takotsubo syndrome (TTS) secondary to thyrotoxicosis. A complex interaction of central and peripheral catecholamines with thyroid homeostasis has been suggested. In this study, we analysed sequential thyroid hormone profiles during the acute phase of TTS., Methods: Thyrotropin (TSH), free T4 (FT4) and free T3 (FT3) concentrations were analysed at predefined time points in 32 patients presenting with TTS or acute coronary syndrome (ACS, n = 16 in each group) in a 2-year period in two German university hospitals. Data were compared to age- and sex-matched controls (10 samples, each of 16 subjects), and an unsupervised machine learning (ML) algorithm identified patterns in the hormone signature. Subjects with thyroid disease and patients receiving amiodarone were excluded from follow-up., Results: Among patients with TTS, FT4 concentrations were significantly higher when compared to controls or ACS. Four subjects (25%) suffered from subclinical or overt thyrotoxicosis. Two additional patients developed subclinical or overt thyrotoxicosis during stay in hospital. In four subjects (25%), FT4 concentrations were increased, despite nonsuppressed TSH concentration, representing an elevated set point of thyroid homeostasis. The thyroid hormone profile was normal in only six patients (38%) presenting with TTS., Conclusion: Abnormal thyroid function is frequent in patients with TTS. Primary hyperthyroidism and an elevated set point of thyroid homeostasis are common in TTS, suggesting a stress-dependent endocrine response or type 2 thyroid allostasis. Thyroid function may be a worthwhile target in treating or preventing TTS., (© 2020 The Authors. Journal of Internal Medicine published by John Wiley & Sons Ltd on behalf of Association for Publication of The Journal of Internal Medicine.)

Background/aim: The association between ejection fraction (EF) and mortality in TTS patients as compared to ACS is limited. This study aims to investigate the association between EF and clinical outcomes in patients with TTS as compared to ACS., Patients and Methods: This study compared in-hospital, and long-term incidence of clinical outcomes for 5 years in patients with TTS and ACS. The study was composed of two groups EF≥35% and EF<35%., Results: The long-term mortality of the EF≥35% for 5 years was significantly higher in TTS patients as compared to ACS (18.1% vs. 7.7%, log-Rank; p<0.01). Irrespective of EF, a non-cardiovascular death was significantly higher in TTS as compared to ACS patients with EF≥35 (6.4% vs. 2.1%; p=0.02) and with EF<35% (21.4% vs. 7.5%; p=0.03)., Conclusion: The long-term mortality is significantly higher in TTS as compared to ACS dominated by a non-cardiovascular cause of death at 5-years-follow-up., (Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Aims: Takotsubo syndrome (TTS) is an acute heart failure syndrome, which shares many features with acute coronary syndrome (ACS). Although TTS was initially described with angiographically normal coronary arteries, smaller studies recently indicated a potential coexistence of coronary artery disease (CAD) in TTS patients. This study aimed to determine the coexistence, features, and prognostic role of CAD in a large cohort of patients with TTS., Methods and Results: Coronary anatomy and CAD were studied in patients diagnosed with TTS. Inclusion criteria were compliance with the International Takotsubo Diagnostic Criteria for TTS, and availability of original coronary angiographies with ventriculography performed during the acute phase. Exclusion criteria were missing views, poor quality of angiography loops, and angiography without ventriculography. A total of 1016 TTS patients were studied. Of those, 23.0% had obstructive CAD, 41.2% had non-obstructive CAD, and 35.7% had angiographically normal coronary arteries. A total of 47 patients (4.6%) underwent percutaneous coronary intervention, and 3 patients had acute and 8 had chronic coronary artery occlusion concomitant with TTS, respectively. The presence of CAD was associated with increased incidence of shock, ventilation, and death from any cause. After adjusting for confounders, the presence of obstructive CAD was associated with mortality at 30 days. Takotsubo syndrome patients with obstructive CAD were at comparable risk for shock and death and nearly at twice the risk for ventilation compared to an age- and sex-matched ACS cohort., Conclusions: Coronary artery disease frequently coexists in TTS patients, presents with the whole spectrum of coronary pathology including acute coronary occlusion, and is associated with adverse outcome., Trial Registration: ClinicalTrials.gov number: NCT01947621., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: journals.permissions@oup.com.)

Background: Cardiogenic shock (CS) is a severe complication of myocardial infarction (MI) or of takotsubo syndrome (TTS). For both diseases, CS is related to a worse long-term outcome. The outcome of CS has not been studied in a direct comparison of patients with MI and patients with TTS., Methods: Mortality and cardiovascular complications were compared in patients presenting with CS based on MI or TTS between 2003 and 2017 during a follow-up of 5 years. A total of 138 patients with TTS and 532 patients with MI were included. Of these, 66 patients with MI and 25 patients with TTS developed CS (12% vs 18%, P = 0.08)., Results: Patients with MI and CS had more often malignant arrhythmias (74% vs 28%, P < 0.01), and need for resuscitation (80% vs 24%, P < 0.01) or death (71% vs 24%, P < 0.01) than patients with TTS and CS during the first 30 days. Although the overall rate of death remained higher in MI than in TTS (75.8% vs 52%, log rank, P < 0.01), deaths occurred in TTS constantly throughout the follow-up time, but not in MI. The incidence of heart failure increased in MI but not in TTS (31.8% vs 4%, P < 0.01) during follow-up., Conclusions: Patients with MI and CS have a worse prognosis than patients with TTS and CS. This is driven by cardiovascular events or death during the first 30 days after the index event. However, patients with TTS and CS show high mortality as well, especially during long-term follow-up., (Copyright © 2019 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.)

Background: Takotsubo syndrome (TTS) occurs predominantly in post-menopausal women but is also found in younger patients., Objectives: This study aimed to investigate age-related differences in TTS., Methods: Patients diagnosed with TTS and enrolled in the International Takotsubo Registry between January 2011 and February 2017 were included in this analysis and were stratified by age (younger: ≤50 years, middle-age: 51 to 74 years, elderly: ≥75 years). Baseline characteristics, hospital course, as well as short- and long-term mortality were compared among groups., Results: Of 2,098 TTS patients, 242 (11.5%) patients were ≤50 years of age, 1,194 (56.9%) were 51 to 74 years of age, and 662 (31.6%) were ≥75 years of age. Younger patients were more often men (12.4% vs. 10.9% vs. 6.3%; p = 0.002) and had an increased prevalence of acute neurological (16.3% vs. 8.4% vs. 8.8%; p = 0.001) or psychiatric disorders (14.1% vs. 10.3% vs. 5.6%; p < 0.001) compared with middle-aged and elderly TTS patients. Furthermore, younger patients had more often cardiogenic shock (15.3% vs. 9.1% vs. 8.1%; p = 0.004) and had a numerically higher in-hospital mortality (6.6% vs. 3.6% vs. 5.1%; p = 0.07). At multivariable analysis, younger (odds ratio: 1.60; 95% confidence interval: 0.86 to 3.01; p = 0.14) and older age (odds ratio: 1.09; 95% confidence interval: 0.66 to 1.80; p = 0.75) were not independently associated with in-hospital mortality using the middle-aged group as a reference. There were no differences in 60-day mortality rates among groups., Conclusions: A substantial proportion of TTS patients are younger than 50 years of age. TTS is associated with severe complications requiring intensive care, particularly in younger patients., (Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Aims: The aim of the present study was to investigate the impact of aspirin on prognosis in takotsubo syndrome (TTS)., Methods and Results: Patients from the International Takotsubo (InterTAK) Registry were categorized into two groups based on aspirin prescription at discharge. A comparison of clinical outcomes between groups was performed using an adjusted analysis with propensity score (PS) stratification; results from the unadjusted analysis were also reported to note the effect of the PS adjustment. Major adverse cardiac and cerebrovascular events (MACCE: a composite of death, myocardial infarction, TTS recurrence, stroke or transient ischaemic attack) were assessed at 30-day and 5-year follow-up. A total of 1533 TTS patients with known status regarding aspirin prescription at discharge were included. According to the adjusted analysis based on PS stratification, aspirin was not associated with a lower hazard of MACCE at 30-day [hazard ratio (HR) 1.24, 95% confidence interval (CI) 0.50-3.04, P = 0.64] or 5-year follow-up (HR 1.11, 95% CI 0.78-1.58, P = 0.58). These results were confirmed by sensitivity analyses performed with alternative PS-based methods, i.e. covariate adjustment and inverse probability of treatment weighting., Conclusion: In the present study, no association was found between aspirin use in TTS patients and a reduced risk of MACCE at 30-day and 5-year follow-up. These findings should be confirmed in adequately powered randomized controlled trials. ClinicalTrials.gov Identifier: NCT01947621., (© 2019 The Authors. European Journal of Heart Failure © 2019 European Society of Cardiology.)

Objective: Takotsubo syndrome (TTS) is characterized by acute left ventricular dysfunction, which can contribute to intraventricular thrombus and embolism. Still, prevalence and clinical impact of thrombus formation and embolic events on outcome of TTS patients remain unclear. This study aimed to investigate clinical features and outcomes of patients with and without intraventricular thrombus or embolism. Additionally, factors associated with thrombus formation or embolism, as well as predictors for mortality, were identified. Approach and Results: TTS patients enrolled in the International Takotsubo Registry at 28 centers in Australia, Europe, and the United States were dichotomized according to the occurrence/absence of intraventricular thrombus or embolism. Patients with intraventricular thrombus or embolism were defined as the ThrombEmb group. Of 1676 TTS patients, 56 (3.3%) patients developed intraventricular thrombus and/or embolism following TTS diagnosis (median time interval, 2.0 days [range, 0-38 days]). Patients in the ThrombEmb group had a different clinical profile including lower left ventricular ejection fraction, higher prevalence of the apical type, elevated levels of troponin and inflammatory markers, and higher prevalence of vascular disease. In a Firth bias-reduced penalized-likelihood logistic regression model apical type, left ventricular ejection fraction ≤30%, previous vascular disease, and a white blood cell count on admission >10×10 3 cells/μL emerged as independent predictors for thrombus formation or embolism., Conclusions: Intraventricular thrombus or embolism occur in 3.3% of patients in the acute phase of TTS. A simple risk score including clinical parameters associated with intraventricular thrombus formation or embolism identifies patients at increased risk., Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01947621.

Recent studies have reported that takotsubo syndrome (TTS) patients are suffering from life-threatening arrhythmias. The aim of our study was to understand the short and long-term usefulness of cardiac implantable electronic devices in TTS patients.We constituted a collective of 142 patients in a bi-centric study diagnosed with TTS between 2003 and 2017. The patient groups, divided according to the treatment with (n = 9, 6.3%) or without cardiac devices (n = 133, 93.7%), were followed-up to determine the importance of devices and its complications. One patient was treated with a permanent pacemaker, five patients with a wearable cardioverter defibrillator, two patients with a subcutaneous defibrillator and one patient with a transvenous defibrillator. Regular device check-up was documented in all patients, presenting an ongoing high-degree AV-block. Neither device complications nor life-threatening tachyarrhythmias were documented after acute TTS event. However, patients comprising the device group suffered significantly more often from a highly reduced EF (30 ± 7.7% versus 39.1 ± 9.7%; p < 0.05), cardiogenic shock with use of inotropic agents (66.6% versus 16.6%; p < 0.05) and cardiopulmonary resuscitation (44.4% versus 5.3%; p < 0.05). Our data confirm the usefulness of pacemaker in TTS patients. However, the cardioverter defibrillator including wearable cardioverter defibrillator may not be recommended.

Background Left ventricular (LV) recovery in takotsubo syndrome (TTS) occurs over a wide-ranging interval, varying from hours to weeks. We sought to investigate the clinical predictors and prognostic impact of recovery time for TTS patients. Methods and Results TTS patients from the International Takotsubo Registry were included in this study. Cut-off for early LV recovery was determined to be 10 days after the acute event. Multivariable logistic regression was used to assess factors associated with the absence of early recovery. In-hospital outcomes and 1-year mortality were compared for patients with versus without early recovery. We analyzed 406 patients with comprehensive and serial imaging data regarding time to recovery. Of these, 191 (47.0%) had early LV recovery and 215 (53.0%) demonstrated late LV improvement. Patients without early recovery were more often male (12.6% versus 5.2%; P =0.011) and presented more frequently with typical TTS (76.3% versus 67.0%, P =0.040). Cardiac and inflammatory markers were higher in patients without early recovery than in those with early recovery. Patients without early recovery showed unfavorable 1-year outcome compared with patients with early recovery ( P =0.003). On multiple logistic regression, male sex, LV ejection fraction <45%, and acute neurologic disorders were associated with the absence of early recovery. Conclusions TTS patients without early LV recovery have different clinical characteristics and less favorable 1-year outcome compared with patients with early recovery. The factors associated with the absence of early recovery included male sex, reduced LV ejection fraction, and acute neurologic events. Clinical Trial Registration URL: http://www.clinicaltrials.gov. Unique identifier: NCT01947621.

Thromboembolic events are a common complication in Takotsubo syndrome (TTS). However, their long-term incidence compared with acute coronary syndrome (ACS) is lacking. In-hospital and long-term incidence of thromboembolic events of 138 consecutive patients with TTS were compared with 138 sex- and age-matched patients with ACS. Predictors of events were analyzed. The incidence of thromboembolic events in TTS was 2-fold higher than ACS (21% vs 9%; P < .01) over a mean follow-up of 5 years. Although the left ventricular ejection fraction (LVEF) at event was significantly lower in TTS compared with ACS (38% [9%] vs 54% [11%]; P < .01), the follow-up LVEF was comparable. Patients with TTS suffering from thromboembolic events were more often treated with anticoagulation compared with ACS (44.8% vs 8.3%, P = .03). However, more patients presenting with ACS (100% vs 48.3%; P < .01) were discharged on aspirin. Only elevated C-reactive protein was a predictor of thromboembolic events using multivariate analysis (hazard ratio 1.1, 95% confidence interval, 1.0-1.2; P < .01). In conclusion, the risk of thromboembolic events in TTS was significantly higher than the risk of thromboembolic events in ACS over a mean follow-up of 5 years.

Background Clinical characteristics and outcomes of takotsubo syndrome (TTS) patients with malignancy have not been fully elucidated. This study sought to explore differences in clinical characteristics and to investigate short- and long-term outcomes in TTS patients with or without malignancy. Methods and Results TTS patients were enrolled from the International Takotsubo Registry. The TTS cohort was divided into patients with and without malignancy to investigate differences in clinical characteristics and to assess short- and long-term mortality. A subanalysis was performed comparing long-term mortality between a subset of TTS patients with or without malignancy and acute coronary syndrome (ACS) patients with or without malignancy. Malignancy was observed in 16.6% of 1604 TTS patients. Patients with malignancy were older and more likely to have physical triggers, but less likely to have emotional triggers compared with those without malignancy. Long-term mortality was higher in patients with malignancy (P<0.001), while short-term outcome was comparable (P=0.17). In a subanalysis, long-term mortality was comparable between TTS patients with malignancies and ACS patients with malignancies (P=0.13). Malignancy emerged as an independent predictor of long-term mortality. Conclusions A substantial number of TTS patients show an association with malignancy. History of malignancy might increase the risk for TTS, and therefore, appropriate screening for malignancy should be considered in these patients. Clinical Trial Registration URL: http://www.clinicaltrial.gov. Unique identifier: NCT01947621.

Aims: We aimed to evaluate the frequency, clinical features, and prognostic implications of cardiac arrest (CA) in takotsubo syndrome (TTS)., Methods and Results: We reviewed the records of patients with CA and known heart rhythm from the International Takotsubo Registry. The main outcomes were 60-day and 5-year mortality. In addition, predictors of mortality and predictors of CA during the acute TTS phase were assessed. Of 2098 patients, 103 patients with CA and known heart rhythm during CA were included. Compared with patients without CA, CA patients were more likely to be younger, male, and have apical TTS, atrial fibrillation (AF), neurologic comorbidities, physical triggers, and longer corrected QT-interval and lower left ventricular ejection fraction on admission. In all, 57.1% of patients with CA at admission had ventricular fibrillation/tachycardia, while 73.7% of patients with CA in the acute phase had asystole/pulseless electrical activity. Patients with CA showed higher 60-day (40.3% vs. 4.0%, P < 0.001) and 5-year mortality (68.9% vs. 16.7%, P < 0.001) than patients without CA. T-wave inversion and intracranial haemorrhage were independently associated with higher 60-day mortality after CA, whereas female gender was associated with lower 60-day mortality. In the acute phase, CA occurred less frequently in females and more frequently in patients with AF, ST-segment elevation, and higher C-reactive protein on admission., Conclusions: Cardiac arrest is relatively frequent in TTS and is associated with higher short- and long-term mortality. Clinical and electrocardiographic parameters independently predicted mortality after CA., (© The Author(s) 2019. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: Clinical variables that predict long-term mortality and recurrence of Takotsubo syndrome (TTS) are not completely understood as the role of acquired corrected QT interval (QTc) prolongation., Aim: To detect the prevalence of QTc interval prolongation in patients with TTS and to evaluate its long-term prognostic impact., Methods: QTc intervals were analysed in 105 patients presenting with symptoms of TTS. These patients were included in an ongoing retrospective cohort database. The cohort was subsequently subdivided into two groups based on the presence (long QT (LQT) group, n = 73, 69.52%) or absence (non-long QT (non-LQT) group, n = 32, 30.43%) of QTc interval prolongation. Patients were followed up over a mean period of 4.2 years. The rate of life-threatening arrhythmia during the first 30 days in the LQT group was comparable with the non-LQT group (10.9 vs 12.5%), whereas in-hospital mortality and 30-day mortality occurred less frequently in the LQT group (2.7 vs 18.75%, P < 0.01)., Results: During this time span, 17 (23.3%) patients with acquired LQT syndrome died, whereas 14 (43.7%) patients with non-LQT duration died. Kaplan-Meier survival rates were significantly higher in the LQT group than those in the non-LQT group (Log-rank-test, P = 0.02). On multivariate analysis, the QTc interval was an independent negative predictor of all-cause mortality (P = 0.02)., Conclusion: The QTc interval at admission is an independent negative predictor of long-term adverse outcome in patients with TTS., (© 2018 Royal Australasian College of Physicians.)

Background: Takotsubo Syndrome (TTS) is an acute reversible left ventricular dysfunction. Recently published studies have highlighted a similar mortality rate as acute coronary syndrome (ACS). We compared the impact of gender differences on the outcome of TTS patients as compared to ACS patient., Design and Methods: We included a collective of 138 patients TTS between 2003 and 2016 at our institution. Patients were divided according to their gender into two groups (Males n=21, 15% and females, n=117, 85%). They were compared with a cohort of 300 patients with a diagnosis of ACS., Results: On the acute phase, in male patients with TTS, a treatment with inotropic was more often required (33.3 vs. 11.5%, P<0.01), were more susceptible to cardiogenic shock (28.6 vs. 12.5%, P<0.04). Concerning the long-term prognosis after the acute event, male patients had higher all-cause mortality over long-term follow-up. A Kaplan-Meier analysis indicated that the mortality of male patients with TTS was significantly higher compared to male patients with ACS (log-rank <0.01), while there was no significant difference between female patients with TTS and ACS (log-rank =0.60, P=0.45). In a multivariate cox regression analysis, male gender (HR 2.7, 95% CI: 1.1-6.5, P=0.02) GFR <60 ml/min (HR 2.8, 95% CI: 1.2-6.0, P=0.01) and history of cancer (HR 3.6, 95% CI 1.4-9.3, P<0.01) were independent predictors of 5-year mortality., Conclusions: Considerable evidence suggests that TTS compared to ACS implicates more significant clinical short-term events on male patients and it may be associated with poorer long-term prognosis., (© The Author(s) 2019. Published by Oxford University Press on behalf of the Association of Physicians. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Previous studies revealed that patients with Takotsubo syndrome (TTS) have a higher mortality rate than the general population and a comparable mortality to acute coronary syndrome (ACS). Repolarisation abnormalities, namely T-wave amplitude, may provide incremental prognostic information, in addition to traditional risk factors in ACS. This study was performed to determine the short- and long-term prognostic impact of inverted T-waves in TTS patients, as compared to ACS patients., Methods and Results: Our institutional database constituted a collective of 138 patients diagnosed with TTS from 2003 to 2017, as well as 532 patients suffering from ACS. Patients with TTS or with ACS (n = 138 per group) were matched for age and sex and assessed retrospectively and prospectively and divided into two groups, TTS with inverted T-waves (n = 123) and ACS with inverted T-waves (n = 80). In-hospital complications such as respiratory failure with the need of respiratory support (60.2% vs 6.3%; P < 0.01), thromboembolic events (13.8% vs 2.5%; P < 0.01) and cardiogenic shock (18.9% vs 8.8%; P = 0.05) were significantly more presented in TTS as compared to ACS patients. Among cardiovascular risk factors diabetes mellitus (23.6% vs 45.0%; P < 0.01) and arterial hypertension (57.7% vs 78.8%; P < 0.01) were more presented in ACS patients as compared to TTS patients. Short-term mortality was similar, however the long-term mortality of 5 years was significantly higher in the TTS group (25.2% vs 7.5%; P < 0.01). In univariate analysis were male gender, EF < 35%, GFR < 60 mL/min, cardiogenic shock, inotropic drugs and history of cancer predictors of 5-year mortality. The multivariate analysis showed only male gender (HR 2.7, 95% CI 1.1-6.5; P = 0.02), GFR < 60 mL/min (HR 2.8, 95% CI 1.2-6.0; P = 0.01) and history of cancer (HR 3.6, 95% CI 1.4-9.3; P < 0.01) as independent predictors of 5-year mortality., Conclusion: Rates of long-term mortality were significantly higher in TTS patients showing inverted T-waves compared with patients diagnosed with ACS with inverted T-waves. However, T-inversion was not an independent predictor of 5-year mortality in the multivariate analysis., (© 2019 Stichting European Society for Clinical Investigation Journal Foundation.)

Background: Prognosis of Takotsubo syndrome (TTS) remains controversial due to scarcity of available data. Additionally, the effect of the triggering factors remains elusive., Objectives: This study compared prognosis between TTS and acute coronary syndrome (ACS) patients and investigated short- and long-term outcomes in TTS based on different triggers., Methods: Patients with TTS were enrolled from the International Takotsubo Registry. Long-term mortality of patients with TTS was compared to an age- and sex-matched cohort of patients with ACS. In addition, short- and long-term outcomes were compared between different groups according to triggering conditions., Results: Overall, TTS patients had a comparable long-term mortality risk with ACS patients. Of 1,613 TTS patients, an emotional trigger was detected in 485 patients (30%). Of 630 patients (39%) related to physical triggers, 98 patients (6%) had acute neurologic disorders, while in the other 532 patients (33%), physical activities, medical conditions, or procedures were the triggering conditions. The remaining 498 patients (31%) had no identifiable trigger. TTS patients related to physical stress showed higher mortality rates than ACS patients during long-term follow-up, whereas patients related to emotional stress had better outcomes compared with ACS patients., Conclusions: Overall, TTS patients had long-term outcomes comparable to age- and sex-matched ACS patients. Also, we demonstrated that TTS can either be benign or a life-threating condition depending on the inciting stress factor. We propose a new classification based on triggers, which can serve as a clinical tool to predict short- and long-term outcomes of TTS. (International Takotsubo Registry [InterTAK Registry]; NCT01947621)., (Copyright © 2018 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: The pathophysiology of takotsubo syndrome (TTS) is unclear so far. There is strong association of the occurrence of TTS and malignant diseases. An association between malignant diseases and myocardial infarction (MI) was found recently and ascribed to common molecular and lifestyle mechanisms., Aim: To compare the outcome of patients with MI or TTS and malignant diseases in a matched cohort., Methods: Patients with TTS or with MI (n = 138 per group) were matched for age and sex and assessed retrospectively and prospectively. Occurrence of malignant diseases and clinical outcome was followed up over 4 years., Results: At the time of the index event, 8 (5.8%) MI patients and 17 (12.3%) TTS patients were already diagnosed with cancer. During follow up, the rate of patients who developed cancer was significantly higher in the TTS group than in the MI group (log rank P = 0.01). Mortality was higher in the TTS group, but also in the subgroup of TTS patients with cancer (log rank P < 0.05). In the multivariate analysis, male gender, renal impairment and the history of cancer was associated with an increased risk for death., Conclusions: Patients with TTS have more often malignant diseases than patients with MI. Cancer patients with TTS have a worse clinical outcome. The underlying mechanism is unclear yet, but the results point at TTS being the syndrome of an extracardiac disease rather than a disease of cardiac origin. Longer and closer follow up of patients with TTS and further studies addressing the mechanism of TTS are needed.

Aims: Recent studies have highlighted that takotsubo syndrome (TTS) is associated with a poor clinical outcome. Our study was conducted to determine the short- and long-term prevalence, recurrence rate and impact of life-threatening arrhythmias (LTA) on the clinical outcome of TTS., Methods and Results: Our institutional database constituted a collective of 114 patients diagnosed with TTS between 2003 and 2015. The patient groups, divided according to the presence (n = 13, 11.4%) or absence (n = 101, 88.6%) of LTAs, were followed-up over a period of 3 years so as to determine the clinical outcome. Our analyses suggest that patients comprising the LTA group suffered significantly more often from an acute cardiovascular event including cases of a newly diagnosed atrial fibrillation (38.4% vs. 2.9%), cardiogenic shock with use of inotropic agents (53.8% vs. 14.8%) and cardiopulmonary resuscitation (61.5% vs. 1%). The short-term recurrence rate of a LTA episode was 15.3%, while the long-term recurrence rate of any LTA was around 5%. Whereas, in-hospital mortality was significantly higher in TTS associated with LTAs, the overall survival rate over 3 years was similar. A multivariate Cox regression analysis suggested atrial fibrillation, EF ≤ 35%, cardiogenic shock, and glomerular filtration rate <60 mL/min. as independent predictors of adverse outcome., Conclusion: The short- as well as the long-term prevalence and recurrence of LTAs in TTS patients is high. The long-term mortality rates were similar to the TTS patients presenting without any LTAs. LTAs in TTS could be triggered by a concomitant atrial fibrillation.

Aim: Takotsubo syndrome (TTS) patients have a higher mortality rate than the general population. Our study was conducted to determine the short- and long-term outcome of TTS patients associated with a significantly compromised mitral annular plane systolic excursion (MAPSE) on hospital admission., Methods and Results: Our institutional database constituted a collective of 53 patients diagnosed with TTS between 2003 and 2016. The patients were classified into two groups based on the MAPSE, with those presenting with an MAPSE <1 cm on admission categorized into one group (n = 20, 38%) and those presenting with MAPSE ≥1 cm (n = 33, 62%) categorized into another group. Preliminary results indicated that patients with an MAPSE < 1 cm had a greater risk of developing thromboembolic events. The long-term mortality was significantly higher in TTS patients with an MAPSE < 1 cm. In the multivariate Cox regression analysis, cardiogenic shock (hazard ratio 3.5; 95% confidence interval: 1.2-10.7; P = 0.02) and MAPSE < 1 cm (hazard ratio 5.1; 95% confidence interval: 1.3-19.2; P = 0.01) figured as independent predictors of the mortality., Conclusion: Although the short-term mortality rates among TTS patients diagnosed with a reduced MAPSE on admission were as similar as without reduced MAPSE, the long-term mortality rates among TTS patients diagnosed with a reduced MAPSE on admission were significantly higher. There is an urgent need for randomized trials, which could help define uniform clinical management strategies for high-risk TTS patients.

Background: Recent hypotheses have suggested the pathophysiological role of catecholamines in the evolution of the Takotsubo syndrome (TTS). The extent of cardiac and circulatory compromise dictates the use of some form of supportive therapy. This study was designed to investigate the clinical outcomes associated with catecholamine use in TTS patients., Methods: Our institutional database constituted a collective of 114 patients diagnosed with TTS between 2003 and 2015. The study-patients were subsequently classified into two groups based on the need for catecholamine support during hospital stay (catecholamine group n = 93; 81%, non-catecholamine group = 21; 19%). The primary end-point of our study was all-cause mortality., Results: Patients receiving catecholamine support showed higher grades of circulatory and cardiac compromise (left ventricular ejection fraction (LVEF) 39.6% vs. 32.7%, p-value < 0.01) and the course of disease was often complicated by the occurrence of different TTS-associated complications. The in-hospital mortality (3.2% vs. 28.5%, p < 0.01), 30-day mortality (17.2% vs. 51.4%, p < 0.01) as well as long-term mortality (38.7% vs. 80.9%, p < 0.01) was significantly higher in the group of patients receiving catecholamine support. A multivariate Cox regression analysis attributed EF ≤ 35% (HR 3.6, 95% CI 1.6-8.1; p < 0.01) and use of positive inotropic agents (HR 2.2, 95% CI 1.0-4.8; p 0.04) as independent predictors of the adverse outcome., Conclusion: Rates of in-hospital events and short- as well as long-term mortality were significantly higher in TTS patients receiving catecholamine support as compared to the other study-patients. These results need further evaluation in pre-clinical and clinical trials to determine if external catecholamines contribute to an adverse clinical outcome already compromised by the initial insult.

Takotsubo cardiomyopathy (TC) is a life-threatening syndrome with ambiguous pathophysiology. The interdependency between heart failure and kidney failure (KF) is well established, but the influence of KF on TC outcome is not known. This single-center cohort from January 2003 to September 2015 consisted of 114 consecutive patients with TC. They were divided into 2 groups according to the presence (n = 32, 29.6%) or absence (n = 76, 70.3%) of KF. The end point of this retrospective study was a composite of in-hospital events, all-cause mortality, rehospitalization due to heart failure, stroke, and recurrence of TC (mean follow-up: 5 years). Although there were no differences in baseline characteristics between patients with/without KF, we found a significantly higher mortality rate in those with KF, 1 (7.9% vs 21.8%, P < .05), 2 (11.8% vs 31.5%, P < .05), and 5 years (22.3% vs 43.7%, P < .05) after the index event. There were no differences in life-threatening arrhythmias, cardiogenic shock, cardiopulmonary resuscitation, and thromboembolic events in both groups at the index event. Patients with TC and KF have a much worse long-term prognosis. This is clinically relevant, but the mechanisms responsible remain to be determined.

Recent studies have indicated that patients with takotsubo cardiomyopathy (TTC) have a higher mortality rate than the general population. There is a distinct possibility that TTC could be associated with adverse life-threatening complications like cardiopulmonary failure. Our institutional database constituted a collective of 114 patients diagnosed with TTC. The frequency, determinants and predictors of cardiopulmonary failure were assessed. The patients were subsequently classified into two groups based on the presence (n = 44, 38.6%) or absence (n = 70, 61.4%) of cardiopulmonary failure. Multivariable logistic-regression analysis identified impaired left ventricular function defined as ≤35% at presentation and life-threatening arrhythmia as a positive significant independent predictor of cardiopulmonary failure. A majority of the patients with cardiopulmonary failure were treated with either non-invasive or invasive ventilator support (88%), while 48% of the patients required treatment with catecholamine. The in-hospital mortality rate was greater in the cardiopulmonary failure group. Cardiopulmonary failure patients were at ongoing increased risk of death with a higher mortality at 30-day, 1-year and at 5 years of follow-up. Cardiopulmonary failure is a frequent complication in TTC with an increased short- and long-term mortality. Patient susceptible to this condition could be identified by a reduced ejection fraction and life-threatening arrhythmia.

Aims: Previous studies revealed that patients with Takotsubo cardiomyopathy (TTC) have a higher mortality rate than the general population. Supraventricular tachycardia is a well-known complication of TTC. This study was performed to determine the short- and long-term prognostic impact of atrial fibrillation associated with TTC patients., Methods and Results: Our institutional database constituted a collective of 114 patients diagnosed with TTC from 2003 to 2015. The patients were divided into two groups according to the presence (n = 21, 18.4%) or absence (n = 93, 81.5%) of atrial fibrillation. The endpoint was a composite of in-hospital events (thromboembolic events and life-threatening arrhythmias), all-cause mortality, rehospitalization due to heart failure, stroke, and the recurrence of TTC. The in-hospital mortality, 30-day mortality, and long-term mortality were significantly higher in the atrial fibrillation group. Kaplan-Meier analysis indicated a significantly lower event-free survival rate over a mean follow-up of 3 years in the atrial fibrillation group than that in the non-atrial fibrillation group (log-rank, P < 0.01). In a multivariate cox regression analysis, atrial fibrillation (hazard ratio, HR 2.3, 95% confidence interval, CI: 1.1-4.9, P < 0.05) and EF ≤ 35% (HR 2.0, 95% CI: 1.1-3.8, P < 0.05) were the only independent predictors of a primary endpoint., Conclusion: Rates of in-hospital events and short- as well as long-term mortality were significantly higher in TTC patients suffering from atrial fibrillation compared with patients without atrial fibrillation., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2016. For permissions please email: journals.permissions@oup.com.)

Background and Aim: Takotsubo cardiomyopathy (TC) is an important differential diagnosis of coronary artery disease (CAD), mimicking acute coronary syndrome in clinical symptoms, biomarker profiles and ST-elevation in ECG. Absence of occlusive coronary disease is an essential criterion distinguishing both diseases. The aim of the study was to explore the influence of co-existing incidental CAD on poorer clinical outcomes and all-cause mortality in TC., Design, Methods and Results: Our mono-centric study cohort constituted 114 consecutive patients diagnosed with TC between 2003 and 2015. The primary endpoint was the all-cause mortality. Additionally, we compared the incidence of thromboembolic events, life-threatening arrhythmias, cardiogenic shock and in-hospital death. There was no significant difference in gender distribution or mean age in both groups. Patients diagnosed with a co-existing CAD (n = 22), had a more pronounced cardiovascular risk profile. The all-cause mortality among patients with co-existing CAD after a 2-year follow-up was higher than those diagnosed with lone TC (22.7 vs. 5.4 %, P = 0.07). In a multivariate cox regression analysis CAD (HR 3.5, 95 %CI 1.0-11.6; P = 0.04), LVEF ≤ 35% (HR 3.8, 95% CI 0.0-0.6, P = 0.01) and cardiogenic shock (HR 3.8, 95% CI 1.2-11.3; P = 0.01) were independent predictors of the primary endpoint., Conclusion: Our study reveals that co-existing CAD impairs the outcome in patients with TC. The diagnostic work-up for TC should therefore not necessarily hinge on ruling out CAD., (© The Author 2017. Published by Oxford University Press on behalf of the Association of Physicians. All rights reserved. For Permissions, please email: journals.permissions@oup.com)

Background: Takotsubo Cardiomyopathy (TTC) is a transient disorder of ventricular wall dysfunction, mostly induced by physical or emotional stress. TTC may be associated with adverse cardiac events. The association of cancer and its clinical impact in TTC patients has not been described yet., Methods: In 114 consecutive patients presenting with TTC between January 2003 and September 2015, we studied the frequency of cancer diagnosis, and compared the clinical course and the occurrence of a clinical endpoint of cancer and non-cancer patients during a follow up of 4.2years., Results: Of the 114 patients, 16 (14.0%) had a malignancy already diagnosed at TTC, and further 11 patients received the diagnosis during follow up. Cancer patients had higher frequency of atrial fibrillation and lower hemoglobin levels at admission than patients without cancer. While the occurrence of in-hospital events was comparable, the diagnosis of cancer at TTC event or during follow up was predictive for a higher rate of the composite endpoint. In the Kaplan-Meier analysis, malignant diseases were strongly associated not only with overall mortality but also with worsened time of event-free survival during the long-term outcome., Conclusions: Prevalence of malignant diseases is high in TTC patients, and is a risk factor for worse outcome. Screening for malignancies should be recommended in all patients presenting with TTC. Further studies are needed to define the association on molecular levels., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: Early research has proposed that patients with Takotsubo syndrome (TTS) could have a higher mortality rate than the general population. Our study was conducted to determine the short- and long-term outcome of TTS patients associated with a significantly compromised left ventricular function on hospital admission., Materials and Methods: Our institutional database constituted a collective of 112 patients diagnosed with TTS between 2003 and 2015. The patients were classified into two groups based on the left ventricular ejection fraction (LVEF), with those presenting with a LVEF > 35% on admission categorized into one group (n = 65, 58%) and those presenting with LVEF ≤ 35% (n=47, 42%) categorized into another group. The endpoint was the all-cause of mortality over a mean follow-up of 1529 ± 1121 days., Results: Preliminary results indicated that patients with an EF ≤ 35% had a significantly greater risk of developing life-threatening arrhythmias, and were much more likely to suffer from cardiogenic shock. Patients often required varying forms of mechanical respiratory support. The in-hospital mortality, 30-day mortality, 1-year mortality and ongoing long-term mortality was significantly higher in TTS patients with an EF ≤ 35%. In a multivariate Cox regression analysis, an EF ≤ 35% (HR 3·3, 95% CI: 1·2-9·2, P < 0·05) was identified as a strong independent predictor of the primary endpoint., Conclusions: In-hospital events as well as short- and long-term mortality rates among TTS patients diagnosed with a significantly reduced LVEF on admission were significantly higher. There is an urgent need for randomized trials, which could help define uniform clinical management strategies for high risk TTS patients., (© 2017 Stichting European Society for Clinical Investigation Journal Foundation.)

Background: Takotsubo cardiomyopathy (TTC) is a relevant differential diagnosis in patients presenting with signs of an acute coronary syndrome. Although recent literature has highlighted some salient features of this disorder, there has been little information elucidating the differences in clinical features, electrocardiographic findings, echocardiographic data and TTC-related complications associated with the different variants of TTC., Methods and Results: Our institutional database constituted a collective of 114 patients diagnosed with TTC between 2003 and 2015 and these patients were subsequently divided into two groups based on the presence (n = 82, 72%) or absence (n = 32, 28%) of the apical form of TTC. The protocol for our proposed study was approved by the Ethics Committee of the University Medical Centre in Mannheim. It was noticed that the patients presenting with the apical form of TTC belonged to an older age group as compared to those presenting with the non-apical form (61.1 ± 8.9 years vs. 69.5 ± 11.2; P  < 0.01). The QTc interval prolongation at index-event was observed to be quantifiably greater in the 'apical variant' patients group (484.8 ± 57 ms vs. 464 ± 34.1 ms; P = 0.06). With respect to cardiovascular risk factors, patients with arterial hypertension did have a higher predilection to present with the apical form (63.4% vs. 43.7%; P = 0.06), however, the impact of smoking was less pronounced in this patient group (24.4% vs. 50%, P = 0.01). Furthermore, our study highlighted a significant impact on ejection fraction (EF), with a compromised left ventricular function (36 ± 9% vs. 42.4 ± 9.7%, P < 0.01) and greater involvement of the right ventricle in the apical variant patients group (23% vs. 3%, P = 0.04). Patients with the apical form also showed a greater tendency to develop TTC-related complications such as cardiogenic shock and required longer monitoring and care in comparison., Conclusions: The apical and non-apical variants of TTC are manifestations of the same syndrome. They differ significantly, however, in their clinical presentation, related complications and prognosis., (© The Author 2016. Published by Oxford University Press on behalf of the Association of Physicians. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Takotsubo cardiomyopathy (TTC), initially defined as a benign disease, is associated with several complications. One of them is a thromboembolism, which is clinically presented by events such as stroke, ventricular thrombi, and peripheral embolization, and can be present at index event of TCC as well as at any time in disease course. Patients with elevated C-reactive protein levels, markedly elevated D-dimers and severely impaired left ventricular function seem to be at higher risk of developing thrombemboli. Treatment strategies prescribed in the management of thombembolic complications in patients with acute myocardial infarction includes a short course of anticoagulation. A similar analogy could also be considered for patients with TTC presenting with this complications. Nevertheless, an individualized close-follow-up is of utmost importance to avoid any relapse and not to oversee any impeding complications in light of dynamic processes in myocardial stunning., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Objective: Takotsubo cardiomyopathy, also known as stress-induced cardiomyopathy (SCM) resembles a reversible cardiomyopathy that is characterized by localized wall motion abnormalities in the absence of stenotic coronary vascular disease. Patients typically present with apical ballooning of the left ventricle (LV), however the right ventricle (RV) is also affected in up to 50.0% of patients. Long-term prognosis of classical SCM resembles that of patients after ST elevation myocardial infarction. Data on long-term prognosis of biventricular compared to classical SCM is controversial. The aim of this study was therefore to analyze patients with biventricular SCM regarding in-hospital outcome and long-term prognosis., Materials and Methods: 114 consecutive patients with SCM were retrospectively analyzed. 88 patients presented with classical SCM, 26 patients (22.8%) were diagnosed with biventricular SCM. Follow-up was conducted for a total of 4.4years. Mean age was 67.1years with 83.3% of patients being female. The primary endpoint was a composite of all-cause mortality, recurrence of SCM and re-hospitalization due to heart failure., Results: Although patients with biventricular SCM presented with a tendency towards an increased rate of cardiogenic shock (30.8% vs. 15.9%; p=0.09) and significantly more usage of inotropic support upon hospital admission (34.6% vs. 13.6%; p=0.01), there was no difference concerning the primary endpoint in both groups (50.0% vs. 44.3%; p=0.31). Furthermore, there was no difference in mortality both in-hospital (7.7% vs. 7.9%; p=0.66) and during long-term follow-up (27.3% vs. 23.1%; p=0.46)., Conclusion: Patients with biventricular SCM have the same in-hospital and long-term outcome compared to classical SCM., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Aims: This study sought to characterize global and regional right ventricular (RV) myocardial function in patients with Takotsubo cardiomyopathy (TC) using 2D strain imaging., Methods: We compared various parameters of RV and left ventricular (LV) systolic function between 2 groups of consecutive patients with TC at initial presentation and upon follow-up. Group 1 had RV involvement and group 2 did not have RV involvement., Results: At initial presentation, RV peak systolic longitudinal strain (RVPSS) and RV fractional area change (RVFAC) were significantly lower in group 1 (-13.2±8.6% vs. -21.8±5.4%, p = 0.001; 30.7±9.3% vs. 43.5±6.3%, p = 0.001) and improved significantly upon follow-up. Tricuspid annular plane systolic excursion (TAPSE) did not differ significantly at initial presentation between both groups (14.8±4.1 mm vs. 17.9±3.5 mm, p = 0.050). Differences in regional systolic RV strain were only observed in the mid and apical segments. LV ejection fraction (LVEF) and LV global strain were significantly lower in group 1 (36±8% vs. 46±10%, p = 0.006 and -5.5±4.8% vs. -10.2±6.2%, p = 0.040) at initial presentation. None of the parameters were significantly different between the 2 groups upon follow-up. A RVPSS cut-off value of >-19.1% had a sensitivity of 85% and a specificity of 71% to discriminate between the 2 groups., Conclusion: In TC, RVFAC, RVPSS, LVEF and LV global strain differed significantly between patients with and without RV dysfunction, whereas TAPSE did not. 2 D strain imaging was feasible for the assessment of RV dysfunction in TC and could discriminate between patients with and without RV involvement in a clinically meaningful way.