Prevalence and long-term prognostic impact of malignancy in patients with Takotsubo syndrome.

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. 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. 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 Takotsubo Syndrome (TTS) shares key pathophysiological mechanisms with Heart Failure (HF), including impaired myocardial contractility, neurohormonal activation, and long-term cardiovascular risk. However, data on its long-term outcomes compared to HF remain limited, leaving uncertainty regarding its true prognostic impact. Purpose To assess the risk of adverse events in patients with TTS compared to those with HF with both reduced or preserved ejection fraction. Methods Retrospective study using data from a large multinational electronic health record network (TriNetX). Adult patients (≥18 years) diagnosed with TTS (ICD-10-CM I51.81) or HF (ICD-10-CM I50.x) between 2018 and 2023 were included in the analysis and categorized into two different groups. Primary outcomes were the risks of all-cause death and of a composite of hospital admission, acute HF, acute myocardial infarction, stroke and ventricular arrhythmias. Secondary outcomes were the risks for each component of the composite outcome and new onset atrial fibrillation. We used Cox regression analysis to calculate hazard ratio (HR) and 95% confidence interval (CI) after propensity score matching (PSM) 1:1. Results We identified 12802 TTS patients (age 66.3±15.3 years, 73.7% females) and 687319 HF patients (69.5±15.9 years, 44.4% females). Before PSM, TTS patients were younger, predominantly female, and with a lower cardiovascular burden compared to HF patients. After PSM, 12800 matched pairs were analyzed. TTS patients showed a lower risk of all-cause death (HR 0.89, 95%CI 0.84-0.95) and composite outcome (HR 0.84, 95%CI 0.82-­0.86) compared to HF patients. Regarding secondary outcomes, TTS patients had a lower risk of acute HF (HR 0.81, 95%CI 0.78-­0.85), ventricular arrhythmias (HR 0.77, 95%CI 0.71-0.85) and new onset atrial fibrillation (HR 0.68, 95%CI 0.59-0.77). Although, they showed a higher risk of acute myocardial infarction (HR 1.44, 95%CI 1.37-1.52) and a similar risk of stroke (HR 1.03, 95%CI 0.95-1.13) (Figure 1, Figure 2). These associations persisted when comparing TTS to HF patients’ subgroups with reduced or preserved ejection fraction. Conclusion TTS patients are at generally lower risk of adverse events compared to HF patients, but have a risk of ischemic complications (acute myocardial infarction, stroke) similar to HF. These findings challenge the conventional view of TTS as a transient condition, highlighting the need for further investigation into its long-term pathophysiological mechanisms.

Background: Takotsubo syndrome (TTS) is a syndrome with ambiguous pathophysiology. Impaired kidney function (KF) seems to impact the outcome of patients with TTS. We hypothesized that KF worsens the outcome among TTS patients and furthermore, TTS patients with concomitant KF experience more adverse events compared to myocardial infarction (MI) patients with concomitant KF. Methods and Results: This retrospective single-center study comprised two groups (cohorts) of patients including patients with TTS and concomitant KF (n = 61, 27.1%) and patients with MI and concomitant KF (n = 164, 72.9%). The clinical outcomes were delineated as short-term outcomes defined as in-hospital adverse events during index hospitalization and long-term outcomes defined as adverse events over five-year clinical follow-ups. All-cause mortality, stroke, cardiopulmonary resuscitation (CPR), life-threatening arrhythmias, need for respiratory support, and cardiogenic shock with subsequent use of inotropic agents during index hospitalization were denoted as in-hospital adverse events. All-cause mortality, rehospitalization due to heart failure, stroke, thromboembolic events, and the recurrence of primary pathology (TTS and MI) were analyzed during five-year follow-ups after index hospitalization. A higher mortality rate was noted among TTS patients with KF compared to TTS without KF. In addition, in-hospital event rates in patients with TTS and concomitant KF compared to MI and concomitant KF were comparable with the exception of a higher rate of respiratory support in TTS patients. The mortality rate was significantly higher among patients with TTS and KF at 4 years (29.5% vs. 15.9%, p = 0.02) and 5 years (34.4% vs. 20.7%, p = 0.03) in comparison to patients with MI and concomitant KF. In contrast, the rate of re-hospitalization related to heart failure was higher at 30 days, and at one-, four-, and five-year follow-ups in patients suffering from MI and KF compared to TTS and concomitant KF. Additionally, the recurrence of MI after 4 and 5 years was higher than the recurrence of TTS (4.9% vs. 15.2%; 4.9% vs. 16.5%). There were no differences in life-threatening arrhythmias and stroke in both groups. Conclusions: Patients with TTS and concomitant KF have higher all-cause mortality when compared to MI and concomitant KF. The mechanisms responsible remain to be determined.

Takotsubo syndrome (TTS), commonly perceived as a benign and reversible condition has received attention due to emerging registry data revealing its prognosis to be comparable to acute coronary syndrome (ACS). Following ACS, a notable subset of patients develops autonomic dysfunction, whith unfavourable prognostic implications. Periodic repolarization dynamics (PRD) and deceleration capacity (DC), derived from ECG signals, are parameters capable of quantifying cardiac autonomic function. In this study, we aimed to assess autonomic dysfunction in patients with TTC in comparison to ST-elevation myocardial infarction (STEMI) patients. Consecutive patients diagnosed with TTS were prospectively recruited into an observational, single-centre cohort study. All patients underwent a 30-minute high-resolution ecg recording. Subsequent recordings were conducted at 4 and 12 months post-acute event. PRD and DC as markers for sympathetic and parasympathetic activity, respectively, were assessed using established methods. The control group comprised patients with STEMI. Statistical comparisons between groups were performed using the Mann-Whitney U-test, with a corrected significance level for multiple testing of α&amp;lt; .017. Between July 2021 and December 2023, 57 patients diagnosed with TTS were recruited (interquartile range [IQR]) 69.0 years (62.0-78.0), 98.3% women. A control group was derived from a pre-existing cohort of STEMI patients, matched through propensity score matching to adjust for age and sex (median age [IQR]: 69.0 [59.0-76.0] years, 98.3% women). At baseline, there was no significant difference in PRD between TTS patients and controls (median [IQR]: TTS: 5.28deg² [3.43-9.93], STEMI: 4.40deg² [2.24-7.21]; p = .04). However, at 4 months post-acute event, PRD was notably higher in TTS patients compared to controls (median [IQR]: TTS: 5.20deg² [2.71-8.17], STEMI: 2.63deg² [1.86-4.92]; p = .011). Interestingly, at 12-month follow-up, PRD in TTS patients did not differ from that of controls (median [IQR]: TTS: 4.55deg² [2.89-8.40], STEMI: 4.15deg² [2.42-6.85]; p = .68). Regarding DC, no significant differences were observed between TTS and STEMI patients at any time point (baseline: median [IQR]: TTS: 3.95 ms [2.27-5.51], STEMI: 3.52 ms [2.30-7.24], p = .51; 4 months: median [IQR]: TTS: 6.63 ms [4.59-8.64], STEMI: 7.41 ms [4.63-9.25], p = .39; 12 months: median [IQR]: TTS: 4.98 ms [4.19-6.67], STEMI: 7.48 ms [4.92-10.28], p = .17). Patients with TTS show substantial signs of cardiac autonomic dysfunction, similar or even higher than acute STEMI patients. This dysfunction persists even up to 4 months after the acute event, whereas STEMI patients show recovery of autonomic function in this 4 month period. DC remained consistent between TTS and STEMI patients across all time points. Further research elucidating the long-term implications of these autonomic alterations is warranted to refine risk stratification and therapeutic strategies in TTS management.

IntroductionFirst described in 1990, there is a paucity of evidence to guide management of Takotsubo Syndrome (TTS) patients. No randomised controlled trial data exists, and no registry data has been...

Cardiac troponin levels are elevated in Takotsubo syndrome (TTS) with significant overlap to acute myocardial infarction (MI). Long and intact cardiac troponin T (cTnT) forms are typical for MI. This study sought to assess whether the fragmentation composition of cTnT release in TTS differs from MI. The concentration of long molecular forms of cTnT (long cTnT) was measured with a novel upconversion luminescence immunoassay and total cTnT with a commercial high-sensitivity cTnT assay in 24 TTS patients and in 84 Type 1 MI patients. The ratio of long to total cTnT (troponin ratio) was determined as a measure of cTnT fragmentation. Troponin ratio was lower in TTS patients [0.13 (0.10-0.20) vs. 0.62 (0.29-0.96), P < 0.001]. In the receiver operating characteristic curve analyses, troponin ratio showed a better predictive power than total cTnT in discriminating TTS and MI patients {area under the curve [AUC] 0.869 [95% confidence interval (CI) 0.789-0.948] vs. 0.766 [95% CI 0.677-0.855], P = 0.047}. When restricting the analysis to patients with total cTnT below 1200 ng/L (maximal value in TTS patients), the respective AUC values for total cTnT and troponin ratio were 0.599 (95% CI 0.465-0.732) and 0.816 (95% CI 0.712-0.921) (P = 0.003). At a cut-off point of 0.12, troponin ratio correctly identified 95% of MI patients and 50% of TTS patients. In contrast to Type 1 MI, only a small fraction of circulating cTnT in TTS exists in intact or long molecular forms. This clear difference in troponin composition could be of diagnostic value when evaluating patients with cTnT elevations and suspicion of TTS. URL: https://www.clinicaltrials.gov; Unique identifier: NCT04465591.

Prediction of short- and long-term mortality in takotsubo syndrome: the InterTAK Prognostic Score.

Long-Term Prognosis of Patients With Takotsubo Syndrome

BackgroundTakotsubo syndrome (TTS) and acute coronary syndrome (ACS) patients have a similar mortality rate. In this study, we sought to determine the short- and long-term outcome of TTS patients as compared to ACS patients both treated with beta-blockers.ObjectivesIn the present study we described the data of 5 years of follow up of 103 TTS and 422 ACS patients both treated with beta-blockers.MethodsData from TTS patients were included retrospectively and prospectively, ACS patients were included retrospectively. All retrospectively included patients have been followed up for 5 years. The end point in this study was the occurrence of death.ResultsTTS affected significantly more women (87.4%) than ACS (34.6%) (p < 0.01). TTS patients suffered significantly more often from thromboembolic events (14.6% versus 2.1%; p < 0.01) and cardiogenic shock (11.9% versus 3.6%; p < 0.01) than the ACS group. TTS patients had a significantly higher long-term mortality (within 5 years) as compared to ACS patients (17.5% versus 3.6%) (p < 0.01). Patients of the TTS group compared to the ACS group did not benefit from combination of beta-blockers and ACE-inhibitors in terms of long-term mortality (p < 0.01). As we compare TTS patients who were treated with beta-blockers and ACE-inhibitors versus single use of beta-blockers there was no difference in long-term mortality (p = 0.918).ConclusionTTS patients had a significantly higher long-term mortality (within 5 years) than patients with an ACS.

A systematic review and meta-analysis were performed to analyse the differences in clinical profiles between takotsubo syndrome (TTS) and acute coronary syndrome (ACS) patients and to consolidate the evidence regarding the mortality predictors in TTS patients. Literature search of PubMed, EMBASE and the Cochrane Central Register was made, and 55 studies with a total of 66,653 TTS patients were included. Compared with ACS subjects, TTS subjects had significantly lower left ventricle ejection fraction (LVEF) values on admission; however, cardiovascular risks were fewer and the recovery LVEF was notably higher at both discharge and follow-up in TTS patients than in ACS patients (all P < 0.05). No significant differences were observed either in-hospital mortality or long-term mortality between the two groups (both P > 0.05). Acute renal failure and malignancies were independent predictors of all-cause in-hospital mortality in TTS patients (both P < 0.05). Male sex (HR = 0.565, 95% CI 0.253-0.876, P < 0.001, I2 = 0.00%), advanced age (HR = 0.054, 95% CI 0.041 to 0.067, P < 0.001, I2 = 0.00%), shock (HR = 1.382. 95% CI 1.050 to 1.714, P < 0.001, I2 = 0.00%) and initial LVEF < 35% (HR = 0.962, 95% CI 0.948 to 0.977, P < 0.001, I2 = 16.8%) were associated with an increased risk of long-time mortality in TTS patients. In conclusion, TTS has significantly different clinical characteristics than ACS. However, the in-hospital and long-term overall mortality rates are not trivial for TTS patients, and some presenting features (underlying diseases, male sex, advanced age, low LVEF and shock) were significantly associated with all-cause mortality.

Takotsubo syndrome is an increasingly recognised cardiac condition that clinically mimics an acute coronary syndrome, but data regarding its prognosis remain controversial. It is currently unknown whether acute coronary syndrome risk scores could effectively be applied to Takotsubo syndrome patients. This study aims to assess whether the Global Registry of Acute Coronary Events (GRACE) score can predict clinical outcome in Takotsubo syndrome and to compare the prognosis with matched acute coronary syndrome patients. A total of 561 Takotsubo syndrome patients was included in this prospective registry. According to the GRACE score, the population was divided into quartiles. The primary endpoint was all-cause mortality and the secondary endpoints were cardiocerebrovascular events (a composite of all-cause mortality, cardiovascular death, recurrence of Takotsubo syndrome and stroke). The median GRACE risk score was 139±27. Takotsubo syndrome patients with a higher GRACE risk score mostly have a higher rate of physical triggers and lower left ventricular ejection fraction on admission. During long-term follow-up, all-cause mortality rates were 5%, 11%, 12% and 22%, respectively, in the first, second, third and fourth quartile (P<0.001). After multivariate analysis, the GRACE risk score was found to be a strong predictor of all-cause mortality (odds ratio (OR) 1.68, 95% confidence interval (CI) 1.28-2.20; P=0.001) and cardiocerebrovascular events (OR 1.63, 95% CI 1.26-2.11; P=0.001). Moreover, all-cause mortality in Takotsubo syndrome patients was comparable with the matched acute coronary syndrome cohort. In Takotsubo syndrome, the GRACE risk score allows us to predict all-cause mortality and cardiocerebrovascular events at long-term follow-up.

One of the most active committees of the Heart Failure Association (HFA) is the Committee on Cardiomyopathies and Structural Heart Disease coordinated by the President, Petar Seferovic, and within that Committee, one of the most productive study groups is that looking at Takotsubo syndrome led by Alexander Lyon, of Imperial College, London (UK). Alex has sent me a report on the activity of his study group that I attach below. Takotsubo syndrome is an acute heart failure syndrome first described in 1990 by Professor Hiraku Sato in Hiroshima, Japan,1 although it was clearly present in human society before this first description. As an acute heart failure syndrome, the HFA of the European Society of Cardiology (ESC) recognised the importance to raise awareness and improve education and understanding of this condition, and appropriate management pathways. In 2014, the HFA taskforce on Takotsubo syndrome was created, and a group of specialists developed the HFA position statement on Takotsubo syndrome, which was published in this Journal in January 2016.2 It remains the second most highly cited paper of 2016 published in the European Journal of Heart Failure (after the updated ESC guidelines on acute and chronic heart failure), and currently has over 316 citations. Dr. Alexander Lyon, chair of the previous HFA Takotsubo syndrome taskforce and the current study group explained that one of the priorities was to make management algorithms for clinicians looking after patients with Takotsubo syndrome easy to understand and deploy in their hospitals. ‘We summarised both a diagnostic algorithm and a treatment algorithm in two pages so they can be printed off and available for review in the coronary care unit and cardiac catheterisation laboratory where these patients are initially assessed and treated. The second aim of the paper was to emphasise the importance of risk stratification following the diagnosis of Takotsubo syndrome during the acute phase given the 4–5% mortality secondary to refractory cardiogenic shock and malignant ventricular arrhythmias.3, 4 Indeed, a recent study published in this Journal highlighted the impact of the severity of the acute heart failure episode on both short-term and long-term clinical outcomes.5 Finally, we also wanted to introduce the awareness that up to 15% of patients are left with long-term cardiac problems with objective abnormalities of cardiac physiology including diastolic impairment, persistently elevated natriuretic peptides, reduced exercise capacity and both atrial and ventricular arrhythmias’. The problems of long-term abnormalities have recently been highlighted by the work of Dr. Dana Dawson who reported abnormalities of cardiac ventricular metabolism, elevated natriuretic peptides and reduced cardiopulmonary exercise test performance in a cohort of symptomatic patients more than 12 months following their Takotsubo syndrome episode.6 There is also emerging evidence of persistent inflammation in the myocardium of some Takotsubo syndrome patients at long-term follow-up which may contribute to both their symptoms and risk of recurrence. In 2016, the HFA initiated the first formal Takotsubo Syndrome Study Group and in May 2018 the study group collaborated with the Myocardial Function Working Group of the ESC to host a workshop in Ravello, Italy, dedicated to understanding the pathophysiology of Takotsubo syndrome. This is an extremely complicated field and multiple avenues of evidence exist, ranging from the direct effects of high-dose catecholamines on a ventricular myocardium, interactions between the heart and the circulatory system, changes in stress response and hypothalamic–pituitary–adrenal axis physiology, vascular changes both in the coronary arteries with potential for vasospasm and microvascular dysfunction, and in the peripheral arteries including autonomic dysregulation. Both clinicians and laboratory scientists who have a specialist interest in adrenergic physiology and Takotsubo gathered together in a truly translational workshop identifying the unmet needs in diagnosis, management during the acute phase, management and treatment in long-term survivors, and the potential to prevent recurrence in those susceptible to recurrent Takotsubo syndrome episodes. A new position paper is under preparation which the workshop attendees hope will help to guide future research strategies and ultimately lead to new diagnostics and treatments to help improve the quality of life, morbidity and mortality of patients with Takotsubo syndrome. This is an example of a growing number of cardiovascular conditions which brings together the heart and the mind, and further collaboration with the Heart and Brain Study Group of HFA will also help to coordinate the psychological components of stress and the impact on the heart, which may be relevant in certain individuals susceptible to Takotsubo syndrome.7 Abnormalities in higher cortical and limbic regions of the brain have been reported in functional brain imaging studies from Takotsubo syndrome survivors, but it is not known what is pre-existing and contributing to susceptibility vs. acquired as a result of the stressful event and sympathetic storm. In addition, there are also abnormalities and disturbances in autonomic neural physiology in Takotsubo syndrome patients following the acute episode, which opens the door to new treatment approaches including the range of treatments developed for other types of heart failure patients to target the autonomic nervous system.8 For a condition first described 29 years ago but clearly present since the origin of the human species, we still have a long way to go to optimise care for these patients who are becoming increasingly recognised in modern health care. Dr. Alexander Lyon, London, UK (Chair). Dr. Birke Schneider, Lubeck, Germany. Prof. Eduardo Bossone, Naples, Italy. Dr. Jelena Ghadri, Zurich, Switzerland. Prof. Elmir Omerovic, Gothenburg, Sweden. Dr. Rodolfo Citro, Salerno, Italy. Prof. Dana Dawson, Aberdeen, UK. Prof. Guido Parodi, Sassari, Italy. Prof. Johannes Backs, Heidelberg, Germany. Dr. Linda Von Laake, Utrecht, The Netherlands. Dr. Kalliopi Keramida, Athens, Greece. Andrew J.S. Coats University of Warwick, Coventry, UK and IRCCS San Raffaele Pisana, Rome, Italy [email protected]

The aim of this study was to investigate the long-term outcome of takotsubo syndrome (TTS) patients with and without hypertension (HT) and to evaluate the effectiveness of treatment with beta-blockers (BBs) and/or renin-angiotensin-aldosterone system inhibitors (RAASi). The study population includes a register-based, multicentre cohort of consecutive patients with TTS, divided into two groups according to the history of HT. Further stratification was performed for BB/RAASi prescription at discharge. The primary outcome was the composite of all-cause death and TTS recurrence at the longest available follow-up. The propensity score weighting technique was used to account for potential confounding. In the overall population (903 patients, mean age 70 ± 11 years), HT was reported in 66% of cases. At a median 2-year follow-up, there was no difference in the risk of the primary composite outcome between patients with and without HT. The adjusted Cox regression analysis showed a significantly lower risk for the primary outcome [adjusted hazard ratio (aHR): 0.69; 95% confidence interval (CI): 0.49-0.99] in patients who received BB vs. those who did not. Renin-angiotensin-aldosterone system inhibitors treatment was not associated with the primary study outcome. The lower risk for the primary outcome with BB treatment was confirmed in patients with HT (aHR: 0.37; 95% CI: 0.24-0.56) but not in patients without (aHR: 1.83; 95% CI: 0.92-3.64; Pinteraction < 0.001). In this TTS study, HT did not affect the long-term risk of adverse events but increased the probability of benefit from BB treatment after discharge. Owing to the favourable outcome impact of BB prescription in TTS patients with HT, a tailored pharmacological therapy should be considered in this cohort.

Autonomic function in Takotsubo syndrome long after the acute phase

Author’s reply