In this observational multicenter study involving 12 Portuguese hospitals, all patients diagnosed with TTS from 2002 to 2016 were included, retrospectively until 2012 and prospectively since 2012.

Patients were selected according to the Mayo Clinic diagnostic criteria: transient abnormality in LV wall motion beyond a single epicardial coronary artery perfusion territory; absence of obstructive CAD or angiographic evidence of acute plaque rupture; new electrocardiographic abnormalities or modest elevation in cardiac troponin levels; and the absence of pheochromocytoma or myocarditis.7

An exception to these criteria was the inclusion of patients who died during the acute phase, prior to complete recovery of myocardial function.

The data were collected by consulting the clinical records of patients diagnosed with TTS, retrospectively before 2012 and prospectively after 2012.

Demographic data, personal history, cardiovascular risk factors, triggering factors, clinical presentation, electrocardiographic findings, coronary angiography findings and complications during hospitalization were collected. Coronary angiography was performed in all patients.

TTS was classified as apical, midventricular, basal or focal according to the LV ballooning pattern on the transthoracic echocardiogram.6

Chronic kidney disease (CKD) was defined as glomerular filtration rate <60 ml/min for at least three months.9

QT interval was measured by each patient's cardiologist. Corrected QT interval (QTc) was calculated using Bazett's formula and was defined as prolonged if >450 ms for males and >470 ms for females.10

Transthoracic echocardiography was performed on admission, at discharge and during follow-up. Complete echocardiographic recovery was defined as the normalization of regional wall motion abnormalities present on the initial transthoracic echocardiogram.

The in-hospital complications included were acute heart failure, cardiogenic shock, new-onset atrial fibrillation (AF), ventricular fibrillation/ventricular tachycardia, complete atrioventricular block, stroke/transient ischemic attack (TIA), LV thrombus and death from any cause.

Acute heart failure was defined as the presence of dyspnea, pulmonary edema and/or oxygen desaturation requiring drug therapy and/or mechanical support.

Cardiogenic shock was defined as systolic blood pressure <90 mmHg with signs of tissue hypoperfusion requiring inotropic agents and/or fluid therapy.

Follow-up data were obtained from clinical visits, medical records and telephone interviews.

The follow-up analysis included all-cause mortality, cardiovascular mortality and major cardiovascular events (stroke/TIA, myocardial infarction and recurrence of TTS).

Cardiovascular mortality was defined as death caused by heart failure, arrhythmia, myocardial infarction, cerebrovascular disease, pulmonary embolism or sudden cardiac death. Any death not covered by these definitions was defined as non-cardiovascular mortality.

Myocardial infarction was defined using the criteria of the third universal definition of myocardial infarction.11

A descriptive analysis was carried out to characterize the sample profile. Continuous variables are presented as means and standard deviation and categorical variables are presented as percentages.

The chi-square test was used to analyze associations between categorical variables, and the Student's, Mann-Whitney and Kruskal-Wallis tests were applied to continuous variables. The Kolmogorov-Smirnov test was used to verify normality of distribution.

Binary logistic regression was used to measure predictors of in-hospital and follow-up events.

A p-value <0.05 (significance level of 95%) was considered statistically significant. The statistical analysis was performed using IBM SPSS version 24.0.

The baseline characteristics of the study population are shown in Table 1.

A total of 234 patients with TTS were included, 210 (89.7%) female, mean age 68±12 years. In 65% of the patients a triggering factor was identified, emotional stress in 46.6% and physical stress in 18.4%. On admission, chest pain was the most frequent symptom (87.2%), followed by dyspnea (21.8%) and syncope (5.6%). The admission electrocardiogram (ECG) revealed negative T waves in 40.2%, ST-segment elevation in 17.9% and prolonged QTc in 10.3%.

In 12.9% of the patients, coronary angiography identified significant CAD in myocardial areas not corresponding to the wall motion abnormalities found on the transthoracic echocardiogram.

Regarding the classification of TTS, the apical form was the most frequent (77.8%), followed by midventricular (15.8%).

Complications and interventions during hospitalization are presented in Table 2.

During hospitalization, 32.9% of the patients had complications, of which acute heart failure was the most frequent (24.4%).

Regarding intensive care measures, 8.1% of patients received inotropic support and 3.4% underwent mechanical ventilation.

During hospitalization, 49.1% of patients completely recovered LV function, while five (2.2%) died.

Factors associated with complications were history of heart failure (p<0.001), CKD (p=0.001), physical stress as triggering factor (p=0.036), presentation without chest pain (p=0.001), presentation with dyspnea (p<0.001), presence of atherosclerotic lesions in the epicardial coronary arteries (p=0.013), and lower left ventricular ejection fraction (LVEF) on admission transthoracic echocardiography (p<0.001) (Table 3).

In multivariate analysis, the presence of atherosclerotic lesions in the coronary arteries (p=0.027), lower LVEF on admission (p=0.003), CKD (p=0.02) and clinical presentation with dyspnea (p=0.019) were independent predictors of in-hospital clinical complications (Table 4).

At the mean follow-up of 33±33 months, 12.2% of the patients had complications.

In 4.4% of patients there was recurrence of TTS, 3.1% had stroke/TIA and 0.4% had myocardial infarction. All-cause mortality was 4.4% and cardiovascular mortality was 0.9% (Table 5).

Prolonged QTc on the admission ECG was associated with clinical complications at follow-up (p=0.001) (Table 6).

The baseline characteristics of our study population were similar to other series with respect to mean age of diagnosis (68±12 years) and the predominance of female gender (90%). TTS more frequently affects women over 50 years of age.6,12–14

Regarding cardiovascular risk factors, hypertension was the most prevalent (68%), followed by dyslipidemia (54%). The prevalence of these factors is in line with that expected for the age group of patients with TTS.

Only 18% of our patients had been diagnosed with diabetes, which is in agreement with the prevalence reported by other series (5-25%).6,12–17 Patients with TTS have a lower prevalence of diabetes compared to patients with acute coronary syndrome.18 It is not known whether the presence of diabetes is a protective factor for TTS, but this is possible in view of the hypothesis that the autonomic neuropathy of diabetes may influence the myocardial response to an adrenergic storm.18

Chest pain is the most common form of clinical presentation of TTS. In our cohort, 87% of the patients presents with chest pain, as in the series by Eitel et al.19 (88%) and Núñez-Gil et al.20 (90.2%). Other series reported slightly lower rates, between 69% and 81%.6,13,14,17,21 Dyspnea is the second most frequent symptom associated with TTS, with a wide range of prevalences ranging between 8% and 47%.6,13,14,17,21–24 In our cohort, dyspnea was the predominant symptom in 21.8% of the patients.

As for the triggering factor, emotional stress was the most common (46.6%), as also observed in the studies by Yayehd et al.14 (45%) and Prevital et al.23 (36%). However, other studies found that physical factors were more important than emotional factors.6,12,13,19,25 In about one third of our patients, no triggering factor was identified, as in several published studies.6,12,13,23,25

Negative T waves were the most frequent finding on the admission ECG (40.2%). Other series reported similar rates.6,19,20,23 However, there are some differences between our data and the literature with regard to ST-segment elevation. In our study, only 17.9% of patients had ST-segment elevation, but other series reported higher rates (38-44%).6,19,23 In our cohort, 17.9% of the patients had pathological Q waves on the admission ECG, while in Yayehd et al.14 and Schneider et al.21 this figure was 29%. In the study by Schneider et al.,21 pathological Q waves were a predictor of complications during hospitalization. However, further studies are needed to understand their prognostic impact in TTS patients.

Prolonged QTc was found in 10.3% of our patients on the initial ECG. Some studies have reported an association between TTS and prolonged QTc, however the prevalence of this association is unknown.26–29

Electrocardiographic changes in TTS are dynamic and differences in time from symptom onset to admission may explain the discrepancies between studies.

The majority of our TTS patients had troponin elevation during hospitalization (89.7%), which is in line with other published series, although these use different types of troponin with different units of measurement, which hampers comparisons of the extent of elevation and consequently the interpretation of its clinical significance.6,14,16,17,19,23,24

TTS is characterized by the presence of LV systolic dysfunction at hospital admission.7

In our population, mean LVEF on admission was similar to other series (43±11%).6,14,17,20,23,30 This suggests that patients with TTS suffer myocardial stunning of similar magnitude, regardless of differences in other clinical variables.

At hospital discharge, 49.1% of the patients showed recovery of myocardial function, which was complete in all patients at follow-up, in accordance with the diagnostic criteria of TTS.

Concerning the classification of TTS, the apical type was the most frequent (77.8%) followed by midventricular (15.8%) and basal (1.7%), similar findings to those in other series.6,24,30

TTS and CAD are not mutually exclusive. Given the mean age at diagnosis and the prevalence of cardiovascular risk factors, CAD can coexist with TTS.31 In our cohort, 12.9% of patients had concomitant CAD. In the literature, reported rates are between 9.8% and 19%.6,25,31–34

Initially, TTS was described as a benign condition.2 However, more recent series have shown high rates of in-hospital complications that should not be overlooked (21.8-52%).6,21,22,30,35,36

In our population, 32.9% of patients presented complications, of which acute heart failure was the most common (24.4%). In fact, acute heart failure is the main clinical complication in TTS, with rates reported in the literature between 16% and 44%.15–17,20,25,35,37

In the heart failure spectrum, cardiogenic shock is the most severe manifestation. In our study, this complication occurred in 8.1% of patients, while other studies report rates between 4.7% and 12.4%.6,13,15,30,34,36 Due to the reversibility of LV dysfunction, it could be expected that cardiogenic shock in TTS would have a lower prognostic impact than in ACS, but Stiermaier et al.30 demonstrated that it is associated with higher short- and long-term mortality.

AF was the most common arrhythmia in our cohort, being found in 15% of our patients, with other series reporting rates between 6% and 15%.13,21,24,38,39 El-Battrawy et al.39 demonstrated that the presence of previously known or first diagnosed AF is associated with higher mortality, both in-hospital and in long-term follow-up.

In our population, 2.6% of the patients had ventricular arrhythmias, a lower figure than in other series, such as Citro et al.37 (4.5%) and Schneider et al.21 (8%).

Complete atrioventricular block, stroke and LV thrombus are less frequent clinical complications, with rates ranging from 0.6% to 3.8%.6,15,21,23,37,40

In our cohort, a history of CKD (p=0.02), clinical presentation with dyspnea (p=0.019), atherosclerotic lesions in the epicardial coronary arteries, and lower LVEF on admission (p=0.003) were predictors of in-hospital clinical complications.

CKD is known to be associated with worse cardiovascular prognosis.41 However, to our knowledge, this association has not yet been reported in TTS.

To our knowledge, our work is the first to identify CAD as a predictor of in-hospital complications in patients with TTS. Parodi et al.31 found no differences in short- and medium-term prognosis in patients with CAD, whereas Bill et al.33 identified this factor as a predictor of medium-term all-cause mortality.

LV systolic dysfunction would be expected to be associated with a worse outcome. In the study by Citro et al.,24 LVEF was a predictor of heart failure, and in series by Schneider et al.21 and Ribeiro et al.,22 LVEF of ≤30% and ≤35%, respectively, predicted in-hospital complications.

Templin et al.,6 studying 1750 patients, identified LVEF on admission, physical stress, troponin level and neurological or psychiatric disease as predictors of complications.

Other series, with significantly smaller numbers of patients, have identified other predictors, such as the presence of pathological Q waves on admission,21 age ≥75 years,37 brain natriuretic peptide and white blood cell count,25 heart rate, and sum of ST-segment elevation on the 12-lead ECG.25

Differences in sample sizes and in the characteristics of study populations result in the identification of different predictors of complications. This makes it difficult to accurately stratify in-hospital risk for TTS patients.

Our series constitutes the second largest series of TTS patients in which predictors of in-hospital complications are identified.

In-hospital mortality in our population was 2.2%, a relatively low figure considering the high rate of acute complications. Other studies report rates between 0% and 12.2%.6,13–16,21,24,25,32,42,43

Asian series25,32,42,43 have higher mortality (8.4-12.2%), probably due to differences in the baseline characteristics of the included patients, such as higher percentages of male gender and physical stress as a triggering factor. In support of this hypothesis, Sobue et al.42 identified male gender and physical stress as predictors of in-hospital mortality. Beyond these factors, it has been demonstrated that in-hospital mortality is associated with underlying serious illness such as sepsis, acute renal injury, respiratory failure and cancer.15,42

The medium and long-term prognosis of TTS patients is described as favorable, with rapid and complete recovery of LV systolic function.7,19,44

Patients in our study had a good prognosis at the mean follow-up of 33±33 months, with all-cause mortality of 4.4%. Other studies, with different follow-up times, reported all-cause mortality between 2.9% and 24.7%.13,16,17,22,43,45–47 In our study, most deaths were from non-cardiac causes (3.5% of the sample). Other series have also shown that medium- and long-term mortality of TTS patients is more often due to non-cardiac causes than to the syndrome itself. Thus, comorbidities significantly affect the prognosis of these patients.13,40,45

The recurrence rate of TTS was 4.4%. Other series have reported rates between 0% and 11.4%.6,13,14,16,17,23,47 Elesber et al.,17 in a study of 100 patients with TTS, observed recurrence in 11.4% at four years of follow-up. Lower rates are reported by series with shorter follow-up.13,14,23

Regarding cardiovascular and cerebrovascular events, in our study 3.1% of patients had stroke/TIA and 0.4% had myocardial infarction. In Templin et al.,6 the rate of major cardiovascular and cerebrovascular events was 9.9%/year and the rate of stroke/TIA was 1.7%/year.

The observed variability in mortality and clinical complications is related to the number of patients included and the follow-up times in the different series.

In our study, prolonged QTc on admission was associated with events in follow-up (p=0.001). Some studies have observed an association between TTS and prolonged QTc, but there is little evidence on its prognostic impact.26,28,43

Song et al.43 found that patients with long QTc presented a higher prevalence of cardiogenic shock and ventricular arrhythmias and lower LVEF compared to the group with normal QT interval. Similarly, Imran et al.28 demonstrated that prolonged QTc was associated with in-hospital clinical complications.