The term “Takotsubo syndrome” (TTS) emerged in the medical literature in the 1990s, in a Japanese book of medicine, to describe a syndrome of symptoms and electrocardiographic changes suggestive of acute myocardial infarction (AMI), but coronary arteries without significant obstructive lesions. ^{1 , 2} The name "takotsubo" comes from the similarity between the cardiac ventriculography in these patients and an old octopus trap used in Japan (in Japanese, “tako” means octopus and “tsubo” means pot/vase). ^{1 , 3}

The pathophysiology of TTS is essentially related to an exacerbated activation of sympathetic autonomic nervous system. However, the mechanism by which catecholamine excess triggers myocardial stunning, with a variety of motion segment dysfunction patterns that characterize this syndrome (dysfunctional apical mid-ventricular, basal or focal segments) is unknown. ¹

Despite the significant increase in the number of patients diagnosed with TTS, ⁴ and publication of international studies on the theme over the last years, ⁵ little is known about current reality of the disease in Brazil.

The aim of this registry was to assess mortality and major adverse cardiac events (MACE) – composed of stroke/transient ischemic accident (TIA), myocardial revascularization and cardiac mortality – in-hospital and during follow-up, in patients diagnosed with TTS according to InterTAK diagnostic criteria.

Since the first description of TTS, no widely accepted criteria for the diagnosis of TTS have been established. The most used criteria are the Mayo Clinic criteria, modified in 2008. ⁶ According to these criteria, although the presence of coronary obstructive lesion does not rule out the diagnosis of TTS, this information is not clearly defined and described as very rare. ⁷ However, other publications have evidenced that up to 10-29% of the patients diagnosed with TTS have concomitant obstructive coronary disease. ^{8 - 10} Therefore, in attempt to define a new consensus and based on the last available data, a new set of diagnostic criteria (InterTAK criteria) was proposed by experts in TTS in 2018 ( Figure 1 ). ¹

Figure 1

Table 1 describes the clinical features of patients at admission. Most patients were women (85.4%); 70.8% had systemic arterial hypertension and 14.6% were diabetic.

Table 1

Age, years (mean ± SD)	71 ± 13
Sex, n (%)
Male	7 (14.6)
Female	41 (85.4)
Race, n (%)
White	35 (72.9)
Black	3 (6.3)
Pardo	10 (20.8)
Systemic arterial hypertension, n (%)	34 (70.8)
Dyslipidemia, n (%)	16 (33.3)
Diabetes, n (%)	7 (14.6)
Smoking, n (%)
No	33 (68.8)
Yes	10 (20.8)
Ex-smoker	5 (10.4)
Previous atrial fibrillation, n (%)	4 (8.3)
Valvular disease, n (%)	8 (16.7)
Rheumatologic/Autoimmune disease, n (%)	9 (18.8)
Oncologic disease, n (%)	6 (12.5)
Previous stroke, n (%)	2 (4.2)
Previous CAD, n (%)	7 (14.6)
Previous heart failure, n (%)	8 (16.7)
Chronic kidney disease, n (%)	7 (14.6)
Previous pulmonary disease, n (%)	10 (20.8)
Family history of early CAD, n (%)	6 (12.5)
Total, n (%)	48 (100)

CAD: coronary artery disease

Most of the cases (75%) manifested with chest pain on presentation, mainly chest pain with anginal characteristics - 47.9% of the study population ( Table 2 ). Regarding the triggering factor, there is a preponderance of physical causes (such as bronchospasm, neoplasia under treatment, surgeries and other concomitant diseases), corresponding to 47.9% of individuals included in the registry.

Table 2

Clinical manifestations
Chest pain, n (%) Atypical pain Typical pain	36 (75) 23 (47.9) 13 (27.1)
Dyspnea, n (%)	10 (20.8)
Syncope, n (%)	2 (4.2)
Triggering factors, n (%) Physical triggers Psychological triggers Not reported	23 (47.9) 15 (31.3) 10 (20.8)
Heart rate, Mean ± SD	82.16±17.7
Systolic blood pressure, median (IQR)	121.5 (110-139.2)
Complementary tests
Electrocardiographic changes, n (%) ST-elevation Anterior wall Lateral wall Inferior wall ST-depression T-wave inversion Nonspecific changes Normal	18 (37.5) 13 (27.1) 9 (18.8) 4 (8.3) 4 (8.3) 23 (47.9) 5 (10.4) 1 (2.1)
Cineangiography during the event, n (%) Coronary obstructive lesion ≥ 50%	44 (91.7) 13 (27)
Type of Takotsubo cardiomyopathy, n (%) Apical Mid-ventricular Basal Focal	42 (87.5) 2 (4.2) 0 4 (8.3)
Echocardiography during the event, n (%) LVEF (%), mean ± SD Left atrial diameter (mm), mean ± SD LV diastolic diameter (mm), mean ± SD Left ventricular systolic diameter (mm), mean ± SD Pericardial effusion, n (%) Moderate/severe mitral insufficiency, n (%) LV outflow tract obstruction, n (%)	41 (85.4) 42.73±9.3 37.5±5.2 47.4±4.3 32.1±4.8 4 (8.3) 5 (10.4) 5 (10.4)
Cardiac nuclear magnetic resonance, n (%)	18 (37.5)
Involvement of the right ventricle at Echo or NMRi, n (%)	2 (4.2)
LV thrombus on Echo or NMRi, n (%)	0
High-sensitivity troponin I* (ng/mL), Median (IQR) Baseline Peak	3.41 (1.90-5.78) 5.38 (3.45-17.44)
CK-MB Mass† (ng/mL), Median (IQR) Baseline Peak	11.3 (6.03-20.05) 16.6 (12.6-26.85)
BNP‡ (pg/mL), Median (IQR)	1788 (501.5-2478.5)
Creatinine (mg/dL), Median (IQR) Baseline Peak	0.98 (0.77-1.37) 1.27 (0.89-2.26)

Reference values: *Troponin I ≤ 0.04 ng/mL / †CK-MB Mass ≤ 4.4 ng/mL / ‡BNP < 100 pg/mL. BNP levels were available for 13 (27%) of the 48 patients included in the study. BNP: brain natriuretic peptide; CKMB: creatine phosphokinase-MB; SD: standard deviation; LVEF: left ventricular ejection fraction; Echo: echocardiogram; IQR: interquartile range; NMRi: nuclear magnetic resonance imaging; LV: left ventricular

Regarding complementary tests ( Table 2 ), what draws attention is that almost all patients (97.9%) had electrocardiographic changes, mainly T-wave inversion (47.9% of the cases). Cineangiography was available during the TTS event for most patients (91.7%), except for four patients (8.3%) who underwent valve replacement surgery and had undergone the test prior to the surgery, and had no evidence of coronary obstructive lesions. In most of TTS patients, there was involvement of the left ventricular apex (87.5%), which is in agreement with the typical presentation of the disease, where apical dysfunction is predominant.

In addition, 10.4% of patients had left ventricular outflow tract obstruction, which increases the severity of the disease due to the increase in the incidence of hypotension and cardiogenic shock. ^{17 , 18}

The main findings of this study were: (1) the use of the InterTAK diagnostic criteria helped in the establishment of the correct diagnosis of TTC in 47.5% of the 101 patients enrolled in the study; (2) there is a considerable number of TTS patients with concomitant coronary artery disease (CAD); (3) a normalization of ventricular function was detected by echocardiographic follow-up in almost all patients; and (4) there was a high prevalence of clinical events in short-term follow-up.

With respect to diagnosis, the TTS diagnosis was initially considered for 101 patients and, after application of the InterTAK criteria, the diagnosis was confirmed in 48 patients (47.5%). This finding reinforces that a correct diagnosis of STT is not easy and requires a systematic approach to the diagnostic criteria, which have evolved over the years.

Some years ago, little attention was paid to the possibility of a TTS patient having important coronary obstructive disease, which has been corrected by the new criteria proposed ( Figure 1 ). Usually, the association between TTS and CAD is not a cause-effect relationship. Despite the rare cases of TTS patients in whom acute coronary syndrome was the cause of TTS, ^{20 - 22} it is believed that, in most cases, the coronary obstructive lesions found in TTS patients are complementary test findings, since the main population affected by the syndrome (postmenopausal women) is also a group with a significant prevalence of CAD. ²³ In the present study, in line with the complementary tests’ results ( Table 2 ), there was a significant prevalence of patients (27% of the study population) with coronary obstructive lesion ≥50% of vessel lumen diameter. This is in agreement with more recent literature data, showing a prevalence of 10-29% of TTS patients with concomitant obstructive coronary disease ^{8 - 10}

Another important issue is the development of electrocardiographic abonrmalities, circumferential dysfunction of ventricular contraction at transthoracic echocardiography, and clinical signs/symptoms (precordial pain and/or hypotension/circulatory shock) in the immediate post-operative period after cardiac surgery. These are possible manifestations of TTS, probably caused by extracorporeal circulation and surgical trauma. In the present study, these patients represented 10.4% of the cases. For the next diagnostic criteria updates, the inclusion of cardiac surgery as trigger for TTS should be considered.

The transient character of left ventricular dysfunction in TTS patients has been consolidated in previous studies and is one of the disease characteristics included in the diagnostic criteria for TTS. ^{1 , 6 , 24 - 26} This feature was corroborated by our findings of the analysis of ventricular function ( Figure 3 B), which supports the correct diagnosis of TTS in our study group.

Regarding morbidity and mortality of TTS, the mortality rate in previous series was lower – in-hospital mortality of 1-2%, ^{27 - 28} – which generated an erroneous idea of the benign character of the disease. More recent studies, including a greater number of patients and longer follow-up, have shown much higher mortality rates (in-hospital mortality 4-5%), compatible with the mortality rate of acute coronary syndrome treated according to current recommendations. ^{8 , 29 - 32}

The largest registry of TTS available, including 1,750 patients, reported an in-hospital mortality rate of 4.1% and overall mortality of up to 5.6% per patient/year and MACE of 9.9% during follow-up. ⁸ Similar mortality and MACE rates were found in our study, reinforcing the severity of the disease.

Another finding that deserves attention is the fact that the events occurred within three months after the diagnosis of TTS. Since ventricular dysfunction is potentially reversible in TTS, we may infer that morbidity and mortality of the disease are concentrated in the first months after the event and, if survives the acute phase, with LVEF recovery, the patient will have an excellent prognosis. However, studies with a larger number of patients and longer follow-up have shown that TTS morbidity and mortality are not limited to the first months after diagnosis, and that MACE may occur for years following the first event, at a rate higher than in general population and similar to CAD patients. ^{8 , 29 , 33} The different results obtained in our study may be due to the relatively small number of patients (n=48) and shorter follow-up, of approximately one year.

The reasons why patients with diagnosis of TTS have higher morbidity and mortality compared with the general population and similar to CAD patients, even in acute phase, are not fully understood. First, it was thought that the fact that some of TTS patients also have CAD could have caused this bias. This was explored by Tornvall et al., ²⁹ who compared a group of patients with TTS and without CAD with further two groups: (a) controls without CAD and TTS; and (b) patients with CAD without TTS. The results were similar to those previously obtained – mortality rate in TTS patients was higher than in controls and similar to the CAD group. Thus, the hypothesis that the concomitance of CAD and TTS would cause higher morbidity and mortality (as compared to healthy controls) became less likely.

Another hypothesis for the high mortality rates after acute phase in TTS patents was based on a population-based study that reported that TTS patients have more comorbidities than patients with previous CAD, including higher rates of past history of stroke/transient ischemic attack, drug abuse, psychiatric disorder, oncologic disease, chronic liver disease and sepsis. ³⁴ Therefore, TTS may be seen as a disorder that often affects already ill patients, with higher morbidity and mortality than the general population.

The treatment of TTS is controversial, and based on clinical experience and experts consensus (level of evidence C), since there are no prospective, randomized clinical trials evaluating therapeutic approaches of these patients. ¹⁹ Figure 5 summarizes the main recommendations for treatment of the TTS today. In the present registry, most patients received heart failure medications during hospitalization and after discharge, including beta-blockers (58.3%) and angiotensin converting enzyme inhibitors (62.5%).

Figure 5

One of the key issues in TTS treatment is to determine the presence or absence of left ventricular outflow tract obstruction. The presence of this condition changes the therapeutic approach, including the possibility of using short-acting beta-blockers in patients with cardiogenic shock. ^{19 , 35} The detection of left ventricular outflow tract obstruction is usually made by echocardiography or hemodynamic measures during cardiac catheterization.

The present study evidenced the high morbidity and mortality of TTS, diagnosed according to the new InterTAK criteria, in a tertiary center in Brazil, especially during hospitalization and within 90 days after the diagnosis. Based on these findings, further research is urgently needed, mainly to establish the most appropriate therapy for this population.