Abstract
Background
Takotsubo syndrome (TTS) is considered as a transient acute heart failure syndrome predominant in females. However, data on Chinese TTS patients are limited. Therefore, this study aimed to investigate the clinical characteristics of Chinese TTS patients, identify prognostic markers.
Methods
A total of 258 TTS patients were enrolled. Data on clinical characteristics and in-hospital major adverse cardiovascular events (MACE) were collected and analyzed. The latter included severe heart failure, shock, malignant arrhythmia, and death.
Results
The average age of TTS patients was 59.3 ± 19.2 years. Female patients accounted for 68.9%. MACE occurred in 41.4% of patients during hospitalization. Compared with males, female TTS patients were older, had more emotional causes, higher proportion of typical apical ballooning type, higher LVEF, more prolonged QTc, as well as lower early repolarization (ER) and MACE ratio (35.6% vs. 53.8%, P = 0.006). Compared to female patients with emotional triggers, those female patients with physical triggers are younger, have a lower proportion of chest pain and abnormal ECG, but are more prone to experiencing MACE. Physical triggers, CKMB, LVEF, non-apical ballooning, ER pattern and premature ventricular beats were independent predictors of in-hospital MACE, whereas age, physical triggers and platelet count were specifically independent predictors for female TTS cases.
Conclusions
Chinese TTS patients demonstrate unique clinical characteristics and in-hospital outcomes. Apart from the well-known fact that male with TTS has high-risk phenotype, our study newly identifies that TTS females with younger age or physical triggers also have worse prognosis, which warrants close attention and follow-up.
Supplementary Information
The online version contains supplementary material available at 10.1186/s12872-025-04788-4.
Keywords: Takotsubo syndrome, Women, Heart failure, Arrhythmia, Triggers, Prognosis
Introduction
Takotsubo syndrome (TTS) is considered a transient acute heart failure syndrome and has been observed in real-world clinical practice for a considerable time [1]. However, the term "Takotsubo syndrome" was coined only three decades ago. In 1990, Sato reported a series of patients who presented with symptoms resembling acute coronary syndrome (ACS) but had normal coronary angiography findings. The characteristic feature of TTS is the resemblance of the heart's shape to an octopus trap during the contracting phase, with hyperactive ventricular base and a hypokinetic apex. Epidemiological studies have revealed a significantly higher incidence of TTS in females compared to males, particularly among middle-aged and elderly women. TTS has been reported worldwide, and it has gained significant attention due to its close resemblance to clinical features of ACS and its distinctive female predominance [1].
The clinical characteristics of TTS patients exhibited regional specificity. For example, there appear to be variations in the clinical characteristics of TTS patients between Western and Asian countries, such as Japan, Korea, and Singapore [2–5]. These differences mainly involve sex ratios, triggers (emotional and physical), and patient outcomes. However, as the country with the largest population in Asia, there is limited available data on the natural course of TTS in China. Therefore, the purpose of this study is to investigate the clinical characteristics of Chinese TTS patients, identify prognostic factors, and provide a comprehensive description of the disease features and outcomes, particularly in female patients.
Methods
Study design and population
This study utilized data from China, enrolling hospitalized patients diagnosed with TTS. The inclusion criteria were based on the International Takotsubo Diagnostic Criteria [1], which encompassed the following: 1) temporary left ventricular regional wall motion dysfunction, characterized by apical ballooning or abnormalities in midventricular, basal, or focal wall motion, exceeding that expected from a single coronary artery supply, can also extend to involve the right ventricle; 2) presence of emotional or physical triggers prior to symptom onset, although not mandatory; 3)Neurologic disorders (e.g. stroke/transient ischaemic attack, seizures, or subarachnoid haemorrhage) and pheochromocytoma may serve as triggers for TTS; 4) presence of new and reversible electrocardiogram (ECG) abnormalities, such as ST-segment elevation, ST-segment depression, T-wave inversion, and QTc prolongation. Some patients may exhibit no abnormalities; 5) elevated levels of cardiac biomarkers, including cardiac troponins, brain natriuretic peptide (BNP), and N-terminal pro-brain natriuretic peptide (NTpro-BNP); 6) the presence of coronary artery stenosis is allowed, but coronary artery disease cannot be sufficient to justify regional wall motion abnormalities and short-term cardiac function recovery; 7) recovery or improvement of ventricular function and cardiac biomarkers during hospitalization, excluding deceased patients; 8) exclusion of infectious myocarditis. For patients who did not undergo coronary angiography, the cases were confirmed through comprehensive clinical evaluation, which included a detailed review of their medical history and specific triggers, the identification of transient wall motion abnormalities on echocardiography extending beyond a single coronary distribution, and serial imaging and ECG examinations during hospitalization that verified the recovery of cardiac function. A total of 258 TTS patients were included in the study. All patients provided informed consent for the use of their records for research purpose. Furthermore, all investigative procedures were conducted in accordance with the principles of the Declaration of Helsinki and the study received approval from the ethics committee of Renmin Hospital of Wuhan University (Ethics Approval Number: WDRY2024-K136, Clinical Trial Number: not applicable).
Data collection
This study gathered comprehensive electronic medical records from January 2013 to June 2023 for all patients who met the inclusion criteria. There were no cases omitted between the first and the last patient. The data collected included admission symptoms and symptoms, as well as triggering factors, past medical history, comorbidities, laboratory tests, results from echocardiography and ECG, cardiac angiography outcomes, and prescribed medication treatments. The laboratory testing methods and units were consistent, except for creatine kinase MB isoenzyme (CKMB), which was reported using the upper limit of the normal range (ULN). All reported clinical and imaging investigations results were obtained from the initial examinations conducted on TTS patients upon admission or during the occurrence of TTS within the hospital setting. Based on the medical records, the study estimated the types of triggering factors, classified the subtypes of TTS, evaluated the elevation of important indicators, and assessed the occurrence of major adverse cardiovascular events (MACE) including severe heart failure (LVEF < 30% or requiring mechanical circulatory support), shock, malignant arrhythmia (ventricular fibrillation, ventricular tachycardia and high grade atrioventricular block), and death. All cases were included in the analysis. However, for the relevant variables, only samples with complete data were analyzed to minimize bias associated with missing data. As for clinical symptoms, when a patient describes a feeling of pressure or discomfort in the chest without a clear sensation of pain, it is usually defined as “chest distress”. On the other hand, “chest pain” is defined as when a patient experiences a definite sensation of pain. ECG parameters were extracted using computer software and subsequently verified manually, and the QTc was calculated using Bazett's formula. Meanwhile, special cases were subjected to detailed analysis and reporting.
Statistical analysis
The differences in general characteristics, laboratory findings, electrocardiography, and imaging examinations in TTS patients were analyzed employing Student’s t-tests for independent samples or Mann–Whitney U tests. Subsequently, the present study examined the differences in various data between male and female patients among the 258 individuals with TTS. Categorical variables were compared using chi-square analysis or Fisher's exact test, depending on the circumstances. Continuous variables were presented as mean ± standard deviation or as median (interquartile range) and were compared via t-tests for independent samples or Mann–Whitney U tests. Finally, logistic regression analysis was performed to investigate the factors associated with sex and MACE. Estimated odds ratios (OR) with 95% confidence intervals (CI) and corresponding p-values were calculated and reported. All data were analyzed using SPSS version 25.0 and GraphPad version 9.0.
Results
General clinical characteristics
In total, 258 Chinese patients with TTS with relatively complete information enrolled in the present study. The mean age was 59.3 ± 19.2 years and women comprised the majority of patients (69.8%, Table 1). Physical triggers were more common than emotional triggers, with 41.4% of patients experiencing MACE during hospitalization. Physical triggers included infections, trauma, thyroid diseases, neurological disorders, and pheochromocytoma, among others. Moreover, elevation of WBC, CRP and cardiac biomarkers such as BNP and NTpro-BNP were observed. Ultrasonography revealed a decreased LVEF (41.5 ± 11.3%) and weakened apical wall motion with enhanced basal contraction. The most common arrhythmias were sinus tachycardia and atrial fibrillation. ECG abnormalities included ST-segment elevation, ST-segment depression, ER pattern, inverted T wave, prolonged QTc interval, and other changes (Fig. 1, Table 2). Then a unique case TTS was discovered in a young male patient after exercise (Fig. 2).
Table 1.
Characteristics of TTS Patients between Female and Male*
| Overall | Female | Male | P value | |
|---|---|---|---|---|
| N = 258 | N = 180 | N = 78 | ||
| Age | ||||
| Age (years) | 59.3 ± 19.2 | 60.9 ± 19.1 | 55.8 ± 19.0 | 0.049 |
| 0 ~ 34 (years) | 32/258 (12.4%) | 16/180 (8.9%) | 16/78 (20.5%) | 0.009 |
| 35 ~ 54 (years) | 64/258 (24.8%) | 42/180 (23.3%) | 22/78 (28.2%) | 0.405 |
| 55 ~ 74 (years) | 105/258 (40.7%) | 79/180 (43.9%) | 26/78 (33.3%) | 0.113 |
| 75 ~ (years) | 57/258 (22.1%) | 43/180 (23.9%) | 14/78 (17.9%) | 0.290 |
| Triggers | ||||
| Emotional | 68/258 (26.3%) | 54/180 (30.0%) | 14/78 (17.9%) | 0.044 |
| Physical | 144/258 (55.8%) | 96/180 (53.3%) | 48/78 (61.5%) | 0.223 |
| Type of TTC | ||||
| Apical ballooning | 215/258 (83.3%) | 161/180 (89.4%) | 54/78 (69.2%) | < 0.001 |
| Midventricular | 19/258 (7.4%) | 4/180 (2.2%) | 15/78 (19.2%) | < 0.001 |
| Biventricular | 17/258 (6.6%) | 10/180 (5.6%) | 7/78 (10.3%) | 0.309 |
| Basal or inverted | 5/258 (1.9%) | 3/180 (1.7%) | 2/78 (2.6%) | 0.867 |
| Focal | 2/258 (0.8%) | 2/180 (1.1%) | 0/78 (0.0%) | 0.35 |
| Clinical presentation | ||||
| Chest distress | 120/258 (46.5%) | 98/180 (54.4%) | 40/78 (51.3%) | 0.640 |
| Chest pain | 100/258 (38.8%) | 78/180 (43.3%) | 22/78 (28.2%) | 0.022 |
| Dyspnea | 32/258 (12.4%) | 28/180 (15.6%) | 4/78 (5.1%) | 0.020 |
| Polypnea | 23/258 (8.9%) | 17/180 (9.4%) | 6/78 (7.7%) | 0.65 |
| Palpitation | 21/258 (8.1%) | 16/180 (8.9%) | 5/78 (6.4%) | 0.504 |
| Nausea and vomiting | 20/258 (7.8%) | 16/180 (8.9%) | 4/78 (5.1%) | 0.300 |
| Hyperhidrosis | 17/258 (6.6%) | 14/180 (7.8%) | 3/78 (3.8%) | 0.242 |
| Cough and sputum | 16/258 (6.2%) | 6/180 (3.3%) | 10/78 (12.8%) | 0.004 |
| Systolic pressure (mmHg) | 118.5 ± 31.1 | 121.0 ± 31.7 | 112.6 ± 28.9 | 0.050 |
| Diastolic pressure (mmHg) | 70.9 ± 18.6 | 71.9 ± 17.3 | 68.5 ± 21.2 | 0.174 |
| Previous history and complications | ||||
| Hypertension | 88/258 (34.1%) | 68/180 (37.8%) | 20/78 (25.6%) | 0.059 |
| Cardiopathy | 34/258 (13.2%) | 22/180 (12.2%) | 12/78 (15.4%) | 0.490 |
| Diabetes mellitus | 33/258 (12.8%) | 20/180 (11.1%) | 13/78 (16.7%) | 0.220 |
|
Pneumonia (including COVID19) |
24/258 (9.3%) | 6/180 (3.3%) | 18/78 (23.1%) | < 0.001 |
| Other infectious diseases | 18/258 (7.0%) | 12/180 (6.7%) | 6/78 (7.7%) | 0.766 |
| Liver and renal diseases | 20/258 (7.8%) | 10/180 (5.6%) | 10/78 (12.8%) | 0.045 |
| Thyroid disorder | 20/258 (7.8%) | 15/180 (8.3%) | 5/78 (6.4%) | 0.596 |
| Neural system diseases | 20/258 (7.8%) | 12/180 (6.7%) | 8/78 (10.3%) | 0.322 |
| Mental disorder | 14/258 (5.4%) | 8/180 (4.4%) | 6/78 (7.7%) | 0.290 |
| Arrhythmia | 15/258 (5.8%) | 11/180 (6.1%) | 4/78 (5.1%) | 0.096 |
| Post cardiac surgeries | 12/258 (4.7%) | 2/180 (1.1%) | 10/78 (12.8%) | < 0.001 |
| Anemia | 12/258 (4.7%) | 4/180 (2.2%) | 8/78 (10.3%) | 0.005 |
| Therapy | ||||
| DAPT | 94/212 (44.3%) | 70/148 (47.3%) | 24/64 (37.5%) | 0.187 |
| β blocker | 85/212 (40.1%) | 65/148 (43.9%) | 20/64 (31.3%) | 0.084 |
| Diuretics | 74/212 (34.9%) | 52/148 (35.1%) | 22/64 (34.4%) | 0.915 |
| Statins | 63/212 (29.7%) | 51/148 (34.5%) | 12/64 (18.8%) | 0.022 |
| ACEI/ARB | 34/212 (16.0%) | 28/148 (18.9%) | 6/64 (9.4%) | 0.082 |
| NTG | 28/212 (13.2%) | 17/148 (11.5%) | 11/64 (17.2%) | 0.260 |
| Catecholamines | 50/212 (23.6) | 30/148 (30.3%) | 20/64 (31.3%) | 0.094 |
| CCB | 15/212 (7.1%) | 8/148 (5.4%) | 7/64 (10.9%) | 0.149 |
| In-hospital outcome | ||||
| Severe heart failure† | 52/258 (20.2%) | 31/180 (17.2%) | 21/78 (26.9%) | 0.074 |
| Shock | 44/258 (17.1%) | 28/180 (15.6%) | 16/78 (20.5%) | 0.331 |
| Malignant arrhythmia‡ | 24/258 (9.3%) | 12/180 (6.7%) | 12/78 (15.4%) | 0.027 |
| Death | 5/258 (1.9%) | 3/180 (1.7%) | 2/78 (2.6%) | 0.631 |
| MACE | 106/258 (41.1%) | 64/180 (35.6%) | 42/78 (53.8%) | 0.006 |
| MACE (< 55 years) | 46/96 (47.9) | 27/58 (46.6%) | 19/38 (50.0%) | 0.741 |
| MACE (≥ 55 years) | 60/162 (37.0) | 37/122 (30.3%) | 23/40 (57.5%) | 0.002 |
*: values are mean ± SD, or n/N (%)
†: severe heart failure indicated LVEF < 30% or heart failure requiring mechanical circulatory support
‡: malignant arrhythmia included ventricular fibrillation, ventricular tachycardia and high grade atrioventricular block
DAPT dual antiplatelet therapy, ACEI/ARB ACE inhibitor/Angiotensin receptor blocker, NTG nitroglycerin, CCB calcium channel blocker, MACE major adverse cardiac event
Fig. 1.
Representative ECG and ultrasound changes of TTS cases. A-E A 74-year-old female patient developed TTS during pacemaker implantation. A The preoperative ECG showed complete heart block; B The ECG during TTS evidenced extensive ST-segment elevation in anterior leads; C The ECG 8 days after TTS showed T-wave inversion; D Echocardiography during TTS demonstrated apical wall motion abnormalities; E Follow-up echocardiography 8 days later displayed resolved wall motion abnormalities. F–H A 76-year-old female developed TTS secondary to spontaneous pneumothorax. F CT scan indicated pneumothorax; G, H Echocardiography showed apical ballooning and resolution afterwards. I, J ER pattern was presented during TTS respectively from a 49-year-old man with emotional trigger and a 29-year-old man without apparent trigger. Both patients had no prior ECG evidence of the ER pattern. ECG: electrocardiogram; CT: computed tomography; ER: early repolarization
Table 2.
Laboratory test and ECG characteristics of TTS Patients between Female and Male*
| Overall | Female | Male | P value | |
|---|---|---|---|---|
| N = 258 | N = 180 | N = 78 | ||
| Laboratory test | ||||
| White cell (× 10 9) | 11.7 ± 4.8 | 11.6 ± 4.8 | 11.8 ± 5.0 | 0.774 |
| Hemoglobin (g/l) | 115.3 ± 19.8 | 114.4 ± 16.2 | 117.2 ± 26.4 | 0.295 |
| Platelet (× 10 9) | 214.8 ± 75.1 | 217.9 ± 76.7 | 207.7 ± 71.2 | 0.316 |
| CRP (mg/L) | 10.4 (1.7–44.5) | 10.9 (1.5–27.7) | 8.5 (2.1–72.3) | 0.334 |
| BNP (pg/ml) | 1144.6 (485.9–2906.9) | 1006.0 (518.6–3269.0) | 1233.0 (447.4–2636.9) | 0.807 |
| NTpro-BNP (pg/ml) | 6177.0 (1928.0–18853.3) | 5310.5 (2080.0–14116.0) | 8630.0 (558.0–35000.0) | 0.462 |
| CKMB (ULN)† | 1.5 (0.7–2.6) | 1.5 (0.7–2.5) | 1.4 (0.7–3.2) | 0.794 |
| CK (U/L) | 210.5 (108.3–473.0) | 189.0 (110.0–359.0) | 335.0 (93.0–539.5) | 0.149 |
| cTnI (μg/L) | 2.8 (0.6–7.3) | 3.0 (1.1–5.8) | 2.3 (0.4–8.7) | 0.742 |
| Echocardiography | ||||
| LVEF (%) | 41.5 ± 11.3 | 42.5 ± 11.3 | 39.4 ± 11.0 | 0.040 |
| LV end-diastolic volume (ml) | 93.6 ± 17.6 | 91.7 ± 13.8 | 98.0 ± 23.6 | 0.008 |
| LV end-systolic volume (ml) | 54.4 ± 13.5 | 52.0 ± 11.5 | 56.6 ± 16.9 | 0.011 |
| Coronary arterial pathological changes | ||||
| Normal | 96/162 (59.3%) | 68/112 (60.7%) | 28/50 (56.0%) | 0.573 |
| Mild | 42/162 (25.9%) | 34/112 (30.4%) | 8/50 (16.0%) | 0.054 |
| Moderate | 14/162 (8.6%) | 5/112 (4.7%) | 9/50 (18.0%) | 0.005 |
| Severe | 12/162 (7.4%) | 6/122 (5.4) | 6/50 (12.0%) | 0.136 |
| Arrhythmia | ||||
| Sinus tachycardia | 40/258 (15.5%) | 30/180 (16.7%) | 10/78 (12.8%) | 0.433 |
| Atrial fibrillation | 27/258 (10.5%) | 18/180 (10.0%) | 9/78 (11.5%) | 0.711 |
| Atrial flutter | 6/258 (2.3%) | 2/180 (1.1%) | 4/78 (5.1%) | 0.049 |
| Premature atrial beats | 5/258 (1.9%) | 3/180 (1.7%) | 2/78 (2.6%) | 0.631 |
| Supraventricular tachycardia | 7/258 (2.7%) | 2/180 (1.1%) | 5/78 (6.4%) | 0.016 |
| Ventricular tachycardia | 10/258 (3.9%) | 2/180 (1.1%) | 8/78 (10.3%) | < 0.001 |
| Ventricular fibrillation | 12/258 (4.7%) | 8/180 (4.4%) | 4/78 (5.1%) | 0.811 |
| Premature ventricular beats | 17/258 (6.6%) | 9/180 (5.0%) | 8/78 (10.3%) | 0.118 |
| Atrioventricular block | 5/258 (1.9%) | 2/180 (1.1%) | 3/78 (3.8%) | 0.143 |
| ECG | ||||
| ST-segment elevation | 74/258 (28.7%) | 55/180 (30.5%) | 21/78 (26.9%) | 0.556 |
| ST-segment depression | 23/258 (8.9%) | 18/180 (10.0%) | 5/78 (6.4%) | 0.353 |
| Inverted T wave | 56/258 (21.7%) | 52/180 (28.9%) | 12/78 (15.4%) | 0.021 |
| Biphasic T wave | 9/258 (3.5%) | 8/180 (4.4%) | 1/78 (1.3%) | 0.204 |
| Tall peaked T wave | 4/258 (1.6%) | 1/180 (0.6%) | 3/78 (3.8%) | 0.050 |
| Flattened T wave | 10/258 (3.9%) | 10/180 (5.6%) | 0/78 (0.0%) | 0.034 |
| Early repolarization pattern | 61/258 (23.6%) | 32/180 (17.8%) | 29/78 (37.2%) | 0.001 |
| Q-waves | 6/258 (2.3%) | 6/180 (3.3%) | 0/78 (0.0%) | 0.103 |
| Normal ECG | 54/258 (20.9%) | 34/180 (18.9%) | 20/78 (25.6%) | 0.221 |
| HR (bpm) | 94.0 ± 16.8 | 94.2 ± 17.2 | 93.4 ± 15.7 | 0.720 |
| RR interval (ms) | 685.5 ± 117.9 | 686.9 ± 118.8 | 682.4 ± 116.6 | 0.780 |
| PR interval (ms) | 150.4 ± 30.7 | 149.6 ± 32.2 | 152.2 ± 27.0 | 0.530 |
| QRS duration (ms) | 92.1 ± 18.1 | 91.8 ± 13.5 | 93.3 ± 25.1 | 0.535 |
| QT interval (ms) | 382.5 ± 47.8 | 386.6 ± 48.1 | 372.9 ± 45.8 | 0.034 |
| QTc interval (ms) | 462.4 ± 39.7 | 466.8 ± 33.6 | 452.5 ± 50.0 | 0.008 |
*: values are mean ± SD, or median (interquartile range), or n/N (%)
†: the content data represents the multiple of the upper limit of the normal range
CRP C reactive protein, LVEF left ventricular ejection fraction, BNP B-type natriuretic peptide, NTpro-BNP N-terminal pro b-type natriuretic peptide, CK creatine kinase, CKMB creatine kinase MB isoenzyme, cTnI cardiac troponin I
Fig. 2.
The clinical characteristics of a unique TTS case after exercise. A unique case of TTS was discovered in a young male patient after exercise. Two hours after exercise, ventricular fibrillation and loss of consciousness occurred, and the patient was transferred to a hospital. On admission, the ECG showed widespread ST segment elevation in the anterior wall, and echocardiography revealed abnormal wall motion in the anterior and septal walls with reduced cardiac function. Laboratory tests and ECG were reported, and PET/CT imaging showed reduced perfusion in the apex. On the third day, follow-up echocardiography showed improved cardiac function (LVEF: 54%) with no apparent wall motion abnormalities. On the seventh day, cardiac MRI showed no other abnormalities except a small amount of pleural effusion, and the patient was discharged after a two-week hospital stay. A-C Temporal profiles of cTnI, CKMB, NT-proBNP, CRP, and WBC during hospitalization. D The ECG during acute presentation indicated diffuse ST-segment elevation in anterior leads and QT prolongation. E The ECG on day 3 showed partial ST-segment elevation and T-wave inversion. F PET/CT imaging displayed reduced perfusion in the left ventricular apex. cTnI: cardiac troponin I; CKMB: creatine kinase-M; NT-proBNP: N-terminal pro-B-type natriuretic peptide; CRP: C-reactive protein; WB: white blood cell count; PET/CT: positron emission tomography/computed tomography
Sex-related analysis
Women comprised the majority of patients, while there were fewer younger individuals compared to men (0 ~ 34 years: 8.9% vs. 20.5%, p = 0.009; Table 1). The apical ballooning type was observed in 83.3% of patients, while the midventricular, biventricular, basal or inverted, focal types accounted for 7.4%, 6.6%, 1.9%, and 0.8% respectively. Female patients had a higher prevalence of the apical ballooning type and a lower prevalence of the midventricular type. Emotional and physical triggers were reported by 26.3% and 55.8% of patients, respectively, with a higher proportion of female patients reporting emotional triggers (30.0% vs.17.9%, p = 0.044). Interestingly, among younger patients, women experienced more incidences triggered by physical factors and fewer incidences triggered by emotional factors compared to men (Table S1). Chest distress and chest pain were the main presenting symptoms among TTS patients. Compared to male patients, female patients had a higher incidence of chest pain (43.3% vs. 28.2%, p = 0.022) and dyspnea (15.6% vs. 5.1%, p = 0.020) symptoms, as well as higher systolic blood pressure, but a lower incidence of cough and sputum production. Analysis of past medical history and comorbidities revealed that apart from the common conditions of hypertension (34.1%) and diabetes (12.8%), cardiopathy (13.2%) and pneumonia (9.3%, including COVID- 19, Coronavirus Disease 2019) were the major associated diseases in TTS patients. Female patients had a lower proportion of comorbidities, such as pneumonia, post-cardiac surgery, liver and kidney diseases, and anemia. Female patients exhibited a more pronounced elevation of cTnT (IQR, 0.2–1.1 μg/L vs. 0.05–0.5 μg/L, p = 0.002, Table 2). Cardiac ultrasound revealed that female patients had a higher LVEF (42.5 ± 11.1% vs. 39.4 ± 11.0%, p = 0.040), while demonstrating lower LVEDV and LVESV. However, in the younger population, women have lower LVEF compared to men (37.9 ± 11.8 vs. 47.1 ± 11.4, p = 0.032, Table S1). Among the 162 patients who underwent coronary angiography, most TTS patients (92.6%) showed either no abnormalities or mild-to-moderate coronary stenosis, with a lower proportion of female patients presenting with moderate coronary stenosis (4.7% vs. 18.0%, p = 0.005). The primary therapeutic interventions consist of dual antiplatelet therapy, β blockers, diuretics, and statins. Furthermore, there is a greater utilization of statins among female patients in comparison to males (35.1% vs. 34.4%, p = 0.022).
Analysis of ECG revealed abnormalities in 89.9% (232/258) of patients upon admission, with the main findings being sinus tachycardia (15.5%), atrial fibrillation (10.5%), and ST-segment elevation (28.7%), ST-segment depression (8.9%) and inverted T wave (21.7%, Table 2). In contrast to male patients, female patients had a lower proportion of atrial flutter, supraventricular tachycardia, ventricular tachycardia and ER pattern, while exhibiting a higher proportion of inverted T wave (28.9% vs. 15.4%, p = 0.021) and flattened T wave (5.6% vs. 0.0%, p = 0.034), along with longer QT (386.6 ± 48.1 ms vs. 372.9 ± 45.8 ms, p = 0.034) and QTc intervals (466.8 ± 33.6 ms vs. 452.5 ± 50.0 ms, p = 0.008). In the multivariate logistic analysis, age (per 5 years increase, OR: 1.134, p = 0.015), symptoms of dyspnea (OR: 12.100, P = 0.008), pneumonia (OR: 0.155, p = 0.017), NTpro-BNP (per 100 pg/ml increase, OR: 0.996, p = 0.036), CK (per 100 U/L increase, OR: 0.868, p = 0.023), apical ballooning type (OR: 2.491, p = 0.042), ventricular tachycardia (OR: 0.071, p = 0.005) and Inverted T wave (OR: 2.543, p = 0.042) remained independently associated with sex (Fig. 3).
Fig. 3.
Multivariable analysis for factors associated with sex differences among TTS patients. CRP: C-reactive protein; NT-proBNP: N-terminal pro-B-type natriuretic peptide; CK: creatine kinase; LVEF: left ventricular ejection fraction
Features of physical triggers in female TTS cases
Female TTS patients with physical triggers had a higher proportion of younger individuals less than 55 years (0 ~ 34 years, 12.5% vs. 0.0%, p = 0.007; 35 ~ 54 years, 29.2% vs.7.4%, p = 0.002), but a lower percentage in senior individuals older than that age (55 ~ 74 years: 30.2% vs. 72.2%, p < 0.001; Table 3). They also had fewer chest pain symptoms (29.2% vs. 72.2%, p < 0.001) and a lower prevalence of thyroid disease (4.2% vs. 14.8%, p = 0.021). During the episodes, these patients had lower diastolic blood pressure. Laboratory tests and cardiac ultrasound revealed higher levels of WBC (13.0 ± 5.6 × 109 vs 10.7 ± 3.1 × 109, p = 0.006), NTpro-BNP and cTnT, as well as lower hemoglobin content (110.9 ± 17.8 g/l vs 124.5 ± 13.9 g/l, p < 0.001) and LVEF (40.5 ± 11.1% vs. 45.4 ± 10.8%, p = 0.009). It was worth noting that ECG results indicated that female TTS patients with physical triggers exhibited a higher proportion of sinus tachycardia (24.0% vs. 7.4%, p = 0.001) and shorter RR and QT intervals. Additionally, they demonstrated a lower proportion of ST-segment elevation (19.8% vs. 42.6%, p = 0.003) and a higher proportion of individuals with a normal ECG (24.0% vs. 5.6%, p = 0.004). Moreover, the analysis of patient prognosis showed that among females, those with TTS triggered by physical triggers had a higher incidence of MACE (41.7% vs. 14.8%, p = 0.001).
Table 3.
Differences of TTS Patients in Female with Emotional and Physical Triggers*
| Physical | Emotional | P value | |
|---|---|---|---|
| N = 96 | N = 54 | ||
| 0 ~ 34 (years) | 12/96 (12.5%) | 0/54 (0.0%) | 0.007 |
| 35 ~ 54 (years) | 28/96 (29.2%) | 4/54 (7.4%) | 0.002 |
| 55 ~ 74 (years) | 29/96 (30.2%) | 40/54 (74.1%) | < 0.001 |
| Chest pain | 28/96 (29.2%) | 39/54 (72.2%) | < 0.001 |
| Thyroid disorder | 4/96 (4.2%) | 8/54 (14.8%) | 0.021 |
| Diastolic pressure (mmHg) | 69.6 ± 17.7 | 76.2 ± 14.8 | 0.022 |
| LVEF (%) | 40.5 ± 11.1 | 45.4 ± 10.8 | 0.009 |
| white cell (× 10 9) | 13.0 ± 5.6 | 10.7 ± 3.1 | 0.006 |
| hemoglobin (g/l) | 110.9 ± 17.8 | 124.5 ± 13.9 | < 0.001 |
| NTpro-BNP (pg/ml) | 10,600.0 (2,085.0–24,319.0) | 2,710.0 (2,222.0–13,100.0) | 0.041 |
| Sinus tachycardia | 23/96 (24.0%) | 4/54 (7.4%) | 0.001 |
| ST-segment elevation | 19/96 (19.8%) | 23/54 (42.6%) | 0.003 |
| Normal ECG | 23/96 (24.0%) | 3/54 (5.6%) | 0.004 |
| RR interval (ms) | 665.9 ± 120.5 | 702.7 ± 54.9 | 0.036 |
| QT interval (ms) | 391.6 ± 46.6 | 405.9 ± 33.8 | 0.049 |
| MACE | 40/96 (41.7%) | 8/54 (14.8%) | 0.001 |
*: values are mean ± SD, or median (interquartile range), or n/N (%)
LVEF left ventricular ejection fraction, cTnI cardiac troponin I, MACE major adverse cardiac event
Clinical prognosis prediction
Among total TTS patients, 41.1% experienced MACE during hospitalization, with a lower probability of MACE occurrence among female patients (35.6% vs. 53.8%, p = 0.006; Table 1). It was found that the occurrence of MACE in female TTS patients had no significant difference compared to males before the age of 55 (46.6% vs. 50.0%, p = 0.741), but was significantly lower after 55 (30.3% vs. 57.5%, p = 0.002). A multivariable logistic regression analysis in the overall population demonstrated that, physical triggers (OR: 2.526, p = 0.025; Table 4), CKMB levels (per 1 ULN increase, OR: 1.130, p = 0.013), LVEF (per 5% increase, OR: 0.833, p = 0.013), non-apical ballooning type (OR: 4.032, p = 0.001), ER pattern (OR: 2.074, p = 0.042) and premature ventricular beats (OR: 7.606, p = 0.001) were identified as independent predictors of in-hospital MACE. Within the female population, age (per 5 years increase, OR: 0.886, p = 0.016), physical triggers (OR: 2.872, p = 0.033), and platelet count (per 10 × 109 increase, OR: 0.932, p = 0.027) were found to be independent predictors of in-hospital MACE.
Table 4.
Logistic Regression Analysis for Factors Associated with MACE in All and Female TTS patients*
| Univariable | Multivariable | |||
|---|---|---|---|---|
| OR (95% CI) | P Value | OR (95% CI) | P Value | |
| Overall | ||||
| Male | 2.338 (1.351 − 4.048) | 0.002 | 1.199 (0.591 − 2.435) | 0.615 |
| Physical triggers | 4.000 (1.925 − 8.313) | < 0.001 | 2.526 (1.124 − 5.677) | 0.025 |
| Pneumonia | 2.911 (1.236 − 6.853) | 0.014 | 0.723 (0.248 − 5.103) | 0.551 |
|
NTpro-BNP (per 100 pg/ml increase) |
1.002 (1.000 − 1.005) | 0.042 | 1.002 (1.000 − 1.004) | 0.107 |
|
CKMB (per 1 ULN increase) |
1.139 (1.031 − 1.260) | 0.010 | 1.130 (1.026 − 1.246) | 0.013 |
|
LVEF (per 5% increase) |
0.806 (0.714 − 0.911) | 0.001 | 0.833 (0.721 − 0.963) | 0.013 |
| Non-Apical ballooning type | 2.146 (1.112–4.149) | 0.023 | 4.032 (1.799 − 9.090) | 0.001 |
| Early repolarization pattern | 2.495 (1.173–4.532) | 0.003 | 2.074 (1.025 − 4.195) | 0.042 |
| Premature ventricular beats | 3.375 (1.185 − 9.615) | 0.023 | 7.606 (2.224 − 26.015) | 0.001 |
| Female | ||||
|
Age (per 5 years increase) |
0.880 (0.807 − 0.960) | 0.004 | 0.886 (0.803 − 0.997) | 0.016 |
| Physical triggers | 7.200 (2.443 − 21.222) | < 0.001 | 2.872 (1.086 − 7.593) | 0.033 |
|
Platelet (per 10 × 109 increase) |
0.932 (0.886 − 0.990) | 0.030 | 0.932 (0.876 − 0.992) | 0.027 |
|
Early repolarization pattern |
2.582 (1.150 − 5.799) | 0.022 | 1.912 (0.742 − 4.920) | 0.180 |
*: values are odds ratios (OR) with 95% confidence intervals (CI)
LVEF left ventricular ejection fraction, NTpro-BNP N-terminal pro b-type natriuretic peptide, CKMB creatine kinase MB isoenzyme
Discussion
To our knowledge, this study is one of the largest retrospective observational studies of Chinese TTS patients to date (Fig. 4). The study found that TTS patients, predominantly women (68.9%), have an average age of 59.3 ± 19.2 years and are more often triggered by physical rather than emotional factors, with 41.4% experiencing MACE during hospitalization. Female patients tend to be older, have more respiratory distress symptoms, but fewer complications, and show better heart failure and myocardial injury indicators compared to male patients. Compared to females with emotional triggers, females with physical triggers are younger, have a lower proportion of chest pain and abnormal ECG, but are more prone to MACE. Young age and physical triggers are identified as risk factors for in-hospital MACE in female TTS patients. These findings emphasize the importance of considering sex, age, triggers, and associated complications in managing and predicting the prognosis of TTS patients.
Fig. 4.
Central Illustration. Sex-related clinical characteristics and in-hospital MACE in TTS patients. Based on the International Takotsubo Diagnostic Criteria, TTS patients were identified from the hospital database, consisting of 180 females and 78 males. The patients were categorized according to sex and the occurrence of in-hospital MACE, revealing significant differences in age distribution and triggering factors. Subsequently, multivariate logistic regression analysis was performed to identify independent predictors for in-hospital MACE in the entire TTS patient cohort as well as in the female subgroup; NTpro-BNP, CKMB, LVEF, age and platelet are represented as per 100 pg/ml increase, per 1 ULN increase, per 5% increase, per 5 years increase and per 10 × 109 increase. InterTAK: International Takotsubo; MACE: major adverse cardiovascular events; NT-proBNP: N-terminal pro-B-type natriuretic peptide; CKMB: creatine kinase-M; LVEF: left ventricular ejection fraction; ER: early repolarization; PVB: premature ventricular beats
The clinical characteristics of TTS patients have been summarized. Observed elevated WBC and CRP suggested that inflammation may play an important role in the pathogenesis of TTS [6]. The unique case we presented serves as a compelling illustration of this point. Inflammation markers may be associated with the occurrence and prognosis of TTS. The decline in inflammation markers coincided with the recovery of cardiac function and electrocardiographic changes (Fig. 2). Coronary blood flow and myocardial edema may play a significant role in the pathophysiology of TTS [7]. In addition, recent animal experiments suggest that during acute stress, there may be localized abnormalities in myocardial perfusion and potassium ion balance, which could contribute to the occurrence of TTS. In addition, improvement of coronary microcirculation reversed some alterations associated with TTS [8]. These findings may be associated with elevated myocardial injury markers and alterations in ECG observed in TTS patients.
Chinese TTS patients seemingly tend to be younger and have a lower proportion of females, with a higher prevalence of physical triggers, compared with European and American TTS patients (Table 1). Our collaborators recently obtained similar results in the first TTS registry conducted in China [9]. In our study, Chinese TTS patients had an average age of 59.3 years, numerically lower than the results of large studies published in various regions [3, 10, 11]. The female to male ratio of Chinese TTS patients was about 7:3 (69.8%), lower than the nearly 9:1 ratio in Europe and the United States, similar to Asian data (76.6–81.5% in Japan, 82% in Singapore, 69–73.6% in South Korea) [3–5, 10–13]. Interestingly, Templin et al. compared TTS patients in Japan and European countries, the largest study to analyze regional differences in TTS so far. This study showed that Japanese TTS patients had a higher male ratio, more physical triggers, and less emotional triggers [3]. Overall, we believe that the characteristics of Chinese TTS patients differ from those of European and American patients, and are more similar to those of Japanese and other Asian patients.
Previous studies have shown that sex and triggering factors significantly influence the onset and prognosis of TTS patients [10, 14–16]. Female patients have fewer complications and lower levels of heart failure and myocardial injury markers (Table 1, Table 2 and Fig. 3). Previous research suggested that this may be related to the relatively better prognosis of female patients compared to male patients [2, 14, 17–20]. Male patients had a high proportion of pneumonia and ER pattern, relative to female patients. Liu et al. analyzed TTS cases reported during the COVID- 19 pandemic and found there were more male patients were triggered by physical triggers, specifically COVID- 19 pneumonia and a correlation between pneumonia and higher in-hospital mortality rates [21]. TTS patients with adverse rhythm are linked to higher short- and long-term mortality [22]. Notably, ER pattern, especially highly presented in males, is strongly associated with cardiac sudden death and malignant ventricular arrhythmias [23, 24]. In contrast, it has been reported that during the acute phase, women experience a lower frequency of cardiac arrest, which may be related to the lower prevalence of the ER pattern in females [20]. It was found that a higher prevalence of the ER pattern is linked to in-hospital MACE. We have identified key genes related to early repolarization syndrome (SCN5 A, SCN10 A, CACNA1 C and CACNB2b, etc.) [25–28]. Although no data currently exist, it is speculated that some TTS patients may carry ER-associated variants, increasing the risk of sudden fatality. Moreover, female TTS patients triggered by physical factors have less pronounced symptoms and ECG changes, but experience a higher rate of severe outcomes compared to those triggered by emotional factors, warranting heightened clinical attention. (Table 3).
Previous studies in other regions have demonstrated a distinct high-risk phenotype in male TTS patients [2, 14, 17, 18]. However, in individuals under 55 years of age, the incidence of MACE in women increases and reaches a level comparable to that of men (Table 1). Considering that clinical and laboratory data indicate the protective effects of estrogen on the stressed heart, we believe that estrogen in premenopausal women may protect them from TTS [29–32]. This also explains why the age distribution of female patients is uneven, with a concentration after the age of 55 or post menopause, unlike male patients. The protective effects of estrogen against emotional triggers may be highly effective, since only a very small number of women under 55 experience TTS triggered by emotional factors. However, when this defense is breached by physical triggers, which often involve higher levels of adrenaline, these female patients experience more severe impacts [16]. In summary, our analysis leads us to propose that the estrogen protection hypothesis may explain the observed variances in sex, age, and triggering factors affecting the incidence and prognosis of TTS among Chinese patients. It has been reported that other hormones also regulate the outcomes of TTS patients, such as thyroid hormone signatures. Thyroid-derived biomarkers, such as low TSH and FT3 concentrations, high FT4 concentrations, low deiodinase activity and high median thyroid’s secretory capacity are associated with higher long-term mortality and help identify high-risk patients [33].
Study limitations
However, there are several limitations to our study. In this study, we solely observed the occurrence of MACE during the hospitalization period of TTS patients, without conducting long-term follow-up. While concluding that younger female patients are associated with poorer in-hospital prognosis, we also agree that advanced age is one of the risk factors for long-term prognosis in TTS patients. These two observations are not contradictory. Creatinine levels and renal dysfunction may be associated with poor outcomes in TTS patients. Although we reported sex differences among TTS patients with concurrent hepatic and renal diseases, we did not collect data on creatinine levels or glomerular filtration rate [34, 35]. Another limitation is that coronary angiography was performed in only 162 of 258 patients, which may have affected the accuracy of the assessment of coronary artery status. In the future, we plan to establish a larger and more comprehensive TTS database with our collaborators. This will involve clinical registration to further validate our hypotheses and develop a TTS diagnostic scoring system and risk stratification tailored to the Asian population.
Conclusions
In summary, the Chinese TTS patient population exhibits distinct characteristics, including a young age distribution, low proportion of females, high rates of physical triggers. Furthermore, there is significant heterogeneity in the onset and prognosis of TTS patients based on sex, age, and triggering factors, which will be an important consideration for future risk stratification or prognostic scoring in TTS. Apart from the well-known fact that male TTS has a high-risk phenotype, female TTS patients with younger age or physical triggers also have a worse prognosis. Particularly in female patients with physical triggers, ECG manifestations and symptoms may be subtle, yet there is an elevated incidence of MACE, which warrants close management and follow-up.
Supplementary Information
Acknowledgements
We appreciate the technical support from Bo Chen at Renmin Hospital of Wuhan University.
Abbreviations
- TTS
Takotsubo syndrome
- ER
Early repolarization
- ACS
Acute coronary syndrome
- CRP
C reactive protein
- LVEF
Left ventricular ejection fraction
- NTpro-BNP
N-terminal pro b-type natriuretic peptide
- CKMB
Creatine kinase MB isoenzyme
- cTnI
Cardiac troponin I
- DAPT
Dual antiplatelet therapy
- MACE
Major adverse cardiac event
Authors’ contributions
Author Contributions: Dan.H. designed the study. HY.D., LL.W., K.L., C.A., and H.J. performed reference search. HY.D, LL.W., K.L., Dan.H. and H.B.M. coordinated the clinical evaluations. Dan.H. supervised and coordinated the study work. HY.D., LL.W., LC.L., ZH.S., XP.L., ZY.Y., XH.Y., CW.X., and Dan.H. organized and summarized the data. HY.D., GH.F., W.D., Y.H., Q.Z., JL.C., HN.S., JQ.L., J.C., H.J., C.A., H.B.M. and Dong.H. analyzed the data. HY.D. and Dan.H. made the figures and tables. HY.D., LL.W. and Dan.H. wrote the manuscript, and all authors have read the manuscript and agreed with the results presented herein.
Funding
This work was supported by Grants from National Key R&D Program of China (grant no. 2023YFE0118300); National Natural Science Foundation Project of China (grant nos. 82270332, 81670304 and 82370286); Fundamental Research Funds for the Central Universities of China (grant no. 2042022kf1217); National Institutes of Health of USA, NIH R56 (grant no. HL47678); National Institutes of Health of USA, NIH R01 (grant nos. HL138103 and HL152201); Woman Board Foundation Grant from Main Line Health, USA (grant no. 25401); W.W. Smith Charitable Trust (grant no. 06417–5222); and the Wistar and Martha Morris Funds and Sharpe-Strumia Research Foundation (grant no. 06417–5221/5524), USA.
Data availability
Data is provided within the manuscript or supplementary information files.
Declarations
Ethics approval and consent to participate
All investigative procedures were conducted in accordance with the principles of the Declaration of Helsinki and the study received approval from the ethics committee of Renmin Hospital of Wuhan University (Ethics Approval No: WDRY2024-K136).
Consent for publication
All patients provided informed consent for the use of their records for research purpose.
Competing interests
The authors declare no competing interests.
Footnotes
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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Data Availability Statement
Data is provided within the manuscript or supplementary information files.