Clinical characteristics and risk factors of in-hospital mortality in patients with Takotsubo syndrome

An observational and retrospective study was conducted at University Medical Center Ho Chi Minh City. The subjects of the were patients older than 18 years of age who were diagnosed and treated for Takotsubo cardiomyopathy between January 2015 and June 2022.

We selected research subjects by searching from the electronic medical record system of University Medical Center Ho Chi Minh City with the keywords “Takotsubo”, and “stress cardiomyopathy”. The Mayo Clinic criteria (2008) used to diagnose Takotsubo cardiomyopathy includes: (1) Transient hypokinesis, dyskinesis or akinesis of the ventricular walls, with or without the apical region, disproportionate to the dominant coronary artery; (2) Absence of significant coronary artery stenosis or acute atherosclerotic lesion; (3) New electrocardiographic abnormalities (either elevated ST-segment and/or T-wave changes) or elevation in cardiac troponin; and (4) Absence of pheochromocytoma or myocarditis [17].

We utilized the sample size formula,

to estimate a ratio. In this formula, α symbolized a type 1 error, preset at α=0.05, d indicated the estimated error, fixed at d=0.05, and p referred to the estimated proportion. We chose a value of p=5.69%, corresponding to the in-hospital mortality rate derived from a registry analysis of 28,079 patients in the United States who had been diagnosed with Takotsubo cardiomyopathy in 2013–2014 [18]. Consequently, we calculated the minimum number of subjects for the study is 83.

The investigator collected information on demographic, clinical symptoms, laboratory findings, coronary angiography results, treatment and major cardiovascular events occurring during period of hospitalization (all-cause mortality, thromboembolic events, neurological events) according to the available data collection. Comorbidities, including hypertension, coronary artery disease, diabetes mellitus, chronic kidney disease, neuropathy (ischemic stroke and cerebral hemorrhage), and chronic obstructive pulmonary disease, were identified based on the patient’s medical history. Acute heart failure was characterized by symptoms of heart failure, resulting from congestion or reduced cardiac output, with a sudden or unplanned onset, necessitating emergency hospitalization [19]. In Takotsubo syndrome, acute heart failure primarily manifests as left ventricular systolic dysfunction, with potential progression to acute pulmonary edema or cardiogenic shock. Acute respiratory failure was diagnosed based on clinical symptoms, including dyspnea, cyanosis, sweating, tachycardia, hypotension, and impaired consciousness. Additionally, arterial blood gas analysis with PaO₂ (arterial partial pressure of oxygen) <60 mmHg and/or pCO₂ (arterial partial pressure of carbon dioxide) >45 mmHg under room air conditions was employed to support the diagnosis [20]. The primary clinical outcome was all-cause in-hospital mortality, meticulously recorded through electronic medical records. This encompasses cases of patient death during hospitalization, as well as situations where severe illness prompted relatives to opt for home care, facilitating end-of-life care at home.

Data were analyzed using SPSS software version 22.0. Qualitative variables are described by frequency and percentages. Chi-squared test or Fisher’s exact test were used to compare proportions. Continuous variables were tested for normal distribution using the Shapiro-Wilk test, presented as mean±SD (for normal distribution) or median with a 25%–75% interquartile range (for non-normal distribution). The mean of the death and surviving groups was compared using the t-test, and the median of the two groups was compared using the Mann-Whitney U test. Logistic regression analysis was used to identify risk factors for in-hospital mortality. The multivariable model was constructed using variables that showed significance at p<0.2 level in relation to in-hospital mortality.

Statistical significance was determined using a two-sided p-value threshold of less than 0.05, reflecting a high level of confidence in the obtained results.

This study did not affect the process of the patient’s diagnosis, treatment and follow-up and approved by the local ethics committee of University Medical Center at Ho Chi Minh City, number 544/HĐĐĐ-ĐHYD.

According to many previous reports, Takotsubo cardiomyopathy was commonly seen in women, accounting for about 90%, and the average age was 67–70, of which 80% were over 50 years old [11],[21],[22]. However, men accounted for a higher percentage (35.9%) in our study. More recent studies have also shown that the number of men diagnosed with Takotsubo cardiomyopathy is increasing, particularly in the Asian race, and are strongly associated with physical triggers [23]. The increasing prevalence of coronary angiography also results in higher detection of the disease in man compared to before [24].

Diagnosis of Takotsubo cardiomyopathy remains a challenge in practice because of the overlapping manifestations with acute coronary syndromes such as chest pain, elevation of cardiac enzymes and ST-T changes on electrocardiogram [17]. Therefore, coronary and ventricular angiography plays an important role in the diagnosis. 73.7% of patients underwent coronary angiography, the remaining cases were mainly due to clinical conditions not suitable for the procedure (acute renal failure, hemodynamic disorders, coagulopathy...). We used modified Mayo Clinic diagnostic criteria (2008), which is also the most popular diagnostic tool. In most cases, the exclusion of myocarditis and pheochromocytoma is based on clinical signs rather than on imaging and pathology. We recorded 10.5% of patients with significant coronary artery. This rate has fluctuated from 10%–24% in previous reports [11],[25],[26]. The Mayo Clinic diagnostic criteria (2008) have not adequately assessed situations of Takotsubo cardiomyopathy with significant coronary artery stenosis [17]. Some reports have documented the coexistence of Takotsubo cardiomyopathy and acute coronary syndrome, and the acute coronary syndrome itself may be a trigger for Takotsubo cardiomyopathy [26]–[28]. In the setting of regional dyskinesia consistent with coronary artery lesions, cardiac magnetic resonance imaging (MRI) helps differentiate from acute coronary syndromes and myocarditis. Recently, the InterTAK standard was able to overcome the limitations of the Mayo Clinic diagnostic criteria [29].

Common clinical symptoms in patients diagnosed with Takotsubo cardiomyopathy are chest pain, dyspnea, and syncope [12]. Therefore, it is difficult to distinguish from acute coronary syndrome in the initial approach. In our study, the proportion of patients with syncope was less (1.0%), probably due to cognitive impairment and serious acute comorbidities such as pneumonia, infarction. cerebral hemorrhage, post-operative status....

The physical triggers were found more often than the psychological ones, with the highest percentage being infection (37.9%). In fact, it is difficult to fully assess the psychological stress of patients due to severe illness, cognitive disturbances, communication and cultural problems. We also recorded 43.7% cases of unknown trigger. Many other studies have also had similar results, especially men are often associated with physical stress, while women are often associated with mental stress [2],[3],[11].

The median serum concentrations for hs TnT and NT-ProBNP were 224.0 ng/mL and 3,511.0 ng/L, respectively. Most studies found myocardial cell necrosis in Takotsubo cardiomyopathy, but degree of troponin increase was lower compared to acute myocardial infarction (approximately 7.7 times upper limit of normal), and may help predict major cardiovascular events [11]. The concentration of diuretic peptides was increased in 82.9% of cases, often higher than in acute coronary syndromes (approximately 6.12 times the upper limit of normal) [11].

The abnormalities on the electrocardiogram were ST elevation (41.2%), ST depression (20.0%), T wave changes (28.4%), predominantly in the anterior thoracic leads. Regional movement disorder in the apex accounted for the highest rate (76.0%), this is also the classic form of Takotsubo cardiomyopathy. Some other locations were also recorded: the base of the heart (3.1%), the middle of the heart (6.3%), other areas (18.8%). This result was similar to many previous studies [11],[30],[31].

There were 17.6% of patients with ventricular arrhythmias (ventricular tachycardia, torsade de pointes, ventricular fibrillation) and 28.2% of patients with acute heart failure. The incidence of cardiogenic shock was 21.4%, higher than in other studies (about 5%–10%) [11],[32]. These complications are life-threatening in patients with Takotsubo cardiomyopathy and require prompt diagnosis and management.

Left ventricular systolic function recovers within 1–4 weeks in most patients with a diagnosis of Takotsubo cardiomyopathy [4],[6]–[8], however, serious complications during hospitalization have been reported similar to acute coronary syndrome [11]. Specifically, the rate of major cardiovascular events (cardiogenic shock, requiring for vasopressors, cardiac arrest, death) related with Takotsubo cardiomyopathy was comparable to that of acute myocardial infarction (38.2% vs. 32.6%) [32]. In-hospital mortality ranges from 0% to 8% [6],[7],[11],[33]. In our study, the all-cause in-hospital mortality rate was 17.5%, higher than previously reported. This may be due to: (1) the high rate of patients with cardiogenic shock (21.4%) and requiring intensive care: invasive mechanical ventilation (37.9%), renal replacement therapy (7.8%), dobutamine (23.3%), noradrenalin (40.8%); (2) a high proportion of males, most of the triggers appearing during hospitalization and are related to physical problems such as infections, stroke, post-surgery, etc. Patients with triggers related to physical stress have a worse prognosis than psychological stress [3],[34]. Furthermore, the analysis results showed that the severe events of Takotsubo cardiomyopathy were mainly due to left ventricular systolic dysfunction and arrhythmias. No cases of cardiac rupture, neurological events or thromboembolic events were recorded.

The independent risk factors of major events from Takotsubo cardiomyopathy were identified as: older age, multiple chronic comorbidities, physical triggers, acute neuropathy, elevated cardiac enzymes >10 times upper limit, ejection fraction <45%, right ventricular dysfunction, cardiogenic shock, arrhythmia [9]–[14],[35]. Some reports have shown that men have higher mortality rates than women [34],[36]. In our study, the independent risk factor for all-cause in-hospital mortality were acute heart failure and respiratory failure. Differences between studies are due to differences in study population characteristics, sample size and statistical methods.

This study had some limitations. Since this study was an observational, retrospective, and non-control study design, it had certain disadvantages. 35.9% of cases did not fully meet the Mayo clinic criteria, myocarditis and pheochromocytoma were ruled out based on clinical manifestations rather than imaging and pathology. The systematic standard was not used to identify trigger factors, especially psychological stress. Finally, the study was conducted in one center;therefore, it was not representative of the general population.