We collected all case reports from PubMed and the Embase database encompassing dates up to April 27, 2023. The search strategy employed for PubMed was: “ ‘Cardiomyopathy, Takotsubo’ OR ‘Tako-Tsubo Syndrome’ OR ‘Syndrome, Tako-Tsubo’ OR ‘Tako Tsubo Syndrome’ OR ‘Tako-Tsubo Syndromes’ OR ‘Left Ventricular Apical Ballooning Syndrome’ OR ‘Broken Heart Syndrome’ OR ‘Takotsubo Syndrome’ OR ‘Transient Apical Ballooning Syndrome’ OR ‘Apical Ballooning Syndrome’ OR ‘Tako-Tsubo Cardiomyopathy’ OR ‘Cardiomyopathy, Tako-Tsubo’ OR ‘Tako Tsubo Cardiomyopathy’ OR ‘Tako-Tsubo Cardiomyopathies’ OR ‘Stress Cardiomyopathy’ OR ‘Cardiomyopathy, Stress’ AND ‘Pheochromocytomas’ OR ‘Pheochromocytoma, Extra-Adrenal’ OR ‘Extra-Adrenal Pheochromocytoma’ OR ‘Extra-Adrenal Pheochromocytomas’ OR ‘Pheochromocytoma, Extra Adrenal’ OR ‘Pheochromocytomas, Extra-Adrenal’ ”. In Embase, it was: “ ‘Ampulla Cardiomyopathy’ OR ‘Apex Ballooning’ OR ‘Apical Ballooning’ OR ‘Apical Ballooning Syndrome’ OR ‘Broken Heart Syndrome’ OR ‘Left Ventricular Apical Ballooning’ OR ‘Left Ventricular Apical Ballooning Syndrome’ OR ‘Left Ventricular Ballooning’ OR ‘Stress Cardio-myopathy’ OR ‘Stress Cardiomyopathy’ OR ‘Stress Induced Cardiomyopathy’ OR ‘Stress-induced Cardio-myopathy’ OR ‘Tako Tsubo Cardiomyopathy’ OR ‘Tako-Tsubo’ OR ‘Tako-Tsubo Syndrome’ OR ‘Takotsubo’ OR ‘Takotsubo Syndrome’ OR ‘Transient Left Ventricular Apical Ballooning’ OR ‘Transient Left Ventricular Apical Ballooning Syndrome’ OR ‘Takotsubo Cardiomyopathy’ AND ‘Catecholamine-producing Neuroendocrine Tumor’ OR ‘Catecholamine-producing Tumour’ OR ‘Catecholamine-secreting Neuroendocrine Tumor’ OR ‘Catecholamine-secreting Tumor’ OR ‘Catecholamine-secreting Tumour’ OR ‘Epinephrine secreting Tumor’ OR ‘Norepinephrine secreting Tumor’ OR ‘Paraganglioma/Pheochromocytoma’ OR ‘PCC/PGL’ OR ‘PGL/PCC’ OR ‘Pheochromocytoma/Paraganglioma’ OR ‘Catecholamine-producing Tumor’ ”. Exclusion criteria included the absence of Pheo-TTS, ambiguous diagnosis, duplication, other language (not English, German or Chinese) or insufficient information.

Articles were initially screened for titles and abstracts, and full-text articles of potentially relevant reports were reviewed. Reference lists of retrieved full-text studies were scanned to identify additional relevant reports. Only case reports or case series with sufficient information on each case were included. Two researchers searched for Pheo-TTS cases, which were reviewed by senior experts before being summarized.

Demographic data including age, gender and history of cardiovascular risk factors were incorporated into the study. Data on symptoms and signs were recorded in detail, such as neurological and/or psychiatric disorders (dizziness, headache, unconsciousness, or others such as drowsiness, mental agitation, panic, sensory and motor disorders), dyspnea, chest pain symptoms (defined as chest pain, chest tightness or radiating pain), abdominal symptoms (nausea, vomiting, abdominal pain or diarrhea), sweating, and other symptoms (pallor, palpitations, fever or weakness). Tachycardia was defined as an increased heart rate of more than 100 beats per minute. Auxiliary examination data were collected, including electrocardiogram (ECG) information on ST-segment elevation or depression, and T-wave inversion. In order to establish a definitive diagnosis of pulmonary edema, chest computed tomography (CT) or X-ray examinations were reviewed. Transthoracic echocardiography (TTE) was used to assess regional wall motion abnormalities, which were further categorized into typical apical TTS and its atypical forms (global, midventricular, basal or focal). In-hospital complications including the administration of catecholamines, development of cardiogenic shock, requirement for invasive or non-invasive ventilation, occurrence of cardiopulmonary resuscitation, and death from any cause were recorded [10]. We compared the demographic, clinical and imaging features of these patients with those in the general TTS population from the International Takotsubo Registry (InterTAK Registry) [10].

Hierarchical cluster analysis was performed according to the clustering variables of admission symptoms and signs (neurological and/or psychiatric disorders, dyspnea, chest pain, abdominal symptoms, sweating, pulmonary rales, and tachycardia) (Supplementary Table 1 and Supplementary Fig. 1).

Continuous variables were presented as mean $\pm$ standard deviation or median (interquartile range) and compared using Student’s t-test for normally distributed data or Mann-Whitney U test for non-normally distributed data. Categorical variables were presented as numbers (percentages). The Chi-squared test was used for categorical variables with all cell counts $\ge$5 and Fisher’s exact test for categorical variables with any cell counts 5. Logistic regression analysis was performed to evaluate factors associated with in-hospital complications. All analyses were performed with SPSS version 26.0 (IBM Corp., Armonk, NY, USA). Statistical significance was defined as p value 0.05.

We screened 229 articles from PubMed and 495 articles from Embase for eligibility based on our search criteria. Of these, 172 patients met the diagnostic criteria for Pheo-TTS and provided complete information on clinical manifestations and diagnostic information during hospitalization (Fig. 1). The cohort predominantly consisted of women (72.1%), with a mean age of 48.2 $\pm$ 15.4 years (ranging from 16 to 86 years). The prevalences of hypertension and diabetes within this group were 35.5% and 13.4%, respectively.

Fig. 1.

Selection process of Pheo-TTS cases for study inclusion. This flowchart illustrates the methodology employed to select cases of pheochromocytoma-induced Pheo-TTS for inclusion in the study. Beginning with an initial screening of 724 articles from PubMed and Embase, the chart details the criteria applied at each step, including eligibility based on diagnostic criteria and completeness of clinical data, culminating in the final selection of 172 patients for analysis. Pheo-TTS, pheochromocytoma-induced takotsubo syndrome.

The predominant symptom presented by Pheo-TTS patients was chest pain (66.9%), followed by dyspnea (52.3%), abdominal symptoms (47.1%), neurological and/or psychiatric disorders (43.0%), and sweating (30.2%). Less frequent symptoms included pallor, palpitations, fever and weakness. On admission, 85 patients (61.2%) exhibited hypertension, whereas 17 patients (12.1%) presented with hypotension. Tachycardia was observed in more than half of the patients (54.1%), while pulmonary rales were present in nearly one-third (33.7%). ECG analysis revealed ST-segment elevation in 42.6% of cases, ST-segment depression in 29.1%, and T-wave inversion in 17.6%. TTE identified typical (53.8%) and atypical (46.2%) imaging phenotypes. Pulmonary edema was diagnosed by chest CT or X-ray in 57 patients (33.3%).

In-hospital complications occurred in 87 patients (50.6%), with 45.9% requiring invasive or non-invasive ventilation, 37.8% developing cardiogenic shock, 35.5% requiring administration of catecholamines, 16.9% requiring cardiopulmonary resuscitation, and 6.4% resulting in mortality.

Compared to the general TTS population in the InterTAK database, patients with Pheo-TTS presented with distinct demographic and clinical characteristics. Specifically, Pheo-TTS patients were younger (48.2 $\pm$ 15.4 vs. 66.4 $\pm$ 13.1, p 0.001) and more likely to be male (27.9% vs. 10.2%, p 0.001). They were also less likely to report chest pain (33.1% vs. 24.1% p = 0.01), and exhibited a greater prevalence of atypical TTS imaging phenotypes (46.2% vs. 18.3%, p 0.001). Moreover, Pheo-TTS patients experienced a more than a 2.3-fold higher incidence of in-hospital complications (50.6% vs. 21.8%, p 0.001) (Supplementary Fig. 2A–E) [10].

The cluster analysis, based on clinical manifestations at admission, identified in two distinct classifications: a chest pain dominant group (CPD group, n = 86, 50.0%) and a non-chest pain dominant group (non-CPD group, n = 86, 50.0%). The non-CPD group was characterized by younger patients (44.0 $\pm$ 15.2 vs. 52.4 $\pm$ 14.4, p 0.001), and a lower prevalence of hypertension (27.9% vs. 43.0%, p = 0.038) and diabetes (8.1% vs. 18.6%, p = 0.044). This group also exhibited a higher incidence of dyspnea (87.2% vs. 17.4%, p 0.001), neurological and/or psychiatric disorders (53.5% vs. 32.6%, p = 0.006), tachycardia (77.9% vs. 30.2%, p 0.001) and pulmonary rales (59.3% vs. 8.1%, p 0.001) at admission. Furthermore, the non-CPD group had a greater occurrence of pulmonary edema and a lower frequency of ST-segment elevation on ECG (32.9% vs. 52.0%, p = 0.019), but presented with atypical TTS imaging phenotypes more often (58.0% vs. 37.3%, p = 0.031). Notably, adverse in-hospital complications were significantly more common in the non-CPD group compared to the CPD group (70.9% vs. 30.2%, p 0.001) (Table 1).

Univariate logistic regression analysis identified several factors associated with an increased risk of in-hospital complications: a younger age ($\le$50 years), experiencing dyspnea, abdominal symptoms, pulmonary rales, ST-segment depression, and atypical TTS imaging phenotypes (all p 0.05). Conversely, a history of hypertension, the presence of chest pain, and ST-segment elevation were correlated to a lower risk of in-hospital complications (p 0.05) (Fig. 2A). After adjusting for confounders, a multivariate analysis showed that the absence of chest pain (odds ratio [OR] = 0.407, 95% confidence interval [CI] 0.169–0.979, p = 0.045), the presence of abdominal symptoms (OR = 3.939, 95% CI 1.770–8.766, p = 0.001), pulmonary rales (OR = 4.348, 95% CI 1.857–10.179, p = 0.001) and atypical TTS imaging phenotype (OR = 3.397, 95% CI 1.534–7.525, p = 0.003) remained independent predictors of in-hospital complications (Fig. 2B).

Fig. 2.

Factors associated with in-hospital complications of pheochromocytoma-Induced takotsubo syndrome patients. Univariate (A) and multivariable (B) Cox regression analysis. OR, odds ratio; CI, confidence interval; TTS, takotsubo syndrome.