ABSTRACT
Takotsubo cardiomyopathy (TTS) is an acute heart failure syndrome characterized by transient left ventricle (LV) systolic dysfunction, often triggered by physical or emotional stress. Although several registries, observational studies, and meta-analyses have demonstrated an association between malignancy and adverse outcomes in Takotsubo syndrome, data describing the interplay between cancer stage, treatment exposure, ventricular recovery, and mortality in patients with solid malignancies remain limited. Material and methods: We retrospectively analyzed adult patients with solid malignancies treated at a Comprehensive Cancer Center between November 2021 and December 2025 who developed Takotsubo syndrome. TTS was diagnosed according to the InterTAK Diagnostic Score together with characteristic echocardiographic findings and, when indicated, additional anatomical or tissue characterization. Demographic characteristics, cancer type and stage, clinical presentation, electrocardiogram and biomarkers findings, imaging results, and outcomes were collected. Primary outcome was all-cause mortality. Secondary outcomes included cause-specific mortality, recovery of left ventricular systolic function, and resumption of cancer therapy. Results: A total of 26 consecutive patients developed TTS during the study period. Median age 64.5 years (IQR 52.2 - 69.5); 61.5% were female. Advanced or metastatic cancer was present in 42.3% of patients. Sepsis occurred in 50.0%, and major cancer-related surgery in 30.8%. The median InterTAK Diagnostic Score was 75.5 (IQR 64.5–80.0); 73.1% of patients had scores ≥70. Overall mortality was 38.5% (10/26), and all deaths were attributed to cancer-related causes; no cardiac-related deaths occurred. Advanced/metastatic disease was associated with higher mortality (80.0% vs. 18.8%, p = 0.015), and all deaths occurred in patients receiving non-curative treatment. In exploratory multivariable analysis, advanced/metastatic cancer was associated with increased odds of death (adjusted OR 11.49, p = 0.021). Follow-up echocardiography was available in 18 patients; all demonstrated normalization of left ventricular systolic function (LVEF ≥50%), with a median time to documented recovery of 10 days (IQR 6–21). Conclusions: Takotsubo cardiomyopathy syndrome in patients with solid malignancies was associated with high cancer-related mortality, whereas left ventricular dysfunction was largely reversible among survivors. Outcomes appeared to be more associated with oncologic disease burden than with cardiac dysfunction.
Keywords: Takotsubo syndrome, Stress cardiomyopathy, Cardio-oncology, Cancer-associated Takotsubo syndrome, Solid malignancy, Prognosis
INTRODUCTION
Takotsubo cardiomyopathy, also known as stress cardiomyopathy or “broken heart syndrome”, is an acute, reversible form of heart failure characterized by transient left ventricular (LV) dysfunction in the absence of obstructive coronary disease [1]. Typical triggers include sudden emotional or physical stress leading to a catecholamine surge, coronary microvascular spasm, and myocardial stunning [1].
The syndrome classically affects post-menopausal women and often mimics acute myocardial infarction with chest pain, electrocardiogram (ECG) changes, and troponin elevation despite normal coronary arteries. Although Takotsubo cardiomyopathy was once considered benign, contemporary data show it can have serious complications (e.g. cardiogenic shock, arrhythmias) and in-hospital mortality rates comparable to acute coronary syndromes [2]. Long-term outcomes are also not insignificant, with survival rates mirroring those observed in patients with myocardial infarction [3].
Contemporary expert consensus describes TTS as an acute heart failure syndrome with meaningful short-term complications and non-trivial mortality [2]. TTS phenotypes include classic apical ballooning (75-80%), mid-ventricular (10-20%), basal (reverse Takotsubo – 5%) and less common variants (focal and global dysfunction) [4]. Diagnostic work-up commonly includes echocardiography and, when clinically indicated, coronary angiography or equivalent imaging to exclude obstructive coronary disease or alternative causes [2].
Cancer is a frequent comorbidity in TTS populations, and multiple mechanisms have been proposed in the literature, including chemotherapy- or immunotherapy-associated triggers, inflammatory and neurohormonal stress, peri-procedural stress, and critical illness [5]. A recent systematic review and meta-analysis including 189,210 TTS patients across 14 studies, estimated malignancy prevalence in TTS at 8.7% and found that malignancy was associated with higher all-cause mortality at short- and long-term follow-up, along with higher rates of shock, arrhythmia, respiratory support, and major adverse cardiac events [5].
Proposed mechanisms for TTS and cancer association include the immense emotional stress of a cancer diagnosis, the chronic inflammatory and prothrombotic state of malignancy, and circulating paraneoplastic mediators that may affect myocardial β-adrenergic signaling [6,7]. Cancer treatments themselves can precipitate Takotsubo episodes: case reports implicate several chemotherapeutic and biologic agents (e.g. 5-fluorouracil, capecitabine, VEGF inhibitors, taxanes, immune checkpoint inhibitors) as triggers for stress cardiomyopathy [6]. For instance, 5-FU cardiotoxicity can manifest as Takotsubo syndrome, with most reported cases occurring during the first infusion cycle and showing recovery of LVEF within a month after drug cessation [6,7]. Thus, oncology patients represent a vulnerable population in whom Takotsubo cardiomyopathy may be precipitated by both disease-related and iatrogenic stressors.
Despite growing observational evidence, there are no dedicated randomized-trial–driven guidelines for TTS management. Clinical recommendations rely largely on consensus statements and extrapolation from acute heart failure and critical care principles [8]. In parallel, recent cardio-oncology guidance recommends systematic cardiovascular risk assessment and longitudinal surveillance before, during, and after anticancer therapies, with strong emphasis on multidisciplinary collaboration between oncologists, cardiologists, intensivists, and imaging specialists. Such integrated care pathways are particularly relevant for complex overlap syndromes such as TTS occurring in patients with malignancy, in whom multiple triggers, including cancer-related inflammation, treatment-related cardiotoxicity, and physical stressors may coexist [8,9].
Although several registries, cohort studies, and meta-analyses have demonstrated an association between malignancy and adverse outcomes in Takotsubo syndrome, important knowledge gaps remain regarding patterns of ventricular recovery, treatment continuation, and outcome determinants among patients treated within dedicated cardio-oncology programs. We hypothesized that prognosis in cancer-associated Takotsubo syndrome is primarily determined by oncologic disease burden rather than by the severity of myocardial dysfunction.
Therefore, we report a single-center retrospective cohort of 26 adult cancer patients who developed Takotsubo cardiomyopathy at a tertiary oncology center. We describe their baseline characteristics, cancer types and stages, treatment exposures, clinical presentation, cardiac investigations, and outcomes including LVEF recovery and mortality. We also discuss our findings in the context of the emerging cardio-oncology literature, exploring potential mechanisms and the implications for managing cancer patients who experience stress cardiomyopathy.
MATERIAL AND METHODS
Study Design and Setting: We conducted a retrospective cohort study at the Sultan Qaboos Comprehensive Cancer Care and Research Centre (SQCCCRC), a tertiary cancer center in Muscat, Oman. All cases of Takotsubo cardiomyopathy in adult solid cancer patients managed at SQCCCRC between November 2021 and December 2025 were identified through the institutional patient records and cardiology consult database. The study was approved by the SQCCCRC Institutional Review Board, with a waiver of individual informed consent due to the retrospective design. Patient confidentiality was maintained in compliance with institutional ethics guidelines and the Declaration of Helsinki.
Inclusion and Exclusion Criteria: Eligible patients were those aged ≥ 18 years with an established cancer diagnosis who developed Takotsubo cardiomyopathy during their cancer care at SQCCCRC. Takotsubo syndrome was diagnosed using the International Takotsubo Diagnostic Score (InterTAK Score) [10,11], which integrates the following variables: female sex (25 points), emotional trigger (24 points) or physical trigger (13 points), absence of ST-segment depression (12 points), psychiatric disorders (11 points), neurologic disorders (9 points), and QTc prolongation (6 points). Based on the original validation study(10), a score ≥70 points was considered indicative of a high probability of Takotsubo syndrome, whereas scores ≤ 31 indicated a low probability and scores between 32 and 70 an intermediate probability. Because not all patients underwent systematic coronary angiography or coronary computed tomography angiography, the median InterTAK Diagnostic Score and interquartile ranges [IQR] were calculated to provide an estimate of diagnostic certainty across the cohort.
Figure 1 summarizes the institutional diagnostic pathway used for suspected Takotsubo syndrome. Patients underwent initial clinical, electrocardiographic, biomarker, and echocardiographic assessment followed by calculation of the InterTAK Diagnostic Score. Patients with high-probability scores and typical imaging findings were diagnosed clinically, whereas those with low/intermediate scores or atypical presentations underwent further evaluation with coronary angiography, coronary CT angiography, and/or cardiac magnetic resonance imaging to exclude alternative diagnoses including acute myocardial infarction, Myocardial Infarction with Non-Obstructive Coronary Arteries (MINOCA), and myocarditis. This diagnostic approach is consistent with contemporary recommendations for the evaluation of suspected Takotsubo syndrome in patients in whom immediate invasive coronary assessment is not mandatory [2,4].
Fig. 1.
Diagnostic pathway for suspected Takotsubo syndrome in patients with cancer. Patients underwent initial clinical evaluation, echocardiography, and calculation of the InterTAK Diagnostic Score. Further anatomical and tissue characterization was reserved for patients with low/intermediate probability scores or diagnostic uncertainty. Recovery of left ventricular function on follow-up imaging provided additional support for the diagnosis.
In patients who did not undergo invasive coronary evaluation, the diagnosis was supported by the presence of a typical echocardiographic pattern extending beyond a single epicardial coronary territory together with subsequent recovery of left ventricular systolic function on follow-up imaging. Patients with evidence of acute myocardial infarction, defined as a culprit coronary stenosis ≥50% associated with a concordant regional wall-motion abnormality, or with another identifiable cause of cardiomyopathy were excluded.
Data Collection: data was retrospectively collected from electronic medical records, including
Baseline demographics and history: age, sex, and relevant comorbid conditions (pre-existing psychiatric disorders, neurological disorders, history of coronary artery disease, etc.).
Cancer details: type of malignancy, stage of cancer at the time of the Takotsubo event [using Eighth Edition American Joint Committee on Cancer (AJCC) Staging Manual [12]: staging or descriptive terms from oncology records], and current oncologic treatments or recent interventions. Cancer treatment modalities were categorized (e.g. chemotherapy, immunotherapy, radiation, surgery, palliative care, or combination approaches).
Precipitating triggers: any identified emotional stressors or acute physical stressors prior to cardiomyopathy (such as severe illness, sepsis, surgery/procedures). We specifically noted if the Takotsubo episode occurred in the peri-procedural period (within 48 hours of surgery or invasive procedure).
Presenting clinical features: symptoms at cardiac presentation (chest pain, dyspnea, syncope, etc.), vital signs (blood pressure and heart rate) on presentation, and any acute heart failure or shock. We recorded whether patients had signs of acute heart failure (e.g. pulmonary edema) and whether they required ICU admission for hemodynamic support (vasopressors or mechanical ventilation).
Diagnostic findings: ECG findings were collected from the admission electrocardiograms, including any ST-segment changes, T-wave inversions, QT interval prolongation, or arrhythmias noted. Peak cardiac biomarker levels (troponin-I or T and B-type natriuretic peptide [BNP] or NT-proBNP) during the acute episode were recorded. Transthoracic echocardiography parameters were reviewed, particularly the nadir LVEF (lowest ejection fraction during the acute phase) and the pattern of wall-motion abnormality (e.g. apical akinesis vs. variant patterns). Results of coronary angiography were noted if performed, if angiography was not done, we recorded alternative imaging (such as cardiac MRI) or the clinical rationale. The InterTAK diagnostic score was documented to estimate the probability of TTS, with an InterTAK score ≥ 70 points strongly suggestive of Takotsubo syndrome [4].
Primary Outcomes included the in-hospital clinical course and complications, such as arrhythmias, thromboembolism, cardiogenic shock, and septic shock, and all-cause mortality.
Secondary Outcomes included cancer-related mortality, cardiac-related mortality, and left ventricular (LV) functional recovery. LV recovery was assessed based on improvement in left ventricular ejection fraction (LVEF) during follow-up.
Statistical analysis
All analyses were performed using a two-sided significance level of 0.05. Given the small sample size and exploratory nature of this study, effect estimates and 95% confidence intervals were emphasized over dichotomous significance testing. No adjustment for multiple comparisons was performed.
Continuous variables are reported as median and interquartile range (IQR), while categorical variables are presented as counts and percentages. Comparisons between survivors and non-survivors were performed using the Mann–Whitney U test for continuous variables and Fisher's exact test for categorical variables.
To explore factors associated with mortality, univariable logistic regression analyses were performed for selected clinically relevant variables. Because only 10 deaths occurred in the cohort, multivariable modeling was intentionally restricted to a parsimonious model including advanced/metastatic cancer status and log-transformed NT-proBNP, selected a priori based on biological plausibility and to minimize the risk of overfitting. Results are reported as odds ratios (ORs) with 95% confidence intervals. Model discrimination and calibration were assessed using the area under the receiver operating characteristic curve (AUC) and Brier score, respectively. Variance inflation factors (VIFs) were calculated to evaluate multicollinearity.
Time to documented recovery of left ventricular systolic function (defined as LVEF ≥50% on follow-up echocardiography) was analyzed using Kaplan–Meier methods. Because follow-up imaging was not available for all patients and all patients with follow-up eventually recovered ventricular function, these analyses should be considered exploratory and hypothesis-generating. Factors associated with time to recovery were evaluated using Cox proportional hazards regression, including age, sex, systemic anticancer therapy, and advanced/metastatic cancer status as covariates. The proportional hazards assumption was assessed using Schoenfeld residuals and was not violated. Hazard ratios (HRs) with 95% confidence intervals are reported.
Because of the limited sample size and number of outcome events, all regression analyses were considered exploratory and hypothesis-generating. The proportional hazards assumption was assessed using Schoenfeld residuals.
RESULTS
Table 1 summarizes the baseline characteristics of the study population stratified according to the primary outcome of mortality. A total of 26 patients with solid tumors and echocardiographic findings compatible with TTS were included. Median age was 64.5 years [IQR: 52.2-69.5] and 61.5% were female. Advanced cancer was present in 42.3% of cases. Systemic therapy was documented in 57.7%, and palliative treatment was intended in 19.2%. Only 2 patients (7.7%) had known coronary artery disease, and in both cases the coronary disease was mild or non-obstructive.
Table 1.
Baseline characteristics by survival status.
| Variable | Overall (N=26) | Survivors (n=16) | Deaths (n=10) | p-value |
|---|---|---|---|---|
| Age (years) | 64.5 [52.2, 69.5] | 65.5 [52.8, 69.0] | 62.5 [51.0, 70.0] | 0.874 |
| Female sex | 16/26 (61.5%) | 8/16 (50.0%) | 8/10 (80.0%) | 0.218 |
| Hypertension | 10/26 (38.5%) | 4/16 (25.0%) | 6/10 (60.0%) | 0.109 |
| Diabetes mellitus | 9/26 (34.6%) | 6/16 (37.5%) | 3/10 (30.0%) | 1.000 |
| Chronic kidney disease | 5/26 (19.2%) | 2/16 (12.5%) | 3/10 (30.0%) | 0.340 |
| Advanced cancer | 11/26 (42.3%) | 3/16 (18.8%) | 8/10 (80.0%) | 0.015 |
| Systemic anti-cancer therapy around TTS | 15/26 (57.7%) | 11/16 (68.8%) | 4/10 (40.0%) | 0.422 |
| Palliative intent documented | 5/26 (19.2%) | 0/16 (0.0%) | 5/10 (50.0%) | 0.004 |
| Sepsis | 13/26 (50.0%) | 6/16 (37.5%) | 7/10 (70.0%) | 0.226 |
| Septic shock | 9/26 (34.6%) | 4/16 (25.0%) | 5/10 (50.0%) | 0.234 |
| Heart failure presentation | 9/26 (34.6%) | 4/16 (25.0%) | 5/10 (50.0%) | 0.234 |
| Chest pain | 5/26 (19.2%) | 4/16 (25.0%) | 1/10 (10.0%) | 0.617 |
| Psychiatric disorder history | 4/26 (15.4%) | 1/16 (6.2%) | 3/10 (30.0%) | 0.264 |
| Neurological disorder history | 7/26 (26.9%) | 4/16 (25.0%) | 3/10 (30.0%) | 1.000 |
| Emotional trigger reported | 7/26 (26.9%) | 3/16 (18.8%) | 4/10 (40.0%) | 0.369 |
| Peri-procedural trigger | 7/26 (26.9%) | 6/16 (37.5%) | 1/10 (10.0%) | 0.190 |
| Nadir LVEF (%) | 41.0 [35.0-47.0] | 43.0 [35.0-47.0] | 39.5 [35.0-48.0] | 0.653 |
| Peak troponin (ng/L) | 113.5 [29.8-353.8] | 113.5 [29.8-353.8] | 207.5 [85.0-260.2] | 0.653 |
| Peak pro-BNP (pg/mL) | 634.8 [439.0-11327.0] | 4787.5 [634.8-10016.5] | 14589.0 [11327.0-34234.0] | 0.054 |
| Coronary imaging performed | 7/26 (26.9%) | 6/16 (37.5%) | 1/10 (10.0%) | 0.190 |
Cancer Characteristics and Treatment Exposure
Table 2 summarizes the oncologic characteristics of the cohort. Gastrointestinal malignancies were the most common cancer group (30.8%), followed by thoracic (15.4%) and genitourinary malignancies (15.4%). Active malignancy was present in 92.3% of patients, while 42.3% had advanced or metastatic disease. Systemic anticancer therapy had been administered in 57.7% of patients, 30.8% had recently undergone cancer-related surgery, and 19.2% were on palliative care. Two patients (7.7%) were in complete oncologic remission at the time of Takotsubo syndrome presentation.
Table 2.
Oncologic Characteristics of the Study Population (N = 26).
| Cancer type | N (%) |
|---|---|
| Gastrointestinal | 8 (30.8) |
| Thoracic | 4 (15.4) |
| Genitourinary | 4 (15.4) |
| Sarcomas | 3 (11.5) |
| Breast | 2 (7.7) |
| Gynecologic | 2 (7.7) |
| Other malignancies | 3 (11.5) |
| Cancer stage | N (%) |
| Stage I–III | 11 (42.3) |
| Stage IV/Metastatic | 11 (42.3) |
| Other staging* | 4 (15.4) |
| Cancer status at TTS presentation | N (%) |
| Active malignancy | 24 (92.3) |
| Remission | 2 (7.7) |
| Cancer treatment exposure | N (%) |
| Systemic anticancer therapy | 15 (57.7) |
| Recent cancer surgery | 8 (30.7) |
| Radiation therapy | 1 (3.8) |
| Palliative care | 5 (19.2) |
| No cancer treatment initiated | 2 (7.7) |
Gastrointestinal: colorectal adenocarcinoma, gastric adenocarcinoma, gallbladder carcinoma, pseudomyxoma peritonei. Thoracic: Non-Small Cell Lung Cancer and Small Cell Lung Cancer. Genitourinary: urothelial carcinoma and adrenocortical carcinoma. Sarcomas: Ewing sarcoma, chondroblastic osteosarcoma, and intra-abdominal sarcoma. Gynecologic: cervical cancer and endometrial cancer. Other malignancies: adrenocortical carcinoma, neuroendocrine carcinoma, and medulloblastoma. *Other staging: medulloblastoma (M4), low-grade appendiceal mucinous neoplasm with pseudomyxoma peritonei, high-grade abdominal sarcoma, and high-grade small cell carcinoma.
At the time of Takotsubo syndrome presentation, 11 patients (42.3%) had advanced or metastatic disease, whereas 11 (42.3%) had localized or regional disease (Stage I–III). Two patients (7.7%) were in complete oncologic remission under surveillance.
Cancer treatment exposures at the time of Takotsubo syndrome
Eight patients (30.7%) had recently undergone major cancer-related surgery and developed Takotsubo cardiomyopathy in the immediate postoperative period. Ongoing or recent systemic anticancer therapy was documented in a substantial proportion of cases, with at least seven patients (27%) receiving cytotoxic chemotherapy at the time of the event. Chemotherapeutic regimens were heterogeneous and included platinum- and taxane-based combinations, FOLFOX, gemcitabine/docetaxel, and immunomodulatory agents, without a single dominant drug exposure. One patient developed Takotsubo syndrome after combined-modality treatment consisting of surgery, chest radiotherapy, and hormonal therapy for breast cancer. In contrast, five patients (19.2%) were receiving palliative care for metastatic disease and were not on active anticancer therapy. Notably, Takotsubo cardiomyopathy occurred shortly after cancer diagnosis in two patients who had not yet initiated oncologic treatment.
Cardiac presentation
Five patients (19%) reported chest pain at onset. Most patients presented with acute heart failure manifestations, including dyspnea and hypoxemia, or with hemodynamic instability in the context of an acute medical illness.
On admission, vital signs showed substantial variability, with a median heart rate of 100 beats/min (range 58–140). Significant hypotension (systolic blood pressure <90 mmHg) was observed in approximately one-third of patients. Overall, 10 patients (38%) fulfilled criteria for shock, predominantly of distributive (n = 9), while one patient had primarily cardiogenic shock. Clinical evidence of acute pulmonary edema was present in nine patients (35%), and 10 patients (38%) required intensive care unit admission for hemodynamic support and close monitoring.
No sustained ventricular arrhythmias or cardiac arrest occurred during the acute phase. One patient developed rapid atrial fibrillation, which was successfully managed with medical therapy.
Electrocardiographic and biomarker findings
Electrocardiographic abnormalities were present in all patients. None exhibited a classic ST-segment elevation myocardial infarction pattern. The most common finding was diffuse T-wave inversion, observed in 15 patients (58%), typically involving the anterior and inferior leads. QT interval prolongation was documented in eight patients (31%), with QTc values exceeding 500 ms in several cases. Less frequent findings included nonspecific ST–T abnormalities, minimal ST-segment depression, poor R-wave progression, and, in one case, Q waves in leads V1–V3 that initially raised suspicion for anteroseptal infarction but were not associated with obstructive coronary artery disease.
Peak troponin median value was 166 (interquartile range approximately 50–300) and a maximum of 1037. Given an institutional upper reference limit of approximately 14, these values correspond to roughly 10–20-fold elevations in most cases. Natriuretic peptide levels were markedly elevated, consistent with acute heart failure. NT-proBNP values were available in 25 patients and showed a median of approximately 9,000 pg/mL, with a maximum approaching 70,000 pg/mL.
Cardiac phenotype and diagnostic work-up
The median InterTAK Diagnostic Score was 75 (IQR 64 – 80). Nineteen patients (73.1%) had an InterTAK score ≥70, corresponding to a high probability of Takotsubo syndrome. The remaining seven patients (26.9%) had intermediate-probability scores (range 49–61; mean 53) and underwent additional diagnostic evaluation. Among these patients, six underwent coronary angiography, 5 had entirely normal coronary arteries and 1 had mild, non-flow-limiting atherosclerosis. In one case, a delayed cardiac MRI was obtained, which showed the classic findings of Takotsubo (myocardial edema with no late gadolinium enhancement, confirming the absence of infarction or myocarditis). No patient had a low-probability InterTAK score (≤31).
Median nadir LVEF was 41.0% [IQR: 35.0-47.0]. LV wall-motion descriptions were categorized as apical pattern in 16/26 (61.5%), global hypokinesia in 5/26 (19.3%), reversed/basal pattern in 2/26 (7.7%), and others in 3/26 (11.5%).
Outcomes
During the study period, 10 patients died (38.5%). All deaths were attributed to cancer-related causes, and no cardiac-related deaths were observed. The only variables that differed significantly between non-survivors and survivors were the presence of advanced-stage malignancy (80.0% vs. 18.8%, p = 0.015) and palliative treatment intent (50.0% vs. 0%, p = 0.004), respectively (Table 1).
Non-survivors and survivors had comparable nadir LVEF (39.5% vs. 43.0%, p = 0.65). Peak troponin levels were numerically higher among non-survivors (207.5 vs. 113.5, p = 0.65). Similarly, peak NT-proBNP values were markedly higher in non-survivors compared with survivors (14,589.0 vs. 4,787.5), although this difference did not reach statistical significance (p = 0.054).
Follow-up echocardiography was available in 18 of 26 patients (69.2%), including all survivors and two patients who subsequently died. All patients who underwent repeat imaging demonstrated normalization of left ventricular systolic function (LVEF ≥50%), with a median follow-up LVEF of 62.0% and a median absolute improvement of 17.0%. The median time to documented recovery was 10 days (IQR 6–21 days), with the longest documented recovery time being 90 days. Notably, 8 patients (30.7%) recovered cardiac function within one week, 5 patients (19.2%) recovered within 2–3 weeks. A few outliers experienced a more protracted course, two patients required about 8 weeks, and one patient's LVEF normalized only after 3 months. The remaining eight patients died from cancer-related causes before follow-up echocardiography could be performed.
Multivariable modeling of death
In univariable logistic regression analysis (Table 3), advanced-stage malignancy was significantly associated with mortality. In contrast, Takotsubo-related clinical, echocardiographic, and biomarker parameters, including nadir LVEF and log(NT pro-BNP) were not significantly associated with the risk of death. After adjustment, advanced-stage malignancy remained an independent predictor of death (Table 4). The adjusted model showed excellent discrimination (AUC 0.851) with good overall accuracy (Brier score 0.142). Variance inflation factors were low (VIF = 1.15), confirming the absence of significant multicollinearity. Although the model demonstrated good apparent discrimination (AUC 0.851) and calibration (Brier score 0.142), the small number of outcome events limits the stability of the estimates, and these findings should be considered exploratory.
Table 3.
Univariable logistic regression (death).
| Predictor | OR (95% CI) | p |
|---|---|---|
| Age (per 10 years) | 1.15 (0.71–1.87) | 0.565 |
| Male | 0.25 (0.04–1.56) | 0.138 |
| Advanced/metastatic cancer | 17.33 (2.36–127.34) | 0.005 |
| Systemic anti-cancer therapy | 0.30 (0.06–1.58) | 0.156 |
| log (NT Pro-BNP) | 1.67 (0.94–2.99) | 0.081 |
| Nadir LVEF (per 5%) | 0.84 (0.50–1.43) | 0.528 |
| Sepsis | 3.89 (0.72–21.06) | 0.115 |
| Septic shock | 3.00 (0.56–16.07) | 0.200 |
Table 4.
Adjusted logistic regression (death).
| Predictor | OR (95% CI) | p |
|---|---|---|
| Advanced/metastatic cancer | 11.49 (1.44–91.49) | 0.021 |
Model diagnostics (adjusted model): AUC 0.851; Brier score 0.142; VIF = 1.15 for both predictors, suggesting low multicollinearity.
Exploratory Cox proportional hazards regression using LVEF recovery as outcome measure
An exploratory Cox proportional hazards analysis was performed to evaluate factors associated with time to recovery of left ventricular systolic function (Table 5). In exploratory Cox proportional hazards analysis, advanced cancer was associated with a lower rate of documented left ventricular functional recovery over time (HR 0.28, 95% CI 0.09–0.88; p=0.030). Given the limited number of patients with serial echocardiographic assessment, this finding should be interpreted cautiously and considered hypothesis-generating. Kaplan–Meier analysis (Figure 2) demonstrated rapid recovery of systolic function (LVEF ≥50%). Most patients experienced early recovery within the first three weeks, with a median time to recovery of 10 days (IQR 6–21 days). A minority demonstrated delayed recovery up to 90 days.
Table 5.
Cox proportional hazards regressions (Outcome = LVEF recovery).
| Predictor | HR (95% CI) | p |
|---|---|---|
| Systemic anti-cancer therapy | 1.02 (0.32–3.27) | 0.977 |
| Advanced cancer | 0.28 (0.09–0.88) | 0.030 |
| Age (per 10 years) | 0.99 (0.72–1.36) | 0.958 |
| Male | 0.60 (0.21–1.70) | 0.335 |
Advanced/metastatic cancer was associated with slower documented LV recovery (HR <1).
Fig. 2.
Kaplan–Meier analysis of time to left ventricular ejection fraction recovery.
DISCUSSION
This study provides a detailed characterization of Takotsubo syndrome in a cohort of patients with solid malignancies treated at a tertiary comprehensive cancer center. Our findings highlight the distinctive clinical context in which stress cardiomyopathy occurs in oncology and are consistent with the evolving cardio-oncology literature [6,7]. In this cohort, Takotsubo syndrome developed predominantly in the setting of substantial physical or emotional stressors related to cancer and its management, including major oncologic surgery, acute medical illness, and the psychological impact of a new cancer diagnosis. These observations support the concept that malignancy and its treatment may act as potent triggers for stress cardiomyopathy through a combination of systemic inflammation, catecholamine excess, and impaired physiological reserve.
The oncologic profile of our cohort was characterized by a high burden of advanced disease, with 42.3% of patients presenting with advanced or metastatic malignancy and more than 90% having active cancer at the time of the Takotsubo event. Advanced malignancy may increase susceptibility to stress cardiomyopathy through multiple synergistic mechanisms, including reduced physiologic reserve, systemic inflammation, catabolic stress, and repeated exposure to major physical stressors such as surgery, sepsis, and systemic anticancer therapies [3]. In addition, a paraneoplastic contribution has been hypothesized, whereby tumor-related factors may alter catecholamine signaling, endothelial function, or microvascular reactivity [13]. Although the present study cannot establish causality, the observed association between advanced disease and mortality is biologically plausible and consistent with prior reports suggesting that cancer status substantially influences outcomes among patients with Takotsubo syndrome [5,14].
The mortality observed in our cohort (38.5%) was considerably higher than that reported in unselected Takotsubo populations and reinforces the important prognostic impact of malignancy. Contemporary registry studies have challenged the historical perception of Takotsubo syndrome as a benign condition [1,2], demonstrating significant rates of in-hospital complications and mortality. Furthermore, recent cardio-oncology cohorts and meta-analyses have consistently reported worse outcomes among patients with cancer-associated Takotsubo syndrome [6,15]. Our findings extend these observations by showing that mortality occurred predominantly among patients with advanced-stage disease and those receiving palliative care. Patients with advanced cancer experienced a markedly higher risk of death than those with localized disease (80.0% vs. 18.8%, p = 0.015), while all deaths occurred in patients receiving non-curative treatment. Importantly, all deaths were attributed to cancer-related causes, and no cardiac-related deaths were observed.
In contrast, Takotsubo-related clinical severity markers, including nadir left ventricular ejection fraction, were similar between survivors and non-survivors. Although the small sample size precludes definitive conclusions, these findings suggest that oncologic disease burden may be more associated with prognosis than the severity or reversibility of myocardial dysfunction. Importantly, this interpretation should be viewed as hypothesis-generating and requires confirmation in larger prospective studies.
A notable finding was the high rate of recovery of left ventricular systolic function among patients who survived long enough to undergo repeat imaging. Follow-up echocardiography was available in 18 patients, and all demonstrated normalization of left ventricular systolic function, with a median time to documented recovery of 10 days. These findings are consistent with the established reversibility of Takotsubo syndrome and with prior reports demonstrating favorable cardiac recovery despite substantial non-cardiac morbidity [2]. However, this observation should be interpreted in the context of a competing risk of death, as the remaining eight patients died from cancer-related causes before follow-up echocardiography could be performed. Therefore, recovery could only be confirmed among patients who survived to reassessment.
Another clinically relevant observation concerns the relationship between anticancer therapies and Takotsubo syndrome. In our cohort, no single chemotherapeutic agent emerged as a dominant trigger, reflecting the heterogeneity of oncologic treatments. Nevertheless, 27% of patients were receiving active systemic therapy at the time of the event, and several cases occurred in temporal proximity to fluoropyrimidine-based chemotherapy or immune checkpoint inhibition. These observations are consistent with previous reports linking Takotsubo syndrome to fluoropyrimidines, capecitabine, immune checkpoint inhibitors, and selected targeted therapies [9]. However, most cases occurred in the setting of multiple concurrent stressors, including anticancer therapies, systemic inflammation, infection, surgery, and psychological stress acting as interacting contributors rather than isolated causes [14].
These findings support an individualized approach when considering re-exposure to anticancer therapy after recovery of left ventricular function. Recurrence of Takotsubo syndrome is uncommon, with reported rates below 10%, and we observed no recurrences in patients who resumed oncologic treatment [16]. This is consistent with prior series in which most patients were able to safely restart chemotherapy after cardiac recovery with appropriate monitoring [16]. Accordingly, the occurrence of Takotsubo syndrome should not automatically preclude continuation of potentially life-prolonging cancer therapy [17]. Instead, optimal management requires close collaboration between cardiology and oncology teams to balance oncologic urgency with cardiovascular safety and to facilitate timely re-initiation of treatment once the acute cardiac condition has stabilized.
The exploratory analyses evaluating predictors of mortality and ventricular recovery should be interpreted cautiously. Although advanced or metastatic disease emerged as the strongest predictor of mortality in both univariable and adjusted analyses, the small sample size and limited number of outcome events resulted in wide confidence intervals and increase the possibility of model instability and overfitting. Similarly, the Cox proportional hazards analysis suggested slower documented recovery among patients with advanced malignancy, but this finding should be considered hypothesis-generating given the limited number of patients with serial echocardiographic follow-up.
Overall, our findings suggest that Takotsubo syndrome in patients with cancer should be viewed not only as an acute cardiovascular event but also as a marker of substantial systemic illness. Although myocardial dysfunction is frequently reversible among survivors, the broader oncologic context appears to play a major role in determining outcomes. Larger prospective cardio-oncology registries and multicenter studies are needed to validate these findings, clarify underlying mechanisms, and identify strategies to improve both cardiovascular and oncologic outcomes in this vulnerable population.
Limitations
This study has several limitations. First, the cohort size was small (n = 26) and derived from a single specialized cancer center, limiting statistical power and generalizability. As a result, the number of outcome events was limited, increasing the risk of model instability and overfitting. Consequently, the logistic and Cox regression analyses should be interpreted as exploratory and hypothesis-generating rather than confirmatory.
Second, the retrospective design relied on the completeness and accuracy of medical records. Potential trigger events, symptom onset, and the temporal relationship between anticancer therapies and Takotsubo syndrome may not have been uniformly documented. In addition, the absence of a control group of cancer patients without Takotsubo syndrome precluded identification of treatment-specific or malignancy-specific risk factors.
Third, diagnostic certainty was limited by the fact that invasive coronary angiography and cardiac magnetic resonance imaging were not systematically performed in all patients. Although the median InterTAK Diagnostic Score was high (75.5 [IQR 64.5–80.0]), and all patients had intermediate- or high-probability scores, definitive exclusion of alternative diagnoses such as MINOCA, myocarditis, or sepsis-related cardiomyopathy was not possible in every case [10]. However, a validation study conducted in a Middle Eastern population confirmed its robust diagnostic accuracy, reporting 90.9% sensitivity and 100% specificity at a regionally optimized cutoff of ≥36 points, highlighting its applicability and reliability in this population [18]. Nevertheless, all patients demonstrated clinical and echocardiographic features consistent with Takotsubo syndrome, and patients with intermediate-probability scores underwent additional anatomical or tissue characterization before inclusion.
Fourth, follow-up echocardiography was available in only 18 of 26 patients (69.2%). Importantly, the remaining eight patients died from cancer-related causes before repeat imaging could be performed. Therefore, recovery of left ventricular systolic function could only be confirmed among patients who survived long enough to undergo follow-up echocardiography. Although all patients with available follow-up imaging demonstrated normalization of left ventricular function, the possibility of persistent dysfunction among patients who died before reassessment cannot be excluded.
Fifth, an important consideration in this cohort is the potential overlap between Takotsubo syndrome and sepsis-induced cardiomyopathy, particularly given that sepsis was present in 50% of patients. Both conditions may present with acute left ventricular dysfunction, elevated cardiac biomarkers, and hemodynamic instability, creating diagnostic challenges in critically ill patients. However, Takotsubo syndrome typically demonstrates characteristic regional wall-motion abnormalities extending beyond a single coronary territory and is frequently associated with a triggering physical stressor, whereas sepsis-induced cardiomyopathy more commonly presents with global ventricular dysfunction. Nevertheless, some degree of diagnostic overlap cannot be completely excluded, especially in patients who did not undergo comprehensive anatomical or tissue characterization, and this possibility should be considered when interpreting our findings.
Finally, detailed information regarding long-term clinical follow-up was not consistently available, limiting assessment of recurrence, quality of life, functional status, and long-term cardiovascular outcomes. Furthermore, the exploratory analyses evaluating time to left ventricular recovery should be interpreted cautiously given the limited number of patients with serial echocardiographic assessment and the competing risk of death.
FUTURE PERSPECTIVES
Future prospective, multicenter studies are needed to better characterize the epidemiology, pathophysiology, and outcomes of Takotsubo syndrome in patients with cancer. Attention should be directed toward elucidating the mechanistic links between malignancy, anticancer therapies, systemic inflammation, autonomic dysregulation, endothelial dysfunction, and stress cardiomyopathy. Improved understanding of these pathways may help explain why patients with cancer appear to be at increased risk of developing Takotsubo syndrome and experiencing worse overall outcomes.
An important research priority is the development of robust risk stratification strategies capable of identifying patients at greatest risk for Takotsubo syndrome during cancer treatment. Future studies should evaluate the role of clinical characteristics, biomarkers, electrocardiographic findings, and advanced cardiac imaging in predicting disease occurrence, severity, recovery, and recurrence.
In addition, prospective cardio-oncology registries and collaborative studies are needed to define optimal diagnostic pathways, monitoring strategies, and management approaches for this complex population. Such efforts may ultimately facilitate earlier recognition, improve cardiovascular outcomes, and allow safer delivery of potentially life-prolonging oncologic therapies.
CONCLUSIONS
Takotsubo syndrome in patients with cancer represents a clinically important condition at the intersection of cardiology and oncology, occurring in the setting of multimorbidity and multiple concurrent physical and emotional stressors. Despite substantial morbidity, frequent intensive care unit admissions, and high overall mortality largely related to advanced malignancy, recovery of left ventricular systolic function was common among patients who survived to undergo follow-up echocardiography. These findings suggest that outcomes in patients with cancer-associated Takotsubo syndrome are more associated with underlying oncologic disease burden than with the severity or reversibility of myocardial dysfunction.
Conflict of Interest
The authors declare that they have no competing interests.
Availability of Data and Materials
The dataset used and/or analyzed during the current study is available from the corresponding author on reasonable request, subject to institutional and ethical regulations governing patient confidentiality.
Funding statement
This study received no external funding.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The dataset used and/or analyzed during the current study is available from the corresponding author on reasonable request, subject to institutional and ethical regulations governing patient confidentiality.