Takotsubo syndrome (TTS) is a stress-induced cardiomyopathy, characterized by an increased concentration of catecholamines, free radicals, and inflammatory cytokines, endothelial dysfunction, and increased apoptotic activity. High doses of isoprenaline are used in animal models to induce Takotsubo (TT)-like myocardial injury. The aim of the study was to investigate the antiapoptotic effects of liraglutide in experimental TTS and its role in the NF-κB pathway. Wistar rats were pretreated with liraglutide for 10 days, and on days 9 and 10, TT-like myocardial injury was induced with isoprenaline. After the sacrifice on day 11, hearts were isolated for histopathological and immunohistochemical analysis. Liraglutide reduced isoprenaline-induced cardiomyocyte apoptosis by decreasing cleaved caspase-3 (CC3), BCL-2-associated X protein (BAX), and NF-κB and increasing B-cell lymphoma/leukemia-2 (BCL-2). An increase in NF-κB in isoprenaline-treated rats was in positive correlation with proapoptotic markers (BAX and CC3) and in negative correlation with antiapoptotic marker BCL-2. Liraglutide increased BCL-2 and decreased NF-κB, BAX, and CC3, preserving the same correlations of NF-κB to apoptotic markers. It is concluded that liraglutide protects cardiomyocytes against isoprenaline-induced apoptosis in experimental TT-like myocardial injury through downregulation of the NF-κB pathway.

The aim of this viewpoint/commentary on a recent contribution by the Gothenburg takotsubo syndrome (TTS) laboratory, in which the authors provide a comprehensive review/state of the art report on the animal models, currently employed in the elucidation of the pathophysiology of TTS, is to intensify the debate as to what constitutes a suitable TTS animal model with as promising as possible translational potential to the human TTS.

BACKGROUND: The pathophysiology of Takotsubo syndrome (TTS) remains incompletely understood. While coronary microvascular dysfunction (CMD) is a potential pathophysiologic mechanism, evidence is limited.
OBJECTIVE: We sought to evaluate CMD in patients with TTS.
METHODS: Consecutive patients diagnosed with TTS were included and underwent coronary angiography with invasive microvascular function evaluation, including fractional flow reserve, Coronary Flow Reserve (CFR), Index of Microcirculatory Resistance (IMR), and Resistive Reserve Ratio (RRR). Patients had an echocardiography evaluation during their index admission and at approximately 6 weeks.
RESULTS: Thirty patients were included (mean age 74 ±9, 90 % female). Twenty-five patients (83 %) had at least one abnormal coronary microvascular function parameter. Abnormal parameters included CFR<2.5 in 20 patients (67 %), IMR>25 in 18 patients (60 %), and RRR<3.5 in 25 (83 %). Longer time from symptoms to angiography correlated with a higher CFR (r = 0.51, P<0.01), and had an area under the receiver operating characteristic curve of 0.793 (95 % CI 0.60-0.98) for pathologic CFR. Patients with emotional trigger had a lower rate of pathologic IMR compared with non-emotional trigger (36 % vs 81 %, p = 0.01). Follow up echocardiography performed at a median of 1.5 months (IQR 1.15-6) showed an improvement in left ventricular ejection fraction for all patients (from mean of 40 % to 57 %).
CONCLUSIONS: CMD was present in most patients with TTS. The role of microvascular function in TTS may vary according to the clinical presentation and RRR may be more sensitive for the diagnosis of CMD in TTS.

Patients with Takotsubo syndrome displayed endothelial dysfunction, but underlying mechanisms have not been fully clarified. This study aimed to explore molecular signalling responsible for catecholamine excess induced endothelial dysfunction. Human cardiac microvascular endothelial cells were challenged by epinephrine to mimic catecholamine excess. Patch clamp, FACS, ELISA, PCR, and immunostaining were employed for the study. Epinephrine (Epi) enhanced small conductance calcium-activated potassium channel current (ISK1-3) through activating α1 adrenoceptor. Phenylephrine enhanced edothelin-1 (ET-1) and reactive oxygen species (ROS) production, and the effects involved contribution of ISK1-3. H2O2 enhanced ISK1-3 and ET-1 production. Enhancing ISK1-3 caused a hyperpolarization, which increases ROS and ET-1 production. BAPTA partially reduced phenylephrine-induced enhancement of ET-1 and ROS, suggesting that α1 receptor activation can enhance ROS/ET-1 generation in both calcium-dependent and calcium-independent ways. The study demonstrates that high concentration catecholamine can activate SK1-3 channels through α1 receptor-ROS signalling and increase ET-1 production, facilitating vasoconstriction.

Takotsubo syndrome (TTS) is a particular form of acute heart failure that can be challenging to distinguish from acute coronary syndrome at presentation. TTS was previously considered a benign self-limiting condition, but it is now known to be associated with substantial short- and long-term morbidity and mortality. Because of the poor understanding of its underlying pathophysiology, there are few evidence-based interventions to treat TTS. The hypotheses formulated so far can be grouped into endogenous adrenergic surge, psychological stress or preexisting psychiatric illness, coronary vasospasm with microvascular dysfunction, metabolic and energetic alterations, and inflammatory mechanisms. Current evidence demonstrates that the infiltration of immune cells such as macrophages and neutrophils play a pivotal role in TTS. At baseline, resident macrophages were the dominant subset in cardiac macrophages, however, it underwent a shift from resident macrophages to monocyte-derived infiltrating macrophages in TTS. Depletion of macrophages and monocytes in mice strongly protected them from isoprenaline-induced cardiac dysfunction. It is probable that immune cells, especially macrophages, may be new targets for the treatment of TTS.

Background: Although takotsubo syndrome (TTS) is characterized by transient systolic dysfunction of the left ventricle (LV), the time course and mechanism of LV function recovery remain elusive. The aim of this study is to evaluate cardiac functional recovery in TTS via serial cardiac magnetic resonance feature tracking (CMR-FT). Methods: In this Japanese multicenter registry, patients with newly diagnosed TTS were prospectively enrolled. In patients who underwent serial cardiovascular magnetic resonance (CMR) imaging at 1 month and 1 year after the onset, CMR-FT was performed to determine the global circumferential strain (GCS), global radial strain (GRS) and global longitudinal strain (GLS). We compared LV ejection fraction, GCS, GRS and GLS at 1 month and 1 year after the onset of TTS. Results: Eighteen patients underwent CMR imaging in one month and one year after the onset in the present study. LV ejection fraction had already normalized at 1 month after the onset, with no significant difference between 1 month and 1 year (55.8 ± 9.2% vs. 58.9 ± 7.3%, p = 0.09). CMR-FT demonstrated significant improvement in GCS from 1 month to 1 year (-16.7 ± 3.4% vs. -18.5 ± 3.2%, p < 0.01), while there was no significant difference in GRS and GLS between 1 month and year (GRS: 59.6 ± 24.2% vs. 59.4 ± 17.3%, p = 0.95, GLS: -12.8 ± 5.9% vs. -13.8 ± 4.9%, p = 0.42). Conclusions: Serial CMR-FT analysis revealed delayed improvement of GCS compared to GRS and GLS despite of rapid recovery of LV ejection fraction. CMR-FT can detect subtle impairment of LV systolic function during the recovery process in patients with TTS.

The cardiotoxicity of osimertinib, an epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor, has been recently reported when treating EGFR mutation-positive non-small cell lung cancer. In this report, we describe a case of an 81-year-old female patient diagnosed with Takotsubo syndrome (TTS). TTS occurred despite the patient receiving osimertinib retreatment at reduced doses and having no history of cardiac or respiratory disease. The findings of this case suggest that clinicians should consider the possibility of TTS induced by osimertinib.

Background: Takotsubo syndrome (TTS) in male patients is under-studied, particularly in the older population. Methods and Results: From 226 patients with TTS, 44 older male patients (prevalence rate: 19.5%, age: median 77 years) were compared with 182 older female patients (prevalence rate: 80.5%, age: median 80 years). Emotional triggers of TTS were less frequent (2% vs. 19%; P=0.007), whereas physical triggers were more frequent (75% vs. 58%; P=0.040) in older men than in women. Among physical triggers, serious respiratory infection was more common in older men than in women. As initial clues to the diagnosis, ECG T-wave inversion was more frequent (48% vs. 29%; P=0.018) and chest pain and/or dyspnea were less common (23% vs. 38%; P=0.050) in older men than in women. In total, 14 patients (6%) had cardiogenic shock and 41 (18%) had severe heart failure as complications, although there were no significant differences in the frequency of these complications between older men and women. Although cardiac death occurred in 3 female patients (1%) and noncardiac death in 3 male and 5 female patients (4%), there were no significant differences in death rate between older men and women. Conclusions: Emotional triggers of TTS were extremely infrequent whereas physical triggers were common in older men. Although severe heart failure was common, there were no significant differences in the frequency of complications and in-hospital deaths between older men and women.

BACKGROUND: The pathophysiology of Takotsubo syndrome (TTS) is not completely understood and the role of chronic stress is among the main mechanistic links. The aim of this study was to explore whether accumulating hair cortisol concentration (HCC), a novel biomarker of chronic stress, is associated with the occurrence of TTS.
METHODS: A consecutive series of 18 TTS patients and 36 age and sex matched healthy controls were included in our analysis. Hair samples were collected from participants\'\' vertex. The proximal 2.5 cm of hair was cut in equal parts of 0.5 cm, reflecting mean cortisol levels in time intervals of 0-15, 15-30, 30-45, 45-60 and 60-75 days prior to hair collection.
RESULTS: HCC was higher in TTS group compared to controls at any time point and increased over time starting from 75 days prior to the event. The rate of HCC increase was significantly higher in TTS patients versus controls (beta of interaction = 0.48; 95%CI: 0.36-0.60; p < 0.001).
CONCLUSIONS: The steadily increasing trend of HCC in TTS patients suggests that the additive effect of multiple stressful events over several weeks prior TTS onset may disrupt cortisol homeostasis and play a role in TTS pathophysiology.

Modelling human diseases serves as a crucial tool to unveil underlying mechanisms and pathophysiology. Takotsubo syndrome (TS), an acute form of heart failure resembling myocardial infarction, manifests with reversible regional wall motion abnormalities (RWMA) of the ventricles. Despite its mortality and clinical similarity to myocardial infarction, TS aetiology remains elusive, with stress and catecholamines playing central roles. This review delves into current animal models of TS, aiming to assess their ability to replicate key clinical traits and identifying limitations. An in-depth evaluation of published animal models reveals a variation in the definition of TS among studies. We notice a substantial prevalence of catecholamine-induced models, particularly in rodents. While these models shed light on TS, there remains potential for refinement. Translational success in TS research hinges on models that align with human TS features and exhibit the key features, including transient RWMA. Animal models should be comprehensively evaluated regarding the various systemic changes of the applied trigger(s) for a proper interpretation. This review acts as a guide for researchers, advocating for stringent TS model standards and enhancing translational validity.