Frontiers in Cardiovascular Medicine is delighted to present the ‘Reviews in’ series of article collections. Reviews in Takotsubo Syndrome will publish high-quality scholarly review papers with the aim to highlight recent advances in the field, whilst emphasizing important directions and new possibilities for future inquiries. We anticipate the research presented will promote discussion in the Cardiovascular Epidemiology and Prevention community that will translate to best practice applications in clinical, public health and policy settings. The Reviews in Takotsubo Syndrome collection welcomes full-length, mini, or systematic review papers. New articles will be added to this collection as they are published.

Kobe University

Higashi Kakogawa Hospital

Frontiers in Cardiovascular Medicine

Cardiovascular Epidemiology and Prevention

Reviews in Takotsubo Syndrome

Editorial on the Research Topic <a href="https://www.frontiersin.org/research-topics/50974/reviews-in-takotsubo-syndrome">Reviews in takotsubo syndrome</a>Takotsubo syndrome (TTS) is an acute cardiac condition characterized by transient left ventricular systolic dysfunction and regional wall motion abnormalities in the absence of obstructive coronary disease or angiographic evidence of acute plaque rupture. It was first conceptualized by Dr. Sato in 1990 (<a href="#B1">1</a>). Previously thought to be a benign condition, TTS is now recognized to be associated with a substantial in-hospital mortality rate (<a href="#B2">2</a>), wherein the mortality risk in long-term patients with TTS is equivalent to that of acute myocardial infarction, with an all-cause mortality rate of 5.6% per patient-year (<a href="#B3">3</a>–<a href="#B5">5</a>). Moreover, the recurrence rate of TTS has been reported to be 4%–5% (<a href="#B6">6</a>, <a href="#B7">7</a>). Despite several mechanisms being identified in clinical and basic research (i.e., endogenous adrenergic surge, brain-heart axis, coronary vasospasm and microvascular reactivity, metabolic and energetic alterations, and inflammation) (<a href="#B8">8</a>–<a href="#B11">11</a>) to explain the syndrome, and some clinical trials assessing potential interventions for TTS are underway, there are no evidence-based treatments for TTS to date. In four reviews, the current research topic of “Reviews in takotsubo syndrome” nicely summarized important clinical and translational knowledge regarding TTS, thereby contributing to our understanding of its pathogenesis and pathophysiology.In the first review, <a href="https://doi.org/10.3389/fcvm.2023.1244808">Osawa et al.</a> conducted a systemic review and meta-analysis of 14 studies (189,210 patients) published in PubMed and Cochrane Library databases up to December 2022 to investigate the outcomes of patients with TTS and cancer. The authors demonstrated that 8.7% of patients with TTS had current or previous malignancy. Patients with TTS and malignancy had a higher risk of all-cause mortality at the longest follow-up than those with TTS alone. Cancer was significantly associated with an increased risk of in-hospital or 30-day mortality, in-hospital shock, the need for mechanical respiratory support, arrhythmia, and major adverse cardiac events. In contrast, the need for mechanical circulatory support and the risk of cardiovascular death did not differ between TTS patients with and without cancer. In another review, <a href="https://doi.org/10.3389/fcvm.2023.1301383">Tini et al.</a> also provided an overview of contemporary knowledge on the association between TTS and cancer. Although the definition of cancer varies among studies, its prevalence in patients with TTS ranges from 7% to 35%. Several studies have demonstrated an association between cancer and all-cause mortality in patients with TTS. Overall, these two review papers highlight the significant associations between TTS and cancer, underscoring the importance of close collaboration between cardiologists and oncologists to care for patients with TTS and cancer.Midventricular TTS (MV-TTS), characterized by wall motion abnormalities of the middle portion of the left ventricle along with normokinesia or hyperkinesia of the apical and basal portions, is the most frequent atypical subtype. <a href="https://doi.org/10.3389/fcvm.2023.1286975">Padilla-Lopez et al.</a> examined electrocardiograms (ECGs) at three time points (within the first 12 h, at 48 h, and at 5–7 days from symptom onset) in patients with typical TTS (n = 33) and those with MV-TTS (n = 27), as classified by ventriculography. Patients with MV-TTS exhibited a distinctive pattern of ECG abnormalities compared to typical TTS: (1) ST-segment depression in inferolateral leads in the acute phase; (2) less profound and less extensive T-wave inversion that mostly affected leads I, aVL, and V2; and (3) attenuated QT interval prolongation.In the present issue, <a href="https://doi.org/10.3389/fcvm.2024.1351587">Zulfaj et al.</a> reviewed and comprehensively evaluated current animal models of TTS, focusing on their ability to replicate key clinical trials and identifying limitations. In addition, the authors summarized clinical characteristics and potential mechanisms of TTS and introduced a promising novel animal model of TTS. Collectively, this review provides a guide for researchers using animal models of TTS, enhancing translational validity.In summary, this research topic highlights important clinical features of TTS and provides further insights to help us understand its mechanisms in clinical practice. The topic also emphasizes the need for mechanistic translational studies using appropriate animal models, aimed at unveiling precise underlying pathophysiology and developing evidence-based treatment options specifically for TTS in order to improve the prognosis of this syndrome.TH: Writing &#x2013; original draft, Writing &#x2013; review &amp; editing.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

Editorial: Reviews in takotsubo syndrome

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.

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.

Animal models of Takotsubo syndrome: bridging the gap to the human condition

Takotsubo syndrome (TTS) is characterized by a transient left ventricular systolic dysfunction, burdened by significant acute and long-term mortality and morbidity. The prognosis of TTS, especially in the long-term, is influenced by both non-cardiovascular (non-CV) and CV comorbidities, among which cancer is one of the most common. The presence of a malignancy is proven to be associated with higher mortality in TTS. Moreover, a number of anticancer treatments has been reported to possibly cause TTS as a form of cardiotoxicity, even though clearcut associations are lacking. The aim of this narrative review is to sum up contemporary knowledge on the association of cancer and TTS, addressing unmet needs and practical implications. The importance of a close collaboration between cardiologists and oncologists is herein highlighted, both to allow an adequate management of the acute TTS phase, and to actively and safely return to the oncologic management once the acute setting is resolved.

Takotsubo syndrome (TTS) is characterized by a transient left ventricular systolic dysfunction, burdened by significant acute and long-term mortality and morbidity. The prognosis of TTS, especially in the long-term, is influenced by both non-cardiovascular (non-CV) and CV comorbidities, among which cancer is one of the most common. The presence of a malignancy is proven to be associated with higher mortality in TTS. Moreover, a number of anticancer treatments has been reported to possibly cause TTS as a form of cardiotoxicity, even though clearcut associations are lacking. The aim of this narrative review is to sum up contemporary knowledge on the association of cancer and TTS, addressing unmet needs and practical implications. The importance of a close collaboration between cardiologists and oncologists is herein highlighted, both to allow an adequate management of the acute TTS phase, and to actively and safely return to the oncologic management once the acute setting is resolved.

A contemporary update on cancer and takotsubo syndrome

IntroductionTakotsubo syndrome (TTS) encompasses distinct variants, with midventricular (MV) as the most common atypical subtype. While electrocardiogram (ECG) abnormalities are well documented in typical TTS, they are less explored in MV-TTS.</sec>MethodsA retrospective case-control study was conducted where ECGs were reviewed at three time points from symptom onset (within the first 12 h, at 48 h, and at 5–7 days) and compared between patients with typical TTS (n = 33) and those with MV-TTS (n = 27), as classified by ventriculography.</sec>Results12-h ECG findings revealed that typical TTS featured ST-segment elevation through anterior leads V3–V6, with maximal deviation in V3 (0.98 ± 0.99 mm) and V4 (0.91 ± 0.91 mm), whereas MV-TTS featured ST-segment depression in inferior leads (−0.24 ± 0.57 mm in II, −0.30 ± 0.52 mm in III, and −0.32 ± 0.47 mm in aVF) and in precordial leads V4–V6. In 48-h ECG findings, the most significant change was T wave inversion, which was more widespread and deeper in typical TTS, with the most pronounced negative T wave depths, exceeding 3 mm, observed in leads V3–V5; in contrast, in MV-TTS, T wave inversion was evident in fewer leads and showed less depth, with the most pronounced negative T waves reaching 1 mm at most in leads I, aVL, and V2. While the QTc interval was prolonged in both groups at 48 h, this prolongation was more pronounced in typical TTS than in MV-TTS (523 ± 52 ms vs. 487 ± 66 ms; p = 0.029). In ECGs at 5–7 days, results essentially returned to baseline.</sec>ConclusionPatients with MV-TTS exhibited a distinctive pattern of ECG abnormalities, marked by ST-segment depression in inferolateral leads, less profound and less extensive T wave inversion that mostly affected leads I, aVL and V2, and attenuated QT interval prolongation compared to typical TTS.</sec>

Introduction: Takotsubo syndrome (TTS) encompasses distinct variants, with midventricular (MV) as the most common atypical subtype. While electrocardiogram (ECG) abnormalities are well documented in typical TTS, they are less explored in MV-TTS.Methods: A retrospective case-control study was conducted where ECGs were reviewed at three time points from symptom onset (within the first 12 h, at 48 h, and at 5–7 days) and compared between patients with typical TTS (n = 33) and those with MV-TTS (n = 27), as classified by ventriculography.Results: 12-h ECG findings revealed that typical TTS featured ST-segment elevation through anterior leads V3–V6, with maximal deviation in V3 (0.98 ± 0.99 mm) and V4 (0.91 ± 0.91 mm), whereas MV-TTS featured ST-segment depression in inferior leads (−0.24 ± 0.57 mm in II, −0.30 ± 0.52 mm in III, and −0.32 ± 0.47 mm in aVF) and in precordial leads V4–V6. In 48-h ECG findings, the most significant change was T wave inversion, which was more widespread and deeper in typical TTS, with the most pronounced negative T wave depths, exceeding 3 mm, observed in leads V3–V5; in contrast, in MV-TTS, T wave inversion was evident in fewer leads and showed less depth, with the most pronounced negative T waves reaching 1 mm at most in leads I, aVL, and V2. While the QTc interval was prolonged in both groups at 48 h, this prolongation was more pronounced in typical TTS than in MV-TTS (523 ± 52 ms vs. 487 ± 66 ms; p = 0.029). In ECGs at 5–7 days, results essentially returned to baseline.Conclusion: Patients with MV-TTS exhibited a distinctive pattern of ECG abnormalities, marked by ST-segment depression in inferolateral leads, less profound and less extensive T wave inversion that mostly affected leads I, aVL and V2, and attenuated QT interval prolongation compared to typical TTS.

Comparative electrocardiographic analysis of midventricular and typical takotsubo syndrome

BackgroundRecent studies suggested a relationship between Takotsubo syndrome (TTS) and malignancy. However, clinical outcomes of TTS associated with cancer have not been assessed completely. This study was aimed to investigate the outcomes of patients with TTS and cancer.</sec>MethodsWe performed a systematic review and meta-analysis to evaluate the clinical outcomes of TTS in patients with and without malignancy. We systematically reviewed and analyzed 14 studies (189,210 patients) published in PubMed and Cochrane Library databases until December 2022. The primary outcome was all-cause mortality at the longest follow-up.</sec>ResultsThe prevalence of current or previous malignancy in patients with TTS was 8.7% (16,461 patients). Patients with TTS and malignancy demonstrated a higher risk of mortality at the longest follow-up than those with TTS alone (odds ratio [OR], 2.41; 95% confidence interval [CI]; 1.95–2.98; P < 0.001). Moreover, cancer was significantly associated with an increased risk of in-hospital or 30-day mortality (OR 2.36; 95% CI, 1.67–3.33; P < 0.001), shock (OR 1.42; 95% CI, 1.30–1.55; P < 0.001), mechanical respiratory support (OR 1.68; 95% CI, 1.59–1.77; P < 0.001), arrhythmia (OR 1.27; 95% CI, 1.21–1.34; P < 0.001), and major adverse cardiac events (OR 1.69; 95% CI, 1.18–2.442; P < 0.001).</sec>ConclusionsThis study revealed significant associations between previous or active cancer and an increased risk of all-cause mortality and in-hospital adverse events in patients with TTS.</sec>

Background: Recent studies suggested a relationship between Takotsubo syndrome (TTS) and malignancy. However, clinical outcomes of TTS associated with cancer have not been assessed completely. This study was aimed to investigate the outcomes of patients with TTS and cancer.Methods: We performed a systematic review and meta-analysis to evaluate the clinical outcomes of TTS in patients with and without malignancy. We systematically reviewed and analyzed 14 studies (189,210 patients) published in PubMed and Cochrane Library databases until December 2022. The primary outcome was all-cause mortality at the longest follow-up.Results: The prevalence of current or previous malignancy in patients with TTS was 8.7% (16,461 patients). Patients with TTS and malignancy demonstrated a higher risk of mortality at the longest follow-up than those with TTS alone (odds ratio [OR], 2.41; 95% confidence interval [CI]; 1.95–2.98; P &lt; 0.001). Moreover, cancer was significantly associated with an increased risk of in-hospital or 30-day mortality (OR 2.36; 95% CI, 1.67–3.33; P &lt; 0.001), shock (OR 1.42; 95% CI, 1.30–1.55; P &lt; 0.001), mechanical respiratory support (OR 1.68; 95% CI, 1.59–1.77; P &lt; 0.001), arrhythmia (OR 1.27; 95% CI, 1.21–1.34; P &lt; 0.001), and major adverse cardiac events (OR 1.69; 95% CI, 1.18–2.442; P &lt; 0.001).Conclusions: This study revealed significant associations between previous or active cancer and an increased risk of all-cause mortality and in-hospital adverse events in patients with TTS.