Fuzzy boundaries between physical and emotional triggers in Takotsubo syndrome: a scoping review

Abstract

Background

Takotsubo Syndrome (TTS) is a cardiac condition that mimics myocardial infarction, often in the absence of obstructive coronary disease. TTS is typically described as triggered by stressful/traumatic events, which are often categorized as either emotional/psychosocial or physical; nevertheless, emerging evidence suggests that this stark classification may be limiting. We hypothesize that, in most cases, clinicians may overlook possible physical and emotional components or concurrent intense emotional experiences of physical TTS triggers during patients’ assessment.

Methods

We searched through four databases for clinical case reports of TTS patients with clearly identified antecedents that may have elicited the cardiac event.

Results

After a thorough study selection, 219 studies were included in the final scoping review and a total of 259 cases were presented, 210 of which were female. Most of the studies reported in selected literature described physical stressors (n = 135) as triggers of TTS, while 38 reported emotional triggers; in 45 case studies, both physical and affective stressors were present.

Conclusions

Most physical triggers may have an emotional side that seems to be overlooked by physicians; we thus propose a new perspective where the boundaries between physical and emotional stressors in TTS may be fuzzy, promoting the role of clinical psychology in cardiological settings.

Supplementary Information

The online version contains supplementary material available at 10.1186/s12872-026-05716-w.

Introduction

Background

Takotsubo syndrome (TTS), also known as stress cardiomyopathy, is a cardiac syndrome that mimics myocardial infarction, presenting key symptoms such as chest pain, dyspnoea, and hypotensive shock, but without obstructions or spasms in the epicardial coronary arteries [1].

TTS can manifest in several patterns: the typical apical ballooning variant, the rarer midventricular pattern, and the reverse variant, where the basal segments of the left ventricle are affected [2]. While the apical ballooning form is the most common, the rarer variants are often associated with more severe hemodynamic disturbances and worse prognosis [3]. The exact pathophysiology of TTS remains unclear, and whether it represents a maladaptive or protective cardiocirculatory response is still a subject of debate [4]; unquestionably, a significant surge in catecholamines, primarily epinephrine and norepinephrine, is indeed observed in patients with TTS. Notably, also catecholamine-increasing drugs have deemed responsible for inducing TTS, both in human and in animal models [5, 6].

Catecholamine surge stimulates aberrant sympathetic activation and β2-adrenoceptor signalling [7] with a significant modulation by nitrosative and oxidative stress [8] and ultimately causes myocardial stunning, particularly in the apical regions of the heart [7].

The prognosis of TTS has been thoroughly studied: recent studies detected factors associated with higher short- and long-term mortality with Takotsubo mortality, such as older age, and concurrent psychiatric and somatic diseases [9, 10]. Evidence regarding pharmacological management, and β-blocker therapy in particular, remains heterogeneous. Lu and colleagues [9] reported an association between β-blocker use and higher rates of in-hospital complications, whereas more recent studies have suggested a potential reduction in mortality during follow-up [11]. Such variability may depend on pharmacological factors, as most commonly used β-blockers are intentionally β1-selective and have limited activity on β2-adrenoceptors implicated in Takotsubo pathophysiology [12].

TTS is traditionally seen as a consequence of stressful or emotionally intense events, which is why it is also known as “broken-heart syndrome” or “stress cardiomyopathy”, even if in some cases TTS occurs in the absence of a clear trigger [13]. However, there is still debate on the nature of its relationship with previous overwhelming experiences [14, 15]: consistently with this statement, literature illustrates that many TTS patients meet the criteria for a post-traumatic stress disorder diagnosis or exhibit subthreshold traumatic symptoms [16], highlighting the importance of psychological assessment, as already done in studies on other cardiovascular diseases [17].

The response to an intense emotional event also depends on other psychological individual factors: some studies report pre-morbid psychiatric conditions that contribute to the onset of disease, mainly mood and anxiety disorders [18], while others stress the importance of good coping skills, optimism and general emotional wellbeing as protective factors against adverse events that can trigger a TTS event [19].

Some authors point out that some cases of TTS may also occur in the presence of a physical trigger [20], which encompasses events such as surgery, medical procedures, infections, and the effects of substance use [21]. On the other hand, emotional triggers can include a broad range of experiences, from minor altercations with acquaintances to the profound distress of witnessing the death of a loved one [22]. Although physical stressors appear to be more common than emotional ones [23], conflicting findings exist regarding their relative frequency [24].

Neuroscientific evidence stresses the importance of recognizing mind and body as parts of a whole that work together and influence each other in numerous ways [25]: for instance, emotional and bodily inputs activate both the upper and lower portions of the brainstem, which in turn are involved in heartbeat and breathing regulation and autonomic activation [26]; moreover, atherosclerotic accumulations due to epinephrine spillover in the plasma have been related to emotional stress by several authors [27].

At the same time, numerous authors claim that physical stressors often trigger strong emotional responses: for example, undergoing surgery generates fear and anxiety, especially in the perioperative period [28]; furthermore, violent events such as crashes, assaults or injuries often predict intense emotional reactions [29, 30] and/or the development of post-traumatic stress disorder or acute stress disorder symptoms [31].

As pointed out by Templin and colleagues [32], the presence of triggering factors that are both physical and emotional – i.e. mixed triggers – in TTS seems to be rare in comparison to merely physical triggers; however, this rarity may stem from a tendency to overlook emotional correlates during the patient’s assessment, possibly excluding an important information, since mixed triggers seems to be associated with higher mortality [24].

As a result, the distinction between physical and emotional factors may be blurred, especially in the context of stressors; consequently, triggers typically categorized as physical may have emotional implications, and vice versa. To date, only one systematic review [23] has examined physical and emotional triggers through an analysis of clinical case reports, but it did not address the potential interconnection between these stressors.

Objective

In light of the evidence illustrated above, we hypothesize that, in most cases, physical stressors may have an emotional component or interconnect with concurrent intense emotional experiences.

This scoping review seeks to expand on previous studies by analysing case reports of this disease and evaluating whether the authors considered possible concurrent emotional experiences (and vice versa) to further clarify the boundaries and relationship between physical and emotional stressors as precipitants of TTS.

Meterials & methods

Study design

This systematic scoping review was conducted following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) extension for scoping reviews, i.e., PRISMA-ScR [33, 34], which is available in Supplementary materials.

Search strategy

We searched through four databases, namely PubMed, Scopus, Web of Science, and PsycInfo, for case-report studies published from 2010 up to February 2024. We chose 2010 as the starting time for our review, as it marks the year of the most significant update regarding the symptomatology of Takotsubo syndrome, which provided key revisions to the diagnostic criteria [35].

The query string introduced in each of the databases was the following:

(takotsubo syndrome OR tako-tsubo OR stress cardiomyopathy OR takotsubo cardiomyopathy OR apical ballooning) AND (physical stress? OR physical trigger? OR surgery OR illness) AND (emotional stress? OR negative emotions OR grief OR trauma).

Where possible, we selected filters for study design and language to retrieve clinical case studies in English and Spanish; we also conducted a manual screening for additional articles consistent with our research topic using the reference lists of all articles that met the eligibility criteria.

Eligibility and exclusion criteria

We chose to include clinical case studies or reviews of clinical case studies of patients diagnosed with Takotsubo cardiomyopathy in which the authors clearly illustrated potential physical and/or emotional precipitating factors.

The exclusion criteria chosen for this scoping review were the following:

• Studies focusing on patients with a primary diagnosis other than Takotsubo syndrome.

• Every other type of study apart from case-report studies (e.g., RCT, qualitative studies, case-control studies, etc.)

• Case studies that did not consider possible triggering factors or where the authors did not clearly describe a precise precipitating stressor.

• Case studies in which the diagnosis of TTS was inconsistent with 2010 Mayo Clinic criteria (e.g., pheochromocytoma-related TTS).

• Case studies reporting recurrent forms of TTS where authors did not discuss potential stressor(s) for every Takotsubo event experienced by the patient.

Data extraction and categorization

The following data were extracted from each of the included studies: title, name of the authors, year of publication, patient’s sex (male or female) and types (physical or emotional, the distinction between which has been already illustrated in the objective section); we then regroup both trigger types in sub-categories (e.g. as for physical stressors, we included subtypes such as physical traumas, surgery or medical intervention, various kinds of medical disease, etc.). Finally, we reported whether the authors identified an interaction or co-presence between physical and emotional precipitating factors.

Results

Study selection

Figure 1 shows the PRISMA flow diagram that illustrates the study selection process: after inserting the query string on each of the chosen databases, we found a total of 454 articles; after duplicates removal (n = 24), the remaining results were assessed through title and abstract reading. We then excluded 168 articles, since they did not meet the inclusion/exclusion criteria stated before.

Fig. 1.

PRISMA flow diagram

The remaining reports (n = 262) were thoroughly reviewed via full-article reading, thus bringing the total number of case-report studies included in the scoping review to 219: only two of them were in Spanish, while the remaining were written in English.

Patients’ characteristics

Table 1 illustrates demographics, in-hospital mortality and distribution of trigger frequencies across the different case-reports. Most patients described in the case studies were female (n = 210), while n = 49 male patients’ cases were discussed (81.1% vs. 18.9%). The mean age was 57.6 years (± 19.76).

Table 1.

Patients’ characteristics

	N	%
Gender
Male	49	18.9%
Female	210	81.1%
Mean age (years)	57.6 (±19.76)
Male	58.1 (±23.56)
Female	57.6 (±19.78)
Triggers
Physical	136	62.1%
Emotional	38	7.4%
Mixed (physical and emotional)	45	20.5%
In-hospital mortality	6	2,32%

Most of the studies reported in selected literature described physical stressors (n = 136; 62.1%), while n = 38 (17.4%) reported emotional/psychosocial triggers; in n = 45 (20.5%) case studies, both physical and affective stressors were present.

In-hospital mortality was rare in our sample, as it was reported in 2.32% of cases. Other medical data of the patients (e.g., risk factors, blood pressure, etc.) were inconsistently reported or not reported at all across studies and therefore were not included in this table.

Table 2 shows the frequencies of each specific trigger subtype and links each of them to the relevant studies that have discussed it (see Supplementary materials for a complete list of these reports’ references). The most common physical trigger subtype was Surgery or medical intervention (n = 64; 29.2%), while the most frequent emotional/psychosocial one was Emotionally intense or potentially traumatic experience (n = 30; 13.7%).

Table 2.

Trigger types and subtypes

Trigger types	Trigger subtypes	N	%
Physical	Surgery or medical intervention (e.g. dialysis, cardioversion, anesthesia, etc.)	64	29.22%
	Rheumatic disease	1	0.46%
	Metabolic disease (e.g. goiter)	2	0.91%
	Neurologic discase (c.g. delirium)	8	3.65%
	Physical violence (e.g. assault)	3	1.37%
	Adverse effects of drugs or other substances (e.g. alcohol withdrawal, dobutamine,etc.	27	12.33%
	Infection (c.g. sepsis)	7	3.20%
	Complicated delivery (e.g. cesarean section, vaginal tear during delivery, etc.)	1	0.46%
	Cerebrovascular disease (e.g. subarachnoid hemorrhage)	4	1.83%
	Cardiorespiratory disease (e.g, pulmonary embolism)	2	0.91%
	Respiratory disease (e.g. pneumonia)	2	0.91%
	Gastrointestinal disease (e.g. peritonitis)	5	2.28%
	Physical trauma (e.g. car crash, fall, etc.)	17	7.76%
	Intense physical activity	2	0.91%
	Other medical condition or experience (e.g. hyponatremia)	33	15.07%
	Cardiovascular disease (e.g. acute myocardial infarction)	3	1.37%
Emotional	Grief	9	4.11%
	Dramatic news (c.g. recciving a diagnosis)	6	2.74%
	Quarrel or altercation	5	2.28%
	Psychopathology	11	5.02%
	Distress related to medical experiences (e.g. preoperational anxiety, delivery-related stress, etc.)	20	9.13%
	Emotionally intense or potentially traumatic experience	30	13.70%
	Work-related stress	4	1.83%

A Sankey diagram (Fig. 2) illustrates possible emotional/psychosocial components of those triggers deemed as purely physical.

Fig. 2.

Possible emotional/psychosocial components

Discussions

This study aimed to deepen the understanding of stressful events triggering TTS, focusing on the commonly adopted distinction between physical and emotional factors. Through a scoping review of clinical case reports, we sought to clarify the role of these triggers and their potential interaction in the onset of the condition.

In our analysis, we found that most TTS episodes occurred after physical stressors, which is consistent with previous results [21, 36]; nevertheless, physical stressors may have a dual influence, as they may be accompanied by significant emotional responses [20]. For instance, several case studies reported perioperative stress cardiomyopathy, with psychopathology often identified as a contributing factor in its onset [37–40]. For example, Bartoli and colleagues [41] and Khalili and colleagues [42] described patients undergoing surgery who were also severely traumatized by previous experiences. Lee and associates [43] found that several psychopathologies, including PTSD, inversely predicted surgical outcomes. Furthermore, surgery itself may represent a traumatic trigger and, in vulnerable individuals, a potential source of re-traumatization [44, 45].

Surgery and other medical interventions were often associated with distressing emotional experiences, such as preoperative anxiety [46] or the stress of undergoing treatment for severe diseases like cancer [47]. Substantial evidence shows that such medical interventions can provoke significant fear and anxiety, especially in the preoperative period, leading to heightened emotional distress [48, 49]. Notably, anaesthesia itself was a common factor among patients who experienced distress (e.g., [45, 50]). Studies have shown that many patients find the prospect of anaesthesia frightening and manifest concern about revealing personal information, feeling drowsy after surgery or not waking up after [51, 52].

This review identified a few TTS cases as adverse effect of drugs or substance use, which can be classified into two pathways: the first, where TTS is primarily linked to withdrawal symptoms or exposure to illicit substances (e.g., [53, 54]); the second, where TTS is associated with iatrogenic effects from vaccines, therapeutic drugs, or other medical interventions (e.g., [55, 56]). In both cases, the introduction of a substance into the body, whether medication or not, can induce discomfort or alterations in patients. This was observed in three cases where authors stated that these side effects precipitated TTS alongside emotionally intense experiences, such as receiving unwelcome news or experiencing distress from a medical intervention [57–59]. Even without a concurrent psychosocial trigger, the drug or substance itself may provoke strong emotional responses. For example, alcohol withdrawal may induce delusions, paranoia, and anxiety [60], which overlap with emotional responses observed in patients under medication [61].

Several cases of stress cardiomyopathy were reported in the context of other diseases, including cardiovascular [62–64], neurological [65–67], and autoimmune conditions [68, 69]. Additionally, TTS cases were precipitated by infections (e.g., [70–72]), as well as other medical conditions such as hyponatremia, hypothermia, or rhabdomyolysis [73–75].

Being affected by a disease is strongly associated with stress, discomfort, depression, and other psychopathologies [76], which may further contribute to increased vulnerability to TTS [77]. In addition, some of these medical conditions may result from traumatic or intensely stressful events: this was the case of a woman who developed hypothermia and fell into a coma after being buried alive by an avalanche. The authors suggested that both her extremely low temperature and the overwhelming sense of impending doom caused by the traumatic event could have triggered TTS [78].

The last cluster of physical triggers identified in this review was related to injuries, including blunt traumas, falls, and car accidents (e.g., [79–81]), as well as violence [82–84]. These traumatic experiences not only caused physical harm, but also had psychological effects, which, in most cases, were recognized by the authors as potential triggers for TTS. For example, the case presented by Alcaraz-Mor et al. [82] involved a woman who was assaulted at work and developed stress cardiomyopathy accompanied by a panic attack the following day. Injuries constitute a particular case in which individuals experience various psychological reactions, regardless of the presence of visible physical damage, such as social anxiety and avoidance [85, 86]. Furthermore, people suffering from blunt trauma must often confront their sense of fragility and vulnerability [87, 88].

Finally, in some reports, it is hard to identify a psychosocial component, as seen in the two cases induced by intense physical activity, where neither patient exhibited signs of acute or chronic psychological distress [89, 90]. Nevertheless, most of the included reports attributed the onset of TTS to physical stressors without addressing the psychopathological, traumatic, and distressing aspects associated with them.

On the other hand, it is well established that intense emotional stress induces measurable bodily responses (i.e., a physical reaction), including acute sympathetic activation and catecholamine surge, which are related to TTS pathophysiology [91, 92]. From a mechanistic standpoint, current evidence suggests that an acute pulse of catecholamine release may be sufficient to trigger TTS, particularly when combined downstream with biased β2-adrenoceptor post-receptor signalling and inappropriate activation of nitric oxide synthase pathways, ultimately leading to myocardial stunning through nitrosative stress mechanisms [4, 6–8, 92]. In this framework, both emotional and physical stressors may converge on a shared biochemical cascade, suggesting that their clinical distinction may not necessarily reflect fundamentally distinct pathophysiological pathways.

To summarize, while the distinction between physical and emotional triggers is clear in some cases, in others these stressors are not discrete categories but rather exist along a spectrum, defined by fuzzy boundaries. The contribution of Ostachowska and colleagues [93] provides valuable insight into this complexity: the authors suggested that TTS could serve as a protective function by preventing permanent myocardial damage during intense stress, through a mechanism resembling dissociative amnesia, as both involve a surge in catecholamines [94, 95].

Supporting recent findings [23, 91], our review revealed that most TTS patients are female. Many authors claim that gender differences depend on the reduction of oestrogen levels in postmenopausal women, which may lead to an abnormal response from the sympathetic nervous system (SNS), thus increasing the likelihood of experiencing a TTS episode [96]. However, not only is the role of oestrogen in TTS development unclear [97], but it should also be noted that women are generally more vulnerable to the effects of stressful events on cardiovascular risk [98], regardless of the stressor type [99]. Furthermore, within a framework where physical stress could also be emotional stress, women may be more susceptible to TTS due to their heightened exposure to psychosocial stress [100].

Beyond the clinical distinction between physical and emotional stressors, it should be acknowledged that TTS episodes ultimately converge on shared neurochemical pathways, including acute catecholamine surges [6], β2-adrenoceptor signalling [7], and downstream nitrosative stress mechanisms [8]. These shared biochemical processes may further contribute to blurring the boundaries between different types of precipitating stressors.

Conclusions

This scoping review provides a deeper understanding of the differences and potential overlap between TTS stressors of any kind. Although temporal proximity alone does not establish causality, the present review raised the possibility that some stressors described as antecedent events may plausibly act as contributory or interacting factors within a multifactorial pathophysiological process.

In addition, our findings may imply that, in many cases, the psychological consequences and co-occurrences of the so-called physical stressors are often left undiscussed in many reports, which may suggest that healthcare experts often underestimate the psychological impact that a physical trigger has on patients. In fact, other authors report that the psychological features of TTS patients are often underassessed [13, 101] and that this assessment is often carried out well after the cardiac event [17].

Consequently, recognizing this emotional dimension could offer valuable insights into the underlying mechanisms driving the onset of this syndrome and provide a better insight into this complex syndrome.

Limitations

The present study is not without limitations.

First, no formal validation process was employed to assess the cases and regroup them in sub-categories, which may introduce classification bias in the categorization of physical and emotional triggers. Although categorization was performed according to explicit criteria, interpretation of precipitating factors in case reports may remain partially subjective.

Second, because only published case reports explicitly describing precipitating triggers were included, this review is inherently affected by selection bias. Cases in which emotional or physical antecedents were not investigated, insufficiently explored, underreported, or considered clinically irrelevant may have been systematically excluded. As a consequence, the observed distribution of trigger types may reflect reporting practices rather than true epidemiological proportions.

Furthermore, reliance on published case reports exposes the study to publication bias, as unusual, severe, or psychologically salient cases are more likely to be reported in the literature, whereas more typical or less narratively compelling presentations may remain unpublished. Relatedly, reporting bias and ascertainment bias must be considered: in many clinical contexts, emotional aspects are not systematically assessed during acute cardiological evaluation, and therefore their absence in the report does not necessarily imply their absence in the patient’s experience.

In addition, clinical case reports do not represent the typical spectrum of TTS presentation and are intrinsically limited in external validity. Their descriptive nature prevents causal inference, limits generalizability, and precludes quantitative assessment of the relative contribution of different trigger types. The absence of robust empirical and longitudinal data further restricts the clinical applicability of these findings.

Finally, as a scoping review, the present study was designed to explore conceptual boundaries rather than to provide pooled effect estimates or establish causal relationships. Therefore, the conclusions drawn should be interpreted cautiously and viewed as hypothesis-generating rather than practice-changing.

Clinical implications and future directions

This review sheds light on the apparent dichotomy between physical and emotional triggers in TTS, pointing out its inconsistency; in fact, both types share neurophysiological, metabolic, and vascular underlying factors [102]. Importantly, if these triggers converge on common mechanisms, limiting psychological evaluation to patients with an emotional antecedent is conceptually and clinically unjustified. Based on the findings of this review, physicians, particularly cardiologists, should therefore consider the assessment of TTS patients’ mental health regardless of the nature of the eliciting factor. This requires strong collaboration with clinical psychologists, who are fundamental to evaluate patients’ mental functioning and its impact on the onset and prognosis of the disease beyond the immediate cardiological care. Incorporating these assessments into the medical record, along with recommendations for psychological support if indicated, could provide more tailored interventions and enhance patient care.

Future studies should focus on providing quantitative data on the relationship between TTS and its antecedents and on how patients diagnosed with this disease cope with emotions and manage stressful or traumatic events, in order to further refine treatment approaches and improve patient outcomes.

Abbreviations

TTS

Takotsubo syndrome

SNS

sympathetic nervous system

Authors’ contributions

M.S. and F.G. conceptualized the study. M.S., A.M. and F.G. looked for articles to include in the review and selected the relevant case reports. D.A., L.G. and E.C. provided fundamental medical knowledge to improve the quality of the paper. F.G., D.A. and A.T. reviewed and edited the final manuscript.

Funding

This research was supported by a PhD scholarship under the National Recovery and Resilience Plan (PNRR), funded by the European Union – NextGenerationEU [B53C24002870006] and awarded to M.S.

Data availability

Data sharing is not applicable to this article as no datasets were generated or analysed during the current study.

Declarations

Ethical approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.