INTRODUCTION
Epidemiological characteristics of Takotsubo syndrome
The epidemiological characteristics of Takotsubo syndrome (TTS, also known as Takotsubo cardiomyopathy) vary significantly according to sex, age, and other triggering factors. Multiple studies have indicated that females account for more than 80% of patients with TTS, predominantly postmenopausal women[1,2]. For example, a retrospective study of 345 patients with TTS reported that 91% were female, with a mean age of 72 ± 12 years[2]. The global incidence of TTS is increasing. Hospital discharge data in the United States from to 2007-2012 showed that the incidence of TTS increased from 52 to 178 per million discharges, representing a more than threefold increase[3]. Psychological stressors, such as bereavement and sudden emotional events, and physiological stressors, such as infections, surgery, and neurological diseases, are commonly identified. For example, the incidence of TTS among patients with aneurysmal subarachnoid hemorrhage ranges from 2.2% to 7.7%[4,5], while the in-hospital mortality rate among patients with TTS precipitated by infection is 7.1%, which is significantly higher than that observed in other trigger groups[2].
The clinical outcomes of TTS exhibit considerable heterogeneity. The International Takotsubo Registry study indicated that the in-hospital mortality rate among patients with TTS was approximately 3.5%; however, patients with comorbid renal dysfunction had a poorer prognosis. Patients with an estimated glomerular filtration rate < 30 mL/(min∙1.73 m2) at admission have a 1.817-fold higher risk of adverse events than those with estimated glomerular filtration rate > 60 mL/(min∙1.73 m2)[2,6]. Additionally, the recurrence rate of TTS is approximately 1%-2%, and about 35% of recurrent cases present with atypical left ventricular ballooning patterns, such as the mid-ventricular type[7]. Notably, although male patients with TTS account for only 11.9% of cases, their 3-year mortality rate is significantly higher than that of female patients (hazard ratio = 2.61), and they are more likely to have a lower socioeconomic status[8]. These findings suggest that TTS should not be regarded as a benign disease. Its prognosis is closely associated with precipitating factors, comorbid conditions, and sex-related differences.
The role of psychological factors in the pathogenesis of TTS
Multiple studies have supported the role of psychological factors in the pathogenesis of TTS. Case-control studies have demonstrated that the prevalence of anxiety disorders among patients with TTS is as high as 24.4%, which is significantly higher than that among patients with acute myocardial infarction (AMI) (9.4%) and healthy controls (0%)[9]. Furthermore, patients with TTS exhibit significantly higher post-traumatic stress disorder (PTSD) symptom scores within one month after onset compared with patients with AMI (β = 0.55) and healthy controls (β = 0.92), and this difference is independent of depressive symptoms[9]. Long-term follow-up studies have found that patients with TTS continue to report higher depressive symptoms 23 months after onset, as reflected by Patient Health Questionnaire-9 (PHQ-9) scores (5.2 ± 5.2 vs 2.5 ± 2.4 in healthy controls, P = 0.039), as well as greater illness-related anxiety based on Whiteley Index-7 scores (2.1 ± 1.7 vs 0.7 ± 1.3, P = 0.005)[10].
A case report described a patient with TTS and comorbid chronic anxiety who experienced a second recurrence even in the absence of clearly identifiable triggers, suggesting that psychological factors may play a role in recurrence risk in some individuals[11]. Autonomic nervous system dysfunction precipitated by psychological stress plays a central role in TTS pathogenesis. Patients with TTS demonstrate significantly reduced heart rate variability (HRV), which is associated with impaired emotional regulation[12]. A study focusing on female patients with TTS found that those with high levels of psychological distress exhibited poorer systolic blood pressure recovery after acute psychological stress (effect size d = 0.57), suggesting that psychological factors may contribute to TTS pathogenesis by modulating cardiovascular stress reactivity[13]. Collectively, these findings suggest that psychological factors function not only as precipitating events for TTS, but also as modifiers of disease prognosis through persistent autonomic nervous system dysregulation.
Pathobiological mechanisms of TTS
The pathobiological mechanisms of TTS center on sympathetic nervous system hyperactivation and involve catecholamine-mediated toxicity, coronary microvascular dysfunction, and myocardial metabolic abnormalities. Studies have shown that plasma catecholamine levels are significantly elevated in patients with TTS during the acute phase. Even 37 months after onset, these patients exhibited an exaggerated blood pressure response to psychological stress, as shown by the Stroop test (P < 0.001), along with reduced vagal modulation[14]. Coronary microvascular dysfunction is a key pathological feature in TTS. Multiple studies have confirmed that patients with TTS demonstrate reduced coronary flow reserve, microvascular spasms, and endothelial dysfunction, and that these abnormalities are associated with increased sympathetic-mediated vascular reactivity[15,16]. For example, von Willebrand factor levels are significantly higher in patients with TTS than in healthy controls, suggesting that endothelial injury may contribute to TTS pathogenesis[16].
Myocardial metabolic abnormalities also play a significant role in TTS. Metabolomic studies have indicated that patients with TTS exhibit impaired myocardial energy metabolism during the acute phase, characterized by elevated acetyl-CoA levels and reduced tricarboxylic acid cycle turnover[17]. Furthermore, the myocardial tissue in patients with TTS demonstrates contraction-band necrosis, interstitial edema, inflammatory cell infiltration, and pathological changes closely associated with catecholamine-induced cardiomyocyte apoptosis[18]. Reduced estrogen levels in postmenopausal women may exacerbate catecholamine-mediated toxicity. Estrogen exerts protective effects on cardiomyocytes through regulation of β-adrenoceptor expression and antioxidant activity, and its deficiency may increase susceptibility to TTS[15]. Emerging evidence also implicates non-coding RNAs and epigenetic modifications in TTS pathogenesis. For example, specific microRNAs, such as miR-16 and miR-26a, have been found to regulate β-adrenergic receptor signaling and apoptosis pathways in stressed myocardium, potentially modulating susceptibility to catecholamine toxicity[19,20]. Furthermore, psychological stress can induce epigenetic changes, including altered DNA methylation patterns in genes encoding catecholamine synthesis enzymes (e.g., tyrosine hydroxylase), which may contribute to sustained sympathetic hyperactivation[21]. Regarding the protective effects of estrogen mentioned earlier, mechanistic studies suggest that estrogen mitigates catecholamine toxicity by enhancing β2-adrenergic receptor coupling to the protective G(i) protein pathway, and by reducing oxidative stress through upregulation of antioxidant enzymes such as superoxide dismutase[22,23]. Collectively, these mechanisms constitute the stress-nervous system-cardiac pathological pathway underlying TTS and provide potential targets for clinical intervention (Figure 1).
Figure 1 Psychobiological mechanisms and intervention targets in Takotsubo syndrome.
CBT: Cognitive-behavioral therapy; VR: Virtual reality; TCA: Tricarboxylic acid; CMR: Cardiac magnetic resonance.
DIAGNOSTIC TECHNIQUES AND CLINICAL PRACTICE FOR TTS
Imaging diagnostic techniques for TTS
Imaging techniques are central to the diagnosis of TTS, with echocardiography serving as the first-line modality because of its accessibility and rapid availability. Typical TTS presents as left ventricular apical ballooning with basal hypercontractility, reflecting wall motion abnormalities that are not confined to a single coronary artery territory[24]. Two-dimensional strain imaging has further demonstrated the distinction between TTS and AMI. Left ventricular basal longitudinal strain was significantly higher in patients with TTS than in those with AMI (P = 0.02), and in midventricular TTS, an apical strain cutoff value of -7.85% achieved 95% specificity for differentiating atypical from typical forms[25]. Cardiac magnetic resonance (CMR) provides higher diagnostic sensitivity for TTS by detecting myocardial edema, late gadolinium enhancement, and microvascular obstruction. Myocardial edema identified on T2-weighted imaging is a key feature that distinguishes TTS from myocarditis[26]. Beyond the visual assessment of edema and late gadolinium enhancement, quantitative CMR parameters such as T1 mapping and extracellular volume (ECV) fraction offer additional diagnostic value. Native T1 and ECV are typically elevated in acute TTS owing to myocardial edema and inflammation; however, they tend to normalize or show significant improvement during follow-up as the myocardium recovers[27]. This dynamic change can help differentiate TTS from acute myocarditis (where ECV may remain elevated due to fibrosis) and chronic myocardial infarction (where ECV elevation persists due to scar tissue).
Imaging manifestations of less common TTS variants warrant particular attention. For example, in biventricular TTS, echocardiography may demonstrate concurrent hypokinesia of both the left and right ventricular apices, often in association with neurological disorders such as status epilepticus[28]. Reverse Takotsubo, characterized by basal ballooning, presents with preserved apical contraction and reduced basal motion and is more frequently observed in younger patients with a mean age of 60 years and in those without a history of hypertension[29]. Dynamic left ventricular outflow tract obstruction (LVOTO) is a serious complication of TTS. Echocardiography can identify an LVOTO gradient > 30 mmHg; in this setting, inotropic agents such as dobutamine should be avoided, and β-blockers are preferred[30]. Collectively, these imaging characteristics facilitate accurate TTS diagnosis and provide essential information for guiding treatment decisions.
Application of psychological assessment in TTS diagnosis
Psychological assessment serves an important complementary role in TTS diagnosis by facilitating the identification of potential psychological precipitants and prognostic risk factors. Research indicates that patients with TTS frequently report elevated levels of anxiety, with state anxiety scores significantly higher than those of healthy controls, as well as depressive and PTSD symptoms following onset[31,32]. For example, a study of 47 female patients with TTS reported a mean PTSD symptom score of 35, exceeding the clinical cutoff of 33, and anxiety scores were negatively correlated with left ventricular ejection fraction (r = -0.30, P < 0.05)[13]. Psychological assessment instruments, such as the PTSD Checklist (PCL-5) and Hospital Anxiety and Depression Scale, can effectively identify these psychological disturbances and provide an empirical basis for subsequent intervention[32].
The integration of psychological assessment with imaging techniques may further improve diagnostic precision. For example, the degree of myocardial edema detected on CMR was positively correlated with anxiety scores (r = 0.45, P < 0.01), suggesting that psychological stress may contribute to myocardial injury through inflammatory mechanisms[33]. These findings support the incorporation of structured psychological assessment as a routine component of TTS diagnostic evaluation to ensure a comprehensive assessment of both physical and mental health status.
Despite its utility, the integration of structured psychological assessments into routine cardiology practice faces several practical barriers. These include time constraints during acute hospital admissions, lack of trained personnel (e.g., psychologists or trained nurses) in cardiac units, and potential patient reluctance to discuss mental health. To overcome these barriers, brief, nurse-administered screening tools (e.g., the 2-item PHQ for depression) could be implemented. Digital platforms (e.g., tablet-based self-assessment kiosks) offer another scalable solution, allowing patients to complete questionnaires in the waiting room. Furthermore, establishing a clear referral pathway to cardio-oncology or liaison psychiatry services can ensure that patients who screen positive receive appropriate follow-up.
Evolution of clinical diagnostic criteria for TTS
The clinical diagnostic criteria for TTS have evolved from a diagnosis-by-exclusion model to an integrative diagnostic framework. Early diagnostic approaches primarily relied on the Mayo Clinic criteria (2004), which included: (1) Transient left ventricular wall motion abnormalities; (2) Absence of obstructive coronary artery disease; (3) Presence of psychological or physiological stress; and (4) Exclusion of other cardiomyopathies[24]. However, these criteria had several limitations. Approximately 30% of patients with TTS lack clearly identifiable stress precipitants, and the differentiation of atypical forms, such as the midventricular and basal types, was challenging[2]. The InterTAK Diagnostic criteria, proposed by an international expert consensus in 2018, refined diagnostic assessment by introducing a scoring system, with ≥ 50 points required for diagnosis, and incorporating indicators such as electrocardiography changes, biomarkers, and imaging features[34]. For example, the InterTAK criteria assign 15 points for ST-segment elevation on electrocardiography, 10 points for elevated troponin, and 20 points for left ventricular apical ballooning, significantly improving the diagnostic sensitivity (85%) and specificity (90%)[34].
The evolution of the diagnostic criteria also reflects the increasing recognition of special populations. For example, pediatric patients with TTS often present with atypical wall motion abnormalities, such as global hypokinesia, and triggers are frequently neurological disorders, such as intracranial hemorrhage[26]. Pregnancy-associated TTS requires differentiation from peripartum cardiomyopathy, with a diagnosis supported by a history of stress exposure, such as delivery or surgery, and rapid recovery of left ventricular function, typically within 4 weeks[35]. In addition, during the coronavirus disease 2019 pandemic, TTS diagnosis required careful exclusion of myocarditis and viral cardiomyopathy; CMR T2-weighted imaging and late gadolinium enhancement facilitated differentiation[36]. This evolution reflects a transition in TTS diagnosis from a reliance on a single morphological standard to the adoption of a multidimensional and individualized approach, thereby providing more precise guidance for clinical practice.
PSYCHOLOGICAL INTERVENTION STRATEGIES FOR TTS
The role of psychological intervention in TTS treatment
The role of psychological interventions in TTS treatment is receiving increasing attention, with the core objectives of reducing psychological stress, improving autonomic nervous system function, and preventing recurrence. Cognitive-behavioral therapy (CBT) is the most extensively studied intervention. In a published study protocol for an ongoing randomized controlled trial, the authors proposed the evaluation of internet-based CBT. Preliminary findings from a small-sample, uncontrolled pilot study suggested that patients with TTS who received CBT showed a reduction in anxiety scores (from 12 to 7, P < 0.05). However, these results should be interpreted with caution due to the lack of a control group, blinding, and the short follow-up period in this exploratory study[37]. Group psychological support has also demonstrated beneficial effects. A study involving eight patients with TTS who participated in creative workshops on artistic expression and experience sharing reported significantly reduced psychological distress scores (d = 0.62), and participants described enhanced emotional support and improved understanding of their condition[32].
The mechanisms underlying psychological intervention may involve regulation of the autonomic nervous system function. Studies have reported that patients with TTS who underwent CBT demonstrated significantly increased HRV, with the low frequency/high frequency ratio decreasing from 2.5 to 1.8 (P < 0.05), suggesting improved sympathetic-vagal balance[12]. Psychological interventions may exert therapeutic effects by attenuating inflammatory responses. Patients with TTS who received six weeks of psychological support exhibited a substantial decrease in mean plasma interleukin-6 levels (from 120 pg/mL to 22 pg/mL, P < 0.05). Although statistically significant, this magnitude of reduction is unusually large and may be influenced by the small sample size, measurement variability, or regression to the mean. Therefore, this finding requires independent validation in larger, well-controlled studies[38]. These findings suggest that psychological intervention not only improves psychological well-being in patients with TTS but may also influence disease prognosis through physiological pathways.
Psychological support techniques for patients with TTS
Psychological support techniques for patients with TTS are diverse and include individual psychotherapy, group support, art therapy, and internet-based interventions. Individual psychotherapy emphasizes cognitive restructuring and assists patients in identifying and modifying maladaptive thought patterns. For example, in addressing the common fear of recurrent cardiac events among patients with TTS, therapists applied psychoeducation and exposure-based techniques, reducing illness anxiety scores from 18 to 8 (P < 0.01)[32]. Group support interventions reduce social isolation through structured sharing of peer experiences. A group intervention involving 12 patients with TTS demonstrated significantly increased social support scores, from 25 to 38 (P < 0.05), and reduced recurrence rates[32].
Art therapy is particularly relevant to psychological support for TTS. Creative workshops that incorporate painting, writing, and related expressive modalities enable patients to process and communicate emotions. Participants demonstrated significantly increased post-traumatic growth scores from 35 to 52 (P < 0.05)[32]. Internet-based interventions provide accessible treatment options to patients residing in remote areas. A user-centered Internet-based CBT program comprising nine modules, including stress management and emotion regulation, developed with patient input achieved 90% satisfaction[39]. These techniques offer multiple therapeutic options for psychological support in patients with TTS and require individualized selection based on clinical needs.
Impact of psychotherapy on TTS prognosis
Evidence regarding the effect of psychotherapy on the prognosis of TTS is currently limited. To date, no prospective cohort study or randomized controlled trial has reported the effects of psychological interventions on difficult clinical outcomes such as mortality, rehospitalization, or major adverse cardiovascular events in patients with TTS. The only published randomized controlled trial protocol (E-SMINC) is ongoing and has not yet been results[37]. Observational studies have suggested potential improvements in the quality of life and psychological distress; however, these findings require confirmation in well-designed trials with adequate sample sizes and long-term follow-ups. Notably, the relationship between the timing of intervention and prognosis has not been established.
FUTURE RESEARCH DIRECTIONS IN TTS
Future research on psychobiological mechanisms of TTS
Future research on the psychobiological mechanisms of TTS will emphasize molecular-level elucidation in the following areas. First, the interaction between psychological stress and autonomic nervous system function, such as the synergistic activation of the hypothalamic-pituitary-adrenal axis and the sympathetic nervous system under stress, needs to be investigated. Studies have reported significantly elevated cortisol levels in patients with TTS, 25 μg/dL compared with 10 μg/dL in healthy controls (P < 0.05), and these levels are positively correlated with catecholamine concentrations[40]. Second, the roles of inflammation and oxidative stress should be clarified. For example, psychological stress-induced release of inflammatory mediators, such as interleukin-6, may contribute to myocardial injury through activation of the nuclear factor-kappa B pathway; nuclear factor-kappa B expression levels are significantly elevated in myocardial tissue of patients with TTS (P < 0.01)[40]. Third, genetic and epigenetic factors need to be explored. For instance, β-adrenoceptor gene polymorphisms, such as Arg389Gly, may influence susceptibility to TTS; patients carrying the Gly allele demonstrate a significantly higher incidence of TTS compared with those carrying the Arg allele (odds ratio = 2.3, P < 0.05)[41].
With respect to research methodologies, single-cell sequencing, spatial transcriptomics, and related high-resolution techniques are expected to provide novel insights into TTS mechanisms. For example, single-cell sequencing can characterize transcriptomic alterations in cardiomyocytes derived from patients with TTS and identify gene modules associated with catecholamine-mediated toxicity[18]. In addition, refinement of animal models is essential. Rat models based on immobilization stress can replicate the myocardial pathological changes observed in TTS and provide an experimental platform for mechanistic investigations[42]. Collectively, these approaches will further clarify the psychological-nervous system-cardiac pathological pathway underlying TTS and facilitate the identification of targets for precision-based interventions.
Application prospects of novel psychological intervention techniques in TTS
Novel psychological intervention techniques have broad application prospects in TTS. First, digital psychological interventions like virtual reality (VR)-based exposure therapy can simulate stress scenarios that precipitate TTS, such as bereavement or sudden illness, thereby assisting patients in strengthening their ability to cope with stress. A preliminary study reported that patients with TTS who received VR intervention exhibited significantly attenuated cardiovascular stress responses, with systolic blood pressure increasing from 30 mmHg to 15 mmHg (P < 0.05)[39]. Second, biofeedback therapy like real-time HRV monitoring can assist patients in regulating autonomic nervous system function. Studies have demonstrated that this intervention can increase HRV in patients with TTS by 20% (P < 0.05)[12]. Third, the integration of music and painting therapies may improve psychological wellbeing through multisensory stimulation. One study reported that patients with TTS who received combined music and painting therapy had significantly reduced depressive symptoms, with PHQ-9 scores decreasing from 15 to 8 (P < 0.01)[32].
Despite their promise, clinical application of these novel techniques in TTS requires careful consideration of their feasibility and safety. For VR-based exposure therapy, simulated stress scenarios (e.g., simulated bereavement or acute illness) must be carefully titrated to avoid inducing excessive psychological or physiological stress, which could theoretically precipitate recurrence. Patients with a history of severe anxiety or panic disorders may also be contraindicated. Similarly, biofeedback, while generally safe, requires a stable hemodynamic status, and its use in patients with frequent ventricular arrhythmias or severe LVOTO should be approached with caution. The advantages of these techniques include convenience, accessibility, and personalization. For example, internet-based CBT programs can adjust module content according to the patients’ psychological characteristics and are not restricted by geographic location[39]. Future research should prioritize the development of standardized protocols and safety guidelines for these interventions, further evaluating their effectiveness, and examining strategies for integrating them with traditional approaches to optimize psychological support in patients with TTS.
Exploration of personalized treatment strategies for TTS
Personalized treatment strategies for TTS should be developed according to patients’ clinical characteristics, underlying pathobiological mechanisms, and prognostic risk profiles. For example, when stratified by precipitating factors, patients with TTS precipitated by psychological stress may benefit from psychological interventions, whereas those with TTS precipitated by physiological stress such as infection require targeted management of the underlying condition[2]. When stratified by left ventricular ballooning patterns, patients with mid-ventricular TTS may benefit from calcium channel blockers such as diltiazem, whereas patients with typical TTS often demonstrate favorable responses to β-blockers[7]. Additionally, biomarker-guided strategies may inform follow-up and adjunctive therapies. Biomarker-guided strategies represent an exploratory area. For instance, elevated carbohydrate antigen-125 levels have been associated with longer hospital stays[43], suggesting that they could potentially identify patients who might benefit from closer follow-up (e.g., echocardiography every 3 months). However, carbohydrate antigen-125 is not a routine test for TTS, and its predictive value for individual patient outcomes remains uncertain. Therefore, prospective studies are urgently required to validate its clinical utility.
Future directions for personalized treatment include several key domains. First, precision interventions informed by multiomics data show promise. For example, metabolomic findings have raised the hypothesis that metabolic support therapies such as coenzyme Q10 could be beneficial for patients with TTS with evidence of energy metabolism disturbances. However, this is a speculative recommendation lacking clinical trial support[17]. Further randomized controlled trials are required to test this hypothesis. Secondly, artificial intelligence-assisted clinical decision-making with machine-learning models may be used to predict individual responses to psychological interventions, with a reported predictive accuracy of 80%[44]. Finally, novel pharmacological strategies are being developed. Medications targeting catecholamine-mediated toxicity, such as combined use of β-blockers and α-blockers, have been shown to significantly reduce myocardial injury in patients with TTS, with troponin levels reduced by 50% (P < 0.05)[14]. Collectively, these strategies aim to deliver more precise and effective treatments for patients with TTS and improve long-term prognosis.
CONTROVERSIES REGARDING THE EFFECTIVENESS OF PSYCHOLOGICAL INTERVENTIONS IN TTS
Controversies regarding the effectiveness of psychological interventions for TTS primarily involve several domains. The first is the timing of the intervention. Some studies suggest that early psychological intervention, within 1 week of onset, improves prognosis, whereas others report that delayed intervention, initiated 1 month after onset, achieves comparable effects[37]. Second, the choice of intervention modality has an effect. Comparative analyses of CBT and group support have yielded inconsistent findings: One study reported that CBT was superior to group support, with anxiety score reductions of 40% vs 25% (P < 0.05), whereas another study found no significant difference[32,37]. Third, there is uncertainty regarding long-term effectiveness. Most available studies have follow-up periods of < 1 year and lack robust long-term outcome data, and some reports suggest that the benefits of psychological interventions gradually diminish after 6 months[37]. A major limitation of the current evidence is its reliance on small, uncontrolled studies and case series. The only cited randomized controlled trial protocol has not yet reported results[37]. Consequently, the observed benefits of the psychological interventions reported in these studies must be considered preliminary. These controversies may arise from the heterogeneity of the study designs. Variations in sample size, intervention intensity, and follow-up duration can contribute to inconsistent results. Future research should prioritize large-scale, multicenter, randomized controlled trials to clarify the optimal timing, modality selection, and long-term effectiveness of psychological interventions, and to generate more reliable clinical evidence.
CONCLUSION
TTS, conceptualized as a mind-heart disorder, has evolved in research focus from a descriptive characterization of clinical features to the elucidation of psychobiological mechanisms, accompanied by the progressive refinement of diagnostic and therapeutic strategies. However, etiological debates, uncertainty regarding the effectiveness of psychological interventions, and ongoing methodological challenges limit the standardization of clinical management. Future research should emphasize the molecular underpinnings of psychobiological mechanisms, application of emerging psychological intervention technologies, and development of personalized treatment strategies to advance precision diagnosis and effective intervention for TTS. At the same time, strengthening multidisciplinary collaboration and adherence to ethical standards will provide a more robust foundation for TTS research, ultimately enhancing patient prognosis and quality of life.
