There are anatomical structural differences in the brain between patients with TTS and healthy controls (69,70). Studies have shown that neurological and psychiatric comorbidities are more prevalent in patients with TTS compared with those with ACS (9,59). Patients with depression and/or anxiety demonstrate functional and structural adaptations in most brain regions, which can predict the presence of TTS (71). During TTS episodes, stress-related structures in the brain undergo anatomical and neurophysiological changes, indicating that stress-induced alterations in the CNS may activate the SNS, leading to TTS (72). During the acute phase of TTS, changes in the volume of the frontal lobe region, insula, anterior cingulate cortex and amygdala occur (73). Whole-brain network analysis confirmed the specificity of central brain structures related to the limbic/autonomic nervous system, showing reduced resting-state functional connectivity, which is therefore important in TTS (74). Growing evidence highlights the importance of the brain-heart axis in the pathophysiology of TTS (58,75-78). Emotional stress can impair neuronal norepinephrine reuptake, leading to elevated local catecholamine levels that amplify sympathetic neural signaling in the heart. This heightened sympathetic activity may trigger symptom development and increase the risk of adverse cardiac events (79,80). Stress triggers the amygdala, hypothalamus and cingulate gyrus activation, innervating the locus coeruleus (the brain's primary center for norepinephrine synthesis). This activation propagates through noradrenergic neurons to engage the hypothalamic-pituitary-adrenal axis, leading to elevated epinephrine and norepinephrine secretion from adrenal medullary chromaffin cells (60,81). These mechanisms likely play a key role in the increased vulnerability to myocardial stunning and contractile dysfunction in patients with TTS.

Single-photon emission computed tomography (SPECT) imaging in the acute phase of TTS has demonstrated increased cerebral blood flow (CBF) in the basal ganglia, brainstem and hippocampus, accompanied by a notable decrease in the prefrontal cortex (61). Moreover, injury to the insular cortex has been identified as a predominant feature in patients with acute ischemic stroke and is linked to the onset of TTS (18). Given the amygdala's pivotal role in stress response regulation, 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) has demonstrated that elevated baseline amygdala activity is linked to a higher risk of developing TTS (82).

Studies have reported morphological differences in cerebral MRI findings of patients with TTS, including reduced cortical thickness in the left and right anteroventral insula and both cingulate cortices, reduced gray matter volume in the amygdala and diminished structural connectivity within the limbic system, when compared with healthy controls (62). In another study, these findings in patients with TTS were corroborated, revealing reduced gray matter volume in the right subcallosal cortex, right middle frontal gyrus and right insular cortex by the anatomical and resting-state functional MRI (73). However, it remains uncertain whether these changes are a consequence or a cause of TTS.

In summary, structural anatomical abnormalities and functional alterations in cerebral metabolism and perfusion are key contributors to TTS. Using advanced cerebral functional and anatomical imaging techniques, along with biomarker profiling, offers valuable insights into the potential causative role of CNS changes in TTS. However, it remains to be determined whether these CNS changes act as primary drivers of TTS or are secondary phenomena induced by the triggering stimulus affecting the CNS.

Given the preceding physical or emotional stress triggers, SNS overstimulation underpins a common pathogenesis following TTS (6,9,53,83). Heart rate variability, a surrogate of autonomic tone, is markedly depressed during the acute phase, particularly within 48 h of admission. This reduction gradually improves during the subacute phase and typically normalizes within 3 months in the chronic phase (84). A study by Vaccaro et al (85) demonstrated through direct muscle microneurography assessments that TTS cohorts exhibit markedly elevated SNS activity and reduced spontaneous baroreflex control compared with controls. Myocardial iodine-123 metaiodobenzylguanidine (123I-MIBG) studies using planar imaging and SPECT have suggested functional alterations in presynaptic sympathetic neurotransmission in patients with TTS (86). These findings provide a potential pathophysiologic explanation for the observed impairment of LV function in TTS.

While physical or emotional stressors are common experiences, SNS overstimulation alone does not account for why only a small subset of individuals exposed to these stressors go on to develop TTS. The brain-heart axis remains a hot topic that requires further exploration and may hold the key to a deeper understanding of the pathophysiology of TTS (21). Pheochromocytomas and paragangliomas, primary endocrine disorders characterized by heightened SNS activation and episodic excessive catecholamine release, can induce a phenocopy of TTS. This further supports the concept of overstimulation of SNS as a critical mechanism in TTS (87-89). A stressful event initiates the activation of the sympathetic nervous system, resulting in the secretion of catecholamines. This suggests that catecholamines play an important role in the occurrence and development of TTS.

The findings indicate that certain individuals may possess a specific predisposition to developing TTS in response to a catecholamine surge (90). Compared with myocardial infarction (MI) patients, individuals with TTS exhibit elevated levels of circulating plasma dopamine, epinephrine and norepinephrine, underscoring the significance of heightened catecholamine release and SNS stimulation in the pathogenesis (41). Due to epinephrine's short plasma half-life and the delay between symptom onset and medical presentation, the peak catecholamine levels may be much higher than those measured retrospectively (46).

Histopathological and microscopic analyses, including light and electron microscopy, reveal morphological alterations and structural deterioration similar to those observed in conditions of severe catecholamine excess. This excess is known to induce microcirculatory dysfunction and direct cardiotoxicity (91,92). Cardiomyocytes differentiated from induced pluripotent stem cells derived from somatic cells of patients with TTS exhibit enhanced β1-AR signaling and heightened catecholamine-dependent responses, highlighting key mechanisms of the TTS phenotype. Notably, these cellular responses are predominantly mediated through β1-AR signaling in TTS. Excessive catecholamines play a direct role in the development of myocardial contraction band necrosis, which is a pathological characteristic of TTS (60,93). During the fight-or-flight response, the swift release of catecholamines markedly elevates heart rate and contractility via the activation of the cAMP-dependent protein kinase A (cAMP-PKA) signaling pathway dependent on β-adrenergic receptors (β-ARs) (94). Catecholamines secreted by the sympathetic nervous system bind to β-ARs, stimulating the activation of cAMP-PKA in cardiomyocytes. Increased PKA activity enhances Ca²⁺ cycling and increases myocardial contractility; therefore, dysregulation of the PKA signaling pathway may be a pathogenic mechanism leading to TTS cardiomyopathy (94). Epinephrine enhances ACE activity and inhibits ACE2 activity through the α1-adrenergic receptor/Gq/PKC signaling pathway, thereby triggering the release of Ang II (95).

Additionally, the phosphatidylinositol 3-kinase/protein kinase B signaling pathway may be activated by elevated catecholamine levels, a mechanism essential for myocardial cell survival and protecting cardiomyocytes from apoptosis (60,96). 123I-MIBG imaging reveals reduced myocardial activity at the mid-ventricle and apex of patients with TTS on SPECT imaging, alongside elevated systemic circulating catecholamines, reinforcing the hypothesis of catecholamine-induced myocardial stunning (7,42,97). Icariin primarily prevents ISO-induced TTS-like heart failure in rats by maintaining the dynamic balance of the reactive oxygen species (ROS) system, promoting the activity of antioxidant components and inhibiting the expression of Toll-like receptor 4/NF-κB signaling pathway proteins (98). This highlights the important role of catecholamines and their mechanisms of action in the occurrence and development of TTS, as well as emphasizing the potential therapeutic role of icariin in regulating oxidative stress and inflammatory responses.

Despite the compelling findings mentioned, the literature reveals a disparity, as several studies have not consistently shown markedly elevated circulating catecholamine levels in TTS compared with the controls (49,97,99-101). A study by Madhavan et al (102) indicated that plasma concentrations of metanephrine and normetanephrine showed no significant differences. These negative findings were further supported by a study showing that 86.4% of patients with TTS had normal plasma levels of metanephrine and normetanephrine (103). These findings challenge the notion that TTS is solely driven by a systemic catecholamine surge. A likely explanation is localized catecholamine release with rapid reuptake or the initial surge being missed due to delayed sample collection.

Additional considerations include the expression of catecholamine biosynthetic enzymes in myocardial cells. Specific enzymes facilitate the local synthesis of approximately one-third of cardiac adrenaline in the heart. There is evidence of differential localization of phenylethanolamine N-methyltransferase (a marker for adrenergic cells), an enzyme involved in adrenaline biosynthesis, within the myocardium (104-106). Catecholamine-producing enzymes are primarily concentrated in the left heart, with a distinct distribution pattern from the base to the apex of the LV myocardium (105,107). This distribution supports the hypothesis that localized myocardial catecholamine excess may play a key role in the pathogenesis of TTS, even when systemic catecholamine levels are not elevated (108). Localized catecholamine release from intrinsic cardiac stores, through autocrine or paracrine mechanisms, may overload ARs in specific regions of the heart, contributing to the regional myocardial dysfunction characteristic of TTS.

It has been hypothesized that the regional differences in myocardial contractility observed in TTS could be explained by variations in the myocardial ARs distribution. A potential systemic catecholamine excess could activate myocardial ARs, leading to positive inotropy and subsequent myocyte death through PKA activation (109). These include ARs-mediated injury, direct catecholamine toxicity, epicardial vasospasm and an increased cardiac workload (60,110). Functionally, this manifests as transient apical LV ballooning. The apical-basal gradient in β₂-ARs explains the differential regional myocardial responses (40).

Another proposed mechanism for TTS involves a shift in high circulating epinephrine-induced intracellular signal trafficking in ventricular cardiomyocytes. Supranormal levels of epinephrine intensely activate the β1-AR and β2-ARs Gs pathway, changing the Gs adenyl-cyclase pathway to β2-AR Gi signaling (111-113). The shift of Gi signaling offers protection by exerting anti-apoptosis and anti-arrhythmia, safeguarding the LV myocardium from catecholamine excess (40). This Gi signaling subsequently triggers the activation of the p38 MAPK pathway, leading to a negative inotropic effect. This effect is likely mediated through the elevation of sodium-calcium ion exchangers and the suppression of L-type calcium channel currents, which together decrease myofilament sensitivity (114,115).

Studies have revealed regional differences in the density of acetylcholinesterase (AChE)-positive nerves and tyrosine hydroxylase (TH)-positive autonomic nerve endings across the LV. The basal region of the ventricle exhibits a 40% higher density than the apical zone. Additionally, TH-positive nerves are more abundant than AChE-positive nerves in the ventricle (45). The increased density of β2-ARs in the apical myocardium is proposed to compensate for the lower SNS endings of apical LV (46). The regional variation of β2-ARs density from base to apex in the LV may explain the differential myocardial response to increased systemic or local catecholamine excess, thereby accounting for the onset of various TTS phenotypes (46).

The coexistence of CAD and TTS is not mutually exclusive. Angiographic findings in most patients with TTS reveal smooth, UCA or minimal non-obstructive plaques. Early theories suggested that TTS might originate from acute plaque rupture, with subsequent spontaneous thrombus resolution or recanalization facilitated by anti-platelet therapy before angiographic evaluation. However, optical coherence tomography imaging has failed to demonstrate ruptured plaques or intracoronary thrombi in the left anterior descending coronary artery, suggesting these changes in the coronary are unlikely to be the primary mechanism of TTS (116).

Recently, MI with non-obstructive coronary arteries (MINOCA) as a new topic has gained increasing attention. A cohort study identified distinct characteristics differentiating patients with TTS from those with MINOCA. Patients with TTS tend to be older, predominantly female and more likely to have a history of psychiatric conditions. Furthermore, they exhibited higher in-hospital mortality and complication rates but experienced fewer major adverse cardiovascular events than MINOCA patients (117).

Epicardial coronary spasm has been proposed as a potential mechanism underlying TTS. In a clinical study of 30 patients diagnosed with TTS accompanied by LV dysfunction without significant CAD, spontaneous multivessel coronary spasm was observed in three patients during angiography. Additionally, multivessel coronary spasm was provoked in six patients by administering acetylcholine or ergonovine (49). Coronary spasms, either at baseline or during acetylcholine provocation, have been observed in Patients with TTS (50-52). In animal models, norepinephrine does not induce a TTS phenotype, whereas epinephrine and isoprenaline do. This distinction arises because norepinephrine, unlike epinephrine, has minimal impact on β1-ARs or β2-ARs Gi signaling (40).

Studies have shown an increase in spasms of both large and small coronary arteries during the occurrence of TTS, indicating that TTS is associated with coronary endothelial dysfunction (60,95,118,119). Endothelial dysfunction may represent an important pathophysiological link between stress and myocardial dysfunction in TTS (120). Female patients with TTS have been observed to have a higher likelihood of a history of migraine or Raynaud's disease, suggesting vascular or endothelial dysfunction (53,54). In healthy individuals, mental stress has been shown to affect flow-mediated (FMD), endothelium-dependent vasodilation, as assessed by high-resolution ultrasound of the radial artery (55). Patients with TTS exhibited transiently impaired brachial artery FMD in the acute phase compared with those with STEMI and healthy controls. However, within 1-3 weeks, FMD in patients with TTS improved markedly, indicating reversible endothelial dysfunction (57).

In a study, 16 female patients with acute TTS demonstrated elevated thrombolysis in MI (TIMI) frame counts across the three major coronary arteries, despite the absence of obstructive CAD (121). Elesber et al (122) reported that among 42 consecutive female patients with TTS, 29 exhibited an abnormal TIMI myocardial perfusion grade (TMPG), an angiographic index of myocardial perfusion. Patients with abnormal TMPG exhibited higher peak troponin levels than those with normal TMPG. Similarly, ECG findings, including deep T-wave inversion or ST elevation, were more frequently observed in patients with abnormal perfusion. This effect reflects abnormal microvascular perfusion. Similarly, the vasodilatory capacity, marked by a transient reduction in coronary flow reserve, was diminished in acute TTS, as evaluated using transthoracic Doppler echocardiography (123).

Increased production of ROS reduces the availability of nitric oxide (NO) in the cardiovascular system and elevated catecholamine release leads to endothelial dysfunction, which further leads to transient impairment of myocardial contractility (56). Excessive catecholamines may lead to endothelial dysfunction in TTS through Ang II and SK4-related signaling pathways (95). Endothelial dysfunction can be prevented by endothelin (ET)-A receptor antagonist following mental stress (55). ET exhibits potent, long-lasting vasoconstrictor effects, indicating it is relevant to spasm (124). Jaguszewski et al (58) reported that a markedly elevated ET-1 plasma level may contribute to microvascular spasms and they also identified downregulation of miR-125a-5p, a regulator of ET-1 expression, in patients with TTS. Exosomal miR-126-3p, derived from endothelial cells, contributes to ion channel dysfunction by inhibiting RGS3 signaling in cardiomyocytes, providing insights into the mechanisms by which endothelial dysfunction affects cardiomyocytes (125). Furthermore, biopsied coronary microvessels from patients with TTS showed evidence of microvascular endothelial cell apoptosis (126). The infusion of ACh and dobutamine in the coronary arteries reveals that microvascular dysfunction is commonly present in patients with TTS. These findings may help explain the reduced coronary flow reserve and microvascular blood flow observed in TTS.

Women constitute nearly 90% of TTS cases, with the vast majority occurring postmenopause, as evidenced by data from the InterTAK Registry, a consortium of 26 centers across the United States and Europe (9,10). This pronounced disparity in sex, coupled with the significant increase in TTS incidence during postmenopausal years, suggests that the biological decline in estrogen levels may heighten susceptibility to TTS. However, the occurrence of TTS despite exogenous hormone use in some patients indicates that estrogen deficiency alone is unlikely to be the primary factor in its pathophysiology (53).

Estrogen has been shown to modulate contractile function and provide cardioprotection. In the absence of estrogen, ovariectomized female rats exhibit an upregulation of β1-AR and L-type Ca²⁺ channel proteins, alongside a reduction in Na⁺-Ca²⁺ exchange proteins. Estrogen supplementation restores the levels of these proteins to those observed in Sham-operated controls (127). Similarly, estrogen supplementation in ovariectomized rats has been shown to reduce c-fos mRNA expression, a marker of cellular activation, in the paraventricular hypothalamic nucleus, LV and adrenal glands. Additionally, it mitigates emotional stress-induced cardiac dysfunction by attenuating hypothalamus-sympathetic-adrenal outflow from the CNS to target organs (64).

Estrogen supplementation increases the levels of atrial natriuretic peptide and heat shock protein 70, both of which play key roles in providing cardioprotective effects (60). Furthermore, it reduces β1-AR levels, thereby mitigating myocardial necrosis caused by sympathetic overactivity during myocardial ischemia (128). This protective effect is further supported by studies showing that norepinephrine induces less forearm vasoconstriction in women compared with men, a difference attributed to greater β2-ARs sensitivity in women (129). Additionally, TTS has been prevented in a rat model through estrogen supplementation or the combined use of α- and β-ARs (64,130).

Case-control studies challenging the estrogen theory suggest that patients with TTS do not differ markedly from STEMI cohorts or population controls in terms of parity, years since menopause, menopausal status, or history of oophorectomy. Notably, hormone replacement therapy was more prevalent in TTS cohorts than in controls, suggesting that although TTS is more prevalent in postmenopausal women, estrogen deficiency alone is unlikely to be the primary or sole factor contributing to the development of the condition (53).

Overall, it is suggested that sex hormone profiles alone are insufficient to fully explain the underlying mechanisms of TTS. While a clear sex bias exists in TTS cases, the central pathophysiological role of estrogen remains unproven. Nonetheless, estrogen may still play a contributory role in increasing susceptibility to the syndrome.

The involvement of underlying genetic mutations in causing or predisposing individuals to TTS remains uncertain. In certain cases, patients with TTS develop a dilated cardiomyopathy (DCM) phenotype, characterized by incomplete recovery of left ventricular ejection fraction (LVEF) during the convalescence phase. Moreover, reports of familial TTS cases suggest genetic predisposition in some individuals who develop the condition (65,66,131). Genes variations in BAG3, APOE, ADRB1, MFGE8, GRK5, ALB, APOB, SAA1, A2M and C3 may predispose certain individuals to a higher risk of developing TTS compared with others (67,68).

One study by Zaroff et al (132) suggested that ARs polymorphisms, particularly in β1-ARs and β2-ARs, are linked to increased troponin release and reduced LVEF. These polymorphisms have been identified as contributing factors to the heightened risk of cardiac abnormalities observed in patients with SAH. However, whole-exome sequencing study shows similar functional adrenergic polymorphisms in patients with TTS compared with population control (133). Unlike genetic forms of DCM, there is no definitive evidence of a systematic Mendelian inheritance pattern in TTS. Instead, it is more likely that genetics, alongside other risk factors, contributes to an increased susceptibility to TTS when interacting with epigenetic influences (Fig. 3).