Most studies have revealed the effects of adrenergic activation on lipid metabolism in the myocardium, which could accelerate lipid uptake and lipid oxidation (14, 21). Whereas animal models provide evidence that intracellular lipid droplets significantly accumulate in cardiomyocytes during the acute phase of catecholamine overstimulation, which cause myocardial dysfunction in TTS, this metabolic shift is consistent with impaired myocardial FA metabolism, increased intramyocardial lipid accumulation and resultant fatty infiltration in endomyocardial or postmortem biopsy of hearts from patients with TTS (22, 23). The lipid over storage might be explained at least in part by the activation of the Poly(ADP-ribose) polymerase-1 (PARP-1) via SIRT-1 mechanism based on the observation of Bai et al. (24), which decreases energy production, inhibits relevant lipid export and downregulates FA oxidative metabolism. Of note, this toxic intramyocardial lipid accumulation is accompanied by a concomitant impairment in FA uptake (Figure 2). Imaging by PET and single photon emission computed tomography provide support to the decreased ability of apical akinetic areas of the heart to take up FA, as well as the reduction of long-chain FA uptake 3–5 days in post-takotsubo patients (25). These changes is also in-keeping with a shutdown of mitochondrial metabolism, showing a reduction of FA consumption, over storage of uncoupling of oxidative phosphorylation and consequent decline in ATP production, and lead to formation of reactive oxygen species (ROS) by creating lipotoxic intermediates and further aggravate cardiac dysfunction (22, 26, 27). Moreover, excessive lipid and its intermediates, serve as substrates for lipid peroxidation, perturb ion transport processes by impairing intracellular proteins and disrupting the integrity of biomembranes (28). It is reported that malignant arrhythmias in patients with TTS may partly originate from lipid overload mediated the disturbances of voltage-gated potassium ion currents and calcium ion (Ca²⁺) balance and prolongation of action potentials (22, 29). These lines of evidence suggest that oversupply of lipid-related substrates play an important role in the progression of TTS, and, therefore, improvements in cardiac lipid metabolism has been proposed to be a beneficial therapeutic option aimed at protecting myocardial function.

The takotsubo heart is characterized by an overall decrease in myocardial glucose uptake and glycolytic rates in the hypocontractile areas during the acute phase of patients with TTS, and the metabolic abnormalities persist despite restoration of myocardial perfusion (Figure 2) (30, 31). Cardiac PET 18-flourodeoxyglucose, which reflect glucose utilization, has reported that impaired segments exhibit reduced glucose metabolism in the context of normal myocardial perfusion in TTS patients (32). Multiple investigators consider this flow-metabolism mismatch in patients with acute-stage TTS as the metabolic state of stunned myocardium, possibly owing to the fact that shifting levels of metabolites after myocardial stunning cause the decreased activity of key regulatory enzymes of the glycolysis pathway (32, 33). Another possibility is that high levels of circulating catecholamines mediated myocardial insulin resistance (IR) may disturb glucose utilization, thus decreasing glucose uptake (34). Observations that impaired glucose metabolism is related to the reduction of norepinephrine uptake in sympathetic overstimulation of takotsubo cardiomyopathy support this hypothesis (35). Indeed, glucose-insulin-potassium, regarded as a value metabolic intervention to treat TTS, has been reported to facilitate recovery from stunned myocardium by augmenting the amount of available glycolytic substrate (36). Likewise, cyclic adenosine monophosphate-mediated calcium overload and reduced sensitivity to calcium in the hypokinetic regions probably inhibit intracellular translocation of glucose transporter-4 (GLUT4), further contributing to reduced glucose uptake (37). However, animal models of TTS reveal significant increase in glucose uptake as well as metabolites but with reduced availability of final glycolysis metabolites and Krebs intermediates, which are less consistent in contrast to the above-mentioned clinical studies (6). By assessing substrate uptake and metabolism at various time points in the takotsubo rat heart, cardiac glucose uptake tends to increase initially followed by accumulation of glycolysis sugar phosphates, and remain modestly increased in the early compensated stage of TTS but decrease ultimately (21). The impaired glucose metabolism that possibly parallels cardiac dysfunction might be attributable in part to the proposed compensatory mechanism of a cross-regulation of glycolysis and beta-oxidation in an attempt by enhancing the more energy-efficient glycolysis and with the inhibition of β-oxidation via upregulation of gene/protein expression involved in cytoplasmic/mitochondrial glycolysis (6, 38). Therefore, although the early myocardial glucose uptake and its regulatory pathways are enhanced in TTS, the net result of myocardial metabolism is actual metabolite exhaustion and energetic deficit. Interestingly, takotsubo rats and the human condition during the acute phase are found to have increased glucose uptake driven by both cardiac myocytes and non-myocardial cells, such as the activated macrophages (39). In addition, Godsman et al. show upregulated GLUT1, which is primarily involved in cardiac stress responses and predominant isoform present in infiltrating macrophages, rather than the GLUT4 membrane transporter (6, 40). It is likely that the early overall upregulation of glycolysis pathway in the presence of decreased metabolites can also be interpreted by metabolically active macrophage infiltration whilst the absolute myocardial metabolism through glucose pathways actually reduces. The exact mechanism would require further differentiation between myocardial glucose uptake versus inflammatory macrophages during the different stages of acute TTS.

Ketone bodies are primarily produced in the liver from acetyl-CoA and are metabolized in extra-hepatic tissue like myocardium (Figure 2) (41). When myocardial glucose utilization and FA metabolism are impaired, the main ketone body β-hydroxybutyrate (βOHB) is transported through the bloodstream into the heart and then oxidized into acetoacetate, which is further processed into acetyl-CoA utilized in the tricarboxylic acid (TCA) cycle. Two independent studies report that Ketone bodies become the preferred metabolic substrate in the heart in animal models and patients with TTS, indicating a more relevant energy source might be involved in ketone body oxidation in this setting (41, 42). Because the ketone body acetoacetate is preferred over FA by the myocardium according to the hierarchy of cardiac energy usage during acute stress, it favors an adaptive mechanism via ketone body oxidation over FA oxidation to elevate cardiac metabolic efficiency (41, 43). However, increased ketone oxidation suffers from the doubt whether it is accompanied by efficiency improvement in takotsubo hearts. Although the ketone oxidation-associated ketone body uptake and circulating levels of βOHB have been confirmed increased, ketone bodies may not significantly contribute to an increase in myocardial ATP production (44). Consequently, further research is necessary to understand whether the reliance on ketone body oxidation could be regarded as an adaptive or maladaptive response to improve takotsubo cardiac energy and has long-term benefits.

Contemporary evidence strongly suggests that an involvement of the autonomic nervous system, the limbic network, and the renin-angiotensin-aldosterone system (RAAS) support an important role for the neurohumoral system in the pathophysiology of TTS, revealing a deep metabolic connection between the heart and brain.

The sympathetic overdrive remains the cornerstone for TTS pathogenesis with special emphasis on excessive local myocardial catecholamine levels and consequent activation of adrenoceptors in the heart. As evidence supporting increased concentrations of norepinephrine in the coronary sinus in patients with TTS becomes available, it suggests an increase in the local release of myocardial catecholamines and both the cardiac and systemic sympathetic systems that mediate the stress response (14, 63). Initial plasma catecholamine levels among patients with TTS are also several times those in age- and sex-matched patients with Killip class III myocardial infarction and remained substantially elevated even a week after the onset of symptoms. Additionally, increases in local norepinephrine levels released from sympathetic nerve terminals and circulating epinephrine and norepinephrine released from adrenal medullary chromaffin cells have been demonstrated in the acute phase of TTS which might be mediated by neuronally transmitted norepinephrine, further suggesting the activation of the adrenomedullary hormonal system (64). Moreover, TTS patients have evidence of elevated plasma levels of neuropeptide Y, which is stored in postganglionic sympathetic nerves and adrenal chromaffin cells and released in response to stress, along with significantly elevated plasma levels of brain natreuretic peptide and serotonin (63). The enhanced activity of this neuroendocrine stress-response axis is crucial to maintain high levels of stress arousal and related-hormonal output for prolonged periods. Given the central role of sympathetic neurohormonal metabolism in TTS and its well-described associations with clinical outcomes, interest in sympathetic metabolism disorders as a potential treatment target and prognostic value in TTS has increased in recent years.

Recently, the limbic network has been discovered that can mediate the vegetative and endocrine functions of the body during stress conditions of TTS (65). By administering the glucose analog 18F-FDG in the acute phase of TTS, higher neural activity appears in the hippocampus and the other components of the limbic system, which manifests as an increased neuronal glucose metabolism (66). In contrast, decreased metabolism is observed in the pre-frontal cortex during periods of acute mental or physical stress (66, 67). These metabolic alterations were further substantiated by a follow-up study, in which changes in the limbic system appear to persist even after full recovery of cardiac function in TTS.

Finally, the metabolic activity of RAAS is well-represented in both heart and brain, where it becomes activated resulting in elevated plasma neurohormone concentrations in response to acute heart injury and further decompensation. There is evidence that long-term maladaptive activation of RAAS persists in TTS despite “normalization” of LV ejection fraction (LVEF) (68). It further provides a basis for the clinical management of reduction in angiotensin II levels to improve long-term outcomes in TTS patients.

In addition to supporting the clinical relationship between neuroendocrine stimulation and myocardial stunning, the mechanism underlying this association is complex. Beyond the catecholamine-mediated direct myocyte injury, the effects of catecholamine storm systemically, and particularly upon peripheral vasculature, should also be focused on. Extensive research has identified both the central and autonomic nervous systems mediate the stress response in the pathophysiology of TTS (64, 69). As a central principal site for the synthesis of norepinephrine, the activation of locus coeruleus trigger noradrenergic responses after the initial sympathetic overdrive, which in turn stimulates the hypothalamic-pituitary-adrenal axis (3, 14). The result is a surge rapidly in circulating catecholamines, with an afterload dependent mechanism resulting in epicardial and coronary arterial spasm, microvascular dysfunction via the β-adrenoceptor–mediated cAMP-dependent protein kinase pathway and contributing to the development of TTS (3). Notably, from multiple observations, changes of endothelial dysfunction might constitute a strong association between this catecholamine surge and myocardial ischemia, especially in estrogen deficiency-postmenopausal women in TTS. Subsequently validated in an experimental study, Estrogen supplementation largely prevents the stress-induced apical stunning via endothelium-dependent and other independent mechanisms and hypothalamo-sympatho-adrenal outflow from the brain to the target organs (64). Further investigation is needed to clarify the relationship of neuroendocrine stress-response in TTS and whether these responses are pre-existing and contribute to the onset of TTS or are acquired as a consequence of the initial sympathetic storm and TTS episode.

Traditionally recognized as a defining metabolic feature of type 2 diabetes and metabolic syndrome, IR is also a central metabolic manifestation in TTS. Present in most of non-diabetic TTS patients, IR coincides with glucose and lipid metabolism disturbance, defective mitochondrial oxidative metabolism and elevated circulating inflammatory marker (36). Additionally, insulin specifically has been identified to have protective effects on left ventricular contractility and hemodynamics to improve heart function in animal models of catecholamine-induced cardiomyopathy and patients with TTS (36, 70). Since the prevalence of IR in TTS and the well-described association between insulin and pathophysiology, treatment and prognosis of TTS, it appears to be plausible for insulin blood levels as a diagnostic biomarker, which is inversely paralleled with the severity of TTS.

The relationship between IR and TTS initially results from high levels of circulating catecholamines. Researchers reveal significant decreases in pancreatic insulin release and peripheral insulin sensitivity as a consequence of catecholamines overdrive, finally contributing to impaired lipid, glucose and related metabolites utilization of myocardium (27, 70). Subsequently validated in human TTS cohorts, this IR-associated myocardial metabolism variation has also been reported based on metabolomics research results (36). More importantly, these glycolipid changes further result in the development of IR through inducing post-translational modifications of several key factors of the insulin signaling cascade (31). In addition to heightened inflammatory signaling, the mechanistic link between the two is now widely accepted that metabolic abnormalities can phosphorylate insulin receptor substrate (IRS)-1 on serine residues by activating several “stress” kinases, which are major contributors to whole body IR (71). Therefore, improving IR may be a beneficial mechanism aimed at protecting the ischemic myocardium during apical ballooning from the detrimental effects of substrate disorder. In fact, several lines of investigation have been shown that insulin could stimulate glucose uptake in stunned myocardium to reverse the condition of myocardial metabolism from FAs to preferential carbohydrate oxidation for improving cardiac action and metabolic complications (31, 36).

Another common pathophysiologic process of TTS, which significantly impacts the systemic metabolic phenotype, is a shift of metabolic balance toward hypercatabolism, with impairment of the anabolic phase (72). Evidence suggests that excess catecholamines lead to accumulation of metanephrine and normetanephrine of extraneuronal catecholamine metabolites in the circulation, impairments in FA oxidation and increasement of plasma levels of free FA (63). Additionally, norepinephrine overstimulation influences the net cellular synthesis of phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase), two essential enzymes for the anabolic metabolism of glucose, via the β₂-adrenergic receptor signaling pathway, thus blunting gluconeogenesis (63, 72). Aside from the concentration of inhibitory or stimulatory metabolites and the degree of expression and allosteric modification of key regulatory enzymes, changes in metabolic proteins especially transporters, also rapidly control the flux and balance of metabolism pathways in the setting of acute stresses. In 2013, Shao et al. identify the depressed gene expression of ApoB lipoprotein and subsequent decreased lipid export that correlate significantly with cardiac lipotoxicity and downregulation of FA uptake and its oxidative metabolism (22). Since by-products of lipid accumulation or other relevant metabolic intermediates could be released into the plasma compartment, a peripheral blood metabolite signature of hypercatabolism may be detected with metabolomics investigations.

Notably, with elongation of the catabolic phase over the anabolic phase, this metabolic shift causes a depletion of energy storage in cardiomyocytes and a reduced turnover of cell constituents in patients with TTS. Specifically, Kofron et al. find that cell interactions are affected, as a decrease in coupling between cardiomyocytes while an increase in coupling between cardiomyocytes and fibroblasts (73). These observations may ultimately result in alterations in the shape and velocity of action potential predisposing to arrhythmias, fibroblast activation and deposition of extracellular matrix promoting cardiac remodeling, further promoting the development of takotsubo cardiomyopathy.

The diagnosis of TTS is generally based on clinical features in combination with the absence of coronary stenosis and the regional wall-motion abnormalities beyond the territory perfused by a single epicardial coronary artery (34). In patients with acute chest pain and ST-segment elevation urgent diagnostic coronary angiography must be considered to exclude acute myocardial infarction. Patients presenting with stable condition and non-ST-segment elevation could perform CT coronary angiography as an alternative imaging investigation or the International Takotsubo Registry (InterTAK) Diagnostic Score. According to this tool, an InterTAK Score ≤ 70 indicates a low probability for the presence of TTS, while an InterTAK Score ≥ 70 suggests a probability of stress cardiomyopathy of 90% (77). Coronary angiography with left ventriculography should be considered in patients who present with a low probability, while transthoracic echocardiography could be useful in patients with a high score. Of note, in case of positive signals of acute infectious myocarditis, cardiac magnetic resonance imaging should be recommended to exclude infectious myocarditis and confirm the diagnosis of TTS (Figure 3).

Several studies have focused on the potential utility of metabolic imaging, although it has been performed mainly for research purpose to provide additional pathophysiologic information about TTS and has not been determined in the clinical setting. Kurisu et al. (25) note that impairment of myocardial fatty acid metabolism appears to be more severe than myocardial perfusion by using tallium-201 (201Tl) and iodine123-β-Methyl-piodophenyl penta-decanoic acid (123I-BMIPP) dual-isotope myocardial SPECT in 14 postmenopausal women with TTS. More importantly, this metabolic impairment persists during follow-up, even after resolution of myocardial perfusion abnormality and the systolic dysfunction. Similarly, following TTS patients for a longer time, Sato et al. (78) demonstrate a marked perfusion-fatty acid metabolism mismatch in the apical myocardium improved with 6 months. Furthermore, Owa et al. (79) perform serial comparative metabolic and sympathetic nervous imaging in four patients with TTS after the acute event, even though disturbance of cardiac sympathetic innervation persists for 1 year after the improvement of the defective metabolism and perfusion. Recently, in TTS patients who suffered an acute episode > 1 year previously, it has also been shown that reduced cardiac energetic status is in keeping with their exercise and metabolic performance testing (4). Therefore, metabolism-related diagnostic approaches may provide incremental value for the differential and correct diagnosis of TTS, and facilitate therapeutic decision-making in suspected individuals.

To date, there are no randomized clinical trial data or specific guidelines to define the optimal management of TTS patients. Therefore, management algorithms are based on clinical experience and expert consensus. In mild cases with no hemodynamic instability and pulmonary congestion, a short course of diuretic agents and vasodilators to relieve congestion may be sufficient. If hypertension exists, arterial vasodilators and β-Adrenergic blockers are useful. In severe cases complicated by cardiogenic shock, treatment depends on the presence of haemodynamically significant LV outlet tract obstruction (LVOTO). In patients with no LVOTO, inotropic agents, and if not sufficient, early temporary LV assist devices (LVADs) should be considered. In the presence of LVOTO, extracorporeal membrane oxygenation or LVADs as a bridge-to-recovery for refractory cases of TTS with LVOTO or biventricular failure is recommended. If early mechanical support is not available, low dose of levosimendan infusion as a catecholamine-sparing positive inotrope may be with caution. New trial evidence is required to assess the safety and efficacy of levosimendan in these complex patients.

Given that abnormally high sympathetic responses are accepted to have a central role in the pathophysiology of TTS, various types of β-Blockers are often being used acutely and after discharge of patients with TTS. During the acute phase, several clinical cases have demonstrated that β-Blockers, like metoprolol, propranolol and esmolol, are particularly useful in cases with TTS complicated by LVOTO (1, 80). Furthermore, propranolol and phentolamine can prevent necrotic myocardial lesions based on case reports of sympathetic overactivation, whereas necrotic lesions occur in all six patients who received a placebo (81). Of note, β-Blockers have no favorable role on in-hospital mortality in TTS patients with or without LVOTO (82). Indeed, the abrupt withdrawal of metoprolol may even trigger TTS in individual cases (80). For the long-term therapy, β-Blockers, as the most commonly prescribed medication at hospital discharge, have been found to have a protective effect against TTS recurrence (80). Similarly, Labetalol is also deemed valuable in the prevention of recurrent TTS induced by electroconvulsive therapy for depression. However, some observational studies do suggest no beneficial association between long-term β-Blocker use and survival at 1 year in patients with TTS, while angiotensin-converting enzyme inhibitors or angiotensinreceptor blockers are beneficial for survival after propensity matching (83). The authors also report that one-third of patients experience a TTS recurrence during the pharmacotherapy of β-Blockers. As evidences supporting the cardiotoxic effect of high norepinephrine levels through binding to α 1-Adrenergic receptors and the feasibility research of treatment with a combined α- and β-Blocker in the animal model become available (84), carvedilol and labetalol, which both possess the blocker characteristics of non-selective β-Adrenergic receptor and α1-adrenergic receptor, could be considered more for the acute and chronic management of TTS patients. Future randomized clinical trials should certainly evaluate the efficacy, dose, and type of β-Blockers for the treatment of TTS and the prevention of TTS recurrence at follow-up.

Additionally, in contrast to previous perceptions, TTS has long-lasting structural and metabolic alterations associated with a persistent, long-term HF phenotype. Considering the improvements in cardiac function and myocardial energetics of long-term therapy with β-Adrenergic receptor antagonists in HF patients (85), it could be worth identifying the long-lasting regulation mechanisms and metabolic action of β-Blockade or other potential metabolic therapy to better improve the final outcome of patients with TTS. The remaining standard therapies, like mechanical support for acute cardiogenic shock and anticoagulation for patients with severe LV dysfunction, are also thought to indirectly and partly improve cardiac metabolism by diminishing the mechanical workload, thereby sparing the heart energy.

Growing metabolism-related studies serve as important proofs of principle for the application of metabolic modulators to TTS, although there are currently poor understandings of the metabolic regulatory mechanisms over the course of TTS and no definitive and large-scale controlled clinical trials proving the effectiveness of these metabolic or mitochondrial therapeutic intervention for patients with TTS. Given that guidelines available for the management of TTS are absent, therapeutic strategies with the recent evidence from small clinical and animal researches, in particular for targeting substrate utilization and/or oxidative stress, might be promising tools to improve the outcome of patients with TTS beyond that achieved with traditional sympathetic inhibition and symptomatic therapies.

Despite our expanding knowledge of metabolic alterations associated with takotsubo cardiomyopathy, especially the simultaneous dysregulation of glycolytic and beta-oxidation pathways, therapeutic interventions targeting substrate metabolism to manage TTS are lacking in the clinical arena. In terms of a mechanism, myocardial substrate metabolism in the takotsubo heart has been suggested at least a degree of shifting away from FA utilization to preferential carbohydrate oxidation, and thus, further stimulation of glucose myocardial uptake is hypothesized to be beneficial to cardiac bioenergetics, hemodynamics, and restoration of cardiac function. In addition, this approach could also balance overall glucose metabolism between glycolysis and glucose oxidation (27). Indeed, the optimal effects of insulin treatment have been identified in stunned myocardium in light of myocardial IR associated with excessive catecholamine stimulation in TTS with or without diabetes (36). Moreover, insulin therapy combined with infusion of dextrose and potassium solutions and use of β-Adrenoceptor blockers, which could enhance the effectiveness of insulin, improve cardiac performance, exercise capacity, and symptoms, so the complete therapeutic managements should be applied as early as possible in the progress of TTS (36). Another metabolic strategy, estrogen supplementation, increases cardiac glucose uptake and insulin sensitivity, upregulates the cardiac levels of cardioprotective substances and modestly improves LVEF in the human heart (37). However, considering that estrogen replacement is a required condition, but not completely adequate for the treatment of patients with TTS, the detailed mechanism and the viability of this therapeutic approach, especially based on restoring glucose metabolism, are still being questioned. Indeed, the real beneficial effects of estrogen supplementation may be independent of a mild augmentation in cardiac glucose utilization and may instead contribute to alleviating the side effects of increased sympathetic activity on target organs in synergy with insulin therapy and β-Blockers. Therefore, a better understanding of the metabolic link between estrogen and glucose utilization, or whether the time gap exists between this therapeutic action and its full efficacy are needed to disclose.

An alternative therapeutic option is the use of PARP-1 inhibitors for takotsubo cardiomyopathy, which could favorably modulate the deranged metabolism of myocardial FA oxidative pathways by increasing their utilization (6). Furthermore, treatment with PARP-1 inhibitors ameliorate nitrosative stress to further improve energetic impairment in the setting of TTS, but clinical trials investigating their effects remain unsettled (6). In addition, increasing FA uptake with overexpression of ApoB, a myocardial lipid-exporting protein, is found to prevent lipid accumulation and takotsubo-like cardiac dysfunction in mouse models, which is consistent with the evidence that suggests downregulated gene expression of ApoB in the akinetic myocardium is displayed in TTS patients during the acute phase (22). Although the promising results just demonstrated in animal models, these findings suggest that lipid transport system could be a potential therapeutic target and clinical studies should test this in the condition of TTS for which no optimal treatment currently exists.

Modulation of ROS specifically in mitochondria has been a potential target in TTS, given the crucial role of ROS involved in impaired cardiac energetics and metabolic and structural remodeling in progression of takotsubo heart. Hydrogen sulfide (H₂S) is a physiological component mainly produced via cystathionine γ-Lyase (CSE) in the heart, exerting cardioprotective effects on oxidative stress reaction by reducing NADPH oxidase mediated ROS production, thereby functioning as a ROS scavenger (86). In TTS, plasma and myocardial levels of H₂S are significantly decreased, are related to the severity of the disease, while exogenous treatment with sodium hydrosulfide not only recovers the H₂S levels and CSE activity, but also ameliorates cardiac dysfunction and reduces mortality (86, 87). However, because this therapeutic target is underpowered, which has not yet been tested in TTS patients, caution is warranted when discussing H₂S administration in the current guidelines for the treatment of patients with TTS. As other antioxidants, especially α-Lipoic acid, have been proven to be an effective way to ameliorate myocardial dysfunction and remodeling by directly scavenging free radicals and improving antioxidant defense system in TTS patients, future studies and clinical practice should paid enough attention to further translate these mitochondria- targeted antioxidants into clinical conditions (88).

Nrf2 is a transcription factor that actives transcriptional control genes, several antioxidant response elements such as ascorbic acid, SOD, catalase and GPX1, in the presence of ROS (47, 49). Without being a direct antioxidant, Nrf2 nevertheless decreases mitochondrial oxygen stress most likely by driving ROS detoxification pathway, which might be the most powerful endogenous antioxidative signaling pathway to prevent ROS formation in the acute phase of TTS. Nrf2 ameliorates TTS development in various animal models of takotsubo heart, may be safe in TTS patients, and should expand clinic data available from patients with TTS. Given that ROS also have a functional modulation role in modulating Ca²⁺ signaling pathway, targeting the compromised Ca²⁺ release might be an alternative approach. As recently discovered, restoring the abnormalities in cytosolic and mitochondrial Ca²⁺ handling by Ca²⁺-sensitizer levosimendan as an alternative inotrope to catecholamine agent might be promising approaches (89). Finally, increasing SR Ca²⁺ release and reuptake would prevent cardiac hypercontraction, maladaptive cardiac remodeling and Ca²⁺-linked arrhythmias in a rat model of TTS (22). However, clinical application and translation of these ways have not yet been attempted.