Introduction

abchf

ABC Heart Fail Cardiomyop

2764-3107

Sociedade Brasileira de Cardiologia - SBC

10.36660/abchf.20230041

Review Article

Stress Cardiomyopathy (Takotsubo)

0000-0001-8922-4075

Montera

Marcelo Westerlund

Writing of the manuscript ¹

1 Hospital Pró-Cardíaco

Rio de Janeiro

Brazil Hospital Pró-Cardíaco, Rio de Janeiro, RJ – Brazil

Mailing Address: Marcelo Westerlund Montera • Hospital Pró-Cardíaco - Rua Redentor, 111-301. Postal Code 22421-030, Rio de Janeiro, RJ - Brazil E-mail: mmontera@uol.com.br

Potential conflict of interest

No potential conflict of interest relevant to this article was reported.

19 09 2023

09 2023

3 1

e20230041

27 04 2023 08 05 2023 08 05 2023

This is an Open Access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Takotsubo Neuro-Adrenergic Cardiomyopathy Takotsubo Cardiomyopathy Stress Cardiomyopathy

Introduction

Takotsubo Cardiomyopathy (CT), also known as stress-induced cardiomyopathy, is a reversible syndrome that usually presents as an acute coronary syndrome, especially in postmenopausal women. The pathophysiology involves multiple factors, including coronary vasospasm, microcirculation dysfunction, catecholaminergic aggression, and sympathetic hyperactivity. The diagnosis of the classic presentation is the presence of a segmental alteration in the form of ballooning or dyskinesia in the antero-septo-apical region of the left ventricle, associated with hyperdynamia of the basal segments, in the absence of obstructive coronary disease that justifies this alteration in contraction. Initially, it was believed that CT was a self-limiting condition with a good prognosis; however, it is currently recognized as a pathology with a high rate of complications and high morbidity and mortality in the short and long term. Even though the first description was made more than 30 years ago, in 1990, by Sato, the etiology and pathophysiology are still not fully defined, and we still do not have an international guideline for standardizing diagnosis and treatment.

Epidemiology

CT is diagnosed in 1% to 3% of acute coronary syndromes and 0.5% to 0.9% of acute ST-segment elevation myocardial infarctions.¹ It is usually underdiagnosed because the clinical presentation resembles acute coronary syndrome. It characteristically has a higher prevalence in postmenopausal women (80-90%), although patients aged < 50 represent about 10% of cases.² Among younger patients, we observed a higher prevalence of males and atypical forms of CT, with a lower rate of comorbidities, a higher prevalence of psychiatric and neurological disorders, and a higher prevalence of in-hospital complications.² CT has also been described in neonates and children, with equal distribution between genders, and often with ventricular dysfunction and heart failure.³

CT shows an in-hospital mortality rate similar to acute myocardial infarction with ST-segment elevation, with an annual mortality rate of 5.6% and cerebrovascular events of 9.9%. The recurrence rate ranges from 1.5% to 22%, being more frequent in patients < 50 years old.⁴

– Pathogenesis

The main characteristic of Takotsubo is the association of hyperdynamia of the basal portions with anterior or apical akinesia or dyskinesia of the left ventricle, which results in an anatomical configuration of ventricular ballooning. Less frequently, we may have alterations in other segments, such as the mesoventricular and basal segments, and in one-third of the patients, we observed involvement of the right ventricle. These changes in contractility have no anatomical correlation with the distribution of coronary flow. Evolutionarily, changes in contractility are reversible, with full or partial resolution of ventricular dysfunction in hours or weeks.

The different types of changes in contractility, as well as their anatomical distribution, are possibly due to variations in the trunks of sympathetic cardiac activation and the distribution pattern of neuro-adrenoreceptors. These present a more prevalent pattern that makes the apical characteristic the most frequent, but we may have less prevalent variations that confer the different types of the location of the segmental alterations observed in the Takotsubo.^5-12

Several pathophysiological mechanisms for the development of Takotsubo have been proposed, considering sympathetic stimulation as the main factor. The presence in the acute phase of Takotsubo of high levels of serum adrenaline and noradrenaline and of norepinephrine in the coronary sinus indicates hyperactivity of the adrenal medulla as well as local myocardial neuro-adrenergic activity.^13,14

These catecholamines, through different mechanisms, induce contractile hyperstimulation and cardiomyocyte aggression, which are the substrate for the development of apical ballooning in Takotsubo.¹⁵

The frequent demonstration of the presence of physical or emotional stress as a trigger in most patients with Takotsubo,¹⁶ or the association with pathologies of high adrenergic activity such as pheochromocytoma, central nervous system diseases, post-cerebrovascular accident or convulsive crisis, emphasize the central role of sympathetic activity as the main factor for the development of Takotsubo.^17-20 The development of apical ballooning after the infusion of catecholamines, or attenuated after using beta and alpha-blockers, has also been demonstrated.^21-27

Pathophysiological mechanisms of sympathetic hyperactivity:<xref ref-type="bibr" rid="B28">28</xref>,<xref ref-type="bibr" rid="B29">29</xref> (<xref ref-type="fig" rid="f01">Figure 1</xref>)

Figure 1 – Pathophysiology of development of Takotsubo.

a) Cardiotoxicity due to hyperactivation of myocardial neuroreceptors:

In the myocardium, we have sympathetic activity mediated by beta 1 and 2 neuroreceptors and alpha receptors. These neuroreceptors mediate the physiological stimuli of the sympathetic system in the myocardium in positive inotropic, lusitropic, and chronotropic modulation, and when chronically hyperactivated, it is associated with myocardial dysfunction.¹⁶

Sympathetic hyperactivation causes the phenomenon observed in Takotsubo of regional increase in myocardial contractility associated with depression of contractility with ballooning mediated by several pathophysiological mechanisms: hyperactivation of neuroreceptors, inflammatory activation, coronary vasoconstriction, endothelial injury, cardiomyocyte band necrosis and activation of the cellular apoptosis cascade, causing changes in the myocardium in Takotsubo.

The neuro-adrenergic stimulus mediated by norepinephrine released in the synaptic vesicle in the myocardium or by serum adrenaline released by the adrenal gland promotes the activation of myocardial beta-neuroreceptors and alpha-receptors. The stimulation of beta 1 receptors (B1-R), mediated mainly by norepinephrine, promotes the activation of stimulatory G protein (PtnGe), which activates the increase in cyclic Amp that promotes the increase in protein kinase A (PtnQA). PtnQA increases the activity of voltage-gated calcium channels by increasing the calcium levels in the cytosol, causing calcium release by the sarcoplasmic reticulum through activating the ryanodine pump, which is sensitive to calcium in the cytosol. This calcium will bind to the troponin C site, favoring ventricular contraction. In hyperactivation of B1-R, we will have a large increase in PtnQA, which causes a reduction in calcium reuptake by the sarcoplasmic reticulum mediated by Phosfolamban/SERCA2a activity, which becomes dysfunctional, causing an accumulation of calcium in the cytosol. This calcium accumulation is related to several alterations in cardiomyocyte physiology: depression of contractility, inflammatory activation, activation of the apoptosis cascade with reduction of cardiomyocyte mass, promotion of band necrosis, and increase in arrhythmogenic potential by altering phases 2 and 3 of the action potential. Therefore, B1-R hyperactivation promotes increased myocardial contractility and simultaneous myocardial aggression, both mediated by increased calcium in the cytosol.^26-29

Hyperactivation of B2-R mediated by serum adrenaline causes a change in the stimulus pattern via PtnGe to inhibitory PtnG, which promotes the activation of Nitric Oxide Synthetase with increased nitric oxide, which causes depression of contractility and inflammatory activation. The BR have a heterogeneous distribution in the myocardium, with a higher prevalence of B2-R in the anterior and apical region and B1-R in the basal regions of the heart. This heterogeneous anatomical distribution would be the genesis of hypercontractility in the basal portions of the heart and ballooning or akinesia in the apical and anterior regions frequently observed in Takotsubo.³⁰

b) Coronary Vasospasm:

Sympathetic activity causing vasospasm of epicardial coronary arteries has been proposed as a possible cause of Takotsubo, although most patients do not demonstrate coronary spasm even when provocative vasoconstrictive agents are used. The suggestion is that in Takotsubo, oxidative stress induced by sympathetic hyperactivity causes endothelial dysfunction and favors changes in coronary microcirculation.^31-35

c) Microcirculation dysfunction:

The microcirculation dysfunction secondary to sympathetic hyperstimulation has been observed in all patients in the acute phase of Takotsubo, being suggested as an important pathophysiological factor determining myocardial ischemia and ventricular contractile dysfunction based on studies that have demonstrated an altered coronary microvascular response in addition to the increased apoptotic activity of endothelial cells in the microcirculation in patients with Takotsubo. Endothelial and microcirculation dysfunction result from sympathetic alpha-receptor stimulation, promoting vascular dysfunction with reduced vasodilator reserve and favoring microcirculation spasm, with consequent ischemia and contractility depression. This dysfunction in the acute phase proved to be transitory, and its recovery is related to improving the contractile function.^36-40

d) Destabilization or rupture of coronary atherosclerotic plaque:

We can find the presence of atherosclerotic plaques in the anterior descending coronary artery of patients with Takotsubo. In these cases, the use and investigation by intracoronary ultrasound or optical coherence tomography did not demonstrate the presence of ruptured plaques or dissection, emphasizing the need to exclude the presence of unstable coronary disease to confirm the diagnosis of Takotsubo.^41-44

Predisposing factors and triggers for the development of Taktsubo

About 70% of patients who develop Takotsubo usually have emotional or physical stress as a triggering factor, which is common in all individuals.⁴⁵

As only a few people develop Takotsubo, this leads us to the possibility of a genetic and clinical profile predisposing to the development of Takotsubo. By analyzing records and series of cases, we can define the most prevalent clinical profile of patients with Takotsubo by identifying the presence of predisposing factors: hormonal, genetic, psychiatric disorders, and triggers due to physical or emotional stress.

Hormonal

Takotsubo is more frequent in women than men at a 9:1 ratio, predominantly in the postmenopausal phase, indicating that a decline in estrogen levels could play a role in the pathophysiology of the development of Takotsubo. Estrogen acts in the modulation of vasomotor tonus through stimulation of endothelial nitric oxide synthetase and by modulation of neuro-adrenergic vasoconstriction and reduction of central sympathetic activation.^46-49

However, there is a lack of studies that consistently prove the correlation of reproductive hormones with the development of Takotsubo, questioning that these would not have, in isolation, a determining role in its development or prevention.^50,51

Genetic

The possibility of genetic predisposition to Takotsubo has been suggested by some studies that have shown a familial correlation.⁵²However, most studies present conflicting or inaccurate results that demonstrate a polygenic potential or genetic heterogeneity which causes dysregulation of the neuro-adrenergic system, either in its activation or in the polymorphism of the beta and alpha neuro-receptors, which allows the identification of a predisposition line.^53-57

Psychiatric disorders and neurological disorders

A high prevalence of neuropsychiatric conditions has been observed in patients with Takotsubo, with approximately 27% of neurological diseases and 40% with anxiety and depression, as well as in patients with panic syndrome.⁵⁸ Patients with mood disorders have an exacerbated response from the sympathetic system to emotional or physical stress due to greater release with less central and peripheral norepinephrine reuptake.^59,60 The use of antidepressants such as selective norepinephrine reuptake inhibitors increased tissue levels of catecholamines. Both factors increase the sensitivity and degree of sympathetic response to acute stress making these patients susceptible to the development of Takotsubo.^61,62

Physical and emotional stress as triggers

Physical or emotional stress triggers are observed in approximately 70 to 80% of patients. In the International Takotsubo registry, 36% of patients had physical stress, 28% emotional stress, 8% both, and 29% no stress.

Physical stress is more common than emotional stress, affects more men and hospitalized patients, and has a worse prognosis.⁶³

Physical stress is due to surgical procedures, trauma, infectious diseases, medications, and pain.^64-78

Emotional stress is more common in women, postmenopausal women, and outpatients. Situations of emotional stress can be personal or professional, with negative stimuli that generate intense sadness, anger, feelings of dissatisfaction, rejection, fear, anxiety, panic, or confrontation (“Broken Heart Syndrome”), as well as situations of natural disasters or war.^79-81 But also situations with generally unexpected positive stimuli are also related to the triggering of Takotsubo (“Happy Heart Syndrome”) Table 1.⁸²

Table 1 – Physical and Emotional Stress Triggers

Physical Stress Emotional Stress

Postoperative

Sepsis

Renal lithiasis

Pneumonia

Pulmonary thromboembolism

Electrical cardioversion

Atrial fibrillation ablation

Hemorrhagic stroke

Car convulsive crisis

Epilepsy

Pheochromocytoma

Severe asthma attack

Orthopedic trauma

Severe pain

Post-chemotherapy

Drug or alcohol withdrawal syndrome

Hyperthyroidism

Post-cesarean section

Post-infusion of catecholamines

Death of relatives or spouse

Depression

Anxiety crisis

Panic

Job loss

Loss of competition

End of love relationship

Earthquakes, hurricanes, floods

War

Car accident

Intense positive surprise

Marriage

Prize-winning

Reunion with a loved one

Physical Stress	Emotional Stress
Postoperative Sepsis Renal lithiasis Pneumonia Pulmonary thromboembolism Electrical cardioversion Atrial fibrillation ablation Hemorrhagic stroke Car convulsive crisis Epilepsy Pheochromocytoma Severe asthma attack Orthopedic trauma Severe pain Post-chemotherapy Drug or alcohol withdrawal syndrome Hyperthyroidism Post-cesarean section Post-infusion of catecholamines	Death of relatives or spouse Depression Anxiety crisis Panic Job loss Loss of competition End of love relationship Earthquakes, hurricanes, floods War Car accident Intense positive surprise Marriage Prize-winning Reunion with a loved one

Diagnosis

Among all the criteria, the most used in clinical practice are the Mayo Clinic diagnostic criteria and INTERTAK. (Table 2)

Table 2 – Takotsubo diagnostic criteria

Mayo Clinic Revised Criteria INTERTAK criteria

Transient dyskinesia of the LV medial segments, with or without apical involvement; the segmental alteration extends beyond the territory of an epicardial coronary artery; stress triggers often present.

Angiographic absence of obstructive coronary disease or acute plaque rupture.

Acute ECG changes, ST elevation, and/or T-wave inversion or modest troponin changes.

Absence of pheochromocytoma or myocarditis.

Transient LV dysfunction (hypokinesia, akinesia or dyskinesia) presenting as apical or midventricular, basal, or focal segmental ballooning. May have RV involvement. We can transition between different types of segmental change. The segmental change extends beyond the territory of an epicardial coronary artery; however, we rarely have segmental changes corresponding to the territory of a coronary artery.

Physical or emotional stress, or combined, often precede a Takotsubo episode.

Neurological alteration (subarachnoid hemorrhage, stroke, seizures); pheochromocytoma can be a trigger.

Acute ECG changes, with ST elevation or ST depression, T-wave inversion and prolonged QT, and rarely normal ECG.

Moderate elevation of troponin T or I and CK-MB. Frequent elevation of BNP.

Significant coronary disease does not exclude Takotsubo.

Absence of myocarditis.

It predominantly affects postmenopausal women.

Mayo Clinic Revised Criteria	INTERTAK criteria
Transient dyskinesia of the LV medial segments, with or without apical involvement; the segmental alteration extends beyond the territory of an epicardial coronary artery; stress triggers often present. Angiographic absence of obstructive coronary disease or acute plaque rupture. Acute ECG changes, ST elevation, and/or T-wave inversion or modest troponin changes. Absence of pheochromocytoma or myocarditis.	Transient LV dysfunction (hypokinesia, akinesia or dyskinesia) presenting as apical or midventricular, basal, or focal segmental ballooning. May have RV involvement. We can transition between different types of segmental change. The segmental change extends beyond the territory of an epicardial coronary artery; however, we rarely have segmental changes corresponding to the territory of a coronary artery. Physical or emotional stress, or combined, often precede a Takotsubo episode. Neurological alteration (subarachnoid hemorrhage, stroke, seizures); pheochromocytoma can be a trigger. Acute ECG changes, with ST elevation or ST depression, T-wave inversion and prolonged QT, and rarely normal ECG. Moderate elevation of troponin T or I and CK-MB. Frequent elevation of BNP. Significant coronary disease does not exclude Takotsubo. Absence of myocarditis. It predominantly affects postmenopausal women.

The INTERTAK diagnostic criteria incorporate new aspects: (i) dysfunction of the right ventricle or other unusual segments; (ii) no need for the presence of a physical or emotional stress trigger prior to Takotsubo; (iii) neurological alterations and pheochromocytoma as possible triggers for Takotsubo; (iv) possibility of coexistence of significant obstructive coronary disease.

It is proposed to classify Takotsubo according to the type of trigger that precedes it as type 1, 2, 2a, 2b, and 3.^83-86 (Table 3)

Table 3 – Takotsubo’s INTERTAK classification according to trigger type:

Class I: Takotsubo related to an emotional stress trigger

Class II: Takotsubo related to a physical stress trigger

IIa: Secondary to physical activity, medical procedures, acute illnesses.

IIb: Secondary to neurological disorders

Class III: Takotsubo with no identified trigger.

Anatomical types of Takotsubo: (Figure 2)

Figure 2 – Anatomical types of the Takotsubo.

Takotsubo is a transient acute cardiac syndrome with ventricular contractile dysfunction where we have the description of five anatomical types: (Figure 2)

Classic pattern: Seen in about 70% to 80% of patients. Apical akinesia or hypokinesia with hypercontractility of the basal segments, giving the classic octopus-trap appearance that earned the name Takotsubo.

Mesoventricular: Seen in about 15% of patients. Hypokinesia of the middle portion of the left ventricle and hypercontractility of the apical and basal segments.

Inverted or Basal: Seen in about 3% to 5% of patients. Hypokinesia or akinesia of the basal and middle ventricular segments with apical hypercontractility.

Focal: Observed in about 5.5% of patients. Hypokinesia or akinesia of isolated segments, usually anterolaterally

Biventricular or isolated involvement of the right ventricle < 0.5% has an unknown prevalence, its involvement being rare.

Clinical Presentation

The clinical presentation of Takotsubo is more frequent in postmenopausal women who experience unexpected emotional or physical stress, followed by a clinical picture of precordial pain (75%), dyspnea (50%), dizziness (>25%), syncope or pre-syncope (5% to 10%), palpitations due to sinus tachycardia, or in more severe clinical forms such as acute heart failure, cardiogenic shock or sudden aborted death. The main differential diagnoses in the emergency room are acute coronary syndrome and acute myocarditis. As we usually have a clinical picture similar to an acute coronary syndrome, accompanied by electrocardiographic alterations and elevation of cardiac injury enzymes, despite the absence of obstructive coronary disease, Takotsubo was classified in the last universal definition of acute myocardial infarction as acute myocardial infarction with normal coronaries (MINOCA).⁸⁷

Therefore, referring these patients to coronary angiography for diagnostic confirmation is necessary.^88,89

The clinical admission picture can be predominantly defined by the manifestations of the disease that caused the physical stress, such as stroke, seizures, and the manifestation of Takotsubo may be through the development of ventricular dysfunction on the echocardiogram alone or with unexpected hemodynamic disturbances, such as hypotension or shock. In patients with emotional and physical stress, we observed the clinical picture of precordial pain and palpitations, or dyspnea, more frequently.^90-92

ECG

The ECG is abnormal in most patients with Takotsubo (>95%),¹¹ with changes usually suggestive of coronary ischemic disease in the ST segment and T wave. In the acute phase, we found ST-segment elevation in 44%, usually involving the anterior, apical, and lateral leads suggesting extensive anterior infarction, ST-segment infraction being uncommon, occurring in 8%, and T wave inversion being diffuse affecting 41%, pathological Q waves in 15%, and left bundle branch block in 5%. Twenty-four to 48 hours after the onset of symptoms, we have T wave inversion and significant prolongation of the QT interval, predisposing to polymorphic ventricular tachycardia (torsade de pointes) and ventricular fibrillation. T wave inversion and QT interval lengthening are related to the presence of myocardial edema, and subsequent gradual resolution may take days to weeks. The analysis of ECG alterations is highly accurate in differentiating acute myocardial infarction, such as the presence of ST-segment elevation in aVR and in anteroseptal leads V1 to V4, or ST-segment elevation in aVR with T-wave inversion, have high accuracy. However, due to the high prevalence of acute coronary disease with clinical and electrocardiographic characteristics similar to Takotsubo, all patients require assessment by coronary angiography with ventriculography for the differential diagnosis.^93-100

Biomarkers

Virtually all patients with Takotsubo have an enzymatic elevation of myocardial necrosis. Troponin T, or I and CK-MB, are elevated in >90% of patients on admission. The enzymatic peak is substantially lower than that of acute myocardial infarction, demonstrating a dissociation between enzyme levels with the extent of ECG changes and ventricular dysfunction. The presence of elevated enzyme levels is correlated with a worse prognosis.

Natriuretic peptides (BNP and pro-BNP) are frequently elevated, correlating with the degree of myocardial functional changes and ventricular dysfunction. They peak within 48 hours, and it may take months to normalize. ^101-103

Echocardiogram (<xref ref-type="table" rid="t5">Table 5</xref>)

Table 5 – Imaging methods in evaluating the Takotsubo and its characteristics

Methods Characteristics

Echocardiogram
Acute phase method

Method most used in practice for early identification of segmental alteration and raising the suspicion of Takotsubo:

Segmental alteration and ventricular function

Complications: mitral regurgitation, cardiac thrombus, LVOT, pericardial effusion

Recovery follow-up

CMR
Subacute or late phase method

Extension of segmental change, function

RV involvement

Complications: Mitral regurgitation, cardiac thrombus, LVOT, pericardial effusion

Differential diagnosis: myocarditis, CAD.

CAG
Acute phase method

CAD and MINOCA evaluation

Segmental alteration and ventricular function

Complications: mitral insufficiency, cardiac thrombus, LVOT.

Angio CT-Coronary
Subacute phase method

CAD and MINOCA evaluation

Nuclear medicine
Subacute or late phase method

Late diagnostic confirmation

Late differential diagnosis of MINOCA or myocarditis

Methods	Characteristics
Echocardiogram	Acute phase method Method most used in practice for early identification of segmental alteration and raising the suspicion of Takotsubo: Segmental alteration and ventricular function Complications: mitral regurgitation, cardiac thrombus, LVOT, pericardial effusion Recovery follow-up
CMR	Subacute or late phase method Extension of segmental change, function RV involvement Complications: Mitral regurgitation, cardiac thrombus, LVOT, pericardial effusion Differential diagnosis: myocarditis, CAD.
CAG	Acute phase method CAD and MINOCA evaluation Segmental alteration and ventricular function Complications: mitral insufficiency, cardiac thrombus, LVOT.
Angio CT-Coronary	Subacute phase method CAD and MINOCA evaluation
Nuclear medicine	Subacute or late phase method Late diagnostic confirmation Late differential diagnosis of MINOCA or myocarditis

LVOT: left ventricular outflow tract obstruction; RV: right ventricle; CAD: coronary artery disease; CMR: cardiac magnetic resonance;CAG: coronary angiography.

Transthoracic echocardiography (ECHO) is essential in the acute phase of CT to establish the initial diagnostic suspicion. The characteristic pattern of segmental alteration is the presence of apical and mesoventricular akinesia or dyskinesia of the anteroseptal segments with hyperdynamia of the basal segments. In addition to defining the CT pattern (apical, medial or basal), the echocardiogram will quantify the degree of dysfunction and assess the presence of complications such as intracavitary thrombus, left ventricular outflow tract obstruction (LVOT), mitral insufficiency secondary to LVOT or ventricular dilation. Although ECHO alterations may be strongly suggestive of Takotsubo, they do not allow for the differentiation or ruling out of AMI or myocarditis. ECHO is of great value in confirming the diagnosis by monitoring improvement in ventricular dysfunction or as a prognostic marker.^104-107

Cardiac Magnetic Resonance (CMR) (<xref ref-type="table" rid="t5">Table 5</xref>)

CMR is usually after the first 24-48 hours of admission. The importance of CMR lies not only in assessing the extent of ventricular dysfunction but also in the differential diagnosis of myocarditis.

CMR findings involve ventricular functional analysis with quantification of the extent of segmental alterations, degree of ventricular dysfunction, assessment of right ventricular involvement and the presence of complications such as intracardiac thrombus and intracardiac obstruction, and morphological analysis with the investigation of myocardial edema, of inflammation and fibrosis through late gadolinium enhancement (LGE) analysis.

Myocardial edema is observed in the acute phase through the T2 technique of CMR, with the demonstration in the T2 phase of an intense increase in the signal, having a diffuse distribution, being able to be transmural, and strongly related to the regions with alteration in contractility, not having a correlation with coronary anatomy, which differentiates it from AMI and myocarditis, which presents edema without correlation with changes in contractility and is more common in the lateral and epicardial walls. LGE is usually absent, which helps differentiate myocarditis or acute myocardial infarction. However, positive LGE has been described, predominantly in the apical region, with reduced signal intensity, with reports of persistent transmural LGE. The persistence of a positive LGE is associated with a worse evolutionary prognosis with the potential for arrhythmias.^108-114

Nuclear medicine (<xref ref-type="table" rid="t5">Table 5</xref>)

Myocardial scintigraphy with 123I-mIBG has been used to assess the sympathetic system’s activity in the myocardium through the activity of uptake of neuroreceptors. In the acute phase of Takotsubo, there is a reduction in myocardial uptake corresponding to regions with contractile dysfunction, consistent with dysfunction in the activity of sympathetic neuroreceptors, with a reduction in uptake in the apical and anterior regions of the myocardium being more common. These abnormalities can persist for several months, where 123I-mIBG has a diagnostic confirmation role in cases that remained undiagnosed or in doubt during hospitalization or patients with a previous history without confirmation. The presence of positive 123I-mIBG and its extension correlate with a worse prognosis in the development of heart failure and mortality.^115,116

Coronary angiography (CAG) (<xref ref-type="table" rid="t5">Table 5</xref>)

Upon hospital admission, most patients are evaluated by CAG to rule out the diagnosis of AMI. Takotsubo typically does not present an obstructive coronary lesion corresponding to the anatomical region with contractile alteration; therefore, it is necessary to perform CAG for diagnostic confirmation in the acute phase and differentiation of AMI or myocarditis. Because most patients with Takotsubo are elderly, we can find incipient coronary disease in about 10% of patients or other coronary arteries that do not correspond to the compromised anatomical region. In the presence of a significant coronary lesion corresponding to the anatomical region, we must use intravascular evaluation methods such as ultrasound or intracoronary optical coherence tomography to exclude plaque rupture, intracoronary thrombus, or coronary artery dissection, to confirm the diagnosis of Takotsubo. The concomitant performance of ventriculography allows for demonstrating the typical contractile dysfunctions of Takotsubo, in addition to estimating the degree of ventricular dysfunction and assessing the presence of intracardiac thrombus, mitral insufficiency and obstruction of the left ventricular outflow tract.^117-123

Coronary angiotomography (<xref ref-type="table" rid="t5">Table 5</xref>)

Coronary CT angiography has been proposed for stable patients with low suspicion of AMI or late presentation, or as a retrospective analysis of patients with a previous unconfirmed history of Takotsubo, as a non-invasive method for ruling out obstructive coronary disease.¹²⁴

INTERTAK scoring criteria for predicting the diagnosis of Takotsubo

The clinical presentation and alterations in the ECG and the myocardial injury enzymes of Takotsubo are very similar to AMI, and it is impossible to differentiate between both pathologies by any non-invasive method consistently. Therefore, in the acute phase, most patients need to be evaluated by coronary angiography to establish the diagnosis. The INTERTAK score criteria were developed from a diagnostic probability model involving seven clinical and electrocardiographic variables that are more prevalent in patients with Takotsubo than patients with AMI, where the greater the sum of points, the greater the probability of diagnosing Takotsubo. This model is proposed as a guide for questioning the probability of a diagnosis and not for a diagnostic statement.¹²⁵ (Table 4)

Table 4 – Clinical predictors for the diagnosis of Takotsubo

Criterion Score Takotsubo prediction (Or) p

Women 25 68 p<0.001

Emotional Trigger 24 65 p<0.001

Physical Trigger 13 8.7 p<0.001

Absence of SST infrastructure 12 7.2 p<0.001

Psychiatric disorder 11 7.0 p<0.001

Neurological disorder 9 4.9 p<0.001

Prolonged QTc 6 2.8 p=0.006

Criterion	Score	Takotsubo prediction (Or)	p
Women	25	68	p<0.001
Emotional Trigger	24	65	p<0.001
Physical Trigger	13	8.7	p<0.001
Absence of SST infrastructure	12	7.2	p<0.001
Psychiatric disorder	11	7.0	p<0.001
Neurological disorder	9	4.9	p<0.001
Prolonged QTc	6	2.8	p=0.006

The sum of points presents a capacity to predict the diagnosis of Takotsubo in the acute phase, with a greater capacity to predict the diagnosis with a sum of values > 70 points, indicating a probability > 85%, whereas values < 35 points have a 95% possibility of diagnosis be of acute coronary disease. In elderly patients with high frailty, clinically stable, we can use the point criterion to assess the risk and benefit of performing the CAG or starting antiplatelet therapy and opting for the integrated diagnosis of multimodality imaging to define the diagnostic probability and follow-up of ventricular dysfunction.

Integrated Multimodality Diagnostics

The ability of the integrated multimodality diagnosis to confirm the diagnosis of Takotsubo and its differentiation with AMI and myocarditis, as well as the detection of cardiac complications, will be related to the clinical scenarios and evolutionary phases of Takotsubo in which they were performed. These will define differentiated actions of the different modalities in the diagnostic evaluation of Takotsubo and differential diagnoses:¹²⁶

Classic Takotsubo: Usually caused by a triggering factor, in a female patient in the postmenopausal phase, often with precordial pain and/or dyspnea, ECG, and cardiac enzymes indicative of myocardial injury. In this scenario, the diagnosis is focused on the acute coronary syndrome, and Takotsubo is a secondary suspicion, where the appearance of apical and anterior dysfunction and basal hyperdynamia, with apical ballooning, on the echocardiogram may suggest Takotsubo. However, it does not allow for a positive diagnosis. In this scenario in the emergency room, performing CAG is necessary to rule out the diagnosis of acute myocardial infarction and define or suggest the diagnosis of Takotsubo or the case of non-significant coronary disease associated with MINOCA. Performing CMR is essential as it strengthens the diagnosis of Takotsubo or suggests myocarditis or MINOCA, in addition to assessing the extent and degree of ventricular dysfunction and the presence of cardiac complications, and has prognostic value.

Non-classical Takotsubo: is the presentation without identifying a precipitating or triggering factor, with clinical syncope, dizziness, or aborted sudden death, usually in male patients, who may or may not be elderly, without ST-segment elevation on the ECG, mild enzymatic elevation, where the echocardiogram is not strongly indicative of Takotsubo, with medial or basal segmental change. In this scenario, CMR plays a more significant role in evaluating the differential diagnosis of myocarditis, and in stable patients, we can indicate coronary angiotomography to assess the presence of CAD. In these patients, if diagnostic doubt remains, performing myocardial scintigraphy with MIBG may help establish or rule out the diagnosis of Takotsubo.

Intra-hospital Takotsubo: is usually associated with physical stress resulting from pathologies or post-procedures and may have a classic presentation of apical ballooning or atypical presentation with a segmental alteration. The echocardiogram in this scenario is important for diagnostic guidance, prognosis, and follow-up of ventricular dysfunction in terms of its response to therapy or spontaneous involution.

The differential diagnosis is related to acute myocardial infarction or metabolic cardiomyopathy in this context. In unstable patients, it is usually not feasible to perform CMR, and according to the degree of clinical suspicion, it will be necessary to perform CAG to assess the diagnosis of CAD.

After clinical and hemodynamic stabilization, CMR can be performed to assess the extent of the degree of ventricular dysfunction. In this scenario, the echocardiogram plays an important role in following the evolution of ventricular dysfunction and the development of cardiac complications.

Takotsubo of late confirmation: is when patients have a previous history of suggestive diagnosis without confirmation. CMR and coronary angiotomography can help clarify the diagnosis in patients with persistent dysfunction. In patients without ventricular dysfunction, performing MIBG, which can demonstrate alterations in the uptake of neuroreceptors within 12 months after the event, may suggest the diagnosis in case it is positive but does not exclude it in case it is negative.

Treatment

Although CT was initially described as benign, approximately 52% of patients have some complications, and 11% have more than two complications contributing to a higher mortality rate.¹²⁷ The in-hospital mortality rate varies from 2.4 to 4.1%, while pulmonary edema and cardiogenic shock rates range from 6 to 9% and 9 to 11.4%, respectively.⁸ In-hospital mortality from CT is higher than from uncomplicated acute myocardial infarction. Therefore CT cannot be handled as a low-risk pathology.¹²⁸

The therapeutic approach to patients with CT is based on the pathophysiological rationale, case series publications, retrospective analyzes or expert opinion, and the use of recommendations from other guidelines regarding the treatment of complications with acute heart failure since we do not have a specific guideline for the therapeutic handling of the CT. The therapeutic approach can be divided according to the clinical presentation and in-hospital evolution into uncomplicated CT and complicated CT.¹²⁹ In uncomplicated CT, patients may be asymptomatic or present with a clinical picture of precordial pain, with changes in the ECG, enzymes, and dysfunction on the echocardiogram, without clinical signs of heart failure, hemodynamic instability, or significant arrhythmias. They usually present a benign in-hospital evolution, with normalization of ventricular function mostly until hospital discharge. Patients with complicated CT present on admission or during in-hospital evolution, acute heart failure, cardiogenic shock, thromboembolic events, or frequent ventricular arrhythmias. These patients have a worse in-hospital prognosis with higher mortality and length of stay.¹²⁹

Uncomplicated Takotsubo therapeutic approach

Patients with uncomplicated CT usually evolve with spontaneous regression of the segmental change in ventricular contractility, so the therapeutic approach focuses on maintaining clinical support and controlling comorbidities, with prophylactic heparin and the use of antiplatelet agents and statins in the presence of coronary disease. The use of converting enzyme inhibitors has shown benefit in improving survival at the end of 1 year and reducing the risk of recurrence; however, the use of beta-blockers has not shown any clinical benefit in improving survival or recurrence at 30 days and 1-year post-discharge.¹³⁰ Despite the absence of evidence to support the use of beta-blockers, their use in clinical practice has been usual due to the pathophysiological rationale of hyperadrenergy.

In the presence of long QT, patients should be maintained on continuous electrocardiographic monitoring during hospitalization, even after ventricular function normalization, due to the high risk of malignant ventricular arrhythmias.¹³¹

Therapeutic approach to complicated Takotsubo

In complicated CT, complications have a variable prevalence, and we can classify them as follows:

Frequent: Heart Failure (3-46%), LVOT (12-25%), Cardiogenic Shock (6-20%), Mitral Insufficiency (14-25%);

Occasional: Atrial fibrillation (4.5%-25%), left ventricular intracavitary thrombus (2-9.2%), cardiac arrest (4-6%);

Rare: Tachyarrhythmias (2-5%), bradycardias (2-5%), death (1-5%).

Acute heart failure

The management of acute heart failure in patients with CT should follow the treatment recommended by the guidelines, with ventilatory support, diuretics, converting enzyme inhibitors, angiotensin receptor blockers, sacubitril-valsartan, beta-blockers and mineralocorticoid receptor antagonists and inhibitors of receptors SGLT2.^132,133 In patients with LVOT, the use of drugs that reduce pre- and afterload, such as venous or arterial vasodilators and diuretics, should be avoided, as they can aggravate the degree of obstruction.

The use of beta-blockers in this group of patients demonstrated clinical benefit with a higher 2-year survival rate, particularly in patients with arterial hypertension or who developed cardiogenic shock in the acute phase.¹³⁴

Cardiogenic shock

Cardiogenic shock can occur 6% to 20% within the first 72 hours of admission. The first point to be observed in the treatment is whether the hypotension is due to LVOT or diffuse left ventricular contractile failure since 20 to 25% of patients have LVOT.¹³⁵

Patients with LVOT can present anterior systolic movement of the mitral valve with consequent mitral regurgitation. Using vasoactive amines, inodilators, vasodilators, diuretics, and intra-aortic balloon pumps should be avoided as they worsen the LVOT obstruction. Treatment is volume expansion and a short-acting intravenous selective beta-blocker such as Esmolol.¹³⁶ In patients with cardiogenic shock refractory to pharmacological intervention, mechanical circulatory support with ECMO would be indicated, and implantation should be performed as early as possible.¹³⁷

In patients where cardiogenic shock results from pump failure, using vasoactive amines such as noradrenaline is frequent in clinical practice. However, the European Society of Cardiology recommends that they be avoided or used in low doses due to the potential of aggravating myocardial aggression and ventricular dysfunction and prolonging the shock condition.¹³⁸ Ansari et al. demonstrated in patients that used vasoactive amines when compared to those who did not, higher in-hospital mortality (3.2% vs. 28.5%, p < 0.01), 30-day mortality (17.2% vs. 51.4%, p < 0.01) and long-term mortality (38.7% vs. 80.9%, p < 0.01), with logistic regression analysis was a determining factor of worse prognosis. (HR 2.2, 95% CI 1.0–4.8; p= 0.04).¹³⁹

In patients with arterial hypotension or cardiogenic shock, levosimendan, and milrinone, in the absence of LVOT, are alternatives to vasoactive amines because they do not activate neuro-adrenergic receptors. Using Levosimendan in several cases demonstrated clinical and ventricular function improvement without developing adverse events or LVOT. Levosimendan should be given at a dose of 0.1 mg/kg/min without bolus for 24 hours.^140,141

Patients with cardiogenic shock, who do not show an initial response to pharmacological support, should be evaluated as soon as possible by the shock team for the implantation of mechanical circulatory support. The intra-aortic balloon alone did not demonstrate benefits in improving survival, and the use of ECMO associated with Impella or IAB should be evaluated.^142-144

Arrhythmias

Patients with CT may have supraventricular or ventricular arrhythmias, with the potential for thromboembolic complications and increased mortality. Acute atrial fibrillation should be initially managed with anticoagulation and heart rate control with short-acting intravenous beta-blockers; electrical cardioversion may be indicated in hemodynamically unstable patients. Malignant arrhythmias can occur in 8% of patients, 75% with ventricular tachycardia and ventricular fibrillation.^145,146 Treatment in the acute phase may involve magnesium sulfate, short-acting intravenous beta-blockers, and electrical cardioversion. Amiodarone effectively controls ventricular arrhythmias, but we must observe whether there is a long QT, which can be aggravated by amiodarone. In frequent VT unresponsive to pharmacological treatment associated with long QT, we can use a pacemaker to increase the heart rate, and in patients with hemodynamic instability or cardiogenic shock, the implant of mechanical circulatory support with ECMO.^147,148

Intracardiac thrombus

Intracardiac thrombus (ICT) formation in the left ventricle on CT can occur in up to 2.5% of patients, and the development of cardioembolic events in 0.8% of this population. Thrombus formation can occur in the in-hospital phase or within 2 weeks after discharge. In the presence of ICT, we risk systemic embolization events of 1% to 2%. The presence of apical ballooning, LVEF < 35%, and high levels of Troponin I are predictors of the development of ICT, and prophylactic anticoagulation with DOACs is indicated. Apical ballooning without associated troponin elevation does not require prophylactic anticoagulation. In the presence of ICT detected by echocardiogram or cardiac magnetic resonance, anticoagulation with DOACs is indicated and should be maintained for at least 3 months.^149-151

Follow-up of patients after hospital discharge <xref ref-type="bibr" rid="B152">152</xref>-<xref ref-type="bibr" rid="B155">155</xref>

In the post-hospital discharge follow-up, we have several objectives to be evaluated, such as 1) involution of the segmental alteration and improvement of the ventricular function; 2) involution of intracavitary thrombus; 3) involution of myocardial edema; 4) CT follow-up; 5) evaluation of ventricular arrhythmias.

An echocardiogram and magnetic CMR are performed for anatomical and functional assessments 30 days and 3 months after discharge. Along with this assessment, the risk of developing arrhythmias should also be assessed, especially in patients with persistent long QT or with ventricular arrhythmias observed on the 24-hour electrocardiogram. Patients with intracavitary thrombus must remain anticoagulated with DOACs for at least three months, with follow-up by echocardiogram or CMR. The maintenance of ACE inhibitors/ARBs in patients with ventricular dysfunction improves survival at the end of 1 year, and no benefit was observed with the use of beta-blockers.¹⁵²

The long-term prognosis of CT is benign, with over 90% of patients completely recovering within 2 months. The long-term recurrence rate varies between 1.8% and 10%. For women over 50, persistent ventricular dysfunction, emotional lability, psychiatric disorders, and vasovagal reflex alteration present a greater risk for recurrence. Male patients, who had advanced heart failure at admission, and people with diabetes had lower long-term survival.^153,154 The use of ACEI/ARBs or beta-blockers was not effective in reducing the recurrence rate.¹³⁰ This was also observed in the treatment or correction of factors or triggers, such as anxiety, depression, bronchial asthma, or the fact of avoiding invasive procedures.

References 1

1. Sattar Y, Siew KSW, Connerney M, Ullah W, Alraies MC. Management of Takotsubo Syndrome: A Comprehensive Review. Cureus. 2020;12(1):e6556. doi: 10.7759/cureus.6556.

Sattar

Siew

KSW

Connerney

Ullah

Alraies

Management of Takotsubo Syndrome: A Comprehensive Review

Cureus 2020 12 1

e6556

10.7759/cureus.6556

2. Cammann VL, Szawan KA, Stähli BE, Kato K, Budnik M, Wischnewsky M, et al. Age-Related Variations in Takotsubo Syndrome. J Am Coll Cardiol. 2020;75(16):1869-77. doi: 10.1016/j.jacc.2020.02.057.

Cammann

Szawan

Stähli

Kato

Budnik

Wischnewsky

et al

Age-Related Variations in Takotsubo Syndrome

J Am Coll Cardiol 2020 75 16 1869 1877

10.1016/j.jacc.2020.02.057

3. Topal Y, Topal H, Doğan C, Tiryaki SB, Biteker M. Takotsubo (Stress) Cardiomyopathy in Childhood. Eur J Pediatr. 2020;179(4):619-25. doi: 10.1007/s00431-019-03536-z.

Topal

Doğan

Tiryaki

Biteker

Takotsubo (Stress) Cardiomyopathy in Childhood

Eur J Pediatr 2020 179 4 619 625

10.1007/s00431-019-03536-z

4. Akashi YJ, Nef HM, Lyon AR. Epidemiology and Pathophysiology of Takotsubo Syndrome. Nat Rev Cardiol. 2015;12(7):387-97. doi: 10.1038/nrcardio.2015.39.

Akashi

Nef

Lyon

Epidemiology and Pathophysiology of Takotsubo Syndrome

Nat Rev Cardiol 2015 12 7 387 397

10.1038/nrcardio.2015.39

5. Y-Hassan S, De Palma R. Contemporary review on the Pathogenesis of Takotsubo Syndrome: The Heart Shedding Tears: NOREPINEPHRINE Churn and Foam at the Cardiac Sympathetic Nerve Terminals. Int J Cardiol. 2017;228:528-36. doi: 10.1016/j.ijcard.2016.11.086.

Y-Hassan

De Palma

Contemporary review on the Pathogenesis of Takotsubo Syndrome: The Heart Shedding Tears: NOREPINEPHRINE Churn and Foam at the Cardiac Sympathetic Nerve Terminals

Int J Cardiol 2017 228 528 536

10.1016/j.ijcard.2016.11.086

6. Y-Hassan S, Yamasaki K. History of Takotsubo Syndrome: Is the Syndrome Really Described as a Disease Entity First in 1990? Some Inaccuracies. Int J Cardiol. 2013;166(3):736-7. doi: 10.1016/j.ijcard.2012.09.183.

Y-Hassan

Yamasaki

History of Takotsubo Syndrome: Is the Syndrome Really Described as a Disease Entity First in 1990? Some Inaccuracies

Int J Cardiol 2013 166 3 736 737

10.1016/j.ijcard.2012.09.183

7. Dote K, Sato H, Tateishi H, Uchida T, Ishihara M. Myocardial Stunning due to Simultaneous Multivessel Coronary Spasms: A Review of 5 Cases. J Cardiol. 1991;21(2):203-14.

Dote

Sato

Tateishi

Uchida

Ishihara

Myocardial Stunning due to Simultaneous Multivessel Coronary Spasms: A Review of 5 Cases

J Cardiol 1991 21 2 203 214

8. Templin C, Ghadri JR, Diekmann J, Napp LC, Bataiosu DR, Jaguszewski M, et al. Clinical Features and Outcomes of Takotsubo (Stress) Cardiomyopathy. N Engl J Med. 2015;373(10):929-38. doi: 10.1056/NEJMoa1406761.

Templin

Ghadri

Diekmann

Napp

Bataiosu

Jaguszewski

et al

Clinical Features and Outcomes of Takotsubo (Stress) Cardiomyopathy

N Engl J Med 2015 373 10 929 938

10.1056/NEJMoa1406761

9. Y-Hassan S, Tornvall P, Törnerud M, Henareh L. Capecitabine Caused Cardiogenic Shock Through Induction of Global Takotsubo Syndrome. Cardiovasc Revasc Med. 2013;14(1):57-61. doi: 10.1016/j.carrev.2012.10.001.

Y-Hassan

Tornvall

Törnerud

Henareh

Capecitabine Caused Cardiogenic Shock Through Induction of Global Takotsubo Syndrome

Cardiovasc Revasc Med 2013 14 1 57 61

10.1016/j.carrev.2012.10.001

10. Eitel I, von Knobelsdorff-Brenkenhoff F, Bernhardt P, Carbone I, Muellerleile K, Aldrovandi A, et al. Clinical Characteristics and Cardiovascular Magnetic Resonance Findings in Stress (Takotsubo) Cardiomyopathy. JAMA. 2011;306(3):277-86. doi: 10.1001/jama.2011.992.

Eitel

von Knobelsdorff-Brenkenhoff

Bernhardt

Carbone

Muellerleile

Aldrovandi

et al

Clinical Characteristics and Cardiovascular Magnetic Resonance Findings in Stress (Takotsubo) Cardiomyopathy

JAMA 2011 306 3 277 286

10.1001/jama.2011.992

11. Cramer MJ, De Boeck B, Melman PG, Sieswerda GJ. The ‘Broken Heart’ Syndrome: What can be Learned from the Tears and Distress? Neth Heart J. 2007;15(9):283-5. doi: 10.1007/BF03086000.

Cramer

De Boeck

Melman

Sieswerda

The ‘Broken Heart’ Syndrome: What can be Learned from the Tears and Distress?

Neth Heart J 2007 15 9 283 285

10.1007/BF03086000

12. Sharkey SW, Windenburg DC, Lesser JR, Maron MS, Hauser RG, Lesser JN, et al. Natural History and Expansive Clinical Profile of Stress (Tako-Tsubo) Cardiomyopathy. J Am Coll Cardiol. 2010;55(4):333-41. doi: 10.1016/j.jacc.2009.08.057.

Sharkey

Windenburg

Lesser

Maron

Hauser

Lesser

et al

Natural History and Expansive Clinical Profile of Stress (Tako-Tsubo) Cardiomyopathy

J Am Coll Cardiol 2010 55 4 333 341

10.1016/j.jacc.2009.08.057

13. Wittstein IS, Thiemann DR, Lima JA, Baughman KL, Schulman SP, Gerstenblith G, et al. Neurohumoral Features of Myocardial Stunning due to Sudden Emotional Stress. N Engl J Med. 2005;352(6):539-48. doi: 10.1056/NEJMoa043046.

Wittstein

Thiemann

Lima

Baughman

Schulman

Gerstenblith

et al

Neurohumoral Features of Myocardial Stunning due to Sudden Emotional Stress

N Engl J Med 2005 352 6 539 548

10.1056/NEJMoa043046

14. Kume T, Akasaka T, Kawamoto T, Yoshitani H, Watanabe N, Neishi Y, et al. Assessment of Coronary Microcirculation in Patients with Takotsubo-Like Left Ventricular Dysfunction. Circ J. 2005;69(8):934-9. doi: 10.1253/circj.69.934.

Kume

Akasaka

Kawamoto

Yoshitani

Watanabe

Neishi

et al

Assessment of Coronary Microcirculation in Patients with Takotsubo-Like Left Ventricular Dysfunction

Circ J 2005 69 8 934 939

10.1253/circj.69.934

15. Paur H, Wright PT, Sikkel MB, Tranter MH, Mansfield C, O’Gara P, et al. High Levels of Circulating Epinephrine Trigger Apical Cardiodepression in a β2-Adrenergic Receptor/Gi-Dependent Manner: A New Model of Takotsubo Cardiomyopathy. Circulation. 2012;126(6):697-706. doi: 10.1161/CIRCULATIONAHA.112.111591.

Paur

Wright

Sikkel

Tranter

Mansfield

O’Gara

et al

High Levels of Circulating Epinephrine Trigger Apical Cardiodepression in a β2-Adrenergic Receptor/Gi-Dependent Manner: A New Model of Takotsubo Cardiomyopathy

Circulation 2012 126 6 697 706

10.1161/CIRCULATIONAHA.112.111591

16. Wittstein IS, Thiemann DR, Lima JA, Baughman KL, Schulman SP, Gerstenblith G, et al. Neurohumoral Features of Myocardial Stunning due to Sudden Emotional Stress. N Engl J Med. 2005;352(6):539-48. doi: 10.1056/NEJMoa043046.

Wittstein

Thiemann

Lima

Baughman

Schulman

Gerstenblith

et al

Neurohumoral Features of Myocardial Stunning due to Sudden Emotional Stress

N Engl J Med 2005 352 6 539 548

10.1056/NEJMoa043046

17. Giavarini A, Chedid A, Bobrie G, Plouin PF, Hagège A, Amar L. Acute Catecholamine Cardiomyopathy in Patients with Phaeochromocytoma or Functional Paraganglioma. Heart. 2013;99(19):1438-44. doi: 10.1136/heartjnl-2013-304073.

Giavarini

Chedid

Bobrie

Plouin

Hagège

Amar

Acute Catecholamine Cardiomyopathy in Patients with Phaeochromocytoma or Functional Paraganglioma

Heart 2013 99 19 1438 1444

10.1136/heartjnl-2013-304073

18. Finsterer J, Wahbi K. CNS Disease Triggering Takotsubo Stress Cardiomyopathy. Int J Cardiol. 2014;177(2):322-9. doi: 10.1016/j.ijcard.2014.08.101.

Finsterer

Wahbi

CNS Disease Triggering Takotsubo Stress Cardiomyopathy

Int J Cardiol 2014 177 2 322 329

10.1016/j.ijcard.2014.08.101

19. Suzuki H, Matsumoto Y, Kaneta T, Sugimura K, Takahashi J, Fukumoto Y, et al. Evidence for Brain Activation in Patients with Takotsubo Cardiomyopathy. Circ J. 2014;78(1):256-8. doi: 10.1253/circj.cj-13-1276.

Suzuki

Matsumoto

Kaneta

Sugimura

Takahashi

Fukumoto

et al

Evidence for Brain Activation in Patients with Takotsubo Cardiomyopathy

Circ J 2014 78 1 256 258

10.1253/circj.cj-13-1276

20. Abraham J, Mudd JO, Kapur NK, Klein K, Champion HC, Wittstein IS. Stress Cardiomyopathy after Intravenous Administration of Catecholamines and Beta-Receptor Agonists. J Am Coll Cardiol. 2009;53(15):1320-5. doi: 10.1016/j.jacc.2009.02.020.

Abraham

Mudd

Kapur

Klein

Champion

Wittstein

Stress Cardiomyopathy after Intravenous Administration of Catecholamines and Beta-Receptor Agonists

J Am Coll Cardiol 2009 53 15 1320 1325

10.1016/j.jacc.2009.02.020

21. Shao Y, Redfors B, Scharin Täng M, Möllmann H, Troidl C, et al. Novel Rat Model Reveals Important Roles of β-Adrenoreceptors in Stress-Induced Cardiomyopathy. Int J Cardiol. 2013;168(3):1943-50. doi: 10.1016/j.ijcard.2012.12.092.

Shao

Redfors

Scharin Täng

Möllmann

Troidl

et al

Novel Rat Model Reveals Important Roles of β-Adrenoreceptors in Stress-Induced Cardiomyopathy

Int J Cardiol 2013 168 3 1943 1950

10.1016/j.ijcard.2012.12.092

22. Sachdeva J, Dai W, Kloner RA. Functional and Histological Assessment of an Experimental Model of Takotsubo’s Cardiomyopathy. J Am Heart Assoc. 2014;3(3):e000921. doi: 10.1161/JAHA.114.000921.

Sachdeva

Dai

Kloner

Functional and Histological Assessment of an Experimental Model of Takotsubo’s Cardiomyopathy

J Am Heart Assoc 2014 3 3

e000921

10.1161/JAHA.114.000921

23. Redfors B, Ali A, Shao Y, Lundgren J, Gan LM, Omerovic E. Different Catecholamines Induce Different Patterns of Takotsubo-Like Cardiac Dysfunction in an Apparently Afterload Dependent Manner. Int J Cardiol. 2014;174(2):330-6. doi: 10.1016/j.ijcard.2014.04.103.

Redfors

Ali

Shao

Lundgren

Gan

Omerovic

Different Catecholamines Induce Different Patterns of Takotsubo-Like Cardiac Dysfunction in an Apparently Afterload Dependent Manner

Int J Cardiol 2014 174 2 330 336

10.1016/j.ijcard.2014.04.103

24. Dias A, Gil IJN, Santoro F, Madias JE, Pelliccia F, Brunetti ND, et al. Takotsubo Syndrome: State-of-the-art Review By an Expert Panel - Part 1. Cardiovasc Revasc Med. 2019;20(1):70-9. doi: 10.1016/j.carrev.2018.11.015.

Dias

Gil

IJN

Santoro

Madias

Pelliccia

Brunetti

et al

Takotsubo Syndrome: State-of-the-art Review By an Expert Panel - Part 1

Cardiovasc Revasc Med 2019 20 1 70 79

10.1016/j.carrev.2018.11.015

25. Ghadri JR, Wittstein IS, Prasad A, Sharkey S, Dote K, Akashi YJ, et al. International Expert Consensus Document on Takotsubo Syndrome (Part I): Clinical Characteristics, Diagnostic Criteria, and Pathophysiology. Eur Heart J. 2018;39(22):2032-46. doi: 10.1093/eurheartj/ehy076.

Ghadri

Wittstein

Prasad

Sharkey

Dote

Akashi

et al

International Expert Consensus Document on Takotsubo Syndrome (Part I): Clinical Characteristics, Diagnostic Criteria, and Pathophysiology

Eur Heart J 2018 39 22 2032 2046

10.1093/eurheartj/ehy076

26. Nef HM, Möllmann H, Troidl C, Kostin S, Voss S, Hilpert P, et al. Abnormalities in intracellular Ca2+ Regulation Contribute to the Pathomechanism of Tako-Tsubo Cardiomyopathy. Eur Heart J. 2009;30(17):2155-64. doi: 10.1093/eurheartj/ehp240.

Nef

Möllmann

Troidl

Kostin

Voss

Hilpert

et al

Abnormalities in intracellular Ca2+ Regulation Contribute to the Pathomechanism of Tako-Tsubo Cardiomyopathy

Eur Heart J 2009 30 17 2155 2164

10.1093/eurheartj/ehp240

27. Nef HM, Möllmann H, Akashi YJ, Hamm CW. Mechanisms of Stress (Takotsubo) Cardiomyopathy. Nat Rev Cardiol. 2010;7(4):187-93. doi: 10.1038/nrcardio.2010.16.

Nef

Möllmann

Akashi

Hamm

Mechanisms of Stress (Takotsubo) Cardiomyopathy

Nat Rev Cardiol 2010 7 4 187 193

10.1038/nrcardio.2010.16

28. Rona G. Catecholamine Cardiotoxicity. J Mol Cell Cardiol. 1985;17(4):291-306. doi: 10.1016/s0022-2828(85)80130-9.

Rona

Catecholamine Cardiotoxicity

J Mol Cell Cardiol 1985 17 4 291 306

10.1016/s0022-2828(85)80130-9

29. Heather LC, Catchpole AF, Stuckey DJ, Cole MA, Carr CA, Clarke K. Isoproterenol Induces in Vivo Functional and Metabolic Abnormalities: Similar to Those Found in the Infarcted Rat Heart. J Physiol Pharmacol. 2009;60(3):31-9.

Heather

Catchpole

Stuckey

Cole

Carr

Clarke

Isoproterenol Induces in Vivo Functional and Metabolic Abnormalities: Similar to Those Found in the Infarcted Rat Heart

J Physiol Pharmacol 2009 60 3 31 39

30. Paur H, Wright PT, Sikkel MB, Tranter MH, Mansfield C, O’Gara P, et al. High Levels of Circulating Epinephrine Trigger Apical Cardiodepression in a β2-Adrenergic Receptor/Gi-Dependent Manner: A New Model of Takotsubo Cardiomyopathy. Circulation. 2012;126(6):697-706. doi: 10.1161/CIRCULATIONAHA.112.111591.

Paur

Wright

Sikkel

Tranter

Mansfield

O’Gara

et al

High Levels of Circulating Epinephrine Trigger Apical Cardiodepression in a β2-Adrenergic Receptor/Gi-Dependent Manner: A New Model of Takotsubo Cardiomyopathy

Circulation 2012 126 6 697 706

10.1161/CIRCULATIONAHA.112.111591

31. Spieker LE, Hürlimann D, Ruschitzka F, Corti R, Enseleit F, Shaw S, et al. Mental Stress Induces Prolonged Endothelial Dysfunction Via Endothelin-A Receptors. Circulation. 2002;105(24):2817-20. doi: 10.1161/01.cir.0000021598.15895.34.

Spieker

Hürlimann

Ruschitzka

Corti

Enseleit

Shaw

et al

Mental Stress Induces Prolonged Endothelial Dysfunction Via Endothelin-A Receptors

Circulation 2002 105 24 2817 2820

10.1161/01.cir.0000021598.15895.34

32. Vasilieva E, Vorobyeva I, Lebedeva A, Urazovskaya I, Kalinskaya A, Skrypnik D, et al. Brachial Artery Flow-Mediated Dilation in Patients with TAKO-TSUBO Cardiomyopathy. Am J Med. 2011;124(12):1176-9. doi: 10.1016/j.amjmed.2011.05.033.

Vasilieva

Vorobyeva

Lebedeva

Urazovskaya

Kalinskaya

Skrypnik

et al

Brachial Artery Flow-Mediated Dilation in Patients with TAKO-TSUBO Cardiomyopathy

Am J Med 2011 124 12 1176 1179

10.1016/j.amjmed.2011.05.033

33. Tsuchihashi K, Ueshima K, Uchida T, Oh-mura N, Kimura K, Owa M, et al. Transient Left Ventricular Apical Ballooning without Coronary Artery Stenosis: A Novel Heart Syndrome Mimicking Acute Myocardial Infarction. Angina Pectoris-Myocardial Infarction Investigations in Japan. J Am Coll Cardiol. 2001;38(1):11-8. doi: 10.1016/s0735-1097(01)01316-x.

Tsuchihashi

Ueshima

Uchida

Oh-mura

Kimura

Owa

et al

Transient Left Ventricular Apical Ballooning without Coronary Artery Stenosis: A Novel Heart Syndrome Mimicking Acute Myocardial Infarction. Angina Pectoris-Myocardial Infarction Investigations in Japan

J Am Coll Cardiol 2001 38 1 11 18

10.1016/s0735-1097(01)01316-x

34. Fiol M, Carrillo A, Rodriguez A, Herrero J, García-Niebla J. Left Ventricular Ballooning Syndrome due to Vasospasm of the Middle Portion of the Left Anterior Descending Coronary Artery. Cardiol J. 2012;19(3):314-6. doi: 10.5603/cj.2012.0055.

Fiol

Carrillo

Rodriguez

Herrero

García-Niebla

Left Ventricular Ballooning Syndrome due to Vasospasm of the Middle Portion of the Left Anterior Descending Coronary Artery

Cardiol J 2012 19 3 314 316

10.5603/cj.2012.0055

35. Zhang Z, Jin S, Teng X, Duan X, Chen Y, Wu Y. Hydrogen Sulfide Attenuates Cardiac Injury in Takotsubo Cardiomyopathy by Alleviating Oxidative Stress. Nitric Oxide. 2017;67:10-25. doi: 10.1016/j.niox.2017.04.010.

Zhang

Jin

Teng

Duan

Chen

Hydrogen Sulfide Attenuates Cardiac Injury in Takotsubo Cardiomyopathy by Alleviating Oxidative Stress

Nitric Oxide 2017 67 10 25

10.1016/j.niox.2017.04.010

36. Pelliccia F, Greco C, Vitale C, Rosano G, Gaudio C, Kaski JC. Takotsubo Syndrome (Stress Cardiomyopathy): An Intriguing Clinical Condition in Search of its Identity. Am J Med. 2014;127(8):699-704. doi: 10.1016/j.amjmed.2014.04.004.

Pelliccia

Greco

Vitale

Rosano

Gaudio

Kaski

Takotsubo Syndrome (Stress Cardiomyopathy): An Intriguing Clinical Condition in Search of its Identity

Am J Med 2014 127 8 699 704

10.1016/j.amjmed.2014.04.004

37. Meimoun P, Malaquin D, Sayah S, Benali T, Luycx-Bore A, Levy F, et al. The Coronary Flow Reserve is Transiently Impaired in Tako-Tsubo Cardiomyopathy: A Prospective Study Using Serial Doppler Transthoracic Echocardiography. J Am Soc Echocardiogr. 2008;21(1):72-7. doi: 10.1016/j.echo.2007.05.024.

Meimoun

Malaquin

Sayah

Benali

Luycx-Bore

Levy

et al

The Coronary Flow Reserve is Transiently Impaired in Tako-Tsubo Cardiomyopathy: A Prospective Study Using Serial Doppler Transthoracic Echocardiography

J Am Soc Echocardiogr 2008 21 1 72 77

10.1016/j.echo.2007.05.024

38. Rigo F, Sicari R, Citro R, Ossena G, Buja P, Picano E. Diffuse, Marked, Reversible Impairment in Coronary Microcirculation in Stress Cardiomyopathy: A Doppler Transthoracic Echo Study. Ann Med. 2009;41(6):462-70. doi: 10.1080/07853890903022793.

Rigo

Sicari

Citro

Ossena

Buja

Picano

Diffuse, Marked, Reversible Impairment in Coronary Microcirculation in Stress Cardiomyopathy: A Doppler Transthoracic Echo Study

Ann Med 2009 41 6 462 470

10.1080/07853890903022793

39. Kume T, Akasaka T, Kawamoto T, Yoshitani H, Watanabe N, Neishi Y, et al. Assessment of Coronary Microcirculation in Patients with Takotsubo-Like Left Ventricular Dysfunction. Circ J. 2005;69(8):934-9. doi: 10.1253/circj.69.934.

Kume

Akasaka

Kawamoto

Yoshitani

Watanabe

Neishi

et al

Assessment of Coronary Microcirculation in Patients with Takotsubo-Like Left Ventricular Dysfunction

Circ J 2005 69 8 934 939

10.1253/circj.69.934

40. Galiuto L, De Caterina AR, Porfidia A, Paraggio L, Barchetta S, Locorotondo G, et al. Reversible Coronary Microvascular Dysfunction: A Common Pathogenetic Mechanism in Apical Ballooning or Tako-Tsubo Syndrome. Eur Heart J. 2010;31(11):1319-27. doi: 10.1093/eurheartj/ehq039.

Galiuto

De Caterina

Porfidia

Paraggio

Barchetta

Locorotondo

et al

Reversible Coronary Microvascular Dysfunction: A Common Pathogenetic Mechanism in Apical Ballooning or Tako-Tsubo Syndrome

Eur Heart J 2010 31 11 1319 1327

10.1093/eurheartj/ehq039

41. Delgado GA, Truesdell AG, Kirchner RM, Zuzek RW, Pomerantsev EV, Gordon PC, et al. An Angiographic and Intravascular Ultrasound Study of the Left Anterior Descending Coronary Artery in Takotsubo Cardiomyopathy. Am J Cardiol. 2011;108(6):888-91. doi: 10.1016/j.amjcard.2011.05.012.

Delgado

Truesdell

Kirchner

Zuzek

Pomerantsev

Gordon

et al

An Angiographic and Intravascular Ultrasound Study of the Left Anterior Descending Coronary Artery in Takotsubo Cardiomyopathy

Am J Cardiol 2011 108 6 888 891

10.1016/j.amjcard.2011.05.012

42. Pawłowski T, Mintz GS, Kulawik T, Gil RJ. Virtual Histology Intravascular Ultrasound Evaluation of the Left Anterior Descending Coronary Artery in Patients with Transient Left Ventricular Ballooning Syndrome. Kardiol Pol. 2010;68(10):1093-8.

Pawłowski

Mintz

Kulawik

Gil

Virtual Histology Intravascular Ultrasound Evaluation of the Left Anterior Descending Coronary Artery in Patients with Transient Left Ventricular Ballooning Syndrome

Kardiol Pol 2010 68 10 1093 1098

43. Eitel I, Stiermaier T, Graf T, Möller C, Rommel KP, Eitel C, et al. Optical Coherence Tomography to Evaluate Plaque Burden and Morphology in Patients with Takotsubo Syndrome. J Am Heart Assoc. 2016;5(12):e004474. doi: 10.1161/JAHA.116.004474.

Eitel

Stiermaier

Graf

Möller

Rommel

Eitel

et al

Optical Coherence Tomography to Evaluate Plaque Burden and Morphology in Patients with Takotsubo Syndrome

J Am Heart Assoc 2016 5 12

e004474

10.1161/JAHA.116.004474

44. Hoyt J, Lerman A, Lennon RJ, Rihal CS, Prasad A. Left Anterior Descending Artery Length and Coronary Atherosclerosis in Apical Ballooning Syndrome (Takotsubo/Stress Induced Cardiomyopathy). Int J Cardiol. 2010;145(1):112-5. doi: 10.1016/j.ijcard.2009.06.018.

Hoyt

Lerman

Lennon

Rihal

Prasad

Left Anterior Descending Artery Length and Coronary Atherosclerosis in Apical Ballooning Syndrome (Takotsubo/Stress Induced Cardiomyopathy)

Int J Cardiol 2010 145 1 112 115

10.1016/j.ijcard.2009.06.018

45. Templin C, Ghadri JR, Diekmann J, Napp LC, Bataiosu DR, Jaguszewski M, et al. Clinical Features and Outcomes of Takotsubo (Stress) Cardiomyopathy. N Engl J Med. 2015;373(10):929-38. doi: 10.1056/NEJMoa1406761.

Templin

Ghadri

Diekmann

Napp

Bataiosu

Jaguszewski

et al

Clinical Features and Outcomes of Takotsubo (Stress) Cardiomyopathy

N Engl J Med 2015 373 10 929 938

10.1056/NEJMoa1406761

46. Ueyama T, Kasamatsu K, Hano T, Tsuruo Y, Ishikura F. Catecholamines and Estrogen are Involved in the Pathogenesis of Emotional Stress-Induced Acute Heart Attack. Ann N Y Acad Sci. 2008;1148:479-85. doi: 10.1196/annals.1410.079.

Ueyama

Kasamatsu

Hano

Tsuruo

Ishikura

Catecholamines and Estrogen are Involved in the Pathogenesis of Emotional Stress-Induced Acute Heart Attack

Ann N Y Acad Sci 2008 1148 479 485

10.1196/annals.1410.079

47. Sader MA, Celermajer DS. Endothelial Function, Vascular Reactivity and Gender Differences in the Cardiovascular System. Cardiovasc Res. 2002;53(3):597-604. doi: 10.1016/s0008-6363(01)00473-4.

Sader

Celermajer

Endothelial Function, Vascular Reactivity and Gender Differences in the Cardiovascular System

Cardiovasc Res 2002 53 3 597 604

10.1016/s0008-6363(01)00473-4

48. Komesaroff PA, Esler MD, Sudhir K. Estrogen Supplementation Attenuates Glucocorticoid and Catecholamine Responses to Mental Stress in Perimenopausal Women. J Clin Endocrinol Metab. 1999;84(2):606-10. doi: 10.1210/jcem.84.2.5447.

Komesaroff

Esler

Sudhir

Estrogen Supplementation Attenuates Glucocorticoid and Catecholamine Responses to Mental Stress in Perimenopausal Women

J Clin Endocrinol Metab 1999 84 2 606 610

10.1210/jcem.84.2.5447

49. Sung BH, Ching M, Izzo JL Jr, Dandona P, Wilson MF. Estrogen Improves Abnormal Norepinephrine-Induced Vasoconstriction in Postmenopausal Women. J Hypertens. 1999;17(4):523-8. doi: 10.1097/00004872-199917040-00010.

Sung

Ching

Izzo

Jr Dandona

Wilson

Estrogen Improves Abnormal Norepinephrine-Induced Vasoconstriction in Postmenopausal Women

J Hypertens 1999 17 4 523 528

10.1097/00004872-199917040-00010

50. Chiriboga ASL, Yoon JW, Freeman WD, Odunukan OW, Cheshire WP Jr. Takotsubo Cardiomyopathy in the Setting of Acute Hydrocephalus Secondary to Neurocysticercosis. Clin Auton Res. 2016;26(3):235-41. doi: 10.1007/s10286-016-0348-8.

Chiriboga

ASL

Yoon

Freeman

Odunukan

Cheshire

Takotsubo Cardiomyopathy in the Setting of Acute Hydrocephalus Secondary to Neurocysticercosis

Clin Auton Res 2016 26 3 235 241

10.1007/s10286-016-0348-8

51. Quick S, Speiser U, Richter N, Youssef A, Waessnig N, Strasser RH, et al. Transient Global Amnesia and Broken Heart Syndrome: Two Faces of One Pathology. Clin Auton Res. 2015;25(3):189-91. doi: 10.1007/s10286-015-0284-z.

Quick

Speiser

Richter

Youssef

Waessnig

Strasser

et al

Transient Global Amnesia and Broken Heart Syndrome: Two Faces of One Pathology

Clin Auton Res 2015 25 3 189 191

10.1007/s10286-015-0284-z

52. Tak T, Sharma U, Karturi S, Gharacholou SM. Familial Tako-tsubo Cardiomyopathy: Clinical and Echocardiographic Features Including Magnetic Resonance Imaging Findings. WMJ. 2018;117(4):171-4.

Tak

Sharma

Karturi

Gharacholou

Familial Tako-tsubo Cardiomyopathy: Clinical and Echocardiographic Features Including Magnetic Resonance Imaging Findings

WMJ 2018 117 4 171 174

53. Zaroff JG, Pawlikowska L, Miss JC, Yarlagadda S, Ha C, Achrol A, et al. Adrenoceptor Polymorphisms and The Risk of Cardiac Injury and Dysfunction after Subarachnoid Hemorrhage. Stroke. 2006;37(7):1680-5. doi: 10.1161/01.STR.0000226461.52423.dd.

Zaroff

Pawlikowska

Miss

Yarlagadda

Achrol

et al

Adrenoceptor Polymorphisms and The Risk of Cardiac Injury and Dysfunction after Subarachnoid Hemorrhage

Stroke 2006 37 7 1680 1685

10.1161/01.STR.0000226461.52423.dd

54. Gujja KR, Aslam AF, Privman V, Tejani F, Vasavada B. Initial Presentation of Pheochromocytoma with Takotsubo Cardiomyopathy: A Brief Review of Literature. J Cardiovasc Med. 2010;11(1):49-52. doi: 10.2459/JCM.0b013e32832d862f.

Gujja

Aslam

Privman

Tejani

Vasavada

Initial Presentation of Pheochromocytoma with Takotsubo Cardiomyopathy: A Brief Review of Literature

J Cardiovasc Med 2010 11 1 49 52

10.2459/JCM.0b013e32832d862f

55. Sharkey SW, Maron BJ, Nelson P, Parpart M, Maron MS, Bristow MR. Adrenergic Receptor Polymorphisms in Patients with Stress (Tako-Tsubo) Cardiomyopathy. J Cardiol. 2009;53(1):53-7. doi: 10.1016/j.jjcc.2008.08.006.

Sharkey

Maron

Nelson

Parpart

Maron

Bristow

Adrenergic Receptor Polymorphisms in Patients with Stress (Tako-Tsubo) Cardiomyopathy

J Cardiol 2009 53 1 53 57

10.1016/j.jjcc.2008.08.006

56. Vriz O, Minisini R, Citro R, Guerra V, Zito C, De Luca G, et al. Analysis of Beta1 and Beta2-Adrenergic Receptors Polymorphism in Patients with Apical Ballooning Cardiomyopathy. Acta Cardiol. 2011;66(6):787-90. doi: 10.1080/ac.66.6.2136964.

Vriz

Minisini

Citro

Guerra

Zito

De Luca

et al

Analysis of Beta1 and Beta2-Adrenergic Receptors Polymorphism in Patients with Apical Ballooning Cardiomyopathy

Acta Cardiol 2011 66 6 787 790

10.1080/ac.66.6.2136964

57. Goodloe AH, Evans JM, Middha S, Prasad A, Olson TM. Characterizing Genetic Variation of Adrenergic Signalling Pathways in Takotsubo (Stress) Cardiomyopathy Exomes. Eur J Heart Fail. 2014;16(9):942-9. doi: 10.1002/ejhf.145.

Goodloe

Evans

Middha

Prasad

Olson

Characterizing Genetic Variation of Adrenergic Signalling Pathways in Takotsubo (Stress) Cardiomyopathy Exomes

Eur J Heart Fail 2014 16 9 942 949

10.1002/ejhf.145

58. Mausbach BT, Dimsdale JE, Ziegler MG, Mills PJ, Ancoli-Israel S, Patterson TL, et al. Depressive Symptoms Predict Norepinephrine Response to a Psychological Stressor Task in Alzheimer’s Caregivers. Psychosom Med. 2005;67(4):638-42. doi: 10.1097/01.psy.0000173312.90148.97.

Mausbach

Dimsdale

Ziegler

Mills

Ancoli-Israel

Patterson

et al

Depressive Symptoms Predict Norepinephrine Response to a Psychological Stressor Task in Alzheimer’s Caregivers

Psychosom Med 2005 67 4 638 642

10.1097/01.psy.0000173312.90148.97

59. Alvarenga ME, Richards JC, Lambert G, Esler MD. Psychophysiological Mechanisms in Panic Disorder: A Correlative Analysis of Noradrenaline Spillover, Neuronal Noradrenaline Reuptake, Power Spectral Analysis of Heart Rate Variability, and Psychological Variables. Psychosom Med 2006;68:8-16. doi: 10.1097/01.psy.0000195872.00987.db.

Alvarenga

Richards

Lambert

Esler

Psychophysiological Mechanisms in Panic Disorder: A Correlative Analysis of Noradrenaline Spillover, Neuronal Noradrenaline Reuptake, Power Spectral Analysis of Heart Rate Variability, and Psychological Variables

Psychosom Med 2006 68 8 16

10.1097/01.psy.0000195872.00987.db

60. Neil CJ, Chong CR, Nguyen TH, Horowitz JD. Occurrence of Tako-Tsubo cardiomyopathy in Association with Ingestion of Serotonin/Noradrenaline Reuptake Inhibitors. Heart Lung Circ. 2012;21(4):203-5. doi: 10.1016/j.hlc.2011.12.004.

Neil

Chong

Nguyen

Horowitz

Occurrence of Tako-Tsubo cardiomyopathy in Association with Ingestion of Serotonin/Noradrenaline Reuptake Inhibitors

Heart Lung Circ 2012 21 4 203 205

10.1016/j.hlc.2011.12.004

61. Summers MR, Lennon RJ, Prasad A. Pre-Morbid Psychiatric and Cardiovascular Diseases in Apical Ballooning Syndrome (Tako-Tsubo/Stress-Induced Cardiomyopathy): Potential Pre-Disposing Factors? J Am Coll Cardiol. 2010;55(7):700-1. doi: 10.1016/j.jacc.2009.10.031.

Summers

Lennon

Prasad

Pre-Morbid Psychiatric and Cardiovascular Diseases in Apical Ballooning Syndrome (Tako-Tsubo/Stress-Induced Cardiomyopathy): Potential Pre-Disposing Factors?

J Am Coll Cardiol 2010 55 7 700 701

10.1016/j.jacc.2009.10.031

62. Delmas C, Lairez O, Mulin E, Delmas T, Boudou N, Dumonteil N, et al. Anxiodepressive Disorders and Chronic Psychological Stress are Associated with Tako-Tsubo Cardiomyopathy- New Physiopathological Hypothesis. Circ J. 2013;77(1):175-80. doi: 10.1253/circj.cj-12-0759.

Delmas

Lairez

Mulin

Delmas

Boudou

Dumonteil

et al

Anxiodepressive Disorders and Chronic Psychological Stress are Associated with Tako-Tsubo Cardiomyopathy- New Physiopathological Hypothesis

Circ J 2013 77 1 175 180

10.1253/circj.cj-12-0759

63. Isogai T, Yasunaga H, Matsui H, Tanaka H, Ueda T, Horiguchi H, et al. Out-Of-Hospital Versus In-Hospital Takotsubo Cardiomyopathy: Analysis of 3719 Patients in the Diagnosis Procedure Combination Database in Japan. Int J Cardiol. 2014;176(2):413-7. doi: 10.1016/j.ijcard.2014.07.110.

Isogai

Yasunaga

Matsui

Tanaka

Ueda

Horiguchi

et al

Out-Of-Hospital Versus In-Hospital Takotsubo Cardiomyopathy: Analysis of 3719 Patients in the Diagnosis Procedure Combination Database in Japan

Int J Cardiol 2014 176 2 413 417

10.1016/j.ijcard.2014.07.110

64. Rajani R, Przedlacka A, Saha M, de Belder A. Pancreatitis and the Broken Heart. Eur J Emerg Med. 2010;17(1):27-9. doi: 10.1097/MEJ.0b013e32832cf70d.

Rajani

Przedlacka

Saha

de Belder

Pancreatitis and the Broken Heart

Eur J Emerg Med 2010 17 1 27 29

10.1097/MEJ.0b013e32832cf70d

65. Aggarwal V, Krantz MJ. Migratory Takotsubo Cardiomyopathy in the Setting of Cholecystitis. Am J Med. 2012;125(12):e5-6. doi: 10.1016/j.amjmed.2012.03.009.

Aggarwal

Krantz

Migratory Takotsubo Cardiomyopathy in the Setting of Cholecystitis

Am J Med 2012 125 12 e5 e6

10.1016/j.amjmed.2012.03.009

66. Gale M, Loarte P, Mirrer B, Mallet T, Salciccioli L, Petrie A, et al. Takotsubo Cardiomyopathy in the Setting of Tension Pneumothorax. Case Rep Crit Care. 2015;2015:536931. doi: 10.1155/2015/536931.

Gale

Loarte

Mirrer

Mallet

Salciccioli

Petrie

et al

Takotsubo Cardiomyopathy in the Setting of Tension Pneumothorax

Case Rep Crit Care 2015 2015 536931

10.1155/2015/536931

67. Elikowski W, Kudliński B, Małek-Elikowska M, Foremska-Iciek J, Baszko A, Skrzywanek P. Takotsubo Cardiomyopathy in a Young Woman after a Traffic Accident with Blunt Chest Trauma. Pol Merkur Lekarski. 2016;40(240):372-6.

Elikowski

Kudliński

Małek-Elikowska

Foremska-Iciek

Baszko

Skrzywanek

Takotsubo Cardiomyopathy in a Young Woman after a Traffic Accident with Blunt Chest Trauma

Pol Merkur Lekarski 2016 40 240 372 376

68. Y-Hassan S, Settergren M, Henareh L. Sepsis-Induced Myocardial Depression and Takotsubo Syndrome. Acute Card Care. 2014;16(3):102-9. doi: 10.3109/17482941.2014.920089.

Y-Hassan

Settergren

Henareh

Sepsis-Induced Myocardial Depression and Takotsubo Syndrome

Acute Card Care 2014 16 3 102 109

10.3109/17482941.2014.920089

69. Eliades M, El-Maouche D, Choudhary C, Zinsmeister B, Burman KD. Takotsubo Cardiomyopathy Associated with Thyrotoxicosis: A Case Report and Review of the Literature. Thyroid. 2014;24(2):383-9. doi: 10.1089/thy.2012.0384.

Eliades

El-Maouche

Choudhary

Zinsmeister

Burman

Takotsubo Cardiomyopathy Associated with Thyrotoxicosis: A Case Report and Review of the Literature

Thyroid 2014 24 2 383 389

10.1089/thy.2012.0384

70. Smith SA, Auseon AJ. Chemotherapy-Induced Takotsubo Cardiomyopathy. Heart Fail Clin. 2013;9(2):233-42. doi: 10.1016/j.hfc.2012.12.009.

Smith

Auseon

Chemotherapy-Induced Takotsubo Cardiomyopathy

Heart Fail Clin 2013 9 2 233 242

10.1016/j.hfc.2012.12.009

71. Modi S, Baig W. Radiotherapy-Induced Tako-Tsubo Cardiomyopathy. Clin Oncol. 2009;21(4):361-2. doi: 10.1016/j.clon.2009.01.005.

Modi

Baig

Radiotherapy-Induced Tako-Tsubo Cardiomyopathy

Clin Oncol 2009 21 4 361 362

10.1016/j.clon.2009.01.005

72. Brezina P, Isler CM. Takotsubo Cardiomyopathy in Pregnancy. Obstet Gynecol. 2008;112(2 Pt 2):450-2. doi: 10.1097/AOG.0b013e3181662cfe.

Brezina

Isler

Takotsubo Cardiomyopathy in Pregnancy

Obstet Gynecol 2008 112 2 Pt 2 450 452

10.1097/AOG.0b013e3181662cfe

73. Citro R, Lyon A, Arbustini E, Bossone E, Piscione F, Templin C, et al. Takotsubo Syndrome after Cesarean Section: Rare But Possible. J Am Coll Cardiol. 2018;71(16):1838-9. doi: 10.1016/j.jacc.2018.02.035.

Citro

Lyon

Arbustini

Bossone

Piscione

Templin

et al

Takotsubo Syndrome after Cesarean Section: Rare But Possible

J Am Coll Cardiol 2018 71 16 1838 1839

10.1016/j.jacc.2018.02.035

74. Dundon BK, Puri R, Leong DP, Worthley MI. Takotsubo Cardiomyopathy Following Lightning Strike. Emerg Med J. 2008;25(7):460-1. doi: 10.1136/emj.2007.048876.

Dundon

Puri

Leong

Worthley

Takotsubo Cardiomyopathy Following Lightning Strike

Emerg Med J 2008 25 7 460 461

10.1136/emj.2007.048876

75. Citro R, Patella MM, Bossone E, Maione A, Provenza G, Gregorio G. Near-Drowning Syndrome: A Possible Trigger of Tako-Tsubo Cardiomyopathy. J Cardiovasc Med. 2008;9(5):501-5. doi: 10.2459/JCM.0b013e3282f03aca.

Citro

Patella

Bossone

Maione

Provenza

Gregorio

Near-Drowning Syndrome: A Possible Trigger of Tako-Tsubo Cardiomyopathy

J Cardiovasc Med 2008 9 5 501 505

10.2459/JCM.0b013e3282f03aca

76. Davin L, Legrand V, Legrand D. A Frozen Heart. Eur Heart J. 2009;30(15):1827. doi: 10.1093/eurheartj/ehp149.

Davin

Legrand

A Frozen Heart

Eur Heart J 2009 30 15 1827

10.1093/eurheartj/ehp149

77. Arora S, Alfayoumi F, Srinivasan V. Transient Left Ventricular Apical Ballooning after Cocaine Use: Is Catecholamine Cardiotoxicity the Pathologic Link? Mayo Clin Proc. 2006;81(6):829-32. doi: 10.4065/81.6.829.

Arora

Alfayoumi

Srinivasan

Transient Left Ventricular Apical Ballooning after Cocaine Use: Is Catecholamine Cardiotoxicity the Pathologic Link?

Mayo Clin Proc 2006 81 6 829 832

10.4065/81.6.829

78. Stout BJ, Hoshide R, Vincent DS. Takotsubo Cardiomyopathy in the Setting of Acute Alcohol Withdrawal. Hawaii J Med Public Health. 2012;71(7):193-4.

Stout

Hoshide

Vincent

Takotsubo Cardiomyopathy in the Setting of Acute Alcohol Withdrawal

Hawaii J Med Public Health 2012 71 7 193 194

79. Tagawa M, Nakamura Y, Ishiguro M, Satoh K, Chinushi M, Kodama M, et al. Transient Left Ventricular Apical Ballooning Developing after the Central Niigata Prefecture Earthquake: Two Case Reports. J Cardiol. 2006;48(3):153-8.

Tagawa

Nakamura

Ishiguro

Satoh

Chinushi

Kodama

et al

Transient Left Ventricular Apical Ballooning Developing after the Central Niigata Prefecture Earthquake: Two Case Reports

J Cardiol 2006 48 3 153 158

80. Chan C, Elliott J, Troughton R, Frampton C, Smyth D, Crozier I, et al. Acute Myocardial Infarction and Stress Cardiomyopathy Following the Christchurch Earthquakes. PLoS One. 2013;8(7):e68504. doi: 10.1371/journal.pone.0068504.

Chan

Elliott

Troughton

Frampton

Smyth

Crozier

et al

Acute Myocardial Infarction and Stress Cardiomyopathy Following the Christchurch Earthquakes

PLoS One 2013 8 7 e68504

10.1371/journal.pone.0068504

81. Butterly SJ, Indrajith M, Garrahy P, Ng AC, Gould PA, Wang WY. Stress-Induced Takotsubo Cardiomyopathy in Survivors of the 2011 Queensland Floods. Med J Aust. 2013;198(2):109-10. doi: 10.5694/mja12.11620.

Butterly

Indrajith

Garrahy

Gould

Wang

Stress-Induced Takotsubo Cardiomyopathy in Survivors of the 2011 Queensland Floods

Med J Aust 2013 198 2 109 110

10.5694/mja12.11620

82. Ghadri JR, Sarcon A, Diekmann J, Bataiosu DR, Cammann VL, Jurisic S, et al. Happy Heart Syndrome: Role of Positive Emotional Stress in Takotsubo Syndrome. Eur Heart J. 2016;37(37):2823-9. doi: 10.1093/eurheartj/ehv757.

Ghadri

Sarcon

Diekmann

Bataiosu

Cammann

Jurisic

et al

Happy Heart Syndrome: Role of Positive Emotional Stress in Takotsubo Syndrome

Eur Heart J 2016 37 37 2823 2829

10.1093/eurheartj/ehv757

83. Chazal HM, Del Buono MG, Keyser-Marcus L, Ma L, Moeller FG, Berrocal D, et alA. Stress Cardiomyopathy Diagnosis and Treatment: JACC State-of-the-Art Review. J Am Coll Cardiol. 2018;72(16):1955-71. doi: 10.1016/j.jacc.2018.07.072.

Chazal

Del Buono

Keyser-Marcus

Moeller

Berrocal

et al

A. Stress Cardiomyopathy Diagnosis and Treatment: JACC State-of-the-Art Review

J Am Coll Cardiol 2018 72 16 1955 1971

10.1016/j.jacc.2018.07.072

84. Ghadri JR, Sarcon A, Diekmann J, Bataiosu DR, Cammann VL, Jurisic S, et al. Happy Heart Syndrome: Role of Positive Emotional Stress in Takotsubo Syndrome. Eur Heart J. 2016;37(37):2823-9. doi: 10.1093/eurheartj/ehv757.

Ghadri

Sarcon

Diekmann

Bataiosu

Cammann

Jurisic

et al

Happy Heart Syndrome: Role of Positive Emotional Stress in Takotsubo Syndrome

Eur Heart J 2016 37 37 2823 2829

10.1093/eurheartj/ehv757

85. Daoko J, Rajachandran M, Savarese R, Orme J. Biventricular Takotsubo Cardiomyopathy: Case Study and Review of Literature. Tex Heart Inst J. 2013;40(3):305-11.

Daoko

Rajachandran

Savarese

Orme

Biventricular Takotsubo Cardiomyopathy: Case Study and Review of Literature

Tex Heart Inst J 2013 40 3 305 311

86. Kato K, Ishibashi I, Ghadri JR, Templin C. Biventricular Takotsubo Syndrome. Eur Heart J. 2019;40(26):2171. doi: 10.1093/eurheartj/ehz198.

Kato

Ishibashi

Ghadri

Templin

Biventricular Takotsubo Syndrome

Eur Heart J 2019 40 26 2171

10.1093/eurheartj/ehz198

87. Thygesen K, Alpert JS, Jaffe AS, Chaitman BR, Bax JJ, Morrow DA, et al. Fourth Universal Definition of Myocardial Infarction (2018). J Am Coll Cardiol. 2018;72(18):2231-64. doi: 10.1016/j.jacc.2018.08.1038.

Thygesen

Alpert

Jaffe

Chaitman

Bax

Morrow

et al

Fourth Universal Definition of Myocardial Infarction (2018)

J Am Coll Cardiol 2018 72 18 2231 2264

10.1016/j.jacc.2018.08.1038

88. Akashi YJ, Nef HM, Lyon AR. Epidemiology and Pathophysiology of Takotsubo Syndrome. Nat Rev Cardiol. 2015;12(7):387-97. doi: 10.1038/nrcardio.2015.39.

Akashi

Nef

Lyon

Epidemiology and Pathophysiology of Takotsubo Syndrome

Nat Rev Cardiol 2015 12 7 387 397

10.1038/nrcardio.2015.39

89. Pilgrim TM, Wyss TR. Takotsubo Cardiomyopathy or Transient Left Ventricular Apical Ballooning Syndrome: A Systematic Review. Int J Cardiol. 2008;124(3):283-92. doi: 10.1016/j.ijcard.2007.07.002.

Pilgrim

Wyss

Takotsubo Cardiomyopathy or Transient Left Ventricular Apical Ballooning Syndrome: A Systematic Review

Int J Cardiol 2008 124 3 283 292

10.1016/j.ijcard.2007.07.002

90. Del Buono MG, O’Quinn MP, Garcia P, Gerszten E, Roberts C, Moeller FG, et al. Cardiac Arrest due to Ventricular Fibrillation in a 23-Year-Old Woman with Broken Heart Syndrome. Cardiovasc Pathol. 2017;30:78-81. doi: 10.1016/j.carpath.2017.06.007.

Del Buono

O’Quinn

Garcia

Gerszten

Roberts

Moeller

et al

Cardiac Arrest due to Ventricular Fibrillation in a 23-Year-Old Woman with Broken Heart Syndrome

Cardiovasc Pathol 2017 30 78 81

10.1016/j.carpath.2017.06.007

91. Stöllberger C, Wegner C, Finsterer J. Seizure-Associated Takotsubo Cardiomyopathy. Epilepsia. 2011;52(11):e160-7. doi: 10.1111/j.1528-1167.2011.03185.x.

Stöllberger

Wegner

Finsterer

Seizure-Associated Takotsubo Cardiomyopathy

Epilepsia 2011 52 11 e160 e167

10.1111/j.1528-1167.2011.03185.x

92. Jung JM, Kim JG, Kim JB, Cho KH, Yu S, Oh K, et al. Takotsubo-Like Myocardial Dysfunction in Ischemic Stroke: A Hospital-Based Registry and Systematic Literature Review. Stroke. 2016;47(11):2729-36. doi: 10.1161/STROKEAHA.116.014304.

Jung

Kim

Cho

et al

Takotsubo-Like Myocardial Dysfunction in Ischemic Stroke: A Hospital-Based Registry and Systematic Literature Review

Stroke 2016 47 11 2729 2736

10.1161/STROKEAHA.116.014304

93. Ogura R, Hiasa Y, Takahashi T, Yamaguchi K, Fujiwara K, Ohara Y, et al. Specific Findings of the Standard 12-Lead ECG in Patients with ‘Takotsubo’ Cardiomyopathy: Comparison with the Findings of Acute Anterior Myocardial Infarction. Circ J. 2003;67(8):687-90. doi: 10.1253/circj.67.687.

Ogura

Hiasa

Takahashi

Yamaguchi

Fujiwara

Ohara

et al

Specific Findings of the Standard 12-Lead ECG in Patients with ‘Takotsubo’ Cardiomyopathy: Comparison with the Findings of Acute Anterior Myocardial Infarction

Circ J 2003 67 8 687 690

10.1253/circj.67.687

94. Kurisu S, Inoue I, Kawagoe T, Ishihara M, Shimatani Y, Nakamura S, et al. Time Course of Electrocardiographic Changes in Patients with Tako-Tsubo Syndrome: Comparison with Acute Myocardial Infarction with Minimal Enzymatic Release. Circ J. 2004;68(1):77-81. doi: 10.1253/circj.68.77.

Kurisu

Inoue

Kawagoe

Ishihara

Shimatani

Nakamura

et al

Time Course of Electrocardiographic Changes in Patients with Tako-Tsubo Syndrome: Comparison with Acute Myocardial Infarction with Minimal Enzymatic Release

Circ J 2004 68 1 77 81

10.1253/circj.68.77

95. Sharkey SW. Electrocardiogram Mimics of Acute ST-Segment Elevation Myocardial Infarction: Insights from Cardiac Magnetic Resonance Imaging in Patients with Tako-Tsubo (Stress) Cardiomyopathy. J Electrocardiol. 2008;41(6):621-5. doi: 10.1016/j.jelectrocard.2008.06.015.

Sharkey

Electrocardiogram Mimics of Acute ST-Segment Elevation Myocardial Infarction: Insights from Cardiac Magnetic Resonance Imaging in Patients with Tako-Tsubo (Stress) Cardiomyopathy

J Electrocardiol 2008 41 6 621 625

10.1016/j.jelectrocard.2008.06.015

96. Kosuge M, Ebina T, Hibi K, Morita S, Okuda J, Iwahashi N, et al. Simple and Accurate Electrocardiographic Criteria to Differentiate Takotsubo Cardiomyopathy from Anterior Acute Myocardial Infarction. J Am Coll Cardiol. 2010;55(22):2514-6. doi: 10.1016/j.jacc.2009.12.059.

Kosuge

Ebina

Hibi

Morita

Okuda

Iwahashi

et al

Simple and Accurate Electrocardiographic Criteria to Differentiate Takotsubo Cardiomyopathy from Anterior Acute Myocardial Infarction

J Am Coll Cardiol 2010 55 22 2514 2516

10.1016/j.jacc.2009.12.059

97. Johnson NP, Chavez JF, Mosley WJ 2nd, Flaherty JD, Fox JM. Performance of Electrocardiographic Criteria to Differentiate Takotsubo Cardiomyopathy from Acute Anterior ST Elevation Myocardial Infarction. Int J Cardiol. 2013;164(3):345-8. doi: 10.1016/j.ijcard.2011.07.029.

Johnson

Chavez

Mosley

2nd Flaherty

Fox

Performance of Electrocardiographic Criteria to Differentiate Takotsubo Cardiomyopathy from Acute Anterior ST Elevation Myocardial Infarction

Int J Cardiol 2013 164 3 345 348

10.1016/j.ijcard.2011.07.029

98. Behr ER, Mahida S. Takotsubo Cardiomyopathy and the Long-QT Syndrome: An Insult to Repolarization Reserve. Europace. 2009;11(6):697-700. doi: 10.1093/europace/eup081.

Behr

Mahida

Takotsubo Cardiomyopathy and the Long-QT Syndrome: An Insult to Repolarization Reserve

Europace 2009 11 6 697 700

10.1093/europace/eup081

99. Matsuoka K, Okubo S, Fujii E, Uchida F, Kasai A, Aoki T, et al. Evaluation of the Arrhythmogenecity of Stress-Induced “Takotsubo cardiomyopathy” from the Time Course of the 12-Lead Surface Electrocardiogram. Am J Cardiol. 2003;92(2):230-3. doi: 10.1016/s0002-9149(03)00547-2.

Matsuoka

Okubo

Fujii

Uchida

Kasai

Aoki

et al

Evaluation of the Arrhythmogenecity of Stress-Induced “Takotsubo cardiomyopathy” from the Time Course of the 12-Lead Surface Electrocardiogram

Am J Cardiol 2003 92 2 230 233

10.1016/s0002-9149(03)00547-2

100

100. Migliore F, Zorzi A, Marra MP, Basso C, Corbetti F, De Lazzari M, et al. Myocardial Edema Underlies Dynamic T-Wave Inversion (Wellens’ ECG Pattern) in Patients with Reversible Left Ventricular Dysfunction. Heart Rhythm. 2011;8(10):1629-34. doi: 10.1016/j.hrthm.2011.04.035.

Migliore

Zorzi

Marra

Basso

Corbetti

De Lazzari

et al

Myocardial Edema Underlies Dynamic T-Wave Inversion (Wellens’ ECG Pattern) in Patients with Reversible Left Ventricular Dysfunction

Heart Rhythm 2011 8 10 1629 1634

10.1016/j.hrthm.2011.04.035

101

101. Nguyen TH, Neil CJ, Sverdlov AL, Mahadavan G, Chirkov YY, Kucia AM, et al. N-Terminal Pro-Brain Natriuretic Protein Levels in Takotsubo Cardiomyopathy. Am J Cardiol. 2011;108(9):1316-21. doi: 10.1016/j.amjcard.2011.06.047.

Nguyen

Neil

Sverdlov

Mahadavan

Chirkov

Kucia

et al

N-Terminal Pro-Brain Natriuretic Protein Levels in Takotsubo Cardiomyopathy

Am J Cardiol 2011 108 9 1316 1321

10.1016/j.amjcard.2011.06.047

102

102. Randhawa MS, Dhillon AS, Taylor HC, Sun Z, Desai MY. Diagnostic Utility of Cardiac Biomarkers in Discriminating Takotsubo Cardiomyopathy from Acute Myocardial Infarction. J Card Fail. 2014;20(1):2-8. doi: 10.1016/j.cardfail.2013.12.004.

Randhawa

Dhillon

Taylor

Sun

Desai

Diagnostic Utility of Cardiac Biomarkers in Discriminating Takotsubo Cardiomyopathy from Acute Myocardial Infarction

J Card Fail 2014 20 1 2 8

10.1016/j.cardfail.2013.12.004

103

103. Akashi YJ, Musha H, Nakazawa K, Miyake F. Plasma Brain Natriuretic Peptide in Takotsubo Cardiomyopathy. QJM. 2004;97(9):599-607. doi: 10.1093/qjmed/hch094.

Akashi

Musha

Nakazawa

Miyake

Plasma Brain Natriuretic Peptide in Takotsubo Cardiomyopathy

QJM 2004 97 9 599 607

10.1093/qjmed/hch094

104

104. Kurisu S, Kihara Y. Tako-Tsubo Cardiomyopathy: Clinical Presentation and Underlying Mechanism. J Cardiol. 2012;60(6):429-37. doi: 10.1016/j.jjcc.2012.06.015.

Kurisu

Kihara

Tako-Tsubo Cardiomyopathy: Clinical Presentation and Underlying Mechanism

J Cardiol 2012 60 6 429 437

10.1016/j.jjcc.2012.06.015

105

105. Citro R, Lyon AR, Meimoun P, Omerovic E, Redfors B, Buck T, et al. Standard and Advanced Echocardiography in Takotsubo (Stress) Cardiomyopathy: Clinical and Prognostic Implications. J Am Soc Echocardiogr. 2015;28(1):57-74. doi: 10.1016/j.echo.2014.08.020.

Citro

Lyon

Meimoun

Omerovic

Redfors

Buck

et al

Standard and Advanced Echocardiography in Takotsubo (Stress) Cardiomyopathy: Clinical and Prognostic Implications

J Am Soc Echocardiogr 2015 28 1 57 74

10.1016/j.echo.2014.08.020

106

106. Sharkey SW, Maron BJ. Epidemiology and Clinical Profile of Takotsubo Cardiomyopathy. Circ J. 2014;78(9):2119-28. doi: 10.1253/circj.cj-14-0770.

Sharkey

Maron

Epidemiology and Clinical Profile of Takotsubo Cardiomyopathy

Circ J 2014 78 9 2119 2128

10.1253/circj.cj-14-0770

107

107. Lyon AR, Bossone E, Schneider B, Sechtem U, Citro R, Underwood SR, et al. Current State of Knowledge on Takotsubo Syndrome: A Position Statement from the Taskforce on Takotsubo Syndrome of the Heart Failure Association of the European Society of Cardiology. Eur J Heart Fail. 2016;18(1):8-27. doi: 10.1002/ejhf.424.

Lyon

Bossone

Schneider

Sechtem

Citro

Underwood

et al

Current State of Knowledge on Takotsubo Syndrome: A Position Statement from the Taskforce on Takotsubo Syndrome of the Heart Failure Association of the European Society of Cardiology

Eur J Heart Fail 2016 18 1 8 27

10.1002/ejhf.424

108

108. Eitel I, von Knobelsdorff-Brenkenhoff F, Bernhardt P, Carbone I, Muellerleile K, Aldrovandi A, et al. Clinical Characteristics and Cardiovascular Magnetic Resonance Findings in Stress (Takotsubo) Cardiomyopathy. JAMA. 2011;306(3):277-86. doi: 10.1001/jama.2011.992.

Eitel

von Knobelsdorff-Brenkenhoff

Bernhardt

Carbone

Muellerleile

Aldrovandi

et al

Clinical Characteristics and Cardiovascular Magnetic Resonance Findings in Stress (Takotsubo) Cardiomyopathy

JAMA 2011 306 3 277 286

10.1001/jama.2011.992

109

109. Abbas A, Sonnex E, Pereira RS, Coulden RA. Cardiac Magnetic Resonance Assessment of Takotsubo Cardiomyopathy. Clin Radiol. 2016;71(1):e110-9. doi: 10.1016/j.crad.2015.10.020.

Abbas

Sonnex

Pereira

Coulden

Cardiac Magnetic Resonance Assessment of Takotsubo Cardiomyopathy

Clin Radiol 2016 71 1 e110 e119

10.1016/j.crad.2015.10.020

110

110. Eitel I, Behrendt F, Schindler K, Kivelitz D, Gutberlet M, Schuler G, et al. Differential Diagnosis of Suspected Apical Ballooning Syndrome Using Contrast-Enhanced Magnetic Resonance Imaging. Eur Heart J. 2008;29(21):2651-9. doi: 10.1093/eurheartj/ehn433.

Eitel

Behrendt

Schindler

Kivelitz

Gutberlet

Schuler

et al

Differential Diagnosis of Suspected Apical Ballooning Syndrome Using Contrast-Enhanced Magnetic Resonance Imaging

Eur Heart J 2008 29 21 2651 2659

10.1093/eurheartj/ehn433

111

111. Haghi D, Fluechter S, Suselbeck T, Kaden JJ, Borggrefe M, Papavassiliu T. Cardiovascular Magnetic Resonance Findings in Typical Versus Atypical Forms of the Acute Apical Ballooning Syndrome (Takotsubo Cardiomyopathy). Int J Cardiol. 2007;120(2):205-11. doi: 10.1016/j.ijcard.2006.09.019.

Haghi

Fluechter

Suselbeck

Kaden

Borggrefe

Papavassiliu

Cardiovascular Magnetic Resonance Findings in Typical Versus Atypical Forms of the Acute Apical Ballooning Syndrome (Takotsubo Cardiomyopathy)

Int J Cardiol 2007 120 2 205 211

10.1016/j.ijcard.2006.09.019

112

112. Nakamori S, Matsuoka K, Onishi K, Kurita T, Ichikawa Y, Nakajima H, et al. Prevalence and Signal Characteristics of Late Gadolinium Enhancement on Contrast-Enhanced Magnetic Resonance Imaging in Patients with Takotsubo Cardiomyopathy. Circ J. 2012;76(4):914-21. doi: 10.1253/circj.cj-11-1043.

Nakamori

Matsuoka

Onishi

Kurita

Ichikawa

Nakajima

et al

Prevalence and Signal Characteristics of Late Gadolinium Enhancement on Contrast-Enhanced Magnetic Resonance Imaging in Patients with Takotsubo Cardiomyopathy

Circ J 2012 76 4 914 921

10.1253/circj.cj-11-1043

113

113. Naruse Y, Sato A, Kasahara K, Makino K, Sano M, Takeuchi Y, et al. The Clinical Impact of Late Gadolinium Enhancement in Takotsubo Cardiomyopathy: Serial Analysis of Cardiovascular Magnetic Resonance Images. J Cardiovasc Magn Reson. 2011;13(1):67. doi: 10.1186/1532-429X-13-67.

Naruse

Sato

Kasahara

Makino

Sano

Takeuchi

et al

The Clinical Impact of Late Gadolinium Enhancement in Takotsubo Cardiomyopathy: Serial Analysis of Cardiovascular Magnetic Resonance Images

J Cardiovasc Magn Reson 2011 13 1 67

10.1186/1532-429X-13-67

114

114. Wu KC, Weiss RG, Thiemann DR, Kitagawa K, Schmidt A, Dalal D, et al. Late Gadolinium Enhancement by Cardiovascular Magnetic Resonance Heralds an Adverse Prognosis in Nonischemic Cardiomyopathy. J Am Coll Cardiol. 2008;51(25):2414-21. doi: 10.1016/j.jacc.2008.03.018.

Weiss

Thiemann

Kitagawa

Schmidt

Dalal

et al

Late Gadolinium Enhancement by Cardiovascular Magnetic Resonance Heralds an Adverse Prognosis in Nonischemic Cardiomyopathy

J Am Coll Cardiol 2008 51 25 2414 2421

10.1016/j.jacc.2008.03.018

115

115. Matsuura T, Ueno M, Iwanaga Y, Miyazaki S. Importance of Sympathetic Nervous System Activity During Left Ventricular Functional Recovery and its Association with In-Hospital Complications in Takotsubo Syndrome. Heart Vessels. 2019;34(8):1317-24. doi: 10.1007/s00380-019-01359-4.

Matsuura

Ueno

Iwanaga

Miyazaki

Importance of Sympathetic Nervous System Activity During Left Ventricular Functional Recovery and its Association with In-Hospital Complications in Takotsubo Syndrome

Heart Vessels 2019 34 8 1317 1324

10.1007/s00380-019-01359-4

116

116. Cimarelli S, Sauer F, Morel O, Ohlmann P, Constantinesco A, Imperiale A. Transient Left Ventricular Dysfunction Syndrome: Patho-Physiological Bases Through Nuclear Medicine Imaging. Int J Cardiol. 2010;144(2):212-8. doi: 10.1016/j.ijcard.2009.04.025.

Cimarelli

Sauer

Morel

Ohlmann

Constantinesco

Imperiale

Transient Left Ventricular Dysfunction Syndrome: Patho-Physiological Bases Through Nuclear Medicine Imaging

Int J Cardiol 2010 144 2 212 218

10.1016/j.ijcard.2009.04.025

117

117. Kurisu S, Inoue I, Kawagoe T, Ishihara M, Shimatani Y, Nakama Y, et al. Prevalence of Incidental Coronary Artery Disease In Tako-Tsubo Cardiomyopathy. Coron Artery Dis. 2009;20(3):214-8. doi: 10.1097/MCA.0b013e3283299260.

Kurisu

Inoue

Kawagoe

Ishihara

Shimatani

Nakama

et al

Prevalence of Incidental Coronary Artery Disease In Tako-Tsubo Cardiomyopathy

Coron Artery Dis 2009 20 3 214 218

10.1097/MCA.0b013e3283299260

118

118. Hussain MA, Cox AT, Bastiaenen R, Prasad A. Apical Ballooning (Takotsubo) Syndrome with Concurrent ST-Segment Elevation Myocardial Infarction. BMJ Case Rep. 2017;2017:bcr2017220145. doi: 10.1136/bcr-2017-220145.

Hussain

Cox

Bastiaenen

Prasad

Apical Ballooning (Takotsubo) Syndrome with Concurrent ST-Segment Elevation Myocardial Infarction

BMJ Case Rep 2017 2017 bcr2017220145

10.1136/bcr-2017-220145

119

119. Gaibazzi N, Ugo F, Vignali L, Zoni A, Reverberi C, Gherli T. Tako-Tsubo Cardiomyopathy with Coronary Artery Stenosis: A Case-Series Challenging the Original Definition. Int J Cardiol. 2009;133(2):205-12. doi: 10.1016/j.ijcard.2007.12.037.

Gaibazzi

Ugo

Vignali

Zoni

Reverberi

Gherli

Tako-Tsubo Cardiomyopathy with Coronary Artery Stenosis: A Case-Series Challenging the Original Definition

Int J Cardiol 2009 133 2 205 212

10.1016/j.ijcard.2007.12.037

120

120. Previtali M, Repetto A, Panigada S, Camporotondo R, Tavazzi L. Left Ventricular Apical Ballooning Syndrome: Prevalence, Clinical Characteristics and Pathogenetic Mechanisms in a European Population. Int J Cardiol. 2009;134(1):91-6. doi: 10.1016/j.ijcard.2008.01.037.

Previtali

Repetto

Panigada

Camporotondo

Tavazzi

Left Ventricular Apical Ballooning Syndrome: Prevalence, Clinical Characteristics and Pathogenetic Mechanisms in a European Population

Int J Cardiol 2009 134 1 91 96

10.1016/j.ijcard.2008.01.037

121

121. Napp LC, Ghadri JR, Bauersachs J, Templin C. Acute Coronary Syndrome or Takotsubo Cardiomyopathy: The Suspect May Not Always be the Culprit. Int J Cardiol. 2015;187:116-9. doi: 10.1016/j.ijcard.2015.03.255.

Napp

Ghadri

Bauersachs

Templin

Acute Coronary Syndrome or Takotsubo Cardiomyopathy: The Suspect May Not Always be the Culprit

Int J Cardiol 2015 187 116 119

10.1016/j.ijcard.2015.03.255

122

122. Delgado GA, Truesdell AG, Kirchner RM, Zuzek RW, Pomerantsev EV, Gordon PC, et al. An Angiographic and Intravascular Ultrasound Study of the Left Anterior Descending Coronary Artery in Takotsubo Cardiomyopathy. Am J Cardiol. 2011;108(6):888-91. doi: 10.1016/j.amjcard.2011.05.012.

Delgado

Truesdell

Kirchner

Zuzek

Pomerantsev

Gordon

et al

An Angiographic and Intravascular Ultrasound Study of the Left Anterior Descending Coronary Artery in Takotsubo Cardiomyopathy

Am J Cardiol 2011 108 6 888 891

10.1016/j.amjcard.2011.05.012

123

123. Patel SM, Lennon RJ, Prasad A. Regional Wall Motion Abnormality in Apical Ballooning Syndrome (Takotsubo/Stress Cardiomyopathy): Importance of Biplane Left Ventriculography for Differentiating from Spontaneously Aborted Anterior Myocardial Infarction. Int J Cardiovasc Imaging. 2012;28(4):687-94. doi: 10.1007/s10554-011-9911-5.

Patel

Lennon

Prasad

Regional Wall Motion Abnormality in Apical Ballooning Syndrome (Takotsubo/Stress Cardiomyopathy): Importance of Biplane Left Ventriculography for Differentiating from Spontaneously Aborted Anterior Myocardial Infarction

Int J Cardiovasc Imaging 2012 28 4 687 694

10.1007/s10554-011-9911-5

124

124. Nance JW, Schoepf UJ, Ramos-Duran L. Tako-Tsubo Cardiomyopathy: Findings on Cardiac CT and Coronary Catheterisation. Heart. 2010;96(5):406-7. doi: 10.1136/hrt.2009.185306.

Nance

Schoepf

Ramos-Duran

Tako-Tsubo Cardiomyopathy: Findings on Cardiac CT and Coronary Catheterisation

Heart 2010 96 5 406 407

10.1136/hrt.2009.185306

125

125. Ghadri JR, Cammann VL, Jurisic S, Seifert B, Napp LC, Diekmann J, et al. A Novel Clinical Score (InterTAK Diagnostic Score) to Differentiate Takotsubo Syndrome from Acute Coronary Syndrome: Results from the International Takotsubo Registry. Eur J Heart Fail. 2017;19(8):1036-42. doi: 10.1002/ejhf.683.

Ghadri

Cammann

Jurisic

Seifert

Napp

Diekmann

et al

A Novel Clinical Score (InterTAK Diagnostic Score) to Differentiate Takotsubo Syndrome from Acute Coronary Syndrome: Results from the International Takotsubo Registry

Eur J Heart Fail 2017 19 8 1036 1042

10.1002/ejhf.683

126

126. Citro R, Okura H, Ghadri JR, Izumi C, Meimoun P, Izumo M, et al. Multimodality Imaging in Takotsubo Syndrome: A Joint Consensus Document of the European Association of Cardiovascular Imaging (EACVI) and the Japanese Society of Echocardiography (JSE). J Echocardiogr. 2020;18(4):199-224. doi: 10.1007/s12574-020-00480-y.

Citro

Okura

Ghadri

Izumi

Meimoun

Izumo

et al

Multimodality Imaging in Takotsubo Syndrome: A Joint Consensus Document of the European Association of Cardiovascular Imaging (EACVI) and the Japanese Society of Echocardiography (JSE)

J Echocardiogr 2020 18 4 199 224

10.1007/s12574-020-00480-y

127

127. Almendro-Delia M, Gil IJN, Lobo M, Andrés M, Vedia O, Sionis A, et al. Short- and Long-Term Prognostic Relevance of Cardiogenic Shock in Takotsubo Syndrome: Results from the RETAKO Registry. JACC Heart Fail. 2018;6(11):928-36. doi: 10.1016/j.jchf.2018.05.015.

Almendro-Delia

Gil

IJN

Lobo

Andrés

Vedia

Sionis

et al

Short- and Long-Term Prognostic Relevance of Cardiogenic Shock in Takotsubo Syndrome: Results from the RETAKO Registry

JACC Heart Fail 2018 6 11 928 936

10.1016/j.jchf.2018.05.015

128

128. Santoro F, Gil IJN, Stiermaier T, El-Battrawy I, Guerra F, Novo G, et al. Assessment of the German and Italian Stress Cardiomyopathy Score for Risk Stratification for In-hospital Complications in Patients with Takotsubo Syndrome. JAMA Cardiol. 2019;4(9):892-99. doi: 10.1001/jamacardio.2019.2597.

Santoro

Gil

IJN

Stiermaier

El-Battrawy

Guerra

Novo

et al

Assessment of the German and Italian Stress Cardiomyopathy Score for Risk Stratification for In-hospital Complications in Patients with Takotsubo Syndrome

JAMA Cardiol 2019 4 9 892 899

10.1001/jamacardio.2019.2597

129

129. Matta AG, Carrié D. Epidemiology, Pathophysiology, Diagnosis, and Principles of Management of Takotsubo Cardiomyopathy: A Review. Med Sci Monit. 2023;29:e939020. doi: 10.12659/MSM.939020.

Matta

Carrié

Epidemiology, Pathophysiology, Diagnosis, and Principles of Management of Takotsubo Cardiomyopathy: A Review

Med Sci Monit 2023 29

e939020

10.12659/MSM.939020

130

130. Isogai T, Matsui H, Tanaka H, Fushimi K, Yasunaga H. Early β-Blocker Use and In-Hospital Mortality in Patients with Takotsubo Cardiomyopathy. Heart. 2016;102(13):1029-35. doi: 10.1136/heartjnl-2015-308712.

Isogai

Matsui

Tanaka

Fushimi

Yasunaga

Early β-Blocker Use and In-Hospital Mortality in Patients with Takotsubo Cardiomyopathy

Heart 2016 102 13 1029 1035

10.1136/heartjnl-2015-308712

131

131. Madias C, Fitzgibbons TP, Alsheikh-Ali AA, Bouchard JL, Kalsmith B, Garlitski AC, et al. Acquired Long QT Syndrome from Stress Cardiomyopathy is Associated with Ventricular Arrhythmias and Torsades de Pointes. Heart Rhythm. 2011;8(4):555-61. doi: 10.1016/j.hrthm.2010.12.012.

Madias

Fitzgibbons

Alsheikh-Ali

Bouchard

Kalsmith

Garlitski

et al

Acquired Long QT Syndrome from Stress Cardiomyopathy is Associated with Ventricular Arrhythmias and Torsades de Pointes

Heart Rhythm 2011 8 4 555 561

10.1016/j.hrthm.2010.12.012

132

132. Marcondes-Braga FG, Moura LAZ, Issa VS, Vieira JL, Rohde LE, Simões MV, et al. Emerging Topics Update of the Brazilian Heart Failure Guideline - 2021. Arq Bras Cardiol. 2021;116(6):1174-212. doi: 10.36660/abc.20210367.

Marcondes-Braga

Moura

LAZ

Issa

Vieira

Rohde

Simões

et al

Emerging Topics Update of the Brazilian Heart Failure Guideline - 2021

Arq Bras Cardiol 2021 116 6 1174 1212

10.36660/abc.20210367

133

133. McDonagh TA, Metra M, Adamo M, Gardner RS, Baumbach A, Böhm M, et al. 2021 ESC Guidelines for the Diagnosis and Treatment of Acute and Chronic Heart Failure: Developed by the Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure of the European Society of Cardiology (ESC) with the Special Contribution of the Heart Failure Association (HFA) of the ESC. Rev Esp Cardiol. 2022;75(6):523. doi: 10.1016/j.rec.2022.05.005.

McDonagh

Metra

Adamo

Gardner

Baumbach

Böhm

et al

2021 ESC Guidelines for the Diagnosis and Treatment of Acute and Chronic Heart Failure: Developed by the Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure of the European Society of Cardiology (ESC) with the Special Contribution of the Heart Failure Association (HFA) of the ESC

Rev Esp Cardiol 2022 75 6 523

10.1016/j.rec.2022.05.005

134

134. Silverio A, Parodi G, Scudiero F, Bossone E, Di Maio M, Vriz O, et al. Beta-Blockers are Associated with Better Long-Term Survival in Patients with Takotsubo Syndrome. Heart. 2022;108(17):1369-76. doi: 10.1136/heartjnl-2021-320543.

Silverio

Parodi

Scudiero

Bossone

Di Maio

Vriz

et al

Beta-Blockers are Associated with Better Long-Term Survival in Patients with Takotsubo Syndrome

Heart 2022 108 17 1369 1376

10.1136/heartjnl-2021-320543

135

135. Schneider B, Athanasiadis A, Schwab J, Pistner W, Gottwald U, Schoeller R, et al. Complications in the Clinical Course of Tako-Tsubo Cardiomyopathy. Int J Cardiol. 2014;176(1):199-205. doi: 10.1016/j.ijcard.2014.07.002.

Schneider

Athanasiadis

Schwab

Pistner

Gottwald

Schoeller

et al

Complications in the Clinical Course of Tako-Tsubo Cardiomyopathy

Int J Cardiol 2014 176 1 199 205

10.1016/j.ijcard.2014.07.002

136

136. Santoro F, Ieva R, Ferraretti A, Fanelli M, Musaico F, Tarantino N, et al. Hemodynamic Effects, Safety, and Feasibility of Intravenous Esmolol Infusion During Takotsubo Cardiomyopathy with Left Ventricular Outflow Tract Obstruction: Results From A Multicenter Registry. Cardiovasc Ther. 2016;34(3):161-6. doi: 10.1111/1755-5922.12182.

Santoro

Ieva

Ferraretti

Fanelli

Musaico

Tarantino

et al

Hemodynamic Effects, Safety, and Feasibility of Intravenous Esmolol Infusion During Takotsubo Cardiomyopathy with Left Ventricular Outflow Tract Obstruction: Results From A Multicenter Registry

Cardiovasc Ther 2016 34 3 161 166

10.1111/1755-5922.12182

137

137. Bonacchi M, Maiani M, Harmelin G, Sani G. Intractable Cardiogenic Shock in Stress Cardiomyopathy with Left Ventricular Outflow Tract Obstruction: Is Extra-Corporeal Life Support the Best Treatment? Eur J Heart Fail. 2009;11(7):721-7. doi: 10.1093/eurjhf/hfp068.

Bonacchi

Maiani

Harmelin

Sani

Intractable Cardiogenic Shock in Stress Cardiomyopathy with Left Ventricular Outflow Tract Obstruction: Is Extra-Corporeal Life Support the Best Treatment?

Eur J Heart Fail 2009 11 7 721 727

10.1093/eurjhf/hfp068

138

138. Redmond M, Knapp C, Salim M, Shanbhag S, Jaumdally R. Use of Vasopressors in Takotsubo Cardiomyopathy: A Cautionary Tale. Br J Anaesth. 2013;110(3):487-8. doi: 10.1093/bja/aes586.

Redmond

Knapp

Salim

Shanbhag

Jaumdally

Use of Vasopressors in Takotsubo Cardiomyopathy: A Cautionary Tale

Br J Anaesth 2013 110 3 487 488

10.1093/bja/aes586

139

139. Ansari U, El-Battrawy I, Fastner C, Behnes M, Sattler K, Huseynov A, et al. Clinical Outcomes Associated with Catecholamine Use in Patients Diagnosed with Takotsubo Cardiomyopathy. BMC Cardiovasc Disord. 2018;18(1):54. doi: 10.1186/s12872-018-0784-6.

Ansari

El-Battrawy

Fastner

Behnes

Sattler

Huseynov

et al

Clinical Outcomes Associated with Catecholamine Use in Patients Diagnosed with Takotsubo Cardiomyopathy

BMC Cardiovasc Disord 2018 18 1 54

10.1186/s12872-018-0784-6

140

140. Santoro F, Ieva R, Ferraretti A, Ienco V, Carpagnano G, Lodispoto M, et al. Safety and Feasibility of Levosimendan Administration in Takotsubo Cardiomyopathy: A Case Series. Cardiovasc Ther. 2013;31(6):e133-7. doi: 10.1111/1755-5922.12047.

Santoro

Ieva

Ferraretti

Ienco

Carpagnano

Lodispoto

et al

Safety and Feasibility of Levosimendan Administration in Takotsubo Cardiomyopathy: A Case Series

Cardiovasc Ther 2013 31 6 e133 e137

10.1111/1755-5922.12047

141

141. Yaman M, Arslan U, Kaya A, Akyol A, Ozturk F, Okudan YE, et al. Levosimendan Accelerates Recovery in Patients with Takotsubo Cardiomyopathy. Cardiol J. 2016;23(6):610-615. doi: 10.5603/CJ.a2016.0100.

Yaman

Arslan

Kaya

Akyol

Ozturk

Okudan

et al

Levosimendan Accelerates Recovery in Patients with Takotsubo Cardiomyopathy

Cardiol J 2016 23 6 610 615

10.5603/CJ.a2016.0100

142

142. Santoro F, Gil IJN, Stiermaier T, El-Battrawy I, Moeller C, Guerra F, et al. Impact of Intra-Aortic Balloon Counterpulsation on All-Cause Mortality among Patients with Takotsubo Syndrome Complicated by Cardiogenic Shock: Results from the German-Italian-Spanish (GEIST) Registry. Eur Heart J Open. 2023;3(1):oead003. doi: 10.1093/ehjopen/oead003.

Santoro

Gil

IJN

Stiermaier

El-Battrawy

Moeller

Guerra

et al

Impact of Intra-Aortic Balloon Counterpulsation on All-Cause Mortality among Patients with Takotsubo Syndrome Complicated by Cardiogenic Shock: Results from the German-Italian-Spanish (GEIST) Registry

Eur Heart J Open 2023 3 1 oead003

10.1093/ehjopen/oead003

143

143. Mariani S, Richter J, Pappalardo F, Bělohlávek J, Lorusso R, Schmitto JD, et al. Mechanical Circulatory Support for Takotsubo Syndrome: A Systematic Review and Meta-Analysis. Int J Cardiol. 2020;316:31-9. doi: 10.1016/j.ijcard.2020.05.033.

Mariani

Richter

Pappalardo

Bělohlávek

Lorusso

Schmitto

et al

Mechanical Circulatory Support for Takotsubo Syndrome: A Systematic Review and Meta-Analysis

Int J Cardiol 2020 316 31 39

10.1016/j.ijcard.2020.05.033

144

144. Napierkowski S, Banerjee U, Anderson HV, Charitakis K, Madjid M, Smalling RW, et al. Trends and Impact of the Use of Mechanical Circulatory Support for Cardiogenic Shock Secondary to Takotsubo Cardiomyopathy. Am J Cardiol. 2021;139:28-33. doi: 10.1016/j.amjcard.2020.09.047.

Napierkowski

Banerjee

Anderson

Charitakis

Madjid

Smalling

et al

Trends and Impact of the Use of Mechanical Circulatory Support for Cardiogenic Shock Secondary to Takotsubo Cardiomyopathy

Am J Cardiol 2021 139 28 33

10.1016/j.amjcard.2020.09.047

145

145. Pant S, Deshmukh A, Mehta K, Badheka AO, Tuliani T, Patel NJ, et al. Burden of Arrhythmias in Patients with Takotsubo Cardiomyopathy (Apical Ballooning Syndrome). Int J Cardiol. 2013;170(1):64-8. doi: 10.1016/j.ijcard.2013.10.041.

Pant

Deshmukh

Mehta

Badheka

Tuliani

Patel

et al

Burden of Arrhythmias in Patients with Takotsubo Cardiomyopathy (Apical Ballooning Syndrome)

Int J Cardiol 2013 170 1 64 68

10.1016/j.ijcard.2013.10.041

146

146. Brown KH, Trohman RG, Madias C. Arrhythmias in Takotsubo Cardiomyopathy. Card Electrophysiol Clin. 2015;7(2):331-40. doi: 10.1016/j.ccep.2015.03.015.

Brown

Trohman

Madias

Arrhythmias in Takotsubo Cardiomyopathy

Card Electrophysiol Clin 2015 7 2 331 340

10.1016/j.ccep.2015.03.015

147

147. Ahmed AE, Serafi A, Sunni NS, Younes H, Hassan W. Recurrent Takotsubo with Prolonged QT and Torsade de Pointes and Left Ventricular Thrombus. J Saudi Heart Assoc. 2017;29(1):44-52. doi: 10.1016/j.jsha.2016.07.004.

Ahmed

Serafi

Sunni

Younes

Hassan

Recurrent Takotsubo with Prolonged QT and Torsade de Pointes and Left Ventricular Thrombus

J Saudi Heart Assoc 2017 29 1 44 52

10.1016/j.jsha.2016.07.004

148

148. Möller C, Eitel C, Thiele H, Eitel I, Stiermaier T. Ventricular Arrhythmias in Patients with Takotsubo Syndrome. J Arrhythm. 2018;34(4):369-75. doi: 10.1002/joa3.12029.

Möller

Eitel

Thiele

Eitel

Stiermaier

Ventricular Arrhythmias in Patients with Takotsubo Syndrome

J Arrhythm 2018 34 4 369 375

10.1002/joa3.12029

149

149. Santoro F, Stiermaier T, Tarantino N, De Gennaro L, Moeller C, Guastafierro F, et al. Left Ventricular Thrombi in Takotsubo Syndrome: Incidence, Predictors, and Management: Results From the GEIST (German Italian Stress Cardiomyopathy) Registry. J Am Heart Assoc. 2017;6(12):e006990. doi: 10.1161/JAHA.117.006990.

Santoro

Stiermaier

Tarantino

De Gennaro

Moeller

Guastafierro

et al

Left Ventricular Thrombi in Takotsubo Syndrome: Incidence, Predictors, and Management: Results From the GEIST (German Italian Stress Cardiomyopathy) Registry

J Am Heart Assoc 2017 6 12

e006990

10.1161/JAHA.117.006990

150

150. El-Battrawy I, Gietzen T, Lang S, Ansari U, Behnes M, Zhou X, et al. Short- and Long-Term Incidence of Thromboembolic Events in Takotsubo Syndrome as Compared with Acute Coronary Syndrome. Angiology. 2019;70(9):838-43. doi: 10.1177/0003319719842682.

El-Battrawy

Gietzen

Lang

Ansari

Behnes

Zhou

et al

Short- and Long-Term Incidence of Thromboembolic Events in Takotsubo Syndrome as Compared with Acute Coronary Syndrome

Angiology 2019 70 9 838 843

10.1177/0003319719842682

151

151. Ding KJ, Cammann VL, Szawan KA, Stähli BE, Wischnewsky M, Di Vece D, et al. Intraventricular Thrombus Formation and Embolism in Takotsubo Syndrome: Insights From the International Takotsubo Registry. Arterioscler Thromb Vasc Biol. 2020;40(1):279-87. doi: 10.1161/ATVBAHA.119.313491.

Ding

Cammann

Szawan

Stähli

Wischnewsky

Di Vece

et al

Intraventricular Thrombus Formation and Embolism in Takotsubo Syndrome: Insights From the International Takotsubo Registry

Arterioscler Thromb Vasc Biol 2020 40 1 279 287

10.1161/ATVBAHA.119.313491

152

152. Madias JE. Takotsubo Cardiomyopathy: Current Treatment. J Clin Med. 2021;10(15):3440. doi: 10.3390/jcm10153440.

Madias

Takotsubo Cardiomyopathy: Current Treatment

J Clin Med 2021 10 15 3440

10.3390/jcm10153440

153

153. Sager HB, Schunkert H, Kurowski V. Recurrent Mid-Ventricular Tako-Tsubo Cardiomyopathy: Three Episodes of a Uniform Cardiac Response to Varying Stressors. Int J Cardiol. 2011;152(1):e22-4. doi: 10.1016/j.ijcard.2010.09.081.

Sager

Schunkert

Kurowski

Recurrent Mid-Ventricular Tako-Tsubo Cardiomyopathy: Three Episodes of a Uniform Cardiac Response to Varying Stressors

Int J Cardiol 2011 152 1 e22 e24

10.1016/j.ijcard.2010.09.081

154

154. Stiermaier T, Moeller C, Oehler K, Desch S, Graf T, Eitel C, et al. Long-Term Excess Mortality in Takotsubo Cardiomyopathy: Predictors, Causes and Clinical Consequences. Eur J Heart Fail. 2016;18(6):650-6. doi: 10.1002/ejhf.494.

Stiermaier

Moeller

Oehler

Desch

Graf

Eitel

et al

Long-Term Excess Mortality in Takotsubo Cardiomyopathy: Predictors, Causes and Clinical Consequences

Eur J Heart Fail 2016 18 6 650 656

10.1002/ejhf.494

155

155. Santoro F, Mallardi A, Leopizzi A, Vitale E, Rawish E, Stiermaier T, et al. Current Knowledge and Future Challenges in Takotsubo Syndrome: Part 2-Treatment and Prognosis. J Clin Med. 2021;10(3):468. doi: 10.3390/jcm10030468.

Santoro

Mallardi

Leopizzi

Vitale

Rawish

Stiermaier

et al

Current Knowledge and Future Challenges in Takotsubo Syndrome: Part 2-Treatment and Prognosis

J Clin Med 2021 10 3 468

10.3390/jcm10030468

Study association

This study is not associated with any thesis or dissertation work.

Ethics approval and consent to participate

This article does not contain any studies with human participants or animals performed by any of the authors.

Sources of funding: There were no external funding sources for this study.

Artigo de Revisão

Cardiomiopatia de Estresse (Takotsubo)

0000-0001-8922-4075

Montera

Marcelo Westerlund

Redação do manuscrito ¹

1 Brasil Hospital Pró-Cardíaco, Rio de Janeiro, RJ – Brasil

Correspondência: Marcelo Westerlund Montera • Hospital Pró-Cardíaco - Rua Redentor, 111-301. CEP 22421-030, Rio de Janeiro, RJ - Brasil E-mail: mmontera@uol.com.br

Potencial conflito de interesse

Não há conflito com o presente artigo

Takotsubo Cardiomiopatia Neuro-Adrenergica Takotsubo Cardiomiopatia Cardiomiopatia por Estresse

Introdução

A Takotsubo Cardiomiopatia (TC) também conhecida como cardiomiopatia induzida por estresse, é uma síndrome reversível que se apresenta usualmente como síndrome coronariana aguda, especialmente nas mulheres na fase pós-menopausa. A fisiopatologia envolve múltiplos fatores, incluindo vasoespasmo coronariano, disfunção da microcirculação, agressão catecolaminérgica e hiperatividade simpática. O diagnóstico da apresentação clássica é a presença de alteração segmentar em forma de balonamento ou discinesia da região antero-septo-apical do ventrículo esquerdo, associada a hiperdinamia dos segmentos basais, na ausência de doença coronariana obstrutiva que justifique esta alteração na contração. Inicialmente se acreditava que a TC era uma condição autolimitada de bom prognóstico, não obstante, atualmente é reconhecida como uma patologia com alto índice de complicações e uma morbidade e mortalidade elevadas a curto e longo prazo. A despeito de que a primeira descrição tem sido há mais de 30 anos, em 1990 por Sato, a etiologia e fisiopatologia ainda permanecem não plenamente definidas e ainda não temos uma diretriz internacional com a normatização do diagnóstico e tratamento.

Epidemiologia

A TC é diagnosticada em 1% a 3% das síndromes coronarianas agudas e em 0.5% a 0.9% dos infartos agudos do miocárdio com supra do segmento do ST.¹ É usualmente subdiagnosticada pois a apresentação clínica se assemelha a síndrome coronariana aguda. Caracteristicamente tem maior prevalência em mulheres na fase pós-menopausa (80-90%), embora pacientes com idade < 50 anos representem cerca de 10% dos casos.² Entre os pacientes mais jovens observamos uma maior prevalência do sexo masculino e das formas atípicas da TC, com menor taxa de comorbidades, maior prevalência de distúrbios psiquiátricos e neurológicos e maior prevalência de complicações intra-hospitalares.²A TC também tem sido descrita em neonatais e crianças, com igual distribuição entre os sexos, e frequentemente com disfunção ventricular e insuficiência cardíaca.³

A TC apresenta uma mortalidade intra-hospitalar semelhante ao infarto agudo do miocárdio com supra do segmento ST, com uma taxa anual de mortalidade de 5,6% e de eventos cerebrovasculares de 9,9%. A taxa de recorrência varia de 1,5% a 22 % sendo mais frequente nos pacientes < 50 anos.⁴

– Patogenia

A principal característica da Takotsubo é a presença de associação de hiperdinamia das porções basais com acinesia ou discinesia anterior ou apical do ventrículo esquerdo, o que resulta numa configuração anatômica de balonamento ventricular. Com menor frequência podemos ter alteração em outros segmentos, como o mesoventricular e o basal, e em um terço dos pacientes observamos o acometimento do ventrículo direito. Estas alterações na contratilidade não apresentam correlação anatômica com a distribuição do fluxo coronário. Evolutivamente, as alterações na contratilidade são reversíveis com total ou parcial resolução da disfunção ventricular em horas ou semanas.

Os diferentes tipos de alteração na contratilidade, assim como a sua distribuição anatômica, são possivelmente devidos a variações nos troncos de ativação cardíaca simpática e no padrão de distribuição dos neuro adrenoreceptores. Estes apresentam um padrão mais prevalente que fazem que a característica apical seja a mais frequente, mas, podemos ter variações menos prevalentes que conferem os diferentes tipos de localização das alterações segmentares observadas na Takotsubo.^5-12

Vários mecanismos fisiopatológicos para o desenvolvimento da Takotsubo têm sido propostos, considerando a estimulação simpática como principal fator. A presença na fase aguda da Takotsubo de níveis elevados de adrenalina e noradrenalina sérica e de norepinefrina no seio coronário indicam uma hiperatividade da medula adrenal como também neuro-adrenérgica local miocárdica.^13,14

Estas catecolaminas, por diversos mecanismos induzem o hiperestímulo contrátil e a agressão do cardiomiócito, que são o substrato para o desenvolvimento do balonamento apical na Takotsubo.¹⁵

A demonstração frequente da presença de estresse físico ou emocional como gatilho na maioria dos pacientes com Takotsubo,¹⁶ ou a associação com patologias de atividade adrenérgica elevada como feocromocitoma, doenças do sistema nervoso central, pós- acidente vascular cerebral ou crise convulsiva, enfatizam o papel central da atividade simpática com principal fator para o desenvolvimento de Takotsubo.^17-20 Também foi demonstrado o desenvolvimento de balonamento apical após a infusão de catecolaminas, ou atenuado após a utilização de beta e alfabloqueadores.^21-27

Mecanismos fisiopatológicos da hiperatividade simpática:<xref ref-type="bibr" rid="B28">28</xref>,<xref ref-type="bibr" rid="B29">29</xref> (<xref ref-type="fig" rid="f01002">Figura 1</xref>)

Figura 1 – Fisiopatologia do desenvolvimento da Takotsubo.

a) Cardiotoxicidade por hiperativação dos neuro-receptores miocárdicos:

No miocárdio temos a atividade simpática mediada pelos neuro-receptores beta 1 e 2 e alfa-receptores. Estes neuro-receptores mediam os estímulos fisiológicos do sistema simpático no miocárdio na modulação inotrópica, lusitrópica e cronotrópica positivas, e quando está hiperativado cronicamente está associado à disfunção miocárdica.¹⁶

A hiperativação simpática ocasiona o fenômeno observado na Takotsubo de aumento regional da contratilidade miocárdica associada à depressão da contratilidade com balonamento mediada por vários mecanismos fisiopatológicos: hiperativação dos neuro-receptores, ativação inflamatória, vasoconstricção coronariana, lesão endotelial, necrose em banda dos cardiomiócitos e ativação da cascata de apoptose celular, ocasionando as alterações no miocárdio na Takotsubo.

O estímulo neuro-adrenérgico mediado pela norepinefrina liberada na vesícula sináptica no miocárdio ou pela adrenalina sérica liberada pela glândula suprarrenal, promovem a ativação dos beta-neuro receptores e alfa-receptores miocárdicos. O estímulo dos beta 1 receptores (B1-R) mediado principalmente pela norepinefrina, promove a ativação da proteína G estimuladora (PtnGe), que ativam o aumento do Amp-cíclico que promove o aumento da proteína quinase A (PtnQA). A PtnQA aumenta a atividade dos canais de cálcio voltagem dependentes aumentando os níveis de cálcio no citosol ocasionado a liberação de cálcio pelo reticulo sarcoplasmático através da ativação da bomba de rianodina, sensíveis ao cálcio no citosol. Este cálcio ira se ligar ao sitio C da troponina, favorecendo a contração ventricular. Na hiperativação dos B1-R teremos um grande aumento da PtnQA, que ocasiona uma redução da recaptação do cálcio pelo reticulo sarcoplasmático mediado pela atividade Fosfolamban/SERCA2a, que se torna disfuncionante, ocasionando um acúmulo de cálcio no citosol. Este acúmulo de cálcio está relacionado a várias alterações na fisiologia do cardiomiócito: depressão da contratilidade, ativação inflamatória, ativação da cascata da apoptose com redução da massa de cardiomiócitos, promoção de necrose em banda, aumento do potencial arritmogênico por alterar as fases 2 e 3 do potencial de ação. Portanto, a hiperativação dos B1-R promove aumento da contratilidade miocárdica e simultaneamente agressão miocárdica, mediadas ambas por aumento no cálcio no citosol.^26-29

A hiperativação dos B2-R mediada pela adrenalina sérica, ocasiona uma mudança do padrão de estímulo via pela PtnGe para PtnG inibitória, que promove a ativação da Óxido Nítrico Sintetase com aumento do óxido nítrico que ocasiona depressão da contratilidade e ativação inflamatória. Os B-R apresentam uma distribuição heterogênea no miocárdio, com uma maior prevalência de B2-R na região anterior e apical e os B1-R nas regiões basais do coração. Esta distribuição anatômica heterogênea, seria a gênese da hipercontratilidade nas porções basais do coração e balonamento ou acinesia nas regiões apicais e anteriores frequentemente observados na Takotsubo.³⁰

b)Vasoespasmo Coronariano:

A atividade simpática ocasionando vasoespasmo de coronárias epicárdicas tem sido proposta como uma possível causa da Takotsubo, embora a maioria dos pacientes não demonstrem espasmo coronariano mesmo quando são utilizados agentes vasoconstrictores provocativos. A sugestão é que na Takotsubo o estresse oxidativo induzido pela hiperatividade simpática, ocasione disfunção endotelial e favoreça a alteração na microcirculação coronariana.^31-35

c) Disfunção da microcirculação:

A disfunção da microcirculação secundária à hiperestimulação simpática tem sido observada em todos os pacientes na fase aguda da Takotsubo, sendo sugerida como um importante fator fisiopatológico determinante para isquemia miocárdica e disfunção contrátil ventricular, baseando-se em estudos que demonstraram uma resposta microvascular coronariana alterada além de aumento de atividade apoptótica das células endoteliais da microcirculação nos pacientes com Takotsubo. A disfunção endotelial e da microcirculação decorrem do estímulo simpático do Alfa-receptor, promovendo a disfunção vascular com redução da reserva vasodilatadora e favorecimento do espasmo da microcirculação, com consequente isquemia e depressão da contratilidade. Esta disfunção na fase aguda demonstrou ser transitória, e sua recuperação está relacionada à melhora da função contrátil.^36-40

d) Desestabilização ou rutura de placa aterosclerótica coronariana:

Podemos encontrar presença de placas ateroscleróticas na coronária descendente anterior dos pacientes com Takotsubo. Nestes casos, a utilização e investigação por ultrassom intra-coronariano ou tomografia por coerência ótica, não demonstraram a presença de placas rotas ou dissecção, enfatizando a necessidade de exclusão da presença de doença coronária instável para confirmação do diagnóstico de Takotsubo.^41-44

Fatores predisponentes e gatilhos para o desenvolvimento de Taktsubo

Cerca de 70% dos pacientes que desenvolvem Takotsubo usualmente apresentam estresse emocional ou físico como fator desencadeador, os quais são usuais em todos os indivíduos.⁴⁵

Como somente algumas pessoas desenvolvem a Takotsubo, nos leva à possibilidade da existência de perfil genético e clínico predisponentes ao desenvolvimento de Takotsubo. Por meio da análise dos registros e serie de casos, podemos definir o perfil clínico mais prevalente dos pacientes que apresentam Takotsubo com a identificação da presença de fatores predisponentes: hormonal, genético, distúrbios psiquiátricos e gatilho por estresse físico ou emocional.

Hormonal

A Takotsubo é mais frequente em mulheres do que em homens numa taxa 9:1, predominantemente na fase pós-menopausa, indicando que um declínio nos níveis de estrogênio poderia ter um papel na fisiopatologia do desenvolvimento da Takotsubo. O estrogênio tem atuação na modulação do tônus vasomotor através da estimulação da óxido nítrico sintetase endotelial e por modulação da vasoconstrição neuro-adrenérgica e redução da ativação simpática central.^46-49

Contudo, faltam estudos que comprovem de forma consistente a correlação dos hormônios reprodutivos com o desenvolvimento de Takotsubo, questionando que estes não teriam, de forma isolada, um papel determinante para o seu desenvolvimento ou prevenção.^50,51

Genético

A possibilidade da predisposição genética para Takotsubo, tem sido sugerida por alguns estudos que demonstraram uma correlação familiar.⁵²Mas a maioria dos estudos apresentam resultados conflitantes ou não precisos que demonstrem um potencial poligênico ou de heterogeneidade genética que ocasione uma desregulação do sistema neuro-adrenérgico, seja em sua ativação ou no polimorfismo dos beta e alfa neuro-receptores, que permitam identificar uma linha de predisposição.^53-57

Alterações psiquiátricas e alterações neurológicas

Uma elevada prevalência de condições neuropsiquiátricas tem sido observada nos pacientes com Takotsubo, com cerca de 27% de doenças neurológicas e 40% com ansiedade e depressão, assim como em pacientes com síndrome do pânico.⁵⁸Os pacientes com distúrbios do humor tem uma resposta exacerbada do sistema simpático ao estresse emocional ou físico em decorrência de apresentarem uma maior liberação com menor recaptação de norepinefrina central e periférica.^59,60 O uso de antidepressivos como inibidores seletivos de recaptação da norepinefrina aumentou os níveis teciduais de catecolaminas. Ambos os fatores aumentam a sensibilidade e grau de resposta simpática ao estresse agudo tornando estes pacientes suscetíveis ao desenvolvimento de Takotsubo.^61,62

Gatilhos por estresse físico e emocional

A presença de gatilho por estresse físico ou emocional é observada em cerca de 70 a 80% dos pacientes. No registro Internacional de Takotsubo, 36% dos pacientes apresentaram estresse físico, 28% emocional, 8% ambos e 29% sem estresse.

O estresse físico é mais comum que o emocional, acomete mais homens e pacientes internados e apresenta um prognóstico pior.⁶³

O estresse físico é decorrente de procedimentos cirúrgicos, trauma, doenças infecciosas, medicamentos e dor. ^64-78

O estresse emocional é mais comum em mulheres, em fase pós-menopáusica, e em pacientes não internados. As situações de estresse emocional podem ser de caráter pessoal ou profissional, com estímulos negativos que geram intensa tristeza, raiva, sentimento de insatisfação, rejeição, medo, ansiedade, pânico ou por enfrentamento (“Síndrome do Coração Partido”), como também situações de desastres naturais ou guerra.^79-81 Mas também situações com estímulos positivos geralmente inesperados, também estão relacionados ao desencadeamento de Takotsubo (“Síndrome do Coração Feliz”) Tabela 1.⁸²

Tabela 1 – Gatilhos de estresse Físicos e Emocionais

Estresse Físico Estresse Emocional

Pós-operatório

Sepse

Litíase renal

Pneumonia

Tromboembolismo pulmonar

Cardioversão elétrica

Ablação de fibrilação atrial

Acidente vascular cerebral hemorrágico

Crise convulsivante de carro

Epilepsia

Feocromocitoma

Crise intensa de asma

Trauma ortopédico

Dor intensa

Pós-quimioterapia

Síndrome de abstinência a drogas ou álcool

Hipertireoidismo

Pós-cesariana

Pós-infusão de catecolaminas

Falecimento de parentes ou cônjuge

Depressão

Crise de ansiedade

Pânico

Perda de emprego

Perda de competição

Término de relacionamento amoroso

Terremotos, furacões,inundações

Guerra

Acidente de carro

Surpresa positiva intensa

Casamento

Ganho de prêmio

Reencontro com ente querido

Estresse Físico	Estresse Emocional
Pós-operatório Sepse Litíase renal Pneumonia Tromboembolismo pulmonar Cardioversão elétrica Ablação de fibrilação atrial Acidente vascular cerebral hemorrágico Crise convulsivante de carro Epilepsia Feocromocitoma Crise intensa de asma Trauma ortopédico Dor intensa Pós-quimioterapia Síndrome de abstinência a drogas ou álcool Hipertireoidismo Pós-cesariana Pós-infusão de catecolaminas	Falecimento de parentes ou cônjuge Depressão Crise de ansiedade Pânico Perda de emprego Perda de competição Término de relacionamento amoroso Terremotos, furacões,inundações Guerra Acidente de carro Surpresa positiva intensa Casamento Ganho de prêmio Reencontro com ente querido

Diagnóstico

Entre todos os critérios os mais utilizados na prática clínica são os critérios diagnósticos da Clínica Mayo e o INTERTAK. (Tabela 2)

Tabela 2 – Critérios diagnósticos de Takotsubo

Critérios Revisados da Clínica Mayo Critérios da INTERTAK

Discinesia transitória dos segmentos mediais do VE, com ou sem envolvimento apical; a alteração segmentar estende-se além do território de uma coronária epicárdica; gatilho por estresse frequentemente presente.

Ausência angiográfica de doença coronária obstrutiva ou ruptura aguda de placa.

Alterações agudas no ECG, supra-ST e/ou inversão de onda T ou alterações modestas da troponina.

Ausência de feocromocitoma ou miocardite.

Disfunção transitória do VE (hipocinesia, acinesia ou discinesia) apresentando-se como balonamento apical ou mesoventricular, basal, ou alteração segmentar focal. Pode ter envolvimento do VD. Podemos ter transição entre os diferentes tipos de alteração segmentar. Alteração segmentar estende-se além do território de uma coronária epicárdica; contudo, raramente temos alteração segmentar correspondente ao território de uma coronária.

Estresse físico ou emocional, ou combinados, frequentemente precedem episódio de Takotsubo.

Alteração neurológica (hemorragia subaracnóidea, AVC, convulsões); feocromocitoma pode ser gatilho.

Alterações agudas no ECG, com Supra ou infra de ST, inversão de onda T e QT prolongado, e raramente ECG normal.

Moderada elevação de troponina T ou I e CK-MB. Frequente elevação do BNP.

Doença coronariana significativa não exclui Takotsubo.

Ausência de miocardite.

Predominantemente acomete mulheres na fase pós-menopausa.

Critérios Revisados da Clínica Mayo	Critérios da INTERTAK
Discinesia transitória dos segmentos mediais do VE, com ou sem envolvimento apical; a alteração segmentar estende-se além do território de uma coronária epicárdica; gatilho por estresse frequentemente presente. Ausência angiográfica de doença coronária obstrutiva ou ruptura aguda de placa. Alterações agudas no ECG, supra-ST e/ou inversão de onda T ou alterações modestas da troponina. Ausência de feocromocitoma ou miocardite.	Disfunção transitória do VE (hipocinesia, acinesia ou discinesia) apresentando-se como balonamento apical ou mesoventricular, basal, ou alteração segmentar focal. Pode ter envolvimento do VD. Podemos ter transição entre os diferentes tipos de alteração segmentar. Alteração segmentar estende-se além do território de uma coronária epicárdica; contudo, raramente temos alteração segmentar correspondente ao território de uma coronária. Estresse físico ou emocional, ou combinados, frequentemente precedem episódio de Takotsubo. Alteração neurológica (hemorragia subaracnóidea, AVC, convulsões); feocromocitoma pode ser gatilho. Alterações agudas no ECG, com Supra ou infra de ST, inversão de onda T e QT prolongado, e raramente ECG normal. Moderada elevação de troponina T ou I e CK-MB. Frequente elevação do BNP. Doença coronariana significativa não exclui Takotsubo. Ausência de miocardite. Predominantemente acomete mulheres na fase pós-menopausa.

Os critérios diagnósticos da INTERTAK incorporam novos aspectos: (i) disfunção do ventrículo direito ou de outros segmentos não usuais; (ii) a não necessidade da presença de um gatilho de estresse físico ou emocional antecedendo a Takotsubo; (iii) alterações neurológicas e feocromocitoma como possíveis gatilhos para Takotsubo; (iv) possibilidade de coexistência de doença coronariana obstrutiva significativa.

Sendo proposta a classificação da Takotsubo de acordo com o tipo de gatilho que a antecede em tipo 1, 2, 2a, 2b e 3.^83-86 (Tabela 3)

Tabela 3 – Classificação INTERTAK da Takotsubo de acordo com o tipo de gatilho:

Class I: Takotsubo relacionada a gatilho de estresse emocional

Class II: Takotsubo relacionada a gatilho de estresse físico

IIa: Secundária à atividade física, procedimentos médicos, doenças agudas.

IIb: Secundaria a distúrbios neurológicos

Class III: Takotsubo sem gatilho identificado.

Tipos anatômicos de Takotsubo: (<xref ref-type="fig" rid="f02002">Figura 2</xref>)

Figura 2 – Tipos anatômicos da Takotsubo.

A Takotsubo é uma síndrome cardíaca aguda de caráter transitório com disfunção contrátil ventricular onde temos a descrição de cinco tipos anatômicos: (Figura 2)

Padrão clássico: Observado em cerca de 70% a 80% dos pacientes. Acinesia ou hipocinesia apical com hipercontratilidade dos segmentos basais, conferindo o aspecto clássico de armadilha de polvo que conferiu o nome de Takotsubo.

Mesoventricular: Observado em cerca de 15% dos pacientes. Hipocinesia da porção média do ventrículo esquerdo, e hipercontratilidade dos segmentos apical e basal.

Invertida ou Basal: Observado em cerca de 3% a 5% dos pacientes. Hipocinesia ou acinesia dos segmentos basais e médio ventriculares com hipercontratilidade apical.

Focal: Observado em cerca de 5,5% dos pacientes. Hipocinesia ou acinesia de segmentos isolados, usualmente anterolateral

Biventricular ou acometimento isolado do ventrículo direito < 0,5%: apresenta uma prevalência desconhecida, sendo considerado raro o seu acometimento.

Apresentação Clínica

A apresentação clínica da Takotsubo é mais frequente em mulher em fase pós menopausa que apresenta um estresse emocional ou físico inesperado, sendo seguida de quadro clínico de dor precordial (75%), dispneia (50%), tonteiras (>25%), sincope ou pré-sincope (5% a 10%), palpitações devido a taquicardia sinusal, ou em formas clínicas mais severas como insuficiência cardíaca aguda, choque cardiogênico ou morte súbita abortada. Os principais diagnósticos diferenciais na sala de emergência são com a síndrome coronariana aguda e a miocardite aguda. Como usualmente temos quadro clínico semelhante à síndrome coronariana aguda, acompanhado de alterações eletrocardiográficas e elevação de enzimas de injúria cardíaca, apesar de ausência de doença cornaria obstrutiva, a Takotsubo foi classificada na última definição universal de infarto agudo do miocárdio, como infarto agudo do miocárdio com coronárias normais (MINOCA).⁸⁷

Sendo, portanto, necessário encaminhar estes pacientes para cineangiocoronariografia para confirmação diagnóstica.^88,89

O quadro clínico admissional pode ser predominantemente definido pelas manifestações da doença que ocasionou o estresse físico, como acidente vascular encefálico, convulsões, e a manifestação da Takotsubo poderá ser por meio de somente o desenvolvimento de disfunção ventricular ao ecocardiograma, ou com distúrbios hemodinâmicos inesperados como hipotensão ou choque. Nos pacientes com estresse físico ou emocional, observamos com maior frequência o quadro clínico de dor precordial e palpitações, ou de dispneia.^90-92

ECG

O ECG encontra-se anormal na maioria dos pacientes com Takotsubo (>95%),¹¹ sendo usual alterações sugestivas de doença isquêmica coronariana do segmento ST e onda T. Na fase aguda encontramos supra do segmento ST em 44% usualmente envolvendo as derivações anterior, apical e lateral sugerindo infarto anterior extenso, infra do segmento ST sendo incomum, ocorrendo em 8%, a inversão da onda T é difusa e acomete a 41%, e a presença de ondas Q patológicas em 15% e bloqueio de ramo esquerdo 5%. Após 24 a 48 horas do início dos sintomas, temos inversão da onda T e importante prolongamento do intervalo QT, predispondo à taquicardia ventricular polimórfica (torsade de pointes) e fibrilação ventricular. A inversão de onda T assim como alongamento do intervalo QT, estão relacionados com presença de edema miocárdico, sendo que a subsequente gradual resolução pode levar de dias a semanas. A análise das alterações no ECG apresenta uma alta acurácia na diferenciação do infarto agudo do miocárdio, como a presença de supra do segmento ST em aVR e na derivação antero-septal V1 a V4, ou supra do segmento ST em aVR com inversão de onda T, apresentam alta acurácia. Contudo em função da alta prevalência de doença coronariana aguda com as características clínicas e eletrocardiográficas semelhantes ao Takotsubo, todos os pacientes necessitam avaliação por coronariografia com ventriculografia para o diagnóstico diferencial.^93-100

Biomarcadores

Praticamente todos os pacientes com Takotsubo apresentam elevação enzimática de necrose miocárdica. Troponina T ou I e CK-MB, estão elevadas em >90% dos pacientes na admissão. O pico enzimático é substancialmente inferior ao do infarto agudo do miocárdio, demonstrando uma dissociação entre os níveis enzimáticos com as extensões das alterações no ECG e com a disfunção ventricular. A presença de níveis enzimáticos elevados está correlacionada com pior prognóstico.

Os peptídeos natriuréticos (BNP e pro-BNP) encontram-se frequentemente elevados correlacionando com o grau das alterações funcionais miocárdicas e disfunção ventricular. Apresentam pico em 48 horas, podendo levar meses para sua normalização.^101-103

Ecocardiograma (<xref ref-type="table" rid="t5002">Tabela 5</xref>)

Tabela 5 – Métodos de imagem na avaliação da Takotsubo e suas características

Métodos Características

Ecocardiograma
Método de fase aguda

Método mais utilizado na prática para identificação precoce da alteração segmentar e levantar a suspeita de Takotsubo:

Alteração segmentar e função ventricular

Complicações: Insuficiência mitral, trombo cardíaco, OTSVE, derrame pericárdio

Seguimento da recuperação

RMC
Método de fase subaguda ou tardia

Extensão do alteração segmentar, função

Acometimento do VD

Complicações: Insuficiência mitral, trombo cardíaco, OTSVE, derrame pericárdico

Diagnóstico diferencial: miocardite, DAC.

CAT
Método de fase aguda

Avaliação de DAC e MINOCA

Alteração segmentar e função ventricular

Complicações: Insuficiência mitral, trombo cardíaco, OTSVE.

Angio TC-Coronárias
Método de fase subaguda

Avaliação de DAC e MINOCA

Medicina nuclear
Método de fase subaguda ou tardia

Confirmação diagnóstica tardia

Diagnóstico diferencial tardio de MINOCA ou miocardite

Métodos	Características
Ecocardiograma	Método de fase aguda Método mais utilizado na prática para identificação precoce da alteração segmentar e levantar a suspeita de Takotsubo: Alteração segmentar e função ventricular Complicações: Insuficiência mitral, trombo cardíaco, OTSVE, derrame pericárdio Seguimento da recuperação
RMC	Método de fase subaguda ou tardia Extensão do alteração segmentar, função Acometimento do VD Complicações: Insuficiência mitral, trombo cardíaco, OTSVE, derrame pericárdico Diagnóstico diferencial: miocardite, DAC.
CAT	Método de fase aguda Avaliação de DAC e MINOCA Alteração segmentar e função ventricular Complicações: Insuficiência mitral, trombo cardíaco, OTSVE.
Angio TC-Coronárias	Método de fase subaguda Avaliação de DAC e MINOCA
Medicina nuclear	Método de fase subaguda ou tardia Confirmação diagnóstica tardia Diagnóstico diferencial tardio de MINOCA ou miocardite

OTSVE: obstrução do trato de saída do ventrículo esquerdo; VD: ventrículo direito; DAC: doença arterial coronariana; RMC: ressonância magnética cardíaca; CAT: cineangiocoronariografia.

O ecocardiograma transtoráxico (ECO) é essencial na fase aguda da TC para estabelecer a suspeita diagnóstica inicial. O padrão característico de alteração segmentar é a presença de acinesia ou discinesia apical e mesoventricular dos segmentos antero-septal com hiperdinamia dos segmentos basais. O ecocardiograma além de definir o padrão da TC (apical, medial ou basal), quantificará o grau de disfunção e avaliará a presença de complicações como trombo intracavitário, obstrução do trato de saída do ventrículo esquerdo (OTSVE), insuficiência mitral secundária a OTSVE ou por dilatação ventricular. As alterações ao ECO embora possam ser fortemente sugestivas de Takotsubo, não permitem diferenciar ou afastar o IAM ou a miocardite. O ECO apresenta um grande valor na confirmação do diagnóstico, por meio do seguimento da melhora da disfunção ventricular, ou como marcador de prognóstico.^104-107

Ressonância Magnética Cardíaca (RMC) (<xref ref-type="table" rid="t5002">Tabela 5</xref>)

A RMC é usualmente após as primeiras 24-48 horas da admissão. A importância da RMC está não só na avaliação da extensão da disfunção ventricular como também para o diagnóstico diferencial de miocardite.

Os achados na RMC envolvem a análise funcional ventricular com quantificação da extensão das alterações segmentares, grau de disfunção ventricular, avaliação do acometimento do ventrículo direito e a presença de complicações como trombo intracardíaco e obstrução intracardíaca, e análise morfológica com pesquisa de edema miocárdico, de infamação e fibrose através da análise do realce tardio do gadolínio (RT).

O edema miocárdico é observado na fase aguda através na técnica de T2 da RMC, com a demonstração na fase T2 de um intenso aumento do sinal, tendo distribuição difusa, podendo ser transmural, e fortemente relacionado com as regiões com alteração na contratilidade, não tendo correlação com a anatomia coronariana, o que o diferencia do IAM e da miocardite que apresenta edema sem correlação com as alterações da contratilidade e sendo mais comum em parede lateral e epicárdico. O RT usualmente está ausente, o que ajuda na diferenciação da miocardite ou do infarto agudo do miocárdio. Contudo, tem sido descrito RT positivo com predomínio na região apical, com intensidade de sinal reduzida, com relatos de RT transmural persistente. A persistência de RT positivo tem demonstrado relação com pior prognóstico evolutivo com potencial de arritmias.^108-114

Medicina Nuclear (<xref ref-type="table" rid="t5002">Tabela 5</xref>)

A cintilografia miocárdica com 123I-mIBG tem sido utilizada para avaliar a atividade do sistema simpático no miocárdio através da atividade de captação dos neuro receptores. Na fase aguda da Takotsubo se observa uma redução na captação miocárdica correspondentes as regiões com disfunção contrátil, consistente com disfunção da atividade dos neuro receptores simpáticos, sendo mais comum a redução de captação na região apical e anterior do miocárdio. Estas anormalidades podem persistir por vários meses, onde o 123I-mIBG tem um papel de confirmação diagnóstica nos casos em que permaneceram sem diagnóstico ou em dúvida durante a internação ou pacientes com história prévia sem confirmação. A presença de 123I-mIBG positivo e sua extensão têm correlação com pior prognóstico no desenvolvimento de insuficiência cardíaca e mortalidade.^115,116

Cineangiocoronariografia (CAT) (<xref ref-type="table" rid="t5002">Tabela 5</xref>)

A maioria dos pacientes são avaliados pela CAT na admissão hospitalar para afastar o diagnóstico de IAM. A Takotsubo tipicamente não apresenta lesão coronariana obstrutiva correspondente à região anatômica com alteração contrátil, portanto, sendo necessária a realização de CAT para confirmação diagnóstica na fase aguda e diferenciação de IAM ou miocardite. Em decorrência de que grande parte dos pacientes com Takotsubo são idosos, podemos encontrar em cerca de 10% dos pacientes, doença coronariana incipiente ou em outras coronárias não correspondentes à região anatômica comprometida. Na presença de lesão coronariana significativa correspondente a região anatômica, devemos utilizar métodos de avaliação intravascular como ultrassom ou tomografia de coerência ótica intracoronariana, para a exclusão de ruptura de placa, trombo intracoronário ou dissecção coronariana, para confirmarmos o diagnóstico de Takotsubo. A realização concomitante de ventriculografia, permite demonstrar as disfunções contráteis típicas da Takotsubo além de estimar o grau de disfunção ventricular e avaliar a presença de trombo intracardíaco, insuficiência mitral e obstrução do trato de saída do ventrículo esquerdo.^117-123

Angiotomografia coronariana (<xref ref-type="table" rid="t5002">Tabela 5</xref>)

A angiotomografia coronariana tem sido proposta para os pacientes estáveis com baixa suspeita de IAM ou com apresentação tardia, ou como análise retrospectiva de pacientes com história prévia não confirmada de Takotsubo, como método não invasivo para a exclusão de doença coronariana obstrutiva.¹²⁴

Critérios de pontos da INTERTAK para prever o diagnóstico da Takotsubo

A apresentação clínica, alterações no ECG e nas enzimas de injuria miocárdica da Takotsubo são muito semelhantes ao IAM não sendo possível a diferenciação entre ambas as patologias de forma consistente por nenhum método não invasivo. Portanto na fase aguda, a maioria dos pacientes necessitam ser avaliados pela coronariografia para o estabelecimento do diagnóstico. Os critérios de pontos da INTERTAK foram desenvolvidos a partir de um modelo de probabilidade diagnóstica que envolve sete variáveis clínicas e eletrocardiográficas de maior prevalência em pacientes com Takotsubo comparados com pacientes com IAM, onde quanto maior o somatório de pontos, maior a probabilidade do diagnóstico de Takotsubo. Este modelo se propõe como um guia para o questionamento da probabilidade de diagnostico e não para afirmativa diagnostica.¹²⁵ (Tabela 4)

Tabela 4 – Preditores clínicos para o diagnóstico de Takotsubo

Critério Pontuação Predição de takotsubo (or) p

Sexo feminino 25 68 p<0,001

Gatilho Emocional 24 65 p<0,001

Gatilho Físico 13 8,7 p<0,001

Ausência de infra-SST 12 7,2 p<0,001

Distúrbio psiquiátrico 11 7,0 p<0,001

Distúrbio neurológico 9 4,9 p<0,001

QTc prolongado 6 2,8 p=0,006

Critério	Pontuação	Predição de takotsubo (or)	p
Sexo feminino	25	68	p<0,001
Gatilho Emocional	24	65	p<0,001
Gatilho Físico	13	8,7	p<0,001
Ausência de infra-SST	12	7,2	p<0,001
Distúrbio psiquiátrico	11	7,0	p<0,001
Distúrbio neurológico	9	4,9	p<0,001
QTc prolongado	6	2,8	p=0,006

O somatório de pontos apresenta uma capacidade de previsão de diagnóstico de Takotsubo na fase aguda, com maior capacidade de previsão diagnóstica com somatório dos valores > 70 pontos, indicando uma probabilidade > 85%, já valores < 35 pontos têm 95% de possibilidade do diagnóstico ser de doença coronariana aguda. Em pacientes idosos com alta fragilidade, clinicamente estáveis, podemos utilizar o critério de pontos para avaliar o risco e benefício da realização do CAT, ou do início de terapêutica antiplaquetária, e optarmos pelo diagnóstico integrado de multimodalidade de imagem para a definição da probabilidade diagnóstica e seguimento evolutivo da disfunção ventricular.

Diagnóstico integrado de multimodalidade

A capacidade do diagnóstico integrado de multimodalidade de afirmar o diagnóstico da Takotsubo e a sua diferenciação com IAM e miocardite, assim como de detecção de complicações cardíacas, estarão relacionados aos cenários clínicos e às fases evolutivas da Takotsubo em que foram realizados. Estas definirão atuações diferenciadas das diversas modalidades na avaliação diagnóstica da Takotsubo e dos diagnósticos diferenciais:¹²⁶

Takotsubo clássica: Usualmente ocasionada por um fator desencadeador ou gatilho, em paciente do sexo feminino em fase pós-menopausa, frequentemente com dor precordial e ou dispneia, ECG e enzimas cardíacas indicativas de injuria miocárdica. Neste cenário o diagnóstico está voltado para a síndrome coronariana aguda e a Takotsubo é uma suspeita secundária, onde o aspecto de disfunção apical e anterior e hiperdinamia basal, com balonamento apical, ao ecocardiograma pode sugerir Takotsubo, mas não permite a afirmativa diagnóstica. Neste cenário na sala de emergência, a realização de CAT é necessária para afastar o diagnóstico de infarto agudo do miocárdio e definir ou sugerir o diagnóstico de Takotsubo ou o caso de doença coronariana não significativa associada a presença de MINOCA. A realização de RMC é fundamental por fortalecer o diagnóstico de Takotsubo ou sugerir miocardite ou MINOCA, além de avaliar a extensão e grau de disfunção ventricular e a presença de complicações cardíacas e de ter valor prognóstico.

Takotsubo não clássica: é a apresentação sem a identificação de fator precipitante ou gatilho, com clínica de sincope, tonteiras ou morte súbita abortada, geralmente em pacientes do sexo masculino, podendo ou não serem idosos, sem supra de segmento ST no ECG, elevação enzimática discreta, onde o ecocardiograma não é fortemente indicativo de Takotsubo, com alteração segmentar medial ou basal. Neste cenário a RMC tem um papel mais significativo para avaliação no diagnóstico diferencial com miocardite, e em pacientes estáveis podemos indicar a angiotomografia coronariana para avaliar a presença de DAC. Nestes pacientes, no caso de permanecer a dúvida diagnóstica, a realização de cintigrafia miocárdica com MIBG poderá ajudar a estabelecer ou afastar o diagnóstico de Takotsubo.

Takotsubo intra-hospitalar: está usualmente associada a estresse físico decorrente de patologias ou pós-procedimentos, podendo ter apresentação clássica de balonamento apical ou atípica com alteração segmentar. O ecocardiograma neste cenário é importante para orientação diagnóstica, prognóstica e seguimento da disfunção ventricular quanto a sua resposta à terapêutica ou involução espontânea.

Neste contexto o diagnóstico diferencial está relacionado ao infarto agudo do miocárdio ou cardiomiopatia metabólica. Nos pacientes instáveis usualmente não é factível a realização da RMC, e de acordo com o grau de suspeição clínica se fará necessário a realização de CAT para avaliar o diagnóstico de DAC.

Após a estabilização clínica e hemodinâmica, podemos realizar a RMC para avaliar a extensão do grau de disfunção ventricular. O ecocardiograma, neste cenário, tem importante papel no seguimento da evolução da disfunção ventricular e do desenvolvimento de complicações cardíacas.

Takotsubo de confirmação tardia: é quando os pacientes apresentam história prévia de diagnóstico sugestivo sem confirmação. Nos pacientes com disfunção persistente, a RMC e a angiotomografia coronariana podem ajudar a elucidar o diagnóstico. Nos pacientes sem disfunção ventricular a realização de MIBG que pode demonstrar alterações na captação dos neuro receptores em até 12 meses após o evento, podendo sugerir o diagnóstico no caso de ser positivo, mas não afasta no caso de ser negativo.

Tratamento

Embora inicialmente a TC tenha sido descrita como uma condição benigna, cerca de 52% dos pacientes apresentam algum tipo de complicação e 11% com mais de duas complicações que contribuem para uma maior taxa de mortalidade.¹²⁷ A taxa de mortalidade intra-hospitalar varia de 2,4 a 4,1%, enquanto as taxas de edema pulmonar e choque cardiogênico variam de 6 a 9% e 9 a 11,4%, respectivamente.⁸ A mortalidade intra-hospitalar da TC é superior à mortalidade do infarto agudo do miocárdio não complicado. Portanto a TC não pode ser manuseada como uma patologia de baixo risco.¹²⁸

A abordagem terapêutica dos pacientes com TC se baseia no racional fisiopatológico, e publicações de serie de casos, análises retrospectivas ou opinião de especialistas, e a utilização de recomendações de outras diretrizes respeito ao tratamento de complicações com insuficiência cardíaca aguda, uma vez que não temos uma diretriz especifica de manuseio terapêutico da TM. A abordagem terapêutica pode ser dividida de acordo com a apresentação clínica e a evolução intra-hospitalar, em TC não complicada e TC complicada.¹²⁹Na TC não complicada os pacientes podem ser assintomáticos ou apresentar um quadro clínico de dor precordial, com as alterações no ECG, enzimas e disfunção ao ecocardiograma, sem clínica de insuficiência cardíaca, instabilidade hemodinâmica ou arritmias significativas. Usualmente apresentam uma evolução intra-hospitalar benigna, com normalização da função ventricular em sua maioria até a alta hospitalar. Os pacientes com TC complicada, apresentam na admissão ou durante a evolução intra-hospitalar, quadro de insuficiência cardíaca aguda, choque cardiogênico, eventos tromboembólicos ou arritmias ventriculares frequentes. Estes pacientes cursam com pior prognóstico intra-hospitalar com maior mortalidade e tempo de permanência.¹²⁹

Abordagem terapêutica da Takotsubo não complicada

Os pacientes com TC não complicada usualmente evoluem com regressão espontânea da alteração segmentar da contratilidade ventricular, portanto, a abordagem terapêutica é focada na manutenção do suporte clínico e no controle das comorbidades, com a utilização de heparina profilática e o uso de antiagregantes e estatina na presença de doença coronariana. O uso de inibidores da enzima de conversão demonstrou benefício em melhora da sobrevida ao fim de 1 ano e redução do risco de recorrência, entanto que o uso de betabloqueadores, não demonstrou nenhum benefício clínico na melhora da sobrevida ou recorrência em 30 dias e 1 ano pós-alta.¹³⁰ Apesar da ausência de evidências que suportem o uso de betabloqueadores, a sua utilização na prática clínica tem sido usual, em decorrência do racional fisiopatológico de hiperadrenergismo.

Na presença de QT longo, os pacientes devem ser mantidos em monitorização eletrocardiográfica continua durante o período de internação, mesmo após a normalização da função ventricular, pelo alto risco de arritmias ventriculares malignas.¹³¹

Abordagem terapêutica da Takotsubo complicada

Na TC complicada, as complicações apresentam uma prevalência variável e podemos classificá-las como:

Frequentes: Insuficiência cardíaca (3-46%), OTSVE (12-25%) choque cardiogênico (6-20%), insuficiência mitral (14-25%);

Ocasionais: Fibrilação atrial (4,5%-25%), trombo intracavitário do ventrículo esquerdo (2-9,2%), parada cardíaca (4-6%);

Raras: Taquiarritmias (2-5%), bradicardias (2-5%), morte(1-5%).

Insuficiência cardíaca aguda

O manuseio da insuficiência cardíaca aguda nos pacientes com TC deve seguir o tratamento preconizado pelas diretrizes, com suporte ventilatório, diuréticos, inibidores da enzima de conversão, bloqueadores do receptor da angiotensina, sacubitril-valsartana, betabloqueadores e antagonistas dos receptores de mineralocorticoides e inibidores dos receptores SGLT2.^132,133 Nos pacientes que apresentam OTSVE, deve ser evitada a utilização de fármacos que reduzam a pré e pós-carga, como os vasodilatadores venosos ou arteriais e os diuréticos, pois podemos agravar o grau de obstrução.

O uso de betabloqueadores neste grupo de pacientes demonstrou benefício clínico com uma maior taxa de sobrevida em 2 anos, particularmente nos pacientes portadores de hipertensão arterial ou que desenvolveram choque cardiogênico na fase aguda.¹³⁴

Choque cardiogênico

O Choque cardiogênico pode ocorrer de 6 % a 20% dentro das primeiras 72 horas da admissão. O primeiro ponto a ser observado no tratamento é se a hipotensão decorre de OTSVE ou de falência contrátil difusa do ventrículo esquerdo, uma vez que 20 a 25% dos pacientes apresentam OTSVE.¹³⁵

Os pacientes com OTSVE, podem apresentar movimento sistólico anterior da valva mitral com consequente insuficiência mitral. A utilização de aminas vasoativas, inodilatadores, vasodilatadores, diuréticos e balão intra-aórtico, devem evitados por ocasionarem o agravamento da obstrução do TSVE. O tratamento é expansão volêmica e betabloqueador seletivo intravenoso de curta duração, como Esmolol.¹³⁶Nos pacientes com choque cardiogênico refratário a intervenção farmacológica, o suporte mecânico circulatório com ECMO estaria indicado, devendo o implante ser o mais precoce possível.¹³⁷

Nos pacientes onde o choque cardiogênico decorre da falência da bomba, a utilização de aminas vasoativas como a noradrenalina, é frequente na pratica clínica. No entanto a recomendação da Sociedade Europeia de Cardiologia é que devem ser evitadas ou utilizadas em baixas doses, pelo potencial de agravar a agressão miocárdica e a disfunção ventricular e promover um prolongamento do quadro de choque.¹³⁸ Ansari et al., demonstraram nos pacientes que utilizaram aminas vasoativas quando comparados com os que não utilizaram, uma maior mortalidade intra-hospitalar (3,2% vs. 28,5%, p < 0,01), mortalidade em 30 dias (17,2% vs. 51,4%, p < 0,01) e mortalidade a longo prazo (38,7% vs. 80.9%, p < 0,01), sendo que na análise de regressão logística foi fator determinante de pior prognóstico. (HR 2,2; 95% CI 1,0–4,8; p= 0,04).¹³⁹

A utilização de levosimendan, milrinona em pacientes com hipotensão arterial ou choque cardiogênico, na ausência de OTSVE, são opções às aminas vasoativas por não ativarem os receptores neuro-adrenérgicos. A utilização do Levosimendan em uma série de casos demonstrou melhora clínica e da função ventricular sem desenvolver eventos adversos ou OTSVE. O Levosimendan deve ser feito na dose de 0.1 mg/kg/min sem bolus por 24 horas.^140,141

Os pacientes com choque cardiogênico, que não apresentam uma resposta inicial ao suporte farmacológico, devem ser avaliados o mais rapidamente possível pelo time de choque para o implante de suporte mecânico circulatório. A utilização do Balão intra-aórtico isoladamente não demonstrou benefícios na melhora da sobrevida, devendo ser avaliado o uso da ECMO associado ao Impella ou BIA.^142-144

Arritmias

Os pacientes com TC podem apresentar arritmias supraventriculares ou ventriculares, com potencial de complicações tromboembólicas e de aumento da mortalidade. A fibrilação atrial aguda deve ser manuseada inicialmente com anticoagulação e controle de frequência cardíaca com betabloqueadores intravenosos de curta duração, podendo ser indicada a cardioversão elétrica nos pacientes com instabilidade hemodinâmica. Arritmias malignas podem ocorrer em 8% dos pacientes, sendo em 75% destes taquicardia ventricular e a fibrilação ventricular.^145,146 O tratamento na fase aguda pode envolver sulfato de magnésio, betabloqueador intravenoso de curta duração e cardioversão elétrica. A amiodarona é eficaz no controle das arritmias ventriculares, mas devemos observar se há presença de QT longo, que pode ser agravada pela amiodarona. Nas TV frequentes não responsivas ao tratamento farmacológico associadas a QT longo, podemos utilizar marcapasso para aumento da frequência cardíaca, e nos pacientes evoluídos com instabilidade hemodinâmica ou choque cardiogênico, o implante de suporte mecânico circulatório com ECMO.^147,148

Trombo intracardíaco

A formação de trombo intracardíaco (TIC) no ventrículo esquerdo na TC pode ocorrer em até 2,5% dos pacientes e o desenvolvimento de eventos cardioembólicos em 0,8% desta população. Sendo que a formação do trombo pode ocorrer na fase intra-hospitalar ou em até 2 semanas após a alta. Na presença de TIC temos um risco de eventos de embolização sistêmica de 1% a 2%. A presença de balonamento apical, FEVE < 35% e níveis elevados de Troponina I, são preditores de desenvolvimento de TIC, sendo indicada a anticoagulação profilática com DOACs. O balonamento apical sem elevação de troponina associada não necessita anticoagulação profilática. Na presença de TIC detectado pelo ecocardiograma ou ressonância magnética cardíaca, a anticoagulação com DOACs esta indicada e deve ser mantida pelo período mínimo de 3 meses.^149-151

Seguimento dos pacientes pós alta hospitalar <xref ref-type="bibr" rid="B152">152</xref>-<xref ref-type="bibr" rid="B155">155</xref>

No seguimento pós alta hospitalar, temos vários objetivos a serem avaliados, como: 1) involução da alteração segmentar e melhora da função ventricular; 2) involução de trombo intracavitário; 3) involução do edema miocárdico; 4) seguimento do QT; 5) avaliação de arritmias ventriculares.

As avaliações anatômicas e funcionais são feitas pelo ecocardiograma e RMC magnética com 30 dias e 3 meses pós alta. Em conjunto com esta avaliação, deve-se também avaliar o risco do desenvolvimento de arritmias principalmente nos pacientes com QT longo persistente ou com arritmias ventriculares, observadas no eletrocardiograma de 24 horas. Os pacientes com trombo intracavitário, devem permanecer anticoagulados com DOACs pelo período mínimo de três meses, com seguimento pelo ecocardiograma ou RMC. A manutenção de IECA/BRA nos pacientes que apresentaram disfunção ventricular, tem benefício na melhora da sobrevida ao fim de 1 ano, e não se observou benefício com o uso de betabloqueadores.¹⁵²

O prognóstico a longo prazo da TC é benigno, com mais de 90% dos pacientes com recuperação completa ao fim de 2 meses. A taxa de recorrência a longo prazo varia entre 1,8% e 10%. As mulheres acima de 50 anos, a persistência de disfunção ventricular, labilidade emocional, distúrbios psiquiátricos, e alteração do reflexo vaso-vagal, apresentam um maior risco para a recorrência. Os pacientes do sexo masculino, que apresentaram insuficiência cardíaca avançada na internação, e os diabéticos, apresentam uma menor sobrevida a longo prazo.^153,154 O uso de IECA/BRA ou betabloqueadores não demonstraram eficácia na redução da taxa de recorrência.¹³⁰Isso também foi observado no tratamento ou correção dos fatores ou gatilhos, como ansiedade, depressão, asma brônquica ou o fato de evitar procedimentos invasivos.

Vinculação acadêmica

Não há vinculação deste estudo a programas de pós-graduação.

Aprovação ética e consentimento informado

Este artigo não contém estudos com humanos ou animais realizados por nenhum dos autores.

Fontes de financiamento: O presente estudo não teve fontes de financiamento externas.