REVIEW

CURRENT
OPINION Takotsubo syndrome: diagnostic work-up and clues
into differential diagnosis
Marco Giuseppe Del Buono a,b, Nicola Potere a, Juan Guido Chiabrando a,c,
Edoardo Bressi a,d, and Antonio Abbate a

Purpose of review
Takotsubo syndrome represents an increasingly recognized clinical entity characterized by a reversible
acute myocardial dysfunction, often triggered by an emotional or physical stress, and independent of an
underlying epicardial coronary artery disease. The diagnosis is often challenging because of the
nonspecific clinical presentation and the inconclusive noninvasive diagnostic imaging.
Recent findings
The present review provides a brief overview of Takotsubo syndrome clinical presentation and guides the
clinician through the diagnostic work-up of Takotsubo syndrome, highlighting clues into differential
diagnosis. A review of clinical management is also provided.
Summary
Despite increasing awareness and recognition, the diagnosis of Takotsubo syndrome remains challenging
and Takotsubo syndrome is often underdiagnosed or misdiagnosed. The prompt recognition of Takotsubo
syndrome portends relevant prognostic and therapeutic implications.
Keywords
broken heart, differential diagnosis, stress cardiomyopathy, Takotsubo

INTRODUCTION clinicians prompt identify Takotsubo syndrome,

Takotsubo syndrome, also known as stress cardiomy-
opathy, broken heart syndrome, or apical ballooning
syndrome, is an increasingly recognized clinical syn-
drome characterized by an abrupt systolic and dia-
stolic myocardial dysfunction, commonly occurring
after an emotional or physical stressful event, that is
reversible in its course, and is independent of the
presence of an underlining epicardial coronary artery
disease (CAD) [1]. The term was first introduced by
Sato et al. [2] describing a condition of acute left
highlighting clues into differential diagnosis.
DIAGNOSTIC CRITERIA
Many efforts have been devoted to define Takotsubo
syndrome, and several criteria have been proposed
over the last years. The most commonly used diagnos-
tic criteria for Takotsubo syndrome are the Revised
Mayo Clinic Criteria, however, new diagnostic criteria,
the InterTAK diagnostic criteria, have been published
&&

ventricular dysfunction associated with apical wall
motion abnormalities, named ‘Takotsubo’ because of
the similarity of the shape of systolic left ventriculo-
gram with an octopus trap commonly used in Japan.
Owing to its self-limiting course, Takotsubo syndrome
was initially believed to be a benign syndrome associ-
ated with favorable prognosis, however, it has been
found to be associated with a considerable risk of
&&
mortality, recurrence, and complications [1,3,4 ,5].
Despite the increase in its awareness, Takotsubo
syndrome still remains largely underdiagnosed and
misdiagnosed, because of its deceptive clinical presen-
tation and heterogeneity of cardiovascular findings.
We herein review the diagnostic work-up to help
recently (summarized in Table 1) [6,7 ]. For instance,
neurologic disorders (e.g., subarachnoid hemorrhage,
a
VCU Pauley Heart Center, Virginia Commonwealth University, Rich-
mond, Virginia, USA, bDepartment of Cardiovascular and Thoracic Sci-
ences, Catholic University of the Sacred Heart, Rome, Italy, cDepartment
of Cardiology, Hospital Italiano, Buenos Aires, Argentina and dUnit of
Cardiac Sciences, Campus Bio-Medico University of Rome, Rome, Italy
Correspondence to Antonio Abbate, ‘Roberts’ Professor of Cardiology,
VCU Pauley Heart Center, Department of Internal Medicine, Division of
Cardiology, West Hospital, West Wing 5-020, 1200 E Broad Street, P.O.
Box 980204, Richmond, VA 23298, USA. Tel: +1 804 828 0513;
e-mail: antonio.abbate@vcuhealth.org
Curr Opin Cardiol 2019, 34:673–686
DOI:10.1097/HCO.0000000000000672

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Ischemic heart disease

stroke, seizures) as well as pheochromocytoma are

KEY POINTS now listed among potential triggers for Takotsubo
&&

 Takotsubo syndrome or stress cardiomyopathy is an syndrome [7 ]. Whether these represent different

acute cardiac disorder characterized by a transient left
ventricular systolic and diastolic dysfunction associated
with a nonnegligible rate of mortality and complications.
 Patients affected by Takotsubo syndrome often present
with nonspecific signs and symptoms (i.e., chest pain,
dyspnea, elevation of cardiac biomarkers) and ECG
abnormalities (transient ST-segment elevation, T-wave
inversion, QTc prolongation), making this diagnosis
challenging for clinicians.
 Takotsubo syndrome must be promptly differentiated from
CAD and other conditions associated with chest pain and
ECG abnormalities for appropriate management.
 Patient demographics (i.e., postmenopausal female)
and history (i.e., presence of Takotsubo syndrome
triggers including emotional or physical stress,
neurological, and psychiatric disorders) may help
physicians to recognize this entity.
 Despite increasing awareness and recognition,
Takotsubo syndrome still remains largely
underdiagnosed and misdiagnosed.
entities or not is still debated, however, they share
common clinical characteristics, cardiac imaging find-
ings, catecholaminergic-mediated pathophysiology,
and histopathological features, which do not largely
differ from other emotional or physical-triggered
Takotsubo syndrome [3,8,9].
CLINICAL PRESENTATION
The most common presenting symptoms in patients
with Takotsubo syndrome are chest pain and dys-
pnea. Syncope, signs of heart failure, hemodynamic
instability because of malignant arrhythmias or
acute pump failure may be present, although less
frequently [3]. Cardiac arrest because of ventricular
arrhythmias also represents a possible presentation
for Takotsubo syndrome [10]. The quality of chest
pain generally resembles angina, and it may help
differentiating from other conditions such as, but
not limited to pleuritic chest pain in patients with
acute pulmonary embolism or migrating chest pain
in patients with acute aortic dissection. The clinical

Table 1. Diagnostic criteria

International Takotsubo diagnostic criteria (InterTAK diagnostic criteria)
1. Patients show transient left ventricular dysfunction (hypokinesia, akinesia, or dyskinesia) presenting as apical ballooning or
midventricular, basal, or focal wall motion abnormalities. Right ventricular involvement can be present. Apart from these regional wall
motion patterns, transitions between all types can exist. The regional wall motion abnormality usually extends beyond a single epicardial
vascular distribution; however, rare cases can exist where the regional wall motion abnormality is present in the subtended myocardial
territory of a single coronary artery (focal Takotsubo syndrome)a
2. An emotional, physical, or combined trigger can precede the Takotsubo syndrome event, but this is not obligatory
3. Neurologic disorders (e.g., subarachnoid hemorrhage, stroke/transient ischemic attack, or seizures) as well as pheochromocytoma may
serve as triggers for Takotsubo syndrome
4. New-onset ECG abnormalities are present (ST-segment elevation, ST-segment depression, T-wave inversion, and QTc prolongation);
however, rare cases exist without any ECG changes
5. Serum levels of cardiac biomarkers (troponin and creatine kinase) are moderately elevated in most cases; significant elevation of brain
natriuretic peptide is common
6. Significant coronary artery disease is not a contradiction in Takotsubo syndrome
7. Patients have no evidence of infectious myocarditisb
8. Postmenopausal women are predominantly affected
Revised Mayo Clinic Criteria
1. Transient hypokinesis, akinesis, or dyskinesis of the left ventricular mid-segments with or without apical involvement; the regional wall
motion abnormalities extend beyond a single epicardial vascular distribution; a stressful trigger is often but not always presentc
2. Absence of obstructive coronary disease or angiographic evidence of acute plaque ruptured
3. New electrocardiographic abnormalities (either ST-segment elevation and/or T-wave inversion) or modest elevation in cardiac troponin
4. Absence of pheochromocytoma or myocarditis. In both of the above circumstances, the diagnosis of stress cardiomyopathy should be
made with caution, and a clear stressful precipitating trigger must be sought

a
Wall motion abnormalities may remain for a prolonged period of time or documentation of recovery may not be possible. For example, death before evidence of
recovery is captured.
b
Cardiac magnetic resonance imaging is recommended to exclude infectious myocarditis and diagnosis confirmation of Takotsubo syndrome.
c
There are rare exceptions to these criteria such as those patients in whom the regional wall motion abnormality is limited to a single coronary territory.
d
It is possible that a patient with obstructive coronary atherosclerosis may also develop stress cardiomyopathy. However, this is very rare in our experience and in
the published literature, perhaps because such cases are misdiagnosed as an acute coronary syndrome.

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presentation is often unspecific and challenging for
clinicians, making Takotsubo syndrome often rec-
ognized belatedly in the clinical course or even
misdiagnosed. Furthermore, coexisting acute ill-
nesses (e.g., acute respiratory failure, sepsis), acting
as triggers, can conceal the clinical presentation and
aggravate the hemodynamic status [1,3]. These ‘sec-
ondary’ or ‘bystander’ forms of Takotsubo syndrome
are more difficult to detect and consequently the
diagnosis can be easily missed [1,3].
DIFFERENTIAL DIAGNOSIS
There are several entities that clinicians should be
aware of in a patient presenting at emergency
department with chest pain, especially if associated
with electrocardiographic (ECG) abnormalities
(Figs. 1–6; Table 2). A comprehensive clinical assess-
ment and a multimodality imaging approach are
therefore required to guide through the correct
diagnosis and treatment.
PRETEST PROBABILITY
In many of the cases, Takotsubo syndrome affects
postmenopausal woman after an intense emotional
(e.g., death of relatives, catastrophic events) or physical
stressful event (e.g., acute respiratory failure, sepsis,
surgery) [11], and therefore the patient demographics
and clinical history are of fundamental importance to
guide the diagnostic path. Hormonal conditions (such
as postmenopausal state, female sex) and comorbid-
ities associated with chronic coronary microvascular
dysfunction (i.e., diabetes, asthma/chronic obstruc-
tive pulmonary disease) seem to increase the suscepti-
bility of myocardium damage following an enhanced
neuro-autonomic catecholaminergic surge [1,12–14].
Why this happens only in a small portion of the
patients after a stressful event remains unclear. How-
ever, an altered limbic processing and a defective
autonomic integration have been recently described
in patients with Takotsubo syndrome, supporting the
central pathophysiological role of brain–heart axis in
&& &
this syndrome [1,15 ,16 ]. Because of the closely
resembling clinical presentation with acute coronary
syndrome (ACS), the InterTAK diagnostic score has
been recently introduced to help differentiate Takot-
&&
subo syndrome from ACS [17 ]. This score comprises
seven variables, each of which is assigned a score value
(female sex: 25 points; emotional stress: 24 points; no
ST-segment depression: 12 points; acute, former, or
chronic psychiatric disorder: 11 points; prolonged QTc
time more than 460 ms, female sex: 6 points; https://
www.takotsubo-registry.com/takotsubo-score.html)
and provides a pretest probability for Takotsubo syn-
drome versus ACS. It is worth noting, however, that
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Takotsubo syndrome Del Buono et al.
Takotsubo syndrome can affect individuals of both
sexes and across the entire life span [1,3].
DIAGNOSTIC TOOLS
Cardiac biomarkers
Cardiac biomarker usually present a particular behav-
ior, as generally serum troponin and creatine kinase
myocardial-band (CKMB) levels are disproportion-
ately low compared with the extent of wall motion
abnormalities and with the generally higher B-type
natriuretic peptide (BNP) and N-terminal prohor-
mone of brain natriuretic peptide plasma levels
[3,18]. In fact, the BNP/troponin and BNP/CKMB
ratios may help to differentiate Takotsubo syndrome
from ACS with a 95% specificity with the threshold of
BNP/Troponin T ratio at least 1272 and BNP/CKMB
ratio at least 29.9. Nevertheless, these ratios present
low sensitivity (52 and 50%, respectively) [19].
Electrocardiographic abnormalities
Takotsubo syndrome typically presents with ECG
abnormalities, which resembles those presenting in
ACS or other cardiac causes of chest pain (Table 2)
[20]. In the first 24 h, transient ST-segment elevation
can occur, most commonly in anterior leads, with-
out mirroring ST depression, often followed (after
24 h) by a sequence of negative T waves, transient T-
wave reversion, and developing of deep T-wave
inversion associated with corrected QT (QTc) inter-
val prolongation [3,21]. In clinical practice, the
initial ST-segment elevation is often missed, making
T-wave inversion and QTc prolongation the most
commonly encountered ECG abnormalities at diag-
nosis [3]. ST-segment depression occurs in less than
10% of patients, and its presence should suggest an
alternative diagnosis of ACS, as highlighted by the
&&
InterTAK diagnostic score [3,17 ]. Several criteria
have been proposed to discriminate ECG findings of
Takotsubo syndrome compared with ACS [22]. Con-
comitant ST elevation in aVR (the antipode of aVR)
and in the anterior-septal leads, presenting only in a
minority of patients (12% of cases), is considered
100% specific for Takotsubo syndrome versus ST-
segment elevation acute myocardial infarction
(STEMI), with a positive predictive value of 100%.
In the setting of non-ST elevation ACS, ST-segment
elevation in aVR with concomitant T-wave inver-
sion in any lead, which is found only in 8% of cases,
is also 100% specific of Takotsubo syndrome with a
100% positive predictive value. [22]. A transient
attenuation in the amplitude of QRS complexes
(compared with previous ECGs) or low-voltage
QRS on admission has also been described [23].
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Ischemic heart disease

FIGURE 1. Apical Takotsubo syndrome in a 63-year-old patient presenting with acute chest pain and dyspnea after an intense
emotional stress. Electrocardiogram (a): T-wave inversion involving predominantly the anterolateral leads, prolonged QTc
interval (530 ms). Coronary angiography (b, top): normal right and left coronary arteries. Ventriculography (b, bottom)
regional akinesia localized to the apical segments. Cardiac magnetic resonance (c): transmural edema at mid-apical segments
(left) in absence of late gadolinium enhancement (right). Lab tests: peak troponin I 0.884 ng/ml (n.v. <0.004 ng/ml) and
N-terminal pro-b-type natriuretic peptide level 3743 pg/ml (n.v. <150 pg/ml).

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 Takotsubo syndrome Del Buono et al.

FIGURE 2. Mid-ventricular Takotsubo syndrome in a 73-year-old patient with chest pain following laparoscopic
cholecystectomy. Electrocardiogram (a): nonspecific ST/T-wave abnormalities. QTc is within the normal limits. Coronary
angiography (b, top): normal right and left coronary arteries. Ventriculography (b, bottom): regional akinesia localized to the
mid-segments. Cardiac magnetic resonance (c): transmural edema in the area of ventricular dysfunction (left) in absence of
late gadolinium enhancement (right). Lab tests: peak troponin I 1.2 ng/ml (n.v. <0.004 ng/ml) and N-terminal pro-b-type
natriuretic peptide (NT-proBNP) level 5714 pg/ml (n.v. <150 pg/ml).

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Ischemic heart disease

FIGURE 3. ST-segment elevation acute myocardial infarction in a 50-year-old patient presenting with acute chest pain.
Electrocardiogram (a): ST-segment elevation predominantly in the anterolateral leads associated with mirroring ST-segment
depression in the inferior leads. QTc is within the normal limits. Coronary angiography (b): acute occlusion of the proximal left
anterior coronary artery (left) with normal right coronary artery (right). Cardiac magnetic resonance (c): transmural edema at
the level of interventricular septum and anterolateral wall (left) associated with areas of late gadolinium enhancement with a
transmurally more than 50% and areas of microvascular obstruction (right). Lab tests: peak troponin I 213 ng/ml (n.v.
<0.004 ng/ml) and N-terminal pro-b-type natriuretic peptide (NT-proBNP) level 245 pg/ml (n.v. <150 pg/ml).

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 Takotsubo syndrome Del Buono et al.

FIGURE 4. Myocardial infarction due to paradoxical embolism in a young patient with history patent foramen ovale
presenting with acute chest pain. Electrocardiogram (a): ST-segment elevation in the inferior leads. QTc is within the normal
limits. Coronary angiography (b): distal occlusion (‘amputation’) of the posterolateral branch of right coronary artery. Lab
tests: peak troponin I 34 ng/ml (n.v. <0.004 ng/ml) and N-terminal pro-b-type natriuretic peptide (NT-proBNP) level 44 pg/ml
(n.v. <150 pg/ml).

However, owing to the high variability of ECG Echocardiography

features according to patient characteristics (i.e.,
pattern of wall motion abnormality, triggers, time
from symptoms onset), ECG alone should not be
used to differentiate between Takotsubo syndrome
and ACS [24].
The initial assessment of wall motion abnormalities
is usually performed using transthoracic echocardi-
ography. Transthoracic echocardiography is the
most common and simple method enabling detec-
tion of global and segmental left ventricular wall

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Ischemic heart disease

FIGURE 5. Myocarditis in a 47-year patient with chest pain 2 weeks following a ‘flu-like’ episode. Electrocardiogram (a):
nonspecific ST/T-wave abnormalities with subtle ST-segment depression in inferior leads. QTc is within the normal limits.
Coronary angiography (b, top): normal right and left coronary arteries. Ventriculography (b, bottom): regional akinesia
localized to the (basal)-mid segments with sparing of the apical and basal segments. Cardiac magnetic resonance (c):
transmural edema in the area of ventricular dysfunction (left) with areas of subepicardial and patchy distribution of late
gadolinium enhancement (right). Lab tests: peak troponin I 54 ng/ml (n.v. <0.004 ng/ml), N-terminal pro-b-type natriuretic
peptide (NT-proBNP) level 478 pg/ml (n.v. <150 pg/ml), C-reactive protein 15 mg/l (n.v. <5 mg/l).

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 Takotsubo syndrome Del Buono et al.

FIGURE 6. Apical variant of hypertrophic cardiomyopathy in a 58-year-old patient presenting with chest pain.
Electrocardiogram (a): deep and symmetric inverted T waves involving predominantly the anterolateral leads associated to
1-mm ST depression and prolonged QTc interval (511 ms). Ventriculography (b, top) ‘ace-of-spades’-like shape at end-systole.
Coronary angiography (b, bottom): normal right and left coronary arteries. Cardiac magnetic resonance (c): presence of
apical hypertrophy with systolic apical cavity obliteration. Lab tests: Troponin I less than 0.004 ng/ml (n.v. <0.004 ng/ml)
and N-terminal pro-b-type natriuretic peptide (NT-proBNP) level 287 pg/ml (n.v. <150 pg/ml).

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 682
Table 2. Differential diagnosis of patients with Takotsubo syndrome
Clinical presentation Pretest probability ECG Echocardiography Coronary angiography Cardiac MRI Biomarkers

Takotsubo syndrome
Chest pain, dyspnea, syncope,
palpitations, SCD. Usually in
postmenopausal female and
often precepted by an emotional
or physical stress
InterTAK diagnostic ST-segment elevation, T- Apical, midventricular, Absence of culprit Edema: transmural ventricular NT-proBNP and BNP""
score wave inversion, QTc basal or focal hypo/ obstructive CAD and/or edema in the areas of Troponin and CKMB
prolongation; ST- akinesia intravascular imaging ventricular dysfunction mildly"
segment depression is suggestive of acute Cine-CMR: regional wall Increased BNP/troponin
less common plaque destabilization. motion abnormalities and BNP/CKMB ratio
Ischemic heart disease

Ventriculography according to the anatomical

identifies the anatomical patterns
variant LGE: absent (cut-off > 5 SD)
Myocardial infarction

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Chest pain, dyspnea, arrhythmias,
heart failure/cardiogenic shock,
SCD
MINOCAb epicardial spasm; unstable microvascular dysfunction; plaque disruption; non-angiographically obstructive coronary embolism/thrombosis; non-angiographically obstructive SCAD
Chest pain, dyspnea, arrhythmias,
heart failure/cardiogenic shock,
SCD
Compared with those patients
with MI because of obstructive
CAD, MINOCA patients are
more commonly younger and
women
Myocarditis
Chest pain, dyspnea, acute heart
failure, SCD; usually in middle
age population often preceded
by an upper respiratory
infection or enteritis.
InterTAK diagnostic ST-segment elevation Regional wall motion
score (STEMI), ST-segment
depression, and/or T-
wave inversion
(NSTEMI)
– ST-segment elevation or ST- Regional wall motion
segment depression
and/or T-wave inversion
– Nonspecific ST and/or T- Global systolic dysfunction
wave changes (diffuse
ST-segment elevation is
usually seen in
myopericarditis).
Coronary artery disease
abnormalities according
with epicardial coronary
artery distribution
Absence of angiographic
abnormalities according
with epicardial coronary
artery distribution
Absence of obstructive
(sometimes regional or
segmental). Pericardial
involvement may be also
present.
Edema: subendocardial or Troponin and CKMB
with acute plaque transmural at sites of wall levels""
rupture and thrombus motion abnormalities BNP and NT-proBNP
formation Cine-CMR: regional wall mildly"
motion abnormalities
according to epicardial
coronary artery distribution
LGE: bright LGE, typically
subendocardial or
transmural in an epicardial
coronary artery distribution
Edema: subendocardial or Troponin and CKMB
obstructive CAD FFR transmural at sites of wall levels""
may be considered in motion abnormalities BNP and NT-proBNP
selected patients with Cine-CMR: regional wall mildly"
borderline stenosis. motion abnormalities
Intravascular imaging according to epicardial
(IVUS and OCT) and coronary artery distribution
provocative tests are LGE: bright LGE, typically
often needed subendocardial or
transmural in an epicardial
coronary artery distribution
Edema: Subepicardial, basal Troponin and CKMB
CAD or angiographic and lateral mildly"
evidence of acute Cine-CMR: Global, or BNP and NT-proBNP
plaque rupture. regional contractile mildly"
dysfunction.
LGE: Low intensity or bright;
typically focal, ‘patchy’,
subepicardial or

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midventricular with a
noncoronary distribution
Acute pulmonary embolism

Volume 34  Number 6  November 2019

 Table 2 (Continued)
Clinical presentation Pretest probability ECG Echocardiography Coronary angiography Cardiac MRI Biomarkers

Chest pain, dyspnea, heart failure,
cardiogenic shock, SCD; usually
in patients with deep venous
thrombosis and/or history of
prior thromboembolism, recent
major surgery, trauma/
immobilization, antiphospholipid
antibodies, active malignancy,
pregnancy, oral contraceptives,
and myeloproliferative disorders
Hypertrophic cardiomyopathy
Chest pain, heart failure,
arrhythmias, SCD. Apical
variant (Yamaguchi syndrome)
is most common in Asian
population
Pheochromocytoma-related Takotsubo syndromea
Chest pain, dyspnea, arrhythmias,
heart failure/cardiogenic shock.
Wells and modified Tachycardia and Increased right ventricle Not necessary for Not necessary for diagnosis Troponin and CKMB
Wells criteria; nonspecific ST-segment size, decreased right diagnosis normal or mildly"
Geneva score and T-wave changes ventricle function, BNP and NT-proBNP
(S1Q3T3 pattern, right tricuspid regurgitation, mildly"
ventricular strain, new flattening of D-dimer""
right bundle branch interventricular septum,
block are present in less McConnell’s sign,
than 10%). Rarely thrombus in transition
widespread deep T-
wave inversion is seen
– Voltage of left ventricular Severe left ventricular Absence of obstructive Edema: often locates within Troponin and CKMB are
hypertrophy, strain hypertrophy with left CAD. Ventriculography LGE areas but can locate usually within the normal
pattern ventricular wall thickness unmasks the spade-like outside of LGE limits
Giant T-wave inversion 15 mm (not otherwise configuration of the left Cine-CMR: apical or BNP and NT-proBNP
in anterior leads is explained) in any ventricular cavity at end- localized myocardial mildly"
common in the apical myocardial segment diastole in the apical hypertrophy (which can be
variant of HCM variant of HCM missed by
echocardiography)
LGE: insertion point of the
left and right ventricles or in
the most hypertrophied
myocardial regions
InterTAK diagnostic ST-segment elevation, T- Apical, midventricular, Absence of culprit Edema: transmural ventricular NT-proBNP and BNP""
score wave inversion, QTc basal, or focal hypo/ obstructive CAD and/or edema in the areas of Troponin and CKMB

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Episodes of elevation in blood prolongation; ST- akinesia. Global intravascular imaging ventricular dysfunction mildly"
pressure, headache, sweating, segment depression is dysfunction is also suggestive of acute Cine-CMR: regional wall Increased BNP/troponin
palpitations, and panic attack less common possible plaque destabilization. motion abnormalities and BNP/CKMB ratio
may present either during Ventriculography according to the anatomical
presentation or preceding days identifies the anatomical patterns
variant LGE: absent; however, focal
areas of LGE may be
detected (mid-wall,
subepicardial, or patchy
distribution)

BNP, B-type natriuretic peptide; CAD, coronary artery disease; CKMB, creatine kinase myocardial-band; CMR, cardiac magnetic resonance; FFR, fractional flow reserve; HCM, hypertrophic cardiomyopathy; LGE, late
gadolinium enhancement; MINOCA, myocardial infarction with no obstructive coronary arteries; NSTEMI, non-ST elevated myocardial infarction; NT-proBNP, N-terminal prohormone of brain natriuretic peptide; OCT,
optimal coherence tomography; SCAD, spontaneous coronary artery dissection; SCD, sudden cardiac death; SD, standard deviation; STEMI, ST-elevated myocardial infarction; upward arrow ("): increased serum levels.
a
Pheochromocytoma and acute cerebrovascular events (e.g., stroke, seizures, traumatic brain injury) are considered ‘Takotsubo syndrome phenocopies’ to differentiate them from Takotsubo syndrome. Pheochromocytoma
may represent a robust and durable substrate for Takotsubo syndrome, precipitating an acute event following a stressful trigger. Because they share similar pathophysiology, clinical characteristics, cardiac imaging
findings and histopathological features, which do not substantially differ from other emotional or physical-triggered Takotsubo syndrome, they have been recently included as triggers of Takotsubo syndrome in the last
InterTAK diagnostic criteria. However, it is worth noting that whereas pheochromocytoma and acute cerebrovascular events may present as global hypokinesis, Takotsubo syndrome is associated with regional wall

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motion abnormalities rather than global dysfunction.
b
Myocarditis and TS are no longer listed in the MINOCA group and considered independent entiteies.

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Takotsubo syndrome Del Buono et al.

683
Ischemic heart disease
motion, systolic and diastolic function and the
presence of complications such as mitral regurgita-
tion because of dynamic left ventricular outflow
tract obstruction (LVOTO) or papillary muscle dys-
function, apical thrombus formation and myocar-
dial wall rupture [1]. Although the name ‘Takotsubo’
refers to the most typical pattern of left ventricular
dysfunction involving the apex, echocardiography
may also identify the different Takotsubo syndrome
patterns of left ventricular systolic dysfunction (i.e.,
apical, mid-ventricular, basal or reverse, and focal
type), as well as right ventricular impairment. The
wall motion abnormalities (hypokinesis, akinesis, or
dyskinesis) are typically regional and extend beyond
the distribution of a single epicardial coronary artery
[1]. Additionally, left ventricular ejection fraction is
typically lower than that observed in the setting of
acute myocardial infarction [3]. Myocardial defor-
mation imaging, using speckle-tracking technique
with the assessment of multidirectional left ventric-
ular deformation, increases the sensitivity in detect-
ing myocardial abnormalities, and portends
independent prognostic value [25]. The determina-
tion of the pattern of left ventricular systolic dys-
function in Takotsubo syndrome also provides
valuable information on treatment strategies (i.e.,
anticoagulation in patients with large areas of apical
akinesia or apical thrombus; use of inotropes in
patients with LVOTO) [26].
Coronary angiography, ventriculography, and
intracoronary imaging
Owing to the difficulty in differentiating Takotsubo
syndrome from ACS, and the potential overlap of
these two pathologies, coronary angiography is usu-
ally performed first to rule out acute atherothrom-
botic lesions in the coronary arteries. Patients with
Takotsubo syndrome generally have normal or near-
normal epicardial coronary arteries at coronary angi-
ography [27]. This explains why Mayo Clinic Criteria
for the diagnosis of Takotsubo syndrome required the
absence of obstructive CAD, although the possibility
of overlapping of Takotsubo syndrome and obstruc-
tive CAD was mentioned in the footnotes [6] (Table 1).
Nevertheless, because of the epidemiological associa-
tion of CAD in patients with Takotsubo syndrome, it
is not uncommon that the two conditions coexist,
without necessarily sharing a direct causal association
(i.e., bystander finding) [27]. As such, the regional
wall motion abnormalities extend beyond the terri-
tory perfused by a single epicardial coronary artery. In
patients without finding of significant CAD, ventri-
culography is usually performed as it is useful to detect
Takotsubo syndrome and differentiate anatomical
variants. In selected circumstances, when coronary
684 www.co-cardiology.com
Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.
angiography shows normal or nearnormal coronary
arteries and ventriculography results inclusive, intra-
vascular imaging with intravascular ultrasound
(IVUS) and optimal coherence tomography (OCT),
as well as intracoronary provocative (with acetylcho-
line or ergonovine) tests may help elucidate the
&
underlying pathophysiology [28 ,29,30]. IVUS and
OCT may allow to identify plaque rupture or erosion
as causative mechanisms of myocardial infarction
&
with no obstructive coronary arteries [28 ]. Notably,
these findings have never been found among patients
with Takotsubo syndrome, making an acute athero-
thrombotic event with rapid and complete lysis of the
thrombus an unlikely mechanism of Takotsubo syn-
drome [29,30]. Furthermore, intracoronary provoca-
tive tests may unmask coronary epicardial or
&
microvascular coronary spam [28 ]. However, these
tests should be pursued only when the diagnosis is
uncertain and/or coronary artery spasm is suspected.
Cardiac computed tomography angiography
Cardiac computed tomography scan provides
information on both epicardial coronary anatomy
and ventricular wall motion abnormalities.
Although coronary angiography still remains the
diagnostic modality of choice in the urgent set-
ting, cardiac computed tomography scan might be
considered in selected cases, such as patients with
very low risk of CAD, suspected Takotsubo syn-
drome recurrence or conditions in which coronary
angiography is associated with high risk of com-
plications (bleeding diathesis, active bleeding,
very frail patients) [1].
Cardiac magnetic resonance
Cardiac magnetic resonance (CMR) provides
detailed and additional information on left and
right ventricular systolic function, extension of wall
motion abnormalities, complications, and it plays a
&
pivotal role in the differential diagnosis [1,31,32 ].
Transmural edema distribution corresponds to the
areas of wall motions abnormalities and this feature
contrasts with acute myocardial infarction, in which
edema usually matches with coronary distribution
[31]. T2-STIR-imaging is currently the gold standard
for assessment of myocardial edema, however, novel
techniques, such as T1 mapping, allow a quantita-
tive tissue characterization and a more accurate
detection of myocardial edema. T1 mapping usually
reveals a global left and right ventricular edema
during the acute phase of Takotsubo syndrome, that
persists, albeit reduced, in the acute dysfunctional
&
segments even at 4-month follow-up [32 ]. The
presence/absence of late gadolinium enhancement
Volume 34  Number 6  November 2019

(LGE) and its distribution at the level of myocardial
wall can discriminate Takotsubo syndrome, myocar-
dial infarction, and myocarditis. A feature of Takot-
subo syndrome is the absence of LGE [cutoff value of
>5 standard deviation (SD) above the mean]. Differ-
ently, myocardial infarction displays bright suben-
docardial or transmural enhancement following a
coronary distribution, whereas myocarditis produ-
ces mid-wall or sub-epicardial enhancement with a
‘patchy’ noncoronary distribution. However, minor
LGE can be found in Takotsubo syndrome when LGE
is defined at a cutoff value of more than 3 SD above
the mean [31]. Furthermore, LGE has higher sensitiv-
ity and specificity than echocardiography in detect-
ing left ventricular thrombi [31]. Finally, CMR is
useful to assess myocardial complications associated
with Takotsubo syndrome, such as right ventricular
involvement, pericardial effusion, mitral regurgita-
tion, LVOTO, and myocardial ruptures [33].
THERAPEUTIC IMPLICATIONS
The early detection of Takotsubo syndrome and a
thorough search of complications are crucial in deter-
mining the appropriate treatment (e.g., pharmaco-
logical and mechanical hemodynamic support,
anticoagulation, timing for coronary angiography,
and reperfusion strategies) and improve prognosis.
Takotsubo syndrome is generally a reversible condi-
tion often requiring a conservative management.
Nevertheless, the risk of severe in-hospital complica-
tions and long-term mortality in the overall Takot-
subo syndrome population is strikingly similar to
&&
that of patients with ACS [4 ]. ECG monitoring is
recommended because of the risk of arrhythmias.
Continuous hemodynamic monitoring is required
because of a 10–15% risk of developing cardiogenic
shock, whose management depends on the presence
of a significant LVOTO, usually within the first days
after the admission [1,3]. In absence of randomized
clinical trials, there is no evidence for the use of
antiplatelet medications after final diagnosis of
Takotsubo syndrome. In the cases of apical balloon-
ing with large areas of wall motion abnormality,
systemic anticoagulation should be considered until
left ventricular systolic function has recovered [1].
Angiotensin-converting enzyme inhibitors and
angiotensin-receptor blockers have been found to
be effective in preventing recurrence and improving
survival at one-year follow-up [3,34]. Finally, patients
with a prior episode of Takotsubo syndrome have
persistent limiting symptoms and reduced exercise
capacity compared with age-matched healthy con-
trols because of the persistence of a subclinical cardiac
dysfunction despite the recovery of left ventricular
& &
ejection fraction [32 ,35 ].
0268-4705 Copyright ß 2019 Wolters Kluwer Health, Inc. All rights reserved.
Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.
Takotsubo syndrome Del Buono et al.
CONCLUSION
Awareness of key diagnostic features of Takotsubo
syndrome may help the physicians to consider this
underdiagnosed and misdiagnosed condition and to
correctly manage the appropriate diagnostic work-
up and treatment. A timely diagnosis and an appro-
priate treatment is of key importance in preventing
Takotsubo syndrome complications and improving
its prognosis.
Acknowledgements
None.
Financial support and sponsorship
None.
Conflicts of interest
There are no conflicts of interest.
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Volume 34  Number 6  November 2019