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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

Authors:
  • Sana Kliniken Lübeck

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Takotsubo syndrome is an acute reversible heart failure syndrome that is increasingly recognized in modern cardiology practice. This Position Statement from the European Society of Cardiology Heart Failure Association provides a comprehensive review of the various clinical and pathophysiological facets of Takotsubo syndrome, including nomenclature, definition, and diagnosis, primary and secondary clinical subtypes, anatomical variants, triggers, epidemiology, pathophysiology, clinical presentation, complications, prognosis, clinical investigations, and treatment approaches. Novel structured approaches to diagnosis, risk stratification, and management are presented, with new algorithms to aid decision-making by practising clinicians. These also cover more complex areas (e.g. uncertain diagnosis and delayed presentation) and the management of complex cases with ongoing symptoms after recovery, recurrent episodes, or spontaneous presentation. The unmet needs and future directions for research in this syndrome are also discussed.
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European Journal of Heart Failure (2015) REVIEW
doi:10.1002/ejhf.424
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
Alexander R. Lyon1,2,*, Eduardo Bossone3, Birke Schneider4, Udo Sechtem5,
Rodolfo Citro6, S.Richard Underwood1,2,MaryN.Sheppard
7, Gemma A. Figtree8,9,
Guido Parodi10, Yoshihiro J. Akashi11, Frank Ruschitzka12, Gerasimos Filippatos13,
Alexandre Mebazaa14, and Elmir Omerovic15
1National Heart and Lung Institute, Imperial College, London, UK; 2NIHR Cardiovascular Biomedical Research Unit, Royal Brompton Hospital, London, UK; 3Cardiology
Division, ‘Cava d’Tirreni and Amal Coast’ Hospital, Heart Department, University of Salerno, Italy; 4Medizinische Klinik II, Sana Kliniken Lübeck, Germany; 5Department of
Cardiology, Robert Bosch Krankenhaus, Stuttgart, Germany; 6University Hospital ‘San Giovanni di Dio e Ruggi d’Aragona’, Heart Department, Largo Città di Ippocrate, Salerno,
Italy; 7Department of Cardiovascular Pathology, St George’s University Medical School, London, UK; 8North Shore Heart Research, Kolling Institute, University of Sydney,
Australia; 9Department of Cardiology, Royal North Shore Hospital, Sydney, Australia; 10Invasive Cardiology, Careggi Hospital, Florence, Italy; 11Division of Cardiology,
Department of Internal Medicine, St. Marianna University School of Medicine, Kawasaki, Japan; 12Clinic for Cardiology, University Hospital Zurich, Zurich, Switzerland;
13Department of Cardiology, Attikon University Hospital, University of Athens Medical School, Athens, Greece; 14Université Paris Diderot; U942 Inserm, Département
d’Anestéhsie-Réanimation Hôpitaux Universitaires Saint Louis-Lariboisière, Paris, France; and 15Department of Molecular and Clinical Medicine/Cardiology, Sahlgrenska Academy,
University of Gothenburg, Gothenburg, Sweden
Received 18 December 2014; revised 25 July 2015; accepted 4 August 2015
Takotsubo syndrome is an acute reversible heart failure syndrome that is increasingly recognized in modern cardiology practice. This Position
Statement from the European Society of Cardiology Heart Failure Association provides a comprehensive review of the various clinical
and pathophysiological facets of Takotsubo syndrome, including nomenclature, denition, and diagnosis, primary and secondary clinical
subtypes, anatomical variants, triggers, epidemiology, pathophysiology, clinical presentation, complications, prognosis, clinical investigations,
and treatment approaches. Novel structured approaches to diagnosis, risk stratication, and management are presented, with new algorithms
to aid decision-making by practising clinicians. These also cover more complex areas (e.g. uncertain diagnosis and delayed presentation) and
the management of complex cases with ongoing symptoms after recovery, recurrent episodes, or spontaneous presentation. The unmet
needs and future directions for research in this syndrome are also discussed.
..........................................................................................................
Keywo rds Takotsubo syndrome stress heart failure risk stratication
Executive summary
Nomenclature: ‘Takotsubo syndrome’ is recommended as the
formal name for this condition, and the term cardiomyopathy
is avoided.
*Corresponding author: NIHR Cardiovascular Biomedical Research Unit, Royal Brompton Hospital, Sydney Street, London SW3 6NP, UK. Tel +44 207 352 8121,Fax+44 207
3518776, Email: a.lyon@ic.ac.uk
................
Diagnosis:anewsetofsevendiagnosticcriteriaispro-
posed incorporating anatomical features, ECG changes, car-
diac biomarkers, and reversibility of the myocardial dysfunction
(Box 1;Diagnostic algorithm).
Clinical subtypes: classication as ‘primary’ or ‘secondary’ Takot-
subo syndrome, depending on clinical context and presence of
©2015 The Authors
European Journal of Heart Failure ©2015 European Society of Cardiology
2A.R. Lyon et al.
Takotsubo Syndrome Diagnostic Algorithm
a major medical, surgical, obstetric, or psychiatric emergency
triggering the Takotsubo syndrome episode.
Tr i gg e r s : a stressful trigger is typical but not always present.
Triggers can be emotional or physical, including acute medical,
surgical, obstetric, or psychiatric emergencies (Table 1).
Anatomical variants: three common and several rare anatomical
variants are currently recognized (Table 2).
...................
Epidemiology: Takotsubo syndrome is increasingly recognized
and reported, and many features suggest a different pathophys-
iological condition from coronary atherosclerosis. Takotsubo
syndrome appears to be more common than previously recog-
nized, but the precise incidence is not known.
Complications: cardiac and non-cardiac complications are com-
mon during the acute episode (Table 3).
©2015 The Authors
European Journal of Heart Failure ©2015 European Society of Cardiology
Current state of knowledge on Takotsubo syndrome 3
Takotsubo Syndrome Management Algorithm
©2015 The Authors
European Journal of Heart Failure ©2015 European Society of Cardiology
4A.R. Lyon et al.
Box 1Heart Failure Association diagnostic criteria for Takotsubo
syndrome
1. Transient regional wall motion abnormalities of LV or RV myocardium which are frequently, but not always, preceded by a
stressful trigger (emotional or physical).
2. The regional wall motion abnormalities usuallyaextend beyond a single epicardial vascular distribution, and often result in
circumferential dysfunction of the ventricular segments involved.
3. The absence of culprit atherosclerotic coronary artery disease including acute plaque rupture, thrombus formation, and
coronary dissection or other pathological conditions to explain the pattern of temporary LV dysfunction observed (e.g.
hypertrophic cardiomyopathy, viral myocarditis).
4. New and reversible electrocardiography (ECG) abnormalities (ST-segment elevation, ST depression, LBBBb, T-wave inversion,
and/or QTc prolongation) during the acute phase (3 months).
5. Signicantly elevated serum natriuretic peptide (BNP or NT-proBNP) during the acute phase.
6. Positive but relatively small elevation in cardiac troponin measured with a conventional assay (i.e. disparity between the
troponin level and the amount of dysfunctional myocardium present).c
7. Recovery of ventricular systolic function on cardiac imaging at follow-up (3–6 months).d
aAcute, reversible dysfunction of a single coronary territory has been reported.
bLeft bundle branch block may be permanent after Takotsubo syndrome, but should also alert clinicians to exclude other cardiomy-
opathies. T-wave changes and QTc prolongation may take many weeks to months to normalize after recovery of LV function.
cTroponin-negative cases have been reported, but are atypical.
dSmall apical infarcts have been reported. Bystander subendocardial infarcts have been reported, involving a small proportion of the
acutely dysfunctional myocardium. These infarcts are insufcient to explain the acute regional wall motion abnormality observed.
Risk stratication: after conrmed or suspected diagnosis of
Takotsubo syndrome, risk stratication is recommended to
guide treatment (Management algorithm;Box 4).
Treatment: a new management algorithm is proposed, based
on risk stratication into higher risk and lower risk pathways
(Management algorithm).
Recurrence: management of recurrent Takotsubo syndrome and
the role of prophylactic treatment are discussed. Currently
no evidence supports prophylactic treatment after the rst
presentation.
Introduction
Takotsubo syndrome is an acute and usually reversible heart failure
syndrome rst described in 1990 which is increasingly recognized
with access to urgent coronary angiography for patients with
acute ‘cardiac’ chest pain.1Since the initial description, the clinical
community has increasingly recognized that this syndrome is dis-
tinct from acute coronary syndrome (ACS), although the initial pre-
sentation has similar features to ST-segment elevation myocardial
infarction (STEMI) or non-ST-segment elevation myocardial infarc-
tion (NSTEMI).210Early access to diagnostic coronary angiog-
raphy has helped identify this condition, and the number of case
reports, series, and registries reported has increased over the last
25 years, offering different insights into this syndrome.11
To date there have been no randomized trials to dene the opti-
mal management of patients with suspected Takotsubo syndrome,
with respect to both diagnosis and treatment. The increasing vari-
ety of clinical contexts in which this syndrome has been described
......................................................................................
implies that multiple pathophysiological processes may converge to
generate a similar clinical phenotype. As a result, clinical decisions
are challenging, and many patients currently receive a ‘default’ ACS
management strategy.
The published literature on Takotsubo syndrome and related
stress-induced cardiac syndromes consists of case reports, case
series, observational cohorts from screening discharge coding
across healthcare networks, and data collected from national
Takotsubo syndrome registries. These registries vary in size but
are generally considered small by contemporary standards (<600
patients). This current published information is level of evidence
C for conventional clinical guidelines. This document is a Position
Statement and not a guideline; current evidence was reviewed
by a group of experts with a specialist interest in Takotsubo syn-
drome who provided their opinion and consensus of the current
best practice for the diagnosis and management of patients with
Takotsubo syndrome.
Nomenclature
Various names have been used to describe the acute appear-
ance now classically described as a ‘Takotsubo cardiomyopathy’
or ‘Takotsubo syndrome’, following the initial label given by Sato
and colleagues in 1990 and 1991, which reects the resem-
blance of the left ventricle at end-systole to the octopus pots of
Japanese sherman in the Hiroshima sh markets.12Many alter-
natives names have been used, including stress or stress-induced
cardiomyopathy,13apical ballooning syndrome,3ampullary-shaped
©2015 The Authors
European Journal of Heart Failure ©2015 European Society of Cardiology
Current state of knowledge on Takotsubo syndrome 5
Ta b l e 1Triggers for secondary Takotsubo syndrome
Endocrine
e.g. Phaeochromocytoma, thyrotoxicosis (endogenous and iatrogenic), SIADH, Addisonian crisis, multiple endocrine neoplasia 2A syndrome,
hyperglycaemic hyperosmolar state, hyponatraemia, severe hypothyroidism, Addison’s disease, adrenocorticotropin hormone deciency,
autoimmune polyendocrine syndrome II
Neurological and neurosurgical
Acute neurosurgical emergencies (e.g. subarachnoid haemorrhage, acute head injury, acute spinal injury)
Acute neuromuscular crises, especially if involving acute ventilatory failure (e.g. acute myasthenia gravis, acute Guillain– Barré syndrome)
Epileptic seizures, limbic encephalitis, ischaemic stroke, posterior reversible encephalopathy syndrome
Respiratory
Acute exacerbation of asthma or COPD (especially with excessive use of inhaled beta2-agonists)
Acute pulmonary embolism
Acute pneumothorax
Obstetric, e.g. miscarriage, labour, emergency Caesarean section
Psychiatric
Acute anxiety attack/panic disorder
Attempted suicide
Drug-withdrawal syndromes
Electroconvulsive therapy
Gastrointestinal, e.g. acute cholecystitis, biliary colic, acute pancreatitis, severe vomiting, severe diarrhoea, pseudomembranous colitis,
peritonitis
Infection
Severe sepsis
Babesiosis
Cardiological
Dobutamine stress echocardiography
Radiofrequency arrhythmia ablation
Pacemaker implantation
Electrical DC cardioversion for atrial brillation
Post-cardiac arrest including ventricular brillation
Haematological
Blood transfusions
Thrombotic thrombocytopenic purpura
Surgical
Many cases have been reported during induction of general anaesthesia or during non-cardiac surgery or interventional procedures under
local or general anaesthesia (e.g. cholecystectomy, hysterectomy, rhinoplasty, Caesarean section, radiofrequency liver ablation,
radiotherapy, colonoscopy, difcult urinary catheterization, carotid endarterectomy)
Medication and illicit drugs
Epinephrine injection
Nortriptyline overdose, venlafaxine overdose, albuterol, ecanide, metoprolol withdrawal, 5-uorouracil, duloxetine
Cocaine abuse
SIADH, syndrome of inappropriate antidiuretic hormone secretion.
cardiomyopathy,14,15and ‘broken heart syndrome’ in the context
of bereavement.16
The authors suggest ‘Takotsubo syndrome’ as a unifying term
for this clinical entity. ‘Takotsubo’ has now become engrained
in both medical literature and teaching, and several Takotsubo
registries have been established.1721Since the diagnosis is cur-
rently based on a series of clinical observations (see below),
there is consensus that it fulls the denition of a clinical syn-
drome. The term ‘cardiomyopathy’ implies a primary disease of
the cardiac muscle and in clinical cardiology is usually applied to
a primary heart muscle disorder of genetic or unknown origin.
Patients with Takotsubo syndrome do not appear to have a pri-
mary muscle disorder, and no common genetic basis has been
.......................................
identied. The full recovery of patients and the low rate of major
adverse cardiac events at follow-up in reported series strongly
suggest that Takotsubo syndrome is different from the primary
cardiomyopathies.
Denition
Takotsubo syndrome and associated variants are a form of acute
and usually reversible heart failure syndrome. It may be a form of
acute catecholaminergic myocardial stunning, as there is no occlu-
sive CAD to explain the pattern of temporary LV dysfunction
observed. Patients with Takotsubo syndrome have typical features
that must be identied to conrm the diagnosis. Several previous
©2015 The Authors
European Journal of Heart Failure ©2015 European Society of Cardiology
6A.R. Lyon et al.
Table 2 Anatomical variants of Takotsubo syndrome
Variant Estimated prevalence
................................................................
Apical with or without MLV variant
(typical)
75– 80%
MLV 10–15%
Inverted or basal 5%
Biventricular Clinical <0.5%; CMR 33%
Right ventricular Unknown
Apical tip sparing Unknown
Possible atypical variants
Global Unknown
Focal Unknown
CMR, cardiac magnetic resonance; MLV, mid-left ventricular;
Table 3 In-hospital and long-term outcome of
Takotsubo syndrome
Complication/outcome Frequency
................................................................
Acute complications
Right ventricular involvement 18– 34%
Acute heart failure 12– 45%
LV outow tract obstruction 10– 25%
Mitral regurgitation 14– 25%
Cardiogenic shock 6 20%
Arrhythmias
Atrial brillation 5– 15%
Ventricular arrhythmias 4– 9%
Bradycardia, asystole 2– 5%
Thrombus formation 2– 8%
Pericardial tamponade <1%
Ventricular wall rupture <1%
In-hospital mortality 1–4.5%
Recurrence 5– 22%
5-year mortality 3– 17%
diagnostic criteria have been proposed, including those by the
Mayo Clinic (modied in 2008), the Japanese Takotsubo Cardiomy-
opathy Group, the Gothenburg Group, and the Takotsubo Italian
Network.4,20,2224
We have reviewed, adapted, and amended these criteria to
generate the new 2015 Heart Failure Association of the Euro-
pean Society of Cardiology (HFA) Takotsubo Syndrome Diagnos-
tic Criteria (Box 1). Although this condition predominantly affects
post-menopausal women (90% of all cases reported, particularly
in larger cohorts), men and younger women can have this condi-
tion. Therefore, these demographic features are not a mandatory
part of the proposed diagnostic criteria. Takotsubo syndrome is
reversible—a critical feature that helps to differentiate it from
many other acute heart failure syndromes. Timelines of recovery
vary depending on the severity of the acute episode. As a guide,
LVEF usually recovers by 12 weeks, but ECG changes and BNP
levels may take 6 12 months to recover and, in some cases, can
remain permanently abnormal, e.g. if myocardial scarring occurs.
........................................................................................................................................................................
Distinguishing Takotsubo syndrome from acute infective
myocarditis can be challenging if there is evidence of acute
myocardial oedema and inammation in a typical anatomical
distribution, as is common during the acute episode of Takotsubo
syndrome (Box 2).2527 This could be considered a form of acute
catecholaminergic myocarditis, given the appearance on T2-STIR
cardiac magnetic resonance (CMR) and the rise in cardiac tro-
ponin. A careful history and other clinical features can normally
differentiate these conditions (e.g. the stressful trigger, if present,
in Takotsubo syndrome vs. the viral prodromal illness with fever
in acute infective myocarditis).28
Another difference from the modied Mayo diagnostic crite-
ria is the inclusion of phaeochromocytoma. In patients with this
condition, and particularly those with an epinephrine-secreting
phaeochromocytoma, acute Takotsubo syndrome may result from
a catecholamine storm, in an analogous manner to a catecholamine
storm after a sudden stressful experience.2934 The pathophys-
iology and clinical phenotype are identical, and therefore the
consensus of the authors was to include patients with phaeochro-
mocytoma but to consider them as cases of secondary Takotsubo
syndrome (Table 1).
Clinical subtypes: primary
and secondary Takotsubo
syndrome
Takotsubo syndrome comes to the attention of medical personnel
in a variety of clinical scenarios and contexts. Cases can be classied
as either primary or secondary Takotsubo syndrome.
Primary Takotsubo syndrome
In primary Takotsubo syndrome, the acute cardiac symptoms are
the primary reason for seeking care, usually from emergency med-
ical services, acute cardiac services, or the primary care physician.
Such patients may or may not have clearly identiable stressful
triggers (often emotional). Potential co-existing medical conditions
may be the predisposing risk factors but are not the primary cause
of the catecholamine rise. These cases can be considered primary
Takotsubo syndrome, and their clinical management depends on
the specic complications.
Secondary Takotsubo syndrome
A substantial proportion of cases occur in patients already hos-
pitalized for another medical, surgical, anaesthetic, obstetric, or
psychiatric condition. In these patients, sudden activation of the
sympathetic nervous system or a rise in catecholamines precipi-
tates an acute Takotsubo syndrome as a complication of the pri-
mary condition or its treatment. We propose that such cases
be diagnosed as secondary Takotsubo syndrome. Their manage-
ment should focus not only on the Takotsubo syndrome and its
cardiac complications but also on the condition that triggered the
syndrome. Examples of medical conditions reported to trigger
secondary Takotsubo syndrome are listed in Table 1.
©2015 The Authors
European Journal of Heart Failure ©2015 European Society of Cardiology
Current state of knowledge on Takotsubo syndrome 7
Box 2 Differences between Takotsubo syndrome and acute
myocarditis
Category Takotsubo syndrome Acute myocarditis
Gender and age 90% female. Majority >50 years and
post-menopausal.
No sex prevalence. More frequent in the young.
Preceding events Stressor trigger identiable in 70% of
cases.
Symptoms and signs of infection often present (fever,
chills, headache, muscle aches, general malaise, cough,
nausea, vomiting, diarrhoea).
Cardiac symptoms Chest pain, dyspnoea, palpitations. Chest pain, dyspnoea, peripheral oedema, fatigue, and
palpitations.
Clinical signs Pericardial rub rare. Pericardial rub may be present.
ECG at admission ST changes such as ST-segment elevation
or non ST-segment elevation. Deep T
wave inversion. QT prolongation. Rarely
normal.
ST-segment elevation or depression, negative T-wave,
bundle branch block, atrioventricular block, low voltage,
and/or ventricular arrhythmias. Normal in several cases.
Cardiac enzymes Low/moderate troponin rise. Discrepancy
between the large amount of
dysfunctional myocardium and peak
troponin level.
Frequently signicant troponin rise, proportional to the
hypokinetic area. Normal in several cases.
Other biomarkers C-reactive protein (CRP) mildly elevated
unless infective trigger. BNP moderately
or signicantly elevated.
Erythrocyte sedimentation rate and CRP elevated. BNP
basically elevated. Acute viral serology may be detected.
Echocardiography Apical ballooning, anatomical variants,
‘circumferential pattern’, left ventricular
outow tract obstruction (LVOTO),
right ventricular (RV) involvement,
transient mitral regurgitation.
Localized or diffuse wall motion abnormalities of LV
and/or RV dilatation, increased wall thickness,
pericardial effusion.
Cardiac magnetic
resonance imaging
High T2 signal intensity (oedema), late
gadolinium enhancement (LGE) usually
absent acutely. If present acutely patchy
LGE which usually resolves at follow-up.
Absence of typical infarct LGE pattern.
High T2 signal intensity (oedema), LGE with
non-ischaemic distribution (often epicardial). Absence
of typical infarct LGE pattern.
Histological ndings Contraction band necrosis. Inltration of many inammatory cells. Interstitial oedema.
Viral genome, separation
of virus, or
identication of virus
by antibody titre
Rare and usually absent where measured. Often positive.
Prognosis 50% of cases have acute complications,
4–5% mortality.
Variable but majority full recovery. Highest mortality with
fulminant myocarditis.
Therapy Supportive. Supportive. Immunosuppression in severe cases if giant
cell myocarditis suspected.
Anatomical variants
Primary and secondary Takotsubo syndromes encompass an array
of anatomical variants (Table 2;Figure 1).35 37 The initial report
of Takotsubo syndrome described what is now considered the
classical pattern: LV regional wall motion abnormality (RWMA)
with apical and circumferential mid-ventricular hypokinesia and
basal hypercontractility. At end-systole, the left ventricle typically
resembles the ‘Takotsubo’ with a narrow neck and globular lower
portion, giving the appearance of virtual apical ballooning. This
............................
typical variant with apical dysfunction is present in 50– 80% cases,
depending on the series.
Two other variants are common: the inverted Takotsubo or
basal variant, with circumferential basal hypokinesia and apical
hypercontractility, also referred to as the ‘nutmeg’ or ‘artichoke’
heart; and the mid left ventricular (MLV) variant, with circum-
ferential mid-ventricular hypokinesia and both basal and apical
hypercontractility.38 40 The end-systolic appearance of the MLV
variant has been likened to a Greek vase or the ace of spades; how-
ever, the basal variant can also resemble the ace of spades (Figure 1).
©2015 The Authors
European Journal of Heart Failure ©2015 European Society of Cardiology
8A.R. Lyon et al.
Figure 1Anatomical variants of Takotsubo syndrome. (A) Ventriculographic appearances showing paired end-diastolic image (above) and
end-systolic image (below) of a mid-ventricular variant (A and B), an inverted Takotsubo variant (C and D), and a typical apical Takotsubo
variant (E and F). Adapted from Haghi et al.138 (B) Cardiac magnetic resonance (CMR) appearances showing paired acute end-diastolic (left),
acute end-systolic (centre), and follow-up end-systolic (right) images for typical apical Takotsubo syndrome (top row), mid-ventricular variant
(middle row), and inverted Takotsubo variant (lower row) (reproduced from Eitel et al.35). (C) Biventricular involvement with LV and RV apical
hypokinesia. White arrows highlight regions of hypokinesia in the end-systolic four-chamber view (adapted from Haghi et al.36).
©2015 The Authors
European Journal of Heart Failure ©2015 European Society of Cardiology
Current state of knowledge on Takotsubo syndrome 9
In both of these variants, reversible LV dysfunction affects more
than one coronary territory, usually in a circumferential pattern,
in the absence of culprit CAD. Rarer variants include biventricu-
lar apical dysfunction, dysfunction sparing the apical tip (possibly a
form of MLV Takotsubo), and isolated right ventricular (RV) Takot-
subo syndrome.36,4143
The affected LV segments may recover at different rates, a pos-
sible explanation for the various anatomical variants observed.
Intriguingly, Takotsubo syndrome may recur as a different anatom-
ical variant in the same patient, suggesting that a person can be
susceptible to more than one subtype.44,45
Epidemiology
Several series of Asian and Western (predominantly Caucasian)
populations suggest that 12% of patients with suspected ACS
are eventually diagnosed with Takotsubo syndrome.7,37 In those
series, the incidence of Takotsubo syndrome was probably under-
estimated. The possibility of pre-hospital sudden cardiac death
from Takotsubo syndrome was not considered and, with increasing
awareness and more widespread access to early coronary angiog-
raphy, Takotsubo syndrome is now recognized more frequently.
The largest reported cohorts are from the Nationwide Inpatient
Sample (NIS-USA). However, these reports were based on ICD-10
(International Disease Classication 10th Revision) discharge cod-
ing, with no uniform system for ensuring correct diagnosis or esti-
mating the number of cases missed. This registry represents 20%
of all US non-federal community hospitals. The rst NIS-USA study
reported data on 6837 patients with Takotsubo syndrome from
2008.46 The second NIS-USA study reported data from 24 701
patients from 2008– 2009; it appears to be a 24-month data set,
but may include patients in the rst study.47 These numbers imply
that there are 50 000– 100 000 cases per annum in the USA, with
similar estimated numbers in Europe.
In the rst study, Takotsubo syndrome was diagnosed in 0.02%
of all acute hospitalizations (6837/33 506 402 patients).46 The
majority (90%) were elderly post-menopausal women (66–80
years of age), a demographic repeated across many published
cohorts. The risk factors included smoking, alcohol abuse, anxiety
states, and hyperlipidaemia. The second study, and largest cohort
to date, reported details of 24 701patients with a discharge
code for Takotsubo syndrome. The demographics were similar
to those in the rst study: 89% were women, the mean age was
66.9 ±30.7 years, and most patients (59.6%) were 65 years old.47
Gender differences
Takotsubo syndrome occurs predominantly in post-menopausal
women. The German Takotsubo syndrome registry includes 324
patients; 91% are female (mean age 68±12 years) and 9% are male
(mean age 66 ±12 years). The demographic and clinical charac-
teristics were similar in men and women.17However, emotional
stress or the absence of identiable triggers was more common
in women. Conversely, a physical stressful triggering event, shock,
or resuscitation on presentation was more common in men, who
also had higher levels of cardiac biomarkers (troponin). In the larger
........................................................................................................................................................................
of the two NIS-USA cohorts, the mortality rate was higher in men
(8.4% vs. 3.6%, P<0.0001), perhaps reecting the higher frequency
of underlying severe critical illness and secondary Takotsubo syn-
drome (36.6% in men vs. 26.8% in women, P<0.0001).47
Age
Elderly patients are considered to be at higher risk of Takotsubo
syndrome and related major complications, and <10% of patients
are below 50 years of age.46,48 In the Takotsubo Italian Network,
Takotsubo syndrome patients older than 65 years have a greater
prevalence of hypertension and cerebrovascular disease, a lower
glomerular ltration rate, and a lower LVEF at discharge compared
with younger patients. Older adults (75 years) have higher rates
of in-hospital complications and in-hospital mortality (6.3% vs. 2.8%
overall in-hospital mortality).18
Pathophysiology
The pathophysiology of Takotsubo syndrome is complex and
reects the integrated and systemic physiological responses to
acute, severe stress and the cardiovascular responses to sud-
den surges in endogenous or exogenously administered cate-
cholamines. The pathophysiology has been extensively reviewed
elsewhere.10,4952
Catecholamines appear to have a central role in the patho-
physiology of Takotsubo syndrome, as the trigger is often a sud-
den, unexpected stress; signs of sympathetic activation are present
at presentation, and secondary medical triggers can also lead to
extreme sympathetic activation. There are two initial elements of
the physiology to consider. The rst is the cognitive centres of
the brain and hypothalamic– pituitary– adrenal (HPA) axis, and how
much epinephrine and norepinephrine are released in response to
a given stress (i.e. the ‘gain’ of the HPA axis). The second is the
response of the cardiovascular system (including the myocardium,
coronary arteries, and peripheral vasculature) and the sympathetic
nervous system to the sudden sympathetic activation and surge in
circulating catecholamines.
Serum catecholamine levels at presentation are signicantly
higher than resting levels in the same patient or in comparable
patients with acute heart failure due to acute myocardial infarction
(MI), suggesting the potential for excessive HPA gain and
epinephrine release.53 Iatrogenic Takotsubo syndrome has been
reported after administration of sympathomimetic drugs (e.g.
dobutamine in stress echocardiography).54
Several hypotheses have been proposed to explain the unique
cardiac appearance in Takotsubo syndrome and the cardiac
response to severe stress. These hypotheses can be broadly
divided into vascular and myocardial causes (Box 3) and may not be
mutually exclusive, as the entire cardiovascular system is exposed
to the same catecholamine storm. Many of these hypotheses are
still being investigated, as there is no current proven pathophysio-
logical mechanism to explain Takotsubo syndrome. There may be a
synergistic combination of more than one factor, and mechanistic
studies have yielded conicting results.
©2015 The Authors
European Journal of Heart Failure ©2015 European Society of Cardiology
10A.R. Lyon et al.
Box 3 Summary of
pathophysiological hypotheses
Vascular Acute multivessel coronary spasm.
Aborted myocardial infarction with
spontaneous recanalization.
Acute increased ventricular afterload.
Myocardial Acute left ventricular outow tract
obstruction.
Direct catecholamine-mediated
myocardial stunning.
Vascular and
myocardial
Integrated cardiovascular physiology (a
cardio-circulatory syndrome).
Genetic susceptibility
The stressful trigger implies that the pathophysiology of Takot-
subo syndrome has a strong environmental component. However,
it is conceivable that some people have a genetic predisposition to
stress-induced Takotsubo syndrome. Although the syndrome is not
considered a primary genetic cardiomyopathy, a number of stud-
ies have explored the possibility of genetic risk factors. A genetic
predisposition has been suggested based on the few familial Takot-
subo syndrome cases described.5558 Conicting results have been
published regarding the presence or absence of functional poly-
morphisms in relevant candidate genes, such as 𝛼1-, 𝛽1-, and
𝛽2-adrenergic receptors, GRK5, and oestrogen receptors. These
studies had relatively small numbers of subjects. Resolving these
conicts will require high-quality phenotyping, identication of can-
didate genes, and sharing of high-number/high-quality data in a
Takotsubo syndrome network.
Clinical presentation
and diagnosis
The typical patient with primary Takotsubo syndrome is a
post-menopausal women who has experienced severe, unexpected
emotional or physical stress.4This may be unheralded or on the
background of elevated levels of stress or anxiety, including in
some cases a formal diagnosis of anxiety or panic disorder.46,59
However, most patients do not have prior history of stress-related
psychological conditions. Nevertheless, it is important to remem-
ber that 10% of cases in the largest reported series (NIS-USA)
were men or younger women, and 30–35% of cohort series
report classical cases in patients with no identiable stressful
trigger.46 Thus, gender, menopausal status, and stressful triggers
are not mandatory features and are not included in our HFA
diagnostic criteria.
Patients with Takotsubo syndrome typically present with acute
chest pain of cardiac origin (angina), breathlessness, and palpi-
tations due to sinus tachycardia or arrhythmia; in more severe
cases, pre-syncope or syncope due to ventricular tachyarrhyth-
mias, severe left ventricular outow tract obstruction (LVOTO), or
........................................................................................................................................................................
cardiogenic shock may be present. Patients may describe a wave
of pressure from the chest to the neck and into the head, con-
sistent with the acute catecholamine and hypertensive surge and
frequently associated with diaphoresis and heightened anxiety.
Such patients should prompt urgent clinical evaluation and rapid
acquisition of a resting 12-lead ECG. These ndings should activate
an ACS treatment pathway according to the ESC guidelines and,
where appropriate, urgent coronary angiography60 (see Diagnostic
algorithm). Coronary computed tomography angiography (CCTA)
may be considered in stable cases, particularly if the patient is
pain free and cardiac imaging (e.g. echocardiography) shows typical
features of Takotsubo syndrome.61
Once the diagnosis of Takotsubo syndrome is suspected in the
catheterization laboratory, early cardiac imaging and assessment
of cardiac biomarkers can help exclude MI and further stratify
risk. Given the spectrum of clinical and anatomical patterns, the
presence or absence of stressful triggers, and the potential pres-
ence of CAD or prodromal viral illnesses, borderline cases exist
(see Diagnostic algorithm). In such cases, CMR imaging with late
gadolinium enhancement (LGE) may be helpful.35,36 CMR is also
complementary to echocardiography to detect complications and
aid risk stratication, and has better sensitivity for detecting LV
apical thrombus.
Secondary Takotsubo syndrome
in specic clinical settings
Takotsubo syndrome can complicate a wide variety of acute
medical and surgical conditions, including elective non-cardiac
procedures (see ‘Secondary Takostubo syndrome’ and Table 1).
Iatrogenic causes during catecholamine administration (e.g. dobu-
tamine stress echocardiography) have also been reported. There-
fore, clinicians should be alert to Takotsubo syndrome in numerous
clinical settings, including the acute medical unit, endocrinol-
ogy ward, neurology ward, anaesthetic room, intensive care
units (including the neuro-intensive care unit), obstetric unit, and
psychiatric ward.
Takotsubo syndrome can be fatal because of mechanisms dis-
cussed below (see ‘Complications and acute prognosis’). Many
of these complications can be readily detected post-mortem in
a conrmed case of Takotsubo syndrome. More difcult is the
case of sudden non-hospital cardiac death in a patients with a
stressful precipitant and a structurally normal heart and coronary
arteries.62 These cases may have medico-legal or criminal implica-
tions, for example where sudden death occurs during restraint in
police custody or in the psychiatric department. A more precise
set of histopathological criteria is needed to help in post-mortem
evaluation and diagnosis of Takotsubo syndrome as a cause of
stress-induced sudden death.
Diagnostic investigations
Biomarkers
Cardiac troponin measured by conventional assays (not high sen-
sitivity) is elevated in >90% of patients with Takotsubo syndrome.
©2015 The Authors
European Journal of Heart Failure ©2015 European Society of Cardiology
Current state of knowledge on Takotsubo syndrome 11
However, the rise in serum troponin or creatinine kinase is dis-
proportionately low relative to the extent of RWMA and car-
diac dysfunction (i.e. widespread segmental akinesia/hypokinesia
of >5 segments and frequently >9 segments in the 17-segment
model).48
During the acute phase of Takotsubo syndrome, serum car-
diac natriuretic peptides (BNP or NT-proBNP) are almost
always elevated, frequently to extremely high levels that corre-
late more closely with the degree of ventricular wall motion
abnormality.6366 The limited evidence to date suggests that BNP
and NT-proBNP are more useful diagnostic biomarkers than
troponin, and it is recommended that they be measured in all
suspected cases if the assay is available. Since normal levels are
extremely rare in Takotsubo syndrome, an elevated natriuretic
peptide level is included in the new diagnostic criteria (Box 1).
NT-proBNP is a valuable marker of myocardial deterioration and
recovery. Low NT-proBNP at admission may reliably indicate a
favourable prognosis and hence is included in our proposed risk
stratication criteria (Box 4).
Other biomarkers have been reported in research studies
but are not currently recommended in routine practice. Serum
catecholamines (epinephrine, norepinephrine, and dopamine),
neuropeptide-Y, and serotonin are typically elevated in Takotsubo
syndrome.53 Catecholamine levels are two to three times higher
in patients with Takotsubo syndrome than in those with acute
MI (Killip class III) at admission. This nding was reinforced by
another study, although not all patients presented with elevated
serum catecholamines.5,67 In a recent study, the prole of circu-
lating microRNAs (small non-coding RNA sequences) differed in
Takotsubo syndrome and STEMI patients,68 supporting a different
pathophysiology and the potential for developing future diagnostic
biomarkers.
Electrocardiography
Abnormalities on ECG are present in >95% of Takotsubo syn-
drome patients during the acute phase.7,48,6971Daily ECGs are
helpful, as a typical evolution has now been dened, and the poten-
tial for worsening of the QT interval is important in risk stratica-
tion and may help distinguish Takotsubo syndrome from STEMI.72
However ECG criteria alone are not sufcient to differentiate
Takotsubo syndrome from STEMI.73
The ECG abnormalities during the acute phase (<12h) are
ST-segment elevation, ST-segment depression, new LBBB, and
sometimes Q-waves, with deep and widespread T-wave inversion
and signicant QT prolongation developing 24 –48 h after the onset
of symptoms or the precipitating stressful trigger (when present).70
If presentation is delayed, T-wave inversion and QTc prolongation
without ST segment elevation might be observed. The QTc pro-
longation is often pronounced (>500 ms), predisposing to torsades
de pointes and ventricular brillation.17,70 Signicant QTc prolon-
gation is seldom seen in STEMI caused by coronary occlusion and
may help to differentiate the two conditions retrospectively; how-
ever, it should not be used for prospective diagnosis. A minority of
Takotsubo syndrome patients may present with a normal ECG, but
this is atypical.
........................................................................................................................................................................
Box 4 Heart Failure Association
risk stratication in Takotsubo
syndrome
Risk factor Higher risk Lower risk
.........................................................
MAJOR RISK FACTORS
Age 75 years See minor risk
factorsa
Systolic BP <110 mmHg 110 mmHg
Clinical pulmonary
oedemab
Present Absent
Unexplained
syncope, VT or VF
Present Absent
LVEF <35% See minor risk
factorsa
LVOTO 40 mmHg Absent or <40
mmHg
Mitral regurgitationcPresent Absent
Apical thrombus Present Absent
New VSD or
contained
Present Absent
LV wall rupture
MINOR RISK FACTORS
Age 7075 years <70 years
ECG
QTc 500 ms <500 ms
Pathological Q
waves
Present Absent
Persistent ST
elevationd
Present Absent
LVEF 3545% 45%
Physical stressor Present Absent
Natriuretic peptides
BNP 600 pg/mL <600 pg/mL
NT-proBNP 2000 pg/mL NT-proBNP
<2000 pg/mL
Bystander
obstructive CAD
Present Absent
Biventricular
involvement
Present Absent
BP, blood pressure; LVOTO, left ventricular outow tract
obstruction; VF, ventricular brillation; VSD, ventricular septal
defect; VT, ventricular tachycardia.
aSee minor criteria regarding LVEF in the absence of major
criteria.
bLower zone (basal) pulmonary rales on clinical examination
or evidence on chest X-ray.
cModerate or severe mitral regurgitation.
d3days.
©2015 The Authors
European Journal of Heart Failure ©2015 European Society of Cardiology
12A.R. Lyon et al.
Coronary angiography and left
ventriculography
Most Takotsubo syndrome patients should have urgent coronary
angiography to exclude STEMI or NSTEMI because they present
with cardiac chest pain and have ST elevation or other changes
that could be interpreted as an ACS. In Takotsubo syndrome, the
epicardial coronary arteries are typically normal and unobstructed;
however, given the predilection for older patients, bystander CAD
can be present. If so, it is important to consider whether the CAD
is sufcient to cause the degree or pattern of LV dysfunction.
Several studies reviewing cohorts of Takotsubo syndrome patients
report bystander CAD in up to 10% of cases.74,75 Although not
causative, bystander CAD is a risk factor for more severe heart
failure during the acute episode (Box 4). Intravascular ultrasound
studies have demonstrated that plaque rupture or intracoro-
nary thrombosis is not present in Takotsubo syndrome.76 Once
causative coronary occlusion, including acute plaque rupture,
thrombus formation, and coronary dissection, has been excluded,
ventriculography should be performed unless there is a con-
traindication, since ventriculography will frequently be diagnostic
for Takotsubo syndrome. This is important as the wall motion
abnormalities may recover in hours and may be missed if imaging
is delayed. The typical pattern of wall motion abnormality is the
apical and mid-wall hypokinesis that earned this condition its
original ‘Takotsubo’ label. However, other anatomical variants may
occur (see ‘Anatomical variants’; Figure 1;Table 2).
Echocardiography
Transthoracic echocardiography with colour and tissue Doppler
should be the rst non-invasive imaging technique to verify
a suspected diagnosis of Takotsubo syndrome. Transthoracic
echocardiography can assess LV morphology and function, iden-
tify anatomic variants, detect potential complications (e.g. LVOTO,
mitral regurgitation, RV involvement, thrombus formation, and
cardiac rupture), and monitor recovery.77 79 Key echocardio-
graphic features during the acute phase consist of a large area
of dysfunctional myocardium extending beyond the territory of a
single coronary artery and usually characterized by symmetrical
regional abnormalities involving the mid-ventricular segments of
the anterior, inferior, and lateral walls (a circumferential pattern).77
Among 227 patients enrolled in the Takotsubo Italian Network,
low LVEF, elevated E/e’ ratio, reversible moderate-to-severe mitral
regurgitation, and age 75 years correlated independently with
major adverse events (acute heart failure, cardiogenic shock, and
in-hospital death).80
Cardiac magnetic resonance
Cardiac magnetic resonance provides 3D anatomical information
that can distinguish Takotsubo syndrome from other cardiac dis-
eases and can help to elucidate its cause and pathophysiology.35 It
can accurately assess both LV and RV regional function and demon-
strate the typical patterns of RWMA (Figure 1;Table 2). Takotsubo
syndrome involves the right ventricle in up to one-third of patients,
........................................................................................................................................................................
and CMR often provides more complete views of the right ventricle
than echocardiography.35 CMR is superior to echocardiography in
detecting apical LV thrombi, and patients with large areas of apical
akinesia may benet from CMR if echocardiography is unclear.81
During the acute phase of Takotsubo syndrome, T2-weighted
CMR shows oedema of the LV myocardium as high signal intensity,
with a diffuse or transmural distribution consistent with the wall
motion abnormality. These features help distinguish Takotsubo
syndrome from myocarditis and acute MI.25 28,82
Typically, LGE is usually absent in Takotsubo syndrome and its
absence is an important distinguishing feature from MI.35 It is
controversial, however, whether minor LGE may be present in
some patients with Takotsubo syndrome during the acute phase
but absent at follow-up CMR. The frequency of LGE depends on
the threshold of signal intensity used to dene its presence.83,84
Atypical cases with small areas of persistent apical transmural LGE
have been reported.
If available, CMR should be considered in all patients with
suspected Takotsubo syndrome in the acute phase (within 7 days).
If availability is limited, it should be reserved for borderline and
indeterminate cases (see Diagnostic algorithm). It is also useful
to conrm recovery of ventricular function on follow-up and to
exclude MI or other conditions that can mimic acute Takotsubo
syndrome.
Coronary computed tomography
angiography
In diagnosing Takotsubo syndrome, it is essential to exclude coro-
nary occlusion and signicant coronary stenosis. This evaluation
is usually done invasively, as the patient typically presents with
a clinical picture closely resembling that of acute MI. However,
for a delayed presentation (>48 h after chest pain starts and the
patient is pain free at the time of presentation) or for retrospective
evaluation of a patient with the typical history of Takotsubo syn-
drome weeks or months previously, coronary stenoses can also be
excluded by CCTA (Box 4). Acquiring information throughout the
cardiac cycle (spiral or helical acquisition mode) during the acute
phase can also demonstrate the typical pattern of systolic dysfunc-
tion but at the price of a higher radiation exposure.85
Currently there is no evidence for delaying invasive coronary
angiography in patients with ongoing acute chest pain and acute
ECG changes. The ESC guidelines for STEMI or ACS should be
followed until culprit CAD has been excluded.60,86
Radionuclide imaging
The role of radionuclide imaging in the diagnosis and management
of Takotsubo syndrome is undetermined. When CMR is unavail-
able, myocardial perfusion scintigraphy may help exclude infarc-
tion in uncertain cases, and there are reports of normal or mildly
reduced perfusion in the dysfunctional segments, but out of keeping
with the scale of contractile dysfunction.87 89
Iodine-123 meta-iodo-benzyl-guanidine (mIBG) has been used
to image myocardial sympathetic nerve terminal activity and to
©2015 The Authors
European Journal of Heart Failure ©2015 European Society of Cardiology
Current state of knowledge on Takotsubo syndrome 13
detect adrenal or ectopic phaeochromocytoma, which may be clin-
ically relevant in these patients, although its precise role remains
to be determined. During the acute phase, there is reduced
mIBG in the dysfunctional myocardial segments, consistent with
a regional disturbance of sympathetic neuronal activity.87,89 The
abnormalities can persist for several months, and mIBG scintig-
raphy may have a role in cases without a diagnosis or when the
presentation is remote from an acute episode (Box 4). Ideally,
mIBG imaging should be combined with myocardial perfusion
scintigraphy to exclude infarction; it is unknown whether per-
sisting innervation abnormalities or increased mIBG washout,
reecting increased sympathetic tone, provides prognostic
information.
Cardiac positron emission tomography using [18F]2-uoro-
deoxy-glucose has shown abnormal glucose metabolism in the con-
text of normal myocardial perfusion in patients with Takotsubo
syndrome; however, it currently has been used only in a research
context.88,90
Complications and acute prognosis
Takotsubo syndrome has generally been regarded as a relatively
benign disease with rapid recovery of LV function. However,
growing evidence suggests it is a more serious acute cardiac
disorder with a variety of complications in 52% of patients
(Table 3).80,91,92
Acute heart failure
Systolic heart failure is the most common complication in the
acute phase of Takotsubo syndrome, occurring in 1245% of
cases.4,6,7,17,80,92 Independent predictors of acute heart failure
are advanced age, low LVEF at presentation, higher admission
and peak troponin levels, and a physical stressor preceding the
onset of symptoms. Mechanical ventilation, inotropic support, and
intra-aortic balloon pumping have been required in a substantial
number of cases (28, 38, and 17%, respectively).93 In some patients,
pulmonary oedema due to acute LV dysfunction is exacerbated by
mitral regurgitation, LVOTO, or both.
Left ventricular outow tract obstruction
During the acute phase, a dynamic intraventricular pressure gra-
dient due to mitral valve systolic anterior motion may develop as
a consequence of myocardial stunning of the apical segments and
hypercontraction of the basal LV myocardium. Signicant LVOTO
with gradients of 20140 mmHg have been observed in 10 25%
of patients, often accompanied by mitral regurgitation.7,80,94 A
mid-ventricular or LVOTO gradient >25 mmHg is considered
haemodynamically signicant, and a gradient 40 mmHg is a
high-risk factor. Abnormal Q waves, hypotension, and cardiogenic
shock are more frequent in these patients. Use of inotropic drugs
or nitrates may exacerbate LVOTO, whereas beta-blockade with
propranolol decreases the gradient.95,96 Normally LVOTO resolves
spontaneously over a few days.
........................................................................................................................................................................
Mitral regurgitation
Acute mitral regurgitation is another potentially serious compli-
cation, occurring in 14– 25% of patients.97,98 LVEF is lower and
pulmonary artery pressure is higher in patients with signicant
regurgitation, who present more often with acute heart failure or
cardiogenic shock. Two independent mechanisms may cause acute
mitral regurgitation: systolic anterior motion of the mitral valve
in association with dynamic LVOTO and apical tethering of the
subvalvular mitral valve apparatus.98,99 In most cases, the mitral
regurgitation decreases as LV function returns to normal, although
recovery may be slower than in patients without acute mitral
regurgitation.
Cardiogenic shock
Cardiogenic shock, primarily due to acute LV dysfunction, occurs
in 420% of patients with Takotsubo syndrome and may be exac-
erbated by RV involvement, LVOTO, or acute mitral regurgitation.
Echocardiography may identify the mechanism and help guide ther-
apy. The mortality due to cardiogenic shock in Takotsubo syndrome
is high (1730%).6,80,91,92,100
Arrhythmias
Arrhythmias are common in patients with Takotsubo syndrome.
New AF has been reported in 5– 15% of cases.6,92,101,102 This
arrhythmia further reduces cardiac output and is often asso-
ciated with the onset of heart failure. Ventricular arrhythmias
occur in 49% of patients during the acute phase of the
syndrome,6,92,101103 causing cardiac arrest in 4–6% of cases.
In rare instances, ventricular arrhythmias have been documented
weeks after the rst manifestation of Takotsubo syndrome,
when LV function had already normalized. Bradycardia due to
atrioventricular block and asystole has also been described.92
Thrombus formation
Thrombus in the akinetic ventricular apex is observed in 2–8%
of Takotsubo syndrome patients, occasionally resulting in stroke
or arterial embolism.92,104,105 Best visualized by CMR imaging in
early post-contrast acquisition sequences, most thrombi develop
25 days after symptom onset, when LV function is still depressed.
However, new thrombus formation and subsequent embolism have
also been described 14 days after symptom onset, when LV systolic
function had already returned to normal. LV thrombi may resolve
with 2 weeks of therapeutic anticoagulation, but a longer course
(usually 3 months) should be considered, and follow-up imaging
is advisable to conrm recovery of apical contractile function.106
Prophylactic anticoagulation in higher risk Takotsubo syndrome
cases has an as yet undetermined role but may be considered (see
Management algorithm for higher risk individuals).
Pericardial effusion
Acute pericarditis with recurrent chest pain, reappearance
of ST-segment elevation, and a small amount of pericardial
©2015 The Authors
European Journal of Heart Failure ©2015 European Society of Cardiology
14A.R. Lyon et al.
effusion has been observed in some patients during the recov-
ery phase of Takotsubo syndrome.107 CMR imaging early after
admission has detected small pericardial effusions in 43% of
patients. Pericardial tamponade requiring pericardiocentesis is rare
(0.05%).108
Ventricular wall rupture
Serious mechanical complications, including ventricular free wall
rupture or interventricular septal perforation, are rare (<1%); they
occur 28 days after symptom onset, often with persistent ST
elevation.92,109,110A high outow tract gradient may favour rupture
of the LV free wall. One case of RV rupture has been described.
Interventricular septum perforation and acquired ventricular septal
defect can complicate Takotsubo syndrome and may be successfully
treated by surgery.111,112
Right ventricular involvement
Patients with biventricular involvement generally have a more
severe clinical course. RV involvement assessed by echocardiog-
raphy or magnetic resonance imaging has been reported (18–34%
cases) and is associated with older age, lower LVEF, a higher fre-
quency of heart failure, pleural effusion, and a longer hospital
stay.92,113Rarely, a pressure gradient or an apical thrombus may
be present in the right ventricle.
Mortality during the acute episode
In large studies and registries of Takotsubo syndrome patients,
the in-hospital mortality rate is 25%; death is mainly caused
by refractory cardiogenic shock or ventricular brillation.80,91,92
In a meta-analysis of 2120 patients in 37 studies, the in-hospital
mortality rate was 4.5%,114consistent with the 4.2% in-hospital
mortality reported in the large NIS-USA Takotsubo syndrome
cohorts.46,47
Recurrence
Data on recurrence of Takotsubo syndrome are limited by the
relatively short observation period in most studies. Five-year
recurrence rates of 5–22% have been reported, with the second
episode occurring 3 months to 10 years after the rst.4,6,22,100
Recurrence of a different anatomical variant has been reported.
Prognosis should be individualized according to the likelihood of
recurrence, the triggering event, and co-existing medical condi-
tions. If a patient has a recurrence, long-term clinical follow-up
should be considered (see Management algorithm).
Long-term prognosis
There are conicting reports and data regarding the long-term sur-
vival of patients after their initial episode of Takotsubo syndrome.
In two studies, 4-year survival was not different from that of an
age- and gender-matched population.115,116However, in two other
........................................................................................................................................................................
studies, survival at 3 years was signicantly lower than that of
a matched general population.100,117In the prospective SWEDE-
HEART registry, 3-year mortality was similar to that of NSTEMI
and STEMI controls, and these results have recently been con-
rmed by data from the INTER-TAK registry.91,118Excess mortality
occurs predominantly in the rst 4 years after diagnosis and is
related to non-cardiac illnesses such as malignancy.116,119Data on
the long-term prognosis of patients with Takotsubo syndrome are
limited.
Most patients recover rapidly after the acute episode and have
no symptoms. However, there is increasing evidence that physio-
logical abnormalities persist after resting contractile abnormalities
have returned to normal ‘macroscopically’, and some patients have
persistent cardiac symptoms after the acute episode,116includ-
ing angina, exertional breathlessness, palpitation, and a tremu-
lous anxiety state, perhaps reecting heightened sympathetic tone.
Although the coronary arteries are unobstructed and ventricu-
lar function has recovered macroscopically, it is helpful to doc-
ument objective evidence of ongoing cardiac abnormalities to
reassure the patient and to guide treatment. Twenty-four-hour
Holter ECG monitors to identify atrial arrhythmias or inappro-
priate sinus tachycardia (continuous or paroxysmal) may be help-
ful, and 24-h ambulatory blood pressure monitoring may detect
transient and inappropriate hypertensive episodes. Persistent ECG
changes and sometimes other evidence of autonomic disturbance
can provide objective evidence and exclude non-cardiac explana-
tions for ongoing symptoms. The absolute frequency of incomplete
recovery is not well reported, and management of these patients
requires specialist care.
Clinical management (see
Diagnostic algorithm
and Management algorithm)
General considerations
There are no randomized clinical trials to support specic treat-
ment recommendations in Takotsubo syndrome. A key feature of
Takotsubo syndrome is recovery of normal cardiac function. The
major objective of in-hospital treatment should be supportive care
to sustain life and to minimize complications during recovery. In
mild cases, no treatment or a short course of limited medical ther-
apy may be sufcient. In severe cases complicated by progressive
circulatory failure and cardiogenic shock, early mechanical support
should be considered as a ‘bridge-to-recovery’.
Diagnostic and management algorithms have been generated to
help guide clinical decision-making. Risk stratication is essential to
select treatment for patients at greatest risk of complications and
to minimize interventions in patients at low risk where evidence for
treatment is lacking. Given the lack of evidence from randomized
controlled trials, the diagnostic and management algorithms are
based on expert consensus and require validation in prospective
trials. One over-riding consideration in a condition with a high
rate of functional recovery is to respect the fundamental ethical
principle in medicine: primum non nocere (rst, do no harm).
©2015 The Authors
European Journal of Heart Failure ©2015 European Society of Cardiology
Current state of knowledge on Takotsubo syndrome 15
Once the diagnosis is conrmed, it may be helpful to enquire
about previous episodes of unexplained chest pain, and in particular
hospital admissions for chest pain or MI. In some cases, the index
presentation is clearly a recurrence of Takotsubo syndrome (see
‘Prevention of recurrence’).
In diagnosing borderline cases, it may be helpful to review
the history to identify stressful triggers or co-existing medical
conditions that may lead to sudden rises in sympathetic neural
activity and systemic catecholamine levels. If the diagnosis is still
uncertain, cardiac mIBG may be considered to evaluate regional
myocardial sympathetic innervation and tone. It may be necessary
to reserve judgement until follow-up imaging at 3 months conrms
recovery of any RWMA present during the acute phase and claries
the presence or absence of permanent LGE by CMR.
Risk stratication
Takotsubo syndrome has been generally regarded as a relatively
benign disease with rapid recovery of LV function. However, a vari-
ety of complications occur in 52% of the patients (Table 3).80,91,92
After diagnosis, we recommend that patients with Takotsubo syn-
drome be triaged according to the risk stratication system shown
in Box 4 and the Management algorithm. Higher risk is dened as
the presence of at least one major or two minor risk factors, with
clinical judgement based on their severity.
Given the high risk of complications, where possible all patients
with Takotsubo syndrome should be admitted to a coronary care
unit or high-dependency unit with ECG monitoring for the rst
24 h while the investigations and risk stratication are completed.
Patients considered at higher risk of in-hospital mortality should
be monitored in a high-dependency or coronary care unit. Patients
at lower risk may be transferred to wards with lower levels of
monitoring and potentially discharged early. Risk is a continuous
variable and may change as new risk factors are identied. This risk
stratication system is a clinical tool to guide clinicians caring for
patients with Takotsubo syndrome. However, given the absence of
randomized trial evidence, it does not replace clinical judgement.
Validation of the risk stratication algorithm requires a prospective
study, and therefore this proposal is currently based on expect
opinion (level of evidence C).
Management of lower risk cases
of Takotsubo syndrome
In milder cases with an LVEF >45% and no complications, the
patient may be considered for early discharge from hospital.
Before discharge, however, a review of medication is recom-
mended, as many patients will have been started on treatment for
ACS before coronary angiography, and indications for antiplatelet
agents and statins should be reviewed. If LVEF is 3545% but
the patient is otherwise at lower risk, heart failure medications
including beta-blockers should be considered. In pre-clinical stud-
ies, metoprolol and carvedilol have been benecial, and these
beta-blockers could be used unless contraindicated (e.g. reversible
airways disease).120,121Some experts suggest that vasoactive drugs,
........................................................................................................................................................................
including ACE inhibitors, should be avoided in patients with normal
cardiac output, as some Takotsubo syndrome patients may have
altered peripheral sympathetic nerve activity associated with low
peripheral vascular resistance.
Takotsubo syndrome patients in the lower risk category should
be followed for 3–6 months after discharge. The follow-up should
include review of medications and cardiac imaging to conrm
recovery of the RWMA.
Management of higher risk cases
of Takotsubo syndrome
General considerations
Takotsubo syndrome cases meeting the criteria for higher risk
should be monitored in a level 2 environment (e.g. coronary
care unit or high-dependency unit) with continuous ECG mon-
itoring and access to resuscitation equipment for at least 72h
after presentation, when risk of life-threatening complications is
greatest.92 The opinion of a specialist (e.g. cardiologist with a
special interest in heart failure) should be sought where avail-
able. Patients with decreased cardiac output should be consid-
ered for regular echocardiographic monitoring. Cessation of drugs
with sympathomimetic properties is advised (e.g. catecholamines,
beta2-agonists). Beta-blockers may be considered in haemodynam-
ically stable patients and in patients with atrial or ventricular tach-
yarrhythmias. In patients with haemodynamically signicant LVOTO
(LVOTO >40 mmHg and systolic blood pressure <110 mmHg),
treatment with a beta-blocker or selective alpha1-agonist (e.g.
phenylephrine) should be considered. Short-acting intravenous
beta-blockers are preferred acutely, providing no contraindications
exist. If any clinical features suggest phaeochromocytoma, appro-
priate diagnostic studies should be performed before beta-blocker
treatment is started.
In patients with Takotsubo syndrome complicated by cardio-
genic shock, continuous haemodynamic monitoring may help guide
treatment selection. In more severe cases of cardiogenic shock
with progressive end-organ dysfunction, avoidance or withdrawal
of exogenous catecholamines is recommended, as they probably
exacerbate or prolong the acute phase. Treatment options include
mechanical support for acute cardiogenic shock, such as tem-
porary LV assist devices (LVADs) and extracorporeal membrane
oxygenation (ECMO) (see below), or, if those options are not avail-
able, low-dose levosimendan infusion as a catecholamine-sparing
positive inotrope. No evidence currently exists to guide treat-
ment choice in these complex patients, and new trial evidence
is required. Expert consensus suggests that unstable patients
with low cardiac output and cardiogenic shock be managed in
a high-dependency unit (level 2) or intensive care unit (level 3)
and that early LVAD or ECMO support be considered. The
use of inotropes (e.g. dobutamine, norepinephrine, epinephrine,
dopamine, milrinone, and isoproterenol) should be generally
regarded as contraindicated in Takotsubo syndrome,122 as further
activation of catecholamine receptors or their downstream molec-
ular pathways might worsen the clinical status and prognosis of
patients with Takotsubo syndrome and cardiogenic shock.120,123,124
©2015 The Authors
European Journal of Heart Failure ©2015 European Society of Cardiology
16A.R. Lyon et al.
Mechanical support
Intra-aortic balloon counterpulsation (IABP) has been used to
treat cardiogenic shock due to Takotsubo syndrome. However,
in light of recent neutral data from the IABP-SHOCK II trial and
the fact that IABP may worsen dynamic LVOTO, the consensus
viewpoint is to avoid use of IABP in Takotsubo syndrome patients.
If a patient with primary Takotsubo syndrome is deteriorating
and has a low cardiac output, cardiogenic shock, and progressive
multiorgan failure, specialist advice about ECMO or LVAD as
a bridge-to-recovery is recommended, as there is an excellent
chance that ventricular function will recover fully.125 128 In cases
of secondary Takotsubo syndrome complicated by cardiogenic
shock, the nature, severity, and prognosis of the underlying medical
condition will determine whether mechanical cardiac support is
warranted during the acute phase.
Levosimendan
The role of levosimendan is more controversial, with mixed
expert opinion based on pre-clinical and limited clinical
experience.120,129 133 In the absence of access to emergency
mechanical support, levosimendan may be preferable to other
inotropes such as dobutamine and epinephrine in patients who
have advancing cardiogenic shock and multiorgan failure. Prospec-
tive randomized studies are required to assess the safety and
efcacy of levosimendan in patients with Takotsubo syndrome and
acute heart failure.
Access to all these advanced care options may vary and depend
upon local expertise.
Preventing thrombo-embolism
Takotsubo syndrome may be associated with blood hyperco-
agulability reecting the vasoconstrictor, platelet activation, or
prothrombotic effects of high catecholamine levels.134 Thrombo-
embolism is a complication in 4% of Takotsubo syndrome
patients. Many patients with Takotsubo syndrome will initially
receive antithrombotic treatment for suspected STEMI including
dual antiplatelet therapy (aspirin and P2Y12receptor antagonists)
and unfractionated or low-molecular-weight heparin. Once MI is
excluded, consensus supports withdrawal of P2Y12receptor antag-
onists (clopidogrel, prasugrel, and ticagrelor).
Oral anticoagulation is recommended if intraventricular throm-
bus is detected in a patient with Takotsubo syndrome in the
absence of high bleeding risk. Apical thrombus resolution and LV
function recovery should be documented before anticoagulation
is withdrawn. The role of prophylactic anticoagulation remains to
be determined. Therapeutic low-molecular-weight heparin should
be considered in cases with extensive segmental akinesia or atrial
brillation.
Follow-up after hospital discharge
Regardless of the severity of their acute episode, all patients should
be offered a follow-up assessment at 3–6 months. It should include
........................................................................................................................................................................
repeat cardiac imaging to conrm the resolution of the acute
RWMA and ECG changes observed and to exclude MI by CMR with
LGE if not performed during the acute admission and in borderline
cases. A review of medication will ensure that any drug therapy
for ACS has been stopped. If LV function has recovered, weaning
from the ACE inhibitor and beta-blocker can be considered in the
absence of other indications.
There is currently no evidence to guide the long-term man-
agement of patients after an episode of Takotsubo syndrome.
Some patients have persistent cardiac symptoms after LVEF and
RWMA have normalized,135 including chest pain, palpitations, and
exertional breathlessness. Further investigations to dene the
cause and treatment are advised, as ongoing cardiac abnormalities
(e.g. microvascular perfusion abnormalities, atrial arrhythmias) may
arise months or years after the acute episode.
Given the high risk of complications during the acute phase,
patients with recurrent episodes of Takotsubo syndrome may
warrant long-term follow-up to identify strategies to minimize or
prevent further recurrence (see below).
Preventing recurrence
Prevention of recurrent Takotsubo syndrome has not been demon-
strated in any study. Intuitively, beta-blockers may provide some
protection against future catecholamine surges. However, recur-
rences have been reported in patients taking beta-blockers, and
one meta-analysis found no impact of beta-blockers on the
risk of recurrence, although recurrence was infrequent in both
arms.136,137 Nevertheless, there may be a role for beta-blockers
in selected patients, such as those with evidence of persistently
elevated sympathetic tone, ongoing cardiac symptoms (not clini-
cally recovered), and persistent anxiety and those with recurrent
Takotsubo syndrome.
There is evidence that anxiety states are more frequent in
some patients with Takotsubo syndrome. Given the high fre-
quency of stressful triggers in cases of primary Takotsubo syn-
drome, the psychological response to stress is another potential
therapeutic target. The benet of psychological counselling and
cognitive behavioural therapy remains to be determined, but they
may have a role in selected cases of recurrence triggered by emo-
tional stressors and in cases of conrmed anxiety disorder.
Late-presenting cases (Box 5)
Some patients have delayed access to medical care or request a
retrospective assessment of ‘troponin-positive chest pain episodes
with normal coronary arteries’ lacking a diagnosis. A careful review
of the history and risk factor prole may alter the probability that
the episode in question was an acute Takotsubo syndrome (Box 5).
Review of ECGs and cardiac biomarkers, if available, may aid
detection of the classical features that discriminate Takotsubo syn-
drome from ACS. Cardiac imaging, including echocardiography and
CMR with LGE, helps exclude MI and other possible conditions.
The role of cardiac mIBG is exploratory and may help demon-
strate regional abnormalities of cardiac sympathetic innervation in
©2015 The Authors
European Journal of Heart Failure ©2015 European Society of Cardiology
Current state of knowledge on Takotsubo syndrome 17
Box 5 Heart Failure Association
management strategy for
late-presenting Takotsubo
syndrome cases and
retrospective review
Late or retrospective review:
Review history
Review risk factors
Review ECGs
Review cardiac biomarker prole (serum natriuretic peptides
and troponin) from acute episode
Consider:
Cardiac MRI +LGE (exclude MI, HCM)
CCTA (exclude obstructive CAD)
Cardiac mIBG
CCTA, coronary computed tomography angiography; HCM,
hypertrophic cardiomyopathy; LGE, late gadolinium enhance-
ment; MI, myocardial infarction; mIBG, iodine-123 meta-iodo-
benzyl-guanidine; MRI, magnetic resonance imaging.
a classical anatomical pattern and in the absence of infarction or
alternative explanation.
Conclusion and future directions
Takotsubo syndrome is a fascinating acute heart failure syndrome,
now increasingly recognized by the medical community. Many facets
of this condition are incompletely understood or characterized,
and current knowledge to guide optimal clinical management is
limited. However, the increasing incidence and the high frequency
of complications during the acute phase underpin the need to
improve care pathways for patients with Takotsubo syndrome.
To date, clinical reports are mostly based on relatively small
cohorts and case series. Therefore, the recommendations of
this Position Statement reect the consensus of expert opinion
(level of evidence C). Randomized controlled trials are needed to
identify optimal diagnostic and management strategies for Takot-
subo syndrome. The potential for national and international reg-
istries to collect larger numbers of patients prospectively should
aid understanding of the epidemiology and natural history. Takot-
subo syndrome networks may also provide the infrastructure
for research studies and, in particular, given the lack of current
evidence-based treatments, for assessing novel therapeutic strate-
gies. Individual hospitals may see no more than 5–30 cases per
annum, and broader networks are required to collect larger num-
bers of patients. Several countries have started to co-ordinate data
collection in regional or national registries, and one international
registry, the InterTAK registry (NCT01947621), has been launched
to gather 10-year follow-up data on a large cohort of prospectively
enrolled patients with conrmed Takotsubo syndrome.
........................................................................................................................................................................................................................
This is the rst Position Statement from the ESC Heart Fail-
ure Association for this acute heart failure syndrome. It will be
updated when further advances in the understanding and manage-
ment of Takotsubo syndrome are available, and particularly when
results from randomized controlled trials are available to provide
a stronger evidence base for clinical decision-making.
Conict of interest: none declared.
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... Takotsubo syndrome (TTS) is a transient but severe myocardial dysfunction, which leads to acute heart failure with the absence of a significant epicardial coronary artery disease [1]. It was originally introduced by Sato et al. in 1990 and has been increasingly recognized. ...
... The diagnosis of focal TTS is much more difficult. LGE-CMR is always required to exclude acute myocardial infarction and myocarditis [1,5,15]. For patients who could not undergo CAG, CCTA, MCE or LGE-CMR, a marked discrepancy between the transient circumferential RWMAs and troponin level is used as the hallmark of TTS, indicating the absence of epicardial coronary artery obstruction [1,15]. ...
... LGE-CMR is always required to exclude acute myocardial infarction and myocarditis [1,5,15]. For patients who could not undergo CAG, CCTA, MCE or LGE-CMR, a marked discrepancy between the transient circumferential RWMAs and troponin level is used as the hallmark of TTS, indicating the absence of epicardial coronary artery obstruction [1,15]. ...
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Background Myocardial dysfunction is common in septic shock and has long been recognized. Takotsubo syndrome is an acute and usually reversible myocardial injury without evidence of an obstructive coronary artery disease, yet little is known about this syndrome in septic shock patients. Case presentation Among 84 septic shock patients admitted to the ICU over a period of 8 months, 7 patients (8.3%) were diagnosed with Takotsubo syndrome. The percentage of men was 71%, and the mean age was 58 (19–87) years. Sudden hemodynamic deterioration and/or dyspnea were the presenting symptoms in 6 patients. T-wave inversion was the major ECG anomaly in 5 patients. The mean left ventricular ejection fraction was 31.8% (20.0–53.0). Mild elevation of cardiac troponin disproportionate to the extent of regional wall motion abnormalities was present in all patients. Cardiac complications occurred in 6 patients. The mean time to recover the cardiac function was 6.5 (3–11) days. In-hospital death was observed in 2 patients. Conclusions Takotsubo syndrome is not uncommon in septic shock patients and may be the cause of some patients with sepsis-induced myocardial dysfunction. New-onset hemodynamic and respiratory worsening could arouse the suspicion of Takotsubo syndrome and prompt the screening for this syndrome using echocardiography in this clinical context.
... Diagnostic work-up for stress cardiomyopathy usually involves electrocardiogram, cardiac biomarkers, coronary angiography, and echocardiography or ventriculography [3]. The electrocardiogram is abnormal in greater than 95% of patients and usually shows signs of ischemia [6]. One review by Templin et al. analyzed 1,750 patients in The International Takotsubo Registry and reported elevated troponin in 87%, elevated brain natriuretic peptide in 82.9%, ST-segment elevation in 43.7%, and reduced left ventricular ejection fraction (LVEF) in 86.5% of patients [2]. ...
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Stress cardiomyopathy is a reversible cause of cardiomyopathy characterized by a transient dysfunction in left ventricular systolic function. It is most common in postmenopausal women and usually occurs following an emotional and/or physical stressor. The classical imaging finding is described as left ventricular apical ballooning. However, several rare variants have been reported with a strikingly different regional distribution of wall motion abnormalities. We describe a case of a 65-year-old female who was found to have stress cardiomyopathy with variant wall motion abnormality on the left ventriculogram without a preceding stressor event. We postulate that there may be a link between stress-induced cardiomyopathy without a preceding stressor event and variant wall motion abnormality patterns.
... Takotsubo syndrome (TTS), previously known as Takotsubo cardiomyopathy or stress cardiomyopathy, is an acute and reversible heart failure that typically occurs after a period of intense emotional or physical stress; symptoms include chest pain and dyspnea and, as a result, can mimic an acute coronary syndrome (1). However, no culprit macrovascular pathology can be found on coronary angiography and a diagnosis of TTS is made due to the observation of the characteristic hypocontractile apex coupled to a hypercontractile base, although variants on this pattern have been observed, e.g., midventricular or basal hypocontractility and also right ventricular involvement (2,3). ...
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Takotsubo syndrome is a well-characterized cause of acute yet reversible heart failure associated with periods of intense emotional stress, often mimicking on presentation an acute coronary syndrome. Animal models of Takotsubo syndrome have been developed, either through the application of a stressor, or administration of exogenous catecholamine. We found that in a model of isoproterenol-induced Takotsubo syndrome in anesthetized rats hyperthermia (40–41°C) would occur after the administration of isoproterenol. Maintenance of this hyperthermia would result in an apical hypocontractility typical of the syndrome, whereas prevention of hyperthermia with active cooling to maintain a euthermic core body temperature prevented (but did not subsequently reverse) apical hypocontractility. In vitro experimentation with isolated cardiomyocytes showed no effect of hyperthermia on either baseline contractility or contractility change after beta-adrenoceptor stimulation. We suggest that the rise in body temperature that is characteristic of catecholamine storm may be a component in the development of Takotsubo syndrome.
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Cancer patients receiving chemotherapy and immunotherapy, particularly those receiving anthracyclines, are at an increased risk of developing cardiovascular complications. Immunotherapy is associated with a spectrum of side effects termed “immune-related adverse events” that include dermatologic, gastrointestinal, hepatic, and endocrine events. Temporary immunosuppression with glucocorticoids, tumor necrosis factor alpha antagonists, and mycophenolate mofetil can be effective in most cases. Immunotherapy-related cardiotoxicity is rare but can have serious consequences for patients. In fact, it includes myocarditis (with impaired ventricular function and heart failure), pericarditis, arrhythmias, noninflammatory ventricular dysfunction (Takotsubo cardiomyopathy), vasculitis, and venous thromboembolism. The mechanisms underlying these complications are not well known, and the few data that are available come from case reports and small retrospective studies. In general, the treatment of these complications is the same as that used in the general population, i.e., according to the guidelines of the International Societies of Cardiology. The aim of this chapter is to describe in detail the management of oncologic patients affected by immunotherapy cardiotoxicity.
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The discovery of immune checkpoint inhibitors (ICIs) as antineoplastic therapies revolutionized the field of oncology, improving the prognosis of different cancers at the cost of possible adverse events, mostly based on immune activation against normal tissues. Most common immune-related adverse events (irAEs) are cutaneous, endocrinological, pulmonary, and gastrointestinal. Cardiovascular irAEs are much less frequently reported but burdened by higher mortality rates. ICI-related cardiotoxicity includes myocarditis, pericardial diseases and, to a lesser extent, the Takotsubo syndrome, arrhythmias, acute coronary syndromes, and vasculitis. The first action recommended for the majority of suspected cardiovascular irAE is the prompt discontinuation of the ICIs and timely administration of high doses of corticosteroids, even if immunosuppressive therapy doesn’t always succeed to reverse cardiological toxicities. Different types of cardiotoxicity can also occur with cell-based immune-therapy treatments (e.g., CAR-T), requiring specific diagnosis and management protocols. Because of the high morbidity and mortality, an early diagnosis of cardiological irAEs is essential for framing the optimal management within an expert multidisciplinary approach for the therapeutic decision-making.
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Takotsubo (stress) cardiomyopathy (TCM) is usually triggered by psychological and/or physical stress. Most often, it is seen in postmenopausal women. Cases of TCM related to pregnancy are rare. We present a unique case of a 35-year-old, two-day postpartum female who was diagnosed with TCM.
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Background: Takotsubo syndrome (TTS) is an important type of acute heart failure with significant risk of acute complications and death. In this analysis we sought to identify predictors for in-hospital clinical outcome in TTS patients and present long-term outcomes. Methods: In this analysis from the Austrian national TTS registry, univariable and multivariable analyses were performed to identify significant predictors for severe in-hospital complications requiring immediate invasive treatment or leading to irreversible damage, such as cardiogenic shock, intubation, stroke, arrhythmias and death. Furthermore, the influence of independent predictors on long-term survival was evaluated. Results: A total of 338 patients (median age 72 years, 86.9% female) from six centers were included. Severe in-hospital complications occurred in 14.5% of patients. In multivariable analysis, high neutrophile-lymphocyte-ratio (NLR; OR 1.04 [95% CI 1.02–1.07], p = 0.009) and low LVEF (OR 0.92 [0.90–0.95] per %, p < 0.001) were significant predictors of severe in-hospital complications. Both the highest NLR tercile and the lowest LVEF tercile were significantly associated with reduced 5-year survival. Conclusions: Low LVEF and high NLR at admission were independently associated with increased in-hospital complications and reduced long-term survival in TTS patients. NLR is a new easy-to-measure tool to predict worse short- and long-term outcome after TTS.
Article
Background Complete heart block is considered a unique and rare complication of Takotsubo cardiomyopathy, an otherwise self-resolving disease. When this occurs, there is a double clinical dilemma: first to find out which triggered the other and second, to decide whether or not to implant a permanent pacemaker. Case presentation We present a case of a 77 years-old female patient, with previous medical history of arterial hypertension, diabetes mellitus, dyslipidemia and bifascicular block known since 2013. She came to the emergency department after recurrent syncopal episodes. At admission a complete heart block was diagnosed, and it was implanted a single chamber temporary pacemaker. The patient remained in disproportional acute decompensated heart failure despite pacemaker implantation. She denied chest pain although referring an episode of self-limiting chest pain 2 days before, after an argument with the family. Blood analysis showed an important rise in NTproBNP and troponin levels. Transthoracic echocardiogram showed a dilated left ventricle with akinesia of apical and mid segments, hyperkinesia of basal segments and severely depressed left ventricle ejection fraction. Coronary angiography showed no significant lesions and the diagnosis of Takotsubo cardiomyopathy was suspected. During the following days, she recovered her own intrinsic rhythm. Electrocardiogram evolved with deep T-wave inversion and prolonged QT interval and transthoracic echocardiogram showed resolution of the previous alterations. Despite complete reversion of rhythm alteration, it was decided to implant a permanent pacemaker. Conclusions We describe a rare, life-threatening and often underdiagnosed complication of the stress cardiomyopathy. Furthermore, we performed a literature revision of this rare complication and discussed the therapeutic challenge encountered in such patients.
Article
Broken Heart Syndrome also known as Takotsubo cardiomyopathy is principally characterized by left ventricular hypokinesis and wall motion abnormalities. These abnormalities usually include apical wall motion defects during the systolic phase of heart contraction. To avoid complications and mortality, early recognition and treatment of Broken Heart are significant.
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The natural history, management, and outcome of takotsubo (stress) cardiomyopathy are incompletely understood. The International Takotsubo Registry, a consortium of 26 centers in Europe and the United States, was established to investigate clinical features, prognostic predictors, and outcome of takotsubo cardiomyopathy. Patients were compared with age- and sex-matched patients who had an acute coronary syndrome. Of 1750 patients with takotsubo cardiomyopathy, 89.8% were women (mean age, 66.8 years). Emotional triggers were not as common as physical triggers (27.7% vs. 36.0%), and 28.5% of patients had no evident trigger. Among patients with takotsubo cardiomyopathy, as compared with an acute coronary syndrome, rates of neurologic or psychiatric disorders were higher (55.8% vs. 25.7%) and the mean left ventricular ejection fraction was markedly lower (40.7±11.2% vs. 51.5±12.3%) (P<0.001 for both comparisons). Rates of severe in-hospital complications including shock and death were similar in the two groups (P=0.93). Physical triggers, acute neurologic or psychiatric diseases, high troponin levels, and a low ejection fraction on admission were independent predictors for in-hospital complications. During long-term follow-up, the rate of major adverse cardiac and cerebrovascular events was 9.9% per patient-year, and the rate of death was 5.6% per patient-year. Patients with takotsubo cardiomyopathy had a higher prevalence of neurologic or psychiatric disorders than did those with an acute coronary syndrome. This condition represents an acute heart failure syndrome with substantial morbidity and mortality. (Funded by the Mach-Gaensslen Foundation and others; ClinicalTrials.gov number, NCT01947621.).
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In patients with heart failure (HF) due to coronary disease, a combined evaluation of perfusion and glucose metabolism by cardiac single photon emission computed tomography (SPECT)/positron emission tomography (PET) can be used to distinguish viable from non-viable myocardium, and current guidelines recommend cardiac SPECT and fluorodeoxyglucose (FDG) PET for viability assessment. Takotsubo cardiomyopathy (TTC) is a disease characterized by acute but reversible HF leaving no scarring. To explore how robust the semi-quantitative viability criteria used in cardiac SPECT and FDG PET stands their ground in a population with TTC. From 1 September 2009 to 1 October 2012, 24 patients suspected of TTC were enrolled in a multimodality cardiac imaging research project. Echocardiography, (99m)Tc SPECT, and (18)F FDG PET were performed during the acute admission and at follow-up 4 months later. Nineteen patients had a final diagnosis of TTC consistent with Mayo Clinic Diagnostic Criteria. Three of these patients were excluded from further analysis, since wall motion abnormalities were not persistent at the time of nuclear imaging. The remaining sixteen patients exhibited a distinct pattern with HF, "apical ballooning" and a perfusion-metabolism defect in the midventricular/apical region. When viability criteria were applied, they identified significant scarring/limited hibernation in the akinetic part of the left ventricle. However, full recovery was found in all TTC patients on follow-up. Using the current guideline-endorsed viability criteria for semiquantitative cardiac SPECT and FDG PET, these modalities failed to demonstrate the presence of viability in the acute state of TTC.
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Case. A 64-year-old Caucasian woman was brought to the emergency department with severe dysphagia and left chest pain for last 4 days. Initial evaluation revealed elevated ST segment in precordial leads on EKG with elevated cardiac enzymes. Limited echocardiogram showed infra-apical wall hypokinesia. Cardiac angiography was done subsequently which showed nonflow limiting mild coronary artery disease. Takotsubo cardiomyopathy was diagnosed and she was treated medically. On the third day of admission, a repeat ECG showed diffuse convex ST-segment elevations in precordial leads, compatible with acute pericarditis pattern of EKG. Decision was made to start colchicine empirically for possible pericarditis. Follow-up EKG in 2 days showed decreased ST-segment elevations in precordial leads. The patient was discharged with colchicine and a follow-up echocardiogram in 4 weeks demonstrated a normal ejection fraction with no evidence of pericarditis. Conclusion. Acute pericarditis can be associated either as a consequence of or as a triggering factor for Takotsubo cardiomyopathy. It is vital for physicians to be aware of pericarditis as a potential complication of Takotsubo cardiomyopathy.
Article
Objective: This study evaluated the frequency, severity and outcome of complications in the clinical course of tako-tsubo cardiomyopathy (TTC). Background: TTC is regarded as a benign disease since left ventricular (LV) function returns to normal within a short time. However, severe complications have been reported in selected patients. Methods: From 37 hospitals, 209 patients (189 female, age 69 ± 12 years) were prospectively included in a TTC registry. Results: Complications developed in 108/209 patients (52%); 23 (11%) had >2 complications. Complications occurred median 1 day after symptom onset, and 77% were seen within 3 days. Arrhythmias were documented in 45/209 patients (22%) including atrial fibrillation in 32 (15%) and ventricular tachycardia in 17 (8%). Of 8 patients resuscitated (4%), 6 survived. Additional complications were right ventricular involvement (24%), pulmonary edema (13%), cardiogenic shock (7%), transient intraventricular pressure gradients (5%), LV thrombi (3%) and stroke (1%). During hospitalization, 5/209 patients (2.5%) died. Patients with complications were older (70 ± 13 vs 67 ± 10 years, p=0.012), had a higher heart rate (91 ± 26 vs 83 ± 19/min, p=0.025), more frequently Q\ waves on the admission ECG (36% vs 21%, p=0.019) and a lower LV ejection fraction (47 ± 15 vs 54 ± 14%, p = 0.002). Multivariate regression analysis identified Q-waves on admission (OR 2.49, 95% CI 1.23-5.05, p=0.021) and ejection fraction ≤ 30% (OR 4.03, 95% CI 1.04-15.67, p=0.022) as independent predictors for complications. Conclusions: TTC may be associated with severe complications in half of the patients. Since the majority of complications occur up to day 3, monitoring is advisable for this time period.
Article
Background Efficacy of chronic drug therapy in prevention of stress-induced cardiomyopathy recurrences is not well established. We therefore aimed to evaluate in this meta-analysis whether pharmacological treatment can effectively prevent takotsubo cardiomyopathy (TTC) recurrences, according to available studies.HypothesisThere is no evidence for preventing TTC recurrence by drug therapy.Methods After a PubMed search, we conducted a meta-analysis of available studies (clinical nonrandomized registries) on efficacy of drug therapy in preventing recurrence of TTC.ResultsA total of 23 (4.5%) TTC recurrences occurred in the 511 patients included in the analysis. Seven studies on the effects of β-blockers on prevention of TTC recurrence were evaluated; the odds ratio (OR) was 0.44 and the 95% confidence interval (CI) was 0.15-1.31. In 5 studies on the effects of angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, the OR was 0.42 and the 95% CI was 0.08-2.36; in 3 studies on statins, the OR was 0.74 and the 95% CI was 0.07-7.3; and in 4 studies on aspirin, the OR was 0.33 with a 95% CI of 0.05-2.17 (P value not significant in all cases).ConclusionsA meta-analysis of the efficacy of different medications through the clinical TTC registries available showed no clinical evidence for a standard drug treatment in the chronic management of TTC. β-Blockers, angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, statins, and aspirin do not seem to significantly reduce recurrences of TTC. Randomized, adequately powered studies are needed to further assess this issue.