InternationalExpertConsensusDocument onTakotsuboSyndrome ... · The clinical expert consensus statement on takotsubo syndrome (TTS) part II focuses on the diagnostic workup, outcome,

International Expert Consensus Document

on Takotsubo Syndrome (Part II) Diagnostic

Workup Outcome and Management

Jelena-Rima Ghadri1 Ilan Shor Wittstein2 Abhiram Prasad3 Scott Sharkey4

Keigo Dote5 Yoshihiro John Akashi6 Victoria Lucia Cammann1 Filippo Crea7

Leonarda Galiuto7 Walter Desmet89 Tetsuro Yoshida10 Roberto Manfredini11

Ingo Eitel12 Masami Kosuge13 Holger M Nef14 Abhishek Deshmukh3

Amir Lerman3 Eduardo Bossone15 Rodolfo Citro15 Takashi Ueyama16dagger

Domenico Corrado17 Satoshi Kurisu18 Frank Ruschitzka1 David Winchester19

Alexander R Lyon2021 Elmir Omerovic2223 Jeroen J Bax24 Patrick Meimoun25

Guiseppe Tarantini17 Charanjit Rihal3 Shams Y-Hassan26 Federico Migliore17

John D Horowitz27 Hiroaki Shimokawa28 Thomas Felix Luscher2930 and

Christian Templin1

International Experts Jeroen J Bax Eduardo Bossone Victoria Lucia Cammann

Rodolfo Citro Domenico Corrado Filippo Crea Walter Desmet Ingo Eitel

Leonarda Galiuto Jelena-Rima Ghadri Thomas Felix Luscher Alexander R Lyon

Roberto Manfredini Patrick Meimoun Federico Migliore Holger M Nef

Elmir Omerovic Frank Ruschitzka Guiseppe Tarantini Christian Templin

Shams Y-Hassan (European sites) Abhishek Deshmukh Amir Lerman

Abhiram Prasad Charanjit Rihal Scott Sharkey David Winchester

Ilan Shor Wittstein (USA sites) Yoshihiro John Akashi Keigo Dote

Masami Kosuge Satoshi Kurisu Hiroaki Shimokawa Takashi Ueyama

Tetsuro Yoshida (Asian sites) John D Horowitz (Australian site)

1University Heart Center Department of Cardiology University Hospital Zurich Zurich Switzerland 2Department of Medicine Johns Hopkins University School of MedicineBaltimore MD USA 3Division of Cardiovascular Diseases Mayo Clinic Rochester MN USA 4Cardiovascular Research Division Minneapolis Heart Institute FoundationMinneapolis MN USA 5Department of Cardiology Hiroshima City Asa Hospital Hiroshima Japan 6Division of Cardiology Department of Internal Medicine St MariannaUniversity School of Medicine Kawasaki Japan 7Department of Cardiovascular Sciences Catholic University of the Sacred Heart Rome Italy 8Department of CardiovascularMedicine University Hospitals Leuven Leuven Belgium 9Department of Cardiovascular Sciences University of Leuven Leuven Belgium 10Department of CardiovascularMedicine Onga Nakama Medical Association Onga Hospital Fukuoka Japan 11Clinica Medica Department of Medical Sciences University of Ferrara Ferrara Italy 12UniversityHeart Center Luebeck Medical Clinic II Department of Cardiology Angiology and Intensive Care Medicine University of Luebeck Luebeck Germany 13Division of CardiologyYokohama City University Medical Center Yokohama Japan 14Department of Cardiology University Hospital Giessen Giessen Germany 15Heart Department UniversityHospital ldquoSan Giovanni di Dio e Ruggi drsquoAragonardquo Salerno Italy 16Department of Anatomy and Cell Biology Wakayama Medical University School of Medicine Wakayama

The opinions expressed in this article are not necessarily those of the Editors of the European Heart Journal or of the European Society of Cardiology

This paper was guest edited by Bernard J Gersh (Mayo Clinic gershbernardmayoedu)

Corresponding author Tel thorn41 44 255 9585 Fax thorn41 44 255 4401 Email christiantemplinuszchdagger Deceased

VC The Author(s) 2018 Published by Oxford University Press on behalf of the European Society of CardiologyThis is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (httpcreativecommonsorglicensesby-nc40)which permits non-commercial re-use distribution and reproduction in any medium provided the original work is properly cited For commercial re-use please contactjournalspermissionsoupcom

European Heart Journal (2018) 39 2047ndash2062 CONSENSUS PAPERdoi101093eurheartjehy077

Downloaded from httpsacademicoupcomeurheartjarticle-abstract392220475025411by Tohoku University useron 14 June 2018

Japan 17Department of Cardiac Thoracic and Vascular Sciences University of Padua Medical School Padova Italy 18Department of Cardiovascular Medicine HiroshimaUniversity Graduate School of Biomedical and Health Sciences Hiroshima Japan 19Division of Cardiovascular Disease Department of Medicine University of Florida GainesvilleFL USA 20NIHR Cardiovascular Biomedical Research Unit Royal Brompton Hospital London UK 21National Heart and Lung Institute Imperial College London UK22Department of Cardiology Sahlgrenska University Hospital Gothenburg Sweden 23Department of Molecular and Clinical Medicine Institute of Medicine SahlgrenskaAcademy Gothenburg University Gothenburg Sweden 24Department of Cardiology Leiden University Medical Center Leiden The Netherlands 25Department of Cardiologyand Intensive Care Centre Hospitalier de Compiegne Compiegne France 26Department of Cardiology Karolinska University Hospital Huddinge Stockholm Sweden27Department of Cardiology Basil Hetzel Institute Queen Elizabeth Hospital University of Adelaide Adelaide Australia 28Department of Cardiovascular Medicine TohokuUniversity Graduate School of Medicine Sendai Japan 29Center for Molecular Cardiology Schlieren Campus University of Zurich Zurich Switzerland and 30Department ofCardiology Royal Brompton amp Harefield Hospital and Imperial College London UK

Received 1 June 2017 revised 23 November 2017 editorial decision 30 January 2018 accepted 11 April 2018 online publish-ahead-of-print 29 May 2018

The clinical expert consensus statement on takotsubo syndrome (TTS) part II focuses on the diagnostic workup outcome andmanagement The recommendations are based on interpretation of the limited clinical trial data currently available and experience ofinternational TTS experts It summarizes the diagnostic approach which may facilitate correct and timely diagnosis Furthermorethe document covers areas where controversies still exist in risk stratification and management of TTS Based on available data thedocument provides recommendations on optimal care of such patients for practising physicians

Keywords Takotsubo syndrome bull Broken heart syndrome bull Acute heart failure bull Consensus statement bull Diagnosticalgorithm

Outline

Diagnostic workup 2048Electrocardiogram 2048

ST-segment elevation 2049T-wave inversion and QT interval prolongation 2049Other electrocardiographic findings 2050

InterTAK Diagnostic Score 2050Biomarkers 2051

Markers of myocardial necrosis 2051B-type natriuretic peptide and N-terminal prohormone of brainnatriuretic peptide 2051Other potential biomarkers 2051

Imaging 2051Coronary angiography and ventriculography 2051Echocardiography 2051Cardiac computed tomography angiography 2052Cardiac magnetic resonance imaging 2053Cardiac nuclear imaging 2053

Perfusion imaging 2053Metabolic imaging 2053Sympathetic nervous imaging 2053

Complications and outcomes 2053Arrhythmias 2055

Ventricular arrhythmias 2055Other cardiac arrhythmias 2055

Recurrence 2055Therapeutic management 2056

Pre-hospital treatment 2056Acute treatment 2056Long-term treatment 2057

Future directions 2058Key questions 2058Prospective approaches 2058

References 2058

Diagnostic workup

A diagnostic algorithm for takotsubo syndrome (TTS) is proposed bythe expert committee (Figure 1) Patients presenting with ST-segmentelevation should undergo urgent coronary angiography (CAG) withleft ventriculography to exclude acute myocardial infarction (AMI) Inpatients with non ST-segment elevation the InterTAK DiagnosticScore can be considered While an InterTAK Score lt_70 points sug-gests a low to intermediate probability of TTS a score gt_70 indicates ahigh probability for the presence of TTS Patients with a low probabil-ity should undergo CAG with left ventriculography while in patientswith a high score transthoracic echocardiography (TTE) should beconsidered In the absence of a circumferential ballooning patternCAG is recommended In stable patients with circumferential balloon-ing pattern coronary computed tomography angiography (CCTA) isfavoured to exclude coronary artery disease (CAD) In unstable pa-tients typical complications of TTS such as left ventricular outflowtract obstruction (LVOTO) should be determined with TTE andCAG to safely rule out AMI In patients with normal coronaries onCCTA or CAG and typical ballooning patterns without lsquored flagsrsquo ofacute infectious myocarditis TTS is the most likely diagnosis and canbe confirmed after follow-up echocardiography In case of positivelsquored flagsrsquo of acute infectious myocarditis cardiac magnetic resonance(CMR) should be performed to confirm the diagnosis

ElectrocardiogramThe initial electrocardiogram (ECG) is abnormal in most patients withTTS usually demonstrating ischaemic ST-segment elevation T-waveinversion or both1ndash4 In the InterTAK Registry ST-segment elevationwas present in 44 ST-segment depression in 8 T-wave inversionin 41 and left bundle branch block in 52 As in acute coronarysyndrome (ACS) the ECG in TTS demonstrates temporal evolutiontypically with resolution of initial ST-segment elevation (if present) fol-lowed by progressive T-wave inversion and QT interval prolongation

2048 J-R Ghadri et al

over several days with subsequent gradual resolution of T-wave in-version and QT interval prolongation over days to weeks5ndash8 The ini-tial and subsequent ECG findings are influenced by several variablesincluding the geographic pattern of left ventricular (LV) ballooningpresence or absence of right ventricular (RV) ballooning time fromsymptom onset to presentation presence of myocardial oedema andrecovery rate of myocardial cellular function

ST-segment elevation

As with ST-segment elevation myocardial infarction (STEMI) the loca-tion and extent of ST-segment elevation in TTS corresponds to theanatomic location of myocardial injury most often the mid and apicalLV segments2 Consequently ST-segment elevation usually involvesprecordial lateral and apical ECG leads closely resembling that of an-terior STEMI due to left anterior descending coronary occlusion910

Lead -aVR (inverse of aVR) representing thorn30 in the frontal plane isgenerally aligned with the LV apex and can be assembled with other

leads to create an lsquoECG maprsquo useful in comparing the ST-segment ele-vation pattern of TTS with that of anterior STEMI391112 ST-segmentelevation in TTS is centred on precordial leads V2ndashV5 and limb leadsII and aVR whereas in anterior STEMI the ST-segment elevationcentres on precordial leads V1ndashV4 and limb leads I and aVL SeveralECG criteria with high sensitivity and specificity have been proposedto reliably distinguish TTS from anterior STEMI312ndash14 Most focus onST-segment elevation in the precordial leads particularly lead V1 asST-segment elevation in this lead is less pronounced in TTS than inanterior STEMI91012 ST-segment elevation limited to the inferiorleads (II III aVF) is distinctly uncommon in TTS Despite these differ-ences overlap exists and an urgent coronary angiogram is necessaryto differentiate TTS from STEMI with certainty9ndash11

T-wave inversion and QT interval prolongation

Progressive T-wave inversion and QT interval prolongation is a com-mon ECG finding in TTS In patients with delayed presentation these

Chest pain andor Dyspnea

ECGST-elevation Non ST-elevation

InterTAK Diagnostic Scoresect

stniop 52xes elameF

Emotional stress 24 points

Physical stress 13 points

No ST-segment depression 12 points

Psychiatric disorders 11 points

Neurologic disorders 9 points

QTc prolongation 6 points

Coronary angiography

le 70 points

Lowintermediate probability of TTS

gt 70 points

High probabilityof TTS

Apical midventricular or

basal ballooning with

circumferential pattern

Distal LAD flow

visualization

Red flags of acute infectious myocarditis

- Signs andor symptoms of viral infections

- Elevated ESR andor CRP

- Pericardial effusion

Check the presence of

Significant MR

RV involvement

TTE follow-up

Coronary culprit

lesions which explain

the whole RWMA

Acute infectious myocarditis

TTS confirmed

Stable patient

Persistend RWMA

Figure 1 Diagnostic algorithm of takotsubo syndrome Applied to patients who are seeking medical emergency departments with eg chest painandor dyspnoea sectThe InterTAK Diagnostic Score did not include patients with pheochromocytoma induced takotsubo syndrome in which atypicalpattern are more frequently noted Except in lead aVR ACS acute coronary syndrome CAD coronary artery disease CCTA coronary computedtomography angiography CMR cardiac magnetic resonance CRP c-reactive protein ECG electrocardiogram ESR erythrocyte sedimentation rateInterTAK International Takotsubo Registry LAD left anterior descending coronary artery LVOTO left ventricular outflow tract obstruction MRmitral regurgitation QTc QT-time corrected for heart rate RV right ventricle RWMA regional wall motion abnormality TTE transthoracic echo-cardiography TTS takotsubo syndrome

Expert Consensus Document on Takotsubo Syndrome Part II 2049

changes may be present on admission in the absence of ST-segmentelevation and can be the only detectable ECG changes and thereforeimportant for the diagnosis The geographic distribution of T-wave in-version closely parallels that of ST-segment elevation and may be anelectrophysiological manifestation of myocardial stunning In TTST-wave inversion is often more prominent and more broadly distrib-uted than in ACS Furthermore T-wave inversion is associated withpresence of myocardial oedema and may persist for several monthseven after LV contractile recovery thus leaving an electrophysiolo-gical footprint of the TTS event515ndash19 QT interval prolongation pro-vides a substrate for torsades de pointes ventricular tachycardia andmay be a prognostic marker for sudden cardiac death1617

Other electrocardiogram findings

Anterior Q-waves (or poor R-wave progression) without accom-panying ST-segment elevation or T-wave inversion a patternsometimes referred to as lsquoanterior infarction age indeterminatersquooccurs with some frequency in TTS Pathologic Q-waves are lessfrequently encountered in TTS than anterior STEMI (15 vs69)14 In TTS as in anterior STEMI Q-waves may occur in theacute phase and regress rapidly with R-wave re-appearance con-sistent with electrical stunning2021 Both J-wave andor frag-mented QRS complexes have been reported acutely the formerassociated with death from cardiac causes andor ventriculartachyarrhythmia22 Low QRS voltage likely representing

myocardial oedema is prevalent in TTS23 Left bundle branchblock is present in around 5 of patients2 ST-segment depressionis uncommon occurring in fewer than 10 of TTS patients but inover 30 of ACS patients2 therefore the presence of ST-segment depression may suggest ACS

InterTAK Diagnostic ScoreThe InterTAK Diagnostic Score was developed by the InternationalTakotsubo Registry to provide clinicians a model to assess the likeli-hood of TTS diagnosis The criteria that make up the InterTAKDiagnostic Score are based on clinical features and ECG to predict theprobability of the presence of TTS and to distinguish TTS from ACS(Figure 1 Figure 2A)24 The InterTAK Diagnostic Score comprises sevenparameters [female sex emotional trigger physical trigger absence ofST-segment depression (except in lead aVR) psychiatric disordersneurologic disorders and QT prolongation] ranked by their diagnosticimportance with a maximum attainable score of 100 points(Figure 2A)24 All parameters can be easily obtained in the emergencydepartment and do not require an imaging modality24

Depending on the disease prevalence this means that patients with30 score points have a predicted probability of lt1 while patients with50 points have a probability of 18 and patients with a score value gt70points have a probability of90 of suffering from TTS (Figure 2B)24

Figure 2 InterTAK Diagnostic Score Predictors for diagnosing takotsubo syndrome by multiple logistic regression analysis Odds ratios of theparameters female sex emotional trigger physical trigger absence of ST-segment depression psychiatric disorders neurologic disorders and QTcprolongation which were chosen to build the InterTAK Diagnostic Score Except in lead aVR (A) Sigmoid curve shows the estimated prevalence oftakotsubo syndrome in clinical practice (B) Modified and reprinted with permission from Ghadri et al24 CI confidence interval OR odds ratio QTcQT-time corrected for heart rate TTS takotsubo syndrome

BiomarkersMarkers of myocardial necrosis

Virtually all cases of TTS exhibit evidence of myocardial necrosis On ad-mission troponin values are usually equally elevated compared to ACShowever peak values are substantially lower compared to the classicalACS2 High admission troponin levels are a predictor for a worsein-hospital outcome2 Typically there is only a slight increase in creatinekinase2 The extent of LV regional wall motion impairment generallygreatly exceeds that of associated myocardial necrosis biomarkers likelyreflecting a large mass of reversibly injured (stunned) myocardium

B-type natriuretic peptide and N-terminal prohormone

of brain natriuretic peptide

Takotsubo syndrome is frequently associated with a substantial increasein the plasma levels of B-type natriuretic peptide (BNP) and N-terminalprohormone of brain natriuretic peptide (NT-proBNP) reaching itspeak approximately 24ndash48 h after symptom onset2526 as a reflection ofregional LV dysfunction A gradual return of BNPNT-proBNP towardsnormal levels occurs within the next few months after presentation27

The degree of NT-proBNP elevation appears directly related to(i) the degree of sympathetic overactivation (as reflected by norme-tanephrine concentrations) (ii) peak C-reactive protein concentra-tions (suggesting that BNP release might be at least in part ofinflammatory origin) and (iii) systolic LV dysfunction [as measured bywall motion score index (WMSI)]25 Peak NT-proBNP levels alsovary with the extent of LV oedema as measured by CMR28

Other potential biomarkers

Interleukin (IL)-6 levels appear less elevated while those of IL-7 aremore elevated in TTS compared with AMI29 However differencesbetween groups were small and unlikely to be of diagnostic utility

Two recently published studies focused on the potential utility ofthe release and circulation of certain microRNAs (miRNAs) in associ-ation with TTS onset3031 Kuwabara et al30 noted that elevation ofcirculating miR-133a appeared to represent an early consequence ofmyocardial injury including TTS and AMI However subsequent ana-lyses of cases of TTS (N = 36) and evolving STEMI (N = 27) suggestedthat the elevation of miR-133a was more marked in STEMI than inTTS Furthermore Jaguszewski et al demonstrated that a unique sig-nature including miR-1 miR-16 miR-26a and miR-133a represents arobust biomarker on admission and can be used to differentiate TTSfrom STEMI patients31 Furthermore the up-regulation of miR-16and miR-26a is known to be associated with stress- and affective dis-orders32ndash34

Especially in patients with biventricular involvement it has been shownthat plasma concentrations of the stress-responsive cytokine growth dif-ferentiation factor-15 increased more rapidly after the onset of TTS35

ImagingCoronary angiography and ventriculography

Although non-invasive imaging modalities are useful in the workup ofpatients with TTS final differential diagnosis from ACS requires coron-ary angiogram which is performed in the context of ST-elevation in pri-mary percutaneous coronary intervention service In case of suspectedTTS with coexisting and significant CAD careful comparison of CAGand biplane ventriculography in similar views is mandatory to search

for a perfusion-contraction mismatch3637 This comparison is essentialfor distinguishing TTS from classical AMI in patients with wall motionabnormalities and obstructive CAD In this regard it has been reportedthat approximately one-third of patients with the classical apical bal-looning show a small zone with preserved contractility in the most dis-tal portion of the apex which is described as the lsquoapical nipple signrsquo38

Furthermore as LVOTO occurs in approximately 20 of patients withTTS39 haemodynamic assessment for the presence of a pressure-gradient in the outflow tract as well as assessment of left ventricularend-diastolic pressure are recommended Figure 3A demonstrates ap-ical ballooning pattern on left ventriculography

Echocardiography

Echocardiography is the most used imaging tool to assess changes inLV function such as symmetric regional wall motion abnormalities(RWMAs)4 Different variants can be identified with echocardio-graphy which include

(1) Apical ballooning hypo- a- or dyskinesia of mid-apical myocardialsegments is typical sometimes associated with hypokinetic mid-seg-ments240 The anterior or entire interventricular septum inferioror midventricular anterolateral wall may also be involved4142 LVtwisting on 2D speckle-tracking imaging is reduced or reversed toclockwise apical rotation and the rate of untwisting (a sensitive indexof regional diastolic dysfunction) is reduced in the acute phase43

(2) Midventricular TTS featured by hypo- a- or dyskinesia of midven-tricular segments most often resembling a cuff2404445

(3) Basal forms where only basal segments are involved240 Thisphenotype is rare and appears commonly in patients with sub-arachnoid haemorrhage46 epinephrine-induced TTS47 orphaeochromocytoma48

(4) Focal TTS mostly involving an anterolateral segment has beendescribed240 Differentiating this unusual TTS type from ACS ormyocarditis requires CMR49

Right ventricular involvement is characterized by RV dilatation withhypo- to akinesia of the free wall and apex in its isolated form5051

In TTS LV wall motion abnormalities extend beyond the distribu-tion of a single coronary artery territory therefore systolic dysfunc-tion appears lsquocircularrsquo at speckle-tracking echocardiography52

A WMSI gt_175 with more than four dysfunctional segments identifiesTTS with 83 sensitivity and 100 specificity53 Doppler estimationof coronary artery flow ameliorates the diagnostic accuracy of wallmotion abnormalities54 whereas adenosine may lead to dramatic im-provements of global and regional LV function41

Intravenous ultrasound contrast agents facilitate wall motion assess-ment especially at the apex52 and constitute a useful method especiallyin patients in whom CAG is not performed mainly due to active bleed-ing or other comorbid conditions that may imbalance the risk-benefitratio of CAG (see Cardiac computed tomography angiography sec-tion) Myocardial opacification is reduced within dysfunctional seg-ments with the transmural perfusion defects being more evident earlyafter TTS onset55 Coronary flow reserve assessed by transthoracicDoppler echocardiography is reduced to 16ndash26 at the levels of theright and left coronary arteries5657 and correlates with indices of LVsystolic but not diastolic function58 In contrast to ischaemic cardiomy-opathy myocardial contraction does not improve with low-dosedobutamine at the early stages5960 However it has also been demon-strated that low dose dobutamine stress echocardiography improved

systolic left ventricular function by normalizing or improving the hypo-kinetic segments61 Moreover in STEMI viable myocardial segmentsexhibit longitudinal shortening while in TTS systolic lengthening (pas-sive motion) is present initially and resolves at follow-up62

Importantly echocardiography allows detection of all acute TTScomplications In LV apical ballooning basal segments are hyperkineticand may cause dynamic LVOTO63 mainly in patients with pre-existingseptal bulge64 which further reduces stroke volume and is associatedwith mitral regurgitation (MR) due to systolic anterior motion of themitral leaflet (Figure 3B)6365 Severe MR may also result from leaflettethering by displacement or dysfunction of papillary muscles Mitral re-gurgitation is estimated to be present in 14ndash25 of TTS patients66

Advanced echocardiographic techniques such as speckle-trackingimaging which reveals a paradoxical (dyskinetic) positive longitudinalsystolic strain of biventricular mid-apical segments67 Echocardiogra-phy also identifies covered rupture of the LV free wall68 as wellas thrombus formation within a dysfunctional LV apex69 or withinleft-atrial appendage even in the absence of atrial fibrillation70 Inde-pendent predictors of adverse outcomes include low left ventricular

ejection fraction (LVEF) increased LV filling pressure and moderate-to-severe MR at 4ndash6 weeks7172

At peak apical and anteroseptal akinesis with basal hyper-contractility produces near-cavity obliteration73

Typically LV contractility recovers completely in 4ndash8 weeks274

Some segments of the LV recover earlier than others displayingincreased apical rotation LV twisting and untwisting and recoveredglobal longitudinal strain4375 Resolution of LVOTO and MR76 occursin parallel with myocardial functional recovery During TTS recur-rence the LV ballooning pattern may resemble the initial event77 oralternatively manifest as other variants78

Cardiac computed tomography angiography

In the presence of life-threatening comorbid conditions such as ter-minal malignancy intracranial bleeding advanced age with frailty andbleeding diathesis invasive CAG may pose a considerable risk forcomplications In a recent study by Murugiah et al79 a substantial pro-portion of patients with TTS as a secondary diagnosis code did notundergo CAG The reasons for not performing CAG were not

Left Ventriculography

Cardiac Magnetic Resonance Imaging 18F-FDG PET 201TI SPECT

EchocardiographyA B

3) 4) 5)

1) 2)2))3)2)1

Figure 3 Apical ballooning illustrated by different imaging modalities Typical takotsubo type with apical ballooning pattern during diastole (A1)and systole (A2) on left ventriculography Dashed lines indicate extent of wall motion abnormality (A3) Modified and reprinted with permissionfrom Templin et al2 Apical four-chamber view obtained by echocardiography showing apical ballooning and left ventricular cavity with bulging of thebasal interventricular septum (white arrow) (B1) B2 reveals left ventricular outflow tract obstruction by pulsed-wave Doppler interrogationModified and reprinted with permission from Merli et al100 Apical ballooning as illustrated by cardiac magnetic resonance imaging The asterisks indi-cate pericardial effusion (C1) and yellow arrows (C2) shows the region of akinesia T2-weighted images on short-axis view demonstrates normal sig-nal intensity of the basal myocardium (C3) and global oedema of the mid and apical myocardium (C4 and C5) Modified and reprinted withpermission from Eitel et al82 Metabolic imaging with positron emission tomography and 18F-flurodeoxyglucose (D1 D3 D5) demonstratesdecreased uptake in the apex and midventricular segments Perfusion imaging using single photon emission computed tomography with 201thalliumchloride (D2 D4 D6) shows a smaller perfusion defect in the apex and midventricular segments Reprinted with permission from Yoshida et al98

described but likely included the mentioned life-threatening comor-bid conditions In such patients non-invasive CCTA may be an appro-priate alternative to CAG Coronary computed tomographyangiography provides information on both coronary artery anatomyand regional LV contraction Assessment of LV contraction by CCTArequires image acquisition throughout the cardiac cycle and thushigher radiation exposure In patients with suspected recurrent TTSand a previous CAG CCTA may be a diagnostic alternativeFurthermore CCTA may be considered instead of CAG in the fol-lowing circumstances in stable patients with low suspicion of ACSsuspected recurrent TTS and patients with elevation of cardiac bio-markers or ECG changes in association with acute critical illnessessuch as sepsis intracranial disease (eg subarachnoid haemorrhage is-chaemic stroke) and other critical conditions known to be compli-cated by TTS

Cardiac magnetic resonance imaging

Cardiac magnetic resonance imaging cannot be used easily in the acutesetting of TTS but is very useful in the subacute phase In addition toidentification of typical RWMAs CMR allows precise quantification ofRV and LV function assessment of additional abnormalitiescomplica-tions (ie pericardial andor pleural effusion LV and RV thrombi) andcharacterization of myocardial tissue (ie oedema inflammation ne-crosisfibrosis) (Figure 3C)8081 Recently specific CMR criteria for TTSdiagnosis at the time of acute presentation were established which in-clude the combination of typical RWMAs oedema and the absenceof evidence of irreversible tissue injury [late gadolinium enhancement(LGE)]82 While LGE is usually absent and predicts complete normal-ization of LV function subtle fibrosis may be present and a sign ofworse outcomes83ndash85 In most TTS patients myocardial oedema ispresent in regions with abnormal systolic function possibly due to in-flammation increased wall stress andor transient ischemia82 and indi-cative of the extent and severity of tissue injury86 CMR is superior toechocardiography for detection of RV involvement82 including iso-lated RV TTS87 which may negatively impact outcome88 Importantlyabsence of LGE in dysfunctional LV regions allows distinction betweenTTS and other conditions including ACS (subendocardial or trans-mural LGE corresponding to a vascular territory) and many cases ofacute myocarditis (frequent but not universal presence of epicardialor lsquopatchyrsquo LGE) Therefore CMR provides incremental value for thedifferential diagnosis and therapeutic decision-making in patients withsuspected TTS89

Cardiac nuclear imaging

Both single photon emission computed tomography (SPECT using201thallium chloride or 99mtechnetium sestamibi) which providessemi-quantitative information and position emission tomography(PET using 13N-ammonia 82Rubidium) which offers quantitativemeasurements have been used in TTS for assessment of perfusionmetabolism and innervation

Perfusion imagingMild reduction of perfusion in dysfunctional segments using myocar-dial perfusion scintigraphy has been noted in some studies whileothers reported normal perfusion90ndash94 However lsquomyocardialthinningrsquo in involved segments during the acute phase of TTS maylead to a reduction in isotope counts because of the partial volume

effect which may mimic reduction of perfusion on SPECT but fol-lowing correction for this factor on PET blood flow in the thinned re-gions (typically in the apex) is indeed maintained while the normallyfunctioning (basal) segments show hyper-perfusion95

Metabolic imagingThe role of metabolic imaging in the clinical setting has not beendetermined and it has been performed mainly for research purposeof investigating the pathophysiology of TTS although it can provideadditional information about the diseased myocardium Both SPECTusing 123I-b-methyl-iodophenyl pentadecanoic acid (which reflectsfatty-acid) and PET using 18F-flourodeoxyglucose (which reflect glu-cose utilization) often show reduced metabolic activity in the im-paired regions while myocardial perfusion is often (near) normal9697

An example with apical TTS is shown in Figure 3D revealing severelyreduced 18F-flourodeoxyglucose uptake in the apex despite onlyslightly reduced perfusion as assessed with 201thallium chloride98

Possibly glucose utilization is disturbed due to insulin resistance as aconsequence of high levels of circulating catecholamines99

Sympathetic nervous imagingMyocardial uptake of 123I-metaiodobenzylguanidine (123I-MIBGimaged with SPECT) reflects myocardial sympathetic innervation123I-MIBG is reduced for months in dysfunctional segments whereasperfusion is almost normal consistent with regional disturbanceof sympathetic neuronal activity101 In the subacute phase of TTS123I-MIBG SPECT can be combined with SPECT perfusion imaging toexclude ACS where both perfusion and innervation are reducedPosition emission tomography imaging has also been used in TTSfor assessment of cardiac innervation with the use 11Chydroxyephedrine102

Complications and outcomes

Although TTS is generally considered a benign disease contemporaryobservations show that rates of cardiogenic shock and death arecomparable to ACS patients treated according to current guide-lines2103ndash108 While TTS is a reversible condition hemodynamic andelectrical instability during the acute phase expose patients to the riskof serious adverse in-hospital events which occur in approximatelyone-fifth of TTS patients (Figure 4)2 This substantial incidence of life-threatening complications necessitates close monitoring and earlyintervention in unstable TTS patients with risk stratification at diagno-sis allowing triage to appropriate care66 Parameters predicting ad-verse in-hospital outcome include physical trigger acute neurologicor psychiatric diseases initial troponin gt10 upper reference limitand admission LVEF lt452 Furthermore male patients have an upto three-fold increased rate of death and major adverse cardiac andcerebrovascular events (MACCE)109 and more often had an underly-ing critical illness further contributing to the higher mortality2 Sobueet al110 demonstrated that physical triggers and male gender are in-dependent risk factors of in-hospital mortality in TTS Data from theTokyo Coronary Care Unit Network revealed that high values ofBNP and white blood cell counts were also linked to higher rates ofin-hospital complications111 Complications included cardiac deathpump failure (Killip grade gt_II) sustained ventricular tachycardia orventricular fibrillation (VTVF) and advanced atrioventricular block

(AV-block) In the study by Takashio et al112 the magnitude and ex-tent of ST-segment elevation with ECG were found to be independ-ent predictors of in-hospital adverse events However those findingswere not confirmed by others Common in-hospital complications

include cardiac arrhythmias113 LVOTO64 cardiogenic shock2 ven-tricular thrombus114 pulmonary oedema115 ventricular septaldefect116 and free wall rupture117 In addition to the demographicparameter of age gt_75 echocardiographic parameters that predict ad-verse in-hospital outcome (acute heart failure cardiogenic shock andin-hospital mortality) include LVEF Eersquo ratio and reversible moderateto severe MR However only reversible moderate to severe MR wasan independent predictor when considering cardiogenic shock anddeath as the composite outcome in this study in addition to heartrate Moreover it has been demonstrated that high heart rate and lowsystolic blood pressure are associated with increased mortality inTTS118 Along with the Charlson comorbidity index and systolic pul-monary artery pressure RV involvement is an independent predictorof acute heart failure and of a composite endpoint including adverseevents such as acute heart failure cardiogenic shock and in-hospitalmortality119

Data on long-term survival are scarce In 2007 Elesber et al120 re-ported that long-term mortality did not differ between a TTS popula-tion and an age- gender- birth- year- and race-matched populationWhile Sharkey et al121 found that all-cause mortality during follow-up exceeded a matched general population with most deaths occur-ring in the first year More recently it has been reported that long-term mortality of patients with TTS122 is similar to (Figure 5A) patientswith CAD103 TTS patient data from the Swedish Angiography andAngioplasty Registry (SCAAR) from 2009 to 2013 were comparedto data from patients with and without CAD and demonstrated thatmortality rates for TTS were worse than in patients without CADand comparable to those of patients with CAD103 In the largest TTSregistry to date death rates are estimated to be 56 and rate ofMACCE 99 per-patient year (Figure 5B)2 suggesting that TTS is nota benign disease A recent study found that patients with the typicalTTS type have a comparable outcome to patients presenting withthe atypical type even after adjustment for confounders suggestingthat both patient groups should be equally monitored in the long-term40 On the other hand 1-year mortality differs between the twogroups as it is driven by clinical factors including atrial fibrillationLVEF on admission lt45 and neurologic disorders rather than by

Acute heart failure (12-45)LVOTO (10-25)Mitral regurgitation (14-25)Cardiogenic shock (6-20)

Atrial fibrillation (5-15)LV-thrombus (2-8)Cardiac arrest (4-6)AV-block ~5

Tachyarrhythmia (2-5)Bradyarrhythmia (2-5)Torsades-de-pointes (2-5)Death (1-45)Ventricular tachycardiafibrillation ~3Acute ventricular septal defect lt1

Frequent

Moderate

In-hospital Complications

Figure 4 Overview of in-hospital complications according to their prevalence AV atrioventricular block LV left ventricle LVOTO left ventricu-lar outflow tract obstruction

Figure 5 Long-term outcome (5-years) of patients with TTScompared to patients with and without CAD (A) Long-term out-come (10-years) of patients with TTS (B) MACCE refers to a com-posite of death from any cause recurrence of takotsubo syndromestroke or transient ischaemic attack or myocardial infarctionCAD coronary artery disease MACCE major adverse cardiac andcerebrovascular event MI myocardial infarction TIA transientischaemic attack TSC takotsubo stress cardiomyopathy Reprintedwith permission from Tornvall et al103 and Templin et al2

TTS type40 In a smaller study predictive factors of long-term mortal-ity in TTS were male sex Killip class IIIIV and diabetes mellitus122

The prognostic role of diabetes mellitus is controversial as it is postu-lated that it may exert a protective effect in TTS given that the preva-lence of diabetes mellitus in TTS is lower than expected for an age-and sex-matched population123 Some studies though limited bytheir population size and experimental design suggest that patientswith diabetes mellitus have a more favourable in-hospital and 1-yearoutcome124125

ArrhythmiasCardiac arrhythmias are important determinants of short-term clin-ical outcome

Ventricular arrhythmias

Life-threatening ventricular arrhythmias such as torsades de pointesVT or VF occur in 30ndash86 and are a frequent cause of death2126ndash

128 Life-threatening ventricular arrhythmias occur most often in thesubacute phase (ie hospital days 2ndash4) and coincide with anterolateralT-wave inversion and QT-interval prolongation129 QTc prolonga-tion at admission occurs in up to half of the patients2 Most malignantarrhythmic episodes are associated with a QTc gt500 ms with pause-dependent torsades de pointes degenerating into VF127128130 Figure 6 shows a patient with apical ballooning (A) On the third dayof hospitalization giant negative T-waves marked QT prolongationand lsquoR on Trsquo premature ventricular beats were noted on ECG (B)Furthermore pause-dependent (lsquolong-short sequencersquo) torsade-de-pointesventricular fibrillation requiring electrical cardioversion wererecorded by telemetry (C)128 Accordingly TTS should be regarded

as a type of acquired long QT syndrome with risk for malignant ar-rhythmic events128130

Cardiac magnetic resonance findings reveal an association be-tween transient myocardial oedema as evidenced by T2-weightedsequences and dynamic T-wave inversion and QT prolonga-tion131132 Thus myocardial oedema may contribute to transmuralor regional (ie from the apex to the base of the LV) repolarizationinhomogeneity QT prolongation thus reflects the delayed and dis-persed ventricular repolarisation that predisposes to local re-excitation and eventually to torsade de pointes or VF131ndash133

Rarely cardiac arrest is the initial presentation of TTS unrelated toQT interval prolongation The mechanism of these potentially lethalarrhythmias is probably distinct from that encountered during thesubacute phase where acute catecholamine toxicity andor myocar-dial ischaemia play a primary role In some cases TTS may not repre-sent the trigger for tachyarrhythmias but rather the consequence ofthe stress of cardiac arrest andor resuscitation which may includeadministration of epinephrine134

Other cardiac arrhythmias

New-onset paroxysmal or persistent atrial fibrillation occurs in 47sinus-node dysfunction in 13 and AV-block in 29 most likelydue to neuro-autonomic imbalance catecholamine stress andincreased vagal tone127130134

RecurrencePatients who survive the initial event have a second event in approxi-mately 5 of cases mostly occurring 3 weeks to 38 years after thefirst event135 Recurrent TTS afflicts men and women and may occur

Figure 6 Arrhythmic complication in takotsubo syndrome Left ventriculography (antero-posterior view) showing the typical apical ballooning pat-tern with akinesia of the mid-apical segments and hyperkinesia of the basal segment (A) A 12-lead electrocardiogram recorded at the third day ofhospitalization showing giant negative T-waves in leads aVL L1 L2 aVF and V4ndashV6 marked QT prolongation (QTc = 552 ms) and lsquoR on Trsquo prematureventricular beats (B) Telemetry recording of a pause-dependent (lsquolong-short sequencersquo) torsade-de-pointesventricular fibrillation which requiredelectrical cardioversion (C) Reprinted with permission from Migliore et al130

at any age including in childhood78136137 Both the triggering eventand the ballooning pattern may differ during recurrent events78

Some have postulated that an index TTS event may protect the af-fected LV regions from recurrent involvement through a mechanismakin to ischaemic lsquopre-conditioningrsquo138 However detailed review ofpublished cases and clinical experience suggest that there are fre-quent examples of recurrence in which the ballooning pattern is simi-lar between episodes thereby making this hypothesis unlikely

Therapeutic management

Guidelines regarding TTS management are lacking as no prospectiverandomized clinical trials have been performed in this patient popula-tion Therapeutic strategies are therefore based on clinical experi-ence and expert consensus (evidence level C) Table 1 reviewscurrent data on medical management of TTS patients139 based ofretrospective analysis2140141 meta-analysis142144 and case series143

Figure 7 summarizes a proposed therapeutic management approachfor patients with TTS

Pre-hospital treatmentAs TTS is clinically difficult to distinguish from ACS upon first presen-tation patients should be transferred to a cardiology unit with imagingcapabilities and a cardiac catheterization laboratory and receiveguideline based treatment of ACS105ndash108 in particular aspirin heparinand if required morphine and oxygen Patients with cardiogenic shockor post cardiac arrest require intensive care Electrocardiogrammonitoring is essential as a prolonged QT-interval may trigger malig-nant ventricular arrhythmias (torsades de pointes) and AV-blockmay occur

Acute treatmentTakotsubo syndrome patients with cardiogenic shock in particularthose with apical ballooning should be promptly evaluated for thepresence of LVOTO which occurs in about 20 of cases39 Thisshould be performed during angiography with LV pressure recordingduring careful retraction of the pigtail catheter from the LV apex be-yond the aortic valve Similarly a pressure gradient can be detectedand quantified using Doppler echocardiography using continuouswave Doppler145 Particularly when using catecholamines serialDoppler studies should be considered to detect an evolving pressuregradient In TTS patients treated with catecholamine drugs a 20mortality has been reported81 although this may represent a selec-tion bias due to the initial presentation of the patients Recently it hasbeen suggested that the Ca2thorn-sensitizer levosimendan could be usedsafely and effectively in TTS as an alternative inotrope to catechol-amine agents143 Furthermore beta-blockers may improve LVOTObut are contraindicated in acute and severe heart failure with lowLVEF hypotension and in those with bradycardia Although evidenceis unproven TTS patients with LVOTO may benefit from the If chan-nel inhibitor ivabradine146147

As catecholamine levels are elevated in TTS beta-blockers seemto be reasonable until full recovery of LVEF but trials supporting thishypothesis are lacking Animal experiments have shown that apicalballooning is attenuated after administration of drugs with both alpha-and beta-adrenoceptor blocking properties148 In an animal modelintravenous metoprolol improved epinephrine-induced apical bal-looning149 However due to the potential risk of pause-dependenttorsades de pointes beta-blockers should be used cautiously espe-cially in patients with bradycardia and QTc gt500 ms Angiotensin-converting-enzyme inhibitors (ACEi) or angiotensin II receptorblockers (ARB) may potentially facilitate LV recovery Diuretics areindicated in patients with pulmonary oedema In addition nitrogly-cerin is useful to reduce LV and RV filling pressures and afterload in

Table 1 Overview of retrospective analyses meta-analyses and case series of medical management for takotsubosyndromea

Authors Study design No of

patients

Outcome

measures

Follow-up time Medication Effect

Santoro et al143 Case series 13 Adverse events During hospitalization Levosimendan Probably beneficial

Isogai et al140 Retrospective 2110 Mortality 30 days b-Blockers Not beneficial

Dias et al141 Retrospective 206 MACE During hospitalization Antiplatelet Beneficial

b-Blockers Not beneficial

Statins Not beneficial

ACEI Not beneficial

Templin et al2 Retrospective 1118 Mortality 1 year b-Blockers Not beneficial

ACEIARB Beneficial

Santoro et al142 Meta-analysis 511 Recurrence 24ndash60 months b-Blockers Not beneficial

ACEIARB Not beneficial

Aspirin Not beneficial

Singh et al144 Meta-analysis 847 Recurrence 19ndash33 months b-Blockers Not beneficial

ACEIARB Beneficial

aReprinted with permission from Kato et al139

ACEi angiotensin-converting-enzyme inhibitor ARB angiotensin-receptor blocker MACE major adverse cardiac event

the case of acute heart failure however the administration of nitro-glycerin in the presence of LVOTO has been found to worsen thepressure gradient and therefore should be avoided in this scenario(see Figure 7)

QT-interval prolonging drugs should be used cautiously in theacute phase because of the risk to induce torsades de pointes or ven-tricular tachycardia and fibrillation

Severe LV dysfunction with extended apical ballooning entails therisk of an LV thrombus and subsequent systemic embolism Althoughevidence is lacking anticoagulation with intravenoussubcutaneousheparin would appear to be appropriate in such patients and post-discharge oral anticoagulation or antiplatelet therapy may be con-sidered on an individual per-patient basis As LV dysfunction andECG abnormalities are reversible an implantable cardioverter-defibrillator for primary or secondary prevention is of uncertain valuein TTS patients experiencing malignant ventricular arrhythmias130150

In case of excessive prolongation of the QT interval or life-threatening ventricular arrhythmias a wearable defibrillator (life vest)could be considered151 The residual risk of malignant arrhythmicevents after recovery from TTS is unknown A temporary

transvenous pacemaker is appropriate for those with haemodynami-cally significant bradycardia

Long-term treatmentThe use of ACEi or ARB was associated with improved survival at1-year follow-up even after propensity matching2 In contrast therewas no evidence of any survival benefit for the use of beta-blockers2

Moreover one-third of patients experienced a TTS recurrence dur-ing beta-blockade2 suggesting that other receptors such as alpha-receptors that are more prevalent in the coronary microcirculationmight be involved

The prevalence of recurrent TTS is relatively low consequentlyconducting randomised trials of pharmacological agents to preventrecurrence is challenging Beta-blocker therapy after hospital dis-charge does not appear to prevent recurrence2144 whereas ACEi orARB are associated with a lower prevalence of recurrence The sig-nificance of this observation remains uncertain and requires vali-dation in other cohorts

If concomitant coronary atherosclerosis is present aspirin and sta-tins are appropriate As TTS mainly occurs in postmenopausal

Figure 7 Management of takotsubo syndrome ACE angiotensin-converting-enzyme ARB angiotensin-receptor blocker AV-block atrioventricu-lar block HF heart failure IABP intra-aortic balloon pump IV intravenous LV left ventricle LVAD left ventricular assist device LVD left ventriculardysfunction LVEF left ventricular ejection fraction LVOTO left ventricular outflow tract obstruction NOAC novel oral anticoagulant QTc QT-time corrected for heart rate RV right ventricle TTS takotsubo syndrome VA-ECMO venoarterial extracorporeal membrane oxygenation VFventricular fibrillation VT ventricular tachycardia

women oestrogen supplementation in those with recurrence is ques-tionable In an animal model oestrogen supplementation partiallyattenuated TTS152 and chronic oestrogen supplementation after oo-phorectomy improved the condition153

Psychiatric disorders (eg depression anxiety) are common in TTSpatients2154 and those might benefit from a combined psycho-cardiologic rehabilitation155 Whether anti-depressants or other psy-chiatric drugs might provide clinical benefit in such patients iscontroversial

Future directions

Over recent years research has shown that TTS is a much more het-erogeneous condition than previously thought Originally believed tobe a benign disease studies have shown that TTS has morbidity andmortality rates that are comparable to those of ACS2103 TTS can af-fect many others aside from postmenopausal women with an emo-tional trigger2135 as originally described and can present as anatypical type rather than apical ballooning40 Still there is much moreto be uncovered surrounding TTS and the underlying pathophysi-ology of the syndrome156

Key questionsMany questions need further investigation Why are women affectedpredominantly What is the role of triggering factors in stress re-sponses of the heart Why do different TTS phenotypes existWhich patients are vulnerable to TTS or prone to recurrence Isthere a genetic predisposition to TTS What is the exact pathogen-esis of TTS Are there specific treatment options in the acute stage ofthis life-threatening syndrome or to prevent recurrence Additionalresearch needs to be conducted to answer these importantquestions

Prospective approachesThe link between the brain and heart seems to play a key role in TTSAdditionally studies on circulating miRNAs suggest there could be agenetic aspect to the pathophysiology of TTS and the predominanceof female patients suggests that TTS could be related to sex hor-mones and the endocrine system Takotsubo syndrome is more thana cardiac disease and it requires a new and interdisciplinary approachto increase awareness among not only cardiologists but physicians atlarge To establish evidence based strategies for effective TTS treat-ment randomized prospective trials will be necessary utilizing a largenumber of patients from multicentre international consortia

FundingJRG has received a research grant ldquoFilling the gaprdquo from the Universityof Zurich

Conflict of interest none declared

References1 Gianni M Dentali F Grandi AM Sumner G Hiralal R Lonn E Apical ballooning

syndrome or Takotsubo cardiomyopathy a systematic review Eur Heart J 2006271523ndash1529

2 Templin C Ghadri JR Diekmann J Napp LC Bataiosu DR Jaguszewski MCammann VL Sarcon A Geyer V Neumann CA Seifert B Hellermann JSchwyzer M Eisenhardt K Jenewein J Franke J Katus HA Burgdorf C

Schunkert H Moeller C Thiele H Bauersachs J Tschope C Schultheiss H-PLaney CA Rajan L Michels G Pfister R Ukena C Bohm M Erbel R Cuneo AKuck K-H Jacobshagen C Hasenfuss G Karakas M Koenig W Rottbauer WSaid SM Braun-Dullaeus RC Cuculi F Banning A Fischer TA Vasankari TAiraksinen KEJ Fijalkowski M Rynkiewicz A Pawlak M Opolski GDworakowski R MacCarthy P Kaiser C Osswald S Galiuto L Crea F DichtlW Franz WM Empen K Felix SB Delmas C Lairez O Erne P Bax JJ Ford IRuschitzka F Prasad A Luscher TF Clinical Features and Outcomes ofTakotsubo (Stress) Cardiomyopathy N Engl J Med 2015373929ndash938

3 Frangieh AH Obeid S Ghadri JR Imori Y DrsquoAscenzo F Kovac M Ruschitzka FLuscher TF Duru F Templin C Inter TAKC ECG criteria to differentiate be-tween Takotsubo (Stress) cardiomyopathy and myocardial infarction J AmHeart Assoc 20165e003418

4 Prasad A Lerman A Rihal CS Apical ballooning syndrome (Tako-Tsubo orstress cardiomyopathy) a mimic of acute myocardial infarction Am Heart J2008155408ndash417

5 Bennett J Ferdinande B Kayaert P Wiyono S Goetschalkx K Dubois CSinnaeve P Adriaenssens T Coosemans M Desmet W Time course of electro-cardiographic changes in transient left ventricular ballooning syndrome Int JCardiol 2013169276ndash280

6 Mitsuma W Kodama M Ito M Tanaka K Yanagawa T Ikarashi N Sugiura KKimura S Yagihara N Kashimura T Fuse K Hirono S Okura Y Aizawa YSerial electrocardiographic findings in women with Takotsubo cardiomyopathyAm J Cardiol 2007100106ndash109

7 Kurisu S Inoue I Kawagoe T Ishihara M Shimatani Y Nakamura S Yoshida MMitsuba N Hata T Sato H Time course of electrocardiographic changes in pa-tients with Tako-Tsubo syndrome comparison with acute myocardial infarctionwith minimal enzymatic release Circ J 20046877ndash81

8 Kosuge M Kimura K Electrocardiographic findings of Takotsubo cardiomyop-athy as compared with those of anterior acute myocardial infarctionJ Electrocardiol 201447684ndash689

9 Sharkey SW Electrocardiogram mimics of acute ST-segment elevation myocar-dial infarction insights from cardiac magnetic resonance imaging in patients withTako-Tsubo (stress) cardiomyopathy J Electrocardiol 200841621ndash625

10 Bybee KA Motiei A Syed IS Kara T Prasad A Lennon RJ Murphy JG HammillSC Rihal CS Wright RS Electrocardiography cannot reliably differentiate tran-sient left ventricular apical ballooning syndrome from anterior ST-segment ele-vation myocardial infarction J Electrocardiol 20074038e1ndash6

11 Chao T Lindsay J Collins S Woldeyes L Joshi SB Steinberg DH Satler LFKent KM Suddath WO Pichard AD Waksman R Can acute occlusion of theleft anterior descending coronary artery produce a typical lsquoTakotsuborsquo left ven-tricular contraction pattern Am J Cardiol 2009104202ndash204

12 Kosuge M Ebina T Hibi K Morita S Okuda J Iwahashi N Tsukahara KNakachi T Kiyokuni M Ishikawa T Umemura S Kimura K Simple and accurateelectrocardiographic criteria to differentiate Takotsubo cardiomyopathy fromanterior acute myocardial infarction J Am Coll Cardiol 2010552514ndash2516

13 Tamura A Watanabe T Ishihara M Ando S Naono S Zaizen H Abe Y YanoS Shinozaki K Kotoku M Momii H Kadokami T Kadota J A new electrocar-diographic criterion to differentiate between Takotsubo cardiomyopathy andanterior wall ST-segment elevation acute myocardial infarction Am J Cardiol2011108630ndash633

14 Ogura R Hiasa Y Takahashi T Yamaguchi K Fujiwara K Ohara Y Nada TOgata T Kusunoki K Yuba K Hosokawa S Kishi K Ohtani R Specific findingsof the standard 12-lead ECG in patients with lsquoTakotsuborsquo cardiomyopathycomparison with the findings of acute anterior myocardial infarction Circ J200367687ndash690

15 Kosuge M Ebina T Hibi K Iwahashi N Tsukahara K Endo M Maejima NNagashima Z Suzuki H Morita S Umemura S Kimura K Differences in nega-tive T waves between Takotsubo cardiomyopathy and reperfused anterioracute myocardial infarction Circ J 201276462ndash468

16 Behr ER Mahida S Takotsubo cardiomyopathy and the long-QT syndrome aninsult to repolarization reserve Europace 200911697ndash700

17 Matsuoka K Okubo S Fujii E Uchida F Kasai A Aoki T Makino K Omichi CFujimoto N Ohta S Sawai T Nakano T Evaluation of the arrhythmogenecityof stress-induced lsquoTakotsubo cardiomyopathyrsquo from the time course of the 12-lead surface electrocardiogram Am J Cardiol 200392230ndash233

18 Migliore F Zorzi A Marra MP Basso C Corbetti F De Lazzari M Tarantini GBuja P Lacognata C Thiene G Corrado D Iliceto S Myocardial edema under-lies dynamic T-wave inversion (Wellensrsquo ECG pattern) in patients with revers-ible left ventricular dysfunction Heart Rhythm 201181629ndash1634

19 Migliore F Zorzi A Perazzolo Marra M Iliceto S Corrado D Myocardial edemaas a substrate of electrocardiographic abnormalities and life-threatening ar-rhythmias in reversible ventricular dysfunction of Takotsubo cardiomyopathyimaging evidence presumed mechanisms and implications for therapy HeartRhythm 2015121867ndash1877

20 Sclarovsky S Nikus K The electrocardiographic paradox of Tako-Tsubo cardio-

myopathy-comparison with acute ischemic syndromes and consideration ofmolecular biology and electrophysiology to understand the electrical-mechanical mismatching J Electrocardiol 201043173ndash176

21 Namgung J Electrocardiographic findings in Takotsubo cardiomyopathy ECGevolution and its difference from the ECG of acute coronary syndrome ClinMed Insights Cardiol 2014829ndash34

22 Shimizu M Nishizaki M Yamawake N Fujii H Sakurada H Isobe M Hiraoka MJ wave and fragmented QRS formation during the hyperacute phase inTakotsubo cardiomyopathy Circ J 201478943ndash949

23 Madias JE Transient attenuation of the amplitude of the QRS complexes in thediagnosis of Takotsubo syndrome Eur Heart J Acute Cardiovasc Care 2014328ndash36

24 Ghadri JR Cammann VL Jurisic S Seifert B Napp LC Diekmann J BataiosuDR DrsquoAscenzo F Ding KJ Sarcon A Kazemian E Birri T Ruschitzka F LuscherTF Templin C InterTAK co-investigators A novel clinical score (InterTAKDiagnostic Score) to differentiate Takotsubo syndrome from acute coronarysyndrome results from the International Takotsubo Registry Eur J Heart Fail2017191036ndash42

25 Nguyen TH Neil CJ Sverdlov AL Mahadavan G Chirkov YY Kucia AMStansborough J Beltrame JF Selvanayagam JB Zeitz CJ Struthers ADFrenneaux MP Horowitz JD N-terminal pro-brain natriuretic protein levels inTakotsubo cardiomyopathy Am J Cardiol 20111081316ndash1321

26 Morita E Yasue H Yoshimura M Ogawa H Jougasaki M Matsumura TMukoyama M Nakao K Increased plasma levels of brain natriuretic peptide inpatients with acute myocardial infarction Circulation 19938882ndash91

27 Akashi YJ Musha H Nakazawa K Miyake F Plasma brain natriuretic peptide inTakotsubo cardiomyopathy QJM 200497599ndash607

28 Neil C Nguyen TH Kucia A Crouch B Sverdlov A Chirkov Y Mahadavan GSelvanayagam J Dawson D Beltrame J Zeitz C Unger S Redpath T FrenneauxM Horowitz J Slowly resolving global myocardial inflammationoedema inTako-Tsubo cardiomyopathy evidence from T2-weighted cardiac MRI Heart2012981278ndash1284

29 Pirzer R Elmas E Haghi D Lippert C Kralev S Lang S Borggrefe M Kalsch TPlatelet and monocyte activity markers and mediators of inflammation inTakotsubo cardiomyopathy Heart Vessels 201227186ndash192

30 Kuwabara Y Ono K Horie T Nishi H Nagao K Kinoshita M Watanabe SBaba O Kojima Y Shizuta S Imai M Tamura T Kita T Kimura T IncreasedmicroRNA-1 and microRNA-133a levels in serum of patients with cardiovascu-lar disease indicate myocardial damage Circ Cardiovasc Genet 20114446ndash454

31 Jaguszewski M Osipova J Ghadri JR Napp LC Widera C Franke J FijalkowskiM Nowak R Fijalkowska M Volkmann I Katus HA Wollert KC Bauersachs JErne P Luscher TF Thum T Templin C A signature of circulating microRNAsdifferentiates Takotsubo cardiomyopathy from acute myocardial infarction EurHeart J 201435999ndash1006

32 Rinaldi A Vincenti S De Vito F Bozzoni I Oliverio A Presutti C Fragapane PMele A Stress induces region specific alterations in microRNAs expression inmice Behav Brain Res 2010208265ndash269

33 Dwivedi Y Evidence demonstrating role of microRNAs in the etiopathology ofmajor depression J Chem Neuroanat 201142142ndash156

34 Baudry A Mouillet-Richard S Schneider B Launay JM Kellermann O miR-16targets the serotonin transporter a new facet for adaptive responses to anti-depressants Science 20103291537ndash1541

35 Stiermaier T Adams V Just M Blazek S Desch S Schuler G Thiele H Eitel IGrowth differentiation factor-15 in Takotsubo cardiomyopathy diagnostic andprognostic value Int J Cardiol 2014173424ndash429

36 Napp LC Ghadri JR Bauersachs J Templin C Acute coronary syndrome orTakotsubo cardiomyopathy the suspect may not always be the culprit Int JCardiol 2015187116ndash119

37 Patel SM Lennon RJ Prasad A Regional wall motion abnormality in apical bal-looning syndrome (Takotsubostress cardiomyopathy) importance of biplaneleft ventriculography for differentiating from spontaneously aborted anteriormyocardial infarction Int J Cardiovasc Imaging 201228687ndash694

38 Desmet W Bennett J Ferdinande B De Cock D Adriaenssens T CoosemansM Sinnaeve P Kayaert P Dubois C The apical nipple sign a useful tool for dis-criminating between anterior infarction and transient left ventricular ballooningsyndrome Eur Heart J Acute Cardiovasc Care 20143264ndash267

39 De Backer O Debonnaire P Gevaert S Missault L Gheeraert P MuyldermansL Prevalence associated factors and management implications of left ventricu-lar outflow tract obstruction in Takotsubo cardiomyopathy a two-year two-center experience BMC Cardiovasc Disord 201414147

40 Ghadri JR Cammann VL Napp LC Jurisic S Diekmann J Bataiosu DR SeifertB Jaguszewski M Sarcon A Neumann CA Geyer V Prasad A Bax JJRuschitzka F Luscher TF Templin C International Takotsubo RegistryDifferences in the clinical profile and outcomes of typical and atypical

Takotsubo syndrome data from the International Takotsubo Registry JAMACardiol 20161335ndash340

41 Galiuto L De Caterina AR Porfidia A Paraggio L Barchetta S Locorotondo GRebuzzi AG Crea F Reversible coronary microvascular dysfunction a commonpathogenetic mechanism in Apical Ballooning or Tako-Tsubo Syndrome EurHeart J 2010311319ndash1327

42 Dewachter P Tanase C Levesque E Nicaise-Roland P Chollet-Martin SMouton-Faivre C Benhamou D Apical ballooning syndrome following peri-operative anaphylaxis is likely related to high doses of epinephrine J Anesth201125282ndash285

43 Meimoun P Passos P Benali T Boulanger J Elmkies F Zemir H Clerc J Luycx-Bore A Assessment of left ventricular twist mechanics in Tako-tsubo cardiomy-opathy by two-dimensional speckle-tracking echocardiography Eur JEchocardiogr 201112931ndash939

44 Haghi D Papavassiliu T Fluchter S Kaden JJ Porner T Borggrefe M SuselbeckT Variant form of the acute apical ballooning syndrome (Takotsubo cardiomy-opathy) observations on a novel entity Heart 200692392ndash394

45 Hurst RT Askew JW Reuss CS Lee RW Sweeney JP Fortuin FD Oh JK TajikAJ Transient midventricular ballooning syndrome a new variant J Am CollCardiol 200648579ndash583

46 Shoukat S Awad A Nam DK Hoskins MH Samuels O Higginson J ClementsSD Jr Cardiomyopathy with inverted Tako-Tsubo pattern in the setting of sub-arachnoid hemorrhage a series of four cases Neurocrit Care 201318257ndash260

47 Y-Hassan S Clinical features and outcome of epinephrine-induced takotsubosyndrome Analysis of 33 published cases Cardiovasc Revasc Med 201617450ndash455

48 Naderi N Amin A Setayesh A Pouraliakbar H Mozaffari K Maleki MPheochromocytoma-induced reverse Tako-Tsubo with rapid recovery of leftventricular function Cardiol J 201219527ndash531

49 Kato K Kitahara H Fujimoto Y Sakai Y Ishibashi I Himi T Kobayashi YPrevalence and clinical features of focal Takotsubo cardiomyopathy Circ J 2016801824ndash1829

50 Haghi D Athanasiadis A Papavassiliu T Suselbeck T Fluechter S Mahrholdt HBorggrefe M Sechtem U Right ventricular involvement in Takotsubo cardiomy-opathy Eur Heart J 2006272433ndash2439

51 Burgdorf C Hunold P Radke PW Schunkert H Kurowski V Isolated right ven-tricular stress-induced (lsquoTako-Tsuborsquo) cardiomyopathy Clin Res Cardiol 2011100617ndash619

52 Mansencal N Pellerin D Lamar A Beauchet A El Mahmoud R Pilliere RMcKenna WJ Dubourg O Diagnostic value of contrast echocardiography inTako-Tsubo cardiomyopathy Arch Cardiovasc Dis 2010103447ndash453

53 Citro R Rigo F Ciampi Q DrsquoAndrea A Provenza G Mirra M Giudice RSilvestri F Di Benedetto G Bossone E Echocardiographic assessment of re-gional left ventricular wall motion abnormalities in patients with Tako-Tsubocardiomyopathy comparison with anterior myocardial infarction Eur JEchocardiogr 201112542ndash549

54 Meimoun P Clerc J Vincent C Flahaut F Germain AL Elmkies F Zemir HLuycx-Bore A Non-invasive detection of Tako-Tsubo cardiomyopathy vs acuteanterior myocardial infarction by transthoracic Doppler echocardiography EurHeart J Cardiovasc Imaging 201314464ndash470

55 Abdelmoneim SS Mankad SV Bernier M Dhoble A Hagen ME Ness SAChandrasekaran K Pellikka PA Oh JK Mulvagh SL Microvascular function inTakotsubo cardiomyopathy with contrast echocardiography prospective evalu-ation and review of literature J Am Soc Echocardiogr 2009221249ndash1255

56 Meimoun P Malaquin D Sayah S Benali T Luycx-Bore A Levy F Zemir HTribouilloy C The coronary flow reserve is transiently impaired in Tako-Tsubocardiomyopathy a prospective study using serial Doppler transthoracic echo-cardiography J Am Soc Echocardiogr 20082172ndash77

57 Rigo F Sicari R Citro R Ossena G Buja P Picano E Diffuse marked reversibleimpairment in coronary microcirculation in stress cardiomyopathy a Dopplertransthoracic echo study Ann Med 200941462ndash470

58 Meimoun P Malaquin D Benali T Boulanger J Zemir H Tribouilloy CTransient impairment of coronary flow reserve in Tako-Tsubo cardiomyopathyis related to left ventricular systolic parameters Eur J Echocardiogr 200810265ndash270

59 Fujiwara S Takeishi Y Isoyama S Aono G Takizawa K Honda H Otomo TMitsuoka M Itoh Y Terashima M Kubota I Meguro T Responsiveness todobutamine stimulation in patients with left ventricular apical ballooning syn-drome Am J Cardiol 20071001600ndash1603

60 Pierard L Picano E Myocardial viability In E Picano ed Stress EchocardiographyFifth Completely Revised and Updated Edition Berlin Heidelberg Springer BerlinHeidelberg 2009 pp 273ndash294

61 Uznanska B Plewka M Wierzbowska-Drabik K Chrzanowski L Kasprzak JDEarly prediction of ventricular recovery in Takotsubo syndrome using stressand contrast echocardiography Med Sci Monit 200915CS89ndashCS94

62 Meimoun P Abouth S Boulanger J Luycx-Bore A Martis S Clerc J

Relationship between acute strain pattern and recovery in Tako-Tsubo cardio-myopathy and acute anterior myocardial infarction a comparative study usingtwo-dimensional longitudinal strain Int J Cardiovasc Imaging 2014301491ndash1500

63 Chandrasegaram MD Celermajer DS Wilson MK Apical ballooning syndromecomplicated by acute severe mitral regurgitation with left ventricular outflowobstructionndashcase report J Cardiothorac Surg 2007214

64 El Mahmoud R Mansencal N Pilliere R Leyer F Abbou N Michaud P NalletO Digne F Lacombe P Cattan S Dubourg O Prevalence and characteristics ofleft ventricular outflow tract obstruction in Tako-Tsubo syndrome Am Heart J2008156543ndash548

65 Parodi G Del Pace S Salvadori C Carrabba N Olivotto I Gensini GF TuscanyRegistry of Tako-Tsubo Cardiomyopathy Left ventricular apical ballooning syn-drome as a novel cause of acute mitral regurgitation J Am Coll Cardiol 200750647ndash649

66 Lyon AR Bossone E Schneider B Sechtem U Citro R Underwood SRSheppard MN Figtree GA Parodi G Akashi YJ Ruschitzka F Filippatos GMebazaa A Omerovic E Current state of knowledge on Takotsubo syndromea Position Statement from the Taskforce on Takotsubo Syndrome of the HeartFailure Association of the European Society of Cardiology Eur J Heart Fail 2016188ndash27

67 Vizzardi E Bonadei I Piovanelli B Bugatti S DrsquoAloia A Biventricular Tako-Tsubo cardiomyopathy usefulness of 2D speckle tracking strain echocardiog-raphy J Clin Ultrasound 201442121ndash124

68 Ishida T Yasu T Arao K Kawakami M Saito M Images in cardiovascular medi-cine Bedside diagnosis of cardiac rupture by contrast echocardiographyCirculation 2005112e354ndashe355

69 Haghi D Papavassiliu T Heggemann F Kaden JJ Borggrefe M Suselbeck TIncidence and clinical significance of left ventricular thrombus in Tako-Tsubocardiomyopathy assessed with echocardiography QJM 2008101381ndash386

70 Buchholz S Ward MR Bhindi R Nelson GI Figtree GA Grieve SM Cardiacthrombi in stress (Tako-Tsubo) cardiomyopathy more than an apical issueMayo Clin Proc 201085863ndash864

71 Citro R Rigo F DrsquoAndrea A Ciampi Q Parodi G Provenza G Piccolo R MirraM Zito C Giudice R Patella MM Antonini-Canterin F Bossone E Piscione FSalerno-Uriarte J Tako-Tsubo Italian Network Investigators Echocardiographiccorrelates of acute heart failure cardiogenic shock and in-hospital mortality inTako-Tsubo cardiomyopathy JACC Cardiovasc Imaging 20147119ndash129

72 Tsuchihashi K Ueshima K Uchida T Oh-Mura N Kimura K Owa MYoshiyama M Miyazaki S Haze K Ogawa H Honda T Hase M Kai R Morii IAngina Pectoris-Myocardial Infarction Investigations in Japan Transient left ven-tricular apical ballooning without coronary artery stenosis a novel heart syn-drome mimicking acute myocardial infarction Angina Pectoris-MyocardialInfarction Investigations in Japan J Am Coll Cardiol 20013811ndash18

73 Margey R Diamond P McCann H Sugrue D Dobutamine stress echo-inducedapical ballooning (Takotsubo) syndrome Eur J Echocardiogr 200910395ndash399

74 Wittstein IS Thiemann DR Lima JA Baughman KL Schulman SP GerstenblithG Wu KC Rade JJ Bivalacqua TJ Champion HC Neurohumoral features ofmyocardial stunning due to sudden emotional stress N Engl J Med 2005352539ndash548

75 Champ-Rigot L Alexandre J Grollier G Milliez P Atypical Tako-tsubo syn-drome a morphologic variant or a step towards recovery Int J Cardiol 2011146256ndash258

76 Brunetti ND Ieva R Rossi G Barone N De Gennaro L Pellegrino PL MavilioG Cuculo A Di Biase M Ventricular outflow tract obstruction systolic anteriormotion and acute mitral regurgitation in Tako-Tsubo syndrome Int J Cardiol2008127e152ndashe157

77 Gogas BD Antoniadis AG Zacharoulis AA Kolokathis F Lekakis J KremastinosDT Recurrent apical ballooning syndrome lsquoThe masquerading acute cardiacsyndromersquo Int J Cardiol 2011150e17ndashe19

78 Ghadri JR Jaguszewski M Corti R Luscher TF Templin C Different wall mo-tion patterns of three consecutive episodes of Takotsubo cardiomyopathy inthe same patient Int J Cardiol 2012160e25ndashe27

79 Murugiah K Wang Y Desai NR Spatz ES Nuti SV Dreyer RP Krumholz HMTrends in short- and long-term outcomes for Takotsubo cardiomyopathyamong medicare fee-for-service beneficiaries 2007 to 2012 JACC Heart Fail20164197ndash205

80 Athanasiadis A Schneider B Sechtem U Role of cardiovascular magnetic reson-ance in Takotsubo cardiomyopathy Heart Fail Clin 20139167ndash176 viii

81 Templin C Ghadri JR Napp LC Takotsubo (Stress) Cardiomyopathy N Engl JMed 20153732689ndash2691

82 Eitel I von Knobelsdorff-Brenkenhoff F Bernhardt P Carbone I Muellerleile KAldrovandi A Francone M Desch S Gutberlet M Strohm O Schuler GSchulz-Menger J Thiele H Friedrich MG Clinical characteristics and cardiovas-cular magnetic resonance findings in stress (Takotsubo) cardiomyopathy JAMA2011306277ndash286

83 Wu KC Weiss RG Thiemann DR Kitagawa K Schmidt A Dalal D Lai SBluemke DA Gerstenblith G Marban E Tomaselli GF Lima JA Late gadoliniumenhancement by cardiovascular magnetic resonance heralds an adverse progno-sis in nonischemic cardiomyopathy J Am Coll Cardiol 2008512414ndash2421

84 Rolf A Nef HM Mollmann H Troidl C Voss S Conradi G Rixe J Steiger HBeiring K Hamm CW Dill T Immunohistological basis of the late gadoliniumenhancement phenomenon in Tako-Tsubo cardiomyopathy Eur Heart J 2009301635ndash1642

85 Heidary S Patel H Chung J Yokota H Gupta SN Bennett MV Katikireddy CNguyen P Pauly JM Terashima M McConnell MV Yang PC Quantitative tissuecharacterization of infarct core and border zone in patients with ischemic car-diomyopathy by magnetic resonance is associated with future cardiovascularevents J Am Coll Cardiol 2010552762ndash2768

86 Eitel I Friedrich MG T2-weighted cardiovascular magnetic resonance in acutecardiac disease J Cardiovasc Magn Reson 20111313

87 Stahli BE Ruschitzka F Enseleit F Isolated right ventricular ballooning syn-drome a new variant of transient cardiomyopathy Eur Heart J 2011321821

88 Kagiyama N Okura H Tamada T Imai K Yamada R Kume T Hayashida ANeishi Y Kawamoto T Yoshida K Impact of right ventricular involvement onthe prognosis of Takotsubo cardiomyopathy Eur Heart J Cardiovasc Imaging201617210ndash216

89 Eitel I Behrendt F Schindler K Kivelitz D Gutberlet M Schuler G Thiele HDifferential diagnosis of suspected apical ballooning syndrome using contrast-enhanced magnetic resonance imaging Eur Heart J 2008292651ndash2659

90 Abe Y Kondo M Matsuoka R Araki M Dohyama K Tanio H Assessment ofclinical features in transient left ventricular apical ballooning J Am Coll Cardiol200341737ndash742

91 Ghadri JR Dougoud S Maier W Kaufmann PA Gaemperli O Prasad ALuscher TF Templin C A PETCT-follow-up imaging study to differentiateTakotsubo cardiomyopathy from acute myocardial infarction Int J CardiovascImaging 201430207ndash209

92 Ito K Sugihara H Kawasaki T Yuba T Doue T Tanabe T Adachi Y Katoh SAzuma A Nakagawa M Assessment of ampulla (Takotsubo) cardiomyopathywith coronary angiography two-dimensional echocardiography and 99mTc-tetrofosmin myocardial single photon emission computed tomography AnnNucl Med 200115351ndash355

93 Cimarelli S Imperiale A Ben-Sellem D Rischner J Detour J Morel O OhlmannP Constantinesco A Nuclear medicine imaging of Takotsubo cardiomyopathytypical form and midventricular ballooning syndrome J Nucl Cardiol 200815137ndash141

94 Cimarelli S Sauer F Morel O Ohlmann P Constantinesco A Imperiale ATransient left ventricular dysfunction syndrome patho-physiological basesthrough nuclear medicine imaging Int J Cardiol 2010144212ndash218

95 Christensen TE Ahtarovski KA Bang LE Holmvang L Soslashholm H Ghotbi AAAndersson H Vejlstrup N Ihlemann N Engstroslashm T Kjaeligr A Hasbak P Basalhyperaemia is the primary abnormality of perfusion in Takotsubo cardiomyop-athy a quantitative cardiac perfusion positron emission tomography study EurHeart J Cardiovasc Imaging 2015161162ndash1169

96 Kurisu S Inoue I Kawagoe T Ishihara M Shimatani Y Nishioka K Umemura TNakamura S Yoshida M Sato H Myocardial perfusion and fatty acid metabol-ism in patients with Tako-Tsubo-like left ventricular dysfunction J Am CollCardiol 200341743ndash748

97 Matsuo S Nakajima K Kinuya S Yamagishi M Diagnostic utility of 123I-BMIPPimaging in patients with Takotsubo cardiomyopathy J Cardiol 20146449ndash56

98 Yoshida T Hibino T Kako N Murai S Oguri M Kato K Yajima K Ohte NYokoi K Kimura G A pathophysiologic study of Tako-Tsubo cardiomyopathywith F-18 fluorodeoxyglucose positron emission tomography Eur Heart J 2007282598ndash2604

99 Dorfman TA Iskandrian AE Takotsubo cardiomyopathy state-of-the-art re-view J Nucl Cardiol 200916122ndash134

100 Merli E Sutcliffe S Gori M Sutherland GG Tako-Tsubo cardiomyopathy newinsights into the possible underlying pathophysiology Eur J Echocardiogr 2006753ndash61

101 Akashi YJ Nakazawa K Sakakibara M Miyake F Musha H Sasaka K 123I-MIBGmyocardial scintigraphy in patients with lsquoTakotsuborsquo cardiomyopathy J NuclMed 2004451121ndash1127

102 Prasad A Madhavan M Chareonthaitawee P Cardiac sympathetic activity instress-induced (Takotsubo) cardiomyopathy Nat Rev Cardiol 20096430ndash434

103 Tornvall P Collste O Ehrenborg E Jarnbert-Petterson H A case-control studyof risk markers and mortality in Takotsubo stress cardiomyopathy J Am CollCardiol 2016671931ndash1936

104 Stiermaier T Eitel C Desch S Fuernau G Schuler G Thiele H Eitel IIncidence determinants and prognostic relevance of cardiogenic shock in pa-tients with Takotsubo cardiomyopathy Eur Heart J Acute Cardiovasc Care 20165489ndash496

105 Roffi M Patrono C Collet JP Mueller C Valgimigli M Andreotti F Bax JJ

Borger MA Brotons C Chew DP Gencer B Hasenfuss G Kjeldsen KLancellotti P Landmesser U Mehilli J Mukherjee D Storey RF Windecker SBaumgartner H Gaemperli O Achenbach S Agewall S Badimon L Baigent CBueno H Bugiardini R Carerj S Casselman F Cuisset T Erol C Fitzsimons DHalle M Hamm C Hildick-Smith D Huber K Iliodromitis E James S Lewis BSLip GY Piepoli MF Richter D Rosemann T Sechtem U Steg PG Vrints C LuisZamorano J Management of Acute Coronary Syndromes in Patients Presentingwithout Persistent ST-Segment Elevation of the European Society ofCardiology 2015 ESC Guidelines for the management of acute coronary syn-dromes in patients presenting without persistent ST-segment elevation taskForce for the Management of Acute Coronary Syndromes in PatientsPresenting without Persistent ST-Segment Elevation of the European Society ofCardiology (ESC) Eur Heart J 201637267ndash315

106 Task Force on the management of ST-segment elevation acute myocardial in-farction of the European Society of Cardiology (ESC) Steg PG James SK AtarD Badano LP Blomstrom-Lundqvist C Borger MA Mario C D Dickstein KDucrocq G Fernandez-Aviles F Gershlick AH Giannuzzi P Halvorsen SHuber K Juni P Kastrati A Knuuti J Lenzen MJ Mahaffey KW Valgimigli M vanrsquot Hof A Widimsky P Zahger D ESC Guidelines for the management of acutemyocardial infarction in patients presenting with ST-segment elevation EurHeart J 2012332569ndash2619

107 Amsterdam EA Wenger NK Brindis RG Casey DE Jr Ganiats TG Holmes DRJr Jaffe AS Jneid H Kelly RF Kontos MC Levine GN Liebson PR MukherjeeD Peterson ED Sabatine MS Smalling RW Zieman SJ American College of CAmerican Heart Association Task Force on Practice G Society forCardiovascular A Interventions Society of Thoracic S American Associationfor Clinical C 2014 AHAACC Guideline for the Management of Patients withNon-ST-Elevation Acute Coronary Syndromes a report of the AmericanCollege of CardiologyAmerican Heart Association Task Force on PracticeGuidelines J Am Coll Cardiol 201464e139ndashe228

108 OrsquoGara PT Kushner FG Ascheim DD Casey DE Jr Chung MK de Lemos JAEttinger SM Fang JC Fesmire FM Franklin BA Granger CB Krumholz HMLinderbaum JA Morrow DA Newby LK Ornato JP Ou N Radford MJ Tamis-Holland JE Tommaso CL Tracy CM Woo YJ Zhao DX Anderson JL JacobsAK Halperin JL Albert NM Brindis RG Creager MA DeMets D Guyton RAHochman JS Kovacs RJ Kushner FG Ohman EM Stevenson WG Yancy CWAmerican College of Cardiology FoundationAmerican Heart Association TaskForce on Practice G 2013 ACCFAHA guideline for the management of ST-elevation myocardial infarction a report of the American College of CardiologyFoundationAmerican Heart Association Task Force on Practice GuidelinesCirculation 2013127e362ndashe425

109 Brinjikji W El-Sayed AM Salka S In-hospital mortality among patients withTakotsubo cardiomyopathy a study of the National Inpatient Sample 2008 to2009 Am Heart J 2012164215ndash221

110 Sobue Y Watanabe E Ichikawa T Koshikawa M Yamamoto M Harada MOzaki Y Physically triggered Takotsubo cardiomyopathy has a higher in-hospital mortality rate Int J Cardiol 201723587ndash93

111 Murakami T Yoshikawa T Maekawa Y Ueda T Isogai T Konishi Y Sakata KNagao K Yamamoto T Takayama M Committee CCUNS Characterization ofpredictors of in-hospital cardiac complications of Takotsubo cardiomyopathymulti-center registry from Tokyo CCU Network J Cardiol 201463269ndash273

112 Takashio S Yamamuro M Kojima S Izumiya Y Kaikita K Hokimoto S SugiyamaS Tsunoda R Nakao K Ogawa H Usefulness of SUM of ST-segment elevationon electrocardiograms (limb leads) for predicting in-hospital complications inpatients with stress (Takotsubo) cardiomyopathy Am J Cardiol 20121091651ndash1656

113 Stiermaier T Eitel C Denef S Desch S Schuler G Thiele H Eitel I Significanceof life-threatening arrhythmias in takotsubo cardiomyopathy J Am Coll Cardiol2015652148ndash2150

114 Icli A Akilli H Kayrak M Aribas A Ozdemir K Short-term warfarin treatmentfor apical thrombus in a patient with Takotsubo cardiomyopathy Cardiovasc JAfr 201627e12ndashe13

115 Bharathi KS Kulkarni S Sadananda KS Gurudatt CL Takotsubo cardiomyop-athy precipitated by negative pressure pulmonary oedema following total thy-roidectomy Indian J Anaesth 201660202ndash205

116 Lu DY Caplow J Quatromoni N Forde-McLean R Owens AT Ventricularseptal defect from Takotsubo syndrome Case Rep Cardiol 201620162693062

117 Jaguszewski M Fijalkowski M Nowak R Czapiewski P Ghadri JR Templin CRynkiewicz A Ventricular rupture in Takotsubo cardiomyopathy Eur Heart J2012331027

118 Bohm M Cammann VL Ghadri JR Ukena C Gili S Di Vece D Kato K Ding KJSzawan KA Micek J Jurisic S DrsquoAscenzo F Frangieh AH Rechsteiner D SeifertB Ruschitzka F Luscher T Templin C InterTAK Collaborators Interaction ofsystolic blood pressure and resting heart rate with clinical outcomes in

takotsubo syndrome insights from the International Takotsubo Registry Eur JHeart Fail 2018 doi 101002ejhf1162

119 Citro R Bossone E Parodi G Rigo F Nardi F Provenza G Zito C Novo GVitale G Prota C Silverio A Vriz O Drsquoandrea A Antonini-Canterin F Salerno-Uriarte J Piscione F Tako-tsubo Italian Network Investigators Independent im-pact of RV involvement on in-hospital outcome of patients with Takotsubo syn-drome JACC Cardiovasc Imaging 20169894ndash895

120 Elesber AA Prasad A Lennon RJ Wright RS Lerman A Rihal CS Four-year re-currence rate and prognosis of the apical ballooning syndrome J Am Coll Cardiol200750448ndash452

121 Sharkey SW Pink VR Lesser JR Garberich RF Maron MS Maron BJ Clinicalprofile of patients with high-risk Tako-Tsubo cardiomyopathy Am J Cardiol2015116765ndash772

122 Stiermaier T Moeller C Oehler K Desch S Graf T Eitel C Vonthein RSchuler G Thiele H Eitel I Long-term excess mortality in Takotsubo cardiomy-opathy predictors causes and clinical consequences Eur J Heart Fail 201618650ndash656

123 Madias JE Low prevalence of diabetes mellitus in patients with Takotsubo syn-drome a plausible 0protective0 effect with pathophysiologic connotations EurHeart J Acute Cardiovasc Care 20165164ndash170

124 Bill V El-Battrawy I Behnes M Baumann S Becher T Elmas E Hoffmann UHaghi D Fastner C Kuschyk J Papavassiliu T Borggrefe M Akin I lsquoDiabetesparadoxrsquo in Takotsubo Cardiomyopathy Int J Cardiol 201622488ndash89

125 Dias A Franco E Rubio M Koshkelashvili N Bhalla V Amanullah S Hebert KFigueredo VM Takotsubo Syndrome does it matter if you have diabetes melli-tus Int J Cardiol 2016224398ndash399

126 Bonello L Com O Ait-Moktar O Theron A Moro PJ Salem A Sbragia PPaganelli F Ventricular arrhythmias during Tako-tsubo syndrome Int J Cardiol2008128e50ndashe53

127 Syed FF Asirvatham SJ Francis J Arrhythmia occurrence with Takotsubo car-diomyopathy a literature review Europace 201113780ndash788

128 Madias C Fitzgibbons TP Alsheikh-Ali AA Bouchard JL Kalsmith B GarlitskiAC Tighe DA Estes NA 3rd Aurigemma GP Link MS Acquired long QT syn-drome from stress cardiomyopathy is associated with ventricular arrhythmiasand torsades de pointes Heart Rhythm 20118555ndash561

129 Brown KH Trohman RG Madias C Arrhythmias in Takotsubo cardiomyop-athy Card Electrophysiol Clin 20157331ndash340

130 Migliore F Zorzi A Peruzza F Perazzolo Marra M Tarantini G Iliceto SCorrado D Incidence and management of life-threatening arrhythmias inTakotsubo syndrome Int J Cardiol 2013166261ndash263

131 Perazzolo Marra M Zorzi A Corbetti F De Lazzari M Migliore F Tona FTarantini G Iliceto S Corrado D Apicobasal gradient of left ventricular myo-cardial edema underlies transient T-wave inversion and QT interval prolonga-tion (Wellensrsquo ECG pattern) in Tako-Tsubo cardiomyopathy Heart Rhythm20131070ndash77

132 Gasparetto N Zorzi A Perazzolo Marra M Migliore F Napodano M CorradoD Iliceto S Cacciavillani L Atypical (mid-ventricular) Takotsubo syndrome in asurvival of out-of-hospital ventricular fibrillation cause or consequence Int JCardiol 2014172e51ndashe53

133 Zorzi A Perazzolo Marra M Migliore F De Lazzari M Tarantini G Iliceto SCorrado D Relationship between repolarization abnormalities and myocar-dial edema in atypical Tako-Tsubo syndrome J Electrocardiol 201346348ndash351

134 Ohkubo K Watanabe I Okumura Y Ashino S Kofune M Nagashima K NakaiT Kasamaki Y Hirayama A Functional atrioventricular conduction block in anelderly patient with acquired long QT syndrome elucidation of the mechanismof block J Electrocardiol 201144353ndash356

135 Sharkey SW Windenburg DC Lesser JR Maron MS Hauser RG Lesser JNHaas TS Hodges JS Maron BJ Natural history and expansive clinical profile ofstress (Tako-Tsubo) cardiomyopathy J Am Coll Cardiol 201055333ndash341

136 Cattaneo M Moccetti M Pasotti E Faletra F Porretta AP Kobza R Gallino AThree recurrent episodes of apical-ballooning Takotsubo cardiomyopathy in aman Circulation 2015132e377ndashe379

137 Srivastava NT Parent JJ Hurwitz RA Recurrent Takotsubo cardiomyopathy ina child Cardiol Young 201626410ndash412

138 Xu B Williams PD Brown M Macisaac A Takotsubo cardiomyopathy does re-currence tend to occur in a previously unaffected ventricular wall regionCirculation 2014129e339ndashe340

139 Kato K Lyon AR Ghadri JR Templin C Takotsubo syndrome aetiology pres-entation and treatment Heart 20171031461ndash1469

140 Isogai T Matsui H Tanaka H Fushimi K Yasunaga H Early b-blocker use andin-hospital mortality in patients with takotsubo cardiomyopathy Heart 20161021029ndash1035

141 Dias A Franco E Koshkelashvili N Bhalla V Pressman GS Hebert K FigueredoVM Antiplatelet therapy in Takotsubo cardiomyopathy does it improve cardio-vascular outcomes during index event Heart Vessels 2016311285ndash1290

142 Santoro F Ieva R Musaico F Ferraretti A Triggiani G Tarantino N Di Biase M

Brunetti ND Lack of efficacy of drug therapy in preventing takotsubo cardio-myopathy recurrence a meta-analysis Clin Cardiol 201437434ndash439

143 Santoro F Ieva R Ferraretti A Ienco V Carpagnano G Lodispoto M Di BiaseL Di Biase M Brunetti ND Safety and feasibility of levosimendan administrationin Takotsubo cardiomyopathy a case series Cardiovasc Ther 201331e133ndashe137

144 Singh K Carson K Usmani Z Sawhney G Shah R Horowitz J Systematic re-view and meta-analysis of incidence and correlates of recurrence of Takotsubocardiomyopathy Int J Cardiol 2014174696ndash701

145 Citro R Lyon AR Meimoun P Omerovic E Redfors B Buck T Lerakis SParodi G Silverio A Eitel I Schneider B Prasad A Bossone E Standard andadvanced echocardiography in Takotsubo (stress) cardiomyopathy clinical andprognostic implications J Am Soc Echocardiogr 20152857ndash74

146 Munzel T Knorr M Schmidt F von Bardeleben S Gori T Schulz E Airbornedisease a case of a Takotsubo cardiomyopathie as a consequence of nighttimeaircraft noise exposure Eur Heart J 2016372844

147 Madias JE If channel blocker ivabradine vs beta-blockers for sinus tachycardiain patients with Takotsubo syndrome Int J Cardiol 2016223877ndash878

148 Ueyama T Kasamatsu K Hano T Yamamoto K Tsuruo Y Nishio I Emotionalstress induces transient left ventricular hypocontraction in the rat via activationof cardiac adrenoceptors a possible animal model of lsquoTako-Tsuborsquo cardiomyop-athy Circ J 200266712ndash713

149 Izumi Y Okatani H Shiota M Nakao T Ise R Kito G Miura K Iwao H Effectsof metoprolol on epinephrine-induced Takotsubo-like left ventricular dysfunc-tion in non-human primates Hypertens Res 200932339ndash346

150 Stiermaier T Rommel KP Eitel C Moller C Graf T Desch S Thiele H Eitel IManagement of arrhythmias in patients with Takotsubo cardiomyopathy is theimplantation of permanent devices necessary Heart Rhythm 2016131979ndash1986

151 Peters S Klein HU WCD LifeVest risk stratification in a case of Tako-Tsubocardiomyopathy with QT interval prolongation Herz 201237219ndash221

152 Ueyama T Kasamatsu K Hano T Tsuruo Y Ishikura F Catecholamines and es-trogen are involved in the pathogenesis of emotional stress-induced acute heartattack Ann N Y Acad Sci 20081148479ndash485

153 Ueyama T Ishikura F Matsuda A Asanuma T Ueda K Ichinose M KasamatsuK Hano T Akasaka T Tsuruo Y Morimoto K Beppu S Chronic estrogen sup-plementation following ovariectomy improves the emotional stress-inducedcardiovascular responses by indirect action on the nervous system and by dir-ect action on the heart Circ J 200771565ndash573

154 Delmas C Lairez O Mulin E Delmas T Boudou N Dumonteil N Biendel-Picquet C Roncalli J Elbaz M Galinier M Carrie D Anxiodepressive dis-orders and chronic psychological stress are associated with Tako-Tsubocardiomyopathymdashnew physiopathological hypothesis Circ J 201377175ndash180

155 Mayer KN Ghadri J-R Jaguszewski M Scherff F Saguner AM Kazemian EBaumann CR Jenewein J Tsakiris M Luscher TF Brugger P Templin CTakotsubo syndromemdasha close connection to the brain a prospectivestudy investigating neuropsychiatric traits IJC Metab Endocr 20161236ndash41

156 Ghadri JR Ruschitzka F Luscher TF Templin C Takotsubo cardiomyopathystill much more to learn Heart 20141001804ndash1812

ehy077-TF1

ehy077-TF22

Japan 17Department of Cardiac Thoracic and Vascular Sciences University of Padua Medical School Padova Italy 18Department of Cardiovascular Medicine HiroshimaUniversity Graduate School of Biomedical and Health Sciences Hiroshima Japan 19Division of Cardiovascular Disease Department of Medicine University of Florida GainesvilleFL USA 20NIHR Cardiovascular Biomedical Research Unit Royal Brompton Hospital London UK 21National Heart and Lung Institute Imperial College London UK22Department of Cardiology Sahlgrenska University Hospital Gothenburg Sweden 23Department of Molecular and Clinical Medicine Institute of Medicine SahlgrenskaAcademy Gothenburg University Gothenburg Sweden 24Department of Cardiology Leiden University Medical Center Leiden The Netherlands 25Department of Cardiologyand Intensive Care Centre Hospitalier de Compiegne Compiegne France 26Department of Cardiology Karolinska University Hospital Huddinge Stockholm Sweden27Department of Cardiology Basil Hetzel Institute Queen Elizabeth Hospital University of Adelaide Adelaide Australia 28Department of Cardiovascular Medicine TohokuUniversity Graduate School of Medicine Sendai Japan 29Center for Molecular Cardiology Schlieren Campus University of Zurich Zurich Switzerland and 30Department ofCardiology Royal Brompton amp Harefield Hospital and Imperial College London UK

Received 1 June 2017 revised 23 November 2017 editorial decision 30 January 2018 accepted 11 April 2018 online publish-ahead-of-print 29 May 2018

The clinical expert consensus statement on takotsubo syndrome (TTS) part II focuses on the diagnostic workup outcome andmanagement The recommendations are based on interpretation of the limited clinical trial data currently available and experience ofinternational TTS experts It summarizes the diagnostic approach which may facilitate correct and timely diagnosis Furthermorethe document covers areas where controversies still exist in risk stratification and management of TTS Based on available data thedocument provides recommendations on optimal care of such patients for practising physicians

Keywords Takotsubo syndrome bull Broken heart syndrome bull Acute heart failure bull Consensus statement bull Diagnosticalgorithm

Outline

Diagnostic workup 2048Electrocardiogram 2048

ST-segment elevation 2049T-wave inversion and QT interval prolongation 2049Other electrocardiographic findings 2050

InterTAK Diagnostic Score 2050Biomarkers 2051

Markers of myocardial necrosis 2051B-type natriuretic peptide and N-terminal prohormone of brainnatriuretic peptide 2051Other potential biomarkers 2051

Imaging 2051Coronary angiography and ventriculography 2051Echocardiography 2051Cardiac computed tomography angiography 2052Cardiac magnetic resonance imaging 2053Cardiac nuclear imaging 2053

Perfusion imaging 2053Metabolic imaging 2053Sympathetic nervous imaging 2053

Complications and outcomes 2053Arrhythmias 2055

Ventricular arrhythmias 2055Other cardiac arrhythmias 2055

Recurrence 2055Therapeutic management 2056

Pre-hospital treatment 2056Acute treatment 2056Long-term treatment 2057

Future directions 2058Key questions 2058Prospective approaches 2058

References 2058

Diagnostic workup

A diagnostic algorithm for takotsubo syndrome (TTS) is proposed bythe expert committee (Figure 1) Patients presenting with ST-segmentelevation should undergo urgent coronary angiography (CAG) withleft ventriculography to exclude acute myocardial infarction (AMI) Inpatients with non ST-segment elevation the InterTAK DiagnosticScore can be considered While an InterTAK Score lt_70 points sug-gests a low to intermediate probability of TTS a score gt_70 indicates ahigh probability for the presence of TTS Patients with a low probabil-ity should undergo CAG with left ventriculography while in patientswith a high score transthoracic echocardiography (TTE) should beconsidered In the absence of a circumferential ballooning patternCAG is recommended In stable patients with circumferential balloon-ing pattern coronary computed tomography angiography (CCTA) isfavoured to exclude coronary artery disease (CAD) In unstable pa-tients typical complications of TTS such as left ventricular outflowtract obstruction (LVOTO) should be determined with TTE andCAG to safely rule out AMI In patients with normal coronaries onCCTA or CAG and typical ballooning patterns without lsquored flagsrsquo ofacute infectious myocarditis TTS is the most likely diagnosis and canbe confirmed after follow-up echocardiography In case of positivelsquored flagsrsquo of acute infectious myocarditis cardiac magnetic resonance(CMR) should be performed to confirm the diagnosis

ElectrocardiogramThe initial electrocardiogram (ECG) is abnormal in most patients withTTS usually demonstrating ischaemic ST-segment elevation T-waveinversion or both1ndash4 In the InterTAK Registry ST-segment elevationwas present in 44 ST-segment depression in 8 T-wave inversionin 41 and left bundle branch block in 52 As in acute coronarysyndrome (ACS) the ECG in TTS demonstrates temporal evolutiontypically with resolution of initial ST-segment elevation (if present) fol-lowed by progressive T-wave inversion and QT interval prolongation

stniop 52xes elameF

le 70 points

gt 70 points

Distal LAD flow

visualization

Significant MR

RV involvement

TTE follow-up

Coronary culprit

the whole RWMA

TTS confirmed

Stable patient

Persistend RWMA

Echocardiography

EchocardiographyA B

3) 4) 5)

1) 2)2))3)2)1

Frequent

Moderate

patients

Outcome

measures

ACEI Not beneficial

ACEIARB Beneficial

Future directions

ehy077-TF1

ehy077-TF22

stniop 52xes elameF

le 70 points

gt 70 points

Distal LAD flow

visualization

Significant MR

RV involvement

TTE follow-up

Coronary culprit

the whole RWMA

TTS confirmed

Stable patient

Persistend RWMA

Echocardiography

EchocardiographyA B

3) 4) 5)

1) 2)2))3)2)1

Frequent

Moderate

patients

Outcome

measures

ACEI Not beneficial

ACEIARB Beneficial

Future directions

ehy077-TF1

ehy077-TF22

Echocardiography

EchocardiographyA B

3) 4) 5)

1) 2)2))3)2)1

Frequent

Moderate

patients

Outcome

measures

ACEI Not beneficial

ACEIARB Beneficial

Future directions

ehy077-TF1

ehy077-TF22

Echocardiography

EchocardiographyA B

3) 4) 5)

1) 2)2))3)2)1

Frequent

Moderate

patients

Outcome

measures

ACEI Not beneficial

ACEIARB Beneficial

Future directions

ehy077-TF1

ehy077-TF22

EchocardiographyA B

3) 4) 5)

1) 2)2))3)2)1

Frequent

Moderate

patients

Outcome

measures

ACEI Not beneficial

ACEIARB Beneficial

Future directions

ehy077-TF1

ehy077-TF22

Frequent

Moderate

patients

Outcome

measures

ACEI Not beneficial

ACEIARB Beneficial

Future directions

ehy077-TF1

ehy077-TF22

Frequent

Moderate

patients

Outcome

measures

ACEI Not beneficial

ACEIARB Beneficial

Future directions

ehy077-TF1

ehy077-TF22

patients

Outcome

measures

ACEI Not beneficial

ACEIARB Beneficial

Future directions

ehy077-TF1

ehy077-TF22

patients

Outcome

measures

ACEI Not beneficial

ACEIARB Beneficial

Future directions

ehy077-TF1

ehy077-TF22

Future directions

ehy077-TF1

ehy077-TF22

Future directions

ehy077-TF1

ehy077-TF22

ehy077-TF1

ehy077-TF22

ehy077-TF1

ehy077-TF22

ehy077-TF1

ehy077-TF22

ehy077-TF1

ehy077-TF22

Documents

InternationalExpertConsensusDocument onTakotsuboSyndrome ... · The clinical expert consensus statement on takotsubo syndrome (TTS) part II focuses on the diagnostic workup, outcome,