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Year:2015
ClinicalFeaturesandOutcomesofTakotsubo(Stress)Cardiomyopathy
Templin,Christian;Ghadri,JR;Diekmann,J;Napp,LC;Seifert,Burkhardt;etal
Abstract:BACKGROUNDThenaturalhistory,management,andoutcomeoftakotsubo(stress)car-
diomyopathyareincompletelyunderstood.METHODSTheInternationalTakotsuboRegistry,acon-
sortiumof26centersinEuropeandtheUnitedStates,wasestablishedtoinvestigateclinicalfeatures,
prognosticpredictors,andoutcomeoftakotsubocardiomyopathy.Patientswerecomparedwithage-and
sex-matchedpatientswhohadanacutecoronarysyndrome.RESULTSOf1750patientswithtakotsubo
cardiomyopathy,89.8%werewomen(meanage,66.8years).Emotionaltriggerswerenotascommon
asphysicaltriggers(27.7%vs.36.0%),and28.5%ofpatientshadnoevidenttrigger.Amongpatients
with takotsubo cardiomyopathy, as compared with an acute coronarysyndrome,rates of neurologic
orpsychiatricdisorderswerehigher(55.8%vs.25.7%)andthemeanleftventricularejectionfraction
wasmarkedlylower(40.7±11.2%vs.51.5±12.3%)(P<0.001forbothcomparisons).Ratesofsevere
in-hospitalcomplicationsincludingshockanddeathweresimilarinthetwogroups(P=0.93).Physical
triggers,acuteneurologicorpsychiatricdiseases,hightroponinlevels,andalowejectionfractiononad-
missionwereindependentpredictorsforin-hospitalcomplications. Duringlong-termfollow-up,therate
ofmajoradversecardiacandcerebrovasculareventswas9.9%perpatient-year,andtherateofdeathwas
5.6%perpatient-year.CONCLUSIONSPatientswithtakotsubocardiomyopathyhadahigherprevalence
ofneurologicorpsychiatricdisordersthandidthosewithanacutecoronarysyndrome.Thiscondition
representsanacuteheartfailuresyndromewithsubstantialmorbidityandmortality.(Fundedbythe
Mach-GaensslenFoundationandothers;ClinicalTrials.govnumber,NCT01947621.).
DOI:https://doi.org/10.1056/NEJMoa1406761
PostedattheZurichOpenRepositoryandArchive,UniversityofZurich
ZORAURL:https://doi.org/10.5167/uzh-112874
JournalArticle
PublishedVersion
Originallypublishedat:
Templin,Christian;Ghadri,JR;Diekmann,J;Napp,LC;Seifert,Burkhardt;etal(2015).Clinical
Features and Outcomes of Takotsubo (Stress) Cardiomyopathy.New England Journal of Medicine,
373(10):929-938.
DOI:https://doi.org/10.1056/NEJMoa1406761
The
new england journal
of
medicine
n engl j med 373;10 nejm.org September 3, 2015
929
The authors’ full names, academic degrees,
and affiliations are listed in the Appendix.
Address reprint requests to Dr. Templin
at the University Hospital Zurich, Univer-
sity Heart Center, Department of Cardiol-
ogy, Rämistr. 100, 8091 Zurich, Switzer-
land, or at christian . templin@ usz . ch.
Drs. Templin and Ghadri contributed
equally to this article.
N Engl J Med 2015;373:929-38.
DOI: 10.1056/NEJMoa1406761
Copyright © 2015 Massachusetts Medical Society.
BACKGROUND
The natural history, management, and outcome of takotsubo (stress) cardiomyopa-
thy are incompletely understood.
METHODS
The International Takotsubo Registry, a consortium of 26 centers in Europe and
the United States, was established to investigate clinical features, prognostic pre-
dictors, and outcome of takotsubo cardiomyopathy. Patients were compared with
age- and sex-matched patients who had an acute coronary syndrome.
RESULT S
Of 1750 patients with takotsubo cardiomyopathy, 89.8% were women (mean age,
66.8 years). Emotional triggers were not as common as physical triggers (27.7%
vs. 36.0%), and 28.5% of patients had no evident trigger. Among patients with
takotsubo cardiomyopathy, as compared with an acute coronary syndrome, rates
of neurologic or psychiatric disorders were higher (55.8% vs. 25.7%) and the mean
left ventricular ejection fraction was markedly lower (40.7±11.2% vs. 51.5±12.3%)
(P<0.001 for both comparisons). Rates of severe in-hospital complications includ-
ing shock and death were similar in the two groups (P = 0.93). Physical triggers,
acute neurologic or psychiatric diseases, high troponin levels, and a low ejection
fraction on admission were independent predictors for in-hospital complications.
During long-term follow-up, the rate of major adverse cardiac and cerebrovascular
events was 9.9% per patient-year, and the rate of death was 5.6% per patient-year.
CONCLUSIONS
Patients with takotsubo cardiomyopathy had a higher prevalence of neurologic or
psychiatric disorders than did those with an acute coronary syndrome. This condi-
tion represents an acute heart failure syndrome with substantial morbidity and
mortality. (Funded by the Mach-Gaensslen Foundation and others; ClinicalTrials
.gov number, NCT01947621.)
ABSTRACT
Clinical Features and Outcomes
of Takotsubo (Stress) Cardiomyopathy
C. Templin, J.R. Ghadri, J. Diekmann, L.C. Napp, D.R. Bataiosu, M. Jaguszewski,
V.L. Cammann, A. Sarcon, V. Geyer, C.A. Neumann, B. Seifert, J. Hellermann,
M. Schwyzer, K. Eisenhardt, J. Jenewein, J. Franke, H.A. Katus, C. Burgdorf,
H. Schunkert, C. Moeller, H. Thiele, J. Bauersachs, C. Tschöpe, H.-P. Schultheiss,
C.A. Laney, L. Rajan, G. Michels, R. Pfister, C. Ukena, M. Böhm, R. Erbel,
A. Cuneo, K.-H. Kuck, C. Jacobshagen, G. Hasenfuss, M. Karakas, W. Koenig,
W. Rottbauer, S.M. Said, R.C. Braun-Dullaeus, F. Cuculi, A. Banning, T.A. Fischer,
T. Vasankari, K.E.J. Airaksinen, M. Fijalkowski, A. Rynkiewicz, M. Pawlak,
G. Opolski, R. Dworakowski, P. MacCarthy, C. Kaiser, S. Osswald, L. Galiuto,
F. Crea, W. Dichtl, W.M. Franz, K. Empen, S.B. Felix, C. Delmas, O. Lairez,
P. Erne, J.J. Bax, I. Ford, F. Ruschitzka, A. Prasad, and T.F. Lüscher
Original Article
The New England Journal of Medicine
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The
new england journal
of
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S
ince its first description in Japan
in 1990,
1
takotsubo (stress) cardiomyopa-
thy has gained worldwide recognition.
However, after nearly 25 years of extensive ef-
forts toward a better understanding of this dis-
order, current knowledge remains limited. The
disease is characterized by transient systolic and
diastolic left ventricular dysfunction with a vari-
ety of wall-motion abnormalities.
2,3
It predomi-
nantly affects elderly women and is often pre-
ceded by an emotional or physical trigger,
4
but
the condition has also been reported with no
evident trigger. In the acute phase, the clinical
presentation, electrocardiographic findings, and
biomarker profiles are often similar to those of
an acute coronary syndrome. Although the cause
of takotsubo cardiomyopathy remains unknown,
the role of the brain–heart axis in the pathogen-
esis of the disease has been described.
5,6
Takotsubo cardiomyopathy, which derives its
name from the Japanese word takotsubo (“octo-
pus pot”) to describe the characteristic balloon-
ing of the left ventricular apex, is generally rec-
ognized as a benign disorder. However, patients
are at risk for recurrence even years after the
first event, and data on in-hospital and long-
term outcomes are limited.
7-10
The potential role
of catecholamine excess in the pathogenesis of
takotsubo cardiomyopathy has been long de-
bated,
11
and as such beta-blockers have been pro-
posed as a therapeutic strategy.
12
Nevertheless,
to our knowledge, no prospective trials evaluating
the therapeutic management have been reported
to date. The aim of this study was to investigate
the clinical features, define prognostic predic-
tors, and assess the clinical course and outcome
of takotsubo cardiomyopathy.
Methods
Study Population
The International Takotsubo Registry (www
. takotsubo-registry . com) was established at Uni-
versity Hospital Zurich in collaboration with 25
cardiovascular centers across 9 countries (Austria,
Finland, France, Germany, Italy, Poland, Switzer-
land, the United Kingdom, and the United States)
(see the Methods section in the Supplementary
Appendix, available with the full text of this ar-
ticle at NEJM.org). Data were collected in accor-
dance with regulations set forth by institutional
review boards. From 2011 through 2014, a core
team of investigators at the University Hospital
Zurich reviewed the records of patients in whom
takotsubo cardiomyopathy had been diagnosed
between 1998 and 2014 (Fig. 1). Patients were
included in the registry on the basis of the Mayo
Clinic diagnostic criteria for this condition,
13
as
follows: the presence of a transient abnormality
in left ventricular wall motion beyond a single
epicardial coronary artery perfusion territory, the
absence of obstructive coronary artery disease or
angiographic evidence of acute plaque rupture,
the presence of new electrocardiographic abnor-
malities or elevation in cardiac troponin levels,
and the absence of pheochromocytoma and myo-
carditis. Exceptions to these criteria were the
presence of coexisting coronary artery disease,
the presence of a wall-motion abnormality that
was congruent with a single coronary artery ter-
ritory in a patient matching all other criteria,
and death during the acute phase before wall-
motion recovery.
When eligibility for inclusion was uncertain,
cases were reviewed by all members of the core
team of investigators to reach consensus. Stan-
dardized forms were used to collect patient data,
including baseline characteristics, triggering fac-
tors (categorized as emotional or physical) (Fig. S2
in the Supplementary Appendix)
9
, cardiovascular
risk factors, coexisting illnesses, results on elec-
trocardiography and echocardiography, laboratory
values, results on coronary angiography, use of
medications, and use of critical care. Takotsubo
cardiomyopathy was classified as apical, mid-
ventricular, basal, or focal (see the Methods sec-
tion in the Supplementary Appendix).
Comparison of Takotsubo Cardiomyopathy
and Acute Coronary Syndrome
We compared a subgroup of 455 patients in whom
takotsubo cardiomyopathy had been diagnosed
with 455 age- and sex-matched patients with an
acute coronary syndrome who either fulfilled
the third universal definition of myocardial
infarction
14
or had unstable angina caused by
obstructive coronary artery disease. Data for
patients with takotsubo cardiomyopathy were
collected from five dedicated study centers (see
the Methods section in the Supplementary Ap-
pendix), and data for patients with an acute coro-
nary syndrome were collected from the Zurich
Acute Coronary Syndrome Registry, since these
centers had the most comprehensive patient
The New England Journal of Medicine
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Copyright © 2015 Massachusetts Medical Society. All rights reserved.
n engl j med 373;10 nejm.org September 3, 2015
931
Clinical Outcomes of Takotsubo Cardiomyopathy
records, including neurologic and psychiatric di-
agnoses according to the Diagnostic and Statistical
Manual of Mental Disorders, fourth edition.
15
Outcomes
We recorded all in-hospital complications, includ-
ing catecholamine use, cardiogenic shock, the
use of invasive or noninvasive ventilation or
cardiopulmonary resuscitation, and death from
any cause. Follow-up analysis included death
from any cause and major adverse cardiac and
cerebrovascular events (a composite of a recur-
rence of takotsubo cardiomyopathy, myocardial
infarction, stroke or transient ischemic attack,
or death from any cause). Follow-up data ob-
tained by core team members were based on
clinical visits, medical records, or telephone in-
terviews. In cases in which the native language
of the patients did not allow for follow-up by
core team members (e.g., in Finland and Italy),
follow-up was obtained by local investigators on
the basis of a dedicated case-report form. One-
year mortality was analyzed in subgroups of
patients who were defined according to the use
of angiotensin-converting–enzyme inhibitors,
angiotensin-receptor blockers, or beta-blockers
as the discharge medication.
Statistical Analysis
Continuous variables are presented as means and
standard deviations or medians and interquar-
tile ranges. Categorical variables are provided
with percentages. We used the Wilcoxon rank-
sum test to compare continuous variables and
the Pearson chi-square test or Fisher’s exact test
to compare categorical variables. For analysis
of recovery of the left ventricular ejection frac-
tion, one-way analysis of variance was performed.
Figure 1. Enrollment, Assignment to Substudies, and Follow-Up.
1750 Patients received the diagnosis of takotsubo cardiomyopathy
between 1998 and 2014
Clinical profile
455 Patients were recruited from the
Zurich Acute Coronary
Syndrome Registry
Analysis of in-hospital
complications
Comparison of 455 patients
from each group matched
for age and sex
468 Had no available information at
30-day follow-up
1282 Were included in 30-day
follow-up analysis
632 Had no available information for
medication-associated survival
analysis
104 Had no information about
medication prescribed at hospital
discharge
72 Died in hospital
456 Had no available information after
discharge
1118 Were included in analysis of survival
associated with medication prescribed
at hospital discharge
1750 Were included in Kaplan–Meier estimates of 30-day and 10-year outcomes
The New England Journal of Medicine
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n engl j med 373;10 nejm.org September 3, 2015
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new england journal
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A two-sided P value of less than 0.05 was con-
sidered to indicate statistical significance.
A chi-square analysis was performed to iden-
tify univariate predictors for in-hospital com-
plications. Variables that were significant in
univariate analysis were included in a multiple
logistic-regression analysis to search for inde-
pendent predictors. Model calibration was as-
sessed with the use of the Hosmer–Lemeshow
test. Odds ratios are reported with 95% confi-
dence intervals.
We used the Kaplan–Meier method to provide
survival estimates, which were assessed with a
log-rank test. For survival related to discharge
medication, two independent propensity scores
were computed for the use of beta-blockers and
angiotensin-converting–enzyme inhibitors or
angiotensin-receptor blockers to limit the influ-
ence of potential confounding variables. For
computation of the propensity scores, a nonpar-
simonious regression with the medication as a
dependent variable and potential confounding co-
variates (age, sex, hypertension, diabetes melli-
tus, left ventricular ejection fraction, heart rate,
use of calcium-channel antagonists, and coro-
nary artery disease) were included. Missing val-
ues were replaced by multiple regression imputa-
tion. We used the Hosmer–Lemeshow test to
evaluate the validity of logistic regression. One-
year survival after discharge was assessed by
means of the log-rank test and Cox regression
with adjustment for the propensity score for
medication use on a logit scale.
The proportional-hazards assumption was ver-
ified by means of plotting the Schoenfeld residu-
als with Stata software, version 13.1 (StataCorp).
All analyses were performed with the use of
SPSS statistical software, versions 21.0 and 22.0
(IBM). All graphs were compiled with the use of
Prism 6 software (GraphPad).
Results
Study Patients
Of the 1750 patients with takotsubo cardiomy-
opathy, 1571 (89.8%) were women (mean [±SD]
age, 66.8±13.0 years), and 1384 of all patients
(79.1%) were women older than 50 years of age
(Table 1, and Tables S1 and S2 and Fig. S1 in the
Supplementary Appendix). The predominant symp-
tom on admission was chest pain (75.9%), fol-
lowed by dyspnea (46.9%) and syncope (7.7%).
Physical triggers were more frequently present
than emotional triggers (36.0% vs. 27.7%), where-
as 7.8% of patients had both triggers. In 28.5%
of patients, takotsubo cardiomyopathy occurred
without any evident trigger. Emotional triggers
were more common among women, whereas
physical triggers were more prevalent among
men (Table 1, and Tables S1 and S2 and Fig. S2
in the Supplementary Appendix).
Apical takotsubo cardiomyopathy was identi-
fied in 81.7% of patients, whereas the midven-
tricular form was found in 14.6%, and basal and
focal forms were diagnosed in 2.2% and 1.5%,
respectively (Fig. 2, Tables S1 and S2 in the Sup-
plementary Appendix, and Videos 1 through 4).
On admission, troponin levels were elevated
in 87.0% of patients, with mean levels similar to
those in patients with an acute coronary syn-
drome. Although troponin levels increased by as
much as a factor of 1.8 during hospitalization
among patients with takotsubo cardiomyopathy,
patients with an acute coronary syndrome had
an increase by a factor of 6 over the admission
value (P<0.001). Creatine kinase was not sub-
stantially elevated in the majority of patients
with takotsubo cardiomyopathy (mean level, fac-
tor of 0.87 of the upper limit of the normal
range). A total of 82.9% of the patients had ele-
vated levels of brain natriuretic peptide on ad-
mission (by a factor of 5.9 of the upper limit of
the normal range), which significantly exceeded
the levels among the patients with an acute
coronary syndrome (Table 1, and Tables S1 and
S2 in the Supplementary Appendix).
Results on electrocardiography on admission
showed sinus rhythm in more than 90% of the
patients with takotsubo cardiomyopathy, who
had a significantly higher heart rate than patients
with an acute coronary syndrome. The rates of
ST-segment elevation were similar in the two
groups. In contrast, ST-segment depression oc-
curred in only 8.3% of patients with takotsubo
cardiomyopathy but in 31.1% of those with an
acute coronary syndrome. Notably, a prolongation
in the QT interval corrected for heart rate was
detectable in a substantial proportion of patients
with takotsubo cardiomyopathy (Table 1, and
Tables S1 and S2 in the Supplementary Appendix).
A reduced left ventricular ejection fraction
(mean value, 40.7±11.2%) was noted in 86.5%
of patients with takotsubo cardiomyopathy on
admission but in only 54.2% of patients with
an acute coronary syndrome (mean value,
51.5±12.3%; P<0.001). Of note, 93.0% of patients
Videos showing
left ventricular
angiography
are available at
NEJM.org
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