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Accepted Manuscript
Comorbidities Frequency in Takotsubo Syndrome: An International CollaborativeSystematic Review Including 1,109 Patients
Francesco Pelliccia, MD, Guido Parodi, MD, Cesare Greco, MD, David Antoniucci,MD, Roman Brenner, MD, Eduardo Bossone, MD, Luca Cacciotti, MD, AlessandroCapucci, MD, Rodolfo Citro, MD, Clément Delmas, MD, Federico Guerra, MD, CostinN. Ionescu, MD, Olivier Lairez, MD, Maiteder Larrauri-Reyes, MD, Pil Hyung Lee,MD, Nicolas Mansencal, MD, Giuseppe Marazzi, MD, Christos G. Mihos, MD, OlivierMorel, MD, Holger M. Nef, MD, Ivan J. Nunez Gil, MD, Ilaria Passaseo, MD, AndresM. Pineda, MD, Giuseppe Rosano, MD, Orlando Santana, MD, Franziska Schneck,MD, Bong Gun Song, MD, Jae-Kwan Song, MD, Andrew W. Teh, MD, PatompongUngprasert, MD, Alberto Valbusa, MD, Andreas Wahl, MD, Tetsuro Yoshida, MD,Carlo Gaudio, MD, Juan Carlos Kaski, MD
PII: S0002-9343(15)00089-3
DOI: 10.1016/j.amjmed.2015.01.016
Reference: AJM 12861
To appear in: The American Journal of Medicine
Received Date: 11 November 2014
Revised Date: 13 December 2014
Accepted Date: 4 January 2015
Please cite this article as: Pelliccia F, Parodi G, Greco C, Antoniucci D, Brenner R, Bossone E,Cacciotti L, Capucci A, Citro R, Delmas C, Guerra F, Ionescu CN, Lairez O, Larrauri-Reyes M, Lee PH,Mansencal N, Marazzi G, Mihos CG, Morel O, Nef HM, Nunez Gil IJ, Passaseo I, Pineda AM, RosanoG, Santana O, Schneck F, Song BG, Song JK, Teh AW, Ungprasert P, Valbusa A, Wahl A, Yoshida T,Gaudio C, Kaski JC, Comorbidities Frequency in Takotsubo Syndrome: An International CollaborativeSystematic Review Including 1,109 Patients, The American Journal of Medicine (2015), doi: 10.1016/j.amjmed.2015.01.016.
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Comorbidities Frequency in Takotsubo Syndrome: An International
Collaborative Systematic Review Including 1,109 Patients
Francesco Pelliccia, MDa*, Guido Parodi, MDb, Cesare Greco, MDa, David Antoniucci,
MDb, Roman Brenner, MDc, Eduardo Bossone, MDd, Luca Cacciotti, MDe,
Alessandro Capucci, MDf, Rodolfo Citro, MDd, Clément Delmas, MDg, Federico
Guerra, MDf, Costin N. Ionescu, MDh, Olivier Lairez, MDg, Maiteder Larrauri-Reyes,
MDi, Pil Hyung Lee, MDj, Nicolas Mansencal, MDk, Giuseppe Marazzi, MDl, Christos
G. Mihos, MDi, Olivier Morel, MDm, Holger M. Nef, MDn, Ivan J. Nunez Gil, MDo, Ilaria
Passaseo, MDe, Andres M. Pineda, MDi, Giuseppe Rosano, MDl,p, Orlando Santana,
MDi, Franziska Schneck, MDn, Bong Gun Song, MDq, Jae-Kwan Song, MDj, Andrew
W Teh, MDr,s, Patompong Ungprasert, MDt, Alberto Valbusa, MDu, Andreas Wahl,
MDv, Tetsuro Yoshida, MDw, Carlo Gaudio, MDa, Juan Carlos Kaski, MDp
a Department of Cardiovascular Sciences, Sapienza University, Rome, Italy;
b Department of Heart and Vessels, Careggi Hospital, Florence, Italy;
c Department of Cardiology, Kantonsspital, CH-St.Gallen, Switzerland;
d Department of Cardiology, University Hospital San Giovanni di Dio e Ruggi
d'Aragona, Salerno, Italy;
e Cardiology Unit, Ospedale Vannini, Rome, Italy;
f Cardiology and Arrhythmology Clinic, Marche Polytechnic University, Ancona, Italy;
g Department of Cardiology, Rangueil university hospital, Toulouse, France;
h Cardiovascular Section, Yale University, New Haven, CT, USA;
i Cardiology Department , Mount Sinai Medical Center, Miami Beach, Florida, USA;
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j Asan Medical Center Heart Institute, University of Ulsan College of Medicine, Seoul,
South Korea;
k Hôpital Ambroise Paré, Service de Cardiologie, Centre de Référence des Maladies
Cardiaques Héréditaires, Université de Versailles Saint-Quentin, Boulogne, France;
l IRCCS San Raffaele Pisana, Rome, Italy;
m Pôle d'activité medico-chirurgicale Cardiovasculaire, Strasbourg, France;
n University of Giessen, Department Cardiology and Angiology, Germany
o Cardiovascular Institute. Hospital Clínico San Carlos, Madrid, Spain;
p Cardiovascular and Cell Sciences Research Institute, St. George’s, University of
London, London, UK;
q Cardiac and Vascular Center, Konkuk University Hospital, Seoul, South Korea;
r Monash University Eastern Health Cardiology Department, Victoria, Australia;
s Department of Cardiology, Austin Hospital, Victoria, Australia;
t Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand;
u IRCCS Azienza Ospedaliera Universitaria San Martino-IST, Genova, Italy;
v Cardiology, University Hospital, Bern, Switzerland;
w Department of Cardiovascular of Medicine, Onga Nakama Medical Association,
Onga Hospital, Onga, Japan.
Text word count : 3,803 (w/o references)
Funding : None.
Conflict of Interest for all authors : None.
Authorship : All authors had access to and participated in writing this manuscript.
Article type : Original paper
Keywords: Cardiomyopathy; Comorbidities; Risk factors; Takotsubo.
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Running head : Takotsubo Syndrome
* Corresponding author:
Francesco Pelliccia, MD, PhD,
Department of Cardiovascular Sciences, Sapienza University,
Via Tommaso Inghirami 85,
00179 Rome, Italy
Tel.: +39 348 3392006
Fax: +39 06 330 62516
E-mail address: f.pelliccia@mclink.it
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ABSTRACT
Background - To identify predisposing factors that can result in the onset of
Takotsubo Syndrome, we performed an international, collaborative systematic review
focusing on clinical characteristics and comorbidities of patients with Takotsubo
Syndrome.
Methods and Results - We searched and reviewed cited references up to August
2013 to identify relevant studies. Corresponding authors of selected studies were
contacted and asked to provide additional quantitative details. Data from each study
were extracted by 2 independent reviewers. The cumulative prevalence of presenting
features and comorbidities was assessed. Nineteen studies whose authors sent the
requested information were included in the systematic review, with a total of 1,109
patients (951 women; mean age: 59-76 years). Evaluation of risk factors showed
that obesity was present in 17% of patients (range: 2-48%), hypertension in 54%
(range: 27-83%), dyslipidemia in 32% (range: 7- 59%), diabetes in 17% (range: 4-
34%), and smoking in 22% (range: 6-49%). Emotional stressors preceded Takotsubo
Syndrome in 39% of patients and physical stressors in 35%. The most common
comorbidities were psychological disorders (24%; range: 0-49%), pulmonary
diseases (15%; range: 0-22%), and malignancies (10%; range: 4-29%). Other
common associated disorders were neurologic diseases (7%; range: 0-22%), chronic
kidney disease (7%; range: 2-27%), and thyroid diseases (6%; range: 0-37%).
Conclusions - Patients with Takotsubo Syndrome have a relevant prevalence of
cardiovascular risk factors and associated comorbidities. Such of associations needs
to be evaluated in further studies.
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KEYWORDS: Acute left ventricular dysfunction; Apical ballooning syndrome;
Cardiomyopathy; Takotsubo cardiomyopathy; Takotsubo syndrome
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Takotsubo Syndrome is a form of acute left ventricular dysfunction mimicking acute
myocardial infarction in both symptomatology and electrocardiographic findings but
without significant coronary artery disease on angiography.1 There is general
consensus that the common etiologic feature of Takotsubo Syndrome is sudden
emotional/physical stress causing a surge in catecholamine levels that lead to
transient left ventricular dysfunction.2 One should consider, however, that an abrupt
rise in catecholamines does not always cause myocardial impairment.3 Available
scientific evidence shows that a variety of different factors can predispose, trigger
and eventually result in the final common clinical manifestation of the syndrome, i.e.
a transient, rapidly reversible form of acute left ventricular dysfunction mimicking
acute myocardial infarction in the absence of obstructive coronary artery disease.4
These factors can be classified as triggers (ie, emotional stressors, physical
stressors, iatrogenic stressors, and neurologic triggers), pathogenic mechanisms (ie,
increased catecholamine levels, coronary vasomotor abnormalities leading to
myocardial ischemia), and predisposing factors (ie, cardiovascular risk factors,
endothelial dysfunction, comorbidities).5 While much information has been obtained
on precipitating events and pathogenic mechanisms,6-10 there is still a paucity of data
on predisposing factors. A proper identification of these additional components of
Takotsubo Syndrome may help in preventing and managing the condition more
effectively.
We aimed to perform the COmorbidity freqUency iN Takotsubo Syndrome
(COUNTS) study, an international, collaborative systematic review focusing on the
clinical characteristics of patients presenting with Takotsubo Syndrome, with special
emphasis on the frequency of comorbidities.
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METHODS
Study Design. This systematic review was conducted following current guidelines,
including the Cochrane Collaboration and Meta-analysis Of Observational Studies in
Epidemiology (MOOSE),11 and the Preferred Reporting Items for Systematic reviews
and Meta-Analyses (PRISMA) amendment to the Quality of Reporting of Meta-
analyses (QUOROM) statement.12 The study was registered at the PROSPERO
International prospective register of systematic reviews of the University of York, UK,
(Registration No. CRD42013005175).13 All corresponding authors of selected studies
were initially contacted and asked to provide additional quantitative details. All
authors who actively participated to the COUNTS study were systematically and
repeatedly queried throughout the study.
Data Sources. We searched and reviewed cited references up to August 2013 to
identify relevant studies. Search key-words were ‘Apical Ballooning Syndrome’,
‘Broken Heart Syndrome’, ‘Stress Cardiomyopathy’, ‘Takotsubo Syndrome’,
‘Takotsubo cardiomyopathy’. We did not search The Cochrane Collaboration
CENTRAL database, as it only includes controlled clinical trials. Published abstracts
from meetings of the American College of Cardiology, American Heart Association
and European Society of Cardiology were also hand-reviewed. Editorials and reviews
from major medical journals published within the last 5 years were also considered
for further information on studies of interest. Exclusion criteria included duplicate
reporting, in which case the manuscript reporting the largest sample of patients with
Takotsubo Syndrome was selected, or if equal, the study with the largest number of
overall patients. In addition, studies were excluded when presenting data were not
available or in case of duplicate publication of results. EMBASE and articles
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published in non-English languages were not taken into consideration as it is very
unlikely that high quality observational studies were published in journals not indexed
in MEDLINE/PubMed and the use of non-English languages in scientific papers
constitutes a language barrier that may jeopardize collection of data. Single case reports
and previous systematic reviews on Takotsubo Syndrome’ were also excluded.
Study Selection. Retrieved citations were first screened independently by two
unblinded investigators (FP and GM) at the title and/or abstract level, with
divergences resolved after consensus. After excluding duplicates, studies were
screened in order to identify potentially suitable articles that should be assessed for
eligibility as full-text. Studies were then selected according to the following explicit
selection criteria (all had to be met for inclusion): (i) diagnosis of Takotsubo
Syndrome on the basis of the Mayo Clinic criteria;14 (ii) inclusion of a minimum of 10
patients; (iii) selection of the most recent publication when a patient population was
reported on in separate publications; (iv) a comprehensive reporting of demographics
and clinical characteristics of study patients.
Data Collection. Corresponding authors of studies selected according to
abovementioned criteria were contacted directly by e-mail and invited to participate in
the COUNTS study. All authors were asked to provide additional data recorded in
their own original case series. Specifically, they were asked to fill a form in order to
specify the frequency of the following conditions: asthma, chronic obstructive
pulmonary disease, pulmonary circulation disorder, hyperthyroidism, subarachnoid
hemorrhage, intracerebral hemorrhage, cerebrovascular accident, drug abuse,
alcohol abuse, anxiety disorder, mood disorder, delirium/dementia, chronic kidney
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disease, chronic liver disease, connective tissue disease, sepsis, malignancy. The
study was highly interactive requiring frequent communications between the
COUNTS coordinating center at Sapienza University in Rome, Italy, and the
investigators. The corresponding author of each of the studies included in the
collaborative systematic review was offered co-authorship in the COUNTS study,
with additional local investigators as appropriate.
Statistical Analysis. Either data extracted directly from the studies included in the
systematic review (i.e. demographics, precipitating events, cardiovascular risk
factors, electrocardiographic and echocardiographic features at referral), or
additional data of the study populations obtained by each author were entered into
pre-specified electronic forms. Continuous variables were reported as mean
(standard deviation). Categorical variables are expressed as n/N (%). Cumulative
prevalence of each parameter was calculated.
RESULTS
Search results. From a total of 295 initial citations that were found, we excluded
those with duplicate reporting, as well as those that were reviews, were not written in
English, or included small case series of patients or patients who were not diagnosed
as having Takotsubo Syndrome on the basis of the Mayo Clinic criteria.
Corresponding authors of the 87 studies which were selected according to explicit
inclusion criteria were asked to participate to the COUNTS study. We then sent the
study protocol and a file to be filled in to the 38 authors who agreed to join the
project. Finally, the 19 studies whose authors sent the requested additional
information on clinical characteristics and comorbidities were included in the
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systematic review.15-33 Selected studies were published previously (between 2007
and 2013) and included series of patients from North America, Europe, Asia and
Australia (Table 1 ). The progress through the different steps of the search results is
illustrated in Figure 1 .
Presenting Features. A total of 1,109 patients were included in the systematic
review (Table 1 ). They were 158 men (14%) and 951 women (86%). The mean age
of the study populations ranged from 59 to 76 years. Cardiovascular risk factors were
assessed in virtually all studies. Obesity was present in 171 patients (17%; range:
2% - 48%). Hypertension was present in 604 patients (54%; range: 27% - 83%).
Dyslipidemia was present in 350 patients (32%; range: 7% - 59%). Diabetes mellitus
was present in 185 patients (17%; range: 4% - 34%). Smoking was reported by 240
patients (22%; range: 6% - 49%). Preceding events and clinical characteristics at
referral could be evaluated in all studies (Table 2). Emotional stressors occurred in
428 patients (39%) and physical stressors in 379 patients (35%), while no
precipitating event could be identified in 139 patients (13%). The majority of patients
complained from chest pain (n=612; 55%), but many patients suffered from dyspnea
(n=283; 26%). Nearly half of patients had ST changes (n=587; 53%) and Q waves or
T changes (n=548; 49%). At echocardiography, left ventricular ejection fraction
averaged between 28% and 54%.
Comorbidities. The prevalence of pulmonary, endocrinologic, neurologic and
psychological diseases was assessed in the majority of selected studies (Table 3 ). In
1045 patients included in 17/19 studies, a pulmonary disease was found in 151
cases (15%). Chronic obstructive pulmonary disease was found in 96 patients (9%;
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range: 0-22%), asthma was reported by 42 patients (4%; range: 0-12%), and a
pulmonary circulatory disorder was present in 13 patients (1%; range: 0-14%). In
1020 patients included in 16/19 studies, endocrinologic disease was found in 64
patients (6%), with hyper- o hypo-thyroidism occurring in 63 patients (6%; range: 0-
37%), and other forms of endocrinologic disease occurring in 1 patient only. In 1099
patients included in 18/19 studies, a neurologic disease was present in 77 patients
(7%). A previous cerebral hemorrhage was found in 11 patients (1%; range: 0-22%),
ischemic stroke or transient ischemic attack had occurred in 64 patients (6%; range:
0-12%), and Parkinson disease was present in 2 patients (0,1%; range: 0-14%). In
1068 patients included in all but one of the studies, psychological disorders were
present in 254 patients (24%). An anxiety disorder was found in 136 patients (13%;
range: 0-36%), mood disorders were reported by 92 patients (9%; range: 0-49%),
and delirium/dementia were present in 26 patients (2%; range: 0-14%). Frequency of
concomitant transient or chronic conditions in patients included in the studies are
reported in Table 4 . Only a minority of patients had a history of drug abuse (2 of 771
patients; 0.3%) and alcohol abuse (35 of 799 patients; 4%), or had had surgery (13
of 1068 patients; 1%). Chronic kidney disease, chronic liver disease and chronic
connective tissue disease were detected in 72 of 1058 patients (7%; range: 2-27%),
17 of 1007 patients (2%; range: 1-7%), and 30 of 1007 patients (3%; range: 4-7%),
respectively. Sepsis was found in 56 of 1099 patients (5%; range: 1-27%).
Malignancy was present in 106 of 1052 patients (10%; range: 4-29%).
DISCUSSION
The COUNTS Study has successfully merged 19 databases of previously published
series of patients with Takotsubo Syndrome. Together, these databases comprises a
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total of > 1,100 patients with Takotsubo Syndrome and therefore this is the largest
collaborative review of such patients with detailed clinical data that has been
conducted so far. The major findings of the study is that patients with Takotsubo
Syndrome have a relevant prevalence of cardiovascular risk factors with frequency
similar to that seen in patients with acute myocardial infarction, along with a high
prevalence of associated comorbidities that can predispose patients to the typical
acute onset of Takotsubo Syndrome.
Clinical Characteristics and Presenting Features. The COUNTS study gives
important information on demographics, triggers and cardiovascular risk factors of
patients with Takotsubo Syndrome. First, this study confirms in a very large
population that Takotsubo Syndrome occur mainly in post-menopausal women. In
fact, 86% of patients were female and average age ranged between 59 and 72
years. These figures are remarkably similar to those of Gianni et al who performed a
systematic review of 14 studies involving 286 patients and found a female
predominance of 89% in a series of patients 58 to 77 years old.34 Noteworthy, the
evidence of an association between Takotsubo Syndrome and menopause supports
the hypothesis that estrogen deficiency is a crucial pre-disposing factor of the
disease.6,34 The hallmark etiologic feature of Takotsubo Syndrome is said to be
sudden emotional stressors, such as disagreement, challenging arguments, or
devastating losses, as the precipitant.35 The results of the COUNTS study, however,
indicate that a preceding emotional stress is not evident in every case, and it would
therefore seem erroneous to assume it as a common trigger for Takotsubo
Syndrome.29 Indeed, emotional stressors occurred in 39% of patients and physical
stressors preceded Takotsubo Syndrome in 34% of patients. It is worth noting that
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physical stressors are likely associated with a sustained surge in catecholamines and
thus might cause an even greater cardiac stress compared with emotional triggers.36
A further important finding of the COUNTS study is the unexpected high prevalence
of cardiovascular risk factors given the absence of obstructive coronary artery
disease, as 17% (range: 2-48%) of patients were obese, 54% (range: 27-83%) had
hypertension , 32% (range: 7- 59%) had dyslipidemia, 17% (range: 4-34%) were
diabetic and 22% (range: 6-49%) were smokers. These data are in agreement with
previous observations of Summer et al,37 who noticed that the majority of their
patients with Takotsubo Syndrome had at least two of the following: hypertension,
hyperlipidemia, diabetes mellitus, history of smoking, or a family history of
cardiovascular disease. Martin et al reported a similar prevalence of comorbid
cardiovascular risk factors - hypertension (42%), smoking (42%), hyperlipidemia
(33%), and coronary artery disease (42%) – which was much higher than one might
expect in healthy women.38 As a matter of fact, patients with Takotsubo Syndrome
have a prevalence of comorbid cardiovascular risk factors higher than the general
population and similar to that seen in patients with acute myocardial infarction.39 In a
large series of 305 women with acute left ventricular dysfunction, Parodi et al found
no difference in the prevalence of hypertension, hypercholesterolemia, and smoking
between those with Takotsubo Syndrome and those with anterior myocardial
infarction.40 The possibility exists therefore that the susceptibility to Takotsubo
Syndrome may, in part, be related to a high prevalence of risk factors leading to pre-
morbid endothelial dysfunction,41 which, in turn, might be a predisposing factor of
Takotsubo Syndrome.38
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Co-morbidities, the ‘Extracardiac’ Predisposing Factors. A careful review of the
available scientific information reveals that the majority of Takotsubo Syndrome
cases occur in patients with several comorbidities that are known to be associated
with excessive catecholamine production, and can now be considered the “missing
link” to better understand the pathophysiology of Takotsubo Syndrome.42 Summers
et al. hypothesized that the susceptibility to Takotsubo Syndrome may in part be
related to pre-morbid chronic psychiatric and cardiovascular diseases.37 More
recently, in a study of all patients hospitalized for Takotsubo Syndrome from 2008
through 2009 and age-matched orthopedic and myocardial infarction controls, El-
Sayed et al found that cerebrovascular accidents, drug abuse, anxiety disorders,
mood disorders, malignancy, chronic liver disease, and sepsis were common co-
morbidities of Takotsubo Syndrome.43
The results of the COUNT study confirm and extend these previous observations
in the largest series of patients with Takotsubo Syndrome reported so far. Indeed,
our international collaborative systematic review revealed that patients with
Takotsubo Syndrome had a relatively high prevalence of psychological disorders
(24%; range: 0-49%), pulmonary diseases (15%; range: 0-22%), malignancy (10%;
range: 4-29%), neurologic diseases (7%; range: 0-22%), chronic kidney disease (7%;
range: 2-27%), and thyroid diseases (6%; range: 0-37%). These findings provide a
reliable confirmation of the strong association between certain comorbidities and
Takotsubo Syndrome.44 Cerebrovascular accidents are correlated with a 10-fold
higher odds of Takotsubo Syndrome, 2 thus supporting a pathophysiologic
mechanism involving excessive catecholamine production as originally proposed by
Greco et al. in the ‘80s.45 Similarly, an increased susceptibility to Takotsubo
Syndrome has been reported in patients with psychological disorders.46 Summers et
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al. demonstrated that women diagnosed with Takotsubo Syndrome were more likely
to have chronic anxiety disorder before the event compared with controls and those
with acute myocardial infarction.37 El-Sayed et al. recently demonstrated that drug
abuse, anxiety disorders, and mood disorders are predictors of Takotsubo
Syndrome, possibly because they are associated with a higher risk for stressful
events.43 The possibility exists that a more frequent exposure to stressful life
circumstances in the setting of increased baseline catecholamine concentrations
may increase the risk of Takotsubo Syndrome.46 The high prevalence of cancer in
patients with Takotsubo Syndrome is in agreement with previous preliminary
observations. Burgdorf et al. reported that patients with Takotsubo Syndrome more
commonly had a previous diagnosis of malignancy or developed malignancies during
follow-up as compared with patients with acute myocardial infarcation.42 Recently,
El-Sayed et al. found that patients with Takotsubo Syndrome have higher odds of
malignancy than orthopedic and myocardial infarction patients in a large population
of patients hospitalized with Takotsubo Syndrome in the United States over a 2-year
period.43 These previous findings along with our data are consistent with a relation
between Takotsubo Syndrome and malignancy, possibly due to paraneoplastic
phenomena.47
Finally, the COUNTS study demonstrates that the association of Takotsubo
Syndrome with drug abuse (0.3%), alcohol abuse (4%), surgery (1%), chronic liver
disease (2%), chronic connective tissue disease (3%), and sepsis (5%) is poor and
likely related to the play of chance. The finding that a history of drug/alcohol abuse is
uncommon is in keeping with the predominant phenotype of patients with Takotsubo
Syndrome, i.e. an aged post-menopausal woman.34 Also, chronic liver and
connective tissue diseases are less likely associated with Takotsubo Syndrome,
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unless an increased catecholamine production occurs possibly as a result of
pharmacologic treatment.-48
The pratical implication of the findings of the COUNTS study is of relevance.
Comorbidity (Charlson index) has been described as the most powerful predictor of
mortality in Takotsubo patients.24 With the current knowledge there are no data
available to recommend proper preventive strategies after the acute event besides
an accurate patient follow-up, an aggressive treatment of cardiovascular risk factors,
and an optimal management of comorbidities.
Study Limitations. There are some intrinsic limitations of the COUNTS study as a
result of study design. In order to standardize the case definition, we excluded a
number of case series (i.e., those that did not specify that patients were diagnosed
as having Takotsubo Syndrome on the basis of the Mayo Clinic criteria as well as
those reporting on fewer than 10 patients). Publication bias remains always a
concern because this investigation could analyze data provided by the authors of
previously published studies who accepted the invitation to participate in the
COUNTS study. Furthermore, we were unable to collect data from all the studies that
were published since development of Mayo Clinic criteria in 2007. Also, our review
does not encompass patients from all continents, though it includes patients from
Western and Eastern countries where the majority of reports on Takotsubo
Syndrome come from. A possible drawback lies on the study-level setting, thus
lacking the precision and flexibility of a patient-level work, which would have enabled
more detailed analyses. Although individual patient data would have provided more
detailed information, patient-level and study-level meta-analysis are often in
agreement,-49 and thus our findings should be consistent with future prospective
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studies in individual patients. Finally, the lack of a control group does not allow one to
draw definite conclusions about the frequency of risk factors and comorbidities in
patients included in the COUNTS study. However, we noticed that prevalences of
cardiovascular risk factors and associated conditions in patients with Takotsubo
Syndrome were higher than those currently found in the general population in
Western and Eastern countries (WHO World Health Statistics, 2014)50 and
resembled those reported in age- and sex-matched patients with acute myocardial
infarction.40
CONCLUSIONS
The COUNTS study provides a unique substrate to support a reliable definition of
clinical characteristics of patients with Takotsubo Syndrome. Indeed, the
demonstration, in the largest series of patients with Takotsubo Syndrome reported so
far, that cardiovascular risk factors and some comorbidities known to be associated
with excessive catecholamine production have a high prevalence in patients with
Takotsubo Syndrome supports- the concept that ‘predisposing factors’ may play a
crucial pathophysiologic role in the acute onset of the syndrome. The novel findings
of a great burden of comorbidities should prompt physicians to increase awareness
on - optimal identification and management of the associated conditions that might
predispose patients to Takotsubo Syndrome or impact on subsequent clinical
outcome.
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References
1. Prasad A, Madhavan M, Chareonthaitawee P. Cardiac sympathetic activity in
stress-induced (Takotsubo) cardiomyopathy. Nat Rev Cardiol. 2009; 6(6): 430-
434.
2. Pilgrim TM, Wyss TR. Takotsubo cardiomyopathy or transient left ventricular
apical ballooning syndrome: a systematic review. Int J Cardiol. 2008; 124(3):
283–292.
3. Y-Hassan S. Acute cardiac sympathetic disruption in the pathogenesis of the
TS: A systematic review of the literature to date. Cardiovasc Revasc
Med. 2014;15(1):35-42.
4. Pelliccia F, Greco C, Vitale C, Rosano G, Gaudio C, Kaski JC. Takotsubo
Syndrome (stress cardiomyopathy): An intriguing clinical condition in search of
its identity. Am J Med. 2014;127(8):699-704.
5. Lee YP, Poh KK, Lee CH, et al. Diverse clinical spectrum of stressinduced
cardiomyopathy. Int J Cardiol. 2009; 133(2): 272–275.
6. Ueyama T, Kasamatsu K, Hano T, Tsuruo Y, Ishikura F. Catecholamines and
estrogen are involved in the pathogenesis of emotional stress-induced acute
heart attack. Ann N Y Acad Sci. 2008; 1148: 479–485.
7. Amariles P. A comprehensive literature search: Drugs as possible triggers of
Takotsubo cardiomyopathy. Curr Clin Pharm. 2011; 6(1): 1-11.
8. Schneider B, Athanasiadis A, Stollberger C, et al. Gender differences in the
manifestation of tako-tsubo cardiomyopathy. Int J Cardiol. 2013; 166(3): 584-
588.
9. Suzuki H, Matsumoto Y, Kaneta T, et al. Evidence for brain activation
in patients with takotsubo cardiomyopathy. Circ J. 2013; 78(1): 256-258.
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10. Jaguszewski M, Osipova J, Ghadri JR, et al. A signature of circulating
microRNAs differentiates takotsubo cardiomyopathy from acute myocardial
infarction. Eur Heart J. 2014; 35(15): 999-1006.
11. Moher D, Cook DJ, Eastwood S, Olkin I, Rennie D, Stroup DF. Improving the
quality of reports of meta-analyses of randomised controlled trials: the
QUOROM statement. Quality of reporting of meta-analyses. Lancet. 1999;
354(9193):1896–1900.
12. Liberati A, Altman DG, Tetzlaff J, et al. The PRISMA statement for reporting
systematic reviews and meta-analyses of studies that evaluate healthcare
interventions: explanation and elaboration. BMJ. 2009; 339: b2700.
13. PROSPERO register. http://www.crd.york.ac.uk/NIHR_PROSPERO/ display_
record.asp?ID=CRD42013005175#.U3Oc3IF_tA0 (30 June, 2014).
14. Bybee KA, Kara T, Prasad A, et al. Systematic review: transient left ventricular
apical ballooning: a syndrome that mimics ST-segment elevation myocardial
infarction. Ann Intern Med. 2004; 141(11): 858-865.
15. Yoshida T, Hibino T, Kako N, et al. A pathophysiologic study of tako-tsubo
cardiomyopathy with F-18 fluorodeoxyglucose positron emission tomography.
Eur Heart J. 2007; 28(21): 2598-2604.
16. Valbusa A, Abbadessa F, Giachero C, et al. Long term follow-up of Tako-
Tsubo-like syndrome: a retrospective study of 22 cases. J Cardiovasc Med
(Hagerstown). 2008; 9(8): 805–809.
17. Eshtehardi P, Koestner SC, Adorjan P, et al. Transient apical ballooning
syndrome — clinical characteristics, ballooning pattern, and long-term follow-up
in a Swiss population. Int J Cardiol. 2009; 135(3): 370-375.
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18. Morel O, Sauer F, Imperiale A, et al. Importance of inflammation and
neurohumoral activation in Takotsubo cardiomyopathy. J Card Fail. 2009;
15(3): 206-213.
19. Nef HM, Möllmann H, Hilpert P, Troidl C, et al. Activated cell survival cascade
protects cardiomyocytes from cell death in Tako-Tsubo cardiomyopathy. Eur J
Heart Fail. 2009;11(8):758-764.
20. Mansencal N, El Mahmoud R, Dubourg O. Occurrence of Tako-tsubo
cardiomyopathy and chronobiological variation. J Am Coll Cardiol. 2010;
55(5):500-501.
21. Teh AW, New G, Cooke J. A single-centre report on the characteristics of Tako-
tsubo syndrome. Heart Lung Circ. 2010;19(2):63-70.
22. Lee PH, Song JK, Sun BJ, et al. Outcomes of patients with stress-induced
cardiomyopathy diagnosed by echocardiography in a tertiary referral hospital. J
Am Soc Echocardiogr. 2010;23(7):766-771.
23. Ionescu CN, Aguilar-Lopez CA, Sakr AE, Ghantous AE, Donohue TJ. Long-
term outcome of Tako-tsubo cardiomyopathy. Heart Lung Circ.
2010;19(10):601–605.
24. Parodi G, Bellandi B, Del Pace S, et al. Tuscany Registry of Tako-Tsubo
Cardiomyopathy. Natural history of Tako-tsubo cardiomyopathy. Chest. 2011;
139(4):887-892.
25. Nascimento FO, Santana O, Perez-Caminero M, Benjo AM. The characteristics
of stress cardiomyopathy in an ethnically heterogeneous population. Clinics
(Sao Paulo). 2011;66(11):1895-1899.
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26. Brenner R, Weilenmann D, Maeder MT, Jörg L, et al. Clinical characteristics,
sex hormones, and long-term follow-up in swiss postmenopausal women
presenting with takotsubo cardiomyopathy. Clin Cardiol. 2012;35(6):340-347.
27. Cacciotti L, Passaseo I, Marazzi G, et al. .Observational study on Takotsubo-
like cardiomyopathy: clinical features, diagnosis, prognosis and follow-up. BMJ
Open. 2012;2(5):5-15.
28. Citro R, Rigo F, Previtali M, et al. Differences in clinical features and in-hospital
outcomes of older adults with tako-tsubo cardiomyopathy. J Am Geriatr Soc.
2012;60(1):93-98.
29. Song BG, Yang HS, Hwang HK, et al. The impact of stressor patterns on
clinical features in patients with Tako-tsubo cardiomyopathy: experiences of two
tertiary cardiovascular centers. Clin Cardiol. 2012;35(11):E6-E13.
30. Núñez-Gil IJ, Molina M, Bernardo E, et al. Tako-tsubo syndrome and heart
failure: long-term follow-up. Rev Esp Cardiol. 2012;65(11):996–1002.
31. Delmas C, Lairez O, Mulin E, et al. Anxiodepressive disorders and chronic
psychological stress are associated with Tako-tsubo cardiomyopathy. Circ
J. 2013;77(1):175-180.
32. Ahmed S, Ungprasert P, Ratanapo S, Hussain T, Riesenfeld EP. Clinical
characteristics of takotsubo cardiomyopathy in north america. N Am J Med Sci.
2013;5(2):77-81.
33. Guerra F, Rrapaj E, Pongetti G, et al. Differences and similarities of
repolarization patterns during hospitalization for Takotsubo cardiomyopathy and
acute coronary syndrome. Am J Cardiol. 2013; 112(11): 1720-1724.
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34. Gianni M, Dentali F, Grandi AM, Sumner G, Hiralal R, Lonn E. Apical ballooning
syndrome or takotsubo cardiomyopathy: a systematic review. Eur Heart J.
2006; 27(13):1523–1529.
35. Kurowski V, Kaiser A, von Hof K, et al. Apical and midventricular transient left
ventricular dysfunction syndrome (tako-tsubo cardiomyopathy): frequency,
mechanisms and prognosis. Chest. 2007; 132(3): 809–816.
36. Patel SM, Chokka RG, Prasad K, Prasad A. Distinctive clinical characteristics
according to age and gender in apical ballooning syndrome (takotsubo/stress
cardiomyopathy): an analysis focusing on men and young women. J Card Fail.
2013;19(5):306-310.
37. Summers MR, Lennon RJ, Prasad A. Premorbid psychiatric and cardiovascular
diseases in apical ballooning syndrome (takotsubo/stress-induced
cardiomyopathy): potential pre-disposing factors)? J Am Coll Cardiol. 2010;
55(7):700-701.
38. Martin EA, Prasad A, Rihal CS, Lerman LO, Lerman A. Endothelial function and
vascular response to mental stress are impaired in patients with apical
ballooning syndrome. J Am Coll Cardiol. 2010;56(22):1840-1846.
39. Weihs V, Szücs D, Fellner B, et al. Stress-induced cardiomyopathy (Tako-
Tsubo syndrome) in Austria. Eur Heart J Acute Cardiovasc
Care. 2013;2(2):137-146.
40. Parodi G, Del Pace S, Carrabba N, et al. Incidence, clinical findings, and
outcome of women with left ventricular apical ballooning syndrome. Am J
Cardiol. 2007;99(2):182-185.
41. Rosano GM, Vitale C, Marazzi G, Volterrani M. Menopause and cardiovascular
disease: the evidence. Climacteric. 2007;10 Suppl 1:19-24.
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42. Burgdorf C, Kurowski V, Bonnemeier H, Schunkert H, Radke PW. Long-term
prognosis of the transient left ventricular dysfunction syndrome (Tako-Tsubo
cardiomyopathy): focus on malignancies. Eur J Heart Fail. 2008;10(10):1015-
1019.
43. El-Sayed AM, Brinjikji W, Salka S. Demographic and co-morbid predictors of
stress (Takotsubo) cardiomyopathy. Am J Cardiol. 2012;110(9):1368–1372.
44. Rossor AM, Pearce SH, Adams PC. Left ventricular apical ballooning
(takotsubo cardiomyopathy) in thyrotoxicosis. Thyroid. 2001;17(2):181-182.
45. Greco C, Cavalletti C, Di Piero V, Argentino C, Scopinaro F. Scintigraphic
demonstration of myocardial ischaemia. Lancet. 1988;2(8605):281.
46. Swaab DF, Bao AM, Lucassen PJ. The stress system in the human brain in
depression and neurodegeneration. Ageing Res Rev. 2005;4(2):141–194.
47. Burgdorf C, Nef HM, Haghi D, Kurowski V, Radke PW. Takotsubo (stress-
induced) cardiomyopathy and cancer. Ann Intern Med. 2010;152(12):830–831.
48. Amariles P. A comprehensive literature search: Drugs as possible triggers of
Takotsubo cardiomyopathy. Curr Clin Pharm. 2011;6(1):1-11.
49. Olkin I, Sampson A. Comparison of meta-analysis versus analysis of variance
of individual patient data. Biometrics. 1998;54(1):317–322.
50. World Health Statistics 2014. Geneve: World Health Organization; 2014.
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Legends
Figure 1.
Flow diagram demonstrating the study selection process in the collaborative
systematic review.
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Table 1. Demographic and prevalence of risk factors in patients included in the studies
Study Year Country No. of Patients
Female sex
Age (years)
Mean (SD)
Obesity Hyper-tension
Dys-lipidemia
Diabetes mellitus
Smoking
Yoshida15 2007 Japan 15 12 (80%) 72 (7) 3 (20%) 4 (27%) 1 (7%) 2 (13%) 4 (27%)
Valbusa16 2008 Italy 22 22 (100%) 76 (7) 7 (32%) 18 (82%) 9 (41%) 4 (18%) 0
Eshtehardi17 2009 Switzerland 41 35 (85%) 65 (11) NA 23 (56%) 16 (39%) 2 (5%) 11 (27%)
Morel18 2009 France 17 17 (100%) 72 (9) 6 (35%) 11 (65%) 6 (35%) 2 (12%) 4 (24%)
Nef 19 2009 Germany 16 15 (94%) 65 (10) 3 (19%) 6 (38%) 2 (13%) NA 2 (13%)
Mansencal 20 2010 France 51 50 (98%) 71 (11) 9 (18%) 21 (41%) 19 (37%) 3 (6%) 12 (24%)
Teh 21 2010 Australia 23 20 (87%) 65 (11) NA 13 (57%) 4 (17%) 1 (4%) 9 (39%)
Lee22 2010 Korea 56 44 (79%) 64 NA NA 25 (45%) 11 (20%) 19 (34%) 13 (23%)
Ionescu 23 2010 USA 27 26 (96%) 68 (14v 13 (48%) 18 (67%) 7 (26%) 3 (11%) 7 (26%)
Parodi 24 2011 Italy 116 106 (91%) 73 (10) NA 63 (54%) 35 (30%) 10 (9%) 28 (24%)
Nascimento 25 2011 USA 64 24 (38%) 74 (13) 5 (8%) 53 (83%) 34 (53%) 21 (33%) 16 (25%)
Brenner 26 2012 Switzerland 17 17 (100%) 67 (13) 0 9 (53%) 10 (59%) 1 (6%) 5 (29%)
Cacciotti 27 2012 Italy 111 105 (95%) 72 (10) 2 (2%) 80 (72%) 33 (30%) 21 (19%) 22 (20%)
Citro 28 2012 Italy 190 175 (92%) 66 (11) 57 (30%) 92 (48%) 65 (34%) 11 (6%) 35 (18%)
Song 29 2012 South Korea 137 101 (74%) 59 NA 7 (5%) 47 (34%) 11 (8%) 25 (18%) 8 (6%)
Nunez Gil 30 2012 Spain 100 89 (89%) 68 (13) 24 (24%) 68 (68%) 50 (50%) 18 (18%) 31 (31%)
Delmas 31 2013 France 51 46 (90%) 73 (11) 3 (6%) 25 (49%) 17 (33%) 6 (12%) 25 (49%)
Ahmed 32 2013 USA 10 10 (100%) 67 NA 1 (10%) 6 (60%) 2 (20%) 3 (30%) NA
Guerra 33 2013 Italy 45 37 (82%) 67 (12) 4 (9%) 22 (49%) 18 (40%) 6 (13%) 8 (18%)
NA = not available.
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Table 2. Preceding events and clinical characteristics at referral of patients included in the studies
TRIGGERS SYMPTOMS 12-LEAD ECG
Study No. of Patients
Preceding emotional stressor
Preceding physical stressor
Unknown Chest Pain
Dyspnoea
ST changes Q-waves or T changes
Initial LV EF (%)
Elevated troponin
Yoshida15 15 6 (4%) 6 (4%) 3 (2%) 13 (87%) NA 13 (87%) 2 (13%) 43±8 13 (87%)
Valbusa16 22 9 (41%) 9 (41%) 4 (18%) 11 (50%) 11 (50%) 9 (41%) 11 (50%) 40±7 22 (100%)
Eshtehardi17 41 19 (46%) 6 (15%) NA 31 (76%) 10 (24%) 16 (39%) 19 (46%) 41±7 NA
Morel18 17 14 (82%) NA 2 (12%) 10 (59%) 10 (59%) 11 (65%) 6 (35%) 36±7 17 (100%)
Nef 19 16 14 (88%) 2 (13%) NA NA NA NA NA 34±10 16 (100%)
Mansencal 20 51 14 (27%) 20 (39%) 17 (33%) 32 (63%) 7 (14%) 28 (55%) 40 (78%) 42±10 50 (98%)
Teh 21 23 13 (57%) 4 (17%) 6 (26%) 23 (100%) NA 16 (70%) 12 (52%) 50±10 21 (91%)
Lee22 56 10 (18%) 46 (82%) NA 10 (18%) 26 (46%) 16 (29%) 45 (80%) 33±NA 23 (41%)
Ionescu 23 27 12 (44%) 8 (30%) NA 21 (78%) 7 (26%) 15 (56%) 6 (22%) 33±13 15 (56%)
Parodi 24 116 45 (39%) 34 (29%) 37 (32%) 85 (73%) 13 (11%) 70 (60%) NA 36±9 27 (23%)
Nascimento 25 64 21 (33%) 32 (50%) 6 (9%) 17 (26%) 32 (50%) 24 (38%) 41 (64%) 30±9 54 (84%)
Brenner 26 17 8 (47%) 6 (35%) 3 (18%) 13 (76%) 5 (29%) 6 (35%) 11 (65%) 54±13 14 (82%)
Cacciotti 27 111 39 (35%) 23 (21%) NA 48 (43%) 11 (10%) 32 (29%) 11 (10%) 37±9 17 (15%)
Citro 28 190 95 (50%) 42 (22%) 53 (28%) 153 (80%) 21 (11%) 114 (60%) 108 (56) 38±6 75 (39%)
Song 29 137 14 (10%) 96 (70%) NA 71 (52%) 77 (56%) 102 (75%) 121 (88%) 40±8 90 (66%)
Nunez Gil 30 100 43 (43%) 10 (10%) NA 88 (88%) 12 (12%) 65 (65%) 87 (87%) 48±11 33 (33%)
Delmas 31 51 25 (49%) 18 (35%) NA 30 (59%) 22 (43%) 14 (27%) 26 (51%) 39±10 45 (88%)
Ahmed 32 10 4 (40%) 3 (30%) 3 (30%) 9 (90%) 4 (40%) 4 (40%) 2 (20%) 28±NA 10 (100%)
Guerra 33 45 22 (49%) 14 (31%) 9 (20%) 35 (78%) 15 (33%) 32 (71%) NA 45±13 45 (100%)
NA = not available.
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Table 3. Prevalence of pulmonary, endocrinologic, neurologic and psychological diseases in patients included in the studies
PULMONARY DISEASE ENDOCRINOLOGIC DISEASE
NEUROLOGIC DISEASE PSYCHOLOGICAL DISORDERS
Study No. of Patients
Asthma
COPD
Pulmonary circulatory disorder
Hyper/ Hypo-
thyroidism
Other
Cerebral hemorrhage
Ischemic Stroke/TIA
Parkinson Anxiety disorder
Mood disorder
Delirium/ dementia
Yoshida15 15 1 (7%) 0 0 0 0 0 0 0 0 0 0
Valbusa16 22 1 (5%) 4 (18%) 0 8 (36%) 1 (5%) 0 1 (5%) 0 5 (23%) 0 0
Eshtehardi17 41 NA NA NA NA 0 0 0 0 NA NA NA
Morel18 17 1 (6%) 1 (6%) 1 (6%) 3 (7%) 0 0 1 (6%) 1 (6%) 0 2 (12%) 0
Nef 19 16 1 (6%) 1 (6%) 0 1 (6%) 0 1 (6%) 0 0 0 0 0
Mansencal 20 51 2 (4%) 2 (4%) 0 0 0 1 (2%) 3 (6%) 0 10 (20%) 3 (6%) 2 (4%)
Teh 21 23 NA NA NA NA NA 0 0 0 1 (4%) NA NA
Lee22 56 6 (11%) 5 (9%) 0 NA NA 0 7 (13%) 0 2 (4%) 1 (2%) 8 (14%)
Ionescu 23 27 1 (4%) 3 (11%) 0 0 0 1 (4%) 0 0 4 (15%) 3 (11%) 0
Parodi 24 116 2 (2%) 20 (17%) 0 7 (6%) 0 0 9 (8%) 0 4 (3%) 4 (3%) 2 (2%)
Nascimento 25 64 7 (11%) 14 (22%) 9 (14%) 1 (16%) 0 0 5 (8%) 0 13 (20%) 16 (25%) 6 (9%)
Brenner 26 17 0 2 (12%) 1 (6%) 1 (6%) 0 0 1 (6%) 0 0 2 (12%) 1 (6%)
Cacciotti 27 111 1 (1%) 6 (6%) 0 0 0 0 6 (6%) 0 40 (36%) 0 1 (1%)
Citro 28 190 7 (4%) 9 (5%) 0 16 (8%) 0 0 2 (1%) 1 (1%) 23 (12%) 14 (7%) 0
Song 29 137 0 3 (2%) 0 2 (1%) 0 3 (2%) 11 (8%) 0 2 (1%) 13 (9%) 2 (1%)
Nunez Gil 30 100 12 (12%) 14 (14%) 0 1 (1%) 0 0 10 (10%) 0 13 (13%) 8 (8%) 1 (1%)
Delmas 31 51 0 5 (10%) NA 18 (35%) 0 5 (10%) 6 (12%) 0 12 (23%) 25 (49%) 3 (6%)
Ahmed 32 10 NA 1 (10%) NA NA NA NA NA NA 2 (20%) 1 (10%) NA
Guerra 33 45 0 6 (13%) 2 (4%) 5 (11%) 0 0 2 (4%) 0 5 (11%) 0 0
NA = not available.
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NA = not available.
Table 4. Frequency of concomitant transient or chronic conditions in patients included in the studies
Study No. of Patients
Drug abuse
Alcohol abuse
Surgery Chronic kidney disease
Chronic liver disease
Connective tissue disease
Sepsis Malignancy
Yoshida15 15 0 1 (7%) 0 4 (27%) 0 0 0 2 (13%)
Valbusa16 22 0 0 1 (5%) 1 (5%) 0 1 (5%) 0 2 (9%)
Eshtehardi17 41 NA NA NA NA NA NA 0 NA
Morel18 17 0 1 (6%) 1 (6%) 0 0 0 0 5 (29%)
Nef 19 16 0 0 0 0 0 0 0 1 (6%)
Mansencal 20 51 0 3 (6%) 0 9 (18%) 0 0 2 (4%) 5 (10%)
Teh 21 23 0 NA 2 (9%) 0 0 0 0 0
Lee22 56 NA NA 0 7 (13%) 4 (7%) 4 (7%) 15 (27%) 11 (20%)
Ionescu 23 27 1 (4%) 2 (7%) 0 0 1 (4%) 0 0 1 (4%)
Parodi 24 116 0 0 0 5 (4%) 4 (6%) 7 (6%) 0 11 (9%)
Nascimento 25 64 0 11 (17%) 0 14 (22%) 1 (2%) 4 (6%) 4 (6%) 10 (16%)
Brenner 26 17 0 0 0 4 (24%) 1 (6%) 0 0 2 (12%)
Cacciotti 27 111 0 1 (1%) 0 5 (5%) 1 (1%) 0 0 11 (10%)
Citro 28 190 0 0 9 (4%) 3 (2%) 0 6 (3%) 1 (1%) 10 (5%)
Song 29 137 0 2 (1%) 0 8 (6%) 2 (1%) 0 29 (21%) 18 (13%)
Nunez Gil 30 100 0 4 (4%) NA 4 (4%) 1 (1%) 6 (6%) 0 x 7 (7%)
Delmas 31 51 NA 7 (14%) 0 6 (12%) NA NA 5 (10%) 3 (6%)
Ahmed 32 10 1 (10%) 2 (20%) 0 NA NA NA NA NA
Guerra 33 45 0 1 (2%) NA 2 (4%) 2 (4%) 2 (4%) 0 7 (16%)
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CLINICAL SIGNIFICANCE
Ref.: Ms. No. 14-1638
" Comorbidities Frequency in Takotsubo Syndrome: An International
Collaborative Systematic Review Including 1,109 patients"
• The COUNTS study demonstrated in the largest series reported so far that
patients with Takotsubo Syndrome have a high prevalence of cardiovascular risk
factors.
• The study revealed that some comorbidities known to be associated with
excessive catecholamine production are common in patients with Takotsubo
Syndrome.
• The optimal identification and management of clinical factors that might
predispose patients to Takotsubo Syndrome or impact on subsequent clinical
outcome is mandatory.