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.

This is a PDF file of an unedited manuscript that has been accepted for publication. As a service toour customers we are providing this early version of the manuscript. The manuscript will undergocopyediting, typesetting, and review of the resulting proof before it is published in its final form. Please

note that during the production process errors may be discovered which could affect the content, and alllegal disclaimers that apply to the journal pertain.

MANUSCRIP

T

ACCEPTED

ACCEPTED MANUSCRIPT1

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;

MANUSCRIP

T

ACCEPTED

ACCEPTED MANUSCRIPT2

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.

MANUSCRIP

T

ACCEPTED

ACCEPTED MANUSCRIPT3

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

MANUSCRIP

T

ACCEPTED

ACCEPTED MANUSCRIPT4

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.

MANUSCRIP

T

ACCEPTED

ACCEPTED MANUSCRIPT5

KEYWORDS: Acute left ventricular dysfunction; Apical ballooning syndrome;

Cardiomyopathy; Takotsubo cardiomyopathy; Takotsubo syndrome

MANUSCRIP

T

ACCEPTED

ACCEPTED MANUSCRIPT6

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.

MANUSCRIP

T

ACCEPTED

ACCEPTED MANUSCRIPT7

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

MANUSCRIP

T

ACCEPTED

ACCEPTED MANUSCRIPT8

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

MANUSCRIP

T

ACCEPTED

ACCEPTED MANUSCRIPT9

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

MANUSCRIP

T

ACCEPTED

ACCEPTED MANUSCRIPT10

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%;

MANUSCRIP

T

ACCEPTED

ACCEPTED MANUSCRIPT11

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

MANUSCRIP

T

ACCEPTED

ACCEPTED MANUSCRIPT12

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

MANUSCRIP

T

ACCEPTED

ACCEPTED MANUSCRIPT13

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

MANUSCRIP

T

ACCEPTED

ACCEPTED MANUSCRIPT14

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

MANUSCRIP

T

ACCEPTED

ACCEPTED MANUSCRIPT15

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,

MANUSCRIP

T

ACCEPTED

ACCEPTED MANUSCRIPT16

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

MANUSCRIP

T

ACCEPTED

ACCEPTED MANUSCRIPT17

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.

MANUSCRIP

T

ACCEPTED

ACCEPTED MANUSCRIPT18

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.

MANUSCRIP

T

ACCEPTED

ACCEPTED MANUSCRIPT19

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.

MANUSCRIP

T

ACCEPTED

ACCEPTED MANUSCRIPT20

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.

MANUSCRIP

T

ACCEPTED

ACCEPTED MANUSCRIPT21

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.

MANUSCRIP

T

ACCEPTED

ACCEPTED MANUSCRIPT22

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.

MANUSCRIP

T

ACCEPTED

ACCEPTED MANUSCRIPT23

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.

MANUSCRIP

T

ACCEPTED

ACCEPTED MANUSCRIPT24

Legends

Figure 1.

Flow diagram demonstrating the study selection process in the collaborative

systematic review.

MANUSCRIP

T

ACCEPTED

ACCEPTED MANUSCRIPT

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.

MANUSCRIP

T

ACCEPTED

ACCEPTED MANUSCRIPT

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.

MANUSCRIP

T

ACCEPTED

ACCEPTED MANUSCRIPT

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.

MANUSCRIP

T

ACCEPTED

ACCEPTED MANUSCRIPT

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%)

MANUSCRIP

T

ACCEPTED

ACCEPTED MANUSCRIPT

MANUSCRIP

T

ACCEPTED

ACCEPTED MANUSCRIPT1

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.