Heart Vessels
DOI 10.1007/s00380-015-0729-2
ORIGINAL ARTICLE
Antiplatelet therapy in Takotsubo cardiomyopathy: does it
improve cardiovascular outcomes during index event?
Andre Dias1,2 · Emiliana Franco1,2 · Nikoloz Koshkelashvili3 · Vikas Bhalla1 ·
Gregg S. Pressman1 · Kathy Hebert4 · Vincent M. Figueredo1,5 
Received: 19 May 2015 / Accepted: 5 August 2015
© Springer Japan 2015
Abstract  Plasma catecholamines may play an important
role in Takotsubo cardiomyopathy (TCM) pathophysiol-
ogy. Patients with disproportionately high catecholamine
responses to stressful events are prone to worse clinical out-
comes. Catecholamines stimulate platelet activation and,
therefore, may determine the clinical presentation and out-
comes of TCM. We conducted a retrospective, descriptive
study TCM patients admitted between 2003 and 2013 to
Einstein Medical Center, Philadelphia, PA, USA and Dan-
bury Hospital, Danbury, CT, USA. A total of 206 patients
met Modified Mayo TCM criteria. Using a multiple logistic
model, we tested whether aspirin, dual antiplatelet therapy
(DAPT) aspirin + clopidogrel, beta blocker, statin, or ACE
inhibitor use were independent predictors of major adverse
cardiovascular events (MACE) during the index hospi-
talization. MACE was defined as in-hospital heart fail-
ure, in-hospital death, stroke or respiratory failure requir-
ing mechanical ventilation. Incidence of in-hospital heart
failure was 26.7 %, in-hospital death was 7.3 %, stroke
was 7.3 % and MACE was 42.3 %. In a multiple logistic
regression model (adjusted for gender, race, age, physical
stressor, hypertension, diabetes, hyperlipidemia, smoking
* Andre Dias
andremacdias@gmail.com
1
Department of Cardiology, Einstein Medical Center, 5501
Old York Road, Philadelphia, PA 19141, USA
2
Western Connecticut Health Network, Danbury, CT, USA
3
Department of Medicine, Einstein Medical Center,
Philadelphia, PA, USA
4
Department of Cardiology, University of Miami, Miami, FL,
USA
5
Sidney Kimmel College of Medicine at Thomas Jefferson
University, Philadelphia, PA, USA
history, body mass index, initial left ventricular ejection
fraction, single antiplatelet therapy, DAPT, beta blocker,
statin, and ACE inhibitor) aspirin and DAPT at the time of
hospitalization were independent predictors of a lower inci-
dence of MACE during the index hospitalization (aspirin:
OR 0.4, 95 % CI (0.16–0.9), P  = 0.04; DAPT: OR 0.23;
95 % CI (0.1–0.55); P < 0.01. Physical stressor itself was
also found to be an independent predictor of worse MACE:
OR 5.1; 95 % CI (2.4–11.5); P < 0.01. In our study, aspi-
rin and DAPT were independent predictors of a lower inci-
dence of MACE during hospitalization for TCM. Prospec-
tive clinical trials are needed to confirm the findings of this
study.
Keywords  Antiplatelets · Takotsubo cardiomyopathy ·
Cardiovascular outcomes
Background
Takotsubo cardiomyopathy (TCM) is a reversible cardio-
myopathy frequently occurring in postmenopausal women
after an emotional or physical stressor. Recent increases in
the number of TCM cases have been reported, and hospi-
tal-related admissions appear to be on the rise [1]. Plasma
catecholamines play an important role in TCM pathophysi-
ology and patients with disproportionately high catecho-
lamine responses to stressful events and increased cardiac
sympathetic sensitivity are prone to worse clinical out-
comes [2–4].
Catecholamines stimulate platelet activation [5–10] and
therefore may play a role in the clinical presentation and
outcomes of TCM.
Aspirin is a non-steroidal anti-inflammatory drug that
acts as an irreversible inhibitor of both cyclooxygenase
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 Heart Vessels

(COX)-1 and COX-2. It promotes endogenous produc- Table 1  Baseline characteristics

tion of anti-inflammatory mediators and can reduce levels Characteristic n = 206 Value
of inflammatory biomarkers, such as C-reactive protein,
tumor necrosis factor-α and interleukin interleukin IL-6. Age (years), mean 67.8
Psychosocial stress may increase the risk of atherothrom- LOS (length of stay-days) ± SD 9 ± 13
botic events by causing an elevation in circulating levels Gender (% females) 87 % (n = 179)
of the proinflammatory IL6. Both IL-6 and IL-7 have been African Americans (%) 25 %
implicated in the pathogenesis of coronary artery disease Cardiovascular risk factors
and left ventricular dysfunction [6, 11].  Hypertension 66 % (n = 141)
Thus, we sought to assess the impact of antiplatelet  Hyperlipidemia 43 % (n = 92)
therapy in reducing major adverse cardiovascular events  Diabetes mellitus 19 % (n = 41)
(MACE) during the index TCM event.  Current smoker 40 % (n = 83)
Clinical presentation
 Chest pain 48 % (n = 100)
Methods  Physical stressor 68 % (n = 142)
 Emotional stressor 31 % (n = 64)
We conducted a retrospective, descriptive study review- Depression 20 % (n = 43)
ing patients with the discharge diagnosis of TCM between Anxiety 22 % (n = 47)
2003 and 2013 at Einstein Medical Center, Philadelphia, Troponin I upon admission (ng/ml) mean ± SD 1.42 ± 3.5
PA, USA and Danbury Hospital, Danbury, CT, USA. Inclu- Peak troponin I during hospitalization (ng/ml) 4.27 ± 9.7
sion criteria were as per the Modified Mayo Criteria rec- mean ± SD
ommendations [7]: (1) akinesia or dyskinesia of the apical Left ventricular ejection fraction (LVEF)
and/or midventricular segments of the left ventricle with  Initial ejection fraction (%) mean ± SD 34.2 ± 10.7
regional wall motion abnormalities that extended beyond  Follow-up ejection fraction (%) mean ± SD 40 ± 25
the distribution of a single epicardial vessel, (2) absence of LV thrombus 3 % (n = 6)
obstructive coronary artery disease, (3) new electrocardio- In-hospital heart failure 27 % (n = 55)
graphic abnormalities, (4) absence of pheochromocytoma In-hospital death 7 % (n = 15)
or myocarditis. A total of 206 TCM patients from differ- Recurrence 3 % (n = 6)
ent racial and ethnic backgrounds (Hispanics, Whites, and Stroke peri-index event 7 % (n = 15)
African Americans) were included. MACE during index event 42 % (n = 90)
Baseline demographic characteristics, past medical his-
MACE major adverse cardiovascular events defined as in-hospital
tory, initial and peak troponin I levels obtained at least
heart failure, in-hospital death, stroke or respiratory failure requiring
8 h apart, 12-lead electrocardiogram, left ventricular ejec- mechanical ventilation
tion fraction (LVEF) assessed by 2-D echocardiogram
and cardiac catheterization data were collected after study
approval by the Institutional Review Board at both sites. Values are presented as number and percentages or
Emergency department and inpatient records were mean  ± standard deviation (SD) in categorical and quan-
reviewed and all medications prescribed during the index titative variables, respectively. Chi squared and the Stu-
hospitalization were documented. TCM patients also had dent t test were used to assess statistical differences in cat-
reassessment of LVEF, within 6 months of the index event, egorical and continuous variables, respectively. A two-tailed
to document LVEF recovery. P < 0.05 was considered statistical significant. All analyses
Using a multiple logistic model, we determined whether were performed employing SPSS v 22.0, Chicago, IL, USA.
aspirin, aspirin + clopidogrel, beta blockers, statins or ACE
inhibitors were independent predictors of MACE during
the index hospitalization. MACE was defined as in-hospital Results
heart failure, in-hospital death, stroke, or respiratory failure
requiring mechanical ventilation. A total of 206 patients met the Modified Mayo Clinic Crite-
The following 14 variables were then included in mul- ria and were eligible for study entry. Table 1 (ADD RACE)
tivariate models: gender, race, age, angina, hypertension, shows the baseline characteristics of the study population.
diabetes, hyperlipidemia, smoking history, body mass Incidence of in-hospital heart failure was 26.7 %, in-hos-
index, initial left ventricular ejection fraction, aspirin, aspi- pital death was 7.3 %, stroke was 7.3 % and MACE was
rin  + clopidogrel, beta blocker, statin, and ACE inhibitor 42.3 %. Table 2 shows the number of patients receiving
use. aspirin, aspirin + clopidogrel, beta blocker, statin and ACE

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Heart Vessels

Table 2  Medications inhibitor during index event. Antiplatelet therapy (aspirin

Medications Value and aspirin + clopidogrel) and beta blockers were the most
prescribed medications during hospital stay (84 and 76 %,
Aspirin alone 41 % (n = 87) respectively). Table 3 shows the number of patients who
Clopidogrel alone 0.5 % (n = 1) exhibited MACE versus no MACE per medication class
Aspirin + clopidogrel 43 % (n = 88) during hospitalization. Overall, in an unadjusted model, the
Beta blocker 75 % (n = 156) use of aspirin, aspirin + clopidogrel, beta blockers, statins
Statin 70 % (n = 146) and ACE inhibitors were associated with a lower inci-
ACE inhibitor 57 % (n = 119) dence of MACE during the index hospitalization. Table 4
shows the baseline characteristics of patients taking dual
ACE angiotensin-converting enzyme

Table 3  MACE versus no MACE

Medications MACE number of patients (%) No MACE number of patients (%) P value

Antiplatelet therapy 67 (38 %) 109 (62 %) <0.01

(aspirin and aspirin + clopidogrel)
Beta blocker 60 (38 %) 96 (62 %) 0.008
Statin 57 (39 %) 89 (61 %) 0.036
ACE inhibitor 45 (38 %) 74 (62 %) 0.047

Table 4  Baseline characteristics DAPT versus no DAPT

Characteristic n = 206 DAPT (n = 88) No DAPT (n = 118) P value

Age (years), mean 67.3 67.9 NS

LOS (length of stay-days) ± SD 5 12 <0.01
Gender (% females) 90 % (n = 80) 84 % (n = 99) NS
Cardiovascular risk factors
 Hypertension 61 % (n = 54) 74 % (n = 97) NS
 Hyperlipidemia 55 % (n = 49) 36 % (n = 43) <0.01
 Diabetes mellitus 20 % (n = 17) 20 % (n = 24) NS
 Current smoker 39 % (n = 44) 37 % (n = 44) NS
Clinical presentation
 Physical stressor 50 % (n = 44) 83 % (n = 98) <0.01
Depression 19 % (n = 17) 22 % (n = 26) NS
Anxiety 28 % (n = 25) 18 % (n = 22) NS
  Troponin I upon admission (ng/ml) mean ± SD 1.6 ± 3.6 1.3 ± 3.5 NS
  Peak troponin I during hospitalization (ng/ml) mean ± SD 4.1 ± 9.8 4.4 ± 9.8 NS
Left ventricular ejection fraction (LVEF)
 Initial ejection fraction (%) mean ± SD 35.5 ± 10.8 33.1 ± 10.8 NS
 Follow-up ejection fraction (%) mean ± SD 42 ± 25 38.5 ± 25 NS
LV thrombus 2.2 % (n = 2) 3.3 % (n = 4) NS
In hospital heart failure 19 % (n = 17) 32 % (n = 38) 0.04
In hospital death 3.4 % (n = 3) 10 % (n = 12) NS
Recurrence 4.5 % (n = 4) 1.7 % (n = 2 NS
Stroke peri-index event 2.2 % (n = 2) 11 % (n = 13) 0.02
MACE during index event 26.1 % (n = 23) 57 % (n = 67) <0.01

DAPT dual antiplatelet therapy, NS non statistically significant

13

Table 5  Multivariate analysis for MACE
Variable MACE during index event P value
Odds ratio (95 % CI)
Single antiplatelet therapy 0.4 (0.16–0.9) 0.04
Dual antiplatelet therapy 0.23 (0.1–0.55) <0.01
Beta blockers 0.67 (0.32–1.5) 0.3
Statins 1.1 (0.5–2.3) 0.8
ACE inhibitor 0.7 (0.35–1.3) 0.2
Physical stressor 5.1 (2.4–11.5) <0.01
Different clinical characteristics are in bold
antiplatelet therapy (DAPT) versus no DAPT and compari-
son between groups.
Table  5 shows the results of a multiple logistic regres-
sion model. Single and DAPT at the time of hospitalization
remained the only independent predictors of a lower inci-
dence of MACE during the index hospitalization [single
antiplatelet therapy: OR 0.4, 95 % CI (0.16–0.9), P = 0.04;
DAPT: OR 0.34, 95 % CI (0.18–0.65), P = 0.001]. DAPT
remained an independent predictor of MACE: OR 0.23;
95 % CI (0.1–0.55); P < 0.01 even after adjusting for phys-
ical stressor trigger. Physical stressor itself was found to be
an independent predictor of worse MACE: OR 5.1; 95 %
CI (2.4–11.5); P < 0.01.
Discussion
Takotsubo cardiomyopathy is an increasingly recognized
clinical entity often presenting similarly to an acute coronary
syndrome. While the pathophysiology involved has not been
completely elucidated, it is believed that plasma catecho-
lamines and exaggerated sympathetic activation may play
important [2–4]. Catecholamines are known to cause platelet
activation [5–10] which could contribute to the clinical pres-
entation of TCM and cardiovascular outcomes. Interleukins
are inflammatory markers implicated in the pathogenesis
of both coronary heart disease and severity of left ventricu-
lar dysfunction. Several interleukins (IL), in particular IL6
and IL7, have been observed to rise in TCM patients [11].
Therefore, we hypothesized that antiplatelet therapy could be
effective in reducing MACE during index event by targeting
inflammation and catecholamine-mediated platelet activation.
Psychosocial stress may increase the risk of athero-
thrombotic events by causing an elevation in circulating
levels of the proinflammatory IL6. Both interleukin 6 and 7
have been implicated in the pathogenesis of coronary artery
disease and left ventricular dysfunction [6, 11].
Aspirin suppresses the production of prostaglandins,
thromboxanes and decreases the plasma levels of inflam-
matory biomarkers such as CRP, IL-6 and TNF-α.
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Heart Vessels
These anti-inflammatory and anti-platelet properties have
been found to have protective cardiovascular effects. Clopi-
dogrel is a selective P2Y12 receptor antagonist that acts via
the inhibition of platelet aggregation. ADP is released from
activated platelets promoting platelet aggregation via bind-
ing to the P2Y1 and P2Y12 receptor subtypes. Clopidogrel
not only inhibits platelet membrane receptors but can also
significantly decrease TNFα levels [6, 11].
Our findings support the use of aspirin and aspi-
rin  + clopidogrel during index event as both remained
independent predictors of lower incidence of MACE during
hospitalization.
According to previous studies [12] not only high lev-
els of catecholamines are detected during the acute phase
of TCM, but also higher levels of epinephrine may lead
to increased platelet activation and aggregation. Núñez-
Gil et al. described no differences in acute markers (ILs)
related to platelet reactivity when comparing TCM to ACS.
IL6 is an inflammatory marker that is believed to play
an important role in the pathogenesis of coronary artery
disease, left ventricular dysfunction and cardiac functional
class [13, 14]. Pirzer et al. [13] observed rising plasma lev-
els of IL6 among TCM patients with left ventricular sys-
tolic dysfunction during the index event.
IL7 is an important cytokine required for human T cell
development and homeostasis, as well as an inflammatory
marker which enhances expression of several inflamma-
tory chemokines. Damas et al. [11] described increased
IL7 plasma levels in patients with angina in comparison to
healthy subjects, postulating that IL7 could be an inflam-
matory mediator whose release from platelets could be
decreased with aspirin. An interesting finding described by
Pirzer et al. [13] was the fact that few days after hospitali-
zation IL7 levels were significantly higher in TCM patients
than those with an acute MI. This would support the impor-
tance of maintaining an appropriate antiplatelet/antiinflam-
matory therapy throughout hospital course after TCM.
The fear that cardiac thrombus formation may occur during
episodes of TC has led previous authors to suggest anticoagu-
lation therapy in all TC patients until wall motion abnormali-
ties improve [15] but data are still limited on this particular
topic. It seems consensual to start anticoagulation in TC
patients who develop left ventricular thrombi [16–18] and may
be adequate to start anticoagulant therapy in patients at higher
risk of thromboembolic disease; however, several factors inter-
fere with this decision: accurate temporal relationship between
stroke and TC is frequently unclear, several TC patients may
have other independent risk factors for stroke and obviously
anticoagulation carries important risks [19, 20].
Given the lack of consensus we believe that additional
therapeutic options such as antiplatelet therapy (DAPT or
aspirin alone) should be considered, particularly since TC
mimics acute coronary syndrome.
Heart Vessels
The results of our study are in alignment with this past
research and provide clinical evidence for the use of aspirin
or aspirin + clopidogrel at least during hospitalization for
TCM, targeting catecholamines and inflammatory media-
tors involved with platelet activation which could lead to
worse cardiovascular outcomes. In our population physical
stressor as a trigger event was clearly an independent pre-
dictor of worse cardiovascular outcomes. Our findings are
consistent with Nunes et al. [21] who recently suggested a
new classification of TCM based on potential triggers upon
presentation (primary and secondary forms) and found that
“secondary forms” of TCM have worse short and long-
term prognoses. We wonder if in this specific group DAPT
would be particularly indicated.
Limitations
This is a retrospective descriptive study and our sample
size is relatively small therefore our results should be inter-
preted with caution and ideally confirmed by large scale
prospective studies.
Conclusions
In our study, aspirin and dual antiplatelet therapy aspi-
rin  + clopidogrel were independent predictors of a lower
incidence of MACE during hospitalization for TCM. Pro-
spective clinical trials are needed to confirm the findings of
this study.
Compliance with ethical standards  12. Núñez-Gil IJ, Bernardo E, Feltes G, Escaned J, Mejía-Rentería
Conflict of interest  The authors declare that they have no conflict
of interest.
Ethical standards  In consideration of the Journal’s taking action in
reviewing and editing our submission, the author undersigned hereby
transfers, assigns, and otherwise conveys all copyright ownership to
the Heart and Vessels in the event that such work is published in the
Heart and Vessels. We wish to ensure you of our compliance with
AMA ethical standards in the treatment of study participants. I warrant
that the material contained in the manuscript represents original work,
has not been published elsewhere, is not under concurrent considera-
tion for publication elsewhere, and all authors have read and approved
the manuscript.
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