218 REVISTA ARGENTINA DE CARDIOLOGA / VOL 77 N 3 / MAY-JUNE 2009

REVIEW
ARTICLE
Stress-Related Cardiomyopathy or Tako-Tsubo Syndrome:
Current Concepts
IVN J. NEZ GIL
1
, MARA LUACES MNDEZ
2
, JUAN C. GARCA-RUBIRA
1
1
Department of Cardiology. Instituto Cardiovascular. Hospital Clnico San Carlos. Madrid, Spain.
2
Department of Cardiology. Hospital de Fuenlabrada. Madrid, Spain
Address for reprints:
Dr. Ivn J. Nez Gil
Avda. del Talgo 83, 1 E
28023 Aravaca (Madrid)
Phone number: 913303148
Fax 913303730
e-mail: [email protected]
SUMMARY
Tako-Tsubo syndrome, also referred to as stress-related cardiomyopathy or apical balloon-
ing syndrome is a condition that has been recently described mimicking an acute coronary
syndrome in its clinical, analytical, electrocardiographic and echocardiographic character-
istics. The diagnosis is made on the basis of coronary arteries with absence of significant
obstruction, a typical left ventricular shape and complete recovery of ventricular function.
This condition occurs mostly in post-menopausal women under some form of physical or
mental stress. Treatment is empirical and similar to that of acute myocardial infarction,
with special attention in the administration of beta blockers and anticoagulation therapy.
Although associated complications, such as heart failure, may occur in the acute phase, its
clinical course is favorable and recurrence is exceptional. These features, as well as the
physiopathology of this syndrome that is becoming more frequent in our environment, are
discussed in this review.
REV ARGENT CARDIOL 2009;77:218-223.
Myocardial Infarction Tako-Tsubo - Heart Failure - Female -Chest Pain
Key words >
DEFINITION AND CLASIFICATION
Tako-Tsubo syndrome is an acute and reversible car-
diomyopathy with symptoms mimicking acute myo-
cardial infarction, increase in biomarkers levels and
ischemic electrocardiographic changes. Image tests
usually show the characteristic apical ballooning with
compensatory hyperkinesis of the basal segments. In
some cases left ventricular function is severely de-
pressed and patients may present with Killip class IV
(cardiogenic shock). Surprisingly, left ventricular dys-
function usually resolves rapidly after initial presen-
tation; biomarkers are mildly elevated, which is in-
consistent with the extension of myocardial affection,
and coronary angiography reveals no critical coronary
lesions.
The disease occurs in all races and some atypical
presentations have been described. Inverted Tako-
Tsubo cardiomyopathy is a variant in which the com-
promise in localized in the inferior or basal segments
(Figure 1, C-D); other atypical presentations include
involvement of mid-ventricular segments (with nor-
mal apex contractility, Figure 1, F-G), of both ventri-
cles, or exclusive involvement of the right ventricle.
All forms of presentation have a similar physiopatho-
logical substrate. In this review we shall refer to the
typical Tako-Tsubo cardiomyopathy. (2-7)
DIAGNOSTIC CRITERIA
Several diagnostic criteria have been described, as
those proposed by Abe (8) or by the Mayo Clinic. (9)
The later were slightly modified in 2008. (10) All four
diagnostic criteria must be met (Table 1).
EPIDEMIOLOGY
The real incidence is uncertain. Apical ballooning is
increasingly reported in the literature and recognized
in clinical practice as more interventional procedures
in the acute setting are performed. (11) Several stud-
ies in the United States have estimated that it may
account for approximately 1-2% of suspected acute
coronary syndromes. (10, 12) A German series and a
French study reported an incidence of 0.1-2.3%, and
0.9%, respectively. (13) According to the American
Heart Association, approximately 732.000 patients are
discharged each year with a diagnosis of myocardial
infarction. (14) Thus, the annual incidence in the
United States would be of 14000 cases. About 90% of
them occur in postmenopausal women. In our series,
85% of patients are women with a mean age of 69
years. (4, 15) Mean age ranges from 58 to 75 years in
the published literature, (10, 16); yet it has also been
described in very elder subjects and in children. (17)
STRESS-RELATED CARDIOMYOPATHY OR TAKO-TSUBO SYNDROME: CURRENT CONCEPTS / Ivn J. Nez Gil et al 219
Apical ballooning may be detected in patients ad-
mitted to the intensive care units with different stress
levels; in theses cases, the prevalence is greater in
men. (18)
Some authors have reported seasonal variations
in the incidence of this syndrome, with special pre-
dominance in summer (7) or in winter (19); however,
we have not been able to confirm this finding in our
series. The influence of family history is not clearly
established. (20)
CLINICAL PRESENTATION
Chest pain is the most common presenting symp-
tom in 50-60% of cases, characterized as rest an-
gina. Dyspnea, syncope or cardiac arrest are less
frequent.
The onset of stress-related cardiomyopathy is typi-
cally triggered by intense emotional or physical stress
in 7% to 86% of cases (9, 16), and 46.2% in our pa-
tients. There was a marked increase in the incidence
of Tako-Tsubo cardiomyopathy in Japan in 2004, ap-
parently as a result of the earthquakes. (21) This as-
sociation makes us believe that increased cardiovas-
cular mortality associated with natural disasters, wars
and sports events (as soccer championship) might be
related with Tako-Tsubo syndrome. (10, 22)Table 2
describes the specific triggers. (10, 16, 23-25)
Fig. 1. A. Left ventriculogra-
phy during diastole of a typi-
cal variant. B. Left ventriculog-
raphy during systole, showing
hypercontractility of the basal
segments. C y D. Atypical vari-
ant with compromise of the in-
ferior segments. E y F. Mid-
ventricular involvement. A, C,
E: Images during diastole. B,
D, F: Images during systole.
Table 1. Mayo Clinic diagnostic criteria
Mayo Clinic Criteria (2008) for diagnosis of Tako-Tsubo syndrome
1 Transient hypokinesis, akinesis, or dyskinesis in the left
ventricular mid segments with or without apical involve-
ment; regional wall motion abnormalities that extend be-
yond a single epicardial vascular distribution; and fre-
quently, but not always, a stressful trigger.
2 Absence of obstructive coronary disease or angiographic
evidence of acute plaque rupture
3 New ECG abnormalities (ST-segment elevation and/or T-
wave inversion) or modest elevation in cardiac troponin
4 Absence of pheochromocytoma and myocarditis
220 REVISTA ARGENTINA DE CARDIOLOGA / VOL 77 N 3 / MAY-JUNE 2009
COMPLEMENTARY TESTS
Cardiac biomarkers present a mild elevation. (7,
10, 26) The prognostic importance of other mark-
ers, such as BNP, is doubtful. (27)
Electrocardiographic abnormalities are the most
common finding: ST-segment elevation/depression
or repolarization anomalies. Two or three days
after initial presentation, ST-segment abnormali-
ties revert and T wave inversion may be seen with
giant and symmetrical T waves, generally in the
precordial leads. At the moment of hospitalization,
T-wave inversion is more frequent among
westerners while ST-segment elevation is more com-
mon among orientals. (2, 28) The electrocardiogram
normalizes within a few days but always later than
the normalization of left ventricular contraction.
The presence of negative T waves is associated with
QT interval prolongation; ventricular arrhytmias
and torsade de pointes are infrequent. (29)There-
fore, the electrocardiogram alone is not capable of
ruling out myocardial infarction. (10)
Transthoracic echocardiography demonstrates the
initial and reversible contraction abnormalities.
(30) It is also useful for the diagnosis of the me-
chanical complications (31), which are infrequent,
or to quantify the presence of left ventricular out-
flow tract obstruction (which may be present in 1
out of 5 cases) (32), or mitral regurgitation (10,
33). Echocardiography may also visualize apical
thrombus (Figure 2 A), which may develop due to
akinesis of the left ventricular apex. Under this
circumstance, anticoagulant therapy should be
prescribed and maintained until complete clot reso-
lution (generally during the first 3 months).
Coronary arteriography and left ventriculography
are needed to confirm the diagnosis. The absence
of coronary obstructions > 50% in all major coro-
nary arteries, ulcerated plaques or coronary throm-
bus corroborate Tako-Tsubo syndrome. (10) Left
ventriculography usually shows the characteristic
apical ballooning, and recovery of ventricular func-
tion is seen if studies are repeated during follow-
up. A few studies performed using intravascular
ultrasound (IVUS) have not solved the mystery
regarding the physiopathology of this syndrome.
(34) Despite most series exclude patients with a
history of coronary artery disease (CAD), the pres-
ence of patients with CAD and one episode of Tako-
Tsubo syndrome has been described in the last
years, showing that both disease entities are not
mutually exclusive. (35) The relation between both
diseases is still unclear. (36)
Cardiac magnetic resonance imaging provides pre-
cise morphologic and functional information with
the added value of the evaluation of the RV. The
study does not reveal focal perfusion defects and
is an excellent tool for differential diagnosis; the
absence of delayed hyperenhancement of the in-
volved regions rules out myocarditis (exclusion
criterion). (37, 38) Some authors recommend per-
forming cardiac magnetic resonance imaging in all
patients in whom the disease is suspected. (39)
SPECT-PET images evaluate transient ventricu-
lar dysfunction and the metabolic activity within
the heart. The use of
201
Tl SPECT images has de-
tected acute perfusion defects that recover com-
pletely. In addition,
123
I MIBG is also useful to
evaluate the uptake of the tracer in the region af-
fected. Positron emission tomography scan has also
detected perfusion defects. (44) Other authors have
found impaired fatty acid metabolism rather than
a disturbed myocardial perfusion. (13)
Endomyocardial biopsy may reveal unspecific and
reversible lesions with histological findings simi-
lar to those observed in catecholamine excess (sub-
arachnoid hemorrhage, pheochromocytoma). (41)
PHYSIOPATHOLOGY
The hypothesis of multivissel coronary spasm was
believed to be responsible of this syndrome; (42) how-
ever, using provocative tests, less than 30% of patients
experienced multivessel spasm. (16) Several mecha-
Table 2. Triggers associated with stress-induced cardiomyopathy
Emotional stressors
Death or disease of a relative
Bad news
Storm
Arguing with social environment
Public speaking
Legal issues
Traffic accident
Surprise party
Financial, gambling or business losses, dismissals
Change of place of residence
Accidental fall with impossibility to sit up
Physical stressors
Noncardiac surgery
Pacemaker implant
Any important disease, asthma, sepsis
Intense pain, bone fractures, renal colic, etc.
Postanesthetic recovery
Opiod discontinuation
Nortriptyline overdose
Cocaine, anphetamines or beta adrenergic agents abuse
Stress tests (exercise stress test, dobutamine)
Thyrotoxicosis
Seizures
STRESS-RELATED CARDIOMYOPATHY OR TAKO-TSUBO SYNDROME: CURRENT CONCEPTS / Ivn J. Nez Gil et al 221
nisms were later proposed, such as myocarditis, non-
obstructive plaques disruption with spontaneous
thrombolysis, microvascular disturbances, (12) ana-
tomical variations (long course of the left anterior
descending coronary artery) (43) left ventricular out-
flow tract obstruction, (32) sepsis (18, 23) and cat-
echolamine and neuropeptide cardiotoxicity. The lat-
ter is the most widely proposed hypothesis that re-
lates to the role of stress in patients with Tako-Tsubo
cardiomyopathy and was evaluated in a study that
demonstrated that plasma catecholamine levels were
markedly higher in patients with stress-related myo-
cardial dysfunction compared with those of patients
with Killip class III myocardial infarction. (44) This
theory is based on the clinical and pathological rela-
tion with emotional (death of relatives, arguing with
neighbors), physical (asthma, surgery), or neurome-
diated stresses (stroke, subarachnoid hemorrhage,
brain trauma and pheochromocytoma). (44) The main
mechanisms underlying its pathogenesis await fur-
ther elucidation: coronary spasm of the major epicar-
dial coronary arteries, microvascular spasm with re-
duction of the coronary flow reserve, endothelial dys-
function or direct myocardial injury (cyclic AMP me-
diated-calcium overload, free radicals). Lyon et al. have
proposed that myocardial affection produced by
catecholamines is greatest at the apical myocardium,
in which the density of adrenergic receptors is high-
est, as it has been demonstrated in canine models.
(45) For this reason, stress cardiomyopathy is a form
of neuromediated myocardial stunning, but with cel-
lular mechanisms different to those caused by tran-
sient episodes of ischemia secondary to coronary ste-
nosis. (46) This theory requires further investigation
and has been criticized. (47)
The great susceptibility of women has been ex-
plained by sex hormones differences between both
genders, and also to postmenopausal changes. (10) In
fact, in animal models, ovariectomized rats subjected
to immobilization stress that received estrogen sup-
plementation were more resistent to the stressor. (48)
Nevertheless, stress-related transient systolic dys-
function is not exclusive of Tako-Tsubo syndrome, as
it may also be seen in other conditions known as stress-
induced cardiomyopathies. Briefly, these diseases in-
clude intracranial conditions (bleeding, stroke, trauma),
pheochromocytoma, neuroblastoma, exogenous intake
of catecholamines, beta-adrenergic agonists, cocaine or
amphetamines, sepsis, surgery, etc. (23)
TREATMENT
There is no established treatment for patients with
Tako-Tsubo cardiomyopathy. However, these patients
should be evaluated and treated initially in a manner
similar to patients with coronary syndromes. Com-
plications should be treated according to the usual
management strategies. Beta blockers should be ini-
tiated to antagonize the theoretical deleterious effect
of catecholamines. (10) Treatment with carvedilol (a
non-cardioselective alpha and beta adrenergic blocker)
has not been studied in randomized trials; however,
this might be a valid therapeutic option considering
the similarity between this syndrome and pheocro-
mocytoma. In patients hemodinamically unstable,
intravenous fluid administration, vasoactive drugs and
inotropic agents (phenylephrine, levosimendan), (49)
might be necessary. In cases of severe circulatory dys-
function, orotracheal intubation, intra-aortic balloon
counterpulsation or a ventricular assist device should
be considered. (10, 50) Patients who are in shock
should undergo urgent echocardiography to determine
if left ventricular outflow tract obstruction is present
(gradient, Figure 2 B). (10) Anticoagulant agents
should be initiated in uncomplicated patients in whom
a thrombus is demonstrated, or with severe left ven-
tricular dysfunction (EF 35%) to prevent thromboem-
bolic events. (51)
Therapy with beta blockers can be continued. Some
authors recommend annual visits until the natural
history of the disease is better known. (10)
PROGNOSIS
Stress-related cardiomyopathy has a favorable prog-
nosis compared to ST-segment elevation or non-ST-
Fig. 2. A. Image of an apical
thrombus. The image dissa-
peared after normalization of
apical diskinesia and three
months of anticoagulant the-
rapy. LV: Left ventricle. RV:
Right ventricle. LA: left atrium.
B. Image of continouos Dop-
pler echocardiography with
left ventricular outflow tract
obstruction and a gradient of
111 mmHg (cross).
222 REVISTA ARGENTINA DE CARDIOLOGA / VOL 77 N 3 / MAY-JUNE 2009
segment elevation myocardial infarction. (12, 16, 37)
However, severe complications, such as heart failure
(13-23%) or death may occur (Desmet reported one
death in a series of 13 patients, 7.7%). (26) In our
experience with 39 typical cases, from 2003 to 2007
most patients presented Killip class I (71.8%), while
class II, III and IV were less frequent (15.4%, 2.6 and
10.3%, respectively). (4, 15) None of our patients died
during hospitalization, and during follow-up (mean
596 months) 2 patients were readmitted due to car-
diovascular disorders and 2 other patients died (1 pre-
sented dyspnea and sudden death and the other with
sepsis). (4, 15) Recurrences are infrequent (3%). (6)
BACKGROUND
Cardiopata de estrs o sndrome de Tako-Tsubo:
conceptos actuales
The popular phrase to die of sorrow refers to the death of
person who had been very upset or as the consequence of
experiencing the death of a relative. In the last years this
expression has proved not be figurative. In the early nineties,
Sato and Dote described a clinical entity mimicking an acute
coronary infarction in its clinical, analytical, electrocardio-
graphic and echocardiographic characteristics. (1)
Surprinsingly, coronary angiography shows absence of
obstructions, and wall motion abnormalities recover
completely within a few weeks. This dysfunction is known
as Tako-Tsubo syndrome due to the shape on left
ventriculography that resembles a tako-tsubo, the Japanese
name for octopus traps that fishermen still use to catch
octopus (Figure 1, A-B). It is also known as transient apical
dyskinesia, broken-heart syndrome or stress-related
cardiomyopathy.
Palabras clave > Infarto del miocardio - Tako-Tsubo - Insuficiencia
cardaca - Mujeres - Dolor de pecho
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