Circulation Journal

Official Journal of the Japanese Circulation Society

Focus Issue on Takotsubo Cardiomyopathy
http://www. j-circ.or.jp

Clinical Management of Takotsubo Cardiomyopathy

Satoshi Kurisu, MD, PhD; Yasuki Kihara, MD, PhD

Takotsubo cardiomyopathy was first reported by Sato et al at Hiroshima City Hospital in 1990 and has become in-
creasingly recognized worldwide. In the clinical setting, takotsubo cardiomyopathy is an important disease that must
be differentiated from AMI promptly for the appropriate management. Prognosis of takotsubo cardiomyopathy is
generally favorable, but serious complications can occur, especially in the early stage. In this review, we summarize
the current knowledge on the clinical management of takotsubo cardiomyopathy.   (Circ J 2014; 78: 1559 – 1566)

Key Words: Cardiomyopathy; Prognosis; Reversible regional wall motion abnormality; Treatment

T
akotsubo cardiomyopathy is an acute cardiac syndrome
mimicking acute myocardial infarction (AMI), and is
characterized by chest symptoms, electrocardiograph-
ic (ECG) changes and reversible regional wall motion abnor-
mality (RWMA) in the apical to mid segments of the left ven-
tricle.1–5 In contrast to AMI, takotsubo cardiomyopathy exhibits
RWMA independent of acute plaque rupture or myocardial
ischemia with coronary atherosclerosis during the early stage.
RWMA occurs in the apical to mid segments of the left ven-
tricle, extending beyond a single coronary territory (Figure 1),
and it usually resolves spontaneously within a matter of days
to a few weeks.
Takotsubo cardiomyopathy was first reported by Sato et al
at Hiroshima City Hospital in 1990,1–3 since when it has be-
come increasingly recognized worldwide. Several mecha-
nisms, including multivessel coronary artery spasm, coronary
microvascular dysfunction or catecholamine toxicity, have
been proposed to explain the pathophysiology, but the precise
mechanism remains unclear. In the clinical setting, takotsubo
cardiomyopathy is an important disease that must be promptly
differentiated from AMI for its appropriate management. Prog-
nosis of takotsubo cardiomyopathy is generally favorable, but
serious complications sometimes occur, especially in the early
stage. In this review, we summarize the current knowledge on
the clinical management of takotsubo cardiomyopathy.
Confirmation of Diagnosis
Patient’s Characteristics
The initial step in the management of takotsubo cardiomyopa-
thy is the confirmation of diagnosis. Takotsubo cardiomyopa-
thy occurs predominantly in postmenopausal elderly women.3–5
Major symptoms are chest pain and dyspnea with ECG chang-
es. The initial presentation is very similar to AMI, but the
symptoms are not as serious as in AMI. The typical descrip-
tion includes the presence of a preceding mental or physical
stress. Mental stress, such as the unexpected death of a relative
or friend, or receiving news of serious diagnosis, and physical
stress such as asthma attack or non-cardiac surgery have been
identified in previous cases.3 These stressors are common events
that anyone may experience. Men account for a minority of
cases; reports range from 4% to 13%.6–8 In men, physical stress
rather than emotional stress is much more associated with the
occurrence.7,8
Electrocardiography
Common abnormalities on the initial ECG are ST-segment
elevation, negative T wave and subsequent QT interval pro-
longation (Figure 2).3–5,9–11 There is a significant variability in
frequency because these ECG changes are time-dependent.12,13
The typical time course of the ECG is as follows.12 ST-seg-
ment elevation usually occurs shortly after onset. Negative T
wave deepens progressively to its first negative peak, which
occurs at approximately 3 days. The negative T wave becomes
shallow for several days and then deepens, the second nega-
tive peak occurring at approximately 2 weeks. QT interval be-
comes prolonged progressively as the negative T wave deep-
ens. These ECG changes are found in takotsubo cardiomyopathy
as well as AMI, and the differential diagnosis is clinically
important for appropriate management. Ogura et al reported
that the absence of reciprocal changes, the absence of abnor-
mal Q wave and the sum of ST-segment elevation in leads
V4–6 more than the sum of ST-segment elevation in leads V1–3
identified takotsubo cardiomyopathy with a high sensitivity
and specificity.14 Kosuge et al recently reported that the com-
bination of ST-segment depression in lead aVR and no ST-
segment elevation in lead V1, or the combination of positive T
wave in lead aVR and no negative T wave in lead aVR, was
more useful in identifying takotsubo cardiomyopathy.15,16
Echocardiography
Echocardiography plays a central role in the diagnosis of ta-
kotsubo cardiomyopathy. Typically, RWMA is found in the
apical to mid segments of the left ventricle, extending beyond
a single coronary territory. Relative compensatory hypercon-
tractility is often found in the basal segment. Other patterns

Received April 2, 2014; revised manuscript received May 6, 2014; accepted May 21, 2014; released online June 12, 2014
Department of Cardiovascular Medicine, Hiroshima University Graduate School of Biomedical and Health Sciences, Hiroshima, Japan
Mailing address:  Satoshi Kurisu, MD, PhD, Department of Cardiovascular Medicine, Hiroshima University Graduate School of Biomedical
and Health Sciences, 1-2-3 Kasumi-cho, Minami-ku, Hiroshima 734-8551, Japan.   E-mail: skurisu@nifty.com
ISSN-1346-9843  doi: 10.1253/circj.CJ-14-0382
All rights are reserved to the Japanese Circulation Society. For permissions, please e-mail: cj@j-circ.or.jp

Circulation Journal  Vol.78, July 2014

1560 KURISU S et al.

Figure 1.   Left ventriculograms in typical

takotsubo cardiomyopathy (Left) and the
apical-sparing variant (Right).

Figure 2.   Electrocardiograms in typical takotsubo cardiomyopathy (Left) and the apical-sparing variant (Right). In typical takot-
subo cardiomyopathy, ST-segment elevation is found in leads I, II, aVL, aVF and V2–6. In the apical-sparing variant, ST-segment
elevation is found only in leads V2 and V3. (Adapted with permission from Kurisu S, et al.18)

Circulation Journal  Vol.78, July 2014

Management of Takotsubo Cardiomyopathy
Figure 3.   Echocardiographic images in cases of left ventricular apical thrombosis. There are 2 types of apical thrombus: mural
thrombus (Upper, arrow) and protruding (Lower, arrow). (Adapted with permission from Kurisu S, et al. 36)
have been reported, such as RWMA in the mid segment with
apical sparing (apical-sparing variant) (Figure 1) or right ven-
tricular involvement.17 The apical-sparing variant shows lim-
ited ECG changes despite RWMA (Figure 2),18 and echocar-
diography plays an important role in the diagnosis of this variant.
Echocardiography is also useful in detecting acute complica-
tions such as cardiogenic shock because of left ventricular
outflow tract (LVOT) obstruction, apical thrombosis or car-
diac rupture.
Coronary Angiography
In patients with suspected takotsubo cardiomyopathy, coro-
nary angiography is useful in confirming the diagnosis. Most
patients have angiographically normal coronary arteries or mild
atherosclerosis. It is an important concept of takotsubo cardio-
myopathy that the RWMA is not related to acute plaque rup-
ture or myocardial ischemia with coronary atherosclerosis.
Because most patients have several coronary risk factors, in-
cluding advanced age, it is natural that obstructive coronary
artery disease is found incidentally; in our experience, in 10%
of Japanese patients with takotsubo cardiomyopathy.19 When
obstructive coronary artery disease exists in the wrapped left
anterior descending artery, it should be carefully assessed wheth-
er it is associated with RWMA in the apical segment.
Biomarkers and Laboratory Evaluation
Most patients have mildly elevated biomarkers of myocardial
Circulation Journal  Vol.78, July 2014
1561
injury such as creatine kinase, creatine kinase-MB or tropo-
nin.1–5 Some patients even have normal levels of these bio-
markers despite RWMA. Brain natriuretic peptide (BNP) and
N-terminal pro-BNP (NT-proBNP) are established biomarkers
of heart failure, and serve as an ancillary marker for the initial
diagnosis as well as follow-up.20,21 Nguyen et al revealed that
BNP and NT-proBNP were substantially elevated and signifi-
cantly increased during the first 24 h after onset of takotsubo
cardiomyopathy, with slow and incomplete resolution during
the 3 months thereafter. They showed that the peak NT-proBNP
level correlated with the severity of RWMA or systolic dys-
function assessed by echocardiography.22 BNP or NT-proBNP
may predict complications during hospitalization.23
Cardiac Imaging
Cardiac computed tomography is suitable for the differential
diagnosis of takotsubo cardiomyopathy and AMI because this
modality can noninvasively detect coronary atherosclerosis as
well as RWMA.24 Magnetic resonance imaging is useful espe-
cially in assessing left ventricular function and detecting api-
cal thrombus or right ventricular involvement.25 Furthermore,
this modality provides information about the myocardium show-
ing RWMA.25,26 The T2-weighted sequence usually reveals
high signal intensity suggesting myocardial edema. Delayed
enhancement with gadolinium, which suggests irreversible myo-
cardial injury in AMI or myocarditis, is almost never detected
in takotsubo cardiomyopathy. Single-photon emission com-
1562
Figure 4.   Electrocardiograms in a case of torsade de pointes. Bradycardia augments QT interval prolongation, resulting in torsade
de pointes. (Adapted with permission from Kurisu S, et al.40)
puted tomography also provides information on the myocar-
dium showing RWMA. Reduced uptake of technetium-99 m
or thallium-201, indicating impaired myocardial perfusion, is
found during the early stage.27,28 Reduced uptake of iodine-
123-β-methyl-p-iodophenyl pentadecanoic acid or iodine-
123-meta-iodobenzylguanidine is also found during the early
stage.27,28 These markers indicate abnormal fatty acid metabo-
lism and sympathetic denervation, respectively, which can be
detected during follow-up even when the RWMA has resolved.
Therapeutic Strategies
General Principles of Therapy
Because the initial presentation mimics AMI, initial manage-
ment should be directed toward the treatment of myocardial
ischemia with oxygen inhalation, intravenous heparin, aspirin
and β-blockers. After confirmation of takotsubo cardiomy-
opathy, aspirin can be discontinued if there is no incidental
coronary artery disease. Thrombolytic agents should not be
administered because they have no benefit in takotsubo car-
diomyopathy, and can give rise to bleeding complications.
Beta-Blockers
The efficacy of β-blockers has not been fully tested. However,
administration of β-blockers would be reasonable when coro-
Circulation Journal  Vol.78, July 2014
KURISU S et al.
nary spasm is not suspected on initial presentation, because
excess catecholamines may be involved in the pathophysiol-
ogy. It is necessary to take care of worsening heart failure or
coronary spasm after initiation of therapy. Beta-blockers may
be also useful in preventing acute complications such as car-
diogenic shock because of LVOT obstruction, ventricular ar-
rhythmias or ventricular rupture.
Renin-Angiotensin-Aldosterone System Blockers
Typically, RWMA resolves spontaneously within a matter of
days to a few weeks. Angiotensin-converting enzyme inhibi-
tors or angiotensin II type 1 receptor blockers would be rea-
sonable during the period when RWMA is present.
Anticoagulation Therapy
Even after confirmation of takotsubo cardiomyopathy, intra-
venous heparin should be continued, if tolerated, to prevent
left ventricular apical thrombosis. This therapy should be con-
tinued with warfarin until resolution of the RWMA in the api-
cal segment. When resolution of RWMA has been confirmed
with echocardiography, warfarin can be discontinued.
Management of Takotsubo Cardiomyopathy
Figure 5.   Electrocardiograms in a case of cardiac rupture. Note that ST-segment elevation persists even 35 h after admission.
(Adapted with permission from Kurisu S, et al.45)
Management of Acute Complications
Congestive Heart Failure
Congestive heart failure is the most common complication,
occurring in approximately 20% of patients.4,10 It occurs more
frequently in patients with right ventricular involvement.29,30
Standard therapies for heart failure such as diuretics or nitro-
glycerin are effective in most cases. In some cases, heart
failure may require aggressive pharmacological therapy with
inotropic agents and mechanical circulatory support with in-
traaortic balloon pumping (IABP). When patients have severe
congestive heart failure or significant hypotension, it is impor-
tant to assess whether LVOT obstruction or mitral regurgita-
tion is associated with their condition.31–33 Echocardiography
plays a central role in the diagnosis of LVOT obstruction or
mitral regurgitation.
Cardiogenic Shock
Hypotension occurs frequently, so it is important to identify
its cause by echocardiography or cardiac catheterization in
order to determine the appropriate management. Cardiogenic
shock can result from LVOT obstruction associated with basal
hypercontractility. LVOT obstruction may be associated with
systolic anterior movement of the mitral valve anterior leaflet
and mitral regurgitation.32 When LVOT obstruction is identi-
fied, nitroglycerin or inotropic agents should be immediately
discontinued to avoid further obstruction. In the absence of
severe heart failure, intravenous fluids or β-blockers would be
Circulation Journal  Vol.78, July 2014
1563
reasonable because they suppress the basal hypercontractility
and increase cardiac filling, thereby reducing the obstruction.34
Verapamil or diltiazem may provide hemodynamically favor-
able effects similar to β-blockers. When coronary spasm is
suspected, calcium-channel blockers would be more appropri-
ate than β-blockers. Phenylephrine may be also effective by
increasing the afterload and left ventricular cavity size in pa-
tients who are intolerant of intravenous fluids and β-blockers.
Cardiogenic shock because of acute pump failure is treated
with intravenous fluids, inotropic agents or IABP. However,
in some cases, inotropic agents and IABP cause LVOT ob-
struction through basal hypercontractility and reduced after-
load, respectively. These adverse effects may cause further
hemodynamic deterioration.35 Echocardiography is also useful
in detecting the adverse effects of these treatments.
Apical Thrombosis
Left ventricular apical thrombosis may occur because of
RWMA in the apical segment. Low blood flow within the api-
cal segment is the presumed cause of apical thrombosis. In our
practice, it was found in 5.3% of Japanese patients during the
early stage.36 There are 2 types of apical thrombus: mural and
protruding (Figure 3). The clinical importance is that the api-
cal thrombosis is a potential source of emboli. Cerebral isch-
emic attack or renal infarction has been identified in previous
cases.37 If apical thrombosis occurs, early resolution of RWMA,
which is the nature of takotsubo cardiomyopathy, may accel-
erate its discharge. It is important to prevent apical thrombosis
1564
in advance, so prophylactic anticoagulation therapy should be
considered to prevent apical thrombosis and further embolic
events until the resolution of RWMA in the apical segment.
Arrhythmias
Madias et al reported that life-threatening ventricular arrhyth-
mias such as torsade de pointes (TdP) and ventricular fibrilla-
tion occurred in 8.6% of patients with takotsubo cardiomy-
opathy.38 They pointed out that patients with corrected QT
(QTc) interval >500 ms had an increased risk of life-threaten-
ing ventricular arrhythmias. Migliore et al also recently re-
ported that TdP requiring external defibrillation occurred in
4.9% of patients with giant negative T waves and QTc interval
>500 ms during the subacute stage.39 The QTc interval chang-
es day to day over several weeks,12 and TdP is likely to occur
in the setting of QTc interval prolongation. Bradycardia, hy-
pokalemia, hypomagnesemia or use of antiarrhythmic drugs
may augment QTc interval prolongation. We reported 2 cases
of both takotsubo cardiomyopathy and bradycardia compli-
cated by TdP (Figure 4), and demonstrated that temporary
ventricular pacing at a high rate was useful in decreasing the
QT interval and preventing its recurrence.40 Purvis et al re-
ported the effect of intravenous magnesium in a case of both
takotsubo cardiomyopathy and hypomagnesemia complicated
by TdP.41 It is necessary to correct the risk factors of QTc in-
terval prolongation to prevent or treat TdP. By the way, Migliore
et al reported that ECG abnormalities and RWMA disappeared
1 month later in patients receiving an implantable cardiovert-
er-defibrillator, and these patients did not require device inter-
ventions during follow-up.39 Those results suggest that arrhyth-
mic events occur during reversible QTc interval prolongation
in the hospital course.
Presumed new onset of atrioventricular (AV) block has
been shown in previous cases.42–44 AV block resolved in some
patients,43 but persisted in others even after resolution of the
RWMA.44 It remains unclear whether the AV block associated
with takotsubo cardiomyopathy requires pacemaker implanta-
tion or when it should be considered. However, when AV
block results in hemodynamic instability or marked QTc in-
terval prolongation, temporary ventricular pacing should be
considered at least.40
Arrhythmias in takotsubo cardiomyopathy should be man-
aged on a case-by-case basis. The reversible nature of this
disease seems not to justify systematic device implantation in
patients who experienced life-threatening ventricular arrhyth-
mias or AV block during hospitalization.
Ventricular Rupture
Left ventricular free wall rupture or septal perforation is a rare
but life-threatening complication (Figure 5).45 It is clinically
difficult to predict its subsequent occurrence on admission.
However, Kumar et al showed that patients with cardiac rup-
ture were older and had higher double product, higher left
ventricular peak systolic blood pressure, higher frequency of
persistent ST-segment elevation and lower frequency of use
of β-blockers.46 These results suggest that cardiac rupture is
associated with higher left ventricular intramural pressure and
wall stress. The study also reported that 10 (83%) of the 12
patients with cardiac rupture died, and 90% of deaths occurred
within approximately 8 days. The role of β-blockers to prevent
cardiac rupture is well-established in AMI,47–49 but remains
unclear in takotsubo cardiomyopathy. However, β-blockers
would be reasonable, at least in patients with high double prod-
uct or persistent ST-segment elevation.
Circulation Journal  Vol.78, July 2014
KURISU S et al.
Course and Prognosis
In most cases, RWMA resolves spontaneously within a matter
of days to a few weeks. However, we previously reported 2
cases of takotsubo cardiomyopathy in which RWMA persisted
for more than 3 months.50 Lee et al51 and Shim et al52 each
recently reported similar cases of persistent takotsubo cardio-
myopathy complicated by apical thrombosis. Thus, in some
cases, RWMA persists despite the usual hospital course during
early stage. The precise reason remains unclear. In these cases,
the patients require long-term management of heart failure or
apical thrombosis.
The in-hospital death rate ranges from 0% to 8%.3–6,53 Prog-
nosis is generally favorable, but a small subset has potentially
life-threatening complications. Several studies have recently
shown that the ECG or echocardiographic findings at initial
presentation may be useful for predicting short-term prognosis
beyond diagnosis. Shimizu et al showed that the J wave, which
appeared transiently only during the very early stage, was
an indicator of cardiac death and/or ventricular tachyarrhyth-
mia.54 Citro et al reported that left ventricular ejection fraction,
E/e’ ratio and reversible moderate to severe mitral regurgita-
tion were independent correlates of major adverse cardiac
events.55 Takotsubo cardiomyopathy can occur in critically ill
patients,53,56 and their outcome appears to be dependent on the
underlying condition rather than the takotsubo cardiomyopa-
thy itself.
Recurrence rate ranges from 0% to 15%.3–6,57 Elesber et al
reported recurrence in 10% of patients over a mean follow-up
of 4.4±4.6 years, and that recurrence was highest within the
first 4 years, subsequently decreasing over the remainder of
their follow-up.57 Several case reports have shown that takot-
subo cardiomyopathy can present with typical RWMA in the
apical segment at initial presentation and atypical RWMA with
apical sparing during a recurrence.58,59 We have previously
reported that takotsubo cardiomyopathy can occur despite
treatment with calcium-channel blockers, nitrates, β-blockers,
statins or aspirin.60 Elesber et al also showed that there was no
difference in the use of angiotensin-converting enzyme in-
hibitors/angiotensin II type 1 receptor blockers, β-blockers,
statins or aspirin between patients with recurrence and those
without.57 These results suggest the limiting medical treatment
for the prevention of takotsubo cardiomyopathy. There ap-
pears to be no consensus regarding the management of long-
term follow-up. It is necessary to clarify the pathophysiology
of takotsubo cardiomyopathy for establishing its optimal man-
agement.61,62
Conclusions
Takotsubo cardiomyopathy is an important disease that has to
be differentiated from AMI promptly for appropriate manage-
ment. Its prognosis is generally favorable, but monitoring the
clinical course is essential to prevent or treat acute complica-
tions. It is necessary to clarify the pathophysiology of takot-
subo cardiomyopathy for establishment of its optimal manage-
ment.
Disclosures
No financial support.
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