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Takotsubo Cardiomyopathy
Introduction
Takotsubo Cardiomyopathy (TC) may be the most poetic all heart diseases
because it links our emotions to the functioning of our hearts. In the short time since its
recognition it has been known by many names including Transient Left Ventricular
Apical Ballooning Syndrome, Human Stress Cardiomyopathy, Ampulla Cardiomyopathy
and, more romantically, Broken Heart Syndrome 3. TC is speculated to occur when
emotional or physical stress causes cardiac dysfunction that resembles acute myocardial
infarction (AMI) but occurs in patients without detectable coronary artery disease (CAD).
The dysfunction most commonly manifests as depressed functioning of the distal and
apical left ventricle and a compensatory hyperkinesis of the basal heart walls. It is this
compensatory mechanism that causes the characteristic ballooning of the apex during
systole for which this syndrome is known 13.
History
The word “Takotsubo” is a Japanese name for a pot used to catch octopus 1. The
pot typically has a rounded bottom and narrow neck, and the ventriculograms of the heart
during TC were thought to resemble this 1. The Japanese pronunciation of “tsu” is
difficult for most Americans, and is roughly equivalent to the American words “cat soup”
if you could leave the “ca” off of the beginning and the “p” off the ending. TC was
initially reported in Japan by Dote and colleagues in a paper published in 1991 3.
Although it was first recognized as a Japanese entity, it appears that with increased
awareness of the condition TC is now recognized to cross cultural and ethnic boundaries
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. The history of research on TC as seen in publication appears to be made in small steps
consisting of retrospective case series, followed by review articles, followed by yet more
case series.
Epidemiology
The exact prevalence of Takotsubo cardiomyopathy is unknown 10. Several risk
factors have been proposed including ethnicity, sex, presence of a stressor and admission
to an intensive care unit. Asian ethnicity was originally thought to be a risk factor for the
sole reason that the condition was first documented in Japan. But awareness probably
played more of a role as TC has now been reported by physicians in Europe, Canada, and
America. It is currently unknown if there is any true genetic susceptibility 10.
Takotsubo cardiomyopathy has consistently been shown to have a female
predominance, particularly in post-menopausal women. In a study of seven patients by
Akasi, six of seven patients with TC were female and the mean age was 75.3 years 1. In a
2004 review of 7 case series Bybee showed that the percentage of patients that were
reported to be female ranged from 82 to 100% 3. Gianni in 2006 did a literature review
using criteria common to many papers published on TC that included a total of 286
patients 9. Of these, 254 were women (88.8%) with mean ages in the series ranging from
58 to 77 years 9.
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An interesting study by Park in 2005 looked at the prevalence of TC in the ICU
setting . He found that of 92 patients admitted to an MICU with a non-cardiac
diagnosis, 26 had LV apical ballooning upon admission or developed it during the course
of their ICU stay 13. LV function normalized in 20 of these patients after a mean of 1
week 13. I was not able to download this paper so as to elaborate to whether these were
true Takotsubo patients meeting the definition criteria or whether the researchers were
including LV apical ballooning from other causes. But this paper suggests that with
further research apical ballooning may be found to be a more common entity in the ICU
than would be expected 13.
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Clinical Presentation
Patients with Takotsubo cardiomyopathy present similar to AMI or congestive
heart failure (CHF) 6. The most commonly reported presenting symptom of TC is chest
pain. In Bybee’s 2004 review of 7 case series chest pain was the presenting symptom in
33-71% of patients 3. Dyspnea was also described as “not uncommon” and there were
also a few cases that presented as syncope 3. Gianni’s 2006 review found that chest pain
and dyspnea were the two most common presenting symptoms with chest pain found in
67.8% of patients and dyspnea in 17.8% 9. Other presentations included cardiogenic
shock in 4.2% and ventricular fibrillation in 1.5% 9.
It is possible that bias has played a role in making chest pain the most common
presenting symptom over dyspnea. In many of the early investigations of TC, the data
sources from which cases were retrospectively taken were from AMI databases 6. This
could have possibly skewed the data away from dyspnea 6. Washman in particular states
that the largest Japanese series was culled retrospectively from the Angina PectorisMyocardial Infarction (AP-MI) investigations 6. This could reasonably be expected to
skew presentation data towards patients who had experienced angina 6.
Some type of stressor is typically thought to precede the onset of TC. In her
analysis of stressors, Gianni divided them into emotional stressors and physical stressors.
Emotional stressors could be found in 26.8% of patients and physical stressors in 37.8%
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. Surprisingly, no stressor was found in 34.2% 9. Stressors that have been reported in the
literature include such events as the death of loved ones, severe illness, automotive
accidents and surgeries 10.
In the Intensive Care Unit, Takotsubo may present differently than in an
ambulatory setting because of other underlying clinical problems and the higher
probability of the patient being intubated and sedated 11. Haghi performed a prospective
study of six patients diagnosed with Takotsubo all of whom were intubated in the ICU 11.
Of the six, three presented with hypotension, one with cardiogenic shock, one with a
large new onset T wave inversion, and one with a decrease in monitored stroke volume
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.
Although patient presentation may be similar to AMI or CHF, the severity of
symptoms may range from mild hypotension to critical heart failure requiring admission
to the critical care unit for inotropic support or multi-organ failure 6. I could find no data
on the quality, radiation or other characteristics of chest pain in TC presentation.
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Pathophysiology
Definition
The most recent definition of Takotsubo cardiomyopathy was proposed by the Mayo
Clinic and set down four criteria for the disease 10:
1. Transient akinesis or dyskinesis of the left ventricular apical and mid-ventricular
segments with regional wall-motion abnormalities extending beyond a single
epicardial vascular distribution
2. Absence of obstructive coronary disease or angiographic evidence of acute plaque
rupture
3. New EKG abnormalities (either ST-segment elevation or T-wave inversion)
4. Absence of recent significant head trauma, intracranial bleed,
pheochromocytoma, obstructive epicardial disease, myocarditis, and hypertrophic
cardiomyopathy
Pathophysiology
The pathophysiology of TC is poorly worked out at this point and still speculative at
best. A list of most proposed possibilities includes 7,9:
1. TC is not a new disease but a variant of AMI
2. TC represents ACS with early reperfusion and stunning without necrosis
3. Catecholamine levels may increase via stress to levels toxic for the myocardium
4. TC is a presentation of atypical myocarditis
5. TC is of a genetic etiology
6. TC is caused by multivessel coronary vasospasm
7. TC is caused by abnormalities in coronary microvascular function
We will run through the ideas behind these proposals although there is not much hard
evidence to prove or disprove them.
ACS/AMI Variant
Some authors have suggested that indeed Takotsubo cardiomyopathy is not a new
disease at all, but an atypical presentation or consequence of ACS. It has been argued that
from the viewpoint of “Bayesian” probability, rare presentations of common diseases
(such as ACS) are much more likely than a new common presentation of a rare disease 14.
Could Takotsubo cardiomyopathy be a type of AMI? AMI generally considered to be
ruled out in TC because there is an absence of significant luminal coronary stenosis upon
angiography and an akinetic area that does not correspond with a single perfusion
territory 4. But ischemia has been known to cause reversible left ventricular dysfunction
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.
In one attempt to link TC and ACS, early investigators in Spain believed that a
left ventricular wall motion similar to that seen in TC could follow from an acute
occlusion of the left anterior descending artery (LAD) that has a well-developed recurrent
segment that causes early and complete spontaneous reperfusion 4. They supported their
theory with intravascular ultrasound in five Takotsubo patients all of which were found to
have complicated eccentric plaques 4.
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But there are many arguments for refuting a link between TC and ACS. First, if
plaque rupture was the culprit, LAD intracoronary thrombi would be expected to be seen
more frequently 5. Secondly, all three major epicardial arteries have had documented
abnormal blood flow during disease presentation 5. Third, patients with TC often do not
have long recurrent distal LAD arteries 5. And lastly, a pathogenesis based upon plaque
rupture would not be reconcilable with the strong female predominance of Takotsubo
syndrome. One would expect the risk factors for TC to more closely follow the common
risk factors for ACS (including maleness) if they were linked 5.
Catecholamine Induced Toxicity
Takotsubo cardiomyopathy has been reported to occur after stressful events when
catecholamine levels would be high. In fact, plasma catecholamines have been shown to
be higher in patients presenting with TC when compared to those presenting with AMI 13.
Epinephrine levels have been reported at a mean 1264 pg/ml in TC versus 376 pg/ml in
AMI 13. Norepinephrine levels have been reported at a mean were 2284 pg/ml versus
1100 pg/ml in AMI 13. In Gianni’s 2006 review, elevated norepinephrine levels were
found in 26 of 35 TC patients and were at levels two to three times higher than in patients
presenting with AMI 9. In animal models, beta-adrenergic receptor density and tissue
catecholamines levels have been seen to differ between the apex and base of the left
ventricle 10. This could explain regional reactive differences to catecholamines upon the
heart 10.
Also, in support of a catecholamine mediated mechanism behind TC is the fact
that LV dysfunction similar to TC has been seen in diseases that increase catecholamine
levels such a head trauma and pheochromocytoma 13. This is why the Mayo Clinic
definition states that these diseases must be excluded before a diagnosis of TC is made.
Atypical Myocarditis
The idea that TC represents an atypical form of myocarditis does not have much
support at all. Endocardial biopsies performed on TC patients have not shown evidence
of myocarditis and neither have serum markers 13.
Genetic Etiology
As discussed earlier, because the original cases of takotsubo cardiomyopathy
were described in Japanese patients, it was thought that this disease might have a genetic
bias. But with increased clinical awareness of the disease this seems to not be holding
true. There has been a report published suggesting a familial link as well 8. The report
discusses a mother who has had two episodes of TC and her daughter who had a focal
mid-inferior wall akinesis described as a Takotsubo variant 8. There is no further
evidence to support a hereditary basis at this time.
Multivessel Coronary Vasospasm
Since the area of the heart affected in Takotsubo by definition falls in multiple
arterial territories, it has been also proposed that TC could be due to multivessel coronary
vasospasm. Attempts to support this theory have primarily focused on showing
spontaneous or induced vasospastic events during angiography. The results of this have
been limited and inconsistent 10. Gianni reported spontaneous multivessel epicardial
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vasospasm during coronary angiography in 3 out of 212 patients with TC 9. Multivessel
vasospasm provoked by ergonovine or acetylcholine was reported to occur in 24 of 84
patients 9.
Other Questions To Be Answered
Aside from the broad question of the pathogenesis of TC, there are other
questions that if answered may help in our understanding of this disease. First of which is
the question of why this disease seems to have a predilection for post-menopausal
women. This is not the group that would be expected to be at highest risk for ACS. Do
sex hormones play a role in controlling coronary vessel reactivity to sympathetic
stimulation 9? Is this group more susceptible to myocardial stunning 9? And does a
reduction in estrogen led to an alteration in endothelial function that may play a role in
causing this 9? Secondly, the question arises as to why the left ventricular apex seems to
be such a vulnerable area in TC. Is the apex more intolerant to high levels of
catecholamines? Or is there an unrecognized anatomical component to this disease such
as the orientation of fibers, radius of curvature at the apex, or an unknown characteristic
of the distal vasculature 6.
Diagnosis
Takotsubo cardiomyopathy has a very similar presentation to AMI, especially in
the ambulatory setting, and so is initially worked up with ACS protocols. TC is a
diagnosis of exclusion and can’t be diagnosed until an angiography is performed and the
results show a lack of significant occlusion 6.
12-Lead ECG
ECG results in TC patients are often very similar to those of an anterior infarct
with ST segment changes, secondary T wave changes and prolonged QT interval 10. In
Ogura’s comparison of ECGs in 13 patients with TC and 13 with anterior AMI he noted
several differences 2. He found that the TC group had less frequent abnormal Q waves
then in the anterior AMI group, fewer T wave inversions and no reciprocal changes in the
inferior leads 2.
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Q waves are thought to develop because of myocardial necrosis and local intramyocardial
conduction delays. The absence of necrosis and less delaying than in AMI is postulated to
be the reason for lessened Q waves 2.
Cardiac Enzymes
Cardiac enzymes (CE) have been reported to increase in TC but not as
significantly as is AMI 13. In Bybee’s study of 7 case series he found 56-100% had peak
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CE above the upper limit of normal although there is discrepancy as to which CE marker
was reported in different case series 3. Often peak CE were those taken at initial
presentation and then levels began to drop which is different from the normal increasing
curve of CE which peak after admission and then begin to fall 3. Gianni’s review reported
that Troponin I was positive in 86.2% of TC patients and CK-MB positive in 73.9%
although mean values for these CE were not reported 9.
Cardiac Catheterization
By definition, in Takotsubo cardiomyopathy there is no evidence of plaque
rupture or obstruction.
Echocardiography and Ventriculograms
Echocardiography and ventriculograms show apical ballooning with akinesis or
dyskinesis of the apical left ventricle 13. Left ventricular ejection fraction has been
reported to be reduced to an average of 20 to 49% 13.
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Treatment
There are no established algorithms for TC and as most patient present as ACS,
they are treated according to ACS guidelines 10. Specific therapies used are dictated by
the clinical course of the patient 10. Outflow tract gradients can be managed by
medications that decrease the gradient such as beta-blockers, calcium channel blockers or
increased afterload and by the avoidance of therapies that would increase the gradient
such as diuretics, pressors and IABPs 10. Normal management of complications such as
arrhythmia and pulmonary edema is also required 10. In UpToDate the following
treatment guidelines are suggested 13:
 If the patient is hemodynamically stable
o Initiate a beta-blocker
o Initiate an ACEI or ARB in patients without an LVOT gradient
o Diuresis of patients in heart failure without LVOT gradient
o Initiate aspirin
 If the patient is hypotensive
o Cautious fluid resuscitation
o Initiate inotropes if no significant outflow obstruction
o If moderate to severe outflow obstruction beta-blockers can be tried with
cautious use of alpha agonists as a second line agent if beta-blockers fail
 If hypotensive patient does not respond to medical management
o Intraaortic balloon pump
Prognosis and Complications
Heart failure is the most common complication of takotsubo cardiomyopathy and
was reported in Gianni’s review to occur in 17.7% of patients 9. Other possible
complications include:
1. Hemodynamic compromise (treat with pressor agents or balloon pumps)
2. Supraventricular and ventricular arrhythmias
3. Intraventricular pressure gradient and mitral regurgitation
4. LV thrombus
5. Ventricular free wall rupture
6. Pulmonary edema
In-hospital mortality has been reported to be anywhere from 0 to 8% 13. Ventricular
function returns to normal usually within one to four weeks 13.
Summary
I have to admit that I was disappointed while researching this paper. I spent a
month in Seattle, Washington last fall on a Cardiology consult service during which we
had two cases of takotsubo cardiomyopathy. The first was a woman after childbirth and
the second was a post-surgical patient. The attending cardiologist was surprised to be
treating multiple cases of this supposedly rare disease and spent a little time giving us an
overview of it. I took an interest in this disease and wanted to research it more mainly
because of the connection he described between our hearts and our heads. And my
disappointment has been in just how little has been discovered about the pathophysiology
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of Takotsubo cardiomyopathy and the head-heart connection more than fifteen years after
it was first described.
References
1. Akasi Y.J. The Clinical Features of Takotsubo Cardiomyopathy. Q J Med 2003;
96: 563-573
2. Ogura, Riyo. Specific Findings of the Standard 12-Lead ECG in Patients with
‘Takotsubo’ Cardiomyopathy. Circ J 2003; 67: 687-690
3. Bybee, Kevin. Systematic Review: Transient Left Ventricular Apical Ballooning:
A Syndrome that Mimics ST-Segment Elevation Myocardial Infarction. Ann
Intern Med. 2004; 141: 858-865.
4. Ibanez, Borja. Comment on Systematic Review: Transient Left Ventricular Apical
Ballooning: A Syndrome that Mimics ST-Segment Elevation Myocardial
Infarction. Ann Intern Med. 2005; 142: 677
5. Bybee, Kevin. Response to Comments on Systematic Review: Transient Left
Ventricular Apical Ballooning: A Syndrome that Mimics ST-Segment Elevation
Myocardial Infarction. Ann Intern Med. 2005; 142: 677
6. Wachsman, Daniel. Takotsubo Cardiomyopathy: A Little-Known
Cardiomyopathy Makes its Debut. Cardiology 2004; 102: 119-121
7. Boulouffe, Caroline. Stress-Induced Cardiomyopathy: Takotsubo Left Ventricular
Dysfunction. AJEM 2006; 11; 10: 243-244
8. Cherian, John. Can Takotsubo Cardiomyopathy be Familial? International Journal
of Cardiology 2007; 121: 74-75
9. Gianni, Monica. Apical Ballooing Syndrome or Takotsubo Cardiomyopathy: A
Systematic Review. European Heart Journal 2006; 27: 1523-1529
10. Guttormsen, Brian. Transient Left Ventricular Apical Ballooning: A Review of
the Literature. Wisconsin Medical Journal 2006; 105; 3: 49-54
11. Haghi, Dariusch. Takotsubo Cardiomyopathy (Acute Ventricular Apical
Ballooning Syndrome) Occurring in the Intensive Care Unit. Intensive Care Med
2006; 32: 1069-1074
12. Akashi, Y.J. Cardiac Autonomic Imbalance in Patients with Reversible
Ventricular Dysfunction Takotsubo Cardiomyopathy. Q J Med 2007; 100: 335343
13. Reeder, Guy. Stress-Induced (Takotsubo) Cardiomyopathy. UpToDate. May 9,
2007
14. Ibanez, Borja. Takotsubo Syndrome: A Bayesian Approach to Interpreting Its
Pathogenesis. Mayo Clinic Proceedings 2006; 81: 732-735
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