Reverse Takotsubo Cardiomyopathy after an Episode of Serotonin Syndrome Case

Reverse Takotsubo
after an Episode of Serotonin Syndrome
Nishaki Kiran Mehta, MD
Gerard Aurigemma, MD
Zahi Rafeq, MD
Oscar Starobin, MD
Stress-induced cardiomyopathy is characterized by transient left ventricular dysfunction,
usually followed by complete resolution. It is precipitated by severe stress, and the most
common variant (takotsubo) is marked by apical hypokinesis and ballooning with basal
hyperkinesis. Serotonin syndrome is best understood as excess serotonergic activity in the
central and peripheral nervous system. This imposes significant stress on the body. We report what we believe is the 1st case of serotonin syndrome as an indirect cause of stressinduced cardiomyopathy with a reverse takotsubo profile. (Tex Heart Inst J 2011;38(5):
Key words: Antidepressive
agents, second-generation/
adverse effects; antipsychotic agents/adverse effects;
catecholamines; depression;
echocardiography; monoamine oxidase inhibitors;
serotonin syndrome/chemically induced/diagnosis/prevention & control; stress,
stress cardiomyopathy;
takotsubo cardiomyopathy,
reverse/diagnosis/physiopathology; ventricular dysfunction, left/diagnosis/etiology/
From: Department of Medicine (Dr. Mehta), and Division of Cardiovascular
Medicine, Department of
Medicine (Drs. Aurigemma,
Rafeq, and Starobin), University of Massachusetts
Medical School, Worcester,
Massachusetts 01605
Address for reprints:
Nishaki Kiran Mehta, MD,
Department of Medicine,
George Washington University, 2150 Pennsylvania Ave.
NW, Washington, DC 20037
E-mail: [email protected]
© 2011 by the Texas Heart ®
Institute, Houston
tress-induced cardiomyopathy—the broken-heart syndrome or takotsubo cardiomyopathy—was first described in 1990 in Japan. Since then, this syndrome has been increasingly recognized in Europe and the United States.1,2
Although the initial presentation is alarming for its resemblance to acute coronary
syndrome, myocardial dysfunction does not follow any coronary artery distribution,
there is no obstructive coronary disease on angiography, and the left ventricular (LV)
dysfunction resolves. Wall-motion abnormalities are confined to the apex in the classic takotsubo variant, but increasingly other patterns have been recognized, including
exclusive basilar involvement, termed “reverse takotsubo.”3,4 The long-term prognosis
is generally good, and a recent long-term follow-up study showed that most nonsurvivors died of noncardiac causes.5
Serotonin syndrome is characterized by increased synaptic serotonin and is often a
consequence of drug interactions. The diagnosis is made primarily from history and
from clinical examination on the basis of the Hunter criteria6 ; no laboratory test is
available for confirmation. Patients present with cognitive, autonomic, and somatic manifestations of serotonin excess. Management is primarily supportive, with use
of benzodiazepines. In severe cases, serotonin antagonists such as cyproheptadine are
We describe the case of a patient who presented with serotonin syndrome and concomitant stress-induced cardiomyopathy with a reverse takotsubo pattern.
Case Report
In May 2010, a 46-year-old woman with no significant cardiac history but with a
history of depression, and under treatment with monoamine oxidase (MAO) inhibitors and lithium, presented with severe headache, chest discomfort, lightheadedness,
and nausea.
The patient had been in her usual state of health until 2 days before admission,
when she felt more anxious than usual. Having in the past experienced occasional chest discomfort when anxious, she observed that her increased chest discomfort
correlated with increased perceived stress over the preceding 2 days. She had a longstanding history of depression that had been resistant to electroconvulsive therapy, and
at the time of presentation she was taking 60 mg of isocarboxazid in 2 divided doses
(recently increased from 40 mg in 2 divided doses) and low-dose lithium (300 mg
twice a day). However, because she believed that her depression was not adequately
controlled, she had taken 500 mg of phenethylamine on the day of admission. Twenty minutes after taking this medication, she developed severe headache, worsening
chest discomfort, lightheadedness, and nausea. At that time, her systolic blood pressure measured at home was approximately 210 mmHg, so she took herself to a local
hospital, where a chest radiograph was consistent with congestive heart failure. Ser-
Reverse Takotsubo after Serotonin Syndrome
Volume 38, Number 5, 2011
otonin syndrome was suspected on the basis of the patient’s history. She was started on a nitroglycerin drip
and was administered intravenous furosemide 40 mg
and lorazepam 3 mg. She then became hypotensive and
subsequently received intravenous fluids. At that time,
an electrocardiogram (ECG) revealed ST depression in
the lateral and inferior leads (Fig. 1A) with an elevated
troponin I level of 0.65 ng/mL (normal level, <0.03 ng/
mL). She was then transferred to our institution for further management.
Upon the patient’s arrival, her blood pressure was
89/55 mmHg; her heart rate, 102 beats/min; her respiratory rate, 22 breaths/min; and her oxygen saturation
level, 99% on 2 liters. An ECG in the emergency department showed sinus rhythm, with resolution of the
ST-T changes that the ECG from the outside hospital
had shown (Fig. 1B). She was given intravenous fluids for her low blood pressure and a full-strength aspirin. Physical examination showed hyperreflexia of grade
3+ in all extremities. Because of initial concern about
serotonin syndrome, she was transferred to the intensive care unit for close monitoring. Her troponin I level
peaked at 6.3 ng/mL, and transthoracic echocardiography showed markedly reduced LV systolic function
with severe basal hypokinesis, but with sparing of the
apex. The right ventricle was mildly dilated and displayed reduced systolic function. Moderate mitral and
tricuspid regurgitation with mild pulmonary hypertension were noted (Fig. 2A).
She was initially treated for non-ST-segment–
elevation myocardial infarction (NSTEMI), but cardiac catheterization was negative for obstructive coronary
disease. Left ventriculography showed basal hypokinesis with apical hyperkinesis (Fig. 3). Her blood pressure improved with intravenous hydration, and she was
eventually discharged from the hospital with a diagnosis of stress-induced cardiomyopathy and serotonin
syndrome. She was placed on a regimen of aspirin, lowdose -blocker, and an angiotensin-converting enzyme
inhibitor. She was also restarted on a lower dose of isocarboxazid with lithium, and she was advised to avoid
A 2-week follow-up echocardiogram showed complete resolution of the wall-motion abnormalities, together with an estimated LV ejection fraction of 0.60
(Fig. 2B).
Stress-induced cardiomyopathy is a condition characterized by transient dysfunction of the ventricular apex
Fig. 1 Electrocardiograms show A) ST-T depressions in the
inferolateral distribution during the acute phase of stress-induced
cardiomyopathy and B) subsequent resolution of these changes.
Texas Heart Institute Journal
Fig. 2 Transthoracic echocardiograms show A) dilation of the
base of the left ventricle during the acute episode, with normal
contraction of the apex; and B) resolution of the left ventricular
dysfunction 2 weeks later.
Click here
image: Fig. 2A.
are available
Click here for real-time motion image: Fig. 2B.
Reverse Takotsubo after Serotonin Syndrome
Fig. 3 Left ventriculogram shows basal hypokinesis of the left
ventricle with apical hyperkinesis.
Real-time motion image is available at
Click here for real-time motion image: Fig.
with absence of coronary artery disease.8 As the name
implies, this condition is precipitated by physiologic or
mental stress, as demonstrated by some elegant studies.9,10 It generally affects postmenopausal women more
frequently than it does men, and occurs typically in the
6th or 7th decade of life.8 Neuroendocrine, hormonal, neuropsychological, and vascular causes have been
proposed to explain the pathogenesis of this condition.
Of these, vascular or myocardial dysfunction mediated
by catecholamine excess is the most accepted theory.11,12
Different types of stress-induced cardiomyopathy have
been described in the medical literature. Right ventricular dysfunction has recently been described and is generally accompanied by severe LV involvement.13 The most
common type of stress-induced cardiomyopathy fits the
typical takotsubo pattern and is characterized by apical hypokinesis and ballooning, with normal basal LV
function. This pattern of LV dysfunction is thought to
be due to increased density of -adrenergic receptors in
the apex with subsequent diversion of Gs protein coupling to an inhibitory pathway via Gi protein coupling,
in the setting of catecholamine excess.14 This inhibition
is proposed to stun the apical myocardium and lead to
hypokinesis.14 Other types of stress-induced cardiomyopathy are midventricular (the mid segment of the ventricle
is hypokinetic) and reverse takotsubo (basal hypokinesis with preserved apical function) patterns.4 The pattern
of wall-motion abnormality displayed in our patient fits
the category of reverse takotsubo previously reported in
cases of pheochromocytoma 15 and acute pancreatitis.16
Neither the pathophysiology nor the long-term prognosis of these different types of stress cardiomyopathy is
well understood.
Reverse Takotsubo after Serotonin Syndrome
The clinical presentation of stress-induced cardiomyopathy is similar to that of acute coronary syndrome:
in regard to ECG changes, ST elevations in the anterolateral leads are the most common manifestation.17 Our
patient had ST depressions in the anterolateral leads that
were consistent with the reverse morphology of her presentation. Modest elevations of cardiac enzymes have
been seen, and a recent study 17 reported that most patients diagnosed with stress-induced cardiomyopathy
had troponin T and troponin I levels of less than 6 ng/
mL and 15 ng/mL, respectively. Troponin T was also
found to be inversely correlated with LV ejection fraction.17 Our patient’s troponin I level peaked at 6.3 ng/
mL. The clinical presentation can be complicated by
pulmonary edema and hypotension resulting from poor
forward flow,18 as was seen in our patient.
The preliminary diagnosis is made by echocardiography, which shows segmental hypokinesis that is inconsistent with any particular coronary artery distribution.
Multivessel coronary artery disease might be suspected,
but many stress-induced cardiomyopathy patients have
low cardiovascular risk, as was seen with our patient.
The LV ejection fraction generally ranges between 0.20
and 0.49.19 Although cardiac computed tomography,
magnetic resonance imaging scans, and nuclear perfusion tests are useful as diagnostic adjuncts, the exclusion of concomitant coronary artery disease needs to be
done via cardiac catheterization or stress testing, in accordance with the Mayo Clinic criteria for the diagnosis of stress-induced cardiomyopathy.3
Because stress-induced cardiomyopathy accounts for
only 1% to 2% of acute coronary syndromes, the initial
approach should focus on management of the presumed
acute myocardial infarction.3 Complicated stress cardiomyopathy presenting with hypotension requires careful
consideration of whether the patient has an underlying
LV outflow tract obstruction. This obstruction would
be caused by compensatory hyperkinesis of the base of
the heart, with associated anterior motion of the mitral
valve during systole. In the absence of outflow obstruction, hypotension can be managed with pressors such
as dopamine, dobutamine, and noncatecholamine pressors (for example, levosimendan), or with an intra-aortic balloon pump or intravenous fluids.20
The complications are associated primarily with poor
ventricular ejection fraction. These include arrhythmias, valvular abnormalities, thrombus formation with
subsequent embolization, pulmonary edema, and hypotension. Given the transient nature of this syndrome
and its complete resolution, the mortality rate is low (estimated to be <8%).17 Right ventricular involvement has
been associated with a higher risk of pulmonary edema,
hypotension, and a poor prognosis.13 As anticipated in
the case of our patient, the 2-week follow-up echocardiogram showed complete resolution the cardiomyopathy.
Volume 38, Number 5, 2011
Serotonin syndrome is characterized by serotonin excess and is diagnosed using the Hunter criteria.6 These
criteria include a history of ingestion of serotonergic
drugs, inducible or spontaneous clonus with hypertonism, hyperreflexia, or fever. Our patient had hyperreflexia with hypertension at the time of presentation.
She also had a classic history of combining phenethylamine use with the use of a MAO inhibitor (isocarboxazid) and lithium. Phenethylamine is a natural
monoamine alkaloid and is generally rendered inactive by MAO, upon extensive first-pass metabolism.21
Conversely, a rise of 1,000-fold in phenethylamine concentration can be seen with concomitant use of MAO
inhibitors.22 The combination of phenethylamine, isocarboxazid, and lithium has been implicated in serotonin syndrome.7,23 Our patient had received lorazepam
at the outside hospital, which could have subdued a dramatic presentation of serotonin syndrome. The management of serotonin syndrome is to discontinue the
offending medications and to administer benzodiazepines for agitation and clonus, sympathomimetics for
hypotension, and nitroprusside or -blockers for hypertension.7 Notably, our patient had concomitant takotsubo that would preclude use of sympathomimetics;
therefore, her blood pressure was restored with intravenous fluids. In severe cases, serotonin antagonists (such
as cyproheptadine) and atypical antipsychotics (such
as olanzapine) have been used. To our knowledge, this
is the 1st report of a case in which serotonin syndrome
led to stress-induced cardiomyopathy with a reverse
takotsubo pattern. The underlying pathophysiology is
unclear. Phenethylamine is known to release endogenous catecholamines, but the role of catecholamines as a
cause of stress cardiomyopathy has been questioned.22,24
An alternative possibility is direct overstimulation of
serotonin receptors in the heart. Yet in our patient the
causative sequence could well have been indirect: serotonin syndrome led to physiologic stress, physiologic
stress to a hyperadrenergic state, and the hyperadrenergic state to stress-induced cardiomyopathy.
Individual susceptibility to stress, rates of recurrence,
and the benefit of -blockers in preventing recurrence
are among the matters that require further research.
We would like to thank Sriramana Kanginakudru, PhD,
for critical review and technical help.
1. Seth PS, Aurigemma GP, Krasnow JM, Tighe DA, Untereker
WJ, Meyer TE. A syndrome of transient left ventricular apical
wall motion abnormality in the absence of coronary disease: a
perspective from the United States. Cardiology 2003;100(2):
Texas Heart Institute Journal
2. Aurigemma GP, Tighe DA. Echocardiography and reversible
left ventricular dysfunction. Am J Med 2006;119(1):18-21.
3. Prasad A, Lerman A, Rihal CS. Apical ballooning syndrome
(tako-tsubo or stress cardiomyopathy): a mimic of acute myocardial infarction. Am Heart J 2008;155(3):408-17.
4. Kurowski V, Kaiser A, von Hof K, Killermann DP, Mayer B,
Hartmann F, et al. Apical and midventricular transient left
ventricular dysfunction syndrome (tako-tsubo cardiomyopathy): frequency, mechanisms, and prognosis. Chest 2007;132
5. Song BG, Hahn JY, Cho SJ, Park YH, Choi SM, Park JH, et
al. Clinical characteristics, ballooning pattern, and long-term
prognosis of transient left ventricular ballooning syndrome.
Heart Lung 2010;39(3):188-95.
6. Dunkley EJ, Isbister GK, Sibbritt D, Dawson AH, Whyte IM.
The Hunter Serotonin Toxicity Criteria: simple and accurate
diagnostic rules for serotonin toxicity. QJM 2003;96(9):63542.
7. Ables AZ, Nagubilli R. Prevention, recognition, and management of serotonin syndrome. Am Fam Physician 2010;81(9):
8. 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):1523-9.
9. Watanabe H, Kodama M, Okura Y, Aizawa Y, Tanabe N,
Chinushi M, et al. Impact of earthquakes on Takotsubo cardiomyopathy. JAMA 2005;294(3):305-7.
10. Park JH, Kang SJ, Song JK, Kim HK, Lim CM, Kang DH,
Koh Y. Left ventricular apical ballooning due to severe physical stress in patients admitted to the medical ICU. Chest
11. Abraham J, Mudd JO, Kapur NK, Klein K, Champion HC,
Wittstein IS. Stress cardiomyopathy after intravenous administration of catecholamines and beta-receptor agonists. J Am
Coll Cardiol 2009;53(15):1320-5.
12. Sato A, Yagihara N, Kodama M, Mitsuma W, Tachikawa H,
Ito M, et al. Takotsubo cardiomyopathy after delivery in an
oestrogen-deficient patient. Int J Cardiol 2011;149(2):e78-9.
13. Fitzgibbons TP, Madias C, Seth A, Bouchard JL, Kuvin JT,
Patel AR, et al. Prevalence and clinical characteristics of right
ventricular dysfunction in transient stress cardiomyopathy.
Am J Cardiol 2009;104(1):133-6.
14. Heubach JF, Ravens U, Kaumann AJ. Epinephrine activates
both Gs and Gi pathways, but norepinephrine activates only
the Gs pathway through human beta2-adrenoceptors overexpressed in mouse heart. Mol Pharmacol 2004;65(5):131322.
15. Gervais MK, Gagnon A, Henri M, Bendavid Y. Pheochromocytoma presenting as inverted takotsubo cardiomyopathy:
a case report and review of the literature. J Cardiovasc Med
(Hagerstown) 2010 Feb 11. [Epub ahead of print]
16. Van de Walle SO, Gevaert SA, Gheeraert PJ, De Pauw M,
Gillebert TC. Transient stress-induced cardiomyopathy with
an “inverted takotsubo” contractile pattern. Mayo Clin Proc
17. Sharkey SW, Lesser JR, Menon M, Parpart M, Maron MS,
Maron BJ. Spectrum and significance of electrocardiographic
patterns, troponin levels, and thrombolysis in myocardial
infarction frame count in patients with stress (tako-tsubo)
cardiomyopathy and comparison to those in patients with STelevation anterior wall myocardial infarction. Am J Cardiol
18. Akashi YJ, Goldstein DS, Barbaro G, Ueyama T. Takotsubo
cardiomyopathy: a new form of acute, reversible heart failure.
Circulation 2008;118(25):2754-62.
19. Wittstein IS, Thiemann DR, Lima JA, Baughman KL, Schulman SP, Gerstenblith G, et al. Neurohumoral features of
Reverse Takotsubo after Serotonin Syndrome
myocardial stunning due to sudden emotional stress. N Engl J
Med 2005;352(6):539-48.
Villareal RP, Achari A, Wilansky S, Wilson JM. Anteroapical
stunning and left ventricular outflow tract obstruction. Mayo
Clin Proc 2001;76(1):79-83.
Yang HY, Neff NH. Beta-phenylethylamine: a specific substrate for type B monoamine oxidase of brain. J Pharmacol
Exp Ther 1973;187(2):365-71.
Sabelli HC, Borison RL, Diamond BI, Havdala HS, Narasimhachari N. Phenylethylamine and brain function. Biochem Pharmacol 1978;27(13):1707-11.
Chung Hwang E, Van Woert MH. Comparative effects of
substituted phenylethylamines on brain serotonergic mechanisms. J Pharmacol Exp Ther 1980;213(2):254-60.
Kim S, Yu A, Filippone LA, Kolansky DM, Raina A. Inverted-Takotsubo pattern cardiomyopathy secondary to pheochromocytoma: a clinical case and literature review. Clin
Cardiol 2010;33(4):200-5.
Reverse Takotsubo after Serotonin Syndrome
Volume 38, Number 5, 2011