Case Reports Reverse Takotsubo Cardiomyopathy 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): 568-72) S 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, psychological/complications; stress cardiomyopathy; takotsubo cardiomyopathy, reverse/diagnosis/physiopathology; ventricular dysfunction, left/diagnosis/etiology/ ultrasonography 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: nishakim@gwu.edu © 2011 by the Texas Heart ® Institute, Houston 568 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 given.7 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 phenethylamine. 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). Discussion Stress-induced cardiomyopathy is a condition characterized by transient dysfunction of the ventricular apex A A B B 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 forimages real-time motion image: Fig. 2A. Real-time motion are available at www.texasheart.org/ journal. Click here for real-time motion image: Fig. 2B. Reverse Takotsubo after Serotonin Syndrome 569 Fig. 3 Left ventriculogram shows basal hypokinesis of the left ventricle with apical hyperkinesis. Real-time motion image is available at www.texasheart.org/ Click here for real-time motion image: Fig. journal. 3. 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. 570 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. Acknowledgment We would like to thank Sriramana Kanginakudru, PhD, for critical review and technical help. References 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): 61-6. 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 (3):809-16. 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): 1139-42. 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 2005;128(1):296-302. 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 2006;81(11):1499-502. 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 2008;101(12):1723-8. 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 571 20. 21. 22. 23. 24. 572 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