Case in Point Epinephrine-Induced Takotsubo

Kamalakar Surineni, MBBS, MPH; Muhammad R. Afzal, MD; Rajat Barua, MD, PhD; and Deepak Parashara, MD

Treatment of an allergic reaction led to stress-induced transient cardiomyopathy and provided evidence to support the role of epinephrine in the pathogenesis of this disease.

akotsubo cardiomyopathy akinesis, or dyskinesis of the LV mid- CASE REPORT (TCM) is a transient left segments with or without apical in- A 60-year-old man with a history of ventricular (LV) wall mo- volvement; the regional wall motion hypertension, alcohol abuse, tobacco T tion abnormality often abnormalities extend beyond a single use, non-Hodgkin lymphoma, and associated with acute medical ill- epicardial vascular distribution; a recently diagnosed squamous cell nesses, catastrophic life events, stressful trigger is often but not al- carcinoma of the right glossopalatine and intense physical or emotional ways present; (2) absence of obstruc- fossa was admitted to the chemo- stress.1,2 Takotsubo cardiomyopa- tive coronary disease or angiographic therapy infusion clinic at the Kansas thy also is known as stress-induced evidence of acute plaque rupture; City VAMC to receive his first dose of transient cardiomyopathy, api- (3) new electrocardiographic abnor- cetuximab. Forty-five minutes after cal ballooning syndrome, ampulla malities (either ST-segment elevation starting the test-dose infusion, the cardiomyopathy, and broken heart and/or T-wave inversion) or modest patient developed shortness of breath syndrome. The first reported case elevation in cardiac ; and along with hives on his trunk and occurred in 1990 in Japan and ac- (4) absence of pheochromocytoma extremities. His blood pressure was counts for 2% of all suspected and .4 80/50 mm Hg; heart rate, 100 bpm; acute coronary syndromes. Post- Depending on the part of the LV 16 breaths per minute respiration menopausal women seem to be at involved, TCM can be classified rate; and oxygen saturation by pulse a higher risk for developing the into apical ballooning variant (most oximetry was 90% on ambient air. disease, as about 90% of takotsubo common), an inverted or reverse ta- The patient reported no , cardiomyopathy occurs in post- kotsubo variant (basal akinesis with and a cardiac examination was unre- menopausal women.3 hyper dynamic apex), or a midven- markable without wheezing on lung Diagnosis of TCM is difficult, tricular takotsubo variant.5 auscultation. and there is an ongoing debate Several investigators have pro- A clinical diagnosis of acute ana- about the diagnostic criteria. The posed the role of catecholamine in phylaxis reaction was considered; Mayo Clinic proposed the following the pathogeneses of TCM.6,7 Previ- the test dose of cetuximab was dis- criteria: (1) transient hypokinesis, ous case reports have shown that continued, and the patient was the clinical circumstances with el- given 50 mg of diphenhydramine, evated catecholamine can result in followed by an inadvertent admin- Dr. Parashara and Dr. Barua are cardiologists, 8,9 Dr. Afzal was a cardiology fellow at the time TCM. The authors recently en- istration of 1 mg of epinephrine in- the article was written, and Dr. Surineni is a countered a case of a patient who travenously (recommended dose researcher, all at the Kansas City VAMC in Mis- developed apical ballooning TCM 0.1 mg). After 3 minutes of admin- souri. Dr. Parashara also is chief of the cardi- ology laboratory at the after an inadvertent injection of a istration of the medication, the pa- Kansas City VAMC. high dose of epinephrine. tient’s blood pressure increased to

28 • FEDERAL PRACTITIONER • OCTOBER 2016 www.fedprac.com 190/110 with a pulse rate of 120 bpm. An electrocardiogram (EKG) Figure 1. An Electrocardiogram Showing ST Elevation in the showed ST elevation in the precor- Precordial and Inferior Leads Consistent With Inferior and dial and inferior leads consistent Anterior Myocardial Injury with inferior and anterior myo- cardial injury (Figure 1). Pertinent laboratory studies revealed normal serum potassium (4.4 mEq/L), ele- vated serum glucose (219 mg/dL), and elevated troponin-I, (1.180 ng/ mL; reference range 0-0.3 ng/mL). An emergent transthoracic echocar- diogram showed a LV ejection frac- tion of 40% with akinesis involving the apical anterior, mid and distal an- teroseptal, and anterolateral wall with no significant valvular abnormalities (Figures 2 and 3). Given these echocardiographic excess, coronary , micro- and β-adrenoreceptor blockers sig- findings, persistent EKG changes, vascular dysfunction, and dynamic nificantly attenuated these changes.7 and elevated troponin levels, an midcavity or LV outflow tract ob- However, myocardial necrosis emergent coronary angiography struction.1,10 The hypothesis impli- alone cannot explain the entire pic- along with left ventriculography was cating catecholamine excess in the ture, because most patients with performed. The left ventriculogram pathogenesis of TCM is supported TCM regain full recovery of LV func- demonstrated apical ballooning con- by animal studies.7 These studies tion within several days of the event, sistent with TCM (Figures 4 and 5). suggest that catecholamines possi- and the degree of LV dysfunction is The left epicardial coronary arteries bly play a role by “direct toxicity to inconsistent with the mild elevations did not reveal any obstructive disease myocardial cells” as evidenced by in cardiac biomarkers. This explana- (Figure 6). histologic findings of myofibrillar tion leads to the second hypothesis The subsequent hospital course degeneration, contraction band ne- that proposes a “signal trafficking” was unremarkable, and the patient crosis, and leukocyte infiltration in role of catecholamines. According was discharged on guideline-directed harvested hearts from experimental to this theory, the supraphysiologic medications for systolic dysfunc- animals and patients undergoing au- doses of the catecholamines induce tion (ie, beta blockers and angioten- topsy.7,11 Similarly, cultured cardio- a switch in receptor coupling from sin-converting-enzyme inhibitors). myocytes exposed to high doses of Gs to Gi-proteins thus decreasing Serum levels of epinephrine were epinephrine showed apoptic changes. the contractility of the muscle. This not checked. A follow-up echocar- Pretreatment of these cells with α- switch protects the cardiac myocytes diogram performed after 8 weeks showed complete recovery of the LV Figure 2. Four Chamber View Figure 3. Four Chamber View function (Figures 7a and 7b). The at End Diastole at End Systole temporal sequence of events was highly suggestive of TCM, possibly due to the supratherapeutic dose of epinephrine. DISCUSSION The pathogenesis of stress-induced cardiomyopathy is not fully under- stood. Various hypotheses have been suggested, including catecholamine

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Figure 4. Left Ventriculogram Figure 5. Left Ventriculogram Figure 6. Angiogram Displaying at End Diastole at End Systole Normal Left Coronary System

Figure 7. Complete Recovery of the left ventricul REFERENCES 1. Komamura K, Fukui M, Iwasaku T, Hirotani S, A B Masuyama T. Takotsubo cardiomyopathy: patho- physiology, diagnosis and treatment. World J Cardiol. 2014;6(7):602-609. 2. Wittstein IS, Thiemann DR, Lima JAC, et al. Neurohumoral features of myocardial stunning due to sudden emotional stress. N Engl J Med. 2005;352(6):539-548. 3. Parodi G, Del Pace S, Carrabba N, et al. Incidence, clinical findings, and outcome of women with left ventricular apical ballooning syndrome. Am J Car- diol. 2007;99(2):182-185. 4. Madhavan M, Prasad A. Proposed Mayo Clinic criteria for the diagnosis of Tako-Tsubo car- diomyopathy and long-term prognosis. Herz. from excess stimulation and slows the role of catecholamines in the 2010;35(4):240-243. 5. Kawai S, Kitabatake A, Tomoike H; Takotsubo 7 the apoptosis. pathophysiology of TCM. It is hoped Cardiomyopathy Group. Guidelines for diagno- The role of estrogen also has been that this report will help clinicians to sis of takotsubo (ampulla) cardiomyopathy. Circ J. 2007;71(6):990-992. implicated in the pathogenesis of TCM. suspect, recognize, and manage this 6. Lyon AR, Rees PS, Prasad S, Poole-Wilson PA, From a prevalence standpoint, almost disease and be aware of possible iat- Harding SE. Stress (Takotsubo) cardiomyopa- thy—a novel pathophysiological hypothesis to 90% of TCM occurs in postmeno- rogenic causes. ● explain catecholamine-induced acute myocar- pausal women.11,12 Estrogen plays a dial stunning. Nat Clin Pract Cardiovasc Med. 2008;5(1):22-29. critical role in protecting the myocar- Author disclosures 7. Paur H, Wright PT, Sikkel MB, et al. High levels dium, possibly by down regulating The authors report no actual or poten- of circulating epinephrine trigger apical cardiode- pression in a β2-adrenergic receptor/Gi-dependent β-adrenergic receptors. Postmeno- tial conflicts of interest with regard to manner: a new model of Takotsubo cardiomyopathy. pausal women who do not receive es- this article. Circulation. 2012;126(6):697-706. 8. Abraham J, Mudd JO, Kapur NK, Klein K, Cham- trogen replacement therapy lose this pion HC, Wittstein IS. Stress cardiomyopathy after protection and may be more vulner- Disclaimer intravenous administration of catecholamines and beta-receptor agonists. J Am Coll Cardiol. able to the catecholamine surge that The opinions expressed herein are 2009;53(15):1320-1325. is associated with stress.11 Overall, the those of the authors and do not nec- 9. Wedekind H, Möller K, Scholz KH. Tako-tsubo cardiomyopathy. Incidence in patients with catecholamines play a central role in essarily reflect those of Federal . [in German]. Herz. the pathogenesis. This case suggests Practitioner, Frontline Medical Com- 2006;31(4):339-346. 10. Khullar M, Datta BN, Wahi PL, Chakravarti that exogenous administration of munications Inc., the U.S. Govern- RN. Catecholamine-induced experimental epinephrine in suprapharmacologic ment, or any of its agencies. This cardiomyopathy—a histopathological, histo- chemical and ultrastructural study. Indian Heart J. doses can be sufficient to replicate the article may discuss unlabeled or in- 1989;41(5):307-313. stressful situation and induce TCM. vestigational use of certain drugs. 11. Ueyama T, Hano T, Kasamatsu K, Yamamoto K, Tsuruo Y, Nishio I. Estrogen attenuates the emo- Please review the complete prescrib- tional stress-induced cardiac responses in the CONCLUSION ing information for specific drugs or animal model of Tako-tsubo (Ampulla) cardio- myopathy. J Cardiovasc Pharmacol. 2003;42(suppl The authors’ case report describes the drug combinations—including indica- 1):S117-S119. induction of apical ballooning TCM tions, contraindications, warnings, and 12. Sharkey SW, Lesser JR, Zenovich AG, et al. Acute and reversible cardiomyopathy provoked by stress by administration of supratherapeutic adverse effects—before administering in women from the United States. Circulation. doses of epinephrine and supports pharmacologic therapy to patients. 2005;111(4):472-479.

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