American Journal of Therapeutics 23, e597–e600 (2016)

Ergotamine-Induced Takotsubo Cardiomyopathy Ebru Ozpelit, MD,1* Mehmet E. Ozpelit,2 Bahri Akdeniz,1 and Özhan Göldeli1

Takotsubo cardiomyopathy (TC) is a recently increasing diagnosed disease showed by transient apical or mid-apical left ventricular dysfunction. It is known as a disease of postmenopausal women, which is usually triggered by emotional or physical stress. Although the trigger is mostly endogenous, some drugs have also been reported as the cause. Published case reports of TC associated with drug usage consist of sympathomimetic drugs, inotropic agents, thyroid hormone, cocaine, and 5-fluorouracil. We present an unusual case of TC in which the possible trigger is ergotamine toxicity. Keywords: takotsubo cardiomyopathy, ergotamine

INTRODUCTION Takotsubo cardiomyopathy (TC) is a recently increasing diagnosed disease showed by transient apical or mid-apical left ventricular dysfunction. It is known as a disease of postmenopausal women, which is usually triggered by emotional or physical stress. We present an unusual case of TC in which the possible trigger is ergotamine toxicity.

CASE REPORT A 53-year-old women presented to the outpatient clinic with dyspnea and chest pain ongoing for the past 2 days. She also complained about burning sensation in both arms. Her medical history included a cardiac surgery for secundum-type atrial septal

1

Department of Cardiology, School of Medicine, Dokuz Eylul University, Izmir, Turkey; and 2Department of Cardiology, Medical Park Hospital, School of Medicine, Izmir University, Izmir, Turkey. The authors have no conflicts of interest to declare. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions this article on the journal’s Web site (www.americantherapeutics.com). *Address for correspondence: Assistant Professor, Dokuz Eylul _ University Hospital, Inciraltı, Izmir, Turkey. E-mail: ebru. [email protected]

defect 25 years ago and a recent lower respiratory tract infection. She also had concomitant neurological diseases such as migraine and restless leg syndrome. On further evaluation, the ECG showed negative T waves in all leads with a mild QT prolongation (QTc 5 460 milliseconds) (Figure 1). Laboratory examination showed increased troponin I levels (0.6 ng/mL). Leukocyte count, CRP, serum electrolytes, CK-MB, and other routine laboratory parameters were in normal ranges. The initial diagnosis was unstable angina pectoris and thus a coronary angiography was performed in the next step. Coronary angiography showed normal coronary arteries with no stenosis, but ventriculography was demonstrative for an apical balooning (Figure 2). Transthoracic echocardiography approved the mid-apical akinesia with basal hyperkinesia (Figure 3; see Supplemental Digital Content 1, Video, http://links.lww. com/AJT/A17). Echocardiography was also demonstrative for a slight right ventricular enlargement and pulmonary hypertension that were thought to be secondary to atrial septal defect history. On the 10th day of admission, echocardiography showed nearly complete normalization of left ventricular dysfunction (Figure 4; see Supplemental Digital Content 2, Video, http:// links.lww.com/AJT/A18). Electrocardiographic findings did not change significantly during the hospital stay. Owing to these findings, the final diagnosis was TC. When the patient was further questioned for possible triggers, although there was no emotional or physical stress, a recent history of polymedication including antimigraine drugs and antibiotics was evident. The

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FIGURE 1. T-wave inversion in anterior and inferior leads.

patient received clarithromycin 1000 mg/d for the past 14 days, which was prescribed for lower respiratory tract infection. She also received ergotamine tartarate 1.5 mg/d for the past 5 days owing to her increased migraine headache. She was already on therapy for restless leg syndrome including pramipexole 0.25 mg/d and fluoxetine 20 mg/d. This polymedication including neurogenically active drugs raised the suspicion whether the trigger for TC was the medication itself. When the drugs she used were analyzed in detail, ergotamine toxicity was seen as

a possible etiology. Ergotamine, because of its a-adrenergic effects and extensive first pass metabolism through cytochrome p450-3A4 isoenzyme, could possibly cause such a condition in the presence of concomitant use of clarithromycin and fluoxetine that were powerful inhibitors of CYP450.1 The proposed mechanisms of TC, coronary microvasculature vasospasm and excess catecholamine, could readily be a consequence of ergotamine toxicity.2 The patient’s complaint of burning sensation in arms was also thought to be a sign of ergotism, which is called

FIGURE 2. Apical ventriculography.

FIGURE 3. Diskinetic apeks on echocardiography.

balooning

of

left

American Journal of Therapeutics (2016) 23(2)

ventricle

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Ergotamine-Induced Takotsubo Cardiomyopathy

FIGURE 4. Disappearence of wall motion abnormality on echocardiography.

St. Anthony’s fire.3 Her peripheral pulses were normal with no cyanosis in extremities. Ergotamine tartarate and clarithromycin were stopped during the hospital stay. She was warned against possible drug interactions while using ergotamine. Clinical followup was uneventful for the next 6 months with totally normal left ventricular functions.

DISCUSSION TC is a syndrome of transient cardiac dysfunction precipitated by intense emotional or physical stress. Catecholamine-induced myocardial dysfunction, coronary microcirculatory dysfunction, diffuse epicardial arterial spasm, and neurologically mediated myocardial stunning are the potential mechanisms of TC.4 Although the trigger is mostly endogenous, some drugs have also been reported as the cause. Published case reports of TC associated with the drug usage consist of sympathomimetic drugs, inotropic agents, thyroid hormone, cocaine, and 5-fluorouracil.5 To the best of our knowledge, the present case is the first to define the association between ergotamine toxicity and TC. Ergotamine is a commonly used drug in the treatment and prevention of migraine headache. It is structurally similar to endogenous catecholamines and indolamines. In therapeutic concentrations, ergotamine acts as an agonist of a-adrenergic, serotonergic, and dopaminergic receptors.1 It causes vasoconstriction www.americantherapeutics.com

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mainly by stimulating a-adrenergic and serotonergic receptors. Although its toxicity is rare, several causes of ergotism have been published so far. Typical presentation is the lower-limb ischemia; however, it can also cause coronary vasospasm and myocardial infarction.6 Chronic treatment with ergotamine and/or other serotonergic medications may also cause heart valve dysplasia and dysfunction similar to that seen in carcinoid heart disease.7 Many reported cases of ergotamine-induced cardiovascular toxicity and ergotamine-related cardiopathy were associated with chronic excessive dosing. However, recent cases have been mostly described after extremely small doses of ingestion. Today, the main reason of ergotamine toxicity occurring in therapeutic doses is drug–drug interactions.8 Ergotamine has a very low bioavailability from oral administration as a result of extensive first pass metabolism through cytochrome P450-3A4 isoenzyme. Inhibition of this isoenzyme by concomitant use of some drugs may lead to an increase in serum ergotamine concentration and strongly predispose to ergotamine toxicity even at recommended doses. Today, the most known cyp3A4 inhibitors are HIV protease inhibitors, macrolide antibiotics (especially clarithromycin), azole antifungals, and some antidepressants (including fluoxetine).9 Concomitant use of ergotamine, clarithromycin, and fluoxetine in this case strongly suggests the possibility of ergotamine toxicity. Considering the proposed mechanisms of TC, including coronary vasospasm in microvasculature and neurogenic myocardial stunning, ergotamine toxicity could be a reasonable background in such a clinical picture. Coexistence of burning sensation in arms also raised this possibility, as this was a specific sign of ergotism called St. Anthony’s fire. Because laboratory evaluation of serum ergotamine levels is impossible, we could not analyze the serum levels. However, all other examples of ergotism in literature are also based on the diagnosis and clinical picture, and not biochemical analysis. Discontinuation of ergotamine is the first step in management of such a case. So, awareness of this association between ergotamine usage and TC will prevent unnecessary interventions in similar cases.

CONCLUSIONS This case is the first to define the association between ergotamine toxicity and TC. Considering the frequent usage of ergotamine as an antimigraine drug and the high possibility of ergotism with concomitant usage of American Journal of Therapeutics (2016) 23(2)

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many agents, this case represents an important clinical situation which all the physicians should be aware off.

REFERENCES 1. Tfelt-Hansen P, Saxena PR, Dahlöf C, et al. Ergotamine in the acute treatment of migraine: a review and European consensus. Brain. 2000;123:9–18. 2. Sharma AK, Singh JP, Heist EK. Stress cardiomyopathy diagnosis, pathophysiology, management, and prognosis. Crit Pathw Cardiol. 2011;10:142–147. 3. De Costa C. St Anthony’s fire and living ligatures: a short history of ergometrine. Lancet. 2002;359:1768–1770. 4. Akashi YJ, Nakazawa K, Sakakibara M, et al. The clinical features of takotsubo cardiomyopathy. QJM. 2003;96:563–573.

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Ozpelit et al 5. Amariles P. A comprehensive literature search: drugs as possible triggers of Takotsubo cardiomyopathy. Curr Clin Pharmacol. 2011;6:1–11. 6. Wells KE, Steed DL, Zajko AB, et al. Recognition and treatment of arterial insufficiency from cafergot. J Vasc Surg. 1986;4:8–15. 7. Setola V, Hufeisen SJ, Grande-Allen KJ, et al. 3,4-methylenedioxymethamphetamine (MDMA, “Ecstasy”) induces fenfluramine-like proliferative actions on human cardiac valvular interstitial cells in vitro. Mol Pharmacol. 2003;63: 1223–1229. 8. Schiff PL. Ergot and its alkaloids. Am J Pharm Educ. 2006; 70:98. 9. Shapiro LE, Shear NH. Drug interactions: proteins, pumps, and P-450s. J Am Acad Dermatol. 2002;47:467– 484.

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Ergotamine-Induced Takotsubo Cardiomyopathy.

Takotsubo cardiomyopathy (TC) is a recently increasing diagnosed disease showed by transient apical or mid-apical left ventricular dysfunction. It is ...
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