Drug-Induced Takotsubo Cardiomyopathy

Abstract

Background:

The most plausible hypothesis for takotsubo cardiomyopathy (TCM) is a catecholamine surge. Direct administration of catecholamines or medications causing catecholamine surge is frequently used in clinical practice.

Methods:

A Medline/PubMed database search was conducted for case reports or series of drug-induced TCM. All reported cases of drug-induced TCM were systemically identified and analyzed.

Results:

We identified 157 cases of drug-induced TCM. Fifty-seven (36.3%) cases were related to the administration of exogenous catecholamines. In 50 (31.9%) other cases, there was potential adrenergic effect. This included drugs with adrenergic vasoconstriction properties (3.2%), hyperadrenergic state due to alcohol or opioid withdrawal (7.7%), inhibitors of catecholamine reuptake (14.7%), anaphylactic reaction that is accompanied by catecholamine release (3.2%), and psychological or somatic stress coinciding with the administration of a drug that was thought to be the culprit (3.2%). Overall, 68.2% of these drug-induced TCM cases were catecholamine related. In 14 (8.9%) cases, the likely etiology of cardiomyopathy was chemotherapy-induced coronary vasospasm.

Conclusion:

Our systematic review showed that over two-thirds of drug-induced TCM cases were due to direct or indirect catecholamine stimulation. The lowest effective dose and shortest duration of catecholamines should be utilized, and alternative therapies should be considered if feasible.

Introduction

Transient reversible left ventricular systolic dysfunction is reported with increasing frequency. It may or may not be accompanied by regional wall motion abnormalities, in the form of apical ballooning or other forms. This condition is described in pheochromocytoma, a stress-induced cardiomyopathy, which develops as a result of emotional or somatic stress (takotsubo), and in subarachnoid hemorrhage, cerebrovascular accidents, or other neurologic conditions (neurogenic stunned myocardium). These conditions share the same morphologic substrate known as contraction band necrosis that is characterized by focal hypercontraction and lysis of small groups of myocardial cells, hypercontracted sarcomeres, dense eosinophilic transverse bands, and an interstitial mononuclear inflammatory response. ¹ Patients often present with chest pain, heart failure symptoms, or both have electrocardiogram (ECG) changes (ST-T changes or QT prolongation) and mildly elevated cardiac enzymes (often disproportionately low relative to ECG changes). On imaging, both normally and abnormally moving segments have typical perfusion, ² cardiac catheterization does not reveal critical stenoses of the coronary arteries, and left ventricular dysfunction often normalizes within few weeks. There are several theories on pathophysiology of takotsubo cardiomyopathy (TCM), but catecholamine surge is described as the most plausible mechanism. ³ Because catecholamines are commonly used in clinical practice, similar cardiac abnormality produced by adrenergic drugs could be an additional argument in favor of this pathophysiology, although β-receptor overstimulation may not be the only mechanism responsible for left ventricular systolic dysfunction. ⁴ In this article, we are systematically reviewing published case reports on drug-induced TCM.

Methods

A Medline/PubMed database search for case reports until October 2016 was performed using the keywords Takotsubo cardiomyopathy, Tako-tsubo cardiomyopathy or stress cardiomyopathy, and iatrogenic or drug induced. We also manually searched references in the articles, the PubMed search returned. All case reports were reviewed for the appropriate TCM diagnosis. Each case was further examined in order to identify the most likely underlying the cause of transient changes in myocardial contractility.

Results

A total 157 cases were reported in the literature as drug-induced TCM. The comprehensive list of the medications reported is summarized in the Tables 1 to 3. In 57 (36.3%) cases, TCM was related to the administration of exogenous catecholamines (Table 1). Epinephrine was the most common drug causing TCM (25 cases) followed by dobutamine (19 cases). In 50 (31.9%) other cases, there was potential adrenergic effect. This included drugs with direct sympathomimetic effect such as midodrine, adrenergic activation due to alcohol and opioid withdrawal, inhibitors of catecholamine reuptake, and anaphylactic reaction accompanied by catecholamine release (Table 2). Overall, 68.2% of cases of drug-induced TCM were catecholamine related. In other 14 (8.9%) cases, the likely etiology of cardiomyopathy was chemotherapy-induced coronary vasospasm (Table 4).

Table 1.

Exogenous Catecholamine-Induced Takotsubo-Induced Cardiomyopathy.

Citations	Drugs	Use	Comments
Saeki et al 5	Epinephrine	Asthma	0.3 mg subcutaneously 8 doses over 4 hours
Keshtkar et al 6	Nebulized epinephrine	Acute airway obstruction	1 μg/5 mL nebulization therapy twice total
Esnault et al 7	Epinephrine	Iatrogenic	1 mg once subcutaneously
Sundboll et al 8	Epinephrine and cocaine	Biopsy of tumor	Topical use with 3.2 mg of epinephrine and 320 mg of cocaine
Kajander et al 9	Epinephrine	Anaphylaxis	Epinephrine 0.1 mg IV
Khoueiry et al 10	Epinephrine	Anaphylaxis	Epinephrine 1 mg IV
Brunetti et al 11	Epinephrine	Local anesthesia	Epinephrine 0.4 mg into nasal area for dacryocystectomy
Copetti et al 12	Epinephrine	Pulseless electrical activity	Epinephrine 1 mg IV 3 times within 15 minutes
Magri et al 13	Epinephrine	Anaphylaxis	0.5 mg once IM
Winogradow et al 14	Epinephrine	Anaphylaxis	1 mg once IV
Dewachter et al 15	Epinephrine	Shock	Cumulative dose 30 mg IV
Harle et al 16	Epinephrine	Accidental injection	1 mg IV once
Volz et al 17	Epinephrine	Self-injection	2 mg IV once
Zubrinich et al 18	Epinephrine	Angioedema	0.3 mg IM once
Manivannan et al 19	Epinephrine	Accidental injection	0.5 mg IV twice
Lainez et al 20	Epinephrine/norepinephrine	Anaphylaxis	NA
Litvinov et al 21	Epinephrine	Anaphylaxis	5 mg IM injection inadvertently
Patankar et al 22	Epinephrine	Angioedema	3 mg IM injection inadvertently
Von Knobelsdorff-Brenkenhoff et al 23	Epinephrine	Endoscopic sinus surgery	Intranasal epinephrine
Abraham et al 24	Epinephrine (6 cases), dobutamine (3 cases)	Stress echocardiography for dobutamine (n = 3, dobutamine 30-40 μg/kg/min); suicidal ideation (n = 1, 40 mg epinephrine IV), liposuction (n = 1, 1 mg epinephrine IV), cosmetic facial surgery (n = 1, 1 mg epinephrine IV), keloid scar repair (n = 1, unknown dose of epinephrine into a superficial vein), rectal vein bleeding during colonoscopy (n = 1, 5 mg epinephrine into bleeding rectal vein), vasovagal syncope (n = 1, 1 mg epinephrine once IV)	9 case series
Fineschi et al 25	Dobutamine	Stress echocardiography	40 μg/kg/min
Chia et al 26	Dobutamine	Stress echocardiography	40 μg/kg/min
D’Aloia et al 27	Dobutamine	Stress echocardiography	30 μg/kg/min
Shah et al 28	Dobutamine	Stress echocardiography	30 μg/kg/min
Arias et al 29	Dobutamine	Stress echocardiography	40 μg/kg/min
Saito et al 30	Dobutamine	Vasospasm after subarachnoid hemorrhage	6 μg/kg/min
Mosley et al 31	Dobutamine	Stress echocardiography	10-40 μg/kg/min
Margey et al 32	Dobutamine	Stress echocardiography	10-40 μg/kg/min
Chaparro-Munoz et al 33	Dobutamine	Stress echocardiography	5-20 μg/kg/min
Silberbauer et al 34	Dobutamine	Stress echocardiography	10 μg/kg/min
Bruder et al 35	Dobutamine	Stress echocardiography	NA
Skolnick et al 36	Dobutamine	Stress echocardiography	5-40 μg/kg/min
Brewington et al 37	Dobutamine	Stress echocardiography	5-40 μg/kg/min
Cherian et al 38	Dobutamine	Stress echocardiography	5-40 μg/kg/min
Kumar et al 39	Dobutamine	Stress echocardiography	NA
Abe et al 40	Dopamine	Hypotension	20 μg/kg/min
Subramaniam et al 41	Norepinephrine	Inadvertent bolus	NA
Law et al 42	Norepinephrine and phenylephrine	Shock	NA
Quick et al 43	Norepinephrine	Septic shock	NA
Nakao et al 44	Isoproterenol	Electrophysiology study	0.3-0.7 μg/min
Mendoza et al 45	Inhaled terbutaline	Respiratory failure	NA
Lee et al 46	Intraocular phenylephrine	Anterior uveitis	10% phenylephrine
Chung et al 47	Synephrine	Supplement	NA
Sharrett et al 48	Inhaled albuterol	COPD	NA
Parsa et al 49	Inhaled albuterol	Asthma	10 inhalations before admission
Venditti et al 50	Salmeterol	Bronchitis	NA

Abbreviations: COPD, chronic obstructive pulmonary disease; IM, intramuscular; IV, intravenous; NA, not applicable.

Table 2.

Other Adrenergic-Induced Takotsubo-Induced Cardiomyopathy (Reuptake Inhibitor, Anaphylaxis, Withdrawal, Adrenergic Vasopressors, and Psycho or Somatic Stress).

Citations	Drugs	Use	Dosing	Comments
Cocaine/amphetamine/methamphetamine
Butterfield et al 51	Cocaine	Illegal use	NA	Inhibiting the reuptake of serotonin, norepinephrine, and dopamine
Arora et al 52	Cocaine	Illegal use	NA	Inhibiting the reuptake of serotonin, norepinephrine, and dopamine
Daka et al 53	Cocaine	Illegal use	NA	Inhibiting the reuptake of serotonin, norepinephrine, and dopamine
Sarkar et al 54	Cocaine	Illegal use	NA	Inhibiting the reuptake of serotonin, norepinephrine, and dopamine
Chokshi et al 55	Cocaine	Illegal use	NA	Inhibiting the reuptake of serotonin, norepinephrine, and dopamine
Fulcher et al 56	Methamphetamine	Overdose	NA	Sympathomimetic agents
Srikanth et al 57	Methamphetamine	Illegal use	NA	Sympathomimetic agents
Al-Abri et al 58	Fluoroamphetamine	Illegal use	NA	Sympathomimetic agents
Alsidawi et al 59	Dextroamphetamine and Amphetamine	Adderall overdose	NA	Sympathomimetic agents
Movahed et al 60	Amphetamine	Abuse	NA	Sympathomimetic agents
Serotonin norepinephrine reuptake inhibitors
Forman et al 61	Milnacipran	Fibromyalgia	50 mg twice daily	Inhibition of norepinephrine reuptake
Selke et al 62	Duloxetine	Depression	20 mg daily	Inhibition of norepinephrine reuptake
Bergman et al 63	Duloxetine	Diabetic neuropathy	60 mg daily	Inhibition of norepinephrine reuptake
Christoph et al 64	Venlafaxine	Depression and overdose	300 mg daily	Inhibition of norepinephrine reuptake
Rotondi et al 65	Duloxetine	Stress urinary incontinence	40 mg daily	Inhibition of norepinephrine reuptake
Neil et al 66	Venlafaxine	Anxiety, depression, overdose	37.5 to 375 mg daily	Inhibition of norepinephrine reuptake
Kitami et al 67	Lithium	Bipolar disorder	Intoxication	Inhibition of norepinephrine reuptake
De Roock et al 68	Nortriptyline	Overdose	1000 mg once	Inhibition of reuptake of norepinephrine
Opioid/medication withdrawals
Sarcon et al 69	Opioid withdrawal		(MS contin 100 mg 4 times daily)	Opioid withdrawal causes catecholamine surge
Saiful et al 70	Methadone withdrawal	IV drug abuse	NA	Opioid withdrawal causes catecholamine surge
Alexandre et al 71	Alcohol withdrawal	NA	NA	Hyperadrenergic state by alcohol withdrawal
Suzuki et al 72	Alcohol withdrawal	NA	NA	Hyperadrenergic state by alcohol withdrawal
Kireyev et al 73	Baclofen withdrawal	Muscular spasticity due to MVC	Baclofen pump	Hyperadrenergic state by baclofen withdrawal
Pizon et al 74	Baclofen withdrawal	Chronic back pain	Baclofen pump	Hyperadrenergic state by baclofen withdrawal
Lemesle et al 75	Methadone withdrawal	Heroin abuse	120 mg daily	Opioid withdrawal causes catecholamine surge Methadone withdrawal due to naltrexone
Jefic et al 76	Abrupt metoprolol withdrawal	NA	NA	Hyperadrenergic state by β-blocker withdrawal
Tomcsanyi et al 77	Carvedilol	NA	NA	Hyperadrenergic state by β-blocker withdrawal
	Bisoprolol	NA	NA	Hyperadrenergic state by β-blocker withdrawal
Rivera et al 78	Oxycodone withdrawal	NA	NA	Opioid withdrawal causes catecholamine surge
Maruyama et al 79	Buprenorphine withdrawal	NA	Abrupt discontinuation of buprenorphine	Two-year-old girl. Sympathetic nerve stimulation by withdrawal
Anaphylaxis
Santoro et al 80	Ceftriaxone	Respiratory infection (not specified)	1 g IM once	Anaphylaxis due to ceftriaxone causing compensatory catecholamine release
Sun et al 81	Ceftriaxone	Respiratory infection (not specified)	NA	Anaphylaxis due to ceftriaxone causing compensatory catecholamine release
Suk et al 82	Cefotetan	Surgery prophylaxis	1 g IV once	Anaphylaxis due to ceftriaxone causing compensatory catecholamine release
Sacco et al 83	Meperidine	Colonoscopy premedication for sedation	50 mg once IV	Anaphylaxis due to meperidine
Ng et al 84	Rituximab	Chronic lymphocytic leukemia	NA	Anaphylactic reaction by description developed in fifth cycle of rituximab infusion
Psychologic or somatic stress
Romano et al 85	Risperidone, barbiturates, and benzodiazepine	Suicidal attempt	NA	Psychologic stress
Courand et al 86	Sulprostone	Cesarean delivery	NA	Psychologic stress
Mehta et al 87	Isocarboxazid, lithium, phenethylamine	NA	Isocarboxazid 30 mg twice daily, lithium 300 mg twice daily, phenethylamine 500 mg once on admission	Psychologic stress due to serotonin syndrome
Koh et al 88	Dipyridamole	Stress myocardial perfusion imaging	0.5 mg/kg	Psychologic stress due to dipyridamole injection
Parodi et al 89	Potassium chloride	Dilution of anesthesia medications for epidural injection instead of sodium chloride	NA	Psychologic stress (cesarean-section) Inadvertent injection

Abbreviations: MS, morphine sulfate; MVC, motor vehicle collison; NA not applicable.

Table 3.

Chemotherapy-Induced Coronary Vasospasm, Noncatecholamine Vasoconstrictors, or Unknown Mechanism.

	Drugs	Use	Dosing	Comments
5-FU or capecitabine
Qasem et al 90	Capecitabine	Breast cancer	NA	Coronary vasospasm
Klag et al 91	Capecitabine	Breast cancer	1500 mg once at the first day	Coronary vasospasm
Lim et al 92	5-FU	Rectal adenocarcinoma	450 mg/m2 weekly	Coronary vasospasm
Grunwald et al 93	5-FU	Colon cancer	NA	Coronary vasospasm
Ozturk et al 94	5-FU	Gastric cancer	400 mg/m2 bolus, and 2400 mg/m2 46-hour infusion	Coronary vasospasm
Y-Hassan et al 95	Capecitabine	Adenocarcinoma of the cecum	2500 mg twice daily	Coronary vasospasm
Endo et al 96	Capecitabine	Colorectal adenocarcinoma	3600 mg/d	Coronary vasospasm
Calik et al 97	5-FU	Colon cancer	NA	Coronary vasospasm
Basselin et al 98	5-FU	Colon cancer	375 mg/m2 10 doses IV	Coronary vasospasm
Radhakrishnan et al 99	5-FU	Metastatic nasopharyngeal adenocarcinoma	750 mg/m2 daily for 4 days	Coronary vasospasm
Kobayashi et al 100	5-FU	Rectal adenocarcinoma	750 mg/m2 once weekly for 4 weeks	Coronary vasospasm
Gianni et al 101	5-FU	Colorectal adenocarcinoma	350 mg/m2 daily for 5 days every 4 weeks	Coronary vasospasm
Kim et al 102	5-FU	Colon cancer	NA. FOLFOX regimen	Coronary vasospasm
Cerny et al 103	5-FU	Colon cancer	400 mg/m2 bolus, and 2400 mg/m2 46-hour infusion in FOLFOX regimen	Coronary vasospasm
Nonchemotherapy vasoconstrictors
Ozpelit et al 104	Ergotamine tartrate	Migraine	1.5 mg daily for 5 days before admission	α 1 agonist causing vasoconstriction
Citro et al 105	Ergonovine	Uterine bleeding	0.25 mg IV once	α-adrenergic causing vasoconstriction
Garg et al 106	Zolmitriptan	Migraine	2 or 3 times daily	Coronary vasospasm
Ramanath et al 107	Midodrine	Idiopathic hypotension	NA	Adrenergic receptor agonist causing vasoconstriction
Zlotnick et al 108	Pseudoephedrine	Sinus congestion due to respiratory infection	10 mg twice daily	Adrenergic receptor agonist causing vasoconstriction
Kocaoglu et al 109	Zolmitriptan	Migraine	5 mg once orally	Coronary vasospasm
Di Micoli et al 110	Terlipressin	Hepatorenal syndrome	3 mg/d continuous infusion	Noncatecholaminergic vasoconstriction
Y-Hassan et al 111	Bromocriptine	Milk suppression	2.5 mg once	Bromocriptine induced coronary artery spasm
Wang et al 112	Oxymetazoline hydrochloride 0.05% 20 mL bottle	Allergic rhinitis	One bottle in less than 12 hours	α-adrenergic vasoconstriction in coronary artery
Rojas-Marte et al. 113	Overdose of ibuprofen/diphenhydramine	Overdose	NA	Cardiopulmonary resuscitation with massive doses of epinephrine
Placci et al 114	Nandrolone and stanozolol	Performance enhancing	Nandrolone 100 mg/wk and stanozolol 25 mg daily	Unclear. Anabolic androgenic steroid
Damodaran et al 115	IL-2	Melanoma	600 000 U/kg every 8 hours for a maximum of 12 doses every 3 weeks	Unclear
Baldacci et al 116	Entacapone	Parkinson disease	150 mg 4 times daily	Unclear
Melao et al 117	Ipratropium	COPD	NA	Anticholinergic effects
Santoro et al 118	Influenza vaccine	Influenza prevention	NA	Unclear Sympathovagal imbalance
Dziewierz et al 119	Phentermine and anagrelide	Appetite suppression and essential thrombocytopenia	NA for phentermine; anagrelide 2 mg daily	Unclear. Anagrelide causes PDE III inhibition
Proietti et al 120	Anagrelide	Thrombocytopenia	1.5 mg daily	Unclear
Gabriel et al 121	Flecainide	NA	NA	Unclear. Negative inotropic effects
Sandhu et al 122	Atropine	Symptomatic bradycardia	0.5 mg once IV	Anticholinergic effects
Koide et al 123	Levofloxacin and loxoprofen	Upper respiratory infection and back pain	levofloxacin 100 mg once and loxoprofen 60 mg once	Seizure versus GABA receptor antagonism causing sympathetic nerve stimulation

Abbreviations: COPD, chronic obstructive pulmonary disease; FU, fluorouracil; GABA, gamma-aminobutyric acid; IL-2, interleukin 2; IV, intravenous; NA, not applicable; PDE, phosphodiesterase.

Table 4.

Etiology of Takotsubo-Induced Cardiomyopathy.

	n (%)
Exogenous catecholamines	57 (36.3)
Other adrenergic effects	50 (31.9)
Catecholamine reuptake inhibitors/sympathomimetic agents	23
Anaphylaxis	5
Hyperadrenergic state by withdrawal	12
Adrenergic vasoconstrictors	5
Psychological or somatic stress	5
Chemotherapy-induced coronary vasospasm	14 (8.9)
Noncatecholamine vasoconstrictors	4 (2.5)
Unknown mechanism	32 (20.4)
Total	157 (100)

Discussion

Cardiodepressive effect of exogenous catecholamines was established long time ago. In 1994, Movahed et al described a dose-dependent reduction in left ventricular ejection fraction in dogs with left ventricular dilation and contraction band necrosis, with complete recovery in several days. ¹²⁴ Only many years later, when TCM resulting from emotional or physical stress was reported, it became evident that these 2 phenomena may represent, in fact, the same condition. In this review, we collected the cases of drug-induced TCM and showed that 36.3% was due to exogenous catecholamines. Epinephrine was the most common drug associated with TCM followed by dobutamine.

Our systematic review supported that catecolamine surge is the most plausible mechanism for TCM based on 68.2% of drug-induced TCM cases being catecholamine related. This exaggerated sympathetic nerve stimulation theory was validated by the case series with 13 patients with stress cardiomyopathy using neurohumoral assessment. ³ It showed plasma levels of catecholamines (norepinephrine, epinephrine, and dopamine) on hospital stay 1 or 2 in 13 patients with TCM were 2 to 3 times higher than those in 7 control patients with myocardial infarction. By hospital stay 7, 8, or 9, plasma levels of catecholamines went down to one-third to one-half of the peak values. The mean left ventricular ejection fraction on hospital stay 1 was 0.20 but by hospital stay 3, 4, 5, 6, or 7, ejection fraction improved to 0.45. It supports that catecholamine surge is probably central to the mechanism of TCM.

Drugs with direct sympathomimetic effect like midodrine, ¹⁰⁷ ergotamine tartrate, ¹⁰⁴ ergonovine, ¹⁰⁵ oxymetazoline, ¹¹² and pseudoephedrine ¹⁰⁸ are also reported causes of drug-induced TCM. In particular, ergotamine, which is structurally similar to endogenous catecholamines and indolamines, exerts some α-adrenergic effects. ¹⁰⁴ Midodrine is an α-adrenergic receptor agonist and can also trigger takotsubo syndrome. ¹⁰⁷ This mechanism also applies to pseudoephedrine that directly stimulates the adrenergic receptors. ¹⁰⁸ Oxymetazoline is a nasal decongestant–stimulating α-receptors. ¹¹² Also, inhibitors of catecholamine reuptake/sympathomimetic amines could cause drug-induced TCM. They include cocaine (5 cases), ^{51 -54} nortriptyline, ⁶⁸ lithium, ^67,87 and 11 others with the most common drug being venlafaxine (7 cases). ^64,66 Takotsubo in the setting of lithium intoxication can be also explained by the fact that lithium causes catecholamine overload by inhibiting the reuptake of serotonin and norepinephrine. ⁶⁷ In another case, the patient was treated with lithium in combination with phenethylamine that is known to release endogenous catecholamines. ⁸⁷ Phentermine is an amphetamine derivative used as an appetite suppressant, which is thought to be a sympathomimetic amines that stimulate the release of norepinephrine and dopamine from the storage sites in the presynaptic nerve terminals. ¹¹⁹ Other catecholamine-related causes included indirect adrenergic effects, including parasympathetic block (2 cases), ^117,122 sudden withdrawal of β-blockers (3 cases), ^76,77 anaphylactic reactions (5 cases), ^{81 -84,118} withdrawal of opioids (5 cases), ^{69,70,75,78,79} or alcohol (2 cases). ^71,125 Opioid withdrawal is known to cause hyperadrenergic state that leads to catecholamine surge and increased β-receptor sensitivity and subsequently myocardial stunning. Alcohol withdrawal is also accompanied by catecholamine release (in extreme causing delirium tremens). Psychologic or somatic stress was believed to be the catecholamine-related cause of TCM in 8 cases. ¹²¹ In 3 of these cases, the interpretations were that 1 patient had suicidal attempt, ⁸⁵ and another 2 TCM cases were believed to be due to cesarean section. ^86,89

Although the majority of drug-induced TCM cases was explainable with catecholamine surge theory, a couple of researches showed that the majority of patients had normal catecholamine levels in patients with TCM. ^{126 -128} Y-Hassan ¹²⁶ showed that 89% of patients had normal epinephrine level, and 52% of patients had normal norepinephrine levels. Only 3 of 33 patients had remarkably elevated catecholamine and metabolite levels. Another study also reported that all 6 patients had normal epinephrine levels; 3 patients had normal norepinephrine levels, and the other 3 patients had mild elevation of norepinephrine level. ¹²⁷ Yoshioka et al also found that mild elevation in catecholamines was not associated with TCM. ¹²⁸ These results challenged catecholamine surge theory and raised the possibility that other theories may contribute to the development of TCM.

In 17 (11%) cases, the likely etiology of cardiomyopathy was coronary spasm, and in 22 (14.3%) cases, we were unable to explain the origin of TCM. Four capecitabine cases and ten 5-fluorouracil (FU) cases are reported in the literature database as TCM by coronary spasm (Table 3). Zolmitriptan, which increases serotonin release resulting in coronary vasospasm ^106,109 and bromocriptine, ¹¹¹ is also reported to cause vasospasm. In this latter group, chemotherapy-induced takotsubo in the setting of malignancy was the most common. Unlike cases with catecholamine infusions, chemotherapy-induced cases of TCM appear much less uniform and convincing (Table 3).

5-fluorouracil and its prodrug capecitabine are used for the treatment of colorectal, breast, and brain cancers. However, cardiotoxicity is reported in 1% to 18% of patients. ⁹⁵ Cardiac adverse effects of 5-FU include ischemic events (ST-segment changes) with or without angina and sometimes myocardial infarction. A dose-dependent arterial vasoconstriction was demonstrated in isolated rabbit aortic rings following FU administration. Also, plasma levels of endothelin, a strong vasoconstrictor, are elevated in patients with cancer treated with FU and particularly in those developing cardiotoxicity. ¹²⁹ Currently, 5 capecitabine cases and eight 5-FU cases are reported in the literature database as TCM (Table 3). The exact pathogenesis of capecitabine or 5-FU-induced takotsubo disease is unknown, but there are a couple of potential mechanisms: coronary vasospasm and direct drug/metabolite-induced toxic action on myocytes. ⁹⁰ All of cases developed the TCM within 72 hours after the therapy, and in each case, Ejection fraction (EF) recovered to normal within 1 to 2 weeks. Of note, all of capecitabine cases did not have the typical apical ballooning feature in echocardiogram. ⁹⁰ We cannot exclude that with the similarity of clinical presentation, 5-FU-induced TCM represents some different phenomenon.

Although multiple cases are reported in catecholamine-related literature, there are often a single case report on a certain agent in chemotherapy-induced takotsubo-like syndrome. ¹³⁰ Millions of women receive trastuzumab, yet there is only 1 case report on trastuzumab-induced TCM. ¹³¹ In some cases, repeat cardiac imaging to prove reversal of wall motion abnormality was never performed, and the diagnosis of TCM is therefore not definitive. Moreover, coronary angiography was sometimes delayed, and acute coronary event with spontaneous reperfusion could not be excluded. ¹³¹

Also, in chemotherapy-related cases, takotsubo developed in the setting of chemotherapy for malignancy, a stressful situation by itself, and occurrence of such a reaction after the administration of chemotherapeutic agent could be coincidental. ¹³² When takotsubo developed during the treatment for newly diagnosed acute leukemia ¹³⁰ or metastatic melanoma ¹³³ and only occurred after the fourth dose of the culprit medication ¹³⁰ or after 8 weeks of daily intake of pazopanib ¹³⁴ or even after 4 years of sunitinib exposure, ¹³⁵ stress can indeed play a greater role than the particular agent.

Other kinds of chemotherapy may have vasospastic effects that create same pattern of cardiac damage as takotsubo. Combretastatin induces cytoskeletal changes in endothelial cells, increases vascular permeability, and inhibits blood flow, causing endothelial cell apoptosis. ¹³⁶ Vasoconstriction by vasopressin in a patient with already elevated catecholamines levels due to hepatorenal syndrome was also reported to cause TCM. ¹¹⁰

Finally, in number of cases, the role of the pharmacologic agents in the origin of TCM is unclear. ¹³⁷ Ibuprofen was called a cause of TCM, while the patient described in the case suffered cardiac arrest and underwent extensive cardiopulmonary resuscitation with massive doses of epinephrine. ¹¹³ Only handful of cases remain unexplained: androgenic steroids in the setting of hypothyroidism, ¹¹⁴ interleukin 2, ¹¹⁵ entacapone, ¹¹⁶ influenza vaccine, ¹¹⁸ dipyridamole, ⁸⁸ and convulsions and takotsubo in a 97-year-old patient after levofloxacin and a nonsteroidal anti-inflammatory drug loxoprofen. ¹²³

Conclusion

Our systematic review showed that 68.2% of drug-induced TCM cases were due to direct or indirect catecholamine stimulation. The most common medication associated with drug-induced TCM was epinephrine followed by dobutamine. This further strengthens the argument that excess of catecholamines is the underlying mechanism of TCM.