Chemotherapy-Induced Takotsubo Cardiomyopathy

Author Affiliations: From the Division of Cardiology, New York Presbyterian Hospital Weill-Cornell Medical Center, New York, New York. The authors report no conflicts of interest regarding the content herein. Manuscript submitted June 30, 2008 and accepted August 18, 2008. Address for correspondence: S. Chiu Wong, MD, Division of Cardiology, New York, Presbyterian Hospital Weill Cornell Medical Center, Starr Pavillion 4, 520 East, 70th Street, New York, NY 10021. E-mail: scwong@med.cornell.edu

_______________________________________________ ABSTRACT: Two patients presented with takotsubo cardiomyopathy after chemotherapy. Neither of the patients had any known cardiac history until the initiation of chemotherapy. These patients were treated with different chemotherapy regimens appropriate to their malignancies. After chemotherapy initiation, they presented with symptoms ranging from exertional dyspnea to cardiogenic shock requiring intra-aortic balloon pump and pressor support. Cardiac catheterization demonstrated characteristic apical ballooning with nonobstructive coronary artery disease. Both of the patients demonstrated a transient reduction in left ventricular function which resolved on follow-up echocardiography. These cases suggest a potential novel etiology for takotsubo cardiomyopathy.

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J INVASIVE CARDIOL 2008;20:E338–E340 Transient left ventricular apical ballooning, also called takotsubo cardiomyopathy, is an increasingly recognized syndrome characterized by the abrupt onset of chest pain, electrocardiographic abnormalities, and transient akinesis of the left ventricular apical and mid-ventricular segments which may mimic myocardial infarction in the absence of obstructive coronary artery disease.1 This syndrome has been also referred to as stress-induced cardiomyopathy due to its onset with intense physical or emotional stress.2 Postmenopausal women account for the majority of cases, and many cases have been reported recently in North America and Europe.3 However, the underlying mechanisms and etiologies of this syndrome remain unclear. We report two patients who were diagnosed with malignancies, treated with different chemotherapy regimens and subsequently presented with acute/subacute symptoms of takotsubo cardiomyopathy. Case #1. A 67-year-old male with a history of stage III laryngeal squamous-cell carcinoma (SCC) was admitted to the hospital for increasing lethargy. Approximately 3 months prior to presentation, he was found to have a left laryngeal mass, which on biopsy, was identified as a well-differentiated SCC. Computed tomographic (CT) and positron emission tomographic (PET) scans had shown no evidence of metastases. He underwent 5 sessions of external irradiation and received a single dose of cetuximab 3 days prior to the current hospital admission. The initial CT scan of the brain did not reveal any abnormalities. Due to his progressively worsening mental status, a lumbar puncture was performed and the cerebrospinal fluid (CSF) was sent for cultures and viral polymerase chain-reaction (PCR) tests. A blood workup included a septic screen, a toxicology screen and laboratory analysis for electrolytes, vitamin B12, folate and ammonia levels, all of which were normal. A magnetic resonance imaging (MRI) scan of the brain was scheduled. While in the MRI suite, he became acutely hypoxic, requiring emergent intubation. He then developed pulseless electrical activity arrest and was successfully revived after 10 minutes of active cardiopulmonary resuscitation. Electrocardiography (ECG) post cardiac arrest (Figure 1) showed ST-segment elevation in the anterior leads (leads V2–V6). Bedside echocardiography showed markedly impaired left ventricular (LV) function with an ejection fraction (EF) of 20%. Severe hypokinesia was noted over the distal anterior and apical regions. He was in cardiogenic shock and required high-dose inotropic support. The working diagnosis was an acute anterior ST-elevation myocardial infarction. The patient was taken immediately to the cardiac catheterization laboratory for primary percutaneous coronary intervention. However, coronary angiography revealed nonobstructive coronary artery disease (Figure 2). Left ventriculography (Figure 3) revealed severe LV systolic dysfunction with prominent apical ballooning. An intra-aortic balloon pump (IABP) was inserted for hemodynamic support and he was transferred to the coronary care unit for further management. There was a mild rise in cardiac enzymes post procedure, with a peak creatine phosphokinase level of 203 U/L (normal range: 46–295 U/L) and a peak troponin-I level of 0.96 ng/ml (normal range: 0.01–0.04 ng/ml). His clinical condition improved over the next few days and he was successfully weaned off the IABP and vasopressors. An MRI scan of the brain at a later date did not show any abnormalities. CSF cultures and PCR tests were also negative. He was started on a beta-blocker, an angiotensin-converting enzyme (ACE) inhibitor, a statin and aspirin, and was discharged after 10 days of hospitalization. Repeat echocardiography 2 weeks after discharge showed significant improvement in his LV systolic function with an EF of 45% and normalization of the previous wall-motion abnormalities. Case #2. A 75-year-old female with a history of hypertension and hypercholesterolemia was referred for cardiac catheterization following acute onset of dyspnea with abnormal ECG changes. She had a 3-year history of colonic cancer which was detected during a routine colonoscopy. Following resection of the primary tumor, she was treated with 5-FU, leucovorin and oxaliplatin as part of her adjuvant therapy. She remained in clinical remission until this year, when a surveillance positron emission tomographic (PET) scan revealed recurrence of disease. She subsequently underwent systemic chemotherapy with irinotecan and cetuximab, which was later switched to oxaliplatin and capecitabine due to progression of the disease. Immediately following her first chemotherapy session with this new regimen, she experienced acute onset of severe dyspnea. She was admitted to the hospital for a presumed allergic reaction and was treated with steroids. However, the ECG was notable for new-onset deep T-wave inversion in leads V2–V6. A blood test was notable for a peak creatine phosphokinase level of 279 U/L (normal range: 26–140 U/L) and a peak troponin-I level of 4.23 ng/ml (normal range: 0–0.49 ng/ml). Coronary angiography revealed nonobstructive coronary artery disease. Left ventriculography showed moderately reduced LV function with an EF of 35–40%. Furthermore, it demonstrated akinetic anterior and anteroapical walls with a severely hypokinetic inferoapical segment. She was managed medically and was started on beta-blockers and an ACE inhibitor. Follow-up echocardiography 2 weeks later revealed normal LV function with an EF of 59%. Discussion. Takotsubo cardiomyopathy was initially described in Japan, and the clinical features of this syndrome have been well described in subsequent studies.1,2,4 Patients often present with chest pain or dyspnea, ECG changes and elevations in cardiac enzymes that mimic acute coronary syndrome.5 Echocardiography reveals characteristic apical and mid-ventricular wall motion abnormalities, which usually resolve within days to weeks, along with the recovery of ventricular function. Coronary angiography often does not reveal any significant coronary artery disease. Treatment for takotsubo cardiomyopathy is based on the patient’s overall clinical condition regardless of the cause. If the clinical presentation is complicated by cardiogenic shock, hemodynamic support with an IABP and/or vasopressors may be necessary as illustrated in our first case. In the absence of shock, standard medical therapy for LV dysfunction should be administered such as beta-blockers, ACE-inhibitors and diuretics, as necessary, for fluid overload. The prognosis remains favorable due to the transient nature of this disorder. Patients who survive the acute episode usually recover with normal LV function in 3-to-4 weeks. The pathogenesis of this disorder remains unclear and several postulated mechanisms include single- or multi-vessel coronary artery vasospasm, myocarditis, impaired fatty acid metabolism and dynamic mid-cavity obstruction. Several features of the disorder suggest that catecholamine-induced microvascular dysfunction/spasm resulting in myocardial stunning may play an important role in its pathogenesis, as most cases are typically triggered by an acute medical illness or intense emotional or physical stress.6–8 Some reports have described this phenomenon in the setting of acute brain injury, pheochromocytoma crisis and tachycardia-induced cardiomyopathy. Even the induction of general anesthesia has been reported as a possible trigger.9 We describe 2 patients who presented with acute/subacute symptoms of takotsubo cardiomyopathy after initiation of chemotherapy. In the first case, the patient was diagnosed with laryngeal SCC and was started on combination therapy which consisted of cetuximab and radiation therapy. Cetuximab is a chimeric monoclonal antibody that works as an epidermal growth-factor receptor inhibitor and has been approved for use in head and neck cancers. However, in a multicenter, randomized clinical trial,10 it was observed that cardiopulmonary arrest and/or sudden death occurred in 2% of patients treated with combination therapy (cetuximab and radiation therapy) and none in patients treated with radiation therapy alone. This combination of cetuximab and radiation therapy could have provoked an acute cardiopulmonary event in the first patient, thus providing the trigger for the onset of takotsubo cardiomyopathy. Another plausible explanation was that the combination therapy led to his acute delirious state or “brain injury”, which subsequently triggered his sudden clinical deterioration. In the second case, the chemotherapy regimen consisted of an antimetabolite and a platin-based alkylating agent. Transient cardiotoxicity from 5-FU, an antimetabolite, has been reported in the literature.11 Angina from coronary artery vasospasm induced by 5-FU has been well recognized. In addition, more life-threatening complications, such as myocardial infarction, heart failure and cardiac arrest have been reported.12 Capecitabine, another antimetabolite, also has been linked with ischemia, myocardial infarction and cardiomyopathy. Although there are no reports of cardiotoxicity of oxaliplatin, myocardial infarction has been reported with other platin-based alkylating agents, especially in conjunction with 5-FU.13 Finally, direct cardiotoxic effects from these chemotherapeutic agents could have cause microvascular dysfunction/spasm leading to myocardial stunning in both cases. While takotsubo cardiomyopathy has been associated with various triggers, we are not aware of any prior report linking its incidence with exposure to chemotherapeutic agents. The exact mechanism remains unclear and the possible link between chemotherapy and takotsubo cardiomyopathy needs to be further examined.

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