- © 2012 by American Society of Clinical Oncology
takotsubo syndrome in a Patient Treated With Sunitinib for Renal Cancer
- Corresponding author: Gianmauro Numico, Medical Oncology Unit, Ospedale U. Parini, Viale Ginevra 3, 11100, Aosta, Italy; e-mail: gnumico{at}ausl.vda.it.
Introduction
Left ventricular apical ballooning syndrome is a potentially severe, sudden myocardial dysfunction that can mimic myocardial infarction but is not sustained by coronary artery obstruction. The clinical presentation of this syndrome, which is also recognized as takotsubo syndrome, is thoracic pain and dyspnea that occur mostly in postmenopausal women. The most common electrocardiographic features are ST-segment elevation in the precordial leads followed by inversions of T waves and pathologic q waves. Troponin and creatinine-kinase–myocardial band (CK-MB) levels are increased in the majority of the cases. Left ventricular function is usually depressed and the left ventricular ejection fraction is usually severely impaired and ranges between 20% and 40%. At echocardiography, midventricular wall-motion abnormalities, apical akinesia, or dyskinesia with preserved or hyperkinetic contractile function of basal left ventricular segments are characteristic features. The clinical picture seems in agreement with a myocardial infarction; the two major differences are the coronary artery angiography, which is usually normal or demonstrates mild obstruction, and the clinical evolution that is benign and leads to spontaneous improvement. Possible complications of takotsubo syndrome are heart failure, ventricular thrombosis, and arrhythmia. Treatment is essentially supportive.1–3 The disease is largely prevalent in women and has been related with stressful situations or drug exposure. We report a case of takotsubo syndrome that occurred in a patient with renal cell cancer who was taking sunitinib.
Case Report
The patient was a 57-year-old woman with clear-cell renal cancer. After renal surgery in 2005, the tumor recurred in mediastinal nodes in 2007. The patient had been treated with sunitinib at a dose of 50 mg per day for 4 weeks every 6 weeks since January 2007, which achieved a partial response. Subjective toxicities (palmoplantar disesthesia, fatigue, and skin rash) caused a progressive dose reduction to 12.5 mg per day without impairment of the response. During treatment, the patient developed subclinical hypothyroidism, which was treated with tyroxine supplementation, and grade 2 hypertension, which was well controlled with carvedilole.
The patient presented on December 2010 to the medical oncology unit complaining chest pain and severe dyspnea. These symptoms occurred suddenly the day before the visit. At physical examination, the following two features were noticed by the oncologist: a jugular vein distention and a strong ejective systolic murmur. The initial ECG showed ST-segment increase (Fig 1A). Troponin T blood levels were 1,247 ng/L (normal values, 0 to 14 ng/L) at admission. A transthoracic echocardiogram revealed severe global hypokinesis of the left ventricle with apical ballooning in systole and diastole (Figs 2A and 2B, arrows) and severe mitral regurgitation. The ejection fraction was estimated at 15% to 20%. A coronarographic study did not reveal any coronary obstruction.
The patient was treated with angiotensin-converting enzyme inhibitor, β blocker, and prophylactic low-molecular weight heparin and followed up in the intensive care unit. Troponin levels progressively decreased in the next 2 days as did the symptoms of heart failure. The ECG performed on day 4 showed marked T-wave inversion in the anterolateral precordial leads (Fig 1B) but normalized in the following days. A control echocardiogram performed 2 days after the event showed a left ventricular ejection fraction of 35% and of 42% 1 week after. The mitral insufficiency completely resolved, as did the objective finding of the murmur. Unfortunately, the patient developed a left ventricular apical thrombus, and thus, an anticoagulant dose of dalteparin was given. A computed tomography scan of the chest revealed progressive disease. The patient was discharged from the hospital 7 days after the critical episode with mild dyspnea. A second-line treatment with everolimus was initiated. At the 3-month evaluation, no other sign or symptom of heart failure recurred, and the dyspnea gradually improved. The echocardiographic control showed complete disappearance of the ventricular thrombus and a left ventricular ejection fraction of 68%.
Discussion
Several reports have described takotsubo syndrome in association with fluorouracil administration.4–10 Fluorouracil is a well-known cardiotoxic agent, although the exact mechanism of action is not clearly established. To the best of our knowledge, takotsubo syndrome has been recognized in association of sunitinib in only one case by Korean clinicians. In that case, a 48-year old woman developed sudden congestive heart failure after a few weeks of sunitinib treatment, with echocardiographic features that were suggestive of takotsubo syndrome. The clinical and imaging picture completely resolved at the 6-month control. Unfortunately, no angiographic study was performed, and thus, an ischemic event was not formally excluded.11
Sunitinib has a recognized cardiovascular toxicity potential.12 Typical effects are hypertension and reduction of the left ventricular ejection fraction. Moreover, thyroid dysfunction may add some other toxicity on the cardiovascular system. Toxicity does not seem to be related to the duration of drug exposure because it has been described after a few weeks of administration. In the series conducted by researchers of the Harvard Medical School in patients with imatinib-resistant GIST, sunitinib induced cardiac events in 11% of treated patients, the majority of which were congestive heart failures. The decrease of the left ventricular ejection fraction was gradual and occurred mostly in the first 24 weeks of treatment. Two cases of myocardial infarction were described but with no coronarographic or echocardiographic study. Moreover, 18% of patients had a moderate increase of troponine I blood levels (mean, 0.74 ng/mL).13 Telli et al14 of Stanford University reported seven cases of symptomatic cardiac dysfunction among 48 patients treated with sunitinib. However, no case presented with the features of ischemic heart disease or takotsubo syndrome.
Khakoo et al15of the MD Anderson Cancer Center described six cases of symptomatic cardiac dysfunction without any obvious cause that occurred from 4 to 44 days after sunitinib exposure. Although none of these cases was related to ischemic changes, several of them were associated with severe hypertension or had a progressive evolution. Furthermore, three of these patients had been previously treated with potentially cardiotoxic agents, and all of them had pretreatment known risk factors for cardiovascular disease. None of them appeared to have the echocardiographic findings of takotsubo syndrome.15
The clinically evidenced cardiac toxicity has a preclinical basis. Studies conducted on mouse models showed that sunitinib exposure induced cardiomyocyte injury, with mitochondrial swelling and damage at electron microscopy.16 At the molecular level, it was shown that inhibition by sunitinib of adenosine monophosphate–activated protein kinase, which is a kinase that plays key roles in maintaining metabolic homeostasis in the heart, especially in the setting of energy stress, accounts, at least in part, for sunitinib-induced toxicity seen in cardiomyocytes.17
The patient described in our report had developed both low-grade hypertension and subclinical hypothyroidism. However, Takotsubo syndrome developed suddenly after 4 years of sunitinib exposure. The following possible pathophysiologic mechanisms have been suggested to be at the base of takotsubo syndrome: epicardial artery spasm, microvessel myocardial ischemia, increased cathecolamine plasma levels, or myocarditis.18 Although a possible alternative cause such as a stressful personal condition cannot be excluded, we suggest that this clinical picture should be kept in mind when using sunitinib because of possible severe consequences and the frequent resolution with medical supportive treatment.
AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
The author(s) indicated no potential conflicts of interest.
