Secondary Logo

Journal Logo

Takotsubo syndrome: an underdiagnosed complication of 5-fluorouracil mimicking acute myocardial infarction

Ozturk, Mehmet A.a; Ozveren, Olcayb; Cinar, Veyselb; Erdik, Baranc; Oyan, Basakd

Blood Coagulation & Fibrinolysis: January 2013 - Volume 24 - Issue 1 - p 90–94
doi: 10.1097/MBC.0b013e3283597605
CASE REPORTS
Free

Takotsubo syndrome (TTS)/cardiomyopathy is a syndrome that mimics acute myocardial infarction in the absence of coronary artery disease and is characterized by acute onset of chest pain, electrocardiographic abnormalities, and reversible left ventricular dysfunction. It is usually induced by emotional and physical stress. Fluorouracil is one of the most frequently used chemotherapy agents and a relatively common adverse reaction of fluorouracil is cardiotoxicity. Herein we describe a patient without a history of cardiovascular disorder who developed severe heart failure during infusion of fluorouracil for metastatic gastric cancer. Remarkably, the patient did not develop TTS during prior chemotherapy regimen, which also included fluorouracil. The patient's findings were consistent with the proposed TTS diagnostic criteria and coronary angiography was normal, without obstructive coronary artery disease. With supportive care, the patient's cardiac functions returned to normal. TTS is not a well known syndrome to clinicians and this condition appears to occur more frequently than previously thought. In addition to the presented case, a review of the clinical features and outcome of 10 reported cases of fluorouracil-induced TTS is presented.

aDepartment of Internal Medicine

bDepartment of Cardiology

cSchool of Medicine

dDepartment of Medical Oncology, Yeditepe University Hospital, Istanbul, Turkey

Correspondence to Mehmet Akif Ozturk, MD, Department of Internal Medicine, Yeditepe University Hospital, Devlet Yolu, Ankara Cad. No: 102/104, Kozyatagi, 34752 Istanbul, Turkey Tel: +90 216 578 4860; fax: +90 216 578 4969; e-mail: mehmet.ozturk@yeditepe.edu.tr

Received 12 May, 2012

Revised 7 August, 2012

Accepted 15 August, 2012

Back to Top | Article Outline

Introduction

Fluorouracil is the chemotherapy of choice for gastrointestinal cancers, both during the early and metastatic stages. Cardiotoxicity is a relatively common adverse reaction of fluorouracil, which occurs in 1.5–18% of patients treated with fluorouracil [1]. Even though the specific mechanism of fluorouracil-induced cardiotoxicity is yet to be fully elucidated, coronary vasospasm leading to ischemia and direct toxicity to the myocardium have been proposed [2]. Since 2008, the number of reports describing reversible cardiotoxicity due to fluorouracil in the absence of coronary artery disease (CAD) has been increasing.

Takotsubo syndrome (TTS)/cardiomyopathy is an acute cardiac syndrome with reversible left ventricular dysfunction and is characterized by contractile dysfunction of the apical segments and hyperkinesis of the basal left ventricular segments [3]. The clinical presentation and electrocardiographic findings of TTS are similar to those of acute myocardial infarction (MI) in the absence of CAD. [4] TTS was first described in 1990 by Sato et al.[5]. Takotsubo is the Japanese name of an octopus trap that looks similar to the hallmark bulging of the apex of the heart with preserved function of the base during systole [5]. As TTS is thought to be induced by physical or emotional stress [3], this syndrome has also been referred to as stress-induced cardiomyopathy.

At present, only five patients with TTS caused by fluorouracil treatment have been reported [6–10]. To the best of our knowledge, the present case is only the sixth. Interestingly, an extensive literature review showed that at least five additional cases describing the clinical features of TTS without naming it have been published [11–14]. Herein we describe a case of a 48-year-old male patient without a history of cardiovascular disorder who developed TTS during fluorouracil infusion for metastatic gastric adenocarcinoma, as well as a review of all reported cases.

Back to Top | Article Outline

Case report

A 48-year-old male patient underwent total gastrectomy and D2 lymph node dissection for gastric cancer. Pathological examination showed serosal invasion of the gastric wall, tumor involvement in the omentum, and metastases in 26 of 39 dissected lymph nodes. The patient was diagnosed as having stage 4 (T3N3M1) gastric cancer and was treated with six cycles of DCF (docetaxel, cisplatin, and infusional 5-fluorouracil) chemotherapy regimen. Five months after completion of the treatment protocol, the patient presented with ascites. Examination of the ascites fluid showed pathological changes consistent with metastatic involvement, as well as peritonitis. Peritoneal infection was treated with 10 days of empirical antibiotic treatment, after which the FOLFIRI (irinotecan 180 mg/m2, folinic acid 400 mg/m2, 5-fluorouracil 400 mg/m2 bolus, and 2400 mg/m2 46-h infusion) chemotherapy regimen was initiated. At the 34th hour of the planned 46-h infusion, the patient developed tachycardia, which was followed by dyspnea. Fluorouracil infusion was stopped at the 39th hour.

Physical examination showed tachycardia (130 bpm), decreased breath sounds in the basal region of the right lung, and S3 gallop rhythm. Electrocardiogram (ECG) showed sinus rhythm with T wave negativity in the lateral precordial leads (V4 and V5). Transthoracic echocardiogram showed marked left ventricular dysfunction, with hypokinesis of the mid-apical segments and hyperkinesis of the basal segments (Fig. 1). The estimated left ventricular systolic ejection fraction (LVEF) was 15%. Then, 15 h after termination of fluorouracil infusion, the patient developed ventricular tachycardia and ventricular fibrillation. He was subsequently defibrillated and intubated, and then transferred to the intensive care unit. Rhythm was controlled with amiodarone infusion. No increase in the serum creatine kinase-MB level was detected, but the serum troponin-I level was 2.87 ng/ml (normal limit: <0.04 ng/ml). Treatment with cilazapril, carvedilol, and diuretic was started and the patient was extubated 36 h later. Repeat echocardiogram 27 days later showed remarkable improvement in left ventricular function, with an ejection fraction of 50% (Fig. 2). Coronary arteries were nonstenotic in coronary angiography (Fig. 3). The patient was unable to tolerate further courses of chemotherapy due to a decrease in oral intake and intestinal obstruction. He died 13.5 months after initial diagnosis (3.5 months after disease progression).

Figure

Figure

Figure

Figure

Figure

Figure

Back to Top | Article Outline

Discussion

TTS is clinically an acute MI-like cardiomyopathy without coronary artery lesions [15,16]. Approximately 80–90% of cases occur in postmenopausal women and TSS is thought to be induced by physical or emotional stress [3]. For a diagnosis of TTS, all four of the following Mayo Clinic diagnostic criteria must be met: [17]

  1. Transient hypokinesis, akinesis, or dyskinesis of the left ventricular mid-segments, with or without apical involvement, regional wall motion abnormalities extending beyond a single vascular territory, and a stressful trigger is often, but not always, present;
  2. Absence of obstructive CAD (>50% of the luminal diameter) and absence of angiographic evidence of acute plaque rupture;
  3. New electrocardiographic abnormalities consisting of ST-segment elevation or T-wave inversion, and modest elevation in cardiac troponin levels;
  4. Absence of pheochromocytoma or myocarditis.

Patients with TTS usually present with acute chest pain. ECG changes depend on the stage of the syndrome [16,17]. In the acute stage, the ST-segment is elevated and the QT interval is fairly short. During the subacute stage, which can last for days, QT segment prolongation, and large and deep negative T waves are observed in ECG. The recovery stage can persist for days to weeks and flipped T waves are noted during this stage. In contrast to MI, cardiac enzymes are only slightly elevated [16]. Sometimes the heart does not take the characteristic shape of takotsubo with apical ballooning; instead, focal or diffuse wall motion abnormalities are observed [17].

The cardiotoxicity of fluorouracil is a well known side-effect, which is characterized by a broad clinical spectrum ranging from arrhythmias and angina to MI and cardiac arrest [2]. Vasospasm is thought to be the most important pathogenetic factor [2]. The schedule of administration and concomitant use of leucovorin has a significant impact on the risk of cardiotoxicity [18]. Continuous infusion of fluorouracil results in a higher incidence of cardiotoxicity than bolus fluorouracil and oral capecitabine [18]. In addition, continuous infusion fluorouracil regimens consisting of leucovorin are more likely to cause cardiotoxicity [18]. Fluorouracil-induced cardiotoxicity causes death in 8% of patients [19]. Re-challenge with fluorouracil results in the reappearance of cardiac symptoms in 47% of patients and causes death in 13% [19].

Fluorouracil-induced TTS is a recently recognized syndrome [6–10]. To the best of our knowledge, there have been only 10 reported cases, of which five were diagnosed as TTS (Table 1). As the number of reports of TTS increases, it should become more widely recognized. In all previous reports, the patients did not have any known cardiovascular disease, there was no age predilection, and fluorouracil-related TTS occurred in both adults and children. It is a known fact that the schedule of administration of fluorouracil and concomitant use of leucovorin has a significant impact on cardiotoxicity [18]. In six of the previously reported cases, TTS occurred following infusional fluorouracil [6,8,12–14] and in one case, TTS was triggered by capecitabine [9,14]. In six reports, leucovorin was co-administered with fluorouracil [6,8,10,12,14]. In most cases (n = 8), TTS occurred during the first cycle of fluorouracil [6,8,9,11–14]; however, in three cases, it was observed after serial exposure to the drug [7,10]. As such, it is important to monitor patients for cardiotoxicity, particularly during the first cycle of chemotherapy. In most cases, the onset of symptoms occurred during or shortly after fluoropyrimidine exposure. In only one patient, TTS occurred 2 weeks after the completion of fluorouracil-based chemotherapy [7].

Table 1

Table 1

Rapidly progressing left ventricular dysfunction resulted in life-threatening ventricular fibrillation in the presented patient, who had no known cardiac disease or risk factors. The findings were consistent with the diagnostic criteria proposed by the Mayo Clinic [17]. Even though the patient previously tolerated six cycles of infusional fluorouracil-based chemotherapy, he developed TTS when irinotecan, infusional fluorouracil and folinic acid was administered after disease recurrence. Although the exact cause of this late occurrence of TTS was unknown, concomitant administration of leucovorin might have triggered TTS.

The cause of TTS is not fully understood, but several mechanisms have been proposed [20,21]. The most probable mechanism is stress-induced catecholamine release, leading to myocardial stunning. Catecholamine-induced epicardial and coronary artery spasms probably cause myocardial ischemia [22]. As the apical portions of the left ventricle have the highest concentration of sympathetic innervations in the heart, catecholamine release selectively affects the apex [23]. The higher incidence in postmenopausal women suggests that low-level estrogen is a concomitant risk factor for TTS [24].

Another possible mechanism is the action of fluorouracil on intrinsic pathway of coagulation. Fluorouracil-mediated kallikrein-thrombin generation can cause increased concentrations of systemically circulating micro-trombi. It has been shown that fluorouracil with a plasma concentration of 20 μg/ml doubles thrombin generation in recalcified pooled normal plasma [25]. In a patient with a body weight of 75 kg, 500 mg of fluorouracil leads to a plasma concentration of 170 μg/ml [25]. The standard doses of fluorouracil used in metastatic colon cancer are far beyond this dose, that is, 400 mg/m2 bolus followed by 2400 mg/m2 as 46-h infusion. So, fluorouracil-induced kallikrein generation could easily increase more than 10-fold. Although liver can remove activated clotting factors from systemic circulation [26], it may be reasonable to administer low molecular weight heparin during fluorouracil infusion as prophylaxis.

The prognosis of stress-induced TTS is excellent, with a 95% complete recovery rate within 4–8 weeks [3,27]. Following fluoropyrimidine-induced TTS, cardiac functions returned to normal in all of the reported cases and despite its potential life-threatening nature, the mortality rate was 0%. Nonetheless, in two patients in whom fluorouracil was readministered after recovery, TTS recurred and caused death in one [6,13]; therefore, re-challenge with fluorouracil is potentially life-threatening and should only be reserved for those patients in whom there is no reasonable alternative therapy. In such cases, capecitabine could be a better alternative than fluorouracil; however, close cardiac monitoring is essential. In the case reported by Grunwald et al.[8], capecitabine was administered after TTS and did not cause cardiotoxicity.

Fluorouracil is not the only anticancer agent that induces TTS; TTS was also reported to occur in one patient following cetuximab treatment [9] and following bevacizumab treatment in two other patients [28]. TTS appears to occur more frequently than was previously thought. Increased awareness of TTS, its diagnostic criteria, and risk factors by clinicians is important for recognizing the syndrome. As TTS is reversible and treated with supportive measures, it is important to differentiate TTS from acute coronary syndrome to avoid unnecessary interventions.

Back to Top | Article Outline

Acknowledgements

Conflicts of interest

There are no conflicts of interest.

Back to Top | Article Outline

References

1. Teixeira L, Barry S, Debourdeau P, Cohen A, Tournigand C. Cardiotoxicity of 5-fluorouracil. Bull Cancer 2004; 91 (Suppl 3):154–158.
2. Keefe DL, Roistacher N, Pierri MK. Clinical cardiotoxicity of 5-fluorouracil. J Clin Pharmacol 1993; 33:1060–1070.
3. Gianni M, Dentali F, Grandi AM, Sumner G, Hiralal R, Lonn E. Apical ballooning syndrome or takotsubo cardiomyopathy: a systematic review. Eur Heart J 2006; 27:1523–1529.
4. Dote K, Sato H, Tateishi H, Uchida T, Ishihara M. Myocardial stunning due to simultaneous multivessel coronary spasms: a review of 5 cases. J Cardiol 1991; 21:203–214.
5. Sato H, Tateishi H, Uchida T, Dote K, Ishihara M. Tako-tsubo-like left ventricular dysfunction due to multivessel coronary spasm. In: Kodama K, Haze K, Hori M, editors. Clinical aspect of myocardial injury: from ischemia to heart failure [in Japanese]. Tokyo: Kagakuhyoronsha Publishing Co.; 1990. pp. 56–64.
6. Basselin C, Fontanges T, Descotes J, Chevalier P, Bui-Xuan B, Feinard G, Timour Q. 5-Fluorouracil-induced tako-tsubo-like syndrome. Pharmacotherapy 2011; 31:226.
7. Gianni M, Dentali F, Lonn E. 5 Flourouracil-induced apical ballooning syndrome: a case report. Blood Coagul Fibrinolysis 2009; 20:306–308.
8. Grunwald MR, Howie L, Diaz LA Jr. Takotsubo cardiomyopathy and fluorouracil: case report and review of the literature. J Clin Oncol 2012; 30:e11–e14.
9. Kim L, Karas M, Wong SC. Chemotherapy-induced takotsubo cardiomyopathy. J Invasive Cardiol 2008; 20:E338–E340.
10. Kobayashi N, Hata N, Yokoyama S, Shinada T, Shirakabe A, Mizuno K. A case of Takotsubo cardiomyopathy during 5-fluorouracil treatment for rectal adenocarcinoma. J Nihon Med Sch 2009; 76:27–33.
11. Calik AN, Celiker E, Velibey Y, Cagdas M, Guzelburc O. Initial dose effect of 5-fluorouracil: rapidly improving severe, acute toxic myopericarditis. Am J Emerg Med 2012; 30:257e1–e3.
12. Dalzell JR, Samuel LM. The spectrum of 5-fluorouracil cardiotoxicity. Anticancer Drugs 2009; 20:79–80.
13. Radhakrishnan V, Bakhshi S. 5-Fluorouracil-induced acute dilated cardiomyopathy in a pediatric patient. J Pediatr Hematol Oncol 2011; 33:323.
14. Stewart T, Pavlakis N, Ward M. Cardiotoxicity with 5-fluorouracil and capecitabine: more than just vasospastic angina. Intern Med J 2010; 40:303–307.
15. Bybee KA, Prasad A, Barsness GW, Lerman A, Jaffe AS, Murphy JG, et al. Clinical characteristics and thrombolysis in myocardial infarction frame counts in women with transient left ventricular apical ballooning syndrome. Am J Cardiol 2004; 94:343–346.
16. Pernicova I, Garg S, Bourantas CV, Alamgir F, Hoye A. Takotsubo cardiomyopathy: a review of the literature. Angiology 2010; 61:166–173.
17. Kawai S, Kitabatake A, Tomoike H. Guidelines for diagnosis of takotsubo (ampulla) cardiomyopathy. Circ J 2007; 71:990–992.
18. Kosmas C, Kallistratos MS, Kopterides P, Syrios J, Skopelitis H, Mylonakis N, et al. Cardiotoxicity of fluoropyrimidines in different schedules of administration: a prospective study. J Cancer Res Clin Oncol 2008; 134:75–82.
19. Saif MW, Shah MM, Shah AR. Fluoropyrimidine-associated cardiotoxicity: revisited. Expert Opin Drug Saf 2009; 8:191–202.
20. Zeb M, Sambu N, Scott P, Curzen N. Takotsubo cardiomyopathy: a diagnostic challenge. Postgrad Med J 2011; 87:51–59.
21. Lindsay J, Paixao A, Chao T, Pichard AD. Pathogenesis of the Takotsubo syndrome: a unifying hypothesis. Am J Cardiol 2010; 106:1360–1363.
22. Wittstein IS, Thiemann DR, Lima JA, Baughman KL, Schulman SP, Gerstenblith G, et al. Neurohumoral features of myocardial stunning due to sudden emotional stress. N Engl J Med 2005; 352:539–548.
23. Dorfman TA, Iskandrian AE. Takotsubo cardiomyopathy: state-of-the-art review. J Nucl Cardiol 2009; 16:122–134.
24. Kuo BT, Choubey R, Novaro GM. Reduced estrogen in menopause may predispose women to takotsubo cardiomyopathy. Gend Med 2010; 7:71–77.
25. Stief TW. Cytostatics may trigger thrombin generation. Hemost Lab 2009; 2:105–120.
26. Greenberg DL, Davie EW. Blood coagulation factors: their complimentary DNAs, genes and expression. In: Coleman RW, Hirsh J, Marder VJ, Clowes AW, George JN, editors. Hemostasis and thrombosis: basic principles and clinical practice. Philadelphia, Pennsylvania: Lippincott Williams and Wilkins; 2001. pp. 21–57.
27. Prasad A, Lerman A, Rihal CS. Apical ballooning syndrome (tako-tsubo or stress cardiomyopathy): a mimic of acute myocardial infarction. Am Heart J 2008; 155:408–417.
28. Franco TH, Khan A, Joshi V, Thomas B. Takotsubo cardiomyopathy in two men receiving bevacizumab for metastatic cancer. Ther Clin Risk Manag 2008; 4:1367–1370.
Keywords:

cardiomyopathy; fluorouracil; takotsubo

© 2013 Lippincott Williams & Wilkins, Inc.