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 . 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 . 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 . The clinical presentation and electrocardiographic findings of TTS are similar to those of acute myocardial infarction (MI) in the absence of CAD.  TTS was first described in 1990 by Sato et al.. 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 . As TTS is thought to be induced by physical or emotional stress , 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.
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).
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 . For a diagnosis of TTS, all four of the following Mayo Clinic diagnostic criteria must be met: 
- 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;
- Absence of obstructive CAD (>50% of the luminal diameter) and absence of angiographic evidence of acute plaque rupture;
- New electrocardiographic abnormalities consisting of ST-segment elevation or T-wave inversion, and modest elevation in cardiac troponin levels;
- 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 . Sometimes the heart does not take the characteristic shape of takotsubo with apical ballooning; instead, focal or diffuse wall motion abnormalities are observed .
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 . Vasospasm is thought to be the most important pathogenetic factor . The schedule of administration and concomitant use of leucovorin has a significant impact on the risk of cardiotoxicity . Continuous infusion of fluorouracil results in a higher incidence of cardiotoxicity than bolus fluorouracil and oral capecitabine . In addition, continuous infusion fluorouracil regimens consisting of leucovorin are more likely to cause cardiotoxicity . Fluorouracil-induced cardiotoxicity causes death in 8% of patients . Re-challenge with fluorouracil results in the reappearance of cardiac symptoms in 47% of patients and causes death in 13% .
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 . 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 .
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 . 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 . As the apical portions of the left ventricle have the highest concentration of sympathetic innervations in the heart, catecholamine release selectively affects the apex . The higher incidence in postmenopausal women suggests that low-level estrogen is a concomitant risk factor for TTS .
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 . In a patient with a body weight of 75 kg, 500 mg of fluorouracil leads to a plasma concentration of 170 μg/ml . 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 , 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., 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  and following bevacizumab treatment in two other patients . 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.
Conflicts of interest
There are no conflicts of interest.
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
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
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
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
7. Gianni M, Dentali F, Lonn E. 5 Flourouracil-induced apical ballooning syndrome: a case report. Blood Coagul Fibrinolysis
8. Grunwald MR, Howie L, Diaz LA Jr. Takotsubo cardiomyopathy
: case report and review of the literature. J Clin Oncol
9. Kim L, Karas M, Wong SC. Chemotherapy-induced takotsubo cardiomyopathy
. J Invasive Cardiol
10. Kobayashi N, Hata N, Yokoyama S, Shinada T, Shirakabe A, Mizuno K. A case of Takotsubo cardiomyopathy
treatment for rectal adenocarcinoma. J Nihon Med Sch
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
12. Dalzell JR, Samuel LM. The spectrum of 5-fluorouracil
cardiotoxicity. Anticancer Drugs
13. Radhakrishnan V, Bakhshi S. 5-Fluorouracil
-induced acute dilated cardiomyopathy
in a pediatric patient. J Pediatr Hematol Oncol
14. Stewart T, Pavlakis N, Ward M. Cardiotoxicity with 5-fluorouracil
and capecitabine: more than just vasospastic angina. Intern Med J
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
16. Pernicova I, Garg S, Bourantas CV, Alamgir F, Hoye A. Takotsubo cardiomyopathy
: a review of the literature. Angiology
17. Kawai S, Kitabatake A, Tomoike H. Guidelines for diagnosis of takotsubo
. Circ J
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
19. Saif MW, Shah MM, Shah AR. Fluoropyrimidine-associated cardiotoxicity: revisited. Expert Opin Drug Saf
20. Zeb M, Sambu N, Scott P, Curzen N. Takotsubo cardiomyopathy
: a diagnostic challenge. Postgrad Med J
21. Lindsay J, Paixao A, Chao T, Pichard AD. Pathogenesis of the Takotsubo
syndrome: a unifying hypothesis. Am J Cardiol
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
23. Dorfman TA, Iskandrian AE. Takotsubo cardiomyopathy
: state-of-the-art review. J Nucl Cardiol
24. Kuo BT, Choubey R, Novaro GM. Reduced estrogen in menopause may predispose women to takotsubo cardiomyopathy
. Gend Med
25. Stief TW. Cytostatics may trigger thrombin generation. Hemost Lab
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
28. Franco TH, Khan A, Joshi V, Thomas B. Takotsubo cardiomyopathy
in two men receiving bevacizumab for metastatic cancer. Ther Clin Risk Manag