The antimetabolite 5-fluorouracil (FU) is widely used in the treatment of solid tumors, including gastrointestinal, breast, head, and neck cancers. Cardiotoxicity, a rare adverse effect of 5-FU, has a reported incidence of 1.2% to 18% [1,2]. The pathogenesis of 5-FU cardiotoxicity is unclear. The prevalent hypothesis suggests that 5-FU induces coronary vasospasm [1]. We report here a case of 5-FU cardiotoxicity. The patient presented with typical angina and electrocardiographic changes suggestive of an ischemic coronary event during the continuous infusion of 5-FU. The ischemia recurred when the infusion was stopped, and was relieved by administration of nitroglycerin followed by a sublingual calcium channel blocker.

An 83-year-old man who had been diagnosed with stage III_C (T₄N₂M₀) adenocarcinoma of the ascending colon and who had undergone a right hemicolectomy was admitted to Inje University Seoul Paik Hospital to begin adjuvant chemotherapy, using the FOLFOX4 regimen (400 mg/m² 5-FU bolus infusion followed by the continuous infusion of 600 mg/m² 5-FU for 22 hours on days 1 and 2; 200 mg/m² leucovorin as a continuous infusion for 2 hours before 5-FU infusion on days 1 and 2; and infusion of 85 mg/m² oxaliplatin on day 1). The patient's medical history included no cardiovascular risk factors. Baseline echocardiography performed 1 month before admission showed normal left ventricular systolic function and no regional wall motion abnormality. He was treated with 1,500 mg high-dose 5-FU (1,000 mg/m²) per day. On the morning of the 3rd day, he developed a severe, substernal, crushing chest pain during the continuous intravenous infusion of 5-FU (cumulative dose 1,679 mg/m²), which was partially relieved by administering sublingual nitroglycerin. The electrocardiogram (ECG) showed ST segment elevation with a tall T wave in leads I, aVL, and V_4-6, and reciprocal ST segment depression in leads V_1-2 (Fig. 1A). The troponin-I and CK-MB levels were 0.010 ng/mL (reference range, ≤ 0.1) and 3.73 ng/mL (reference range, ≤ 4.94), respectively. Severe hypokinesia of the lateral wall of the left ventricle was noted on a portable bedside echocardiogram. The 5-FU infusion was stopped, and the chest pain and electrocardiographic changes resolved after intravenous infusion of nitroglycerin at 30 µg/min. Emergency coronary angiography was then performed, which revealed significant stenosis in the proximal left circumf lex coronary artery (LCx). Intracoronary nitroglycerin (200 µg) was injected to exclude coronary vasospasm, but no change occurred (Fig. 2). Intravenous ultrasound (IVUS) showed severe luminal narrowing with a heavy concentric plaque in the proximal LCx. Coronary artery spasm with fixed stenosis was considered. Percutaneous coronary intervention of the proximal LCx lesion was performed successfully with the implantation of a drug-eluting stent (3.5 × 16 mm; TAXUS, National Medical Center, Seoul, Korea) (Fig. 3). The patient was transferred to the coronary-care unit, where 8 hours later, he reported a recurrence of the anterior chest pain. The ECG also showed ST segment elevation and reciprocal ST changes similar to those seen in the previous ischemic events (Fig. 1B). The chest pain and ECG changes persisted despite a 100 µg/min nitroglycerin infusion. To rule out acute stent thrombosis, the patient was taken to the cardiac catheterization laboratory. The chest pain and ECG changes were relieved after sublingual administration of 10 mg nifedipine. Repeated coronary angiography showed a widely patent stent (Fig. 4). The postprocedural troponin-I and CK-MB levels were 0.010 and 4.62 ng/mL, respectively. Echocardiography performed the next day also showed the absence of the regional wall motion abnormality and normal left ventricular systolic function. The patient refused chemotherapy and was discharged in a stable condition. He remained free of the symptoms of recurrent angina pectoris.

We present here a case of severe cardiotoxicity mimicking acute anterolateral myocardial infarction occurring in a patient receiving 5-FU chemotherapy for adenocarcinoma of the colon. The cessation of 5-FU administration and the subsequent initiation of treatment with a sublingual calcium channel blocker and nitrate resulted in a successful outcome. Although the mechanism by which 5-FU exerts its cardiotoxic effects is unknown, the resolution of the patient's chest pain and the normalization of his ECG changes with a vasodilator strongly support the vasospastic hypothesis of 5-FU cardiotoxicity.

Many hypotheses regarding 5-FU-induced cardiotoxicity have been formulated. One study postulated that 5-FU-associated cardiotoxicity is due to the uncoupling of the electromechanical mechanisms that underlie normal myocardial function, which might be mediated at the level of the cell membrane [3]. Recently, Kuzel et al. [4] suggested that 5-FU promotes a hypercoagulable state (e.g., coronary artery thrombosis) and observed a significant increase in fibrinopeptide A and a decrease in protein C activity during 5-FU administration.

The incidence of clinically apparent 5-FU cardiotoxicity is less than 10% in patients receiving the drug [5]. Patients with a history of coronary artery disease (CAD) have a significantly increased risk of 5-FU-induced cardiotoxicity [6]. Although our patient did not have a history of CAD, a large atheromatous plaque was found on coronary angiography and IVUS. Therefore, during 5-FU infusion, close, careful monitoring of patients, especially those with pre-existing CAD or CAD risk factors, is mandatory. Prophylactic calcium channel blockers or nitrates should be administered to patients with CAD during 5-FU administration, to prevent vasospasm [7]. One study proposed that impaired renal function is also a risk factor for 5-FU cardiotoxicity. Although it is not clear whether the cardiotoxic metabolites undergo renal excretion, the pathophysiological effect of 5-FU on the myocardium is likely to increase with decreased renal function. Thus it is necessary to clarify which patients may benefit from optimum anti-angina prophylaxis and careful, close monitoring [1].

The incidence of 5-FU-related cardiotoxicity appears to be dependent on the dosage and delivery system. Infusion of 5-FU, which is now being used more frequently and at higher doses instead of bolus therapy, may be a significant factor in the development of 5-FU cardiotoxicity [5]. In one study, nine patients treated with a higher-dose (> 800 mg/m²) continuous infusion of 5-FU died suddenly [5].

Interestingly, despite stopping the 5-FU, the chest pain and ECG changes recurred in our case. One series reported that 19% of the patients developed reversible angina pectoris during treatment, which lasted for up to 12 hours after cessation of the infusion [2]. The possible mechanisms of delayed angina are the late release of potent vasoactive 5-FU metabolites, which accumulate over time due to degradation of 5-FU [8]. Therefore, a calcium channel blocker or nitrates should be administered after stopping the 5-FU when 5-FU-induced cardiotoxicity occurs.

The long-term outcome of patients with 5-FU-related cardiotoxicity has not been investigated extensively. As with our case, Patel et al. [8] recently reported interval improvements in the left ventricular wall motion abnormalities in echocardiography performed 8 to 15 days following the initial study. Other investigators have reported similar reversible left ventricular dysfunction [9]. When cardiotoxicity occurs, 5-FU treatment is usually discontinued due to its very high recurrence rate (90%) [10]. The re-administration of 5-FU is not recommended, and a different chemotherapy regimen should be considered. Interestingly, Meydan et al. [10] continued 5-FU chemotherapy in one group who experienced 5-FU cardiotoxicity due to the absence of an alternative drug and found that subsequent serious, hemodynamic consequences were easily controlled with nitrate treatment. For the remaining patients, either 5-FU was removed from the combination regimen or an alternative drug was started and no cardiotoxicity developed subsequently.

In summary, although 5-FU-associated cardiac toxicity is rare, it may cause angina, myocardial infarction, and even sudden death. Physicians should be aware of this potentially lethal side effect and should start the proper treatment when 5-FU cardiotoxicity develops. This case supports the vasospastic hypothesis of 5-FU cardiac toxicity, indicating that a calcium channel blocker may be effective for prevention or treatment of 5-FU cardiotoxicity.