Cardiac Stunning: An Infrequent Phenomenon with Unclear Etiology
Introduction
5-fluorouracil (5-FU) capecitabine is the cornerstone of chemotherapy in patients with gastrointestinal cancers, colon cancer, head and neck cancer, or breast and pancreatic cancer. The widespread use of this drug has increased the incidence of drug-related cardiotoxicity. 5-FU and related agents can cause cardiac stunning, defined as the short, persistent defect in the contractility of myocardium, which reverses by itself with time once the initial insult is over. Advancing age is a risk factor for the development of drug-related cardiotoxicity, and as the elderly population increases, older adults will have increased potential for exposure to 5-FU. It is important for physicians to consider the possibility of cardiotoxicity in elderly patients undergoing 5-FU chemotherapy for various cancers.
Case Presentation
A 61-year-old male with history of hypertension and hypercholesterolemia presented with iron deficiency anemia (hemoglobin, 6.8 g/dL). Upper endoscopy (EGD) revealed Helicobacter pylori infection, which was treated successfully. He continued to be anemic and required intravenous iron therapy. His EGD was followed by small-bowel video capsule endoscopy. The capsule was retained, and a subsequent kidney/ureter/bladder x-ray of the abdomen revealed a metallic object in the lower left quadrant. The patient underwent laparotomy, showing matted small intestine with innumerable nodules on the visceral peritoneum. Biopsy showed small-bowel adenocarcinoma, stage T4 N0. Gene expression profile testing confirmed the colorectal origin of the malignancy. The patient underwent segmental resection of the small intestine with reanastomosis. Chemotherapy with FOLFOX (folinic acid, 5-FU, oxaliplatin) and bevacizumab was planned. Within 24 hours of administering the first dose of 5-FU intraperitoneally, the patient complained of severe chest pain lasting for 20 hours associated with dyspnea. The chest pain was subclavicular in location on both sides and without any radiation. Computerized tomography scan of the chest with contrast ruled out pulmonary embolism. Electrocardiogram (EKG) showed sinus rhythm, heart rate of 85 bpm, left axis deviation with prolonged QT interval, but essentially negative for any ST-T wave changes. However, serial troponins increased from 0.037 ng/mL to 0.124 ng/mL. Echocardiogram was significant for severely reduced left ventricular systolic function with ejection fraction of 15-20% and a normal right ventricle. Non-ST segment elevation myocardial infarction (NSTEMI) was considered, and the patient underwent cardiac catheterization. Coronary angiography did not reveal any occlusion. Acute nonischemic cardiomyopathy secondary to 5-FU was diagnosed. The chemotherapy was discontinued, and the patient’s cardiomyopathy was treated with aspirin and beta blockers. By the fifth hospital day, he was completely symptom-free, and a follow-up echocardiogram showed improving systolic function with ejection fraction of 40-50%. The patient was discharged home on the sixth day of admission to follow up with a cardiologist in one month for follow-up echocardiogram.
Discussion
Cardiac stunning due to 5-FU is not well-defined. 5-FU tends to cause alteration in cardiac contractility, which resolves over time with discontinuation of the drug. This is thought to be a result of momentary ischemia to the myocardium followed by reperfusion, which is mediated by endothelial, myocyte, neural, or free radical mechanisms,1 modulating the amount of blood flow to a specific region of the myocardium. Nonischemic cardiomyopathy due to 5-FU treatment is an uncommon but observed phenomenon.
Different studies have shown a wide range of incidence and mortality from this phenomenon. The estimated incidence is between 1.2-1.6%, and mortality is around 2.2-13.3%.2,3 The risk appears to be higher in patients with a history of coronary artery disease and chest irradiation, but the associations are inconsistent in clinical studies.4 The most widely accepted mechanisms for this adverse event are coronary spasms, thrombogenic effects, or direct cardiotoxicity with injury to vascular endothelium leading to toxic myocarditis.5 5-FU gets metabolized in the liver into alpha-fluoro-beta-alanine (FBAL), which is cardiotoxic. Use of the dihydropyrimidine dehydrogenase inhibitor eniluracil or use of the 5-FU derivative S-1, which does not metabolize to FBAL, were associated with decreased cardiotoxicity in a study by Muneoka and colleagues.6 In a review by Saif et al,7 the incidence of cardiotoxicity in patients with pre-existing heart disease was 14%, increasing to 37% in those with additional cardiac risk factors. These patients may develop angina or acute myocardial infarction (MI), leading to cardiogenic shock and sudden death. Symptoms usually develop in the first 24-72 hours, but they can occur after weeks of chemotherapy.
The most common EKG changes seen after 5-FU administration are ST segment depression or elevation along with T-wave inversion in the leads, representing the injured myocardium. QT prolongation can accompany these changes or may occur as a late finding in the EKG. The most common arrhythmias are ventricular extrasystoles, but fatal ventricular tachycardia and complete heart block have also been described.8 Studies reveal conflicting evidence with regard to cumulative dose and mode of administration of 5-FU. Weidmann et al9 showed increased incidence of cardiotoxicity with more than 7 grams of cumulative dose. Tsibiribi and colleagues3 demonstrated clinical and EKG manifestation of cardiotoxicity with doses less than 7 grams. The cardiotoxicity was more pronounced when the drug was administered as a continuous infusion.7
Surprisingly, adding leucovorin infusions to 5-FU resulted in increased toxicity.8 Screening patients for cardiotoxicity risk from 5-FU has limited predictability. Neither the American College of Cardiology nor the National Comprehensive Cancer Network have guidelines for any screening or management protocols for 5-FU–related cardiotoxicity. Many authors suggest a baseline EKG prior to starting chemotherapy and serial EKG, holter monitoring, and coronary unit admission in case of any symptoms or EKG changes from the baseline.10 Management of patients with cardiac toxicity from 5-FU continues to be an unsettled issue. The general consensuses include discontinuation of the drug and treatment of vasospasm with nitrates and calcium-channel blockers.11-13 Elevation of cardiac enzymes, EKG changes, or persistent pain suggestive of myocardial injury require cardiac monitoring in the Coronary Care Unit for a minimum of 72 hours and treatment.14
Cardiology opinions should be sought in these cases, as further interventions may be needed for acute MI. Differences in opinion exist about rechallenging patients who had cardiac toxicity from prior 5-FU exposure. According to one group, patients who had reactions other than acute MI can be rechallenged on 5-FU and 3 doses of transdermal nitrates given 24 hours prior, during, and after the 5-FU administration.1 Successful reports of rechallenges with 5-FU have been reported.15 However, this should be done in closely monitored settings such as an Intensive Care Unit, and preferably with the guidance of the consulting cardiologist. Nevertheless, the majority of oncologists diverge from this opinion considering the high likelihood of recurrence and potentially severe consequences. Studies have shown an 80% recurrence of symptoms in these patients.16 In cases of prior MI with 5-FU, rechallenge with the drug should not be attempted.17
Conclusion
Myocardial toxicity of 5-FU should be considered in any patient with chest pain who had recent exposure to this chemotherapeutic agent. Prompt recognition of this entity and drug withdrawal can decrease mortality. A baseline EKG and 2D echocardiogram before starting the drug may be helpful in differentiating acute MI from chest pain secondary to nonischemic drug toxicity. Cardiology opinion should be sought, and further use of this drug should be avoided if possible. A rechallenge, when considered, should be carried out under strict surveillance.
The authors report no relevant financial relationships.
Dr. Krishnakurup is a Geriatric Fellow; Dr. Witt is from the Department of Hematology & Medical Oncology, and is Chief, Hematology Section; and Dr. Argento is Associate Program Director of Geriatrics, Section of Geriatric Medicine, Bridgeport Hospital/Yale New Haven, CT.
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