a b s t r a c t

Several chemotherapeutic agents are known to be cardiotoxic. One of them, 5-Fluorouracil , has been as- sociated with coronary ischemia and reversible vasospasm. In this report, we describe a 54-year-old man with rectal cancer who developed chest pain during 5-FU infusion. His initial electrocardiogram (ECG), obtained while he was experiencing chest pain, showed Hyperacute T waves in the anterolateral leads. Those waves disap- peared along with the chest pain after administration of sublingual nitroglycerine. An urgent coronary angiogram revealed that the patient had no significant flow-limiting coronary artery disease to account for this chest pain. The final diagnosis was Coronary artery spasm with moderate global left ventricular dilatation suggestive of nonischemic cardiomyopathy. During 3 days of hospitalization, the patient remained pain free and therefore was discharged. To our knowledge, this is the first case report in the emergency medicine literature demonstrat- ing a coronary vasospastic event associated with 5-FU cardiac toxicity.

(C) 2017

Introduction

The incidence of cancer treatment complications is on the rise [1]. 5- Fluorouracil (5-FU) is a chemotherapeutic agent used for many types of solid tumors, particularly colorectal carcinoma and pancreatic neo- plasms [2]. Cardiotoxicity, one of the potential adverse effects of this drug, occurs in 1% to 18% of patients [3-5]. The mechanism of 5-FU cardiotoxicity is unknown; it is hypothesized that intravenous (IV) infu- sion (rather than bolus dosing) induces transient electrocardiographic changes, arrhythmias, and vasospasm as well as cardiac ischemia in pa- tients with underlying coronary artery disease (CAD) [5].

Case report

A 54-year-old man presented to a regional oncology center for his second infusion of 5-FU for stage II rectal carcinoma. His history was sig- nificant for 30 pack-years of smoking, hypertension, and hyperlipid- emia. His only medications were atorvastatin, 40 mg daily, and ramipril, 5 mg daily.

Within 15 min after the infusion began, the patient experienced crushing chest pain, diaphoresis, and nausea. An ECG indicated transient hyperacute T waves over the anterolateral leads (Fig. 1). After

* Corresponding author.

E-mail address: [email protected] (A. Mattu).

administration of sublingual nitroglycerine (NTG), his chest pain re- solved and the T waves and ST segments normalized (Fig. 2). A short time later, he experienced another episode of chest pain (Fig. 3). Multiple doses of NTG were given before the pain resolved once again (Fig. 4). We were concerned that these transient ST elevations were signs of acute MI, so a “code STEMI” was activated and the interventional cardiology team was consulted. The patient received a bolus of heparin, 5000 units IV; as- pirin, 160 mg, chewed; and clopidogrel, 600 mg PO.

During coronary angiography, laboratory testing revealed normal values for electrolytes, complete blood count, and renal function. The first High-sensitivity troponin (hs-TN; Roche Diagnostics, Mannheim, Germany) level was 16 ng/L (ref b 14 ng/L).

Coronary angiography revealed no stenosis in his left main coronary artery and a non-obstructive plaque (30% stenosis) in his left anterior descending artery (LAD). Flow through the LAD was excellent, without lesions or evidence of thrombus. The Circumflex artery (a nondominant vessel) was free from flow-limiting disease, as was the posterior de- scending artery. The right coronary artery had mild atherosclerotic dis- ease with 30% stenosis at its mid-portion. The left ventriculogram showed moderate Left ventricle dysfunction. The LV appeared di- lated with moderate global hypokinesis and an estimated grade 3 LV ejection fraction. Following angiography, 4 h after transfer from the ED, repeat hs-TN level was 24 ng/L. The concentration normalized by the next day.

The patient continued to experience occasional mild episodes of chest pain that resolved with sublingual NTG. Given the vasospastic

http://dx.doi.org/10.1016/j.ajem.2017.02.046

0735-6757/(C) 2017

1038.e4 M. Ben-Yakov et al. / American Journal of Emergency Medicine 35 (2017) 1038.e3-1038.e5

Fig. 1. Hyperacute T waves over the anterolateral leads on initial presentation.

Fig. 2. Normalization of T waves and ST segments after administration of sublingual nitroglycerine.

nature of the pain, the electrocardiographic changes, and the lack of flow-limiting disease, an oral calcium channel blocker was started. His other medications were optimized, and aggressive smoking cessation therapy was initiated. By day 2, the patient was free of chest pain. He was discharged home with follow-up at the oncology center.

Discussion

Coronary vasospasm (also known as Prinzmetal angina [6]) can mimic acute MI. The cardiovascular toxicity of common chemothera- peutic drugs has been described in the oncology and cardiology

Fig. 3. Hyperacute T waves return with recurrent episode of pain.

M. Ben-Yakov et al. / American Journal of Emergency Medicine 35 (2017) 1038.e3-1038.e5 1038.e5

Fig. 4. Resolution of chest pain and Ischemic changes after administration of multiple doses of nitroglycerin.

literature [2,7,8]. The vasospastic effect of 5-FU is well described in the oncology literature [4]; to our knowledge, this is its first report in the emergency medicine literature.

When signs and symptoms of myocardial ischemia emerge in a pa- tient receiving 5-FU, NTG should be given to alleviate possible coronary vasoconstriction. Cardiac catheterization is recommended to look for other causes, especially if high-risk features such as refractory angina, Malignant arrhythmias, and shock are present [9].

Theories for 5-FU-induced cardiotoxicity include induction of new is- chemia on top of pre-existing CAD, endothelial damage, direct myocardial toxicity, induction of global dysfunction, promotion of procoagulable state, and coronary vasospasm [4]. The mechanism of vasoconstriction and spasm can be traced to 5-FU’s alteration of smooth muscle tone via molecular signaling pathways [10]. Patients with pre-existing CAD might be at increased risk for 5-FU cardiotoxicity, so they should be mon- itored carefully and have appropriate cardiovascular management along- side their oncologic treatment, with initiation of prophylactic calcium channel blockers and judicious use of sublingual NTG [7].

The literature is replete with reports on multiple cardiovascular ef- fects of chemotherapeutic drugs [2,5,7,8]. Table 1 summarizes effects of the most common drugs on the cardiovascular system; less common but critical adverse effects include cardiac tamponade, brady-dysrhyth- mias, and QT prolongation [8]. In addition to the increased risk of thromboembolism due to cancer and its treatment [5,8], the emergency physician should be aware of other important cardiovascular adverse effects associated with these drugs: depression of myocardial function

Table 1

Common chemotherapeutic drugs and associated cardiovascular side effects (in relative frequency).

Adapted from Yeh ET, Bickford CL. Cardiovascular complications of cancer therapy: inci- dence, pathogenesis, diagnosis, and management. J Am Coll Cardiol 2009; 53:2231-47.

(resulting in early congestive heart failure), myocardial ischemia, hypo- tension, and hypertension [2,5,7,8].

This case demonstrates a rare vasospastic phenomenon associated with 5-FU. Because this adverse effect can mimic or induce myocardial ischemia, emergency physicians should be aware of it. Standard cardiac emergency treatments still apply to patients affected by chemothera- peutic cardiotoxicity.

Acknowledgment

The manuscript was copyedited by Linda J. Kesselring, MS, ELS.

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   	Common drugs	Relative frequency
   Myocardial depression	Anthracyclines (e.g., doxorubicin)	++++
   Myocardial ischemia	Imatinib (Gleevec) Cyclophosphamide Trastuzumab (Hercepin) Trans-retinoic acids 5-FU Cisplatin Capecitabine IL-2	+++ ++ ++ ++ ++ ++ + ++++
   Hypotension Hypertension	Paclitaxel Rituximab IL-2 Interferon-alpha Trans-retinoic acids Cisplatin Bevacizumab (Avastin)	++ ++ +++ +++ ++ + +++