Anthracycline-induced acute myocarditis and ventricular fibrillation arrest
Authors: Vincent A. Pallazola, Joseph C. Murray, Munjid Al Harthy, Stefan L. Zimmerman, Jonathan Webster, Lukasz P. Gondek
Journal: American Journal of Hematology (2017)

A 47-year old male marathon runner with no notable past medical history and a new diagnosis of intermediate risk acute myelogenous leukemia (AML) was treated with idarubicin, cytarabine, and etoposide induction chemotherapy. His treatment course was complicated by a new onset mild maculopapular rash and culture negative neutropenic fever, which was presumed to be cytarabine syndrome. On day seven of induction, he developed sub-sternal chest pain and a mild troponin elevation without electrocardiographic changes suggestive of ischemia, which resolved with morphine. Etoposide was started on day eight. Later that day the patient began to experience recurrent chest pain, which was refractory to morphine and sublingual nitrate. Etoposide was held and prednisone was started for presumed inflammatory myopericarditis. The patient developed ventricular fibrillation (VF) arrest with return of spontaneous circulation after 35 minutes of cardiopulmonary resuscitation and regained consciousness shortly after. Postarrest electrocardiogram revealed no evidence of ischemia. Given chemotherapy-induced aplasia with profound thrombocytopenia and low suspicion for acute coronary ischemia, percutaneous coronary intervention was deferred. Postarrest transthoracic echocardiogram (TTE) was notable for mild left ventricular hypokinesis (ejection fraction 45%), mild left and right atrial dilation, and a trace pericardial effusion. Contrast-enhanced cardiac computed tomography revealed no underlying coronary artery disease and no structural defects. Magnetic resonance imaging (MRI) showed extensive late gadolinium enhancement (LGE) in a patchy, nonischemic distribution, involving the mid-wall of the septum and the subepicardium of the anterior and lateral walls (Figure 1). Viral cardiomyopathy panel and blood cultures were negative. For cardiac optimization, he was started on a beta-blocker and ACE inhibitor and was bridged with a wearable external defibrillator. A leadless subcutaneous implantable cardiac defibrillator was placed after hematologic recovery. Mid-cavity (A) and apical (B) short axis late gadolinium enhancement (LGE) images obtained 10 minutes after injection of 0.2 mmol/kg of gadolinium contrast (gadobutrol) demonstrating extensive mid-wall late enhancement in the septum and sub-epicardial enhancement in the anterior and lateral walls. Horizontal long axis LGE image (C) demonstrating extensive patchy late enhancement in the septum and lateral wall [Color figure can be viewed at wileyonlinelibrary.com] Anthracyclines, cytarabine and etoposide have all been shown to have the potential to induce varying degrees of cardiotoxicity. Anthracyclines, one of which is idarubicin, have the highest rate of cardiotoxicity of the above agents and are most classically associated with dilated cardiomyopathy.1 Cytarabine has a lower incidence of cardiotoxicity, and although this patient did have an inflammatory response to cytarabine and cases of cytarabine-induced pericarditis were previously reported,2 the incidence of cytarabine-induced acute myocarditis and cardiac arrhythmia is rather low. Finally, etoposide is the least likely agent in this case as symptoms and troponin elevation preceded initiation of the infusion. Anthracyclines can cause dose-dependent dilated cardiomyopathy, with associated arrhythmias favoring atrial tachycardia and atrial fibrillation over ventricular arrythmias.3 Anthracyclines have been shown to have a multifactorial myocytotoxic effect through free radical production, intercalation into DNA, and inhibition of sarcomere maintenance, although troponin elevations are not commonly seen with these agents. Several case reports have implicated anthracyclines in the development of ischemia and ventricular arrhythmias, primarily in patients who were older and/or had higher incidence of cardiac co-morbidities.4-6 There have, however, been only few reports in which patients exposed to anthracyclines developed terminal ventricular arrhythmias in the absence of significant underlying cardiac co-morbidities.7, 8 In this small subset, ventricular arrhythmia is likely to be a direct consequence of myocardial inflammation, as seen in this case with the development of VF arrest following acute myocarditis and troponin elevation. This case demonstrates the utility of cardiac MRI as a noninvasive tool to diagnose acute myocarditis by highlighting a unique myocardial pattern of injury that is inconsistent with coronary ischemic change. Furthermore, MRI was used to risk-stratify this patient for future cardiovascular risk, as both septal and mid-wall LGE and patchy LGE distribution have been associated with 3-fold risk of major adverse cardiac events.9 Given clear evidence of myocarditis as the culprit for his troponin elevation and VF arrest via noninvasive imaging, consolidation with bone marrow transplant was pursued as opposed to traditional chemotherapy to minimize further exposure.