Transient, High-Grade Atrioventricular Block from High-Dose Cyclophosphamide

Abstract

Cyclophosphamide, an alkylation agent, is widely used in stem cell transplantation for its antineoplastic and myeloablative properties. Congestive heart failure, pericarditis, and arrhythmias are well-known cardiac sequelae of high-dose cyclophosphamide therapy; however, high-grade atrioventricular block has rarely been reported. We present the case of a 71-year-old man who developed a high degree of atrioventricular block several hours after therapy with high-dose cyclophosphamide. After treatment with a temporary pacemaker and cessation of cyclophosphamide, the patient experienced no more events. Before administering cyclophosphamide, evaluating patients for underlying conduction abnormalities is advisable. Agents other than cyclophosphamide are available.

Cyclophosphamide is widely used in stem cell transplantation for its antineoplastic and myeloablative properties. In high doses, this drug has cardiotoxic side effects that can result in congestive heart failure, arrhythmias, pericarditis, and death.^1,2 Only rarely have cases been reported of high degrees of atrioventricular (AV) block in association with high-dose cyclophosphamide chemotherapy.^3–5 We present the case of an elderly man who developed transient, high-grade AV block several hours after he had undergone high-dose cyclophosphamide chemotherapy.

Case Report

In October 2011, a 71-year-old man with stage IIA immunoglobulin G-k multiple myeloma presented with disease progression. Two years earlier, he had undergone autologous peripheral blood stem cell transplantation, and at this presentation he was being evaluated for a second such procedure. Too few stem cells had mobilized after injections of granulocyte colony-stimulating factor glycoprotein and plerixafor, so he was given 4 g of cyclophosphamide intravenously.

Several hours later, the patient suddenly experienced a seizure-like event, described as jerky movements of the upper limbs and eyes rolling back. The episode lasted for less than a minute. There was no incontinence and no post-ictal phase. Upon arriving at the emergency department, the patient reported weakness. His vital signs were stable, and he was afebrile; his blood pressure was 144/76 mmHg and his heart rate was 96 beats/min in sinus rhythm. The results of physical, cardiac, and neurologic examinations were normal. Laboratory results included a low potassium level of 3.1 mEq/L; however, a complete blood count, other elements of the comprehensive metabolic panel, and cardiac troponin levels were all within normal range. Computed tomograms of the patient's head were within normal limits. While under emergency care, the patient had another seizure-like episode, at which time telemetry showed a transient, high-grade AV block with asystolic pause (Fig. 1). The event was not preceded by nausea or vomiting, shortness of breath, chest pain, coughing, or straining. The seizure-like activity was attributed to cerebral hypoperfusion consequent to the AV block, and the patient was immediately taken to the cardiac catheterization laboratory for the insertion of a temporary transvenous pacemaker. He was then admitted to the cardiac intensive care unit. During the next 48 hours, telemetry monitoring revealed no AV block and consistent sinus rhythm without further need for ventricular pacing.

Fig. 1 Telemetry strip shows transient, high-grade atrioventricular block with asystolic pause.

A carotid massage slowed the patient's heart rate but did not reproduce the high-grade AV block. An electrocardiogram revealed first-degree AV block but no bundle branch block (Fig. 2). Despite the patient's low potassium level, no U waves or T-wave flattening was evident, so it was unlikely that hypokalemia was responsible for the heart block. Echocardiograms showed normal cardiac structures. The temporal connection between the AV block and the cyclophosphamide therapy prompted us to search the medical literature. On the basis of our findings, we thought that the cyclophosphamide was the most likely cause of our patient's AV block.

Fig. 2 Electrocardiogram reveals first-degree atrioventricular block but no bundle branch block.

Because the patient had no recurrent AV block during the 48 hours of observation, he was discharged from the hospital without a permanent pacemaker. He declined our offer of an event monitor, preferring to obtain one from his primary cardiologist. He was given no more cyclophosphamide, and his therapy was changed to lenalidomide. Follow-up evaluations during the next 6 months yielded no recurrence of heart block.

Discussion

The cardiac sequelae of high-dose cyclophosphamide therapy, such as atrial and ventricular arrhythmias, cardiomyopathy, nonspecific ST-T wave changes, and sinus node dysfunction, are well known.^1,2 We found 2 reports of patients in whom a high degree of AV block developed after high-dose cyclophosphamide therapy.^3,4 One patient was treated only with a temporary pacemaker (as was our patient) and experienced no recurrence. The other patient had evidence of AV block beyond 72 hours and was given a permanent pacemaker; however, Holter monitoring 6 months later revealed no AV block, so the heart block was transient.

Pathoanatomic findings in patients who died of the cardiac effects of cyclophosphamide have included myocardial edema, focal areas of myocardial hemorrhage, and multifocal myocardial necrosis associated with fibrin microthrombi. The possible cause of the conduction anomaly and the AV block is physical damage to the conduction system secondary to microangiopathy or transient spasms caused by cyclophosphamide-induced injury to the capillary endothelium.^6–8 Vagal stimulation might augment any otherwise-reversible damage to the conduction system caused by high-dose chemotherapy, leading to advanced and complete AV block.

Our patient's case highlights a rare but severe cardiac complication of cyclophosphamide chemotherapy and the need for close monitoring with telemetry to yield the correct diagnosis and treatment of this condition. It seems prudent to evaluate patients for conduction abnormalities before instituting cyclophosphamide therapy, and to use alternative agents if necessary. Event monitors are also valuable for documenting any conduction abnormality, especially within 24 hours of induction therapy and in patients with prior histories of heart block or conduction-system disease.