Early detection of myocardial changes with and without dexrazoxane using serial magnetic resonance imaging in a pre-clinical mouse model

Cory V Noel,Nino Rainusso,Matthew Robertson,Cristian Coarfa,Robia Pautler,Jonathan Romero,Prakash Masand

doi:10.1186/s40959-021-00109-8

Abstract

BackgroundCancer therapy-related cardiac dysfunction may occur in pediatric cancer survivors. Identification of early markers of myocardial damage secondary to anthracycline exposure is crucial to develop strategies that may ameliorate this complication.ObjectivesThe purpose of this study was to identify early myocardial changes induced by doxorubicin with and without cardioprotection using dexrazoxane detected by serial cardiac magnetic resonance imaging (CMR) in a pre-clinical mouse model.MethodsSerial CMR examinations were performed in 90 mice distributed in 3 groups: 45 received doxorubicin (DOX group), 30 mice received doxorubicin with dexrazoxane (DOX/DEX group) and 15 mice received saline injections (control group). We obtained the following CMR parameters in all mice: T2, extracellular volume quantification (ECV), myocardial deformation, and functional quantification.ResultsMyocardial edema assessed by T2 time was the earliest parameter demonstrating evidence of myocardial injury, most notable in the DOX group at week 4 and 8 compared with DOX/DEX group. Similarly, global longitudinal strain was abnormal in both the DOX and DOX/DEX groups. However, this change persisted only in the DOX group. The ECV was significantly elevated in the DOX group at the final CMR, while only minimally elevated in the DOX/DEX group. The right and left ejection fraction was decreased, along with the mass to volume ratio in the DOX group. The T2 time, ECV, and deformation correlated with ejection fraction and left ventricular volume.ConclusionsT2 time and deformation by CMR identifies early myocardial injury from anthracyclines. Dexrazoxne did not prevent the initial edema, but the inflammatory changes were not sustained. CMR may be useful for early detection of cardiac dysfunction. Serial CMR demonstrates dexrazoxane minimizes cardiac dysfunction and aids recovery in a mouse model.

Highlights

The rates of survival of pediatric cancers have risen considerably over the past four decades
cardiac magnetic resonance imaging (CMR) may be useful for early detection of cardiac dysfunction
Our study utilizing a pre-clinical mouse model demonstrated that early myocardial changes occur with doxorubicin even when it is administrated in conjunction with dexrazoxane

Summary

Introduction

The rates of survival of pediatric cancers have risen considerably over the past four decades. A class of chemotherapy drugs, have become the mainstay of treatment for different pediatric cancers [1]. The use of anthracyclines is limited by their known deleterious cardiovascular effects [2]. The most common effect of cancer therapyrelated cardiac dysfunction (CTRCD) is left ventricular systolic dysfunction as measured by decreased ejection fraction (EF) [3]. Dexrazoxane decreases the formation of reactive oxygen species in the myocardium which have deleterious effects on cardiomyocytes [6, 7]. There is reluctance to administer dexrazoxane to pediatric patients, a recent study from the Children’s Oncology Group demonstrated improvement in reducing the left ventricular systolic dysfunction and a suggestion of reducing treatment-related mortality [8]. Identification of early markers of myocardial damage secondary to anthracycline exposure is crucial to develop strategies that may ameliorate this complication

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