Novel Approach to Early Detection of Doxorubicin Cardiotoxicity by Gadolinium-Enhanced Cardiovascular Magnetic Resonance Imaging in an Experimental Model

Abstract

Background—: We sought to determine whether cardiovascular magnetic resonance measures of gadolinium (Gd) signal intensity (SI) within the left ventricular myocardium are associated with future changes in left ventricular ejection fraction (LVEF) after receipt of doxorubicin (DOX). Methods and Results—: Forty Sprague-Dawley rats were divided into 3 groups scheduled to receive weekly intravenous doses of normal saline (n=7), 1.5 mg/kg DOX (n=19), or 2.5 mg/kg DOX (n=14). Magnetic resonance determinations of LVEF and myocardial Gd-SI were performed before and at 2, 4, 7, and 10 weeks after DOX initiation. During treatment, animals were euthanized at different time points so that histopathologic assessments of the left ventricular myocardium could be obtained. Within-group analyses were performed to examine time-dependent relations between Gd-SI and primary events (deterioration in LVEF or an unanticipated death). Six of 19 animals receiving 1.5 mg/kg DOX and 10 of 14 animals receiving 2.5 mg/kg DOX experienced a primary event; no normal saline animals experienced a primary event. In animals with a primary event, histopathologic evidence of myocellular vacuolization occurred ( P =0.04), and the Gd-SI was elevated relative to baseline at the time of the event ( P P =0.0001). In all animals (including normal saline) without an event, measures of Gd-SI did not differ from baseline. Conclusions—: After DOX, low serial measures of Gd-SI predict an absence of an LVEF drop or unanticipated death. An increase in Gd-SI after DOX forecasts a subsequent drop in LVEF as well as histopathologic evidence of intracellular vacuolization consistent with DOX cardiotoxicity.