Doxorubicin-associated Cardiac Remodeling Followed by CMR in Breast Cancer Patients

This prospective cohort study was performed at the State University of Campinas, Brazil. The Institutional Review Board of the State University of Campinas approved the study and all participants provided informed consent. Female patients with breast cancer who received anthracycline (doxorubicin or daunorubicin or epirubicin) as part of their chemotherapy protocol were enrolled in the study. Detailed medical history, standard anthropometric data, and measurement hemogram, troponin, CKMB, cholesterol, serum glucose, CRP and biomarkers were obtained. As in adults, chronic anthracycline-related cardiotoxicity typically presents early, within one year after termination of chemotherapy and the peak time for the appearance of symptoms of heart failure is about three months after the last anthracycline dose, patients underwent CMR before and three times serially after DOX (two, five and twelve months). Patients were imaged in supine position in a 3T magnet (Achieva, Philips Medical Systems, Best, The Netherlands). The CMR protocol consisted of electrocardiographically gated cine imaging with steady state free-precession to assess left ventricular (LV) function and LV mass. For imaging of late gadolinium enhancement (LGE) we used an inversion-recovery-prepared, gradient-echo sequence with segmented acquisition, which was triggered every other heartbeat. LGE images were acquired during end-expiratory breath-holding for slices matching the slice locations for cine imaging, starting within 10 min after bolus administration of a cumulative dose of 0.2 mmol/Kg of gadoterate meglumine (Dotarem, Guerbet, Aulnay-sous-Bois, France). T1 was performed with a Look-Locker sequence with a non-slice-selective adiabatic inversion pulse, followed by segmented gradient-echo acquisition for 17 times after inversion, covering approximately two cardiac cycles. The Look-Locker sequence was performed in a single short-axis slice at the level of the mid left ventricle. T1 imaging was repeated in the same LV short-axis slice, once before and five to seven times after the injection of gadolinium to cover an approximately 30-min period of slow contrast clearance. All images were analyzed with MASS CMR software (Mass Research, Leiden University Medical Center, Leiden, the Netherlands). For LV mass and function quantification, the endocardial and epicardial borders of the LV myocardium were manually traced on short-axis cine images at end-diastole and systole. Papillary muscles were excluded from LV mass, and LV mass was indexed to body surface area. For each Look-Locker image series, the endocardial and epicardial borders of the LV were traced and divided into six standard segments. Signal intensity versus time curves for each segment and the blood pool were used to determine segmental T1\* by nonlinear, least-squares fitting to an analytic expression for the magnitude signal measured during the inversion recovery. T1 was calculated from the T1\* and the amplitude parameters to correct for the effects of radiofrequency pulses applied during the inversion recovery. Pairs of R1 values for myocardial tissue and blood data were fit with a two-space water-exchange model of equilibrium transcytolemmal water exchange. The myocardial extracellular volume fraction (ECV) and the intracellular lifetime of water (τic), a cell size-dependent parameter, were adjustable parameters of this model. The measured blood hematocrit was a fixed parameter of the model. All R1 measurements for each patient were used to fit the model to determine ECV and τic.