Abstract 11535: Persistent Qt Prolongation After Doxorubicin Administration at Doses Similar to Adjuvant Breast Cancer Therapy in African Green Monkeys

Abstract

Introduction: Cancer patients undergoing doxorubicin (Dox)-based chemotherapy often experience cardiac repolarization abnormalities, including electrocardiography (ECG)-derived QT and corrected QT (QTc) interval prolongation, which increases the risk for life-threatening arrhythmias such as torsades de pointes. We have previously reported that African Green monkeys exhibit CMR-derived myocardial fibrosis long-term after receiving Dox at doses similar to those experienced by women treated for breast cancer. Here, we sought to determine if QT/QTc prolongation persists after treatment cessation and its association with myocardial fibrosis. Methods: Five female African Green AGMs (AGMs) aged 13±1 years received Dox (30 - 60 mg/m 2 / biweekly IV, total cumulative dose: 240 mg/m 2 ) and underwent 12-lead ECG and CMR imaging with pre- and post-contrast T1 maps from which extracellular volume (ECV) was calculated, before and 15 weeks after the final dose of Dox treatment. A blinded paired and correlation analysis was performed on ECG-derived heart rate (HR), QRS, QT, QTc interval durations and ECV. Results: After Dox, all monkeys exhibited increased QT (BL: 323.2 ± 27.4 ms vs. Post-Dox: 366.4 ± 18.7 ms, p=0.002) and QTc (BL: 440.2 ± 22.8 ms vs. Post-Dox: 500.8 ± 22.0 ms, p=0.009) intervals, without any significant changes in HR or QRS duration (p=0.92 and p=0.47 respectively). Longer QTc intervals were associated with increases in ECV ( r =0.58, p=0.05) (Figure). Conclusions: AGMs that received Dox - in a fashion similar to adjuvant anthracycline chemotherapy for breast cancer- exhibited longer QT and QTc intervals associated with myocardial fibrosis. Our study suggests this may not be solely due to transient ion channel disruption from Dox but rather from persistent changes in the electrophysiological properties of cardiomyocytes and the extracellular matrix. Future longitudinal studies are needed to determine the clinical significance of these findings.