Abstract 9418: Inhibition of Cardiac Mitochondrial Fission as an Effective Intervention Against Trastuzumab-Induced Cardiotoxicity in Rats

Abstract

Introduction: Trastuzumab (TRZ) has been broadly used as a chemotherapeutic agent for the treatment of advanced human epidermal growth factor receptor type 2-expressing malignancies. However, cardiotoxicity exacerbated by TRA has become an adverse clinical manifestation of oncologic treatment. Although cardioprotective outcomes of a mitochondrial division inhibitor (Mdivi-1) have been demonstrated for a wide range of cardiovascular pathologies, the anti-cardiotoxic effects of Mdivi-1 against TRZ are unknown. Hypothesis: Treatment with Mdivi-1 rescues cardiac mitochondrial dysfunction, resulting in improved left ventricular (LV) function in rats with TRZ-induced cardiotoxicity. Methods: Male Wistar rats (n=18) were divided into either TRZ group (4 mg/kg/day for 7 days, I.P., n=12) or control group (CON, n=6). In the TRZ group, rats also received one of the following co-treatments: 1) vehicle (VEH, n=6) or 2) Mdivi-1 (MDV, 1.2 mg/kg/day, n=6) via I.P. injection for 7 days. LV ejection fraction (LVEF) and cardiac mitochondrial function were determined. Results: TRZ-treated rats had impaired cardiac mitochondrial function as shown by increased reactive oxygen species (ROS) production, mitochondrial depolarization (reduced red/green fluorescence intensity), and mitochondrial swelling (reduced absorbance intensity), leading to LV dysfunction (75% LVEF for TRZ vs. 88% LVEF for CON) (Fig. 1A-D). Mdivi-1 co-treatment attenuated cardiac mitochondrial dysfunction and LV dysfunction as evidenced by a decrease in ROS, mitochondrial depolarization, mitochondrial swelling, and increased LVEF (83%, 11% improvement from VEH group) (Fig. 1A-D). Conclusions: Mdivi-1 effectively protected the heart against TRZ-induced cardiotoxicity by attenuating mitochondrial and LV dysfunction, thus indicating that pharmacological inhibition of mitochondrial fission could be a novel anti-cardiotoxicity in TRZ-induced cardiotoxicity.