Abstract 11203: Blood Metabolomes as Non-Invasive Biomarkers and Targets of Metabolic Interventions for Doxorubicin- and Trastuzumab-Induced Heart Failure

Abstract

Introduction: Cardiac metabolic impairment is a critical component of heart failure pathophysiology. However, our understanding on the blood metabolomics and their potential as non-invasive metabolic biomarkers in doxorubicin- and trastuzumab-induced heart failure remains limited. In this study, we identified the changes in blood metabolome levels as well as their associations with cardiac dysfunction and cardiac injury in rats with doxorubicin- and trastuzumab-induced cardiotoxicity. Methods: 8-week-old male Wistar rats were divided into 4 groups (n=6/group) to receive intraperitoneal injection with either 1) 3 mg/kg/day of normal saline solution (NSS) at days 0, 4, 8, 15, 22, and 29 (control group for doxorubicin), 2) 3 mg/kg/day of doxorubicin at days 0, 4, 8, 15, 22, and 29 (doxorubicin group), 3) 4 mg/kg/day of NSS at days 0-6 (control group for trastuzumab), and 4) 4 mg/kg/day of trastuzumab at days 0-6 (trastuzumab group). Four days after the last injected dose, cardiac function was evaluated. The rats were then sacrificed to collect blood and heart for the quantitation of 107 serum and 100 cardiac metabolome levels, respectively, using mass spectrometry-based targeted metabolomics. Results: Strong relationships between 72 and 61 cardiac versus serum metabolomes were found in doxorubicin and trastuzumab groups, respectively. Correlations between cardiac function and cardiac injury versus 28 and 58 serum metabolomes were also shown in doxorubicin and trastuzumab groups, respectively. Importantly, patterns of metabolome change were different between doxorubicin and trastuzumab groups (Figure). Conclusions: Our findings highlight the potential role of blood metabolomes as non-invasive biomarkers to assess the severity and prognosis of doxorubicin- and trastuzumab-induced heart failure. These findings could lead to the development of metabolic targeted therapy specific for the cardioprotection during different phases of cancer treatment.