Abstract 15900: Probing Mitochondrial Dysfunction in Mouse Hearts With Doxorubicin-Induced Cardiotoxicity Using Ungated 4D Oxy-Wavelet MRI

Abstract

Introduction: Despite advances in cancer therapy greatly improving patient survival, more than two-thirds of cancer survivors will still face serious life-threatening cardiomyopathy caused by anti-cancer anthracyclines. Doxorubicin (Dox), a well-known, well studied anthracycline, is a major cause for long-term morbidity and mortality among cancer survivors. Pertinent to this issue is the lack of non-invasive imaging tools that can detect DOX induced cardiomyopathy before irreversible tissue damage is done. Current research of cellular mechanisms underlying DOX-induced cardiotoxicity has shown that mitochondrial dysfunction are central to this cardiomyopathy. Hypothesis: We hypothesize that this mitochondrial dysfunction precedes clinical changes in cardiac strain and left-ventricle ejection fraction. Methods: To probe mitochondrial function non-invasively, we use motion-and-time resolved 4D functional MRI, coined 4D Oxy-Wavelet. Our methodology can capture dynamic changes in the blood oxygenation level dependent (BOLD) signal with high spatiotemporal resolution. Our cyclic hypoxia challenge leverages the need for in-tact mitochondrial function to maintain homeostatic oxygenation during hypoxia. We combine our 4D-fMRI methodology with a cyclic hypoxia challenge to stress-test the mitochondria in a mouse model of DOX-induced cardiotoxicity. We use a novel time-frequency analysis of the event-driven BOLD response to automate the detection of mitochondrial dysfunction in-vivo. Results: C57BL6/J were given Dox over the course of one week. 4D oxy-wavelet MRI was performed at baseline, day 1, 3, 4, and 7 to evaluate the ability to rapidly detect acute DOX induced cardiotoxicity. We found that as early as day one post exposure, mice exhibited a passive response to the hypoxia challenge, representing an inability to maintain homeostatic oxygen and underlying mitochondria dysfunction, that was maintained through this acute period.