Abstract 18141: 3-Dimensional Light-Sheet Fluorescent Microscopy and High-Frequency Ultrasonic Transducers to Characterize Doxorubicin-Induced Cardiac Injury and Regeneration
Introduction: Anthracyclines such as doxorubicin are a cornerstone of chemotherapeutic strategies in various cancers such as breast cancer, lymphoma, sarcoma and pediatric leukemia. Their widespread use, however, is currently limited by anthracycline-induced cardiotoxicity.
Hypothesis: We propose to incorporate light-sheet fluorescent microscopy and pulsed-wave Doppler ultrasound to unravel the 3D architecture and electromechanical coupling of doxorubicin-induced cardiac injury and regeneration in the adult zebrafish model.
Methods and Results: 3-month old zebrafish were injected intraperitoneally with doxorubicin at 20 μg/g of body weight followed by imaging at 3, 30, and 60 days post-injection. We observed an initial decrease in myocardial and endocardial cavity volume at day 3, followed by ventricular remodeling and hypertrabeculation at day 30, and normalization at day 60 (P<0.05 vs. control, n=5). Doxorubicin-injected fish developed ventricular diastolic dysfunction as evidenced by elevated E/A ratios at day 30, normalizing at day 60 (P<0.05 vs. control, n=11-20). Myocardial performance indexes were also elevated at day 30 in the doxorubicin group, indicating worsening of global cardiac function, followed by normalization at day 60 (P<0.05 vs. control, n=9-19). qRT-PCR to investigate the pathways involved in the cardiac injury and regeneration process revealed up-regulation of Notch signaling genes, particularly the ligand Jagged1 and target gene HEY2 at days 30 and 60 (P<0.05 vs. control, n=5). Treatment with the γ-secretase inhibitor DAPT to inhibit Notch signaling attenuated restoration of ventricular function, as demonstrated by persistence of abnormal E/A ratios and myocardial performance indexes at day 60 (P<0.05, n=7-12), thereby implicating Notch pathways in the cardiac regeneration process.
Conclusions: Our results suggest that doxorubicin-induced cardiac injury leads to ventricular remodeling, followed by activation of Notch signaling to promote endocardial hypertrabeculation and restoration of cardiac function.
Author Disclosures: R.R. Packard: None. T. Beebe: None. P. Fei: None. B. Kang: None. Y. Ding: None. N. Jen: None. J. Ma: None. P. Chen: None. J. Tang: None. H. Yen: None. J. Gau: None. Y. Shih: None. Y. Ding: None. K. Shung: None. X. Xu: None. T. Hsiai: None.
- © 2016 by American Heart Association, Inc.