Author + information
- Zachary M. Gertz, MDa,
- Chad Cain, BSa,
- Donatas Kraskauskas, DVMa,
- Teja Devarakonda, BSa,
- Adolfo G. Mauro, PhDa,
- Jeremy Thompson, BSa,
- Arun Samidurai, PhDa,
- Qun Chen, PhDa,
- Sarah W. Gordon, DOb,
- Edward J. Lesnefsky, MDa,b,c,
- Anindita Das, PhDa and
- Fadi N. Salloum, PhDa,∗ (, )@SALLOUMFN@VCUHealth
- aPauley Heart Center, Department of Internal Medicine, Division of Cardiology, Virginia Commonwealth University, Richmond, Virginia
- bMassey Cancer Center, Virginia Commonwealth University, Richmond, Virginia
- cMedical Service, McGuire VA Medical Center, Richmond, Virginia
- ↵∗Address for correspondence:
Dr. Fadi N. Salloum, Virginia Commonwealth University, Division of Cardiology, Box 980204, 1101 East Marshall Street, Room 7-070, Richmond, Virginia 23298.
Objectives Because of its multifaceted cardioprotective effects, remote ischemic pre-conditioning (RIPC) was examined as a strategy to attenuate doxorubicin (DOX) cardiotoxicity.
Background The use of DOX is limited by dose-dependent cardiotoxicity and heart failure. Oxidative stress, mitochondrial dysfunction, inflammation, and autophagy modulation have been proposed as mediators of DOX cardiotoxicity.
Methods After baseline echocardiography, adult male CD1 mice were randomized to either sham or RIPC protocol (3 cycles of 5 min femoral artery occlusion followed by 5 min reperfusion) 1 h before receiving DOX (20 mg/kg, intraperitoneal). The mice were observed primarily for survival over 85 days (86 mice). An additional cohort of 50 mice was randomized to either sham or RIPC 1 h before DOX treatment and was followed for 25 days, at which time cardiac fibrosis, apoptosis, and mitochondrial oxidative phosphorylation were assessed, as well as the expression profiles of apoptosis and autophagy markers.
Results Survival was significantly improved in the RIPC cohort compared with the sham cohort (p = 0.007). DOX-induced cardiac fibrosis and apoptosis were significantly attenuated with RIPC compared with sham (p < 0.05 and p < 0.001, respectively). Although no mitochondrial dysfunction was detected at 25 days, there was a significant increase in autophagy markers with DOX that was attenuated with RIPC. Moreover, DOX caused a 49% decline in cardiac BCL2/BAX expression, which was restored with RIPC (p < 0.05 vs. DOX). DOX also resulted in a 17% reduction in left ventricular mass at 25 days, which was prevented with RIPC (p < 0.01), despite the lack of significant changes in left ventricular ejection fraction.
Conclusions Our preclinical results suggested that RIPC before DOX administration might be a promising approach for attenuating DOX cardiotoxicity.
Dr. Gertz was supported by the Virginia Commonwealth University Department of Internal Medicine Pilot Grant Award. Dr. Lesnesfsky was supported by the Office of Research and Development, Medical Research Service Merit Review Award (2IO1BX001355-01A2). Dr. Salloum was supported by the National Institutes of Health (R01HL133167 and R01HL142281). All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Received July 3, 2019.
- Revision received October 29, 2019.
- Accepted November 4, 2019.
- 2019 The Authors