Author + information
- Received August 14, 2017
- Revision received February 6, 2018
- Accepted February 9, 2018
- Published online June 25, 2018.
- Nabil E. Boutagy, PhDa,∗,
- Jing Wu, PhDb,∗,
- Zhengxi Cai, PhDb,
- Wenjie Zhang, PhDb,c,
- Carmen J. Booth, DVM, PhDd,
- Tassos C. Kyriakides, PhDe,
- Daniel Pfau, BSa,
- Tim Mulnix, PhDb,
- Zhao Liu, PhDa,
- Edward J. Miller, MD, PhDa,
- Lawrence H. Young, MDa,
- Richard E. Carson, PhDb,
- Yiyun Huang, PhDb,
- Chi Liu, PhDb and
- Albert J. Sinusas, MDa,b,∗ ()
- aSection of Cardiovascular Medicine, Department of Medicine, Yale Translational Research Imaging Center, Yale School of Medicine, New Haven, Connecticut
- bDepartment of Radiology and Biomedical Imaging, Yale School of Medicine, New Haven, Connecticut
- cDepartment of Nuclear Medicine, West China Hospital of Sichuan University, Chengdu, China
- dSection of Comparative Medicine, Yale School of Medicine, New Haven, Connecticut
- eYale School of Public Health (Biostatistics), Yale School of Medicine, New Haven, Connecticut
- ↵∗Address for correspondence:
Dr. Albert J. Sinusas, Section of Cardiovascular Medicine, Yale University School of Medicine, P.O. Box 208017, Dana 3, New Haven, Connecticut 06520-8017.
• LVEF is used to detect doxorubicin-induced cardiotoxicity in patients, but this index is variable and has limited ability to detect early cardiotoxicity.
• Doxorubicin induces cardiotoxicity largely through the excessive production of ROS.
• We hypothesized that 18F-DHMT, a PET tracer that detects superoxide production, would provide an early index of cardiotoxicity in rodents.
• 18F-DHMT PET imaging was able to detect an elevation in cardiac superoxide production before a fall in LVEF.
• The early elevation in myocardial superoxide production was associated with only mild myocardial toxicity and occurred before cellular apoptosis or significant activation of MMPs; enzymes associated with myocardial remodeling.
• A drop in LVEF was associated with a significant increase in MMP activation, cellular apoptosis, and significant myocardial toxicity.
Reactive oxygen species (ROS) are involved in doxorubicin-induced cardiotoxicity. The authors investigated the efficacy of 18F-DHMT, a marker of ROS, for early detection of doxorubicin-induced cardiotoxicity in rats. Echocardiography was performed at baseline and 4, 6, and 8 weeks post-doxorubicin initiation, whereas in vivo superoxide production was measured at 4 and 6 weeks with 18F-DHMT positron emission tomography. Left ventricular ejection fraction (LVEF) was not significantly decreased until 6 weeks post-doxorubicin treatment, whereas myocardial superoxide production was significantly elevated at 4 weeks. 18F-DHMT imaging detected an elevation in cardiac superoxide production before a fall in LVEF in rodents and may allow for early cardiotoxicity detection in cancer patients.
↵∗ Drs. Boutagy and Wu contributed equally to this work.
This study was supported by National Institutes of Health grants R01HL123949 (Dr. C. Liu), R01HL113352 (Dr. Sinusas), T32HL098069 (Dr. Sinusas), and S01OD010322 (Dr. Carson). Dr Miller has received grant funding from Bracco, Inc. for FDG-PET examinations in cardiac sarcoidosis unrelated to the present study; and is a consultant for GE, Bracco, Inc., and Alnylam. Dr. Young has received research grant support, unrelated to this study, from Merck, Mifcor, and Novartis (to Yale University); and has as served as a consultant for Portage. Dr. C. Liu has had research contracts with GE Healthcare, Siemens Medical Solutions, and Philips Healthcare. Dr. Sinusas is a paid consultant and limited partner of MicroVide, LLC, which holds patents related to Tc99m-RP805 imaging in heart failure. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
All authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’ institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information, visit the JACC: Basic to Translational Science author instructions page.
- Received August 14, 2017.
- Revision received February 6, 2018.
- Accepted February 9, 2018.
- 2018 The Authors