https://orcid.org/0000-0001-6657-331X
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Abstract
Purpose
Radiation therapy remains part of the standard of care for breast, lung, and esophageal cancers. While radiotherapy improves local control and survival, radiation-induced heart dysfunction is a common side effect of thoracic radiotherapy. Cardiovascular dysfunction can also result from non-therapeutic total body radiation exposures. Numerous studies have evaluated the relationship between radiation dose to the heart and cardiotoxicity, but relatively little is known about whether there are differences based on biological sex in radiation-induced heart dysfunction (RIHD).
Materials and Methods
We evaluated whether male and female inbred Dahl SS rats display differences in RIHD following delivery of 24 Gy in a single fraction to the whole heart using a 1.5 cm beam size (collimater). We also compared the 2.0 cm vs. 1.5 cm collimator in males. Pleural and pericardial effusions and normalized heart weights were measured, and echocardiograms were performed.
Results
Female SS rats displayed more severe RIHD relative to age-matched SS male rats. Normalized heart weight was significantly increased in females, but not in males. A total of 94% (15/16) of males and 55% (6/11) of females survived 5 months after completion of radiotherapy (p < .01). Among surviving rats, 100% of females and 14% of males developed moderate-to-severe pericardial effusions at 5 months. Females demonstrated increased pleural effusions, with the mean normalized pleural fluid volume for females and males being 56.6 mL/kg ± 12.1 and 10.96 mL/kg ± 6.4 in males (p = .001), respectively. Echocardiogram findings showed evidence of heart failure, which was more pronounced in females. Because age-matched female rats have smaller lungs, a higher percentage of the total lung was treated with radiation in females than males using the same beam size. After using a larger 2 cm beam in males which results in higher lung exposure, there was not a significant difference between males and females in terms of the development of moderate-to-severe pericardial effusions or pleural effusions. Treatment of males with a 2 cm beam resulted in comparable increases in LV mass and reductions in stroke volume to female rats treated with a 1.5 cm beam.
Conclusion
Together, these results illustrate that there are differences in radiation-induced cardiotoxicity between male and female SS rats and add to the data that lung radiation doses, in addition to other factors, may play an important role in cardiac dysfunction following heart radiation exposure. These factors may be important to factor into future mitigation studies of radiation-induced cardiotoxicity.
Author contributions
R.A.S., C.B, A.F., and M.J.F. conceived and designed the research. R.A.S., A.F., B.L.F., T.G., J.P., and A.M.S. performed the experiments. R.A.S., C.B., A.F., A.M.S., N.A., A.R.S., C.L., and C.M. analyzed the data. R.A.S., A.F., A.M.S., L.N.P., M.J.F., A.J., and C.B. interpreted results of the experiments. N.A., L.P., A.J., R.A.S., A.F., A.M.S., and C.B. drafted and edited the manuscript.
Manuscript contribution to the field
Radiation therapy remains part of the standard of care for many types of thoracic cancers. While radiotherapy can improve local control and survival, radiation-induced heart dysfunction is a common side effect of thoracic radiotherapy. Numerous studies have evaluated the relationship between radiation dose to the heart and cardiotoxicity, but relatively little is known about whether there are biologic sex-related differences in radiation-induced heart dysfunction. Our results suggest that animal sex influences at least some of the changes associated with RIHD, but that the proportion of the lung receiving radiation in preclinical models, which can be different in male and female rats for a given collimator size centered on the heart, can also influence cardiac toxicity.
Disclosure statement
The authors declare no relevant conflicts of interest. M.J.F. currently is a Principal Research Scientist at Abbvie, but at the time of his contributions to the manuscript, he was employed at the Medical College of Wisconsin.
Additional information
Funding
Notes on contributors
Neal Andruska
Neal Andruska, MD, PhD, is a radiation oncologist at Northwestern Medicine Cancer Center Warrenville and Proton Center in Warrenville, IL. At the time of his work on this paper he was a resident in the Department of Radiation Oncology at Washington University School of Medicine, St. Louis, MO.
Rachel A. Schlaak
Rachel A. Schlaak, PhD, is a Technical Writer at Medtronic in Minneapolis, MN. At the time of her work on this paper she was a graduate student in the Department of Pharmacology and Toxicology at the Medical College of Wisconsin in Milwaukee, WI.
Anne Frei
Anne Frei, BS, is a research program coordinator III in the Department of Radiation Oncology at the Medical College of Wisconsin in Milwaukee, WI.
Aronne M. Schottstaedt
Aronne M. Schottstaedt, MD, is a resident in radiation oncology at the Medical College of Wisconsin in Milwaukee, WI.
Chieh-Yu Lin
Chieh-Yu Lin, MD, PhD, is an Associate Professor in Pathology and Immunology at Washington University School of Medicine, St. Louis, MO. She specializes in cardiothoracic, breast and molecular pathology with research interests in inflammatory cardiovascular diseases and thoracic transplant pathology.
Brian L. Fish
Brian L. Fish, is a normal tissue radiation biologist working with WAG/RijCmcr rats for the past 4 decades. He is a Program Director in Radiation Oncology at the Medical College of Wisconsin in Milwaukee, WI. He specializes in the delayed effects of radiation injury to normal tissues and mitigation of DEARE.
Tracy Gasperetti
Tracy Gasperetti, BS, is the Laboratory Manager of the Radiation Biology lab in the Department of Radiation Oncology at the Medical College of Wisconsin in Milwaukee, WI.
Cedric Mpoy
Cedric Mpoy, MS, is the Founding Executive Director of Optimixt in St. Louis, MO. At the time of his work on this paper he was a Lab Manager in the Department of Radiation Oncology at Washington University School of Medicine, St. Louis, MO.
Jamie L. Pipke
Jamie L. Pipke, BS, is a Research Program Coordinator for the Tissue Bank at the Medical College of Wisconsin in Milwaukee, WI.
Lauren N. Pedersen
Lauren N. Pedersen, PhD is a post-doctoral fellow in the Department of Radiation Oncology at Washington University School of Medicine, St. Louis, MO.
Michael J. Flister
Michael J. Flister, PhD is Director of Therapeutic Discovery Research at Seagen. At the time of his work on this paper he was an Assistant Professor of Physiology at the Medical College of Wisconsin, Milwaukee, WI.
Ali Javaheri
Ali Javaheri, MD, PhD, is an Assistant Professor in the Department of Medicine Division of Cardiology and an Investigator in the Center for Cardiovascular Research at Washington University School of Medicine, St. Louis, MO. He sees patients as a heart failure transplant cardiologist, and he also runs a translational cardiac research laboratory studying the role of lipid metabolism and autophagy in cardiac structure, function, and remodeling.
Carmen Bergom
Carmen Bergom, MD, PhD, is an Associate Professor in the Department of Radiation Oncology and a member of the Alvin J. Siteman Cancer Center at Washington University School of Medicine, St. Louis, MO. She cares for cancer patients clinically, and she also runs a translational laboratory using pre-clinical models to improve the prevention, diagnosis, and treatment of radiation-induced heart dysfunction.