Differences in Radiation-induced Heart Dysfunction in Male Versus Female Rats

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 ( < .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 ( = .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.