Differences in Radiation-Induced Cardiotoxicity Between Age-Matched Male and Female Rats Largely Due to Differences in Lung Doses

Abstract

Radiation therapy (RT) is used by over half of all cancer patients to improve cancer outcomes. However, RT doses can be limited due to risks of side effects, including radiation-induced heart dysfunction (RIHD). Risk factors for RIHD could include factors such as sex, genetic factors, and lung RT doses received. Here we demonstrate differences in male/female rat sensitivity to cardiac RT, but this difference seems to be in large part due to differences in lung doses received between age-matched male and female rats. Inbred Salt Sensitive (SS) rats aged 10-12 weeks received image-guided whole heart RT to 24 Gy to isocenter (AP:2 laterals). Echocardiograms (echos) were performed at baseline, 3, and 5 mo. Dose volume histograms (DVH) were used to determine heart and lung doses. Student’s t-test was used to compare echo values and survival curves were analyzed with Kaplan-Meier and log-rank test. Female SS rats exhibited enhanced cardiotoxicity compared to male SS rats treated with a 1.5 cm collimator. By 6 months post-RT, 5/11 female rats died from heart failure, while 2/16 male rats died (P<0.001). Moderate/large pericardial effusions were present in 6/9 SS female compared to 0/16 SS male rats at 3 mo, and 6/6 SS female compared to 2/16 SS male rats at 6 mo. Females had significantly larger amounts of pleural fluid at 6 mo (12.9 ml vs. 1.73 ml, P<0.001). Cardiac hypertrophy was only observed in females measured by normalized heart weight(P<0.5). At 3 and 6 mo post-RT, IVSd, LVIDd, LVPWd, and LVM echocardiogram parameters were significantly elevated in females vs. males (P<0.01). Female adult rats had ∼20% less lung volume than age-matched male rats. Thus, DVHs revealed female rats treated with a 1.5 cm collimator had significantly higher lung V5 and V20 than male rats (∼16% and ∼8% vs. ∼12% and ∼5%), with similar heart doses. Male rats treated with a 2.0 cm collimator had similar lung doses to female rats treated with the 1.5 cm collimator, and these male rats had similar mortality to female rats at 6 months (4/9, 44% vs. 5/11, 45%), as well as similar pericardial effusions and echocardiogram parameters. These results demonstrate that SS female rats exhibited greater sensitivity to image-guided cardiac RT compared to age-matched male rats treated with a 1.5 cm collimator, although volumes of lung receiving 5 and 20 Gy were much higher in female rats. Male rats treated with a 2.0 cm collimator had similar lung doses to the female rats treated with a 1.5 cm collimator, and had similar severity of RIHD as females treated with 1.5 cm collimator, as measured by mortality and echo parameters. This study adds to data suggesting the amount of lung tissue irradiated may be a predictor of morbidity and mortality in RIHD. This project has the potential to enhance the effectiveness and toxicity profile of RT.