Department of Radiation Oncology, Washington University School of Medicine, St Louis, MO, USA.
Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, WI, USA.
Int J Radiat Biol. 2023;99(7):1096-1108. doi: 10.1080/09553002.2023.2194404. Epub 2023 Apr 28.
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).
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.
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.
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.
放射治疗仍然是乳腺癌、肺癌和食管癌标准治疗的一部分。虽然放射治疗可以提高局部控制率和生存率，但放射性心脏功能障碍是胸部放射治疗的常见副作用。心血管功能障碍也可能由非治疗性全身辐射暴露引起。许多研究已经评估了心脏受照剂量与心脏毒性之间的关系，但对于放射诱导的心脏功能障碍（RIHD）是否存在基于生物性别差异的问题，人们知之甚少。
我们评估了 24Gy 单次全心脏照射（使用 1.5cm 射束大小的准直器）后，雄性和雌性近交 Dahl SS 大鼠是否表现出不同的 RIHD。我们还比较了 2.0cm 与 1.5cm 准直器在雄性中的差异。测量胸腔和心包积液以及校正后的心脏重量，并进行超声心动图检查。
与同龄 SS 雄性大鼠相比，雌性 SS 大鼠的 RIHD 更为严重。雌性的校正后心脏重量显著增加，但雄性没有。放射治疗完成后，94%（15/16）的雄性和 55%（6/11）的雌性大鼠存活 5 个月（<0.01）。在幸存的大鼠中，100%的雌性和 14%的雄性在 5 个月时发展为中重度心包积液。雌性大鼠胸腔积液增加，雌性和雄性的平均校正胸腔积液量分别为 56.6ml/kg±12.1 和 10.96ml/kg±6.4（=0.001）。超声心动图检查结果显示心力衰竭的证据，雌性大鼠更为明显。由于同龄雌性大鼠的肺较小，因此在使用相同射束大小的情况下，女性接受的总肺照射比例高于男性。在使用更大的 2cm 射束治疗雄性大鼠，导致肺部暴露增加后，在中重度心包积液或胸腔积液的发展方面，雄性和雌性之间没有显著差异。用 2cm 射束治疗雄性大鼠导致 LV 质量增加和每搏量减少，与用 1.5cm 射束治疗的雌性大鼠相似。
这些结果表明，SS 大鼠中存在雄性和雌性放射诱导的心脏毒性差异，并为除其他因素外，肺辐射剂量可能在心脏辐射暴露后心脏功能障碍中起重要作用的观点提供了更多的数据。这些因素可能对放射诱导性心脏毒性的未来缓解研究具有重要意义。
