Advances in Preclinical Research Models of Radiation-Induced Cardiac Toxicity

Abstract

Radiation therapy (RT) is an important component of cancer therapy, with >50% of cancer patients receiving RT. As the number of cancer survivors increases, the short- and long-term side effects of cancer therapy are of growing concern. Side effects of RT for thoracic tumors, notably cardiac and pulmonary toxicities, can cause morbidity and mortality in long-term cancer survivors. An understanding of the biological pathways and mechanisms involved in normal tissue toxicity from RT will improve future cancer treatments by reducing the risk of long-term side effects. Many of these mechanistic studies are performed in animal models of radiation exposure. In this area of research, the use of small animal image-guided RT with treatment planning systems that allow more accurate dose determination has the potential to revolutionize knowledge of clinically relevant tumor and normal tissue radiobiology. However, there are still a number of challenges to overcome to optimize such radiation delivery, including dose verification and calibration, determination of doses received by adjacent normal tissues that can affect outcomes, and motion management and identifying variation in doses due to animal heterogeneity. In addition, recent studies have begun to determine how animal strain and sex affect normal tissue radiation injuries. This review article discusses the known and potential benefits and caveats of newer technologies and methods used for small animal radiation delivery, as well as how the choice of animal models, including variables such as species, strain, and age, can alter the severity of cardiac radiation toxicities and impact their clinical relevance.

Keywords: cardiopulmonary toxicity; cardiotoxicity; image-guided radiotherapy; normal tissue toxicity; radiation biology; radiation-induced heart disease; small animal irradiators; thoracic radiation therapy.

Figure 1

Cardiac radiation exposure causes a number of abnormalities. Exposure of the heart and surrounding vasculature to radiation may lead to several adverse structural and functional changes in the heart, in this article collectively referred to as radiation-induced heart dysfunction.

Figure 2

Small animal irradiation techniques allow a wide variety of cardiac and pulmonary exposures and a number of delivery methods. Schematic illustrations of radiation field options that are commonly used to deliver cardiac radiation (top panel), and methods of radiation delivery (bottom panel) in small animal models of radiation-induced heart dysfunction (RIHD).