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.

Animal Models for Radiotherapy Research: All (Animal) Models Are Wrong but Some Are Useful

“…Innovative preclinical models are being developed to assess responses across a range of normal tissue. For example, Schlaak et al [ 8 ] summarise current state-of-the-art preclinical models of radiation-induced cardiac toxicity, describing the progress in experimental irradiation techniques from whole thorax exposures to those using small animal IGRT. Using an interleukin-2 receptor gamma chain knockout (IL2RG −/− ) rat model of T- and B-cell deficiency with image-guided whole-heart exposures, the group investigated the role of acquired immunity radiation-induced heart dysfunction [ 9 ].…”

Montelukast protects H9c2 cardiomyocytes against radiation-induced toxicity

“…Animal models of whole thorax, whole heart, and partial heart irradiation have been established to study cardiac radiation toxicity in vivo [42]. Future use of animal models guided by advanced imaging technology will allow more accurate evaluation of the effect of montelukast on radiation-induced cardiotoxicity.…”

Acquired Immunity Is Not Essential for Radiation-Induced Heart Dysfunction but Exerts a Complex Impact on Injury

“…Additionally, echocardiogram parameters indicative of heart dysfunction were elevated LVIDd, LVIDs, ESV, and EDV, and decreased EF and FS ( Figure 5). The most common types of cardiac dysfunction seen in patients after cardiac RT exposure include pericarditis, pericardial and myocardial fibrosis, coronary artery disease, and/or conduction and valvular abnormalities [1,56]. Wang et al assessed the types of cardiac events in patients treated on dose-escalation trials for stage III non-small-cell lung cancer.…”