Consequences of ionizing radiation exposure to the cardiovascular system

Abstract

Ionizing radiation is widely used in various industrial and medical applications, resulting in increased exposure for certain populations. Lessons from radiation accidents and occupational exposure have highlighted the cardiovascular and cerebrovascular risks associated with radiation exposure. In addition, radiation therapy for cancer has been linked to numerous cardiovascular complications, depending on the distribution of the dose by volume in the heart and other relevant target tissues in the circulatory system. The manifestation of symptoms is influenced by numerous factors, and distinct cardiac complications have previously been observed in different groups of patients with cancer undergoing radiation therapy. However, in contemporary radiation therapy, advances in treatment planning with conformal radiation delivery have markedly reduced the mean heart dose and volume of exposure, and these variables are therefore no longer sole surrogates for predicting the risk of specific types of heart disease. Nevertheless, certain cardiac substructures remain vulnerable to radiation exposure, necessitating close monitoring. In this Review, we provide a comprehensive overview of the consequences of radiation exposure on the cardiovascular system, drawing insights from various cohorts exposed to uniform, whole-body radiation or to partial-body irradiation, and identify potential risk modifiers in the development of radiation-associated cardiovascular disease.

Fig. 1 |. Adverse tissue effects of ionizing radiation exposure.

a, Ionizing radiation comprises electromagnetic radiation, including X-rays, γ-rays or high-energy α-particles or β-particles emitted from different sources. Ionizing radiation interacts with DNA and water, leading to DNA damage and oxidative stress, which together damage organelles and trigger various biological processes, such as protein lipid modification, lipid peroxidation, mitochondrial dysfunction and cell death. b, Early-onset health effects of ionizing radiation are caused by functional cell depletions in highly proliferative tissues in the digestive or haematopoietic system, which underlie acute radiation syndrome characterized by nausea, vomiting and myelosuppression. The late-onset health effects of ionizing radiation manifest across all organs and are characterized by structural or functional damage, accompanied by fibrosis, atrophy and vascular or neural damage. Non-targeted, bystander effects have a major role in the late-onset health effects of low-dose ionizing radiation exposure, emphasizing the active communication between irradiated and non-irradiated cells, which perpetuates the late-onset symptoms after irradiation. LET, linear energy transfer; mtDNA, mitochondrial DNA; RNS, reactive nitrogen species; ROS, reactive oxygen species; TGFβ, transforming growth factor-β; TNF, tumour necrosis factor.

Fig. 2 |. Total-body irradiation and radiation-associated cardiovascular disease.

Ionizing radiation can uniformly affect the cardiovascular system, whether administered via uniform external beam or emission from internal emitters. a, The relationship between radiation dose and disease risk can be linear or take on a linear–quadratic shape, depending on the disease end point considered and the dose calculation. Typically, the risk of radiation-associated cardiovascular disease (CVD) increases gradually and peaks at 10–20 years after radiation exposure. b, Estimating radiation-associated CVD risk is challenging owing to various contributing factors, including study designs (discrepant end points and length of follow-up), inconsistent or inaccurate dosimetry and variable biological effectiveness (dose rate or linear energy transfer (LET)) and background diseases rates among different cohorts. INWORKS, International Nuclear Workers Study; LSS, Life Span Study.

Fig. 3 |. Radiation exposure to the cardiovascular system via radiation therapy.

Partial-body irradiation to the thorax has been linked to cardiovascular complications, and patients with cancer undergoing radiation therapy have an increased risk of cardiovascular disease depending on the mean absorbed heart dose. a, 2D radiation therapy was associated with substantial radiation exposure to the heart. b, The adoption of 3D conformal radiation therapy reduced radiation exposure to the heart (mean heart dose (MHD)) in patients with breast cancer. c, Advanced modalities for radiation therapy (including intensity-modulated radiation therapy (IMRT) and volumetric-modulated arc therapy (VMAT)) minimize the radiation dose delivered to the surrounding tissue. d, Proton or charged particle beam therapy has a distinct Bragg peak to substantially reduce the dose deposition beyond the target site. LAD, left anterior descending coronary artery; NSCLC, non-small-cell lung cancer. Left-hand sides of panels a–d adapted from ref. , CC BY 4.0 (https://creativecommons.org/licenses/by/4.0/). Right-hand side of panel d adapted from ref. , Springer Nature Limited.

Fig. 4 |. Relevance of cardiac substructure exposure to cardiac complications.

Radiation-associated cardiovascular diseases (RACVDs) include complications affecting the coronary, valvular, conduction, pericardial and myocardial systems. Coronary complications arising from radiation exposure, particularly in the mid-distal region of the left anterior descending coronary vessels, include increased risk of coronary stenosis and myocardial infarction (MI). Irradiation of the mitral, aortic and tricuspid valves can lead to valvular complications after a latent period, whereas nodal exposure in the right atrium can cause conduction complications. Pericardial complications include pericardial effusion, which is strongly correlated with pericardial volume exposure, whereas myocardial complications often present without systolic dysfunction and are complicated by concomitant chemotherapy. AV, atrioventricular; AVN, atrioventricular node; HF, heart failure; IHD, ischaemic heart disease; MHD, mean heart dose; SAN, sinoatrial node.

Fig. 5 |. Precision medicine with induced pluripotent stem cell derivatives.

The primary goal of radiation oncology is to control tumours while minimizing normal tissue complications. a–c, Adverse tissue effects from ionizing radiation are determined by a narrow dose range per radiation delivery per fraction, and sensitivity to ionizing radiation varies among patients, in part owing to intrinsic risk modifiers. Future radiation therapy planning can potentially take into consideration patient-specific radiosensitivity levels to establish the optimal therapeutic index (the probability of cancer control minus the probability of normal tissue toxicity). d, The generation of isogenic specialized cells from induced pluripotent stem cells (iSPCs) might facilitate the rapid assessment of radiation risk by understanding how different genotypes respond differently to irradiation and to annotate variants that are associated with radiation toxicity. The adaptation of iPSC-based risk assessment might facilitate radiogenomics to determine the genetic basis of differential radiotoxicity by radiation therapy. CNS, central nervous system; eQTL, expression quantitative trait loci; SNP, single-nucleotide polymorphism.