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.

Introduction

Ionizing radiation contains quanta with enough energy to displace electrons and break chemical bonds and includes electromagnetic radiation, such as X-rays and γ-rays, or high-energy α-particles and β-particles emitted from nuclear decay. Ionizing radiation has been used in various industrial and medical practices, with X-rays in particular having revolutionized the diagnosis and treatment of localized cancer¹. When traversing tissue, ionizing radiation either directly interacts with DNA molecules by displacing electrons, which leads to ionization, or acts indirectly by transferring part of its energy to one of the electrons in a molecule that it traverses, which in turn ionizes the surrounding molecules, such as DNA. Given the high water content in cells, this ionization induces the production of reactive oxygen species or reactive nitrogen species, triggering various biological effects that result in DNA damage, protein or lipid modifications, and damage to the organelles² (Fig. 1a). Incomplete clearance of radiation-damaged cells can lead to adverse cellular responses, including apoptosis and other non-apoptotic forms of cell death (such as necrosis or necroptosis, autophagy-dependent cell death and ferroptosis) and cell inactivation (including mitotic catastrophe and senescence)³. The overall effect of radiation damage on cell survival is not always linearly associated with the absorbed dose, and heterogeneous radiosensitivities across different cell types have been reported (Box 1).

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.

Box 1 | Cellular radiosensitivity: the α/β ratio.

The α/β ratio is a marker of the varying biological responses to radiation: cells with higher α values have a greater propensity for immediate cell death upon irradiation, whereas cells with higher β values have a propensity for delayed biological outcome upon irradiation. The α/β ratio is the ratio of the linear-to-quadratic components in the linear–quadratic (LQ) model of the biological effects on certain tissues (given by C + αD + βD²). In the linear–quadratic model, the linear component αD corresponds to the direct, single radiation track induction of sublethal damage, whereas the quadratic βD² term corresponds to multitrack effects (see the figure, panel a). Although this concept is formulated at the cellular level, it can also be applied at the tissue level. Organs with high α/β ratios, such as those in the reproductive, haematopoietic or intestinal systems, have increased radiosensitivity and thus respond acutely to irradiation (see the figure, panel b). By contrast, in tissues with low α/β ratios (<4 Gy), such as the heart, lung and spinal cord, the biological effects (such as fibrosis and inflammation) have a more complex profile and occur after a much longer period after radiation exposure. Early cardiac irradiation experiments on animal models reported adverse cardiac remodelling with marked histological changes at 6 months after exposure, with estimated α/β ratios ranging from 2.5 Gy to 3.7 Gy (refs. 229–231). However, subsequent data indicate that the heart is actually highly sensitive to irradiation, particularly the electrophysiological functions of the heart^{112,122,164,165}. LET, linear energy transfer. Adapted from ref. 232, Springer Nature Limited.

Determining the health implications of ionizing radiation at the organ level is challenging. Historically, the biological effects of ionizing radiation were classified as either stochastic or tissue reaction effects (previously known as deterministic effects)^4,5. Stochastic effects include cancer or heritable effects owing to acquired mutations in somatic or reproductive cells⁵. Tissue reactions encompass various degenerative or adverse tissue remodelling effects occurring after radiation exposure, which generally transpire only above a certain threshold dose, and with the severity of the effect increasing with dose (Fig. 1b). Tissue reactions were thought to be primarily caused by the depletion of functional parenchymal cells targeted by ionizing radiation, which is true in highly proliferative tissues, such as those in the haematopoietic, spermatogenic and digestive systems. These organ systems are often affected in patients with acute radiation syndrome, which is characterized by nausea, vomiting and myelosuppression, and occurs on a timescale of minutes to hours up to several months after whole-body or substantial partial-body exposure of >1 Gy (ref. 6). Conversely, chronic radiation syndrome develops over a timescale of months to years after an annual whole-body fractionated radiation exposure of >0.7 Gy and is characterized by structural and functional organ impairment accompanied by fibrosis, atrophy and vascular or neural damage^6,7.

Numerous signalling mechanisms, and specifically non-targeted or radiation-induced bystander effects, are likely to have important roles in late-onset chronic radiation syndrome⁷. Bystander effects are biological responses to ionizing radiation observed in non-irradiated cells owing to communication with irradiated cells through gap junctions or via soluble factors⁸. Irradiation at sublethal doses results in epigenetic and metabolic remodelling that leads to senescence associated secretory phenotypes^9,10. Soluble factors include reactive oxygen species or reactive nitrogen species, cytokines, growth factors, chemokines and exosomes from proximal or distal cells (Fig. 1b); these mechanisms have been discussed previously¹¹. Bystander effects can be induced at very low doses, but the magnitude of the effects does not always correlate with radiation dose, highlighting their importance in the long-term health complications associated with ionizing radiation exposure <0.5 Gy (ref. 9).

Emerging evidence indicates that late-onset cardiovascular disease (CVD) and cataract also occur after protracted low-dose ionizing radiation exposure at doses >0.5 Gy (refs. 12,13). In 2012, the International Commission on Radiological Protection acknowledged CVD as a tissue reaction effect⁶. Radiation-associated CVD (RACVD) is a multifaceted syndrome with varying magnitudes of dose and response for different subtypes of CVD. In this Review, we discuss the risks associated with radiation exposure to the cardiovascular system and describe the various types of exposure that have been associated with CVD, their clinical relevance and possible modifying risk factors.

Cardiovascular effects of uniform, whole-body irradiation

Radiation dose is expressed in absorbed dose (the amount of energy that radioactive sources deposit in materials) in grays; 1 Gy is equivalent to 1 J deposited per kilogram of mass. In terms of radiation effects, radiation is expressed as effective dose in sieverts, which accounts for radiation quality and tissue weighting factors to adjust for differences in biological effectiveness of radiation exposure. RACVDs are generally late-onset conditions associated with excess morbidity and mortality in various irradiated populations¹⁴ (Fig. 2a).

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.

Atomic bomb survivors

The Life Span Study¹⁵ (LSS) involved a cohort of ~120,000 survivors of the atomic bombings in Japan, who were prospectively followed up for >60 years from October 1950 to assess the long-term health risks of whole-body radiation exposure. This cohort included individuals who received uniform, whole-body doses ranging from 0 Gy to 4 Gy (predominantly γ-rays, with a small fraction of neutron radiation). A mortality report from the follow-up period 1950–2003 documented an excess relative risk (ERR) per gray of 0.09 (95% CI 0.01–0.17, P = 0.02) for cerebrovascular disease (CeVD) (indicating a 9% increase in mortality per 1 Gy increase) and an ERR/Gy of 0.14 (95% CI 0.05–0.23, P < 0.001) for heart disease¹⁵. The dose–response association became significant for exposures >2 Gy for CeVD and >0.5 Gy for heart disease¹⁵. In a subsequent mortality report that included patient follow-up data up to 2008, specific heart disease subtypes were assessed¹⁶. A significant ERR/Gy of 0.45 (95% CI 0.13–0.85) was documented for valvular heart disease (VHD), 0.36 (95% CI 0.10–0.68) for hypertensive organ damage and 0.21 (95% CI 0.07–0.37) for heart failure (HF). Of note, the ERR/Gy for ischaemic heart disease (IHD) was not significant¹⁶.

Occupational and environmental exposures

Nuclear and medical workers can be subject to moderate to high cumulative doses of radiation (sometimes receiving >1 Gy, but often much less), via highly fractionated low-dose rate exposure. The health risks of occupational exposure are of particular concern for workers who were employed in the mid-twentieth century, when the cumulative doses were generally much higher than those in the modern workforce¹⁷. For example, workers at the Mayak Production Association, the first and largest nuclear materials production complex in Russia, received a high cumulative dose both from external γ-rays (mean cumulative external dose ~0.5 Gy) and from α-particles from plutonium (mean cumulative liver dose ~0.3 Gy), particularly in the early period of plant operations (late 1940s to 1950s)^18–23. After 70 years of follow-up, significant associations were identified between radiation dose and morbidity or mortality related to hypertension²⁴, IHD²⁰, CeVD^18,22 and lower-extremity arterial disease²¹. Unlike the LSS cohort of survivors of the atomic bombings, the contribution of internal exposure from plutonium was high in the Mayak cohort, and this exposure contributed independently (via α-radiation) to the increased risk of CVD^18,20. Similarly, significant associations between radiation exposure and morbidity or mortality related to CVD and CeVD were identified in clean-up workers at the site of the Chernobyl power plant^25–27 and in residents living near to the Techa River, which had been contaminated with radioactive waste from the Mayak nuclear complex²⁸ (Table 1). However, not all occupational or environmental radiation exposure has been linked with an increase in the incidence of, or death from, CVD or CeVD^12,29–35. This discrepancy might be a reflection of the complexity of RACVD manifestations at low-dose ionizing radiation exposure, although low statistical power is another probable explanation for the absence of detectable risk in some groups.

Table 1 |.

Cohorts of individuals exposed to whole-body irradiation with radiation-associated cardiovascular disease

Cohort	Classification (mode of exposure)	Maximum follow-up duration (years)	Mean dose (range) (Gy or Sv)	Dosimetry	Radiation type	Link with CVD or CeVD incidence or mortality	Risk factors used in analysis
Japanese atomic bomb survivors15,16	Irradiation from atomic bomb (acute)	58	0.1 (0–4)	Colon	γ-Ray, neutron	Incidence: HTN, CeVD Mortality: all CVD, CeVD, HOD, HF, VHD	Smoking, HTN, obesity, diabetes mellitus, alcohol intake, education level, SES, city of residence
Mayak workers18–23	Occupational exposure (protracted)	70	0.51 (0 to >4.5)	Colon and liver, in part via film badge and assessment of internal dose	γ-Ray (external), α-particles (internal)	Incidence: HTN, IHD, CeVD, lower-extremity arterial disease Mortality: all CVD, IHD	Smoking, BMI, HTN, alcohol intake, diabetes
Chernobyl emergency clean-up workers25–27	Occupational exposure (protracted)	30	Russia: 0.11 (0–1.99); Ukraine: 1.15–0.25 (0–1.99)	Film badge and group assigned	γ-Ray (external)	Incidence: all CVD, HTN, IHD, CeVD Mortality: all CVD	Ukraine: smoking, diabetes, alcohol intake, cholesterol levels (LDL and total), HTN, concomitant disease
Techa River residents28	Environmental exposure (protracted)	65	0.034 (0–0.995)	Muscle	γ-Ray (external), 137Cs, 89,90Sr (internal)	Mortality: all CVD, IHD	Ethnicity, settlement status
IARC36 and INWORKS37 nuclear workers	Occupational exposure (protracted)	36 (France), 46 (UK), 62 (USA)	IARC: 0.02 (0–1.5); INWORKS: 0.03 (0–1.9)	Colon (IARC), Hp10 (INWORKS), in both cases via film badge	High-energy photons (100–3,000 keV)	Mortality: all CVD, IHD, AMI, CeVD	Employee, SES

AMI, acute myocardial infarction; CeVD, cerebrovascular disease; CVD, cardiovascular disease; HF, heart failure; HOD, hypertensive organ damage; HTN, hypertension; IARC, International Agency for Research on Cancer; IHD, ischaemic heart disease; INWORKS, International Nuclear Workers Study; SES, socioeconomic status; VHD, valvular heart disease.

The International Agency for Research on Cancer (IARC) conducted a study involving nuclear industry workers from 15 countries and found weak evidence of an increased risk of death related to CVD and CeVD and negative trends for IHD and other cardiac end points³⁶. The International Nuclear Workers Study³⁷ (INWORKS) was undertaken to follow up on the three largest national workforces in the IARC study (France, UK and USA) and found that occupational radiation exposure was significantly associated with mortality from CVD (ERR/Sv = 0.22, 90% CI 0.08–0.37), IHD (ERR/Sv = 0.180, 90% CI 0.004–0.360), acute myocardial infarction (AMI) (ERR/Sv = 0.26, 90% CI 0.03–0.51) and CeVD (ERR/Sv = 0.50, 90% CI 0.12–0.94). The exposures in these cohorts were accumulated at uniformly low dose rates, with low cumulative doses (mean 25.2 mSv, ranging from 0 Sv to 1.9 Sv)³⁷. Both INWORKS and the IARC study^38,39 conducted extensive analyses to adjust for dose errors; most analyses minimized the effect of these errors by focusing on radiation dose measured from external beams of high-energy photons (100–3,000 keV) and excluding individuals with substantial exposure to alternative radiation types, such as neutrons or internal emitters^38,39. The results of these studies raise concerns about possible risks associated with low-dose occupational exposure to ionizing radiation, such as in medical workers performing cardiac catheterization procedures who receive protracted ionizing radiation from X-ray equipment⁴⁰. The magnitude of dose varies depending on the type of the procedure performed, but a median annual dose of 5 mSv and a lifetime exposure of 50–200 mSv have been reported in workers in a cardiac catheterization laboratory⁴¹. Furthermore, blood samples from these workers show evidence of genotoxicity or altered redox status^30,42,43, and one study reported a substantial increase in risk factors for CVD (including hypertension and hypercholesterolaemia)⁴¹. Exposure to low-dose ionizing radiation can induce both immediate and long-lasting adverse effects, regardless of the dose received, and two systematic reviews reported a linear trend in morbidity or mortality related to CVD or CeVD across various cohorts exposed to occupational or environmental radiation^12,44. Of note, one systematic review reported substantial interstudy heterogeneity (Fig. 2b), possibly resulting from lifestyle and medical factors known to modify the risk of CVD¹² (Table 1). This heterogeneity was reduced if only higher-quality studies or those with moderate or low dose rates were considered.

Sources of interstudy heterogeneity

Delivery time.

Generalizing RACVD risk estimates derived from the LSS cohort to other populations is challenging, given that the types of exposure between these cohorts might be very different. The atomic bomb survivors in the LSS cohort (single acute exposure, mean dose 0.1 Gy (range 0–4 Gy)) and the Mayak workers (chronic exposure, mean dose ~0.51 Sv (range 0 to >4.5 Sv)) both differ from the INWORKS occupational exposure cohort, who experienced chronic low-dose exposures over a working lifetime. However, the ERR/Gy values in these three groups are similar, at least within a factor of two. One possibility is that the dose rate effect for CVD might be influenced by the delivery time of radiation, which can influence the biological response and potentially mitigate the lethality of the radiation dose. A notable result from the aforementioned systematic review was the increase in ERR/Gy by a factor of approximately two when the radiation dose was delivered in a fractionated manner rather than in an acute manner¹². Furthermore, a fourfold increase in ERR/Gy was observed when the maximum dose received was reduced from >5 Gy to <0.5 Gy (ref. 12). Intriguingly, a steeper dose–response slope for various types of circulatory diseases was observed in patients with tuberculosis who had been exposed to a fractionated fluoroscopic X-ray dose of <0.5 Gy (ref. 45). Consistent with this finding, inflammatory markers and adhesion molecules were found to be upregulated in humans and in experimental animals after exposure to moderate-to-high doses of radiation (0.5–5.0 Gy)^46–49. However, after low or low-to-moderate exposures of <0.5 Gy, the balance shifts towards anti-inflammatory effects⁴⁸. Radiobiological experiments in animals that assessed the effects of acute and chronic radiation exposure have demonstrated an upregulation in proteomic markers and atherosclerotic lesion development that showed marked non-linearity in dose–response^50,51.

Organ dosimetry.

Various measures of organ dose have been used to estimate the risks of CVD associated with radiation exposure. The LSS^15,16 and IARC study³⁶ used colon dose, the Mayak analysis⁵² used external γ-ray dose and the INWORKS cohort³⁷ used personal dose equivalent (Hp(10)), which was measured using a tissue-equivalent film badge worn at the surface of the body. No consensus exists on the most appropriate target organ that should be used to estimate the dose from internal emitters received by certain occupational groups^18,52 (Box 2).

Box 2 | Internal emitters.

Internal emitters result from the introduction of radioactive substances into the body that can emit ionizing radiation from within various tissues. The dosimetry is determined from the administered radioactivity (in becquerels) and converted into absorbed, equivalent or effective dose by multiplying dose coefficients for absorbed organ dose per unit of administered radioactivity. The organ dose resulting from an internal emitter depends on the properties of the radionuclide, pharmacokinetics, residence time, organ radiosensitivity, administration route and patientspecific factors. Findings from certain cohorts with occupational exposure to radiation (such as the Mayak workers) strongly suggest a substantial contribution of internal emitters to cardiovascular risk, independent of the externally received dose. However, a clear association between internal emitters and cardiovascular disease has not been reported elsewhere. Certain internal emitters accumulate in the kidney, and the radiation-associated nephrotoxicity might lead to cardiovascular morbidity through hypertension and systemic inflammation^233,234. The liver is another potentially relevant site, given its role in cholesterol metabolism. Therefore, cardiovascular risks from internal emitters cannot be discounted.

Linear energy transfer.

The radiation weighting factor that is generally used to estimate cancer risk is determined by linear energy transfer (LET), a measure of the energy density deposited along the radiation track. LET values typically vary from ~1 keV/μm for X-rays and γ-rays to ~10 keV/μm for protons, ~10–100 keV/μm for carbon ions and >100 keV/μm for heavier charged particles. Radiation with increased LET more readily ionizes along its tracks and generates more complex and clustered double-strand breaks⁵³, which might underlie the greater efficacy in tumour control. Charged-particle therapy has been adopted clinically partly for this reason⁵⁴. However, high-LET radiation can also damage normal tissue, and the weighting factor related to the risk of CVD that should be applied to the relevant dose in the target organ is unknown. Several experimental animal studies have assessed the changes in cardiac structure and diastolic function that are associated with high-energy heavy ion exposure at levels that are broadly consistent (using unweighted dose) with those resulting from the same doses of external γ-rays^55,56.

Follow-up duration.

Evidence from numerous cohorts has demonstrated an increasing relative risk of radiation-associated CVD with increasing time after exposure^44,57. A systematic review reported that the increase in IHD-related mortality became significant in individuals with chronic occupational exposure to low-dose ionizing radiation after a latency period of ≥10 years (ref. 44). These findings mirror results from a study assessing individuals who experienced environmental radiation exposure, in whom CVD and IHD mortality became significantly associated with radiation dose after a lag time of ≥15 years, but not for a lag time of ≤10 years (ref. 28). However, in the Mayak cohort, only weak indications of changes in CVD and CeVD mortality and IHD morbidity or mortality were observed, with a latency period of up to 30 years (refs. 18,23). Of note, for the incidence of CeVD, there were stronger indications of increasing ERR with increasing latency¹⁸. Although changes in risk with varying lag times were minimal, a meta-analysis documented stronger trends for increased IHD mortality in subgroups with exposures that had a lag time of 10–20 years (ref. 44), suggesting that differences in exposure duration or latency among cohorts might contribute to variation in the relative risk of radiation-associated CVD.

Background disease rate.

A mortality analysis of the Japanese LSS cohort during 1950–2008 reported no elevated risk of IHD-related death¹⁶. However, when interpreting this finding, we need to bear in mind the relatively greater role of hypertension and the lesser role of elevated cholesterol levels as a cause of CVD or CeVD in the Japanese population compared with the Western population⁵⁷. Occupational studies³⁷, particularly older studies of national workforces³⁶, tend not to include data on lifestyle factors (and often include only surrogates, for example, socioeconomic status, assessed via job title or level of education). However, several subsequent and smaller cohort studies^12,23,58 have included data on major lifestyle and clinical risk factors for CVD, in particular blood pressure levels, smoking status, concomitant diabetes mellitus and body mass index, all of which are known to independently modify the risk of CVD or CeVD⁵⁹. Although adjusting for non-radiation risk factors has not consistently affected the significant association between radiation and the incidence of CVD in many studies¹², the interaction between total-body irradiation and these risk factors remains unclear.

Cardiovascular effects of partial-body irradiation: radiation therapy

Ionizing radiation is widely used for diagnostic imaging and radiation therapy, which often exposes the thorax, and sometimes the heart, to radiation (Fig. 3). For diagnostic imaging, the radiation dose varies depending on the imaging procedures (X-rays <0.5 mSv; coronary CT angiography ~20 mSv)⁶⁰. Overall, no changes in the risk of CVD have been found with diagnostic imaging^12,57, although there are indications of excess risks for individuals receiving fluoroscopy as a part of tuberculosis diagnosis⁴⁵. Repeated diagnostic imaging can easily result in patients accumulating an effective radiation dose of >100 mSv, necessitating additional precautions to prevent potential health risks⁶¹. Radiation therapy-associated CVDs have been observed in numerous populations treated for cancer¹² (Table 2 and Supplementary Table 1). A crucial aspect of assessing the population risk of radiation therapy-associated CVD is taking into account the competing risks of a second cancer. This assessment has generally not been performed in evaluations of population risk^12,14, but would involve a straightforward calculation if the mortality for the group of interest (cancer survivors) could be used.

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. 227, CC BY 4.0 (https://creativecommons.org/licenses/by/4.0/). Right-hand side of panel d adapted from ref. 228, Springer Nature Limited.

Table 2 |.

Patients with cancer at risk of radiation therapy-associated cardiovascular disease

Cancer type	Tumour location	Median age at exposure (years)	RT field and modality	RT prescription dose (Gy)	MHD (Gy)	Notesa
Hodgkin lymphoma	Variable; lymph node groups including the mediastinum, hilum, para-aortic infraclavicular, supraclavicular, pectoral, axillary and non-thoracic and extra-nodal sites	Bimodal; 20–40; ≥75	2D (mantle) versus 3D planning (involved-field: 3D-CRT, IMRT, VMAT, PBT)	20–44 (before 2000); 20–30 (after 2000)	<15	Exposure at age <20 years is significantly associated with cardiac mortality and there is a long latency before the development of RACVDs (>20 years after RT); 3D involved-field RT significantly reduced MHD and the risk of RACVDs compared with 2D mantle field RT
Breast cancer	Localized whole or partial breast, chest wall, lymph node (internal mammary chain)	55–65	2D versus 3D planning (tangential 3D-CRT, IMRT, VMAT, PBT)	40–50 whole-breast or regional nodal, with boost (10–16)	<2 for left-sided breast cancer; <1 for right-sided breast cancer	Laterality in cardiac mortality and incidence of CAD, with a long latency period before development of coronary complications (>10 years after RT); tangential 3D-CRT significantly reduced MHD compared with 2D modalities
Oesophageal cancer	Locoregional or locally advanced cases in the upper, middle and lower oesophagus	≥65	3D planning (3D-CRT, IMRT, VMAT, PBT)	50–60	<10	Fast onset of cardiac-related mortality and pericardial complications after RT (<1 year); increase in RT conformality (PBT > IMRT > 3D-CRT) reduces the risk of CVDs
Lung cancer	Locally advanced or early stages of NSCLC in central or peripheral regions	≥65	3D or 4D planning (3D-CRT, IMRT, VMAT, SABR, PBT)	60–74	<10	Fast onset of major cardiac-related events and death after RT; cardiac effects include coronary, myocardial, pericardial and cardiac conduction complications; an increase in RT conformality reduced the risk of CVDs

3D-CRT, 3D conformal radiation therapy; CAD, coronary artery disease; CVD, cardiovascular disease; IMRT, intensity-modulated radiation therapy; MHD, mean heart dose; NSCLC, non-small-cell lung cancer; PBT, proton beam therapy; RT, radiation therapy; SABR, stereotactic ablative body radiotherapy; VMAT, volumetric-modulated arc therapy.

^aThe exact risk of cardiovascular complications is confounded by the use of cardiotoxic chemotherapy.

Childhood cancer

Radiation therapy is a cornerstone of cancer treatment and is used in >50% of patients with cancer. Radiation therapy can be delivered as a sole definitive treatment, as palliative therapy or as an adjuvant to surgery or chemotherapy⁶². However, the adverse effects of radiation therapy are a concern, particularly in children with cancers such as leukaemia, lymphoma, brain tumours and sarcoma, in whom cardiac morbidity can substantially affect quality of life⁶³. The Childhood Cancer Survivor Study^64,65 involved a large, US-based cohort (median age of 6.1 years at diagnosis and 27.7 years at the last follow-up) with mean heart doses (MHDs) ranging from 7.1 Gy to 7.8 Gy. The study reported an excess risk of HF, coronary artery disease (CAD) and VHD for MHD >15 Gy (ref. 65), but these findings were reliant on only partially individualized dosimetry and self-reported health outcomes^64–66. Numerous European studies provided better individualized dosimetry (MHD range 7.5–11.9 Gy) and also reported significant excess cardiac mortality (standardized mortality rate/Gy 1.6, 95% CI 1.2–3.5) with increased risk of cardiac disease in all patients (ERR/Gy 0.6, 95% CI 0.20–2.5) and in patients not receiving concomitant anthracycline treatment (ERR/Gy 0.49, 95% CI 0.26–1.3)^67–69. However, these European studies often lack information on risk factors, such as diabetes and hyperlipidaemia, both of which have been shown to interact with radiation therapy-associated CVD in the Childhood Cancer Survivor Study^64,65. Furthermore, similar to the Childhood Cancer Survivor Study, the European studies often rely on self-assessed health outcome data, albeit with some medical record validation^67–69.

Hodgkin lymphoma

Radiation therapy has been central in the treatment of Hodgkin lymphoma, which has a 5-year relative survival rate of >80% (ref. 70). During radiation therapy, patients generally receive 20–44 Gy of ionizing radiation to the neck and chest region⁷⁰. An early retrospective analysis of patients with Hodgkin lymphoma treated with radiation therapy reported a significantly increased risk of CVD-related hospitalizations and mortality owing to AMI, congestive HF, pericardial effusion or VHD⁷¹. Patients with Hodgkin lymphoma undergoing mediastinal radiation therapy have a greater than fourfold increase in the risk of CVD compared with the general population or with patients undergoing non-mediastinal radiation therapy^72–75. In particular, younger patients (aged <20 years) with Hodgkin lymphoma have the highest risk of RACVD, and the relative risk of RACVD increases with increasing time after treatment^71–74. Concurrent chemotherapy, particularly anthracycline based regimens, such as adriamycin, bleomycin, dacarbazine and vinblastine, is an independent risk factor for the development of VHD and HF^72,74,76. Using MHDs, many studies have shown similar (and significant) ERR/Gy for the incidence of major cardiovascular events⁷⁶, adverse cardiac outcomes⁷⁷ and CAD⁷⁸. Of note, many of the studies reporting radiation therapy-related CVDs discussed earlier primarily involved patients treated in the mid-to-late 1900s with 2D mantle field irradiation, which resulted in a high MHD of 25–30 Gy for a prescribed radiation therapy dose of 30–40 Gy (ref. 79). By contrast, the advent of 3D involved-field radiation therapy led to a substantially reduced prescribed dose (to as low as 20 Gy), with MHDs reduced to <10 Gy and with the volume exposed being <35% (refs. 70,80–83). This change should lead to a considerable reduction in the excess risk of CVD associated with involved-field radiation therapy compared with the use of 2D mantle field irradiation⁸⁴. However, the lifetime cardiovascular risk associated with an MHD of 10 Gy remains considerable¹².

Breast cancer

Radiation therapy is often prescribed as an adjuvant therapy after surgery or with chemotherapy for patients with breast cancer and has been effective in preventing cancer recurrence and reducing mortality⁸⁵. Patients with breast cancer have typically been prescribed dose equivalents of 40–50 Gy, with an additional 10–16 Gy boost dose⁸⁶. Notably, an increase in cardiac morbidity and mortality ratios by laterality (that is, depending on whether the cancer is in the right breast or in the left breast) has been observed in these patients, especially in the incidence of CAD^87–90. Numerous studies of patients with breast cancer undergoing radiation therapy have reported an increase in IHD mortality^91–94. Of note, with the exception of CAD, the risk of other cardiac diseases associated with radiation therapy among patients with breast cancer is often not significantly increased^95–97 and might be complicated by the concomitant use of anthracycline^96,98,99 or targeted treatments¹⁰⁰. Similar to patients with Hodgkin lymphoma, the use of conformal delivery of irradiation at a tangential angle to spare the heart has reduced the MHD⁷⁰. Studies in patients recruited between 2000 and 2010 have shown mixed results and generally have not reported any significant associations between radiation therapy and cardiac morbidity or mortality^101–104.

Oesophageal cancer

Oesophageal cancer more often affects men, presents at an advanced stage and has a poor survival rate¹⁰⁵. Radiation therapy is recommended for locally advanced cases and is prescribed with a dose of 50–60 Gy in conjunction with induction chemotherapy¹⁰⁶. The prognosis of patients with oesophageal cancer after radiation therapy is often poorer than in patients with other types of cancer, given the higher recurrence and metastasis rate¹⁰⁷ and the higher risk of cardiac mortality¹⁰⁸. A more advanced age at the time of treatment (median age ≥65 years) contributes to the development of cardiac morbidity, primarily as pericardial effusion and atrial fibrillation, within 1 year (refs. 109–112). Pericardial effusion is classified as asymptomatic or symptomatic, with a significant association observed between symptomatic cases and an absorbed volume of ≥40 Gy by the heart or pericardium^110,111,113. Two studies of patients with oesophageal cancer have provided quantitative informative regarding the ERR of adverse cardiac events and, notably, take other risk factors into consideration^114,115. In the MD Anderson oesophageal cancer cohort¹¹⁴, MHD was significantly associated with adverse cardiac events (Common Terminology Criteria for Adverse Events (CTCAE)-defined grade 3+ events)¹¹⁴. Similarly, in the Shandong University oesophageal cancer cohort¹¹⁵, a higher MHD was significantly linked with an increased cardiac event rate and poor survival. Advances in treatment planning technology, such as 3D conformal radiotherapy, intensity-modulated radiation therapy (IMRT), volumetric-modulated arc therapy and proton beam therapy, can reduce the risk of cardiac events and improve overall survival^114–116.

Lung cancer

Lung cancer is the leading cause of cancer-related death worldwide¹⁰⁵, and radiation therapy for locally advanced non-small-cell lung cancer (NSCLC) has been associated with substantial cardiotoxicity. Patients with various stages of central or peripheral NSCLC generally receive a radiation therapy dose of >60 Gy with concurrent chemotherapy¹¹⁷. A phase III randomized clinical trial evaluating dose escalation for NSCLC found a significant decrease in overall survival with a higher radiation dose (74 Gy) compared with the standard dose (60 Gy)¹¹⁸, and significant cardiac exposure was observed in the high radiation dose group¹¹⁹. However, a survey of the literature suggests that MHD or cardiac volume exposure is not always associated with the overall survival of patients with NSCLC^120–122, reflecting a challenge in estimating the risks of RACVD for this cancer, given the variation in primary tumour locations and their proximity to the heart¹¹⁷. However, several studies have shown an association between MHD and symptomatic cardiac events^119,123,124, major adverse cardiac events (a composite of non-fatal CeVD, non-fatal myocardial infarction (MI) and cardiovascular death)^125,126, AMI¹²³, CTCAE grade 2+ cardiac events¹²⁷ and CTCAE grade 3+ cardiac events^128,129. Symptomatic pericardial effusion tends to be prevalent when considering CTCAE grade 2+ cardiac events^127,130,131, whereas congestive HF or AMI tends to be more common among the CTCAE grade 3+ cardiac events^123,124,130. Similar to patients with oesophageal cancer, patients with lung cancer are typically older (median age 65 years) than patients with other cancer types, and the development of symptomatic cardiac events can occur within 2 years of treatment^{119,121,126,131}.

Site-specific radiation exposure and RACVD

Modern radiation therapy planning and delivery are continuously evolving, resulting in a decline in doses delivered to non-targeted tissues over time. The strongest supporting evidence for a link between radiation therapy and RACVD was derived from older studies (1970s onwards) on patients with Hodgkin lymphoma who received higher radiation doses and less conformal radiation therapy. Advances in radiation therapy modalities, such as IMRT, volumetric-modulated arc therapy and proton beam therapy, as well as more precise anatomical planning (Box 3), have led to a substantially reduced MHD¹³² and consequently improved CVD and survival outcomes^{114,121,126,130,133–136}. However, certain cardiac substructures remain exposed to radiation, which might result in the continued presence of specific types of RACVD. Subsequently, we describe different subtypes of RACVD that are potentially associated with site-specific radiation exposure (Table 3 and Fig. 4).

Box 3 | Important breakthroughs in radiation therapy.

Fractionation

Fractionation is the technique of dividing a total radiation dose into smaller fractions to provide intervals for tissue repair during radiation therapy. This approach leverages the disparity in α/β ratio between cancer and normal cells. In conventional radiation therapy, doses of 1.8–2.0 Gy per fraction are typically used. Hypofractionation, with doses of 2.1–3.5 Gy per fraction, has been used to improve the control of tumour growth, but is associated with an increased risk of normal tissue complications. However, advances in the use of conformal radiation therapy and intensity-modulated radiation therapy (IMRT), such as stereotactic ablative radiation therapy, have enabled the delivery of radiation at even higher dose per fraction (6–30 Gy).

Conformality

Dose conformality refers to the ability to shape the high-dose region tightly around the planning target without exposing non-tumour tissue. The shift from traditional anterior–posterior irradiation to 3D CT imaging-based anatomical planning marked the beginning of 3D conformal radiotherapy. The further development of IMRT has provided a more sophisticated and precise method of conforming radiation doses to target tissues. Conceptually, radiation can be delivered to the deep-seated target tissue by using multiple radiation beams aimed from different angles.

Precision

Image-guided radiation therapy integrates imaging technology to ensure greater accuracy and dosimetric coverage of the target tissue. The visualization of the tumour with electronic portal imaging or CT scanning before or during radiation therapy allows for serial or even real-time adjustments to account for changes in tumour size and shape over the course of treatment and to correct for organ motion errors (which are especially crucial for the heart). Other imaging modalities, including MRI and PET, have been incorporated into treatment delivery systems. Stereotactic ablative radiation therapy uses both image-guided radiation therapy and IMRT, delivering high dose per fraction in a more precise manner.

Radiation quality

The use of different types of radiation beam, such as protons or charged particles, has led to increased sparing of normal tissue compared with traditional low linear energy transfer types of radiation (such as X-rays and γ-rays). Photon beam intensity decreases exponentially upon penetration of the body, with a substantial portion exiting the distal side. Proton or charged particles have a distinct Bragg peak that distributes a low dose along the beam path and close-to-zero dose beyond the target site, which leads to dose distributions with even greater conformality and a greatly reduced normal tissue dose⁵⁴.

Table 3 |.

Subcategories of radiation therapy-associated cardiovascular disease

Cardiac structure affected	Conditions	Notable patient cohorts	Relevant dosimetry to morbidity	Median time to onset (years)	Dose correlation to cardiovascular morbidity (curve)	Interaction with anthracycline-based chemotherapy	Potential mechanismsa
Coronary artery	AMI, AP, IHD	Hodgkin lymphoma, breast cancer, lung cancer	LAD segment dose (mid-distal)	>10b	Strong correlation with stenosis and ischaemic cardiac events (linear)	Weak	Endothelial inflammation with molecular changes (senescence and coagulation) and functional changes (angiogenesis and barrier function)152,153; coronary vessels are more sensitive than arterial vessels151
Valves	Valvular thickening, valve regurgitation, aortic stenosis	Hodgkin lymphoma	Valvular dose, and chamber dose (LA for mitral, LV for aortic and RV for tricuspid)	>20b	Strong correlation with VHD incidence (exponential)	Strong	Direct aortic valvular irradiation resulted in valvular remodelling154,158; osteogenic and fibrotic factors were secreted by mural cells in the valve after irradiation157
Conduction system	AV block, pathological node syndrome, AF and QTc prolongation	Hodgkin lymphoma, breast cancer and lung cancer	Chamber dose (RA–SA node dose), node dose (SA and AV) and coronary arteries	~2–5	A trend exists but no significant correlation has been reported	Not understoodc	Direct irradiation >5 Gy disrupted beating rate in in vitro models164, and irradiated cardiac spheroids increased cardiac cycle arrhythmia over time165
Pericardium	Pericardial thickening, acute pericarditis and PCE	Lung cancer and oesophageal cancer	Mean pericardial dose and pericardial volume exposure	<1	Strong correlation with the severity of symptoms (linear)	Not understoodd	Pericardial complications are dependent on the volume of lung exposure; unresolved PCE results in CHF with decreased stroke volume172,173
Myocardium	Restrictive HF, HFpEF, HFrEF and fibrosis	All cancers	MHD, heart volume	>10	Often no significant correlation, except for HFpEF (linear)	Very strong, and very strong with platinum-based or targeted therapy	Mitochondrial respiratory and metabolic dysfunction were observed after cardiac irradiation51,183,184; fibrosis and microvascular depletion are often observed before systolic dysfunction181,182

AF, atrial fibrillation; AMI, acute myocardial infarction; AP, angina pectoris; AV, atrioventricular; CHF, congestive heart failure; HF, heart failure; HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction; IHD, ischaemic heart disease; LA, left atrial; LAD, left anterior descending coronary artery; LV, left ventricular; MHD, mean heart dose; PCE, pericardial effusion; RA, right atrial; RV, right ventricular; SA, sinoatrial; VHD, valvular heart disease.

^aPotential mechanisms on the basis of data from animal studies or in vitro experiments.

^bMedian time to develop coronary or valvular complications is strongly influenced by age at exposure to radiation therapy and the dose prescription.

^cThe relationship between cardiac conduction complications and radiation dose has been mostly assessed in patients with breast cancer with low MHD.

^dPericardial complications are mostly notable among patients with oesophageal or lung cancer who have predominantly received chemoradiotherapy.

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.

Coronary artery complications.

Radiation-associated coronary complications, specifically IHD or MI, have been observed in numerous cohorts^78,93. MHD has been the primary dose metric used in the analyses of CVD in various cohorts of patients with cancers and is associated with increased ERR of coronary artery complications^{78,91–93,123,137}, albeit with some exceptions^104,138. Given that MHD is a crude summary of an often-heterogeneous dose distribution in the heart resulting from modern types of radiation therapy with 3D planning¹³⁹, its association with an increased risk of CVD is noteworthy. Several studies have assessed the relationships between coronary artery complications and radiation dose by focusing on the volume exposed^{95,121,126,140}, the chambers of the heart^95,112 or specific segments of the coronary artery^77,140,141. In one study that assessed both MHD and volume of the left ventricle receiving ≥5 Gy (LV–V5) in patients receiving radiation therapy for breast cancer, the volume metric was a better predictor of acute coronary events than MHD⁹⁵. Another study tested a refined dosimetry using five left ventricle segments and six coronary artery segments to compare the relative ratio of the incidence of MI and CAD among patients with left-sided versus right-sided breast cancer¹⁴⁰. The apex of the left ventricle received the highest dose of radiation and showed the strongest correlation with the incidence of MI, whereas among the coronary segments, the mid or distal sections of the left anterior descending (LAD) coronary artery received the highest dose and showed the strongest correlation with the incidence of CAD. Although MHD can still adequately predict the risk of acute coronary events^77,97, several studies have highlighted the improvement in using LAD dosimetry to predict coronary complications^{77,95,121,126,142–144}. Specifically, numerous studies have reported a stronger association between coronary artery stenosis and LAD dosimetry compared with MHD^90,144–148. The examination of baseline coronary artery health using coronary artery calcium score and the early detection of coronary artery stenosis using coronary CT angiography facilitated the early identification of coronary artery complications among asymptomatic patients undergoing radiation therapy^146,147, depending on their age at exposure and the follow-up period^{78,121,137,149}.

The mechanistic pathways underlying irradiation-mediated coronary artery complications have been extensively studied in animal models. A single or fractionated high dose of X-ray to the heart of rabbits has been shown to induce a rapid decline in capillary density and loss of endothelial viability before the onset of any symptoms or structural changes¹⁵⁰. These findings are consistent with autopsy findings showing that high-dose radiation causes vascular lesions, primarily in coronary vessels¹⁵¹. Mechanistically, radiation exposure affects the endothelium by initiating an inflammatory cascade¹⁵², accompanied by both molecular changes (senescence and coagulation) and functional changes (angiogenesis and barrier dysfunction)¹⁵³.

Valvular complications.

Radiation-associated valvular complications involve progressive valvular thickening and calcification with subsequent valve regurgitation and/or aortic stenosis. The prevalence of radiation-induced valvular complications in patients with Hodgkin lymphoma is estimated to range from 2.9% to 17% (ref. 154). VHD generally manifests after an extended period from radiation therapy (>20 years), and the use of anthracycline-based chemotherapy also significantly increases the risk of VHD⁷². Given the advent of technology that allows contouring of valvular structures with CT scanning, retrospective analyses using valvular substructure dosimetry in patients with Hodgkin lymphoma have reported significant variation and a poor correlation with MHD using modern radiation therapy modalities, such IMRT or proton beam therapy^139,155. Two studies have used chamber or valvular dose to assess VHD incidence^83,156. Asymptomatic valvular complications were found to be strongly correlated with chamber volume dose proximal to the corresponding valves⁸³, whereas a significant correlation was also noted between valvular dose and the incidence of VHD¹⁵⁶.

The mechanisms underlying radiation-induced valvular complications are not fully understood, but several studies suggest that direct irradiation might have an important role¹⁵⁴. Primary human aortic valve interstitial cells exposed to 10 Gy of γ-radiation in vitro showed an increased production of osteogenic factors (bone morphogenetic protein 2, osteopontin and alkaline phosphatase) that could potentially contribute to osteogenic morphogenesis¹⁵⁷. Furthermore, targeted irradiation of the aortic valve in a mouse model induced aortic valve remodelling, and an increase in peak aortic jet velocity and mineralization was observed 3 months after irradiation¹⁵⁸. Of note, valvular complications were more evident in mice with a deficiency in apolipoprotein E (Apoe^–/– mouse model).

Conduction complications.

Radiation-associated cardiac conduction complications include atrioventricular block, pathological node syndrome, QTc prolongation, supraventricular arrhythmia and ventricular tachycardia. These conduction complications occur in up to 5% of patients who have received radiation therapy, generally ≥2 months after treatment^{119,159–161}. Patients receiving radiation therapy for breast cancer are more likely to need permanent implantation of a pacemaker than patients with breast cancer who have not received radiation therapy; chemotherapy did not increase the need for a pacemaker in these patients¹⁶². Furthermore, several studies have suggested an effect of radiation on the sinoatrial or atrioventricular nodes^159,160,163. The right atrium dose has been reported to be a stronger predictor of arrhythmias than MHD¹⁵⁹, and when the sinoatrial or atrioventricular node radiation dose was manually contoured, sinoatrial node dose was found to be higher among patients with right-sided breast cancer than those with left-sided breast cancer¹⁶³. A similar study conducted in patients with Hodgkin lymphoma reported a substantial sinoatrial node dose (average mean dose of 6.6 Gy and an average maximum dose of 11.0 Gy), which correlated poorly with MHD¹⁶⁰. The patients in these studies were all treated with conformal radiation therapy with relatively low MHD (~4 Gy), underscoring the potential risk of conduction complications, particularly in patients with right-sided breast cancer, who are traditionally considered to have a lower risk of radiation therapy-associated CVDs^142,163. For patients with a high MHD (>10 Gy), the association between conduction complications and substructure dose is clearer. One study reported that half of all patients with NSCLC who developed grade 3+ acute coronary events within 2 years of radiation therapy had conduction complications¹²¹, whereas another study involving patients with NSCLC demonstrated a significant association between the incidence of atrial fibrillation and overall survival rate with maximal sinoatrial node dose (>20 Gy) and maximal right atrial dose (>19.1 Gy)¹²². Similarly, 21.4% of patients with oesophageal cancer who received radiation therapy developed atrial fibrillation, which was significantly associated with overall survival rate and mean left atrial dose¹¹².

Radiation therapy-associated arrhythmia has also been widely reported. Cardiomyocytes derived from human induced pluripotent stem cells (iPSCs) showed a significant decline in beating rate 48 h after exposure to 5 Gy or 10 Gy of X-ray radiation¹⁶⁴. Irradiated cells that were exposed to higher doses of radiation were more prone to changes in electrophysiological spatial distribution. A similar study using human 3D cardiac spheroids that included diverse cardiac cell types (atrial, ventricular, sinoatrial and atrioventricular node and Purkinje cells) evaluated the cardiac effects of various doses of X-ray irradiation (0.1–2.0 Gy). X-ray-irradiated cardiac spheroids showed a transient increase in beating rate 7 days after irradiation and increased arrhythmia 28 days after irradiation¹⁶⁵.

Pericardial complications.

Patients with Hodgkin lymphoma or oesophageal cancer have an ~30% prevalence of pericardial complications (including thickened pericardium, acute and chronic pericarditis, pericardial fibrosis or delayed pericardial effusion)^166,167, which presents within a few months after radiation therapy¹⁰⁹. Several studies have highlighted an increased incidence of pericardial effusion (ERR/Gy ~5%) in relation to pericardial dose^131,168. Pericardial complications often received less attention than other cardiovascular complications, especially in survivorship studies, given that most asymptomatic cases are self-resolving¹⁶⁷. However, symptomatic pericardial effusion can develop when a substantial volume of the pericardium is exposed to irradiation^109,113,169. Several studies have demonstrated that in patients with oesophageal cancer or NSCLC, symptomatic pericardial effusion (a CTCAE grade 3+ cardiac event) was significantly associated with the volume of the pericardium receiving 50 Gy (refs. 113,168,169). Furthermore, given that ~90% of patients with oesophageal cancer or NSCLC undergo concurrent chemotherapy, the risk of pericardial complications directly caused by radiation exposure is difficult to determine^{113,131,168,169}. Unresolved pericardial complications can lead to constrictive cardiomyopathy and impaired diastolic function^170,171.

Several animal studies have modelled radiation-associated pericardial effusion and cardiomyopathy¹⁷². A study involving Dahl salt-sensitive rats identified a sex-based disparity in the development of pericardial effusion with hypertrophic remodelling and reduced stroke volume¹⁷³. However, male and female rats received different lung doses of radiation by volume, and the sex-specific disparity was resolved when lung doses were matched¹⁷³. Other studies also suggest a cardiopulmonary interaction in survival rates and the development of HF after irradiation^174,175.

Myocardial complications.

Radiation-associated myocardial complications are uncommon and difficult to estimate owing to the substantial interactions with chemotherapy-induced damage. One study reported mildly reduced systolic function in patients with Hodgkin lymphoma undergoing radiation therapy¹⁷⁶. Radiation-associated myocardial complications can include constrictive cardiomyopathy accompanied by pericardial complications and/or congestive cardiomyopathy with diastolic dysfunction^98,177. In patients undergoing conformal radiation therapy for breast cancer, the relative risk of HF with preserved ejection fraction (but not HF with reduced ejection fraction) was found to increase with increasing MHD⁹⁸. Furthermore, imaging studies have reported evidence of myocardial fibrosis in patients undergoing radiation therapy^178,179; an increase in fibrosis owing to haemodynamic or inflammatory stress underlies the development of HF with preserved ejection fraction¹⁸⁰ and is also a hallmark of late tissue response⁶.

Several preclinical studies have also assessed the relationship between radiation dose and myocardial complications. Acute wholeheart irradiation of mice (16 Gy dose) induced myocardial fibrosis, increased inflammation and reduced microvascular density^181,182. Furthermore, a multiomics analysis of C57BL/6 mice that received 16 Gy identified changes in oxidative phosphorylation and lipid metabolism, which were indicative of mitochondrial dysfunction¹⁸³. Apoe^–/– mice subjected to protracted total-body γ-ray irradiation (6 Gy dose) for more than 300 days showed myocardial mitochondrial dysfunction^51,184; somewhat similar changes have been reported in a proteomic analysis of post-mortem heart samples from the Mayak workers¹⁸⁵. Finally, in a study that sought to explore whether genetic factors could modify tissue sensitivity to radiation, the substitution of rat chromosome 3 from the Brown Norway rat strain into the parental Dahl salt-sensitive rat (a highly sensitized model of radiation-induced cardiotoxicity) significantly reduced myocardial complications that were induced by cardiac irradiation (24 Gy) and improved survival by alleviating systolic dysfunction, fibrosis, inflammation and mitochondrial dysfunction¹⁸⁶. This effect was attributed to an increase in the expression of the oxidative stress-modulating transcriptional regulator nuclear factor erythroid 2-related factor 2 (NRF2), which is encoded on rat chromosome 3. The substantial energy demands of the myocardium suggest that myocardial complications associated with radiation exposure might be driven by mitochondrial dysfunction.

Intrinsic risk modifiers

Radiation-induced tissue reactions are primarily caused by the dose and volume of radiation exposure. However, the propagation of tissue reactions varies among individuals owing to intrinsic factors that influence the biological response after radiation exposure. These factors include age at exposure, biological sex and genetics, all of which alter the radiation response and the overall magnitude of radiation associated health risks. Although the importance of these intrinsic risk modifiers has been recognized, incorporating these variables into risk assessments is challenging.

Age at exposure

Exposure to radiation during childhood is often associated with a higher risk of RACVD, partly owing to the longer life expectancy and the fact that developing organs in a child are more sensitive to radiation than fully developed organs in adults¹⁸⁷. Data from the LSS cohort suggest that radiation-associated ERR/Gy for CVD decreased with increasing age at exposure, although some variations were observed across different end points^14,16,188. In patients with cancer, the evidence on the effect of age at exposure on RACVDs is limited because most of these individuals are exposed to radiation in later life, at a narrower age range than the LSS or occupational exposure cohorts. In patients with Hodgkin lymphoma, the likelihood of developing coronary diseases and cardiac death is higher in younger patients than in the overall population undergoing radiation therapy¹⁸⁹. Likewise, the relative risk of IHDrelated death among patients with breast cancer was much higher in patients who were diagnosed at age <60 years than in those diagnosed at age ≥60 years (ref. 190). However, the risk of CVD was not assessed in relation to cardiac dose in either of these two cohorts. The effect of age at exposure on the risk of RACVD has been explored in controlled experiments using rat and mouse models exposed to a wide range of radiation doses and analysed for various end points^191–193. Overall, the results were not consistent, although the degree of perivascular fibrosis and the increase in blood pressure after irradiation were greater in younger rats than in adults¹⁹¹.

One emerging and potentially relevant mechanism for the development of age-related RACVD is clonal haematopoiesis of indeterminate potential (CHIP), a type of somatic mosaicism resulting in the clonal expansion of blood cells that increases the risk of atherosclerotic CVD¹⁹⁴. The prevalence of CHIP increases with age, accompanied by increased variations in CHIP driver genes (DNMT3A, TET2 and ASXL1) and haematological malignancies, a hallmark of age-dependent stochastic effects after irradiation^188,194. As radiation exposure is known to cause haematopoietic stem cell senescence and to accelerate CHIP^195,196 and numerous studies have highlighted an increase in the prevalence of CHIP in different cohorts exposed to radiation^197,198, CHIP might be a potential mechanism for the development of age-related RACVDs.

Biological sex

Evidence from both clinical and animal studies indicates that the degree of radiation-associated toxicity in normal tissues is affected by sex, predominantly owing to hormonal changes⁵. The reproductive system is very radiosensitive and radiation exposure >1 Gy can result in sterility¹⁹⁹. A substantial increase in infertility with endocrine dysfunction has been reported in residents exposed to nuclear waste from the Chernobyl power plant²⁰⁰. Of note, sex hormone receptor signalling is known to confer radioresistance in cancer cells^201,202. Oestradiol is well known for its cardioprotective properties in premenopausal women²⁰³, and the replenishment of oestrogen via hormone replacement therapy has been shown to significantly reduce the risk of coronary complications in patients with breast cancer who have undergone radiation therapy^91,93. Similarly, in animal studies, female mice seem to have greater protection against thoracic radiation-induced cardiotoxicity than male mice, as demonstrated by preserved systolic function and lower levels of inflammatory cytokines^204,205. However, the expected sex-specific disparity in ERR/Gy for heart disease was either absent or contradictory across different studies^16,37,206, a possible reflection of the limitations of the data collected in existing studies, which often lack detailed information on dosimetry and other risk factors for CVD.

Genetic variations

The heterogeneous adverse health effects associated with radiation exposure are in part related to variations in genetic background. From the earliest days of radiation research, differential responses in the development of CVD after acute thoracic radiation have been observed between different strains of rats²⁰⁷ and mice²⁰⁸, as well as in tissue samples from humans²⁰⁹. Considering the substantial variation in baseline coronary health among patients with cancer treated with radiation therapy^121,149, the presence of common genetic variants associated with underlying coronary symptoms (such as coronary artery calcification)²¹⁰ can disproportionally increase the risk of RACVD in certain individuals. Rare genetic diseases that affect DNA damage response include ataxia-telangiectasia (caused by a defect in ATM), Nijmegen breakage syndrome (caused by a variant in NBS1) and Li–Fraumeni syndrome (linked to germline variants in TP53)²¹¹, but the effect of these genetic variants on the development of RACVD is unclear. Measuring the contribution of common or rare genetic variants on the heterogeneous cardiovascular consequences of radiation exposure is challenging, and the field thus far has focused on the variations in gene expression patterns associated with genotype, referred to as ‘expression quantitative trait loci analysis’²¹². To date, several loci have been associated with varying responses to radiation therapy²¹³. However, caution must be exercised in interpreting these results owing to multiple ways in which transcription can be regulated and the limited clinical applicability in the management of radiation therapy-related toxicity²¹⁴.

Future directions

The sources of radiation and the differing levels of exposure pose varying degrees of risk to the cardiovascular system. Advances in radiation therapy modalities have led to a substantial reduction in MHD, but cardiac substructures remain vulnerable to radiation-induced damage. In the future, other types of radiation exposure might become relevant, including radiation from space travel²¹⁵, ultra-high-dose radiation therapy²¹⁶ and radioablation treatments for lung cancer and ventricular tachycardia^217,218. However, the mechanisms underlying the biological effectiveness of different radiation modalities remain unclear, and preclinical studies thus far have provided only very limited data on the variations in intrinsic radiosensitivity associated with genetic polymorphisms.

In 2022, the FDA Modernization Act 2.0 was signed into law to permit the use of alternatives to animal testing, including cell-based assays, such as human iPSCs, organoids and organ-on-chip models²¹⁹. iPSCs offer accessible and scalable sources of human specialized cell types, such as iPSC-derived cardiomyocytes, and the incorporation of CRISPR–Cas9 genome editing will further facilitate genotype–phenotype correlation²²⁰. Moreover, advances in tissue engineering technologies have enabled the creation of increasingly complex multicellular 3D structures, such as self-organizing organoids and engineered heart tissues^221,222. A novel organ-on-a-chip model has been used to examine the effects of low and high LET radiation exposure on different organ structures derived from humans²²³. However, iPSC derivatives have different developmental origins, resulting in cells that are structurally, functionally and metabolically immature²²⁴. Although 3D tissue engineering partially resolves the immaturity observed in 2D monolayer systems, current 3D tissue models lack vascularization and optimal culture medium conditions for long-term maintenance²²⁵, which are crucial for recapitulating late-onset normal tissue effects.

Finally, personalized radiation risk assessment must account for normal tissue toxicity, given that a slight alteration in the prescribed total dose can lead to substantial differences in normal tissue toxicities²²⁶. Although no experimental model is perfect, the use of predictive models, such as iPSC-based models, is valuable for guiding dose optimization to minimize exposure to the most vulnerable areas. Understanding the tolerable range of radiation dose for an individual can increase the therapeutic index by reducing complications in normal tissues, including those in the heart (Fig. 5).

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.

Conclusions

Ionizing radiation is widely utilized in various clinical and industrial applications, but high levels of exposure pose substantial cardiovascular risks. More than a century of research has documented the relationship between radiation exposure and the excess risk of CVDs, leading to improved understanding and subsequent reductions in radiation exposure, by adhering to the ‘as low as reasonably achievable’ principle. Given that health complications after radiation exposure are multifaceted, a precise documentation of dosimetry and risk factors and an extended follow-up period are required to accurately assess risk. In particular, in the context of radiation therapy for cancer, marginal dose variations in the radiation treatment plan can result in substantial differences in latent normal tissue toxicity. A greater understanding of the variations and mechanisms underlying the heterogeneous presentation of normal tissue toxicity will pave the way for adopting applications that involve radiation exposure in a much safer manner in our daily lives.

Key points.

• Radiation exposure can cause tissue reaction effects (formerly known as deterministic effects) that are dependent on radiation energy, timing of exposure and organ radiosensitivity.

• Cardiovascular or cerebrovascular complications have been identified in individuals who have received uniform, whole-body radiation exposure.

• In patients receiving radiation therapy for cancer, partial radiation exposure to the thorax has been linked to cardiovascular complications, the nature of which is dependent on the mean heart dose and volume of exposure.

• Advances in radiation therapy modalities have resulted in substantial reductions in mean heart dose or volume exposure, but distinct complications persist owing to continued exposure of cardiac substructures.

• Intrinsic risk modifiers (including age, sex and genetic predisposition) modulate the onset and progression of radiation-associated cardiovascular disease.