Echocardiography is the first-line imaging modality to assess cardiotoxicity in cancer patients. Owing to its wide availability and accessibility, low-risk profile, and ability to assess systolic and diastolic function, valvular pathophysiology, and pericardial disease, it is ideal technique for screening and diagnosing RT-related cardiovascular toxicity (6).

Traditionally, LV ejection fraction (LVEF) is the gold standard to assess global systolic function. More than 10 percentage points decrease in LVEF to a value below the lower limit of normal [54% for women and 52% for men according to the current European and American recommendations (15)] has been recommended as a cutoff to diagnose cardiotoxicity (16, 17). The 2D biplane Simpson method is the most commonly employed technique, however, it may struggle with image quality (common after RT or mastectomy) and has relatively high inter- and intra-observer variability (18, 19). LV contrast agents may improve image quality and should be used whenever two or more LV segments are not adequately visualized in the apical views (15, 20). Three-dimensional (3D) echocardiography has better reproducibility (19) and should be used in LVEF calculation when available (16, 17).

Myocardial deformation imaging with tissue Doppler and 2D speckle-tracking echocardiography provides incremental value for the assessment of LV function in cancer patients. Global longitudinal strain (GLS) is the most commonly used deformation parameter and a 15% relative reduction in GLS or absolute reduction below −18% suggest cardiotoxicity (16, 17). Several studies have shown that a reduction in GLS is more sensitive than LVEF to evaluate subtle myocardial dysfunction associated with modern RT strategies (Figure 3) (21–24). Erven et al. (21) studied tissue Doppler strain imaging in 75 breast cancer patients (51 left-sided and 24 right-sided) before RT, immediately after RT and at 8 and 14 months after RT (all patients also received anthracycline- and taxane-based chemotherapy before RT). In contrast to the LVEF, which did not change over time, GLS in patients with left-sided breast cancer declined immediately after RT and remained impaired during follow-up (−17.5 ± 1.9% after RT, −16.6 ± 1.4% at 8 months, and −17.7 ± 1.9% at 14 months compared to −19.4 ± 2.4% before RT, P < 0.01). No decline in GLS was observed in patients with right-sided breast cancer. When comparing the segmental strain values, the strain of the anterior LV wall receiving the highest radiation dose was significantly reduced, while the strain of the inferior LV wall receiving the lowest radiation dose did not change. Similar findings were confirmed in breast cancer patients receiving RT without concomitant chemotherapy (22–25). Tuohinen et al. (22) observed a decrease in GLS with speckle-tracking echocardiography as early as 3 days after completion of RT. The changes persisted at 3-year follow-up, when a relative reduction in GLS of more than 15% was present in 27% of patients. Interestingly, while studies with shorter follow-up (up to 1 year after RT) found no changes in LVEF (23, 24), the authors observed as well a significant decline in LVEF (59% at 3-year follow-up vs. 65% at baseline, P < 0.001) (22).

Furthermore, the segmental strain analysis demonstrated that variability in dose distribution across the heart plays an important role in cardiotoxicity. Breast cancer patients had the greatest reductions in myocardial strain in the anterior wall followed by the anteroseptal and the anterolateral walls with a base-to-apex gradient and this was correlated with the segmental distribution of the received radiation dose (25). Moreover, multi-layer strain analysis showed that RT primarily affects the endocardial layer (26). However, it should be noted that not all studies have confirmed these findings. Yu et al. (27) found no change in GLS in breast cancer patients 6 months after RT and Heggemann et al. (28) found only a transient decrease in GLS at 6 and 12 months, followed by an increase to baseline values at 24 months after RT.

A population-based study has shown that the predominant form of heart failure after contemporary RT for breast cancer is heart failure with preserved ejection fraction (LVEF ≥ 50%), implying impaired LV diastolic function (29). This has been linked with autopsy findings of increased myocardial fibrosis (14). However, most echocardiographic studies evaluating RT toxicity in breast cancer patients failed to show significant impairment in traditional echocardiographic diastolic function parameters, i.e., mitral inflow and tissue Doppler annular velocities (21–23). Despite the lack of clear prognostic value, the joint European and American recommendations advocate comprehensive assessment of diastolic function in patients receiving cancer therapy (20, 30). Moreover, contemporary studies have shown impaired early and late global diastolic strain rate 6 weeks after RT (31) and impaired early diastolic strain rate in apical and anteroseptal segments at 3-year follow-up (32). Changes in the apical early diastolic strain rate were present even in patients with preserved GLS and were independently associated with RT dose and cardiovascular comorbidities (32).

Right ventricular (RV) abnormalities may also occur in oncological patients, however, much less is known about RV than LV impairment (20). Christiansen et al. (33) studied 246 childhood cancer survivors (malignant lymphoma or acute lymphoblastic leukemia) 21.7 ± 8.1 years after diagnosis, who had been exposed to chemotherapy, mediastinal RT, or both. Compared with 211 matched controls, there were no differences in RV diastolic dimensions but the mean measures of RV function were all lower in the survivors group: fractional area change (44.5 vs. 48.6%, P < 0.001), tricuspid annular plane systolic excursion (2.24 vs. 2.49 cm, P < 0.001), peak systolic tricuspid annular velocity (12.1 vs. 13.0 cm/s, P = 0.001), and RV free wall strain (−26.5 vs. −28.4%, P < 0.001). Signs of RV systolic dysfunction were 3 times more often in patients with concomitant LV dysfunction. These findings were confirmed in another cohort of 274 adult lymphoma survivors examined with echocardiography 13 ± 6 years after diagnosis (34). After multivariate adjustments, all parameters of RV systolic function were impaired in patients treated with high-dose cardiac RT compared with the patients receiving only chemotherapy. However, RV dysfunction was less common than LV dysfunction (6.2% vs. 30.8%, respectively; P < 0.001) and the majority of patients with RV dysfunction were asymptomatic, leading the authors to conclude that RV dysfunction is most likely of subclinical importance. Impaired global and free wall RV strain was observed in 128 patients with non-small lung cell carcinoma 6 months after receiving chemo- and RT (35). Both strain indices correlated with the mean radiation dose and in multivariate analysis RV free wall strain was an independent predictor of all-cause mortality. Impaired RV function after RT was also demonstrated in patients with breast cancer (36).

Echocardiography is also an excellent method to diagnose valvular heart disease. The echocardiographic characteristics of RT-induced valve disease include fibrosis and calcification of the aortic root, aortic valve annulus and leaflets, mitral valve annulus, and the base and mid-portions of the mitral valve leaflets (2, 20). Typically, the mitral valve tips and the commissures are less affected. Several studies have found high prevalence of asymptomatic valvular heart disease following high-dose mediastinal irradiation for Hodgkin lymphoma (4, 37, 38). Mild or greater aortic regurgitation was the most prevalent condition, occurring in 38–60% of patients (37, 38). Pericardial disease after modern RT is nowadays rare, however, echocardiography is well equipped to diagnose pericardial thickening, pericardial effusion and characteristic hemodynamic features of constrictive pericarditis (2, 20). Furthermore, stress echocardiography (ether exercise, dobutamine or vasodilator) is an important method to diagnose functionally significant coronary artery disease as a consequence of RT (2, 20).

Table 1 summarizes the most important echocardiographic studies to detect RT-induced cardiotoxicity.

Cardiovascular CT provides detailed cross-sectional anatomical imaging of the chest with a powerful depiction of coronary, pericardial, myocardial, and vascular anatomy. It includes non-contrast CT, highly sensitive for calcified tissues, and CT angiography (CTA), where cardiac cavities and vessels are distinguished from the surrounding tissues by contrast medium opacification. The acquisition and reconstruction of images must be synchronized to the ECG to obtain robust motion-free images of moving structures like coronary arteries. The main disadvantages of CT are the ionizing radiation (effective dose in the range of < 1–12 mSv, depending on the scanning protocol), the need for iodine-containing contrast media, and the susceptibility to arrhythmias and breath-hold motion artifacts (39–41).

Cardiovascular CT can be used to assess cardiac chamber dimensions, mass, LV, and RV ejection fraction with good accuracy and reproducibility compared to CMR (42). The temporal resolution in the range of 100 ms allows the evaluation of regional wall motion abnormalities (43), but at the expense of higher radiation dose needed to acquire the whole cardiac cycle. Thus, cardiovascular CT is not the first-choice imaging technique for serial assessment of LV and RV function in suspected RT-induced heart failure. It is used only when echocardiography or CMR are not available.

Cardiovascular CT is a powerful tool to screen for coronary artery disease. To identify calcium deposits in coronary vasculature and to assess the coronary artery calcium (CAC) score, a low radiation dose ECG-gated non-contrast CT scan is performed (Figure 4A) (44). A CAC score predicts atherosclerotic cardiovascular events in a graded fashion, independent of other risk factors, such as age, sex, and ethnicity, and it can identify patients who may benefit from primary prevention measures (45, 46). Non-ECG gated chest CT is routinely performed for chest radiation planning and cancer staging. Although its diagnostic accuracy is lower than the triggered examination, it can reliably detect CAC burden (47, 48). In a population of 939 female breast cancer patients treated with RT, a CAC score ≥ 100 on radiation planning CT was associated with increased incidence of acute coronary events over a 9-year follow-up compared to patients with a CAC score of 0 (hazard ratio 4.95, 95% confidence interval 1.69–14.53, P = 0.004) (47). The relationship was significant even after correcting for confounding factors such as age, cardiovascular risk factors, and mean heart dose. CAC score was a better predictor of all-cause mortality and cardiac events than Framingham risk score in another study with breast cancer patients (49). The international cardio-oncology society consensus statement on therapeutic radiation recommends reviewing available chest CT scans (acquired before or after RT) for the presence of coronary and aortic calcifications to improve cardiovascular risk stratification and guide therapy (statin and/or aspirin use) (50). However, the CAC score threshold (>0, > 10, > 100) that should prompt initiation of cardioprotective therapy is not known.

While CAC scans are limited to identifying coronary calcium deposits, coronary CTA depicts complete coronary anatomy, including non-calcified plaques, but at the expense of slightly higher radiation dose and the use of contrast agents (Figure 4B). Coronary CTA has an excellent negative predictive value in detecting coronary artery disease (51). CTA guided patient care was superior to standard care in reducing cardiovascular death and myocardial infarction among patients with stable chest pain during 5-year follow-up (52). It is unknown whether patients after RT have a higher risk of non-calcified plaque, in which case coronary CTA would be preferred over CAC for screening (50). The international cardio-oncology society recommends screening for coronary artery disease either with CAC, coronary CTA or functional stress testing in patients with prior chest irradiation without documented atherosclerosis at 5-year intervals (50). In an asymptomatic patient already on optimal preventive therapy, repeated screening is not warranted as it would unlikely change the management (50).

Cardiovascular CT is a valuable tool to identify pericardial complications of chest RT (53). Normal pericardium appears on CT as a thin hyperdense layer less than 3 mm thick. Since it is surrounded by low attenuated fat, pericardium can be visualized even without contrast. However, contrast media are essential in differentiating pericardial thickening from small effusion and to identify inflammation. Although rare nowadays, thickening of the pericardium with increased attenuation and pericardial effusion are the hallmarks of acute radiation-induced pericarditis. CT can distinguish between serous transudates [typically with attenuation < 10 Hounsfield units (HU)], non-serous exudates with attenuation 20–40 HU and hemorrhagic effusions with attenuation 40–60 HU (54). With specific CT findings such as pericardial thickening, calcifications, narrowing or tubular deformation of the RV, large atria, and venous congestion, CT can raise suspicion of constrictive pericarditis.

Cardiovascular CT has a vital role in evaluating aortic, valvular and myocardial calcifications. In patients requiring cardiac surgery, preoperative assessment of mediastinal fibrosis and aortic calcifications is essential to determine the suitability of a surgical approach and the site of aortic cross-clamping (55). Significant valvular and/or annular calcifications may present high-risk features for surgical or transcatheter valve procedures. The European guidelines for the management of valvular heart disease favor transcatheter aortic valve implantation to surgical valve replacement in patients with sequelae of chest radiation (56). In patients undergoing coronary artery bypass graft surgery after RT involving the subclavian artery and/or internal mammary artery (i.e., patients with breast cancer receiving regional nodal irradiation) and in whom the latter is being contemplated as a bypass graft, CTA is recommended to evaluate subclavian artery stenosis and internal mammary artery patency (50).

CMR is a relatively new cardiac imaging technique that has witnessed major technical advancements, application to a broad range of cardiovascular diseases, as well as incorporation into consensus statements and clinical practice guidelines in the last 2 decades (57). CMR combines the advantages of tomographic and functional imaging modalities. Due to its high spatial and temporal resolution, excellent contrast between myocardium and blood pool and high reproducibility it has evolved as a gold standard for the assessment of ventricular volumes and systolic function. Furthermore, CMR allows myocardial tissue characterization, blood flow analysis, myocardial perfusion assessment, and provides information on extracardiac findings. This makes CMR a very useful technique to assess cardiotoxicity after cancer therapy. The main limitations to wider clinical application of CMR are its limited availability and relatively high cost. Furthermore, it is contraindicated in patients with severe renal impairment, metal implants and medical devices (e.g., certain implantable cardioverter-defibrillators, pacemakers), claustrophobia, and anxiety attacks. Moreover, the inability to carry out repeated breath holds and the presence of arrhythmias might represent additional problems to acquire high-quality data.

Nuclear cardiology imaging techniques, including multigated radionuclide angiography, single-photon emission computed tomography (SPECT) and positron emission tomography (PET), have been used to assess cardiac disease in cancer survivors (16, 73). ECG-gated protocols, either by myocardial perfusion or blood pool techniques, can give accurate and reproducible measurements of cardiac chamber volumes and ejection fraction and are still considered a reference standard for the assessment of LV function in the setting of cardiotoxicity (16, 74). The recently introduced SPECT with cadmium-zinc-telluride cameras, which allow superior spatial resolution with a low-dose radiation, has demonstrated usefulness in LV diastolic function (75, 76) as well as LV deformation and dyssynchrony (77) assessment. Moreover, ¹²³I-metaiodobenzilguanidine (¹²³I-mIBG) imaging represents the reference for non-invasive evaluation of cardiac adrenergic nervous function and has proven useful in the subclinical cardiac damage assessment as well as in the prognostication of patients with chronic heart failure (78). However, similar to the CT, the main limitation of nuclear imaging is radiation exposure, which ranges between 2 and 8 mSv for SPECT imaging (41) and makes the technique less suitable for serial follow-up of patients receiving cardiotoxic therapies.

Myocardial perfusion imaging with SPECT can provide valuable information on inducible ischemia and myocardial viability (Figure 6). A 14–60% incidence of inducible or new resting perfusion defects with SPECT has been reported in patients with Hodgkin lymphoma, breast and esophageal cancer receiving RT (79–81). Interestingly, a much lower incidence (6–10%) of wall motion abnormities has been described in the same patient cohorts (80, 82). When correlated with coronary angiography findings in Hodgkin lymphoma survivors, perfusion defects with SPECT were associated with a similar sensitivity and much lower specificity to detect 50% coronary artery vessel stenosis (sensitivity 65%, specificity 11%) compared to wall-motion abnormalities with stress echocardiography (sensitivity 59%, specificity 89%) (80). These high false-positive rates of the perfusion defects with SPECT have been attributed to microvascular dysfunction; however, this has not been confirmed with invasive testing.

Myocardial perfusion imaging with PET, most commonly performed with radiotracers ⁸²Ru or ¹³NH₄, offers several advantages over SPECT, including increased spatial and temporal resolution and reliable quantification of absolute myocardial blood flow. PET with ¹⁸F- fluorodeoxyglucose allows assessment of myocardial inflammation and viability (83). PET with ¹⁸F-NaF can identify high-risk coronary atherosclerotic plaques by detecting active calcification processes (84). However, the main disadvantage to wider application of PET is its high cost and low availability, as most of the currently available radiotracers require an on-site cyclotron for their production. With development of new and more stable radiotracers that would target multiple pathophysiological processes, PET offers a great potential for early detection of RT-induced cardiotoxicity.

Large-population studies involving patients with breast cancer and Hodgkin lymphoma have shown a clear dose-effect relationship with adverse cardiac events with no apparent threshold (3, 85, 86). The risk for coronary heart disease increased by 7–16.5% per each Gy increase in the mean heart dose, both with old and modern RT techniques (3, 85, 86). A 10, 30, 40, and 116% percentage increases in the rate of major coronary events were demonstrated in women with breast cancer and mean radiation dose to the heart < 2, 2–4, 5–9, or > 10 Gy, respectively (3). On the other hand, some of the recent studies with modern cardiac imaging techniques have failed to demonstrate significant myocardial injury, questioning the actual cardiotoxicity of modern RT regimens (27, 28, 69, 71). However, there were several important differences between the outcome and the imaging studies. First, the number of patients included in the outcome studies was between 900 and 2,700 compared to < 100 patients in the imaging studies. Furthermore, patients were followed for at least 10 years in the outcome vs. at maximum 2 years in the imaging studies. Therefore, to provide a clear answer about the cardiotoxicity of modern RT regimens and the existence of a potential minimal safe dose, we need additional studies in which large number of patients with different thoracic malignancies will be followed clinically and with modern imaging techniques for longer periods of time.

The RT-induced cardiovascular disease also depends on the type and localization of the thoracic tumor and the dose received by a specific cardiac substructure might be more important for the development of cardiac disease than the mean heart dose (6). In a contemporary study of breast cancer patients treated with RT, the volume of the LV receiving 5 Gy was the most important prognostic dose-volume parameter for the occurrence of acute coronary events (85). Mid and distal left anterior descending coronary artery and distal diagonal branch receive the highest radiation doses with 3DCRT of left-sided breast cancer, and a direct link between these areas and the location of coronary stenoses has been demonstrated (87). Furthermore, several imaging studies have shown that regional myocardial injury correlated with the radiation dose distribution (21, 25, 32, 70). Therefore, future RT studies should focus also on the local cardiotoxic effects.

Several studies have tried to elucidate the best imaging parameters to predict cardiotoxicity in patients after chest RT. Armstrong et al. (88) have compared 2D and 3D echocardiography with CMR in 114 adult survivors of childhood cancer at a median of 28 years after the exposure to anthracycline chemotherapy and/or chest RT. Mean LVEF with 2D echocardiography was on average 5% higher than with CMR and 3D echocardiography. CMR demonstrated better sensitivity to detect LV systolic dysfunction, i.e., the sensitivity for detection of LVEF < 50% was only 25% with 2D echocardiography and 53% with 3D echocardiography (using CMR as a reference standard). The authors concluded that CMR might be indicated for additional cardiac assessment in high-risk cancer survivors, i.e., patients with LVEF 50–59% on 2D echocardiography. Lambert et al. (19) studied the feasibility of several echocardiographic (2D and 3D LVEF, GLS, global circumferential strain) and CMR (LVEF, GLS, and global circumferential strain with feature-tracking) parameters to detect cardiac dysfunction in breast cancer patients treated with chemotherapy and RT. The 3D LVEF and GLS with echocardiography as well as CMR-derived LVEF showed the largest temporal changes in patients who developed cancer therapeutics-related cardiac dysfunction compared with cancer patients without cardiac dysfunction and healthy volunteers (absolute changes in 2D GLS: 1.9, 0.7, and 0.8%; 3D LVEF: 5.2, 2.3, and 1.8%; and CMR LVEF 6.6, 2.7, and 2.2%, respectively). These 3 parameters also had the lowest interobserver and intraobserver variability, making them most suitable for clinical application. Houbois et al. (89) studied the prognostic value of different echocardiographic and CMR strain parameters. 2D GLS provided the highest discriminatory value over baseline clinical risk factors for subsequent cancer therapeutics-related cardiac dysfunction and was recognized as the optimal prognostic parameter with 2D echocardiography. In addition, GLS with feature-tracking CMR provided an additional prognostic value to CMR-derived LVEF (89). On the other hand, Altaha et al. (90) questioned the usefulness of CMR parametric imaging, since the temporal variability for native T1, T2, and ECV values in cancer patients who developed cancer therapeutics-related cardiac dysfunction was similar to the temporal variability in healthy volunteers.

While measuring LVEF and GLS currently represents a cornerstone in detecting and monitoring RT-induced cardiac toxicity (16, 17), future studies should provide new insights about the most sensitive and reliable imaging parameters. Particularly, the role of CMR parametric imaging should be elucidated as the T1, T2, and ECV allow us to monitor tissue processes like edema, inflammation and fibrosis, which are the fundamental processes in RT-induced cardiac toxicity.

In addition to imaging biomarkers, blood-based and genetic biomarkers could help identify patients at higher risk for cardiovascular complications. Classic cardiac biomarkers such as N-terminal pro b-type natriuretic peptide, troponin I and T have been linked to RT-induced cardiotoxicity (21, 91–93). Several other serum biomarkers, involved in oxidative stress, inflammation, and vascular remodeling, have also been studied in patients receiving cancer treatments (92–94) and circulating microRNAs and extracellular vesicles are tested in ongoing clinical trials (95). Furthermore, the association between genetic polymorphisms and the risk of developing cardiovascular disease after chest RT has been demonstrated (96, 97). However, the knowledge about the role of genetic variability for the occurrence of RT-induced cardiotoxicity is limited and further studies are needed in this field (98). Different biomarkers may reflect different cardiac complications of RT and the integration of serum/genetic and imaging biomarkers might serve as a better predictor of RT-induced cardiotoxicity.

Several ongoing clinical trials aim to close the gaps in our current knowledge about RT-induced cardiotoxicity. The CareBest is a single-center prospective clinical trial, which will enroll over 2,000 breast cancer patients undergoing chemotherapy and RT (99). The study protocol includes CMR scanning at 3, 6, and 24 months after treatment and the patients will be followed for 4 years. The primary objective is to evaluate the prognostic value of different CMR parameters (including T1 mapping and strain) to predict clinical outcome (major adverse cardiac events). In addition, temporal relationships between myocardial injury and functional consequences will be studied according to different treatment regimens (e.g., the choice of chemotherapeutic agents, targeted therapy agents, and radiation dose). Another single-center prospective clinical trial will enroll 60 patients with thoracic cancer (breast, esophagus, or lung) undergoing curative chest RT with or without chemotherapy (100). Early cardiotoxicity (1 and 12 weeks after RT) will be studied with speckle-tracking echocardiography, CMR and serum biomarkers. The MEDIRAD EARLY HEART is a multi-center, prospective cohort study including 250 breast cancer patients treated with primary breast-conserving surgery and RT without neoadjuvant or adjuvant therapy (95). The RT-induced cardiotoxicity will be studied with speckle-tracking echocardiography, CMR, coronary CTA, and circulating biomarkers (including novel markers like extracellular vesicles and microRNA) at 6 months and 2 years after RT. We may reasonably assume that these studies will answer some of the questions raised in this section.