Mediastinal radiation therapy is a commonly used treatment modality for malignancies involving the thorax. First described in the mid-1960s, radiation-induced heart disease is an under-recognized phenomenon associated with considerable morbidity and mortality. Radiation-induced heart disease can manifest as pathology of the epicardial and endocardial coronary vessels resulting in coronary obstruction, semilunar and atrioventricular valves resulting in stenosis or regurgitation due to valvular fibrosis, myocardium with resultant cardiomyopathy, and conduction system and pericardium with pericardial constriction and inflammation. In this review, we will discuss radiation-induced coronary artery disease (CAD), focusing primarily on incidence, diagnosis, and management.

Historically, Hodgkin's lymphoma and breast cancer treatments have included thoracic radiation therapy, resulting in exposure of cardiac tissues to radiation. Most of our understanding of radiation effects on cardiac structures has come from these patient populations over the last 50 years. Hodgkin's lymphoma is among the most common cancers in young adults, with an estimated incidence of 3 per 100,000 adults, and has a reported 10-year survival rate upwards of 80%.^1,2 The cumulative incidence of radiation-induced CAD is estimated to be nearly 60% in survivors of Hodgkin's lymphoma 40 years after radiation exposure with a relative risk of 3.2-fold compared with the general population.² Similarly, the relative risk of death from myocardial infarction is estimated to be at least doubled (odds ratio 2.5; confidence interval 2.1-2.9).³ Breast cancer is the most common cancer in women, with a 12.5% lifetime risk in the general population. Early stage breast cancer treatment involves breast conservation surgery and adjuvant/neoadjuvant radiation therapy and confers a 95% 5-year survival rate. Meta analyses have shown that the relative risk of developing radiation-induced CAD in patients with breast cancer receiving left versus right chest radiotherapy is higher.⁴ The largest trial evaluating the impact of radiotherapy in patients with breast cancer showed an increase in non-cancer-related mortality among those treated with radiation therapy, primarily due to vascular causes of death (odds ratio 1.3, p < 0.001).⁵ Taken together, it is clear that patients with thoracic malignancies, such as Hodgkin's lymphoma and breast cancer, treated with radiation therapy have a considerably higher risk of developing radiation-induced CAD compared with the general population. Interestingly, there appears to be a temporal delay between exposure to radiation therapy and development of symptomatic coronary obstruction. In Hodgkin's lymphoma survivors, the median time to development of asymptomatic coronary abnormalities can be as low as 2 years or up to 40 years; an approximate 9- to 10-year delay is typically observed in breast cancer survivors.^3,6

Risk factors for radiation-induced CAD include age at exposure, total radiation dose, volume of tissue exposed, and lack of cardiac shielding techniques. Age at exposure to radiation therapy is inversely associated with risk of developing radiation-induced CAD with younger patients (<25 years), considered to be highest risk group in patients with Hodgkin's lymphoma.² Radiation dose has been directly associated with risk of developing radiation-induced CAD, although no universally "safe" threshold has been identified, likely due to patient comorbidity and anatomic heterogeneity. It is generally accepted that cumulative exposure of greater than 30 Gy results in an increased risk of radiation-induced CAD. Mantle radiation and extended field mantle radiation were the standard of care for several decades for Hodgkin's lymphoma or breast cancer, with radiation exposures significantly higher than 30 Gy.⁷ A study of 2,168 women undergoing radiation therapy for breast cancer in Sweden and Denmark between 1958 and 2001 demonstrated a linear increase in rates of major coronary events at a rate of 7.4% per Gy, with a mean dose to the whole heart of 4.9 Gy.⁸ Whole breast radiation versus partial breast irradiation have been shown to result in significantly lower radiation doses to the left anterior descending artery (LAD) (mean 2.13 Gy ± 0.11 vs. 1.02 ± 0.17), with right-sided partial breast radiation resulting in minimal exposure.⁹ The development of newer cardiac-shielding techniques, such as the multi-leaf collimator modification technique, has been successfully utilized to reduce exposure of coronaries to radiation therapy.¹⁰ The American Society of Clinical Oncology guidelines recommend deep inspiration breath holding and intensity-modulated radiation therapy as two techniques that should be used to minimize total cardiac radiation dose.¹¹

The pathophysiology of radiation-induced CAD is remarkably complex and poorly understood. Radiation exposure is thought to cause both microvascular and macrovascular damage in coronary arteries. Endothelial damage within coronary arteries results in significant changes in the inflammatory and vasoactive substance milieu. Increased pro-inflammatory cytokines, including interleukin 6, C-reactive protein, tumor necrosis factor-alpha and interferon gamma, erythrocyte sedimentation rate, IgG and IgA, along with higher levels of chemoattractants and adherence of inflammatory cells to endothelium, have been observed in irradiated vasculature.¹² A loss of endothelium-derived vasodilators, including nitric oxide, along with increased prothrombotic factors such as thrombomodulin, result in a prothrombotic vasoconstrictive state. The alteration of vascular hemostasis results in markedly increased microvascular fibrosis, resulting in myocardial ischemia. In the macrovasculature, diffuse fibrosis of all layers of the arterial wall has been reported. Plaque formation in radiation-induced CAD is thought to mimic spontaneous atherosclerosis; however, plaques tend to be long, smooth, and more fibrotic with lower lipid burden and often associated with intimal hyperplasia.¹³ Diffuse vascular fibrosis as a result of radiation combined with traditional risk factors for atherosclerotic plaque development, including diabetes mellitus, hypertension, hyperlipidemia, and smoking, result in the accelerated development of obstructive CAD that is observed in this patient population.¹⁴

The diagnosis of radiation-induced CAD has some unique challenges. Symptoms of CAD in this patient population are very heterogeneous with women and the elderly, who often present with atypical anginal symptoms. The majority of patients, however, present with more traditional symptoms of coronary obstruction: angina, dyspnea with exertion, or heart failure. It can be challenging to pinpoint the etiology of chest pain because it can be caused by radiation effects on the pericardium, pleura, chest wall, or rarely spinal cord as well, and dyspnea can often be due to radiation lung disease or valvular heart disease. The temporal delay, often extending to decades, between radiation exposure and development of obstructive coronary disease mandates the maintenance of a high index of suspicion for accurate and timely diagnosis, especially in patients without traditional risk factors for coronary atherosclerosis. There are no unique electrocardiographic findings specific to radiation-induced CAD. The utility of biomarker testing during ongoing radiation treatment to detect myocardial injury has shown mixed results, and traditional biomarkers such as cardiac troponin T or I and creatinine kinase myocardial band can be used to identify acute coronary syndromes in this patient population.¹² Ischemic evaluation in patients with suspected radiation-induced CAD is similar to the general population, including stress testing via echocardiography, myocardial perfusion imaging, or definitive anatomic evaluation with coronary angiography depending on the presenting scenario. Stress perfusion imaging in survivors of breast cancer treated with radiation therapy is reported to have shown mild perfusion defects in up to 42% of women and up to 60% of women with greater than 5% of the left ventricle within the radiation treatment field.¹⁵ Due to the lack of large studies and limited follow-up of these patients, the long-term implications of these findings is unknown.¹⁶ Stress echocardiography has not been specifically studied in this patient population, but there is no reason to suspect a degradation in sensitivity or specificity compared with the general population, and it provides a radiation-free mode of stress imaging. At present, there is insufficient evidence to guide ischemic evaluation of asymptomatic patients, and there is minimal evidence to guide modality or interval of such screening at present. Nonetheless, when coronary ischemia is suspected based on noninvasive testing, coronary angiography should be pursued to define coronary anatomy.

Radiation-induced CAD typically results in ostial or proximal epicardial coronary lesions, characteristically involving the left main trunk, proximal LAD, or right coronary artery, and is thought to be because these areas lie more anterior and central in the mediastinum and are exposed to higher doses of radiation compared with more peripheral, lateral, or posterior areas (Figure 1A). Compared with the general population, in this group of patients ,the relative risk of death from myocardial infarction is estimated to be at double (odds ratio 2.5; confidence interval 2.1-2.9) and need for revascularization via percutaneous approach or coronary bypass surgery has been estimated to occur at rates of 3.2-fold and 1.6-fold, respectively.^1,3 Investigation of borderline lesions by angiography can be performed via intravascular ultrasound (IVUS), fractional flow reserve, or instantaneous wave-free ratio, similar to the general population (Figure 1B). IVUS findings can vary ranging from heavy calcification to significant neointimal hyperplasia, and IVUS can be particularly useful to assess for negative remodeling that is known to occur in these patients. The optimal management of radiation-induced CAD requires a multifaceted approach addressing traditional CAD risk factors by means of lifestyle modification and pharmacologic therapy, as well as careful planning of any revascularization via percutaneous or surgical approach. Personalizing treatment decisions utilizing the heart team model is vital in this patient population (Figure 2). Percutaneous coronary intervention (PCI) outcomes in patients with radiation-induced CAD have been shown to be worse than propensity-match patients with coronary disease with radiation exposure independently associated with higher all-cause.¹⁷ Independent predictors of increased all-cause mortality include balloon angioplasty or bare-metal stent use, SYNTAX score ≥11, New York Heart Association functional class ≥3, history of smoking, and age ≥65 years. Other studies have shown no difference in cardiovascular mortality or target lesion revascularization rates between patients treated with radiation therapy for malignancy before or after coronary stenting compared with the general population, highlighting the comparable durability of PCI in radiation-induced CAD.¹⁸

Figure 1: Coronary Angiography and IVUS Findings in Radiation-Induced CAD

Figure 2: Practical Management Algorithm of Patients With Radiation-Induced CAD

Coronary artery bypass grafting (CABG) in radiation-induced CAD is known to have worse outcomes compared with the general population. Mortality rates after any cardiac surgery are considerably higher regardless of the type of surgery (45 vs. 72%, p < 0.001) at 7.6 years of follow-up, a finding thought to be driven by cardiovascular mortality.¹⁹ Further analysis in this study by Desai et al. showed that in patients undergoing isolated CABG, mortality was significantly different (46 vs. 28%), and radiation heart disease and increasing EuroSCORE ≥8 were associated with worse outcomes on multivariable analysis. Although left internal mammary artery patency rates in patients undergoing CABG post radiation exposure are lower than general population, outcomes remain better when the left internal mammary artery is chosen for bypass of the LAD.³ Concerns have been raised regarding increased risk of sternal dehiscence and infections due to poor wound healing due to radiation exposure compared with general population.²⁰ We believe it is important to consider risk of sternal wound complications especially in frail patients or those with significant deformation of the sternum and chest wall due to underlying lung/chest wall fibrotic changes.

Because radiation exposure damages cardiac valves, coronaries, pericardium, and conduction tissues, a detailed and thorough evaluation for concurrent pathology is vital via an expert heart team approach prior to any revascularization attempts. For patients with symptomatic obstructive CAD in the absence of severe valvular or pericardial disease, percutaneous options, if feasible with acceptable anticipated outcomes, should be pursued first. Over time, if the valvular or pericardial heart disease progresses to the point of requiring intervention, sternotomy can then be pursued if no percutaneous valvular interventions are possible. We believe that a strategy of utilizing sternotomy and surgical intervention as a final option is especially important in this patient population because outcomes in patients undergoing redo cardiac surgery for any cause are known to be far worse in the setting of previous radiation exposure compared with the general population19 A surgical approach of "fix everything in one attempt" should be adopted in this patient population, and consideration should be given to repair/replacement of moderately dysfunctional valves if cardiac surgery is pursued for any reason.

Radiation-induced CAD is a challenging disease that is under-recognized and associated with a high risk of morbidity and mortality. Timely diagnosis requires a high index of suspicion on the part of providers because the presentation can be separated from radiation exposure by decades, and symptoms at presentation can often be considered atypical for coronary obstruction in certain subsets. A thorough evaluation for myocardial, valvular, and pericardial pathology due to radiation should be performed on all patients prior to pursuing PCI or CABG in this patient population. Although all-cause mortality in this patient population is worse than the general population irrespective of modality of revascularization, these patients should undergo complete revascularization preferably with percutaneous options utilized first and reservation of surgical management as a backup if all percutaneous options be inappropriate, unfeasible, or exhausted.

References

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Clinical Topics: Acute Coronary Syndromes, Cardiac Surgery, Cardio-Oncology, Dyslipidemia, Heart Failure and Cardiomyopathies, Invasive Cardiovascular Angiography and Intervention, Noninvasive Imaging, Prevention, Valvular Heart Disease, Atherosclerotic Disease (CAD/PAD), ACS and Cardiac Biomarkers, Aortic Surgery, Cardiac Surgery and Heart Failure, Cardiac Surgery and SIHD, Cardiac Surgery and VHD, Lipid Metabolism, Acute Heart Failure, Heart Failure and Cardiac Biomarkers, Interventions and ACS, Interventions and Coronary Artery Disease, Interventions and Imaging, Interventions and Structural Heart Disease, Angiography, Echocardiography/Ultrasound, Nuclear Imaging, Hypertension, Smoking

Keywords: Coronary Artery Disease, C-Reactive Protein, Tumor Necrosis Factor-alpha, Interferon-gamma, Nitric Oxide, Interleukin-6, Risk Factors, Odds Ratio, Survival Rate, Plaque, Atherosclerotic, Thrombomodulin, Cytokines, Neoadjuvant Therapy, Blood Sedimentation, Vasodilator Agents, Confidence Intervals, Hyperplasia, Constriction, Pathologic, Chemotactic Factors, Cause of Death, Constriction, Standard of Care, Myocardial Infarction, Radiation Injuries, Breast Neoplasms, Pericardium, Cardiomyopathies, Radiation Dosage, Hypertension, Diabetes Mellitus, Inflammation, Comorbidity, Hyperlipidemias, Endothelium, Hemostasis, Smoking, Lipids, Medical Oncology, Atherosclerosis, Myocardium, Lymphoma, Immunoglobulin A, Immunoglobulin G, Angiography, Coronary Angiography, Myocardial Perfusion Imaging, Echocardiography, Stress, Risk Factors, Acute Coronary Syndrome, Mediastinum, Sternotomy, Thoracic Wall, Heart Ventricles, Physical Exertion, Coronary Artery Bypass, Angina Pectoris, Chest Pain, Percutaneous Coronary Intervention, Heart Failure, Heart Valve Diseases, Angioplasty, Balloon, Stents, Heart Valves, Lung Diseases, Dyspnea, Breast Neoplasms, Biomarkers, Cardiotoxicity, Cardiotoxins

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