Introduction

Survival and recurrence data in a variety of thoracic cancers support the merit of radiation therapy.¹ However, the spatial orientation of the radiation field to the heart can result in sustained dose to cardiovascular structures, leading to radiation associated cardiac disease (RACD) with associated morbidity and mortality.² The delayed detrimental cardiovascular effects of such radiotherapy protocols have been recognized more recently, largely due to the latency of presentation.³

Incidence and Manifestations of RACD

Acute cardiac inflammation can occur at the time of radiotherapy or shortly afterwards, resulting in myocarditis or pericarditis. Late cardiovascular effects can manifest clinically years or even decades after treatment resulting in a variety of cardiovascular complications including myocardial fibrosis, valvular heart disease, vasculopathy including coronary artery disease (CAD), pericardial disease, and conduction system dysfunction. Clinically, there is often overlap of pathologies manifesting within individuals, making management quite challenging.

Radiation induced myocardial fibrosis can result in a broad spectrum of myocardial dysfunction spanning progressive stages of diastolic dysfunction to overt systolic heart failure. Biventricular radiation associated fibrosis is diffuse and typically follows a non-ischemic pattern. However, concurrent radiation induced coronary disease can result in ischemia/infarction and coexistent regional fibrosis. The detrimental effects of radiation to myocardial function can be compounded by chemotherapeutic agents, particularly anthracycline and newer agents such as trastuzumab, which are frequently used before or after radiation therapy.^4-6

Radiation therapy to the mediastinum can be associated with significant valvular abnormalities (typically involving aortic and mitral valves) and usually manifesting as progressive valve thickening and calcification, ultimately resulting in valve restriction and dysfunction which presents as stenosis and/or regurgitation.⁷ Often, in addition to the valves, surrounding structures such as the valve annulus, subvalvular apparatus, and aorto-mitral curtain (which extends from the base of the anterior mitral leaflet to the commissure between the non- and left coronary aortic valve cusps) are also frequently involved (Figure 1). In one recent study, aorto-mitral curtain thickening and calcification was recognized as a hallmark of previous heart irradiation and was independently associated with mortality in subjects undergoing cardiac surgery.⁸

Figure 1

While acute pericarditis is now less common with modern radiation protocols, chronic pericarditis may manifest many years after treatment completion.⁹ Chronic pericardial inflammation can result in both parietal and visceral fibrosis and a thickened, rigid and often calcified pericardial sac with resultant constrictive pericarditis.

Radiation induced vasculopathy manifests as both micro- and macro-vascular disease and can be rapidly progressive, despite not being clinically apparent until years or even decades after radiotherapy. Radiation induced coronary vasculopathy typically affects the ostia or proximal aspects of the epicardial coronary arteries; however, the proximal right coronary artery, mid left anterior descending artery, and mid diagonal branches are particularly involved among patients with breast cancer and left sided radiotherapy.¹⁰ The predilection for ostial disease is not well understood, although it likely relates to coronary artery position within the anterior radiation field and perhaps a greater propensity for intimal proliferation. Large vessel vasculopathy after mediastinal irradiation can involve the thoracic aorta and arch branch vessels. Severe ascending aortic calcification may preclude surgical clamping or cannulation, while intraluminal atheroma may embolize during catheterization or surgical manipulation resulting in stroke or peripheral embolization.¹¹

Mediastinal radiation therapy can result in fibrosis of conduction pathways and subsequent arrhythmias. Up to 75% of long-term survivors who received mediastinal radiation therapy have conduction defects on routine electrocardiogram.¹² These significant disturbances include all levels of heart block and sick sinus syndrome. Infra-nodal and right bundle branch blocks are most common, with the anteriorly located right bundle being particularly susceptible. Autonomic dysfunction has been poorly studied, although inappropriate sinus tachycardia has been recognized as a sign of extensive RACD.

Diagnosis, Screening, and Risk Stratification

Due to heterogeneity in presentation in different individuals, the diagnosis of RACD often requires diligent assessment and "connecting the dots." Given the protracted time course and poor outcomes of RACD, serial evaluation of cancer survivors with appropriate screening programs is recommended for evaluation of cardiovascular complications.¹³ Reports suggest 42% of chest irradiated patients have significant asymptomatic valvular disease and 14% have stress induced myocardial ischemia, although the true incidence is likely higher due to under-recognition.^14,15 Typically, screening for CAD should commence within five years of radiation exposure, based upon timing of major coronary events in breast cancer survivors.¹⁶ Due to its later presentation, screening for valvular heart disease is typically delayed until 10 years after radiotherapy, with subsequent imaging then performed at five year intervals.¹³

Echocardiography is the most common screening tool employed for detection and monitoring of RACD. Recommended frequency of echocardiographic screening varies according to the individual, but is typically performed every two years in asymptomatic individuals and more often once symptomatic or clinically indicated. Particular features of RACD include: biventricular systolic and diastolic dysfunction, multi-valvular involvement with mixed valvular dysfunction, prominent calcification (pericardial, valvular, annular, aorto-mitral curtain, and aortic), wall motion abnormalities associated with CAD, and pericardial constriction. It remains to be noted that the presentation can be quiet heterogeneous in individuals and findings not may be observed in everyone. In addition to LV ejection fraction, LV strain assessment enables further assessment of myocardial function and can be useful to distinguish constrictive from restrictive cardiomyopathies. In asymptomatic or subclinical disease, left ventricular strain may be reduced, despite normal LVEF.¹⁷ A link between previous chemo-radiotherapy exposure, abnormal strain and diastolic dysfunction has also been noted.¹⁸ Mortality is higher in those with abnormal strain, even when LVEF is normal, so deformation imaging may be useful in identifying those at risk who may benefit from early intervention.¹⁹ Stress echocardiography enables evaluation for myocardial ischemia and dynamic assessment of radiation induced valvular heart disease. Radiation induced CAD may manifest as resting or inducible regional wall motion abnormalities in typical coronary distributions. However, balanced ischemia from multi-vessel disease may present with global dysfunction and cavity enlargement at peak stress. Stress valvular assessment is typically reserved for symptomatic subjects with mild or moderate disease at rest, whose symptoms appear proportionally worse than expected. Stress may demonstrate increased valvular regurgitation, trans-valvular gradients or pulmonary pressures, along with impaired ventricular contractile reserve.²⁰

Coronary computed tomographic angiography (CTA) is particularly useful in RACD for its negative predictive value, as no coronary calcification portends a very low risk for underlying CAD. Cardiac CTA can also be employed for evaluation of aortic, valvular, myocardial, and pericardial calcification on either contrast or non-contrast imaging. Pre-operative assessment for aortic calcification is important to determine suitability for aortic cross-clamping and cannulation in RACD patients undergoing cardiac surgery. Pericardial calcification, thickening, IVC enlargement, and ventricular conical deformity are suggestive of pericardial constriction. Evaluation of extra-cardiac vascular structures with CT is crucial for surgical planning. Extensive mediastinal fibrosis or lack of a safety margin between the sternum and adjacent structures may necessitate abandonment of a median sternotomy approach for an alternative surgical strategy.²¹ The presence and degree of pulmonary fibrosis on CT adversely impacts upon surgical risk and mortality (Figure 1).²² CT surveillance of non-cardiac structures, including pulmonary pathology, should be performed with non-gated high resolution chest CT given its lower radiation dose. Various radionuclide imaging strategies, including single photon emission CT and positron emission tomography, have been employed to assess myocardial ischemia in RACD, demonstrating that 12% of asymptomatic patients have stress induced perfusion defects.²³

Cardiac magnetic resonance (CMR) provides simultaneous functional and structural data, enabling detection of radiation induced coronary, valvular, and pericardial disease. Cine imaging allows assessment of ventricular volumes and regional wall motion abnormalities, while late gadolinium enhancement helps to determine regions of viability, scar, and regional non-ischemic fibrosis. Qualitative assessment of valvular function can be performed using cine imaging, along with calculation of regurgitant volumes and transvalvular gradients via quantitative flow sequences. CMR T1/T2 weighted sequences and cine imaging are useful for evaluation of radiation induced pericardial thickening, effusions, and features of constrictive physiology including: ventricular conical deformity, diastolic septal bounce, and diastolic chamber restraint. A free breathing sequence can assess for constriction associated respirophasic septal shift, while increased pericardial signal intensity on edema weighted and delayed enhancement imaging suggests acute or sub-acute pericardial inflammation seen in acute radiation induced pericarditis or with chronic effusive or transient constrictive pericarditis. The diffuse distribution of non-ischemic myocardial fibrosis in RACD means that it may be poorly detected using delayed gadolinium enhancement, which relies on normal myocardium as a point of reference for nulling properties. T1 mapping allows quantitation of diffuse fibrosis from myocardial signal intensity curves and may prove useful for radiation induced myocardial disease, but requires further investigation. Cardiac CMR is not optimized for assessment of surrounding structures including lungs and poorly shows calcification as a region of signal void. Alternative imaging strategies are required for these purposes.

Invasive catheterization provides complementary and confirmatory information to non-invasive imaging. Left heart catheterization allows assessment of coronary stenosis severity and disease extent, as well as enabling intervention on amenable, discrete, proximal- to mid-vessel lesions. Right heart studies are useful for calculation of intra-cardiac and pulmonary pressures, while simultaneous left and right heart measurements allow for evaluation of ventricular interdependence, with equalization of pressures confirming the presence of constrictive physiology. Proximal CAD may be underappreciated, especially if ostial in location. Hence, there should be a low threshold for utilizing intra-vascular ultrasound, particularly in the setting of pressure damping or contrast reflux.

Subjects with a history of thoracic radiation should be screened for pulmonary disease, especially if symptomatic. Typically this manifests as pulmonary fibrosis and traction bronchiectasis in severe cases. Concurrent pulmonary disease is independently associated with reduced survival in RACD.²² Clinical examination, chest x-ray, pulmonary function tests including diffusion capacity, and dedicated high resolution CT chest is often required. Pulmonary involvement should be particularly considered when determining suitability for cardiac surgery, as pulmonary complications are a major source of perioperative morbidity and mortality.²² Those with RACD and significant pulmonary involvement may be better managed with non-surgical or percutaneous approaches, even if the cardiac issues cannot be completely resolved.

Management

Often radiation exposure is only realized when cardiac testing suggests a more extensive calcific or fibrotic process than typical for age. An experienced physician team is recommended to guide therapeutic strategies based upon indications, risk, and prognosis. Medical therapy of RACD is typically undertaken according to standard treatment guidelines.

Cardiac Surgery

Cardiac surgery in RACD is often complex and therefore best undertaken by experienced surgeons at an experienced center. As radiation exposure is heterogeneous, patients cannot be uniformly managed and require individualized surgical approaches. In our experience, a "complete" one-time operation should be considered. This is especially important in multi-valve disease, where one valve may have severe dysfunction and another mild or moderate. Even in experienced centers, the outcomes of RACD patients undergoing cardiac surgery are significantly worse than a comparable matched population.²⁴ Furthermore, re-operative surgery in RACD portends increased operative risk and morbidity compared with non-RACD surgery, so every attempt should be made to address all issues with a one-time complete operation. Managing patient expectations is critical, as post-operative complications can significantly impact recovery and quality of life. In a recent study we have demonstrated that RACD patients with severe aortic stenosis have a much worse prognosis following surgical valve replacement as compared to non-RACD matched patients undergoing similar surgery.²⁵ This might suggest that in isolated aortic stenosis, a percutaneous strategy might be the better option.

In terms of surgical approaches, despite the internal thoracic arteries often lying within the radiation field, the majority can still be utilized with good results unless they appear small and fibrotic.²⁶ Given the susceptibility to calcification of the aortic valve, aorto-mitral curtain and mitral valve annulus, consideration should be given to replacing both valves even if disease of one is only moderate. Replacement is favored over repair, as irradiated valve tissue is abnormal, and tends to progressively fibrose and calcify. Given the increased risks of re-operation, use of mechanical prosthesis is appealing, especially for younger patients. However, if other comorbidities preclude lifelong anticoagulation, consideration may be given to bioprosthetic valve replacement with subsequent valve-in-valve transcatheter therapy. Confluent fibrous skeleton calcification extending from the aortic annulus, across the aorto-mitral curtain and to the anterior mitral valve leaflet can often preclude safe valve replacement. These patients also often have a small aortic root and small annular sizes, possibly related to radiation exposure during childhood, progressive fibrosis and/or scar. These combined issues makes a compelling case for double valve replacement; in addition, division of the aorto-mitral curtain and anterior mitral leaflet also allows for better exposure of the posterior mitral annulus for debridement of calcification, suture placement, and reconstruction (the "commando operation," where a patch of autologous or bovine pericardium is fashioned to repair and expand the dome of the left atrium, the mitral annulus, aorto-mitral curtain, aortic annulus, and aortic valve). Pericardiectomy is reserved for constriction with pericardial fibro-calcification or severe recurrent pericarditis despite medical therapy. However, outcomes from pericardiectomy are worse in RACD, likely reflective that pericardial involvement is a marker for severity and extent of disease. This is dramatically demonstrated by 5-year survival rates post-pericardiectomy, which are 79.8% for idiopathic, 55.9% for post-operative and only 11.0% for post-radiation pericardial disease.²⁷

Percutaneous Intervention

Percutaneous techniques provide alternative management strategies in RACD. Transcutaneous valve replacements may be used for initial intervention if surgical access is problematic or if the patient is 'high-risk' due to significant comorbidities. It is also a useful alternative for patients requiring repeat surgery or with extensive ascending aortic calcification. Application of the technique to mitral valve replacement in RACD remains limited and unvalidated long-term. Percutaneous intervention (PCI) for isolated CAD may be considered in myocardial infarction, unstable angina or ischemic left ventricular dysfunction. Although PCI may be preferred for reduced morbidity, CAD in RACD is typically diffuse and extensively calcified (rather than discrete single vessel disease), making stenting less appropriate. When long-term PCI outcomes are compared with non-irradiated, matched controls, those with RACD have higher mortality and worse functional class.²⁸

Conclusion

Management of RACD remains challenging, due to increased rates of morbidity and mortality. Coordinated management by a Center of Excellence is strongly advocated. Timing of surgical intervention must be individualized, based upon the complexity of the radiation associated disease process, comorbidities and technical difficulty. Percutaneous options are increasingly available, although their use and suitability in RACD requires further validation.

References

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Keywords: Angina, Unstable, Angiography, Aorta, Thoracic, Aortic Valve, Aortic Valve Stenosis, Arrhythmias, Cardiac, Breast Neoplasms, Bronchiectasis, Cardiac Catheterization, Cardiomyopathy, Restrictive, Cicatrix, Comorbidity, Constriction, Constriction, Pathologic, Coronary Artery Disease, Coronary Stenosis, Echocardiography, Echocardiography, Stress, Edema, Electrocardiography, Heart Atria, Heart Failure, Systolic, Heart Valve Diseases, Hodgkin Disease, Infarction, Myocardial Infarction, Inflammation, Magnetic Resonance Spectroscopy, Mammary Arteries, Mediastinitis, Mediastinum, Mitral Valve, Myocarditis, Myocardium, Pericardiectomy, Pericarditis, Constrictive, Pericardium, Plaque, Atherosclerotic, Positron-Emission Tomography, Prostheses and Implants, Pulmonary Fibrosis, Radioisotopes, Respiratory Function Tests, Sick Sinus Syndrome, Sternotomy, Sternum, Stroke, Surgeons, Survivors, Tachycardia, Sinus, Tomography, Tomography, X-Ray Computed, Ventricular Dysfunction, Left, X-Rays

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