Radiation therapy is an important component of anticancer treatment. Its use is for different purposes, such as curative, adjuvant, and palliative treatment. Radiotherapy is delivered by external beam, brachytherapy, and systemic therapy to administered either to focused regions only or as a whole-body treatment. Radiotherapy used to treat carcinomas, especially thoracic cancers, such as Hodgkin lymphoma, lung, and breast cancer, carries a high risk of developing cardiovascular side effects. Major cardiac side effects include pericarditis, coronary artery diseases, cardiomyopathy, valvular dysfunction, and heart failure. Pericarditis and pericardial effusions are the early-onset side effects that develop within in weeks while others have a late-onset, often 10-20 years after treatment such as valvular heart disease and heart failure. Major risk factors that increase the likelihood of cardiac toxicity include high radiation dose, adjuvant treatment with cardiotoxic chemotherapy, irradiation of the left side of the thorax (due to heart position), and the presence of other cardiovascular risk factors. Given the importance of radiation therapy in the treatment of malignancy and the high incidence of cardiovascular disease in the Western population, numerous preventive measures have been suggested and used in clinical practice such as dose limitation, beam targeting, charged particle therapy, and patient positioning.[1][2][3][4]

When any tissue is irradiated, the cells comprising the tissue are damaged primarily by the generation of free radicals, most notably the hydroxyl free radical. In addition to releasing pro-inflammatory cytokines, free radicals react with DNA, and cause strand disruption, preventing proper replication and protein synthesis. Cardiomyocytes are stable cells and are therefore relatively resistant to radiation. However, presently-used doses of radiation are sufficient to cause damage to the microvasculature of the myocardium. It results in structural changes of the heart, such as pericardial inflammation, chronic development of fibrosis in the myocardium, valvular heart diseases, fibrosis of conduction system, and endothelial damage in the coronary vessels. The pericardium may become acutely inflamed, leading to pericarditis or pericardial effusion. It can also become chronically fibrotic, resulting in constrictive pericarditis. In the myocardium, the diffuse development of infiltrative fibrosis impairs the ability of the ventricles to relax, resulting in diastolic failure. These fibrotic changes can also affect the conduction system in the heart, and it is one of the main reasons for developing arrhythmias in later life. In the setting of long-term radiation therapy, the valvular endothelium can break-down or become fibrotic, leading to regurgitation or stenosis. The pro-inflammatory effect of radiation on the coronary vasculature mimics atherosclerosis in that endothelial damage promotes fibrin deposition and intimal proliferation, thereby speeding the progression of and worsening coronary artery disease.[5][6][7][8][9]

Specific radiation dosage absorbed by tissue is measured by the Gray (Gy), which measures absorbed radiation and the Sievert (Sv), which considers the effective dose. Both Gray (Gy) and Sievert (Sv) measure one joule of energy absorbed per kilogram. In general, radiation cardiac toxicity is a chronic concern, with the median time to diagnosis of radiation-related cardiovascular disease being 19 years. The heart is affected by radiation in a dose-dependent manner. Higher radiation doses, particularly dose >40 Gy, significantly increase post-radiation-induced mortality. Damaging effects can also be seen even after using doses as low as 2 Gy. Other risk factors associated with radiation-induced heart disease include an earlier age of treatment (such as young children with mediastinal Hodgkin lymphoma), irradiation of the left side of the heart, concurrent treatment with trastuzumab or anthracyclines, prior coronary artery or other heart diseases, or the presence of other cardiovascular risk factors. It is also worth noting that treatment with charged particle therapy, such as protons or carbon ions, minimizes cardiotoxic effects when compared to photon (e.g., X-ray) radiation therapy due to the drop in energy after reaching the particle’s Bragg peak. Radiation cardiac toxicity affects every sub-system of the heart and therefore has a varied presentation. In the acute setting, pericarditis and pericardial effusions may manifest within the first few weeks following irradiation and are treatable as any other acute pericarditis or effusion. Delayed pericarditis, characterized by thickening and fibrosis of the pericardium, can result in restrictive pericarditis. The diseases of the pericardium are documented at doses around 40 Gy. Valvular disease is a late complication. Fibrosis, calcification, and thickening of the valves can occur asymptomatically for over 15 years before becoming clinically apparent. Prominent damage is more common in the left-sided valves and can manifest as stenosis, regurgitation, or a proclivity towards endocarditis. Valvular effects can occur at doses >30 Gy. The myocardium itself is affected by the progressive loss of capillary beds due to oxidative stress, DNA damage, and inflammation of the microvasculature. This damage results in diffuse fibrosis of the myocardium and leads to stiffening, impaired ventricular filling, and can lead to restrictive cardiomyopathy, a diastolic, and eventually systolic heart failure. Severe cardiomyopathy is even more prevalent when using radiation therapy in combination with anthracyclines, such as daunorubicin and doxorubicin, and the monoclonal antibody trastuzumab. Cardiomyocyte toxicity and cardiomyopathy are most common in radiation doses >30 Gy. Arrhythmias are another late effect of radiation therapy because of sinoatrial (SA) and atrioventricular (AV) nodes, as well as the conduction system of the heart damaged by radiation. Transient and asymptomatic arrhythmia may occur within a year of therapy, but permanent damage to the cardiac nodes and bundle branch blocks may manifest over ten years after radiation dosing. Arrhythmia and its association with radio dose are not thoroughly studied; therefore, the absorbed dose associated with arrhythmias is not well described. Atherosclerosis is also worsened by radiation therapy, as the inflammatory effects of radiation accelerate the damage to the vascular endothelium. Premature or worsened coronary artery disease, therefore, is another complication of radiation therapy to the heart. It is associated with poor shielding, left-heart irradiation, and treatment at a younger age. Additionally, pre-existing coronary artery disease (CAD) and atherosclerosis are worsened by radiation therapy, and patients with traditional CAD risk factors such as diabetes mellitus, smoking, hypertension, hyperlipidemia, and male gender are more likely to develop or have worsened CAD after thoracic radiation therapy. Atherosclerotic heart disease is very common in the general population and can undergo further exacerbation by radiation doses as low as 6 Gy.

Prevention of cardiac damage during radiation therapy involves minimizing the radiation dose given, use of charged particle (e.g., proton or carbon ion) therapy, prior CT-guided field planning to minimize cardiac involvement. The use of prone patient position, breast boards, and having the patient hold a deep breath to decrease the involvement of the anterior heart have also been suggested to minimize cardiac damage. It is also important to identify prior risk factors of heart disease in cancer patients before administering thoracic radiation therapy. This intervention includes smoking cessation and treatment of hypertension, hyperlipidemia, and diabetes.

There are currently no guidelines for screening for radiation-induced cardiac toxicity. However, given the known association of the above risk factors, it is reasonable to suggest that the identification of these patients and close follow-up could facilitate early diagnosis and treatment of any cardiac side effects. As with any heart disease, imaging, including cardiac MR, CT, echocardiography, and myocardial perfusion studies, provide the highest diagnostic yield. However, Cardiac MRI is considered the best investigatory option for evaluating radiation-induced heart disease. It is considered a better option to understand the pathology and the severity of the disease in radiation-induced heart toxicity.[1][4][10][11][12][13][14][15][16][17][18]

Generally, the exact detail and pathophysiology of radiation-induced cardiac toxicity are beyond the scope at this point. There are no set screening or prevention guidelines. Therefore, no precise recommendations are possible. However, as mentioned above, there are risks associated with worsened cardiac outcomes following radiation therapy. These include younger age at treatment, radiation doses above 40 Gy (although there is no truly safe dose of radiation), irradiation of the left side (as it involves the left and anterior heart), pre-existing heart disease, and the presence of risk factors for coronary artery disease: diabetes, hypertension, smoking, and hyperlipidemia. These patients must be identified before receiving radiation therapy so that they receive proper follow up. Nursing and other support staff have a critical role in identifying these patients and ensuring that the providing physician is aware of these risk factors so that he can discuss extended cardiac follow-up with the patient. Additionally, nurses involved in the patient intake should remain vigilant for any patient with a remote history of thoracic radiation therapy showing signs or symptoms suggestive of cardiovascular disease. Appropriate identification of risk factors, patient follow-up, and anticipation of cardiac complications, are the key factors to improve the morbidity and mortality in post-radiation cancer patients greatly.[13][17] [Level V]