Continuing Education Activity

Radiation-induced coronary artery disease (RICAD) is the second most common cause of morbidity and mortality in mainly oncology patients treated with radiation therapy (RT). With increased rates of oncologic treatment, the rates of RICAD are increasing in parallel. This activity will discuss in detail the etiology of RICAD, epidemiology, clinical presentation, evaluation, screening recommendations, treatment options, differential diagnosis, and complications, as well as, the role of the interprofessional team.

Objectives:

• Describe the pathophysiology of radiation-induced coronary artery disease.
• Review the presentation of a patient with radiation-induced coronary artery disease.
• Summarize the treatment options for radiation-induced coronary artery disease.
• Review the importance of improving care coordination among interprofessional team members to improve outcomes for patients affected by radiation-induced coronary artery disease.

Introduction

Radiation-induced coronary artery disease (RICAD) is a common cause of morbidity and mortality in mainly oncology patients treated with radiation therapy (RT). With increased rates of oncologic treatment, the rates of RICAD are increasing in parallel. This article will discuss in detail the etiology of RICAD, epidemiology, clinical presentation, evaluation, screening recommendations, treatment options, differential diagnosis, and complications.

Etiology

RICAD primarily is caused by prior mediastinal radiation exposure or therapy. Radiation exposure can be natural or iatrogenic. Most natural exposure does not result in high levels of radiation at a single time, and sources of this type of exposure include radon gas in the ground seeping into basements and crawlspaces, [1] and cosmic rays from sun exposure and high altitude. More often, patients are exposed to radiation through medical imaging or therapy, which explains the high incidence of RICAD in post-RT patients.  The risk of RICAD increases with frequency and duration of radiation exposure, regardless of source.

Epidemiology

RICAD is one of the most feared complications of radiation exposure to the chest. The most common conditions associated with RICAD are breast cancer (BC) and Hodgkin lymphoma (HL). HL survivors treated with radiation therapy have a 2.5 times higher risk of coronary artery disease (CAD), whereas BC patients only have 0.25 times higher risk.[2] [3] [4] [5] [6] The reason for this is patients with HL receive a higher dose of RT than patients with BC, which represents a dose-dependent effect on the development of RICAD. [7]  Even though BC CAD rates are lower, the incidence of CAD increases linearly with time. [8] Interestingly, radiation exposure to the chest at younger ages portends a lower risk of RICAD compared to older populations. Initially, the incidence of RICAD following left-sided RT was higher than right-sided RT. However, more recently, there have been reports of higher rates of RICAD following right-sided RT, specifically involving the right coronary artery. [9] [10] 

Pathophysiology

The pathophysiology of RICAD is poorly understood. One prevailing theory is that it is caused by both microvascular and macrovascular endothelial damage in coronary arteries. [11] Radiation particles (ions) cause the initial cellular injury initiating a pro-inflammatory state. The NF-kB pathway has been considered one factor leading to long-term oxidative stress. [7] Endothelial injury also results in loss of endothelium-derived vasodilators resulting in vasoconstriction. Thrombomodulin, a pro-thrombotic factor, combines with an endothelial injury resulting in a pro-thrombotic vasoconstrictive state with hemostasis. Fibrosis then begins at the microvascular level with progression to larger vessels and predisposes to plaque formation. [12] Occlusion and/or compromised coronary arterial blood flow may result in myocardial ischemia and infarction.

Histopathology

The coronary arteries are particularly vulnerable to RT of the chest. These arteries consist of three wall layers (tunica intima, media, and adventitia), of which only the tunica intima comprises the endothelium. [13] Endothelial cells respond to RT in a variety of ways. Depending on the radiation dose, cells can develop a range of problems, from DNA breakage to apoptosis. [14]  On a histologic level, RT results in a variety of tissue damage, such as cellular loss, an influx of inflammatory cells and markers, and fibrin plaques in advanced disease-causing partial or complete occlusion.

History and Physical

The classic presentation of RICAD is typical chest pain in a young patient that has been formerly exposed to thoracic RT and has no risk factors for CAD. [15] Patients can also present in pulmonary edema, acute heart failure, or valvular disease with a new heart murmur. There may be decades between initial exposure to RT and symptoms of RICAD. Women and the elderly commonly present with atypical chest pain. The two most distinguishing characteristics that separate RICAD from acute coronary syndrome (ACS) is the age at presentation and history of RT. As with the history, the physical exam findings found in RICAD patients can be very similar to ACS. Hypertension and tachycardia may be present. The classic Levine sign, a clenched hand held over the chest, can also be seen in these patients as with ACS. Patients with RICAD may have dyspnea, lower extremity edema, bi-basilar pulmonary crackles, and jugular venous distension. Even with a history and physical, it can be challenging to identify the etiology of chest pain as RT can affect all exposed thoracic tissues resulting in irritation and/or inflammation, including the pericardium, lung parenchyma, pleura, esophagus, and other structures of the chest.

Evaluation

Evaluation is similar to that for ACS. For patients with chest pain, obtain an electrocardiogram, troponin, B-type natriuretic peptide (BNP), D-dimer, and echocardiogram.  If there is a low risk for obstructive CAD, consider a cardiac stress test. If high risk, coronary angiography is indicated. [7] Of note, RICAD affects the region of radiation exposure. Right-sided radiation exposure mainly affects the right coronary artery, whereas left-sided exposure mostly affects the left main and anterior descending artery. 

Treatment / Management

Treatment of RICAD is similar to ACS, which includes pharmacotherapy, percutaneous coronary intervention (PCI), and surgical revascularization. In animal models, captopril [16] and simvastatin [17] decreased the effects of a radiation-induced injury. There is also evidence to support colchicine as prophylactic therapy for RICAD. [18] In addition to treating RICAD, it is important to include regular surveillance for radiation-induced injury to the heart and other mediastinal structures. [7] Annual evaluations and risk factor modification are recommended. Laboratory tests to be monitored include troponin, BNP, and C-reactive protein. The American Society of Echocardiography and European Association of Cardiovascular Imaging recommend a pre-radiation echocardiogram and a repeat in 10 years followed by 5-year intervals. [19]

Differential Diagnosis

The differential for RICAD is similar to the differential list for ACS, as both present the same. A list of potential but not all-inclusive differential diagnosis are listed below:

• Acute coronary syndrome
• Acute pericarditis
• Pulmonary embolism
• Coronary vasospasm
• Cardiac syndrome X
• Pulmonary disease
• Costochondritis
• Kawasaki disease
• Myocarditis
• Esophagitis

Prognosis

RICAD has a good prognosis with current medical therapy.

Complications

Complications of RICAD are similar to CAD including:

• Myocardial ischemia/infarction
• Dysrhythmia
• Valvular disease
• Aortic disease
• Aortic dissection
• Heart failure
• Sudden cardiac death

Consultations

It is recommended that cardiology be consulted.

Deterrence and Patient Education

Patient education starts with the initial discussion prior to the initiation of RT. After informed discussion, patients should be allowed the option to defer RT. Other options for treatment should be offered. Sources of natural radiation exposure may also be discussed.

Pearls and Other Issues

The workup and diagnosis of RICAD are identical to that for CAD and ACS. [7]

Enhancing Healthcare Team Outcomes

RICAD may be overlooked as a potential diagnosis. An interprofessional team approach can sometimes aid in narrowing the diagnosis. Members should include but are not limited to the primary care provider, cardiologist, oncologist, cardiology nurse, and pharmacist. Emergency room providers and nurses may be involved in the initial assessment and treatment. Critical care and cardiology nurses provide treatments, monitor outcomes, and document status for the team. The pharmacist reviews medication choice, check for interactions and provide patient education. [Level 5]