Medical Grand Rounds
New therapies for chronic myelogenous leukemia and chronic lymphocytic leukemia are increasing the number of survivors.
Eoin Donnellan, MD
Department of Internal Medicine, Cleveland Clinic; Clinical Instructor, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH
Dermot Phelan, MD, PhD
Director of Sports Cardiology, Department of Cardiovascular Medicine, Heart and Vascular Institute, Cleveland Clinic
Cian P. McCarthy, MD
Department of Medicine, Massachusetts General Hospital, Boston, MA
Patrick Collier, MD, PhD
Department of Cardiovascular Medicine, Heart and Vascular Institute, Cleveland Clinic; Assistant Professor, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH
Milind Desai, MD
Department of Cardiovascular Medicine, Heart and Vascular Institute, Cleveland Clinic; Professor, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH
Brian Griffin, MD
Head, Section of Cardiovascular Imaging, Department of Cardiovascular Medicine, and Vice Chair, Heart and Vascular Institute, Cleveland Clinic
Address: Dermot Phelan, MD, PhD, Department of Cardiovascular Medicine, Heart and Vascular Institute, J1-5, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195; firstname.lastname@example.org
ABSTRACTRadiation-induced heart disease (RIHD) is a recognized late sequela of chest radiotherapy for conditions such as breast cancer and lymphoma and can involve any cardiac structure. Consensus guidelines from the European Association of Cardiovascular Imaging and the American Society of Echocardiography stress the importance of regular screening for the cardiac effects of radiotherapy. However, a gulf remains between these guidelines and clinical practice.
Advances in radiotherapy over the past 50 years have dramatically improved outcomes in patients with malignancy. Five-year overall survival rates for Hodgkin lymphoma and non-Hodgkin lymphoma now stand at 80%, and breast cancer survival is 90%.1
Increased longevity, however, has come at the cost of late side effects such as radiation-induced heart disease (RIHD). Cardiac dysfunction due to radiation involves a spectrum of disease processes in patients who have undergone mediastinal, thoracic, or breast radiotherapy and may involve any cardiac structure, including the pericardium, myocardium, valves, conduction system, and coronary arteries.
Overall, compared with nonirradiated patients, patients who have undergone chest radiotherapy have a 2% higher absolute risk of cardiac morbidity and death at 5 years and a 23% increased absolute risk after 20 years.2
This article will review the pathophysiology and epidemiology of RIHD and will offer a practical approach to its diagnosis and management.
MOST DAMAGE IS ENDOTHELIAL
Cardiac myocytes are relatively resistant to radiation damage because of their postmitotic state. But endothelial cells remain sensitive to radiation, and the pathophysiology of most forms of RIHD appears to be associated with damage to endothelial cells. Conventional cardiac risk factors such as hyperlipidemia and smoking have been shown to compound and accelerate radiation-induced endothelial damage in animal models.3
Radiation is believed to result in transient increases in oxidative stress, resulting in formation of reactive oxygen species and a subsequent inflammatory response that includes activation of nuclear factor-kappa B. Upregulation of proinflammatory pathways results in increased expression of matrix metalloproteinases, adhesion molecules, and proinflammatory cytokines and downregulation of vasculoprotective nitric oxide.4 Indirect evidence for radiation-induced vascular inflammation comes from numerous studies that demonstrated increased levels of the proinflammatory cytokines interleukin 6, tumor necrosis factor alpha, and interferon gamma in Japanese atomic bomb survivors.5
Risk factors for RIHD are summarized in Table 1.
The volume of heart irradiated is a major determinant of the development of RIHD.6 A retrospective study of 960 breast cancer patients in Stockholm between 1971 and 1976 found that those who had received the highest doses and volumes of cardiac radiation had a threefold higher risk of cardiac death. By comparison, those with lesser volumes of the heart exposed to radiation had no increase in risk of cardiac death compared with the general population.7
Younger age at the time of radiotherapy is associated with an increased risk of RIHD in breast cancer and lymphoma patients. A retrospective analysis of 635 patients under age 21 with Hodgkin lymphoma treated with radiotherapy showed a relative risk of fatal myocardial infarction of 41.5 compared with a general population matched for age, sex, and race.8
Conventional cardiac risk factors such as smoking, hypertension, diabetes, and hyperlipidemia further increase the risk of RIHD, and radiation increases the cardiotoxicity of chemotherapeutic agents such as anthracyclines.9
In general, high-risk patients are defined as those with at least one risk factor for RIHD who underwent anterior or left-sided chest irradiation (Table 1).10
CORONARY ARTERY DISEASE
Ischemic heart disease is the most common cause of cardiac death in patients who have undergone radiation therapy. Atherosclerotic lesions in RIHD are morphologically identical to those in nonirradiated vessels and are characterized by intimal proliferation, accumulation of lipid-rich macrophages, and plaque formation.11
A retrospective single-institution study of 415 patients with Hodgkin lymphoma who had undergone radiation therapy found the incidence of coronary artery disease 20 years later to be 10%. The mean time to development of coronary artery disease was 9 years, and all patients who developed it had at least one conventional cardiac risk factor.12
A meta-analysis of more than 20,000 breast cancer patients who received radiotherapy in 40 randomized controlled trials found an increase in the rate of non-breast-cancer deaths, primarily from vascular causes (annual event ratio 1.27, P < .0001).13
A randomized controlled trial comparing breast cancer patients who underwent preoperative or postoperative radiotherapy vs those who had surgery alone revealed a significantly higher death rate from coronary artery disease in the postradiotherapy group.7
The risk of radiation-induced coronary artery disease is proportional to both the dose and the duration of radiation therapy. A retrospective study of more than 2,000 women undergoing radiotherapy for breast cancer found that the relative risk of coronary artery disease increased linearly by about 7.4% per Gy of radiation to the heart, with no apparent ceiling.14
The distribution of atherosclerotic coronary arteries correlates well with the areas exposed to the highest doses of radiation. For instance, in left-sided breast cancer, the apex and anterior wall of the heart typically receive the highest doses of radiation; consequently, the left anterior descending and distal diagonal branches are most prominently involved.15 In patients with lymphoma who undergo radiotherapy to mediastinal nodes and in breast cancer patients receiving radiotherapy to the internal mammary chain, basal structures may be exposed as well. Ostial lesions can also be seen in these patients.16
The clinical presentation of coronary artery disease in radiotherapy recipients does not differ significantly from that in the general population. Ischemia may be silent, may lead to classic anginal symptoms, or may cause sudden cardiac death. The incidence of silent myocardial infarction has been reported to be higher after mediastinal radiotherapy than it is in the general population, possibly from damage to nerve endings within the radiation field.17
Managing patients with radiation-associated coronary artery disease is challenging, but the therapeutic options remain the same as those in nonirradiated patients and include medical therapy, percutaneous coronary intervention, and coronary artery bypass grafting, depending on the site and extent of disease.18 Although results are conflicting, there does not seem to be a significant difference in the rates of stent restenosis between patients with a history of radiation therapy and the general population.
Percutaneous coronary intervention is generally preferred to coronary artery bypass grafting in these patients for several reasons. Radiation-induced fibrosis of surrounding structures generally makes surgical procedures more difficult,19 and inclusion of the internal mammary artery or internal thoracic artery in the radiation field may result in stenosis of these vessels, rendering them unsuitable for harvesting.20 Moreover, many patients with RIHD have concurrent radiation-induced lung damage, which increases the risk of perioperative pulmonary complications.21
If the coronary lesions are not amenable to percutaneous intervention, a careful valvular evaluation should be performed preoperatively in view of the frequency of radiation-associated valvular disease. In a study of 72 patients with RIHD undergoing coronary artery bypass grafting, 40% required valvular surgery at the time of surgery or shortly thereafter.22
Results of studies of coronary artery bypass graft outcomes in patients with a history of thoracic radiation therapy have been conflicting, but success seems to depend on the status of the internal mammary and internal thoracic arteries.23 Therefore, the patency of these vessels should be elucidated preoperatively by angiography and intraoperatively by visual inspection of the vessels for fibrosis.
A large single-institution study by Wu et al24 revealed higher short-term and long-term mortality rates in patients with RIHD undergoing cardiac surgery than in control patients without RIHD undergoing similar procedures.
Radiation therapy may directly affect heart valves, and both stenotic (Figure 1) and regurgitant lesions have been described. Pathologic findings include leaflet retraction, fibrotic thickening, and late calcification.25
The precise mechanism of radiation-induced valvular disease is unknown but is thought to be a change in the phenotype of valvular interstitial cells from a myofibroblast to an osteoblast-like cell. Radiation results in significant expression of osteogenic factors such as bone morphogenic protein 2, osteopontin, alkaline phosphatase, and runt-related transcription factor 2 by valvular interstitial cells.26
Valvular heart disease is evident in as many as 81% of patients with RIHD, with the aortic and mitral valves affected more commonly than the tricuspid and pulmonic valves.27 Why there are more left-sided valve lesions than pulmonic valve lesions, despite the pulmonic valve’s anterior position in the heart, is unknown but may be due to higher pressures across the left-sided heart valves.
Although valvular disease is common in patients with RIHD, clinically significant disease is not; more than 70% of patients with radiation-induced valvular disease have no symptoms. A study of 38 cases of radiation-induced valvular disease reported a mean time to development of asymptomatic valvular lesions of 11.5 years and an average time to symptomatic valvular dysfunction of 16.5 years, indicating that 5 years seems to be the interval required for progression from asymptomatic to symptomatic valvular RIHD.28
The thickness of the aortomitral curtain (the junction between the base of the anterior mitral leaflet and the aortic root) is an independent predictor of the long-term risk of death in patients with valvular RIHD.29
Management of patients with valvular RIHD poses a major clinical conundrum because of the high rates of perioperative morbidity and death in patients with a history of chest radiotherapy. In one study,23 the long-term mortality rate was 45% in postradiotherapy patients undergoing single-valve surgery and 61% in those undergoing surgery on two or more valves, compared with 13% and 17% in patients with no history of chest radiotherapy.23
Furthermore, valve repair is an unattractive option in these patients because of high failure rates of mitral valve and tricuspid valve repair attributed to ongoing radiotherapy-induced valvular changes after repair.30
As a result, valve replacement is generally preferred in this group. Patients should be advised of the higher risk of perioperative and long-term morbidity and death associated with open heart surgery than in the general population, and that the risks are even higher with repeat open heart surgery.
This risk has implications for the choice of replacement valves in younger patients. Bioprosthetic valves, which deteriorate over time, may not be advisable. Transcatheter aortic valve replacement has been successful in radiation-induced valvular disease and may become the preferred method of aortic valve replacement.31
New therapies for chronic myelogenous leukemia and chronic lymphocytic leukemia are increasing the number of survivors.