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- ↵*Reprint requests and correspondence:
Dr. Lisa A. Mendes, Vanderbilt University Medical Center, Cardiology, 2311 Pierce Avenue, Nashville, Tennessee 37232-8802, USA.
The heart and great vessels were once thought to be relatively resistant to the damaging effects of radiation therapy (1,2). But there is now clear evidence that thoracic irradiation may cause acute inflammation and progressive fibrosis of the pericardial, myocardial, and endocardial (valvular and arterial) tissues (3–6). As new therapies have improved survival, many patients with cancer are now at risk for the cardiovascular complications of radiation therapy administered years or even decades earlier (7).
Most clinical information about the cardiac effects of thoracic radiation is based on studies of patients with breast cancer or Hodgkin's disease who developed symptomatic disease during the course of treatment or during follow-up. Pericardial disease is one of the most common manifestations of radiation-induced cardiac injury. Acute pericarditis may occur early in the course of treatment, but constrictive or effusive pericarditis may also develop months to years after therapy (5,6,8). Other late complications include myocardial fibrosis and cardiomyopathy, accelerated coronary artery disease, conduction abnormalities, and valvular dysfunction (8–11).
The overall incidence of clinically detectable heart injury after thoracic irradiation is approximately 30%, although patients treated with mantle radiation for Hodgkin's disease are at highest risk for developing cardiac complications because of the proximity of the radiation field to cardiac structures (6). In one large study of 2,232 survivors of Hodgkin's disease (mean age 29 years at treatment) the risk of death from heart disease after a mean follow-up of 9.5 years was 3.9% (12). Of the 88 cardiac deaths 55 were due to myocardial infarction. The average age at death from infarction was 49 years, with 22 deaths in patients <45 years of age. Significant mortality also resulted from cardiomyopathy, valve dysfunction, and pericardial disease. The relative risk for cardiac death was highest for patients who received a total radiation dose to the chest of >30 Gy and were <20 years of age at the time of their treatment. Subcarinal blocking techniques to limit radiation exposure to the heart did not significantly reduce the risk of myocardial infarction but reduced the incidence of other forms of cardiac injury. The persistently high rates of myocardial infarction despite cardioprotective techniques likely result from continued exposure of the proximal coronary arteries to full-dose radiation (5).
The risk of radiation-induced cardiac injury may be further increased by the concomitant use of anthracycline-based chemotherapy, especially when larger cumulative doses of doxorubicin (>450 mg/m2) are used, when radiation and chemotherapy are given concurrently, and when high dose-volumes of cardiac radiation are administered (13–15). In addition, other known cardiac risk factors such as tobacco use, hypertension, and hyperlipidemia further increase the risk of coronary atherosclerosis, myocardial infarction, and sudden death (16,17).
Despite the insights gathered from previous studies, little is known about the prevalence of preclinical heart disease following thoracic radiation, and whether asymptomatic patients would benefit from systematic screening. In this issue of the Journal, Heidenriech et al. (18)address this problem by using electrocardiography and echocardiography to examine 254 patients with no symptoms or physical signs of heart disease who had received at least 35 Gy of mantle radiation as treatment for Hodgkin's disease. Time from irradiation to examination ranged from 2 to 33 years (mean 15 years). When these patients were compared with age-matched controls, patients treated with thoracic radiation had a much higher prevalence of valve disease, especially aortic regurgitation, and the severity of disease increased with time following therapy. Sixty percent of patients more than 20 years post-irradiation had at least mild aortic regurgitation, whereas 15% had moderate or severe aortic regurgitation. Despite the high prevalence of aortic valve disease in these patients, aortic regurgitation was rarely diagnosed by physical examination. Thus, echocardiography was clearly a useful screening tool to detect valve disease for which endocarditis prophylaxis should be recommended. In addition to valve disease, pericardial thickening, regional hypokinesis, mildly depressed left ventricular systolic function, and lower left ventricular mass were far more often observed in the radiation-treated patients.
How does this new information help the clinician evaluate the asymptomatic patient who has received thoracic radiation? This study clearly shows that a significant percentage of patients with Hodgkin's disease who were treated with mediastinal radiation developed significant valvular disease or mild left ventricular dysfunction, two abnormalities that are easily detected by echocardiography and may benefit from therapy (19). Importantly, the prevalence and severity of these abnormalities increased considerably over time, making a strong argument for screening because they remained clinically unrecognized. On the other hand, as the authors note, radiation therapy has been modified in the past 30 years to reduce the total radiation dose administered and to better shield the cardiac structures. The prevalence of these cardiac abnormalities will thus likely decrease in patients treated more recently. More patients will have to be screened in the future to identify those that might potentially benefit from intervention.
In addition, although resting echocardiography is an excellent tool for evaluating valve or ventricular dysfunction, it is less useful for diagnosing coronary artery disease or pericardial thickening. More sensitive techniques, such as computerized tomography or magnetic resonance imaging, may prove much more effective in detecting such pathologies. Prognostic assessment of coronary arterial disease with exercise echocardiography to reduce the substantial cardiovascular mortality among these young patients also deserves investigation.
These data may not be applicable to patients who received thoracic radiation for other types of malignancies in which the degree of cardiac exposure and the use of concomitant chemotherapy differ significantly from the present study. However, the high prevalence of cardiac disease argues for close observation of patients with Hodgkin's disease who have received mediastinal radiation. A yearly history and physical examination with close attention to symptoms and signs of heart disease that might otherwise be overlooked in this generally young population is essential. In patients who remain asymptomatic, screening echocardiography 10 years after treatment appears reasonable given the high likelihood of diagnosing significant cardiac pathology. The study by Heidenreich et al. (18)does not address whether treatment of asymptomatic disease will prevent progression of disease or future cardiac events; but these patients may derive benefit from therapies such as antibiotic prophylaxis for significant valve disease and angiotensin II-converting enzyme inhibitors for the treatment of left ventricular dysfunction. Aggressive treatment of cardiac risk factors, especially hyperlipidemia, both at the time of cardiac therapy and during follow-up, may reduce the degree of initial cardiac injury and slow the progression of vascular, myocardial, and valvular fibrosis (19). Finally, newer treatment strategies that use lower total radiation doses, minimize cardiac exposure by subcarinal shielding techniques, and avoid concurrent cardiotoxic chemotherapeutic agents may help reduce the incidence of serious cardiac disease in the future.
↵* Editorials published in the Journal of the American College of Cardiologyreflect the views of the authors and do not necessarily represent the views of JACCor the American College of Cardiology.
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