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Screening for Coronary Artery Disease After Mediastinal Irradiation for Hodgkin's Disease

Paul A. Heidenreich, Ingela Schnittger, H. William Strauss, Randall H. Vagelos, Byron K. Lee, Carol S. Mariscal, David J. Tate, Sandra J. Horning, Richard T. Hoppe, Steven L. Hancock

From the Department of Medicine, Division of Cardiology; Division of Medical Oncology; Department of Radiology, Division of Nuclear Medicine; and Department of Radiation Oncology, Stanford University Medical Center, Stanford, CA

Address reprint requests to Paul A. Heidenreich, MD, 111C Cardiology, Palo Alto VAMC, 3801 Miranda Avenue, Palo Alto, CA 94034; e-mail: heiden{at}stanford.edu

	ABSTRACT

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Purpose: Incidental cardiac irradiation during treatment of thoracic neoplasms has increased risks for subsequent acute myocardial infarction or sudden cardiac death. Identifying patients who have a high risk for a coronary event may decrease morbidity and mortality. The objective of this study was to evaluate whether stress imaging can identify severe, unsuspected coronary stenoses in patients who had prior mediastinal irradiation for Hodgkin's disease.

Patients and Methods: We enrolled 294 outpatients observed at a tertiary care cancer treatment center after mediastinal irradiation doses 35 Gy for Hodgkin's disease who had no known ischemic cardiac disease. Patients underwent stress echocardiography and radionuclide perfusion imaging at one stress session. Coronary angiography was performed at the discretion of the physician.

Results: Among the 294 participants, 63 (21.4%) had abnormal ventricular images at rest, suggesting prior myocardial injury. During stress testing, 42 patients (14%) developed perfusion defects (n = 26), impaired wall motion (n = 8), or both abnormalities (n = 8). Coronary angiography showed stenosis 50% in 22 patients (55%), less than 50% in nine patients (22.5%), and no stenosis in nine patients (22.5%). Screening led to bypass graft surgery in seven patients. Twenty-three patients developed coronary events during a median of 6.5 years of follow-up, with 10 acute myocardial infarctions (two fatal).

Conclusion: Stress-induced signs of ischemia and significant coronary artery disease are highly prevalent after mediastinal irradiation in young patients. Stress testing identifies asymptomatic individuals at high risk for acute myocardial infarction or sudden cardiac death.

	INTRODUCTION

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Mediastinal irradiation has contributed to cure and improved survival in Hodgkin's disease and other mediastinal neoplasms.^1-9 However, incidental irradiation of the heart during the treatment of mediastinal tumors has been associated with increased risks for subsequent death from ischemic and other heart diseases.^10-25 Radiation of the left breast or chest wall during breast cancer therapy using techniques that included underlying myocardium also increased risks for death due to cardiac disease.^26-32 Because of prolonged survival after treatment of these malignancies, substantial populations of patients are at risk for radiation-induced coronary artery disease, acute myocardial infarction, or sudden cardiac death. Many irradiated patients who died suddenly as a result of acute myocardial infarction lacked conventional risk factors for coronary artery disease and reported no symptoms of coronary disease during clinical evaluations shortly before a fatal event.¹⁵ If patients with severe coronary artery disease could be identified, their survival might improve with revascularization or other interventions.³³ We prospectively performed stress echocardiography and nuclear scintigraphy to determine whether these screening tests could identify individuals with unsuspected, severe coronary disease, and to estimate the prevalence of significant coronary disease after the moderately high doses of irradiation used to treat Hodgkin's disease.

	PATIENTS AND METHODS

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Patient Population
The study included Hodgkin's disease patients who received 35 Gy to the mediastinum because prior analyses identified an excess risk for death from myocardial infarction confined to those who received higher radiation doses.¹⁵ These criteria identified 972 patients from a computerized database of 2,294 patients treated for Hodgkin's disease at Stanford University between 1960 and 1995. In this cohort, 345 patients were known to have died. Their causes of death were established by review of clinical records, autopsy or coroner's reports, death certificates, and information from physicians or family members. Six hundred twenty-seven patients were alive at last contact. We contacted 473 (75%) of these patients during routine appointments or by mail regarding participation in a cardiac screening study. We offered to screen patients after informing them about health risks identified in survivors of Hodgkin's disease. We excluded from screening patients who reported a history of coronary artery disease or cardiac interventions, and confirmed their cardiac diagnoses from discharge summaries or procedure reports. Patients were enrolled from October 1994 through November 1998. The Human Subjects Committee at Stanford University Medical Center (Stanford, CA) reviewed and approved the study annually.

Study Protocol
All patients had fractionated serum cholesterol testing, a resting ECG, and a stress echocardiogram. Echocardiograms were performed using commercially available ultrasound scanners (HP Sonos 1500 and 2500; Hewlett Packard, Mountain View, CA), and were recorded on 0.5-in. super video casette recorder tape. Standard parasternal long axis, short axis, and apical four-chamber images were obtained before and after cardiac stress. After baseline echocardiography, 97% of subjects underwent treadmill testing using a Bruce protocol that limited exercise duration by symptoms. Patients who reported impaired walking ability or medications that blocked beta-adrenergic activity (3%) underwent dobutamine cardiac stress using a standardized protocol.¹⁶ Standard treadmill or dobutamine stress protocols and imaging techniques were used.³⁴ ECG abnormalities were quantified using the Duke Treadmill Score.³⁵ Myocardial perfusion imaging was performed during the same stress session starting with the 16th patient. Approximately 2 minutes before peak stress, a radioactive tracer (technetium-99m–labeled tetrofosmin, 12 to 25 mCi) was injected intravenously. Echocardiography was repeated immediately after peak stress. Single-photon emission computed tomography scans of radionuclide distribution during stress were obtained within 60 minutes of injection after completion of the stress echocardiogram. Rest imaging was performed with 3.5 mCi of thallium-201 either before the exercise test or on the day after exercise testing.

Any stress-induced wall motion abnormality, stress-induced perfusion defect, or horizontal or down-sloping ST depression 1 mm on ECG tracings was considered a positive test for ischemia. Patients with a positive stress test were advised to undergo coronary angiography but performance of the procedure was at the discretion of the patient's physician. The results of coronary angiography performed after screening without an intervening event were used to determine the predictive value of noninvasive imaging.

Statistical Analyses
Descriptive data are given as percentages or means ± standard deviation. Differences in mean values were evaluated using the t test and analysis of variance. Differences in proportions were evaluated using the ² test. To estimate radiation dose intensity, biologically effective dose (BED) was calculated from each patient's mediastinal radiation doses using the formula described by Fowler and an estimated /ß ratio of 3 for a late-reacting tissue.³⁶ The volume of myocardium irradiated varied according to radiation blocking techniques, use of chemotherapy before irradiation, and the proximity of mediastinal Hodgkin's disease. This could not be quantified usefully from available records. Relative and absolute risks for heart disease were calculated using the subject-year method, with general population rates from the United States Decennial Life Tables.^37,38 Multivariate analysis was performed using standard least-squares regression if the dependent variable was continuous or logistic regression if the dependent variable was categoric. Multivariate models initially included the following independent variables: age, sex, hypertension (yes/no), diabetes (yes/no), low-density lipoprotein and high-density lipoprotein cholesterol, smoking history (yes/no), chemotherapy (yes/no), irradiation dose in BED, and time after irradiation. Variables were removed from the model sequentially, until only those variables that were predictors (P < .05) of the dependent variable remained. All analyses were performed using JMP statistical software (SAS institute, Cary, NC). A two-tailed P < .05 was considered statistically significant.

	RESULTS

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Prior Coronary Disease and Patients Excluded From Screening
Among the 473 patients evaluated for study, 42 (9%) reported a history of established coronary artery disease with prior myocardial infarction (n = 12), coronary artery bypass graft surgery (n = 16), percutaneous transluminal angioplasty (n = 4), or coronary stenosis verified by angiography and managed medically (n = 10). Seven others reported a history of valvular heart surgery (n = 3), prior pericardiectomy for constrictive pericarditis (n = 1), or congestive heart failure without documented coronary artery disease (n = 3) and did not undergo screening. Of the remaining 424 patients, 308 (73%) agreed to participate and completed testing. Fourteen patients were excluded after testing for mediastinal radiation doses less than 35 Gy (n = 11) or identification of a non-Hodgkin's lymphoma histology (n = 3) on review of records.

Study Patients
Characteristics of the 294 participants are summarized in Table 1 according to the time interval after irradiation. The patients were irradiated between 1964 and 1994 (median, 1982) with 35.0 to 54.6 Gy to the mediastinum (minimum, 35 Gy; 25%, 43.2 Gy; median, 44 Gy; 75%, 44.5 Gy; maximum, 54.6 Gy). At the time of testing, patients irradiated earlier were older, had slightly higher total cholesterol levels, received higher radiation doses to the mediastinum at a higher dose per fraction, and received chemotherapy less often than patients treated more recently. Standard risk factors for coronary artery disease including diabetes, hypertension, elevated low-density lipoprotein cholesterol, reduced high-density lipoprotein cholesterol, and smoking were uncommon.

A positive stress test was more common in older patients (mean ± standard deviation: 48 ± 10 v 41 ± 9 years; P < .0001), males (28% v 13% for females; P = .002), those who had not received doxorubicin (7% doxorubicin v 21% no doxorubicin; P = .02), and those who had received irradiation earlier (means ± standard deviations: positive, 21 ± 6 v negative, 15 ± 7 years earlier; P = .002). No other clinical variables including radiation dose were predictive of a true-positive test. The test characteristics are summarized in Table 5.

The risk of a cardiac event or death after screening was related to patient age, the latent period, dose of radiation received, the presence of wall motion abnormalities on echocardiography, and ischemia on stress testing (wall motion or perfusion). Patients with events tended to be older (46 ± 10 v 41 ± 9 years; P < .0001), had received irradiation earlier (19 ± 7 v 14 ± 7 years; P < .0001), had received higher doses of mediastinal irradiation (BED, 73 ± 6 v 70 ± 7 units; P = .008), were more likely to have abnormal wall motion (34% v 15%; P = .001), and more likely to have ischemia on stress imaging (23% v 12%; P = .02) than those without events. In a proportional hazards model the latency period (hazard ratio [HR], 2.73; 95% CI, 1.81 to 4.11 per 10 years), age (HR, 1.34; 95% CI, 1.03 to 1.76 per 10 years), dose of irradiation (HR, 1.04; 95% CI, 1.00 to 1.09 per BED unit), and presence of wall motion abnormalities (HR, 1.32; 95% CI, 1.01 to 1.72) were associated with event-free survival.

In the cohort of 972 Hodgkin's disease patients who received 35 Gy to the mediastinum and resided in northern California, 53 of 345 deaths were attributed to heart disease (5.5% overall; relative risk, 4.7; 95% CI, 3.4 to 5.9; absolute risk, 33.4 excess death per 10⁴ person-years). Table 6 summarizes the risks for death attributed to acute myocardial infarction, confirms increased risks at all intervals after irradiation, and shows a higher risk among males than females. Nine of the 33 deaths from acute myocardial infarction (27%) occurred before 40 years of age; 14 (42%) occurred within 10 years of treatment for Hodgkin's disease.

	DISCUSSION

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The rates for coronary disease that we observed are higher than reported in studies that have screened general populations for coronary disease. Screening identified three-vessel disease in 1.1% of asymptomatic men in the United States military of similar age to our cohort.⁴¹ Sequential screening tests of male government workers in Italy identified 0.5% with 50% coronary stenosis.⁴² Our screened cohort included women and fewer patients with conventional coronary risk factors than the cohorts in those studies. Glanzmann et al²⁰ found that increased risks for ischemic heart disease were confined to irradiated individuals who had conventional cardiac risk factors. In our study population, conventional risk factors for coronary artery disease, such as older age, tobacco use, diabetes, hypertension, and dyslipidemia, were uncommon and were insensitive indications of coronary risk after mediastinal irradiation.

The severity of coronary disease identified in our patients by screening was similar to that observed among men with definite angina pectoris in the Coronary Artery Surgery Study (CASS) study.⁴³ More than half of those with identified coronary disease had at least one stenosis 70% or left main stenosis 50%. The high rates of significant ostial stenosis in our patients (15% left main, 13% right main) parallels the 16% rate of left main ostial stenosis observed in men with definite angina pectoris in the CASS registry. Ostial stenosis was notably common in a small study of irradiated patients but affected 0.13% to 2.6% of patients in published series of consecutive patients undergoing angiography.^10,44 The high rate of proximal coronary artery disease may account for the increased risks of fatal myocardial infarction and sudden cardiac death documented in this and previous reports.

The true prevalence of severe coronary stenosis may be higher than we documented. Four patients with abnormal stress imaging refused coronary angiography. Among the screened cohort, 24% developed symptomatic heart disease, including 8% with documented coronary insufficiency or death. In a prior study using our cohort we found a high rate of diastolic dysfunction on resting echocardiography, suggesting an increased rate of ischemic heart disease, although the relationship with coronary artery disease was not investigated.²⁵ Additional studies are needed to determine if diastolic function can be used as screening for coronary disease after irradiation.

Screening for coronary disease is useful only if treatment is available that will improve outcome. Few of our patients had conventional, modifiable risk factors for coronary disease. Coronary artery bypass grafting was used to treat eight of 15 patients with coronary disease documented by angiography in our study. Although physicians identified symptoms of ischemia in several patients after abnormal screening tests, most patients were truly asymptomatic, and all patients were judged to be free of cardiac symptoms during clinic evaluations before screening. Although most trials of coronary artery bypass surgery have documented a benefit only in symptomatic patients, surgery yielded a similar survival benefit for asymptomatic or symptomatic patients with left main coronary disease in the CASS study.³³

Our study compared several screening tests that were recorded during a single stress session. As reported in prior studies of nuclear scintigraphy,^41,45 stress-induced perfusion defects proved a less specific sign of significant coronary disease than other tests: 55% of patients with positive studies had no coronary stenoses exceeding 50% on angiography. Such findings may be due to actual perfusion defects caused by small-vessel obstructive disease, endothelial dysfunction, or vascular spasm, or due to false positive tests, where perfusion is actually normal.

We were unable to delineate the importance of radiation dose and dose-intensity due to the limited variation in total mediastinal radiation dose (70% of the patients received mediastinal radiation doses of 43 to 45 Gy). The use of the BED may not completely control for differences in irradiation practices over time. The lower probability of identifying coronary disease on screening within 10 years of therapy may relate to decreased total radiation dose, volume, and dose-intensity in more recently treated patients.

In summary, we found high prevalence rates for stress-induced radionuclide perfusion defects or wall motion abnormalities on echocardiography that led to identification of severe three-vessel or left main coronary disease and prompted revascularization in asymptomatic patients after mediastinal irradiation for Hodgkin's disease. Conventional risk factors for coronary disease were uncommon and did not predict coronary disease. These findings suggest that screening for coronary artery disease should be considered during follow-up care for asymptomatic patients who have received mediastinal irradiation to doses of 35 Gy or more. Although the diagnostic yield will be greater for patients more than 10 years beyond irradiation, we recommend initiating screening 5 years after treatment, given increased risks for cardiac death and myocardial infarction within 5 to 10 years of initial therapy.

	AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

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The authors indicated no potential conflicts of interest.

	AUTHOR CONTRIBUTIONS

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Conception and design: Ingela Schnittger, H. William Strauss, Randall H. Vagelos, Carol S. Mariscal, David J. Tate, Steven L. Hancock

Financial support: Steven L. Hancock

Administrative support: Steven L. Hancock

Provision of study materials or patients: Ingela Schnittger, H. William Strauss, Randall H. Vagelos, David J. Tate, Steven L. Hancock

Collection and assembly of data: Paul A. Heidenreich, Ingela Schnittger, H. William Strauss, Randall H. Vagelos, Byron K. Lee, Carol S. Mariscal, David J. Tate, Steven L. Hancock

Data analysis and interpretation: Paul A. Heidenreich, Ingela Schnittger, H. William Strauss, Randall H. Vagelos, Byron K. Lee, Carol S. Mariscal, David J. Tate, Sandra J. Horning, Richard T. Hoppe, Steven L. Hancock

Manuscript writing: Paul A. Heidenreich, Ingela Schnittger, H. William Strauss, Randall H. Vagelos, Byron K. Lee, Steven L. Hancock

Final approval of manuscript: Paul A. Heidenreich, Ingela Schnittger, H. William Strauss, Randall H. Vagelos, Byron K. Lee, Carol S. Mariscal, David J. Tate, Sandra J. Horning, Richard T. Hoppe, Steven L. Hancock

	ACKNOWLEDGMENTS

 
We thank Saul A. Rosenberg, MD, for contributions to the care of these patients and for strategies to decrease adverse sequelae of Hodgkin's disease therapy, and Anna Varghese for data management.

	NOTES

 
Supported by Grant No. 1 RO1 CA63001 from the National Cancer Institute, National Institutes of Health. P.A.H. was supported by a Career Development Award from the Veterans' Affairs Health Services Research Development Office.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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Submitted May 16, 2006; accepted August 15, 2006.

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