Radiation-induced coronary artery disease

Stoddard et al. American diverse pathologic states, such as intracardiac tumor and thrombus, valvular vegetations, mitral and tricuspid valve prolapse, atherosclerotic plaque, and aortic dissection. Methods to aid in the differentiation of normal cardiac structures from pathology are offered. 6. 7. 8. REFERENCES 1. Miigge 2. 3. 4. 5. A, Daniel WG, Frank G, Lichtlen PR. Echocardiography in infective endocarditis: reassessment of prognostic implications of vegetation size determined by the transthoracic and the transesophageal approach. J Am Co11 Cardiol 1989; 14:631-8. Erbel R, Rohmann S, Drexier M, Mohr-Kahaly S, Gerharz CD, Iversen S, Oeler H, Meyer J. Improved diagnostic value of echocardiography in patients with infective endocarditis by transesophageal approach. A prospective study. Eur Heart J 1988;9:43-53. Erbel R, Engberding R, Daniel W, Roelandt J, Visser C, Rennollet H. Echocardiography in diagnosis of aortic dissection. Lancet 1989;1:457-60. Pearson AC, Labovitz AJ, Tatineni S, Gomez CR. Superiority of transesophageal echocardiography in detecting cardiac source of embolism in patients with cerebral ischemia of uncertain etiology. J Am Co11 Cardiol 1991;17:66-72. Daniel WG, Erbel R, Kasper W, Visser CA, Engberding R, Sutherland GR, Grube E, Hanrath P, Maisch B, Dennig K, Schartl M, Kremer P, Angermann C, Iliceto S, Curtius JM, Miigge A. Safety of transesophageal echocardiography: a mul- Radiation-induced coronary Anil Om, MD, MS, Samer Ellahham, 9. 10. 11. 12. 13. December 1992 Heart Journal ticenter survey of 10,419 examinations. Circulation 1991; 83:817-21. Pearson AC, Caste110 R, Labovitz AJ, Sullivan N, Ojile M. Safety and utility of transesophageal echocardiography in the critically ill patient. AM HEART J 1990;119:1083-9. Bansal RC, Shakudo M, Shah PM, Shah PM. Biplane transesophageal echocardiography: technique, image orientation. and Dreliminarv experience in 131 patients. .J Am Sot Echo 1990;3:348-66. ” Miigge A, Daniel WG, Hausmann D, Godke J, Wagenbreth I, Lichtlen PR. Diaenosis of left atria1 annendaae thrombi bv transesophageal echocardiography: cl&al im$ications anh follow-up. Am J Cardiac Imaging 1990;4:173-9. Zenker G, Erbel R, Kramer G, Mohr-Kahaly S, Drexler M. Harnoncourt K, Meyer J. Transesophageal two-dimensional echocardiography in young patients with cerebral ischemic events. Stroke 1988;19:345-8. Siostrzonek P, Zangeneh M, Gossinger H, Lang W, Rosenmayr G, Heinz G, Stumpflen A, Zeiler K, Schwarz M, Mosslacher H. Comparison of transesophageal and transthoracic contrast echocardiography for detection of a patent foramen ovale. Am J Cardiol 1991;68:1247-9. Dawkins PR, Stoddard MF, Liddell NE, Longaker R, Keedy D, Kupersmith J. Utility of transesophageal echocardiography in the assessment of mediastinal masses and superior vena cava obstruction. AM HEART J 1991;122:1469-72. Karalis DG, Chandrasekaran K, Victor MF, Ross JJ, Mintz GS. Recognition and embolic potential of intraaortic atherosclerotic debris. J Am Co11 Cardiol 1991;17:73-8. Silver M. Gross examination and structure of the heart. In: Silver MD, ed. Cardiovascular pathology. vol 1. New York: Churchill Livingstone, 1983:12-30. artery disease MD, and George W. Vetrovec, MD Richmond, Va. Before the 196Os, the heart was thought to be resistant to the effects of radiation used to treat various oncologic diseases. l-3 Since then a number of case reports have documented that excessive radiation to the heart could lead to the development of pericarditis,4-6 pericardial effusion,6, 7 restrictive cardiomyopathy,8y g valvular abnormalities,8T lo and conduction abnormalities.ll, I2 Whether radiation therapy causes coronary artery disease (CAD) has been a topic of debate for the last several years. With the improveFrom the Division of Cardiology, ical College of Virginia. Received for publication Reprint requests: Anil Richmond, VA 23298. 4/1/41307 1598 April Department 6, 1992; Om, MD, Box of Internal accepted 281, May Medical Medicine. Med- POSITIVE REPORTS OF RADIATION-INDUCED CORONARY DISEASE 20. 1992. College ment in radiation techniques, more and more patients with malignant diseases are now treated with radiation, and significant numbers of these patients are now living for many years after such treatment. This has led to recent interest in radiation-induced CAD, because if radiotherapy in fact causes CAD, clinicians may encounter increasing number of patients with CAD after radiation therapy to the chest, even in the absence of other cardiovascular risk factors. In the present review, we will analyze the experimental and clinical data and establish the role of radiation in the induction of CAD. of Virginia, A number of single or small sample case reports have associated thoracic radiation for the manage- Volume Number Table 124 Radiation-induced 6 1599 I. Summary of casereports implicating radiation-induced coronary artery disease Age Reference Nakhjavan et al.‘:’ Tracy et a1.14 Annest et al.“’ Tommaso et al.‘” Grolloer et al.‘; McReynolds et al.” Tenet et al.lg Dunsmore et a1.2” Sande CAD et al.“’ Radwaner et al.?l Leong et a1.23 No. of cases (years) presentation at Sex Disease requiring radiation Port of radiation 54 F HD 35 51 F M HD HD Anterior Anterior 38 37 39 47 M M M M HD HD Thymoma HD Anterior Anterior 50 F Anterior 33 M Breast carcinoma HD Cardiac shielding used Interval radiation between & CAD Coronary stenosis fyri 10 RCA No No 1.5 12 LAD LAD, No No 16 LAD, LAD, RCA LM NO 5 LM 9 LAD, 13 18 9 - Anterior RCA, Cx RCA RCA RCA, CX 36 M HD Anterior 28 F HD 31 M HD 36 M HD 50 F 27 F Breast carcinoma HD Anterior & Posterior Anterior & posterior Anterior & posterior Anterior 34 M HD HD, Hodgkin’s disease; -, not mentioned; artery; LM. left main artery. CAD, coronary artery disease; Anterior & posterior Anterior RCA, ment of oncologic diseases with the development of CAD many years later 13-23(Table I). In addition, these reports have shown a higher than expected number of casesof isolated left main stenosis. Usual causes of isolated left main stenosis include syphilis, intimal fibrous proliferation,24 trauma during aortic valve replacement,25 and angioplasty of the proximal left anterior descending artery.24 Radiation-induced arteritis of the ascending aorta could involve the ostium of the left main coronary artery, causing isolated stenosis. In addition, for unknown reasons the proximal part of other epicardial coronary arteries have been more involved in radiation-induced CAD. The latent period from the time of radiation to the development of cardiac symptoms in all but two patients reportedr4* 2ohas been more than 5 years, with appearance in some as late as 29 years after radiation. Only a limited number of studies have evaluated long-term follow-up of a large number of patients after thoracic radiation. Host et a1.26 followed 1115 patients who had undergone radical mastectomy for breast cancer and who were randomized to receive either postoperative right coronary Yes after 3000 rads No 10 LM 9 CX No 12 No 4 LM, LAD, cx RCA, Cx No 5.5 LAD No 8 LM No 8 LAD, cx artery; LAD, left anterior descending artery: RCA, Cx, circumflex radiation (rz = 562) or no radiation (n = 553, control group). The type of radiation therapy given varied during the total duration of study. From 1964 to 1967 radiation given was 200 kV x-ray radiation and from 1968 to 1972 cobalt 60 radiation was used and in higher dosages. Protective cardiac shields were not used, and follow-up ranged from 11 to 20 years. Ten patients with stage 1 breast cancer receiving cobalt 60 radiation died of acute myocardial infarction as compared with only one in the control group (p = 0.004 by Fisher’s exact probability test). There was no significant difference in patients dying of acute myocardial infarction for stage 2 breast cancer receiving radiotherapy compared with the controls. Lack of higher cardiovascular deaths for stage 2 breast cancer could be a consequence of higher cancer deaths (approximately 50 SCbefore 8 years) in this group. Therefore half of these patients might have died before the expression of radiation-induced CAD occurred. Patients who manifested radiation-induced CAD in this study had received radiation in higher dosages and without cardiac shielding. Pohjola-Sintonen et al.“’ followed 28 patients who December 1600 Om, Ellahham, and Vetrouec had received radiation therapy for Hodgkin’s disease. Mean period of follow-up was 6.8 years (average 8 to 14 years). Radiation was given only through the anterior port and without any cardiac shielding. Two patients (7 % ) without any cardiovascular risk factors had developed angiographically documented CAD. One was a 31-year-old man and another was a 12year-old boy. McEniery et a1.28described 15 patients who had developed CAD varying from 3 to 29 years after radiation therapy. Mean age of these patients was 48 years (range 26 to 63). Details of radiation ports were not mentioned. Twelve of these patients had at least two cardiovascular risk factors, and therefore a strong cause-and-effect relationship between radiation and CAD was difficult to prove. NEGATIVE REPORTS CORONARY DISEASE OF RADIATION-INDUCED Hancock et a1.2g followed 326 patients with Hodgkin’s disease for 14 years (median) who were randomized to receive radiation alone (n = 167) or radiation combined with chemotherapy (n = 159). Radiation was given with a modern technique with proper cardiac shielding. Although nine patients died of acute myocardial infarction 2 to 19 years after radiation, this was not found to be higher than the expected rate for a nonirradiated age- and sex-matched control population. Mauch et a1.30followed 315 patients with Hodgkin’s diseasetreated with mantle and paraaortic radiation. Mean follow-up was 9 years (range 2 to 16 years). Radiation was given through the anterior and posterior portals with proper cardiac shielding. Three patients died of myocardial infarction 35 to 83 months after radiation but two of these had significant cardiovascular risk factors and therefore radiation alone could not be singled out as the cause of their demise. Boivin and Hutchison31 evaluated 957 patients with Hodgkin’s disease who had received thoracic radiation. Only 268 of these patients were followed for a maximum of 4 years. There was no increase in coronary mortality noted ascompared with amatched population. However, limited duration of follow-up might have skewed the results. ASYMPTOMATIC CORONARY DISEASE All the large prospective studies discussed above considered cardiovascular symptoms or mortality as evidence of radiation-induced CAD. Gottdiener et a1.32 evaluated 25 asymptomatic patients with Hodgkin’s disease who had received radiation therapy 5 to 15 years previously. None of these 25 patients American Heart 1992 Journal had any history of cardiac disease nor had any received any chemotherapeutic agents. Echocardiograms revealed decreased left ventricular end-diastolic dimensions in 12 of 24 (504,) and pericardial effusion in nine (36 9; ) patients. Fifteen patients underwent radionuclide cineangiography. Five patients had normal resting left ventricular ejection fraction that decreased with exercise, and two patients had a low resting ejection fraction; both of these patient,s were found to have angiographically documented CAD. All these patients had received radiation therapy according to old protocols, that is, large dosesof radiation through the single anterior port. This may explain the increased cardiac involvement. Perrault et a1.33demonstrated echocardiographic evidence of right ventricular hypokinesia in 14 of 36 (39”; ) and left ventricular dysfunction in 5 of 40 (13”; ) asymptomatic patients treated with radiation for Hodgkin’s disease and seminoma 5 years before the study. Ventricular dysfunction could have been a consequence of the underlying CAD, which was not evaluated in this study. Similarly, Brosius et a1.3” studied 16 patients at necropsy who had received radiation therapy in the past and who died under t,he age of 25 years. All patients again had received large doses of radiation through the anterior port. Of the 64 major coronary arteries (left main, left anterior descending artery, circumflex, and right coronary artery) in 16 patients, 16 (25r;,) had >75’,.; narrowing in cross-sectional area. In contrast, of the 40 major coronary arteries in 10 age- and sex-matched control subjects, only one had >75 “;# narrowing. The cause of death in these patients was not mentioned in the study. CONCLUSIONS FROM CLINICAL STUDIES Analysis of the existing data demonstrates that a small number of patients who received radiation through the anterior approach without any cardiac shielding later developed CAD. This association is further substantiated by the case reports of 12- and 15-year-old boysZ7*35 sustaining myocardial infarction after radiation without their having any cardiovascular risk factors. In contrast, none of the large studies in which patients received radiotherapy utilizing the modern technique of multiple portals with cardiac shielding revealed a higher incidence of CAD compared with controls. Histology. Histology of radiation-induced CAD has been found to differ from that of spontaneous atherosclerotic CAD. McReynolds et al’s demonstrated severe intimal fibrosis and thickening, with an increase in the number of plasma cells and a paucity of Volume Number 124 6 lipids in presumed radiation-induced CAD. The presence of large bizzare fibroblasts was shown by Fajardo et a1.8 In contrast, atherosclerotic CAD has fibrous tissue as the dominant component of the plaque with abundant lipids and the presence of lymphyocytes.“6, s5 Mechanisms. Excessive radiation to the heart without proper shielding leads to the induction of CAD. However, the precise mechanism is not clearly understood but may be related to the following processes. (I) Radiation causes damage to the vascular endothelial lining, leading to significant fibrosis (radiation arteritis) and narrowing. This has been demonstrated in coronary arteries of beagle dogs after radiation”’ and in biopsies of the aorta in humans undergoing coronary artery bypass surgery for presumed radiation-induced CAD.lg (2) The concomitant presence of hypercholesterolemia has been shown to potentiate the arterial radiation damage. 3g.4o The precise etiology of this synergism is not known. The presence of hypercholesterolemia may overstimulate the repair process of damaged endothelial lining via its effect on platelet aggregation, leading to excessive intimal fibrosis. (3) Concomitant or sequential use of chemotherpeutic agents, especially doxorubicin with radiation, could have an additive effect in the development of cardiomyopathy, as shown in humans41-43 and in rabbits.44,45 Whether or not this synergism translates to CAD is not known. Prevention. Radiation-induced cardiac toxicity depends on the total radiation dose, the treatment time, the heart volume radiated, the radiation source, and the technique. The following precautions may reduce the incidence of radiation-induced cardiovascular complications: (1) careful delineation of tumor volume and extent with the help of computed tomography (CT) scan or magnetic resonance imaging; (2) deliberate direction of the beam so as to avoid the cardiac “hot spot”; (3) judicious blocking or shielding of the cardiac “hot spot”; and (4) restriction of the dose within the tolerance limits if this does not affect the prognosis. Therapy. The management of CAD related to radiation is similar to that of CAD caused by spontaneous atherosclerosis. The majority of radiation-induced CAD is proximally located,15 and lesions are isolated and discrete and therefore should be easily amenable to percutaneous transluminal coronary angioplasty (PTCA). However, reported experience of PTCA in this situation is limited. Sande et al.‘l reported successful PTCA of the midportion of the left anterior descending coronary artery, and Nakhjavan et a1.13 reported similar success with a right Radiation-induced CALI 1601 coronary artery ostial lesion. Extra precautions with PTCA for these patients should be exercised because extensive mediastinal fibrosis may make an emergency coronary artery bypass surgery technically difficult. The rate of restenosis of radiation-induced CAD after PTCA is not known. The frequent occurrence of radiation-induced isolated left main161 17,lg, 2o and ostial lesions13T 28 may necessitate coronary artery bypass surgery.15> 46 The young age of these patients and the lack of other risk factors make the outcome for surgery potentially excellent, particularly with the use of the internal mammary artery conduit. However, if radiation has involved the distal vessels, suturing of the grafts to the distal vessels may be technically difficult. Also, extensive radiation-induced fibrosis may make surgical dissection technically more difficult, but wound healing has been found to be satisfactory in almost all cases. SUMMARY Excessive unprotected radiation to the heart appears to lead to the development of CAD, even in the absence of significant cardiovascular risk factors. The coexistence of such factors may enhance the probability of CAD. The presence of hypercholesterolemia and concomitant or sequential use of chemotherapeutic agents (especially doxorubicin) could further increase this risk. Therapeutic decisions, as with any other manifestation of CAD, relate to the extent of myocardium at jeopardy and to the overall diffuseness of CAD. Management options possible are PTCA or coronary artery bypass surgery. The latter may be required in left main artery stenosis and complicated ostial lesions. 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