Postgraduate Medical Journal (1986) 62, 1055-1058 Postgrad Med J: first published as 10.1136/pgmj.62.733.1055 on 1 November 1986. Downloaded from Myocardial hypertrophy, fibrosis and infarction following exposure ofthe heart to radiation for Hodgkin's disease

Luke O'Donnell', Terence O'Neill', Mary Toner2, Sean O'Briain2 and Ian Graham1 'Adelaide Hospital, 2St. James's Hospital and the Departments ofMedicine and Histopathology, Trinity College, Dublin, Republic ofIreland

Summary: A 35 year old man was treated for stage IIA Hodgkin's disease by radiation to the upper thorax, axillae and neck. Three years later he presented with intractable and ultimately fatal congestive . Autopsy revealed massive biventricular hypertrophy with widespread subendocardial fibrosis and , but with little . Such a complex of features has not previously been described after and cannot be adequately explained by other known causes of heart muscle disease. with extensive subendocardial fibrosis may be part of the spectrum of radiation heart disease.

Introduction Protected by copyright. Radiation-induced heart disease is well described and consumed 40 g of alcohol per day for 15 years. usually manifests as acute or chronic Assessment, including laparotomy and splenectomy, (Cohn et al., 1967; Stewart & Fajardo, 1971; Applefeld revealed right axillary and supra-clavicular lym- et al., 1981) although (Burch et al., 1968), phadenopathy due to lymphocytic predominant Stage myocardial fibrosis (Rubin et al., 1963), valvulitis IIA Hodgkin's disease. Radiation treatment was given (Brosius et al., 1981), coronary artery disease (Tracy et as 3,500 rads in divided doses in a 'mantle' distribution al., 1974) and myocardial infarction (Dollinger et al., to the neck and upper thorax which did not exclude the 1966; McReynolds et al., 1976) also occur. heart. Both axillae were exposed to 3,500 rads and a Echocardiographic and radionuclide ventriculo- boost of 600 rads to the right axilla was given. He graphy abnormalities have also been reported in a received no cytotoxic therapy. substantial proportion of asymptomatic patients who He remained well until three and a half years later previously received radiation therapy (Burns et al., when he developed dyspnoea on exertion, paroxysmal 1983; Gottdiener et al., 1983). We report a case of nocturnal dyspnoea and chest tightness. The pulse was with widespread subendocardial regular with a rate of 120 beats/min, blood pressure fibrosis, massive biventricular hypertrophy, mural was 90/60 mmHg, and thejugular venous pressure was http://pmj.bmj.com/ thrombi and myocardial infarction, a complex of raised to 10cm. The apex beat was displaced laterally features not previously described following radiation and was dyskinetic with a prominent gallop-rhythm. therapy. Bibasal crepitations were heard in the lung fields and ankle oedema was noted. Chest X-ray showed gross with pul- Case report monary congestion. Left and biatrial overload were present on the electrocar- A 35 year old previously healthy male presented with a diogram. and radionuclide ven- on September 25, 2021 by guest. 10 year history of axillary swelling. He had no cardiac triculography showed a severely dilated left ventricle symptoms and cardiovascular examination was nor- with uniformly poor function. Routine haema- mal. There was no history of hypertension. He had tological and biochemical investigations were normal smoked 40 cigarettes per day for 20 years and as were serum iron, total iron binding capacity, serum thyroxine, Coxsackie, cytomegalovirus, Q fever and Correspondence: I. Graham, F.R.C.P.I., F.C.C.P., Depart- toxoplasma titres, and rectal biopsy for amyloid. ment of Cardiology, Adelaide Hospital, Dublin 8, Republic Conventional therapy with digoxin and diuretics of Ireland. was instituted. Over the following year, he was Accepted: 30 May 1986 admitted to hospital on eight occasions with progres- © The Fellowship of Postgraduate Medicine, 1986 1056 CLINICAL REPORTS Postgrad Med J: first published as 10.1136/pgmj.62.733.1055 on 1 November 1986. Downloaded from sive right and left heart failure requiring vasodilator bus. The coronary arteries showed only mild focal therapy and eventually inotropic support. During this atherosclerosis with a maximum stenosis of50% in the period he developed pulmonary Mycobacterium xen- left anterior descending artery 6 cm from its origin and opi infection which responded well to isoniazid and 30% stenoses of the circumflex and right coronary ethambutol. Rifampicin was discontinued because of arteries 2 cm from the origin ofeach. There was a mild the development ofjaundice. Cardiac transplantation obliterative fibrous pericarditis. The valves were nor- was considered and declined. One year after presenta- mal. tion to us the patient died from unresponsive cardiac Ventricular wall histology showed striking suben- failure complicated by a chest infection. docardial fibrosis varying from 1 to 10mm in thick- Post-mortem examination showed no evidence of ness involving all of the left ventricle apart from the Hodgkin's disease, mycobacterial infection or liver lateral wall and involving most of the right ventricle. disease. The heart weighed 820g. There was biven- There was widespread entrapment of myocardial tricular hypertrophy with a muscle thickness of 1.9 cm trabeculae by the fibrosis. This pattern offibrosis with (left ventricle), 0.6 cm (right ventricle) and four cham- myocardial trabecular entrapment reached a thickness ber dilatation. Grossly, the ventricular walls showed of 10mm in the anterior half of the interventricular two fibrotic areas: a transmural area of the posterior septum giving the gross appearance of a discrete area wall (7 x 4cm) extending to the apex and a suben- of infarction (Figure 1). The posterior wall showed docardial area in the anterior half of the septum transmural fibrosis with loss of myocardium consis- (6 x 5 cm). Both areas were covered by mural throm- tent with an area ofischaemic infarction. Special stains indicated that the subendocardial fibrosis was com- posed mainly ofcollagen; however, moderate amounts of elastic fibres were present close to the underlying muscle. Scattered foci oflymphocytes and plasma cells were present in association with the areas of suben-

docardial fibrosis. The myocardial cells showed enlar-Protected by copyright. ged pleomorphic nuclei consistent with hypertrophy. There were occasional small foci of fibrosis scattered throughout the myocardium. The atria demonstrated mild muscle hypertrophy but the atrial appeared normal. Histology ofthe coronary arteries showed eccentric atheromatous plaque formation in the areas seen grossly. There was a mild degree ofintimal thickening ofthe small vessels throughout the myocardium with a modest (10%) reduction in lumen size.

Discussion

The most striking features in our patient were the http://pmj.bmj.com/ presence of widespread subendocardial fibrosis in a massively hypertrophied and dilated heart, a complex which has not been described previously in association with radiation. This was associated with mural throm- bus and an area of transmural infarction despite mild coronary artery disease. Fibrous pericarditis has

frequently been described in patients who have re- on September 25, 2021 by guest. ceived radiation (Cohn et al., 1967; Applefeld et al., 1981) but was only of a mild degree in our patient. The area of myocardial infarction described is not easily explained as there was no discrete clinical episode to suggest myocardial infarction and only mild focal coronary artery disease was noted. Figure 1 Section of left ventricle. L indicates left ven- However, an embolus from the left ventricular mural tricular lumen. Mural thrombus (T) overlies thickened thrombus, a completely resolved coronary artery endocardium (E). Focal interstitial fibrosis (F) is seen thrombosis in a heavy smoker or direct radiation within the myocardium. Haematoxylin and eosin x 50. damage are all possibilities. The degree of both CLINICAL REPORTS 1057 Postgrad Med J: first published as 10.1136/pgmj.62.733.1055 on 1 November 1986. Downloaded from hypertrophy and subendocardial fibrosis is far in conduction defect associated with conducting tissue excess of secondary changes which might be expected fibrosis). The predominant finding in these patients to occur if a myocardial infarction was the primary was widespread patchy fibrosis of the myocardium. event. The hearts were only mildly enlarged (295 g-375 g). Myocardial hypertrophy with dilatation, suben- Burch et al. (1968) described the electron microscopy docardial fibrosis and mural thrombus may be seen in findings in a patient who died from cardiac failure 5 and in the late stages of viral years after mediastinal radiation for thyroid cancer myocarditis. Typical or atypical reaction to viral or but no reference to gross enlargement of the heart or other infections might be expected in a patient with subendocardial fibrosis was made. In a series of 25 Hodgkin's disease, even in remission, as evidenced by patients followed for a median period of 96 months the occurrence of pulmonary infection due to an after mediastinal radiation for Hodgkin's disease atypical mycobacterium in this case. Therefore, coin- Applefeld et al. (1982) noted that one patient had cidental or opportunistic viral myocarditis cannot be clinical evidence of cardiomyopathy. No histological excluded. However, serology for several suspect information was available as the patient was still alive. viruses was negative, inflammatory infiltrate was There appear to be many possible pathological minimal and the degree ofsubendocardial fibrosis was responses of the heart to radiation, including pericar- greater than usually described in association with viral ditis (Cohn et al., 1967; Applefeld et al., 1981), diffuse myocarditis or dilated cardiomyopathy. The gradual myocardial fibrosis (Rubin et al., 1963) and coronary clinical onset would also be unusual for viral myocar- artery disease (Tracy et al., 1974). Why any one ditis. finding should predominate in a particular patient is There was no clinical or pathological evidence of unknown, and it is uncertain why our patient had , hypertrophic obstructive cardio- predominant subendocardial fibrosis with myocardial myopathy, hypertension or valvular disease. Alcohol hypertrophy. Alcohol may have rendered the heart is unlikely to have had a primary role in the aetiology more susceptible to the described injury. Tissue reac-

in view of the quantity ingested and the fact that this tion to radiation is always more pronounced in Protected by copyright. degree ofhypertrophy and subendocardial fibrosis are previously inflamed or damaged areas. The endocar- unusual in myocardial disease due to alcohol abuse. dium as a modified endothelium may also be subject to However, a secondary role for alcohol in accelerating damage similar to the endothelial damage frequently the heart failure is possible. Malnutritional effects found as a radiation effect (Cohn et al., 1967). The often associated with alcohol intake are unlikely as massive hypertrophy may have been secondary to a nutrition was well maintained in our patient. Neither non-compliant left ventricular wall stiffened by the clinical presentation nor autopsy findings suggest subendocardial fibrosis. syndrome or Loffier's . Treated Hodgkin's disease is nowadays associated Many factors suggest the possibility of a direct with an excellent prognosis. Many of the long-term radiation reaction in this case. There is a history of problems in these patients now result from complica- exposure to significant doses of radiation without tions of therapy rather than of the primary disease protection of the heart. The onset of the illness three itself(Carmel & Kaplan, 1976). As more ofthese cured and a half years after radiation is consistent with the patients accumulate it is important to define carefully time lag ofdelayed onset radiation-induced disease. In and be aware of the range of therapy-induced com- addition there is no evidence indicative of viral plications for two reasons. Firstly, so that the therapy http://pmj.bmj.com/ myocarditis or other known forms of car- for the initial disease can be modified and secondly so diomyopathy. that complications of therapy will be recognized as Heart muscle disease other than fibrosis has rarely such and treated accordingly. The possibility of a been described as a complication ofradiation therapy. cardiomyopathy should be considered in patients with Rubin et al. (1963) reported the post-mortem findings cardiac disease who have had previous radiation to the ofthree patients exposed to mediastinal radiation, one mediastinum. of whom died from a cardiac cause (progressive on September 25, 2021 by guest.

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