Complete Atrioventricular Block Following Mediastinal Irradiation: A Report of Six Cases MICHEL S. SLAMA*, DOMINIQUE LE GULUDEC*. CLAUDE SEBAC*. ANTOINE R. LEENHARDT**. JEAN-MARC DAVY*. DENIS E. PELLERIN*. LUC H. DRIEU*. JACQUES VICTORt, CLAUDE BRECHENMACHER*, and GILBERT MOTTE* From tbe *H6pital A. Becl^re. Clamart. France; **H6pitaI Lariboisiere. Paris. France; the tCentre Hospitalier. Angers. France: and tCMCO. Strasbourg. France SLAMA, M.S.. ET Al..: Complete Atrioventricular Block Following Mediastinal Irradiation: A Report of Six Cases. Complete atrioventricular block (AVBJ following radiotherapy has been reported'rarely, usually after high dose mediastinal irrndiafion for Hodgkin's disease or Jung or brens( carcinonia, We report six neiv cases of episodic compJele infranodaJ AVB. requiring permanent pacemtiker impJanlation. The mean age was 48-years old (ranging from 25-60} at the first Adams Stokes attack, mean delay was 12 years after irradiation (10-18). und mean radiation dose was 5.200 rods (4,000-6.500). AU patients had abnormal intervai electrocardiograms (right hundie branch block in tivo, left bundle branch block in three, alternating left and right hundie branch block in one). Electrocardiograms during the episode of AVB or Holter recordings were consistent with infranodai block in all pcititmfs; electrophysioiogicai study performed in five patients confirmed infrunodal AVB in four, and one was normal. Pericardia! disease was constant, which included pericardia! constriction in four patients. Two patients died after failure of pericardiectomy to improve congestive heart failure, due to epicardiai, myocnrdinl. and endocardial involvement. Noncardiac mediastinai iesions were present in four cases. Since this delayed complication may occur in potients of such age that the relation between the AVB and the chest irradiation is questionable, we propose the following eiiologic criteria: high radiation dose (over 4.000 rods); delay of 10 years or more; abnormal interval tracings; pericordiul involvement; and associated cardiac or mediastinai radiation-induced iesions. (PACE, Vol. 14, fuly 1991) atrioventricuiar block, radiation therapy

Introduction Until recently, reports of atrioventricular block (AVB) following chest irradiation' " have considered the conduction system as highly resistant to the effects of radiotherapy, while pericardial,'^"^'^ myocardial,'^ valvular or coronary''^''"'"' involvement were frequently reported, mainly in patients with Hodgkin's disease or breast carcinoma, which were treated with

Address for reprints: Dr. Michel S. Slama, Service de Cardiologie. Hdpital Aninine B6i:lf>re. 157. Rue de la Porte de Trivaux92141 Clamart. France. Kax: (1) 45374961, Received August 15.1990; revision [anuary 28.1991: aucepled January 30. 1991.

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more than 4.000 rads to the chest. Some of these complications are delayed, their frequency seems to rise because of prolonged survival of patients.^** Wo report and discuss a series of six cases of documented AVB following mediastinal irradiation.

Patients' Data (Table I) Case 1 M.B.. age 25. was admitted in September 1981 after five Stokes Adams attacks. He was treated in 1971 for Hodgkin's disease with mediastinal irradiation (total dose 5.100 rads). Physic.al examination, chest X rays, and usual blood tests were normal upon admission. ECG tracings showed

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COMPLETE ATRIOVENTRIGULAR BLOCK FOLLOWING MEDIASTINAL IRRADIATION: A REPORT OF SIX CASES

Table 1.

Age

Delay (Years)

Dose (Rads)

1—B . . .

25

10

5100

2—G 3—A 4—E 5—V

. . . .

41 53 60 54

11 10 10

6—G . . .

55

.. .. .. ..

ECG Basal

AVB

EPS

III II, III II, III III III

HV = 60 msec A * HV = 110 msec HV = 40 msec

14

4500 5000 6000 4000

RBBB LBBB RBBB LBBB RBBB LBBB

18

6500

LBBB

II

PerJcardial Disease

+,s

+

+ .S Infranodal AVB HV = 55 msec A T^ Infranodal AVB H1H2 = 30 msec H^V = 50 msec Infranodal AVB for hr >110

other Radic Lesions

+, s +, s

Pleural Esophageal Cutaneous Pleural

+. s

Patients data. AVB = atrioventricular block; RBBB = right bundle branch bloci^; LBBB = left bundle branch biock; EPS = electrophysiological study; HV = His-ventricle deiay: A = ajmaiine testing; S = surgicai treatment.

complete high ciegree episodic AVB with no escape rhythm during the most recent syncopal episode. Later ECGs showed sinus rhythm with alternating right and left bundle branch block. Electrophysiological study showed a prolonged HV interval (60 ms) increasing to 110 ms after IV ajmaline infusion (1 mg/sec/kg). Two-dimensional echocardiogram showed a moderate pericardial effusion. A permanent DDD pacemaker was implanted. Poricardial constriction developed later, and the pericardiectomy performed in September 1987 failed to improve the hemodynamic status, resulting in early postoperative death from refractory congestive heart failure. Postmortem microscopic study was not available in this case, hecause of refusal of autopsy by the patient's family. Case 2 Mrs. G., age 41, was admitted in January 1982 for Adams Stokes attacks. She was treated in 1971 for Hodgkin's disease with mediastinal radiotherapy [total dose 4,500 rads), Physical examination and usual blood tests were normal upon admission. ECG tracings showed sinus rhythm, normal PR interval, and complete right bundle branch block. Holter recording showed several episodes of second degree (Mobitz II) and one episode of complete AVB. Electrophysiological study showed normal AH and HV intervals and did not allow to induce AVB even after ajmaiine infusion.

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Chest X ray showed a right pleural effusion. Twodimensional echocardiogram showed a slightly reduced end-diastolic left ventricular diameter with normal shortening, abnormal septal motion, and pericardial thickening with a small localized apical effusion, suggestive of chronic pericarditis. A pacemaker was implanted with uneventful evolution. Case 3 M.A., age 53, was admitted in May 1983 for Adams Stokes attacks. He was treated in 1973 for a mediastinal mass (epidermoid carcinoma] with 5.000 rads of chest radiotherapy causing radic esophagitis until 1977, Physical examination was normal. Chest X rays and usual blood tests were normal upon admission. ECG recordings showed either sinus rhythm with complete left bundle branch block, and 2:1 or complete AVB. Two-dimensional echocardiogram showed pericardial thickening with pericardial effusion. Surgery allowed us to obtain a pericardial biopsy (nonspecific fibrosis), to evacuate 2,000 cc of exudative liquid and to implant a pacemaker with epicardial electrodes. Evolution was uneventful. Case 4 Mrs. E., age 60, was admitted in August 1983 for acute pulmonary edema and Adams Stokes at-

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SLAMA, ET AL.

tacks. She was treated in 1973 for thyroid sarcoma by surgery and radiotherapy of the cervical zone and of the chest (total dose 6,000 rads) and had a mild hypertension, which was treated with clonidine. She underwent pericardiocentesis in 1976 for acute pericarditis; the biopsy showed pericardial fihrosis. Physical examination on admission showed upper thoracic radiodormitis, acute pulmonary edema, blood pressure of 150/80 mmHg, and a heart rate 55 beats/min. Usual hlood tests were normal. ECG recordings showed high degree AVB. 2:1 AVB with right bundle branch block. Two-dimensional echocardiogram showed pericardial thickening without pericardia! effusion, rigid diastolic aspect of the left ventricular posterior wall, paradoxical septal motion, and dia-

stolic opening of the pulmonary valve contemporary with the P waves, strongly suggestive of chronic constrictive pericarditis. Right heart catheterization during AVB [escape rhythm 55 beats/ min) showed typical features of pericardial constriction. Electrophysiological study during AVB showed normal AH interval [90 ms) and infranodal AVB. A DDD pacemaker was implanted and pericardiectomy was performed in September 1983; histologic examination showed pericardial fibrosis. ECG obtained during atrial lead replacement, in 1986, showed permanent complete AVB. Case 5 Mrs, V., age 54, was admitted in February 1985 after two Stokes Adams attacks. She was

Figure 1. Postmortem microscopic study of the heart (case 5|; nonspeci/ic fibrosis invoiving the epicardium, myocardium, and endocardium, without lesions of the smalJ arteries. (A) Thick arrows indicate the left bundJe branch, which is almost replaced by fibrous (issues. (B) Thick arrows indicate the right bundie branch, small arrows indicate vacuolar lesions. fCJ Important /ibrosis of the interventricuJar septum, close to the atrioventricular node. F = fibrosis.

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COMPLETE ATRIOVENTRICULAR BLOCK FOLLOWING MEDIASTINAL IRRADIATION: A REPORT OF SIX CASES

treated in 1971 for Hodgkin's disease with radiotherapy (4,000 rads over the mediastinum and 3,700 rads over the clavicular zones] and with chemotherapy. Asymptomatic chronic pericardial effusion was diagnosed in 1972, her ECG was normal nntil 1976; no recording was availahle from 1976 to 1985. She experienced occasional chest pain on exertion since 1983. Upon admission, physical examination showed regular tachycardia 95 beats/min. and was otherwise normal. The X rays showed a round-shaped, slightly enlarged heart with right pleural effusion. Thoracocentesis showed chylous liquid, rich in proteins [47 g/L). The ECG showed sinus rhythm at 95 beats/min, and an increased PR interval (240 ms) with left bundle branch block. The echocardiogram showed pericardial thickening with moderate effusion, a rigid diastolic pattern of the left ventric-

ular posterior wall, and parodoxical septal motion. Coronary and left ventricular angiography were normal (ejection fraction 66%). Cardiac catheterization showed typical features of constrictive pericarditis. Electrophysiological study showed a HV interval of 55 ms; ajmaline infusion induced complete infranodai hlock. A permanent pacemaker was implanted in March 1985. Later evolution was complicated with chronic heart failure due to pericardial constriction, leading to pericardiectomy in January 1986. Macroscopic findings were pleural, pericardial, and epicardial fibrosis. Pericardiectomy failed to improve the hemodynamic status, and the patient died soon postoperatively from refractory congestive heart failure. Postmortem microscopic study of the heart (Fig. 1) showed epicardial, myocardial and endocardial nonspecific fihrosis, extended to both

1 SEC.

I

II

Figure 2. Electrophysioiogicai study (case 6) 2:1 intra-Hisian AVB (AHi = 100 ms;

= 30

ms; H^V = 50 ms).

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SLAMA, ET AL. bundle branches, without lesions of the AV node or the His bundle. There were no lesions of the small arteries. Case 6 M.G., age 55, was admitted in February 1989 after two Stokes Adams attacks. He was treated for Hodgkin's disease in 1971 with 5,000 rads to the mediastinal area and chemotherapy, and in 1979 with 1,500 rads for a recurrence. His cardiac status had been thoroughly investigated previously: a left bundle branch hlock appeared in 1972, he had an anterior myocardial infarct in 1984, and was operated on in 1985 (pericardiectomy for constrictive pericarditis and failed coronary artery hypass graft to the left anterior descending coronary artery). He had a moderate aortic valvular disease (Doppler aortic valve area 1.5 cm^, minor aortic regurgitation) with normal left ventricular ejection fraction (62% by gated hlood pool study). Physical examination upon admission was consistent with the aortic valvular disease. Usual blood tests were normal, FCG tracings showed sinus rhythm with first-degree AVB and left bundle branch block, alternating with 2:1 AVB. Eiectrophysiological study (Fig. 2) showed intra-hisian AVB with a splitting of His-bundle activity recordings (AHi - 100 ms: H.H. = 30 ms; H^V = 50 ms) with 2:1 AVB after Hi activity when sinus rhythm was > 110 beats/min. A permanent pacemaker was implanted in February 1989 with uneventful evolution. Discussion Cardiac lesions following high dose mediastinal irradiation have been often reported. Most of the interest is usually focused on pericardial effusion or constriction, myocardial or coronary lesions, while relatively few reports of AVB are available. To date, 13 cases of radiation-related AVB have been reported'"'' (Table II). The relation between AVB and chest irradiation can be suspected after several questions have been scrutinized: age at the onset of the AVB. delay between radiation therapy and the first syncope, radiation dose. AVB location as defined by FCG and electrophysiological study, pericardial and epicardial lesions, and other noncardiac mediastinal lesions.

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Data from our patients and from previous reports are summarized in Tables I and IL 1. Age at the onset of the AVB: It ranges between 25 and 60 years (mean 48) in our series, consistent witb data from previous reports (25 to 73 years, mean 45). Young age can be a strong argument for a radiation-related lesion of AV pathways, although it is not definite. 2. Delay after irradiation of the chest: It ranges between 10 and 18 years (mean 12 years), which is consistent with previous reports (mean 12 years). Although two cases were reported a few months after irradiation,'* AVB usually occurs more than 10 years after treatment. Reports of sucb delayed complications may be more frequent as the overall survival of patients is improving. A 12year survival rate of 70% was recently reported among 14.225 cases of Hodgkin's disease, pooled in an international database.^" 3. Radiation dose; The mean dose in our patients is 5,200 rads (4.000 to 6,500). which is similar to that of previous reports. The exact dose delivered to the beart is often difficult to ascertain because of delay, multiple fields of irradiation, repeated treatments, and changing protocols. 4. AVB location: All the patients in our series had abnormal interval ECG tracings, with right, left or alternans bundle branch block. Complete infranodai AVB was documented in four out of six patients during electrophysiological study, with or without ajmaline infusion. This pharmacological test is part of the routine of our laboratory, and has been previously described as highly sensitive for the detection of episodic AVB.^^ One patient (case 2) had Mohitz II and complete AVB witb normal electrophysiological study, and one patient (case 3) had no electrophysiological study; clinical and ECG features were strongly suggestive of infranodai AVB. In previous reports, the ECG tracings were not always available, and electrophysiological study was performed in six patients, consistent with nodal AVB in one. and infranoda! AVB in five. Analysis of data from the other cases suggests three more cases of infranodai AVB. Microscopic study of tbe heart was performed in one patient (case 5) who had documented infranodai AVB and severe constrictive pericarditis. It showed severe nonspecific fihrosis of both bundle branches, witbout lesions on tbe AV node or the

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COMPLETE ATRIOVENTRICULAR BLOCK FOLLOWINC MEDIASTINAL IRRADIATION: A REPORT OF SIX CASES

Table II. Age (AVB)

Delay (Years)

Dose (Rads)

Rubin

67

23

AM Tzivoni

25 50

63

Report

Cohen Patri Kereiakes

Prez

ECG Basal

EPS

Pericardial Disease

Massive

LBBB

-

-

6 18

4600-5000 6700

RBBB ^ LAFB -

-

+ -

23

3700

-

-

-

31

11

1 month 5 months

4000 4600 4500 4000

-

68 73 42

33

16

AVB

AVB 1 RBBB

RBBB + LAFB

14

Fischbein

38

13

4900

Mary-Rabine

27

8

4000

AVBI RBBB + LAFB AVBI RBBB + LPFB

EbagostI

42

12

5200

RBBB + LBBB

Velebit

30

13

6300

RBBB

Nodai AVB

+

_ HV = 65 ms Infranodal AVB (intra hisian} HV = 50 A +, infranodal AVB Infranodal AVB HV = 100 msec

_ + . Constrtctive pericarditis -

Other Radrc Lesion Cutaneous pulmonary Cutaneous pleurai Cutaneous pulmonary Pleural

-

-

+

Pulmonary

AH = 145 HV = 75 Infranodal AVB splitted HiH2

-

Pulmonary

_

+

Puimonary stenosis RV outflow tract obstruction

Previous reports of radiation related AVB. Same abbreviations as in Table I,

His bundle and without arterial lesions; the patchy fibrosis extended to the myocardium and the endocardium. Previous microscopic studies performed by Rubin et al.^ showed fibrosis interrupting the left bundle branch and hyalinized vessels, while in the case reported by Cohen et al."^ there was fibrosis of the AV node and both bundle branches, with extension to the endocardium, the myocardium and the epicardium and small arteries lesions. Tbe latter seem to be quite specific of radiation-induced lesions, but were not found in our patient. 5. Pericardial and epicardial involvement: It was present in four of 13 patients from previously reported cases,^'*'^*' but its real frequency is uncertain because cardiac catheterization and twodimensional echocardiography have not always been performed. Some degree of pericardial disease was present in ail our patients; five of six

PACE, Vol. 14

required surgical treatment, either pericardiocentesis [one of six) or pericardiectomy for constrictive pericarditis (four of six). In two cases, pericardiectomy failed to improve hemodynamic status, most probably because of epicardial involvement, as confirmed by histologic findings and consistent with previous reports.^^ 6. Associated radiation-induced lesions: Pleural, esophageal, or cutaneous lesions wore present in four of six patients in our series and in eight of 13 previous cases (including two cases of pulmonary stenosis or right ventricular outflow tract stenosis). The frequency of these lesions is related to the high doses of radiations used. Conclusion From the analysis of our series and of previous cases, we conclude that the relation between

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SLAMA, ET AL.

radiation therapy and AVB can be strongly suspected in patients who had high radiation doses (over 4,000 rads to the cardiac area), usually 10 years or more hefore the onset of AVB, presenting with abnormal interval tracings (bundle branch block), pericardial disease, and other cardiac or mediastinal radiation- induced lesions. The frequency of radiation related AVB, which appears as a delayed complication, is apparently increasing as the overall survival of the patients is improving. References 1. Rubin E, Camara J, Grayzel D, et al. Radiation induced cardiac fibrosis. Am I Med 1963; 34:71-75. 2. Ali MK, Khalil K, Fuller L, et al. Radi at ion-related myocardia! injury. Cancer 1976: 38:1941-1945. 3. Tzivoni D, Ratzkowski E, Biran S, et al. Complete heart block following therapeutic irradiation of the left side of the chest. Chest 1977; 71:231--234. 4. Patri B, Patri H. Bloc auriculoventriculaire succedant & le radiotherapie thoracique. Sem Hop Paris 1977; 53:2141-2142. 5. Mary-Rabine L. Waleffe A, Kutbertus ME. Severe conduction disturbances and ventricular arrhythmias complicating mediastinal irradiation for Hodgkin's disease: A case report. PACE 1980; 3:612-617. 6. Cohen S, Bharati S, Glass J, et a!. Radiotherapy as a cause of complete atrioventricular block in Hodgkin disease. An electrophysiologicai-pathological c:orrelation. Arch Intern Med 1981; 141:676-679. 7. Kereiakes DJ. Morady JF; Ports TA. High degree atrioventricular block after radiation therapy. Am I Cardiol 1983: 51:1233-1234. 8. Velebit V, Von Segesser L, Gabathuler J, et al. Right ventricular outflow obstruction after radiation therapy. J Thorac Cardiovasc Surg 1986; 92:153155.

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9. Fischbein L, Valtier B, Sacbs RN, et al. Bloc auriculo-ventriculaire radique. Arch Mai Coeur 1987; 12:1823-1825. 10. Prez M, Degbeldere CH. Une observation de bloc auriculo-veiitriculaire post radique. Stimucoeur 1988; 15:269-270. 11. Ebagosti A, Gueunoun M, Fevre R, et al. Bloc auriculo-ventriculaire, complication de la radiotherapie du mediastin. Arch Mai Coeur 1989; 82:935-939. 12. Brosius FC, Waller BF. Roberts WC. Radiation beart disease. Analysis of 16 young necropsy patients wbo received over 3500 rads to tbe heart. Am J Med 1981; 70:519-530. 13. Gottdiener JS,KatinMJ, Borer JS, etal. Late cardiac effects of therapeutic mediastinal irradiation. Assessment by echocardiograpby and radionuclide angiography. N Engl J Med 1983; 308:569-572. 14. Fajardo LF, Stewart JR, Cohn KE. Morphology of radiation induced beart disease. Arch Patbol 1968; 86:512-519. 15. Applefeld MM, Cole JF, Pollock SH, et al. The late appearance of cbronic pericardial disease in patients treated by radiotherapy for Hodgkin's disease. Ann Intern Med 1981: 94:338-348. 16. Fowler NO. Constrictive pericarditis. New aspects. Am J Cardiol 1982; 50:1014-1017. 17. Walsh TJ, Baughman KL, Gardner TJ, et al. Constrictive epicarditis as a cause of delayed or absent response to pericardiectomy.) Thorac Cardiovasc Surg 1962; 85:126-132. 18. McReynolds RA, Roberts WC. Coronary heart disea.se after mediastinal irradiation for Hodgkin's disease. Am J Med 1976; 60:39-45. 19. Huff H, Sanders EM. Coronary artery occlusion after radiation. N Engl J Med 1972; 286:780. 20. Somers R. Henry-Amar M, Meerwaldt JH, et al. Treatment strategy in Hodgkin's disease. Colloque INSERM John LIBBEY EUROTEXT Ltd. 1990, 196:169-418. 21. Cuerot C, Coste A, Valere PE, et al. L'epreuve a l'ajmaline dans le diagnostic du bloc auriculo-ventriculaire paroxystique. Arub Mai Coeur 1973; 66:1241.

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