CASE REPORTS

Endomyocardial Disease and EosinophiliaReport of a Case

BRIAN E. JASKI, EDWARD J. GOETZL, M.D.,JONATHAN W. SAID, M.B., CH.B., AND MICHAEL C. FISHBEIN, M.D.

SUMMARY While an association between blood eosinophilia andendomyocardial disease has been recognized, the role of theeosinophil in the pathogenesis of the cardiac lesions remains uncer-tain. In a 69-year-old man with large cell carcinoma of the lung,marked eosinophilia was stimulated by and progressed with thecourse of the neoplasm which was producing an eosinophil chemotac-tic factor. Peripheral blood eosinophils were vacuolated anddegranulated while those in the bone marrow were morphologically

SINCE 1893, when Reinbach first described a right ventric-ular endocardial mural thrombus in a patient witheosinophilia,1 the association between blood eosinophiliaand endomyocardial disease has been recognized in variousclinical entities including Loffler's endocarditis parietalisfibroplastica,2 Davies' African endomyocardial fibrosis,3eosinophilic leukemia,4 and eosinophilic collagen disease.5Although the two latter conditions are characterized bywidespread eosinophil infiltration of other tissues in additionto the heart and lung, it has been suggested that all of thesediseases are representative of a continuum.' 7 Peripheralblood and bone marrow eosinophils from patients withhypereosinophilic disease manifesting cardiac and othertissue infiltration have shown a degree of degranulation andvacuolization greater than normal subjects or patients withtransient eosinophilia.8 9 Labelled autologous eosinophils insuch patients disappear from the circulation more slowlythan normal cells, after an initial phase of rapid clearanceand reappearance, which suggests transient entry into tissuespaces.10 Presumably, massive infiltration of the heart witheosinophils is associated with cardiac dysfunction. Inpatients with cardiac disease, however, no direct causativerole for the eosinophil in the pathogenesis of the cardiaclesions has been established.Our finding of endomyocardial disease in a patient with

chronic peripheral blood eosinophilia and eosinophil infiltra-tion of pulmonary and cardiac tissues secondary to abronchogenic tumor indicates that profound eosinophilia ofdiverse causes may be associated with endomyocardial dis-ease. An apparently unique 300-400 molecular weight pep-tide eosinophil chemotactic factor was recognized in tumor

From the Department of Pathology, Peter Bent Brigham Hospital and theDepartment of Medicine, Robert Breck Brigham Hospital and the HarvardMedical School, Boston, Massachusetts.

Supported by NIH Grant HL 06370-16. Dr. Goetzl is the Director of theLaboratories for the Study of Immunological Diseases of the Howard HughesMedical Institute.Address for reprints: Dr. Michael C. Fishbein, Department of Pathology,

Peter Bent Brigham Hospital, 721 Huntington Avenue, Boston,Massachusetts 02115.

Received September 27, 1977; revision accepted November 14, 1977.

normal. Clinical evidence of cardiac dysfunction developed one monthprior to death. At autopsy, 12 months after the onset of symptoms,endomyocardial disease was present. There were numerouseosinophils in the damaged myocardium and surrounding thepulmonary neoplasm. In patients with endomyocardial disease andeosinophilia, the eosinophil may be directly cardiotoxic or a primarymediator of cardiac damage; therapeutic attempts to reduce thenumber of eosinophils might be of benefit.

tissue extracts, tumor cell media and urine. Functionalchemotactic deactivation of the patient's eosinophils inassociation with rising urinary levels of the peptide factorsuggests that it or other- tumor products induced in vivoalterations in the eosinophils which may contribute to theirpotential for tissue damage.

Case Report

The patient was a 69-year-old white male with an 80-pack year history of cigarette smoking, who presentedfor the first time in January 1975 with shortness of breathand a chronic productive cough. Chest X-rays revealed aright lower lobe lung mass. An open lung biopsy establishedthe diagnosis of large cell bronchogenic carcinoma. FromJanuary to December his clinical course was characterizedby progressive respiratory difficulties and weight loss. Dur-ing that period of time laboratory investigations revealed amarked progressive blood eosinophilia:

Date

1/753/7510/7512/75

WBC

12,26014,60027,00021,200

% Eosinophils

10285065

% Degranulated,VacuolatedEosinophils

Not assessed163448

The peripheral blood eosinophils were markedly de-granulated and many had prominent vacuoles. The extent ofboth abnormalities increased with progression of the level ofeosinophilia during the course of the malignancy.

In November the patient received one dose of Cytoxan,375 mg, and Adriamycin, 30 mg/M2 which did not result inany clinical improvement. By December he had lost 100 lbs,was extremely dyspneic and for the first time developedankle edema and a persistently irregular cardiac rhythm.The electrocardiogram showed frequent atrial extrasystoleswith brief runs of atrial tachycardia, often with aberrantventricular activation. These cardiac abnormalities were

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ENDOMYOCARDIAL DISEASE/Jaski, Goetzl, Said, Fishbein

FIGURE 3. Dense infiltrate of eosinophils within the myocardiumbeneath an endocardial mural thrombus (T). (H & E, X 40.)

FIGURE 1. Opened left ventricle showing the large apical muralthrombus (T) and patchy subendocardial fibrosis (arrows).

thought to be due to pericardial metastases and/or myo-cardial disease. The lung mass and associated pulmonary in-filtrates and pleural effusion precluded accurate radiologicassessment of heart size. On December 22, 1975, 12 monthsafter onset of symptoms, the patient died of respiratoryfailure.

Anatomical Findings

In the lung there was a 7 cm mass originating in the rightmain bronchus which extended into the lung parenchyma,diaphragm, and parietal pericardium. Microscopically, thetumor was composed of very large pleomorphic cells with

FIGURE 2. Beneath the mural thrombus (T), the endocardium (E)is thickened by collagenous tissue which extends into the underlyingmyocardium. (Trichrome, X 40.)

bizarre, hyperchromatic, and sometimes multiple nucleicontaining prominent nucleoli. Mitoses were common. Themain tumor mass was surrounded by a cellular infiltratecomposed mainly of eosinophils which had reduced numbersof cytoplasmic granules. Areas of bronchopneumonia alsowere present in the lung.The heart weighed 420 g and was free of direct involve-

ment by tumor. The left ventricular cavity contained anapical mural thrombus, 4 cm in diameter, superimposed ona thickened endocardium (fig. l). Other similar but smallerthrombi were present in the right and left ventricles.Microscopically, there was organization of the thrombi byconnective tissue proliferating from the endocardium. Theconnective tissue, which contained very few elastic fibers,also extended into adjacent myocardium where areas of in-terstitial and replacement fibrosis were present (fig. 2).There were cellular infiltrates in the myocardium composedalmost entirely of eosinophils (fig. 3) with reduced numbersof cytoplasmic granules adjacent to areas of fibrosis. Focalareas of myocardial necrosis were also present and in-filtrated by eosinophils (fig. 4). The fibrosis, necrosis andeosinophilic infiltrates tended to involve predominantly the

K :FIGURE 4. Necrotic myocardial fibers surrounded by a dense in-filtrate of mature eosinophils. (H & E, X 40.)

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VOL 57, No 4, APRIL 1978

subendocardial myocardium adjacent to areas with over-lying endocardial fibrosis and mural thrombi. The extra andintramural coronary arteries and cardiac valves were nor-mal.

Infiltrates of eosinophils were present in the sinusoids ofthe liver and spleen but not in any other organs. The bonemarrow was hypercellular with a myeloid: erythroid ratio ofapproximately 10: 1. Mature, structurally normal eosino-phils were the predominant cells. Unlike the eosinophils inthe circulation and those seen in the heart and lungs, thebone marrow eosinophils were filled with their character-istic granules. There were no visceral infarcts or other evi-dence of embolization of the intracardiac mural thrombi.No renal or vascular lesions were observed.A peptide of approximately 300-400 molecular weight

with preferential chemotactic activity for eosinophil PMNleukocytes in vitro was isolated from extracts of the tumor,appeared in the patient's urine and was elaborated by long-term cultures of dispersed tumor cells.11 A comparableeosinophil chemotactic factor was isolated from anaplasticlarge cell tumors of the lung of two other patients with eo-sinophilia of the peripheral blood as well as tumor and sur-rounding tissues, but was absent from a pulmonaryadenocarcinoma associated with peripheral bloodeosinophilia and a renal cell carcinoma metastatic to thelung which evoked only pulmonary and pleural eosinophilia.The eosinophil chemotactic peptide was approximately thesame size as the tetrapeptide of the eosinophil chemotacticfactor of anaphylaxis (ECF-A), but was distinctly lessacidic." Eosinophils from this patient and one other who ex-hibited high concentrations of the factor in tumor extractsand urine were hyporesponsive in vitro to their tumor factorand other chemotactic principles, which is functionally con-sistent with a state of chemotactic deactivation.

Discussion

Although the association of endomyocardial disease andeosinophilia is well documented,1-7 12-24 the role of theeosinophils in the pathogenesis of the cardiac lesions isobscure. Many authors feel that the eosinophilia is only anassociated phenomenon,5' 12-14 while others suggest that theeosinophil itself may be cardiotoxic and have a primary rolein causing the endomyocardial lesions."-'7 In our patient,several findings suggest that the cardiac eosinophilia may beassociated with cardiotoxicity regardless of the etiology ofthe eosinophilia. Biochemical studies showed that thepulmonary neoplasm was producing a factor chemotacticfor eosinophils.1" Furthermore, the blood eosinophilia wasstimulated by and progressed with the course of the tumor inthe absence of other diseases known to stimulateeosinophilia, such as collagen-vascular diseases, hyper-sensitivity states, dermatoses, or parasitic infestations. Inaddition, since the eosinophilia preceded the clinical cardiacabnormalities, it seems unlikely to have resulted as a reac-tion to the myocardial damage.

In a study of patients with L6ffler's cardiomyopathy andeosinophilia, Spry and Tai have shown that peripheral bloodeosinophils in this disease were vacuolated anddegranulated9 as were those of our patient, who also ex-hibited comparable changes in the eosinophils of the cardiacand pulmonary lesions. The appearance of chemotactic

deactivation in serial in vitro studies of the patient'seosinophils" implies that the eosinophil chemotactic peptideor other tumor products initially induced in vivo activationof the eosinophils, possibly including degranulation, whichmay enhance their ability to lead to tissue damage. Sprysuggested that the tissue damage in the heart results fromprolonged release of products usually present in eosinophilgranules. Archer and Hirsch postulated that enzymes suchas hydrolases and peroxidases were released from tissueeosinophils and might play a role in inflammatory reactionsand tissue damage.25 26 The specific localization ofeosinophils near the areas of necrosis and fibrosis in the car-diac lesions of patients with endomyocardial diseasesuggests that they may be mediators of the cardiac damage.Cardiac involvement with clinical signs can occur early inthe course of the eosinophilia. In a prospective study ofpatients with chronic eosinophilia, Borer et al. have shownthat echocardiographic abnormalities may be present beforethe patients develop signs or symptoms of cardiac disease.27However, the possibility that eosinophils are regulatory cellsbrought in to confine or control a deleterious tissue responsecaused by some other unknown factors cannot be excluded.

If the eosinophil acts as a primary mediator of cardiacdamage, then therapeutic attempts to reduce the number ofeosinophils in patients with endomyocardial disease andeosinophilia might decrease morbidity and mortality fromcongestive heart failure, arrhythmias and thromboembolicevents. In the past, patients with endomyocardial diseaseand eosinophilia have received steroid therapy with little im-provement.15' 18 This could be because steroids may only in-crease margination of eosinophils without necessarily reduc-ing their absolute number." Barrett and Barrett12 and Blattet al.,19 however, have reported cases in which therapycaused systematic cardiac improvement in parallel with areduction in the number of eosinophils. Therapy which hasthe potential to decrease the number of circulatingeosinophils such as radiotherapy," vincristine, methotrexateor mercaptopurine,"9 leukopheresis,24 hydroxyurea28 ormonospecific anti-eosinophil rabbit serum'9 might be ofbenefit in treating patients with cardiac disease associatedwith eosinophilia.

References

I. Reinbach G: Ueber das Verhalten der Leukocyten bei malignenTumoren. Arch Klin Chir 46: 486, 1893

2. Loffler W:Endocarditis parietalis fibroplastica mit Bluteosinophilie, eineigenartiges Krankheitsbild. Schweir Med Wochenschr 17: 817, 1936

3. DaviesJNP: Endocardial fibrosis in Africans. East Afr Med J 25: 10,1948

4. Thompsen S, Plum P: Eosinophilic leukemia. Acta Med Scand 101:116,1939

5. Engfeldt B, Zetterstrom R: Disseminated eosinophilic "collagen dis-ease." Acta Med Scand 153: 337, 1956

6. Brockington IF, Olsen EGJ: Loffler's endocarditis and Davies' endo-myocardial fibrosis. Am Heart J 85: 308, 1973

7. Roberts WC, Liegler DO, Carbone PP: Endomyocardial disease andeosinophilia. A clinical and pathologic spectrum. AmJ Med 46: 28, 1969

8. Tai PC, Spry CJF: Studies on blood eosinophils.I. Patients with a tran-sient eosinophilia. Clin Exp Immunol 24: 415, 1976

9. Spry CJF, Tai PC: Studies on blood eosinophils. II. Patients withLoffler's cardiomyopathy.Clin ExpImmunol 24: 423, 1976

10. Dale DC, Hubert RT, Fauci AS: Eosinophil kinetics in thehypereosinophilic syndrome. J Lab Clin Med 87: 487, 1976

11. Goetzl EJ, Tashjian AH Jr, Rubin RH, Austen KF: The production of alow molecular weight eosinophil PMN leukocyte chemotactic factor byanaplastic squamous cell carcinomas of human lung. J Clin Invest, inpress

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12. Barrett AJ, Barrett A: Bronchial carcinoma with eosinophilia and car-diomegaly. Br J Dis Chest 69: 287, 1975

13. Libanoff AJ, McMahon NJ: Eosinophilia and endomyocardial fibrosis.Am J Cardiol 37: 438, 1976

14. Solley GO, Maldonado JE, Gleich GJ, Giuliani ER, Hoagland HC,Pierre RV, Brown AL Jr: Endomyocardiopathy with eosinophilia. MayoClin Proc 51: 697, 1976

15. Frenkel R, Grieco MH, Garret R: Loffler's endomyocarditis associatedwith bronchial asthma and eosinophilia. Ann Allergy 34: 213, 1975

16. Yam LT, Li CY, Necheles TF, Katayama I: Pseudoeosinophilia,eosinophilic endocarditis and eosinophilic leukemia. Am J Med 53: 193,1972

17. Brockington IF, Luzzatto L, Osunkoya BO: The heart in eosinophilicleukemia. Afr J Med Sci 1: 343, 1970

18. Shepherd AJN, Walsh CH, Archer RK, Wetherley-Mein G:Eosinophilia, splenomegaly and cardiac disease. Br J Haematol 20: 233,1971

19. Blatt PM, Rothstein G, Miller HL, Cathey WJ: LUffler's endomyocardialfibrosis with eosinophilia in association with acute lymphoblasticleukemia. Blood 44: 489, 1974

20. Kirschberg GJ: Trichinosis presenting as acute myocardial infarction.Can Med Assoc J 106: 898, 1972

21. Odeberg B: Eosinophilic leukemia and disseminated eosinophilic collagendisease - a disease entity? Acta Med Scand 177: 129, 1965

22. Smith LH Jr, Boushey H: Eosinophilia and eosinophilic carditis. CalifMed 3: 388, 1969

23. Zucker-Franklin D: Eosinophil function and disorders. In Advances inInternal Medicine, edited by Stollerman GH. Chicago, Year BookMedical Publishers, 1974

24. ElIman L, Miller L, Rappeport J: Leukopheresis therapy of ahypereosinophilic disorder. JAMA 230: 1004, 1974

25. Archer GT, Hirsch JG: Isolation of granules from eosinophil leucocytesand study of their enzyme content. J Exp Med 118: 277, 1963

26. Archer GT, Nelson M, Johnston J: Eosinophil granule lysis in vitro in-duced by soluble antigen-antibody complexes. Immunology 17: 777, 1969

27. Borer JS, Henry WL, Epstein SE: Echocardiographic observations inpatients with systemic infiltrative disease involving the heart. Am J Car-diol 39: 184, 1977

28. Parrillo JE, Fauci AS, Wolff SM: The hypereosinophilic syndrome:Dramatic response to therapeutic intervention. (abstr) Clin Res 25: 5 19a,1977

29. Mahmoud AAF, Kellerman RW, Warren KS: Production ofmonospecific rabbit antihuman eosinophil serums and demonstration of ablocking phenomenon. N Engl J Med 290: 417, 1974

Energy Requirement for Defibrillationof a Markedly Overweight Patient

REGIS A. DESILVA, M.B., F.R.C.P.(C), AND BERNARD LOWN, M.D.

SUMMARY Recommendations have been made recently that theenergy output of present-day defibrillators be increased above the 400wsec limit. These recommendations are based largely on experimen-tal studies in animals. We report a case of a man weighing 190.1 kg(418.2 lb), successfully resuscitated with a single 400 wsec shockafter a prolonged episode of ventricular fibrillation. The observationin this patient as well as data derived from cardiovascular experience

DIRECT CURRENT DEFIBRILLATION of the heart isa standard method promoted by its procedural simplicityand sanctioned by its high success rate. Recently, Tacker,Geddes and coworkers1 2 presented data in both animal andman indicating that the standard instruments in current useprovide insufficient energy for heavy subjects. They con-cluded that presently available devices are inadequate fordefibrillating 35% or more of patients weighing in excess of50 kg." This has led to the recommendation thatdefibrillators be manufactured capable of delivering largerelectrical energies.'' The very opposite point of view hasbeen reached by Pantridge et al.4 5 and Crampton et al.,6 7who have counseled the use of lower energies for cardiacresuscitation. The issue is of great importance. If Tackerand coworkers are correct, heavy subjects are denied thechance of resuscitation. On the other hand, if the claimsrelating to the need for more energy are insubstantial,numerous patients will be subjected to injurious currents,

From the Cardiovascular Division, Peter Bent Brigham Hospital and theCardiovascular Research Laboratories, Department of Nutrition, HarvardSchool of Public Health, Boston, Massachusetts.

Supported in part by Grants HL-05242 and HL-07776 from the NHLBI.Address for reprints: Bernard Lown, M.D., Department of Nutrition, Har-

vard School of Public Health, 665 Huntington Avenue, Boston,Massachusetts 02115.

Received August 24, 1977; revision accepted November 7, 1977.

indicates that weight is not a significant factor in the successful out-come following defibrillation in adults. Many variables primarilyrelated to the clinical condition of the heart influence the results ofcountershock. There are no valid studies at present to support theclaim that high-energy defibrillators are necessary. In fact, im-plementation of such a recommendation is premature and possiblydangerous.

and in some the chance of successful resuscitation will bejeopardized. Because information on the energy re-quirements for defibrillating patients weighing in excess of150 kg is not available, we report the following pertinent ex-perience.

Case Report

A 30-year-old white male with acromegaly for six yearsand atypical chest pain for two years, noted occasional dizzyspells associated with palpitation. He was on hormonalreplacement therapy, and warfarin. He was admitted to thePeter Bent Brigham Hospital for weight reduction prior tocardiac catheterization and coronary angiography.He was massively obese, weighing 198.5 kg (436.7 lb) and

175 cm (68.9 inches) tall. Skull and acral enlargement wasobvious. Pulse rate was 75 beats/min with occasional extra-systoles. Blood pressure was 120/80 mm Hg in the supineposition. The cardiac findings were within normal limits.The electrocardiogram showed sinus rhythm at a rate of56/min with frequent unifocal ventricular premature beats(VPBs). PR interval was 0.18 sec, QRS 0.09 sec and the axiswas -30°. There were nonspecific ST and T wave abnor-malities. Ambulatory monitoring for 24 hours demonstratedfrequent unifocal VPBs, couplets and short runs of 3-5 beatventricular tachycardia. A posteroanterior chest roentgeno-

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B E Jaski, E J Goetzl, J W Said and M C FishbeinEndomyocardial disease and eosinophilia. Report of a case.

Print ISSN: 0009-7322. Online ISSN: 1524-4539 Copyright © 1978 American Heart Association, Inc. All rights reserved.

is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231Circulation doi: 10.1161/01.CIR.57.4.824

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