sarcoidosis: a pattern of clinical morphological presentationsarcoidosis evenin the...

Br Heart J 1987;57:256-63

Sarcoidosis: a pattern of clinical and morphologicalpresentation

HANNAH VALANTINE, WILLIAM J McKENNA,PETROS NIHOYANNOPOULOS,ANDREW MITCHELL,* RODNEY A FOALE, M J DAVIES, CELIA M OAKLEY

From the Division of Cardiovascular Disease, Royal Postgraduate Medical School, Hammersmith Hospital,London

SUMMARY The diagnosis of cardiac sarcoidosis, particularly when there is no overt systemicinvolvement, is frequently delayed because of its varied manifestations. Focal left ventricular wallmotion abnormalities were recognised in five patients with sarcoidosis. Three patients showedabnormal regional wall motion in the basal portion of the ventricular septum and free wall withsparing of the apex. The angiographic appearances supported the echocardiographic findingswhich were atypical of ischaemic heart disease. The remaining two patients both had diffuse leftventricular hypokinesia, with a focal abnormality that was most pronounced in the anteroapicalregion; this pattern is often seen with coronary disease.The recognition by echocardiography or angiography of focal abnormalities of wall motion

affecting the basal portion of the ventricular septum should suggest the possibility of myocardialsarcoidosis even in the absence of recognised systemic manifestations.

Focal abnormalities of left ventricular wall motionare uncommon except in coronary artery disease inwhich the distribution is dependent on coronaryartery anatomy. It is therefore unusual to find wallmotion abnormalities localised to the basal part ofthe septum with sparing of the apical portion. Thisreport of five cases shows that although sarcoidgranuloma can occur anywhere in the heart a patternof fibrosis distinct from coronary disease may berecognised by echocardiography and angiography.

Patients and methods

We studied five men aged 29, 36, 37, 45, and 46years. One was black and the remainder were white.Systemic sarcoidosis had been diagnosed because atleast two organ systems were affected and there waseither positive lymph node histology or a Kveimtest. All patients underwent cardiac catheterisation,

Requests for reprints to Dr William J McKenna, Division of Car-diovascular Disease, Royal Postgraduate Medical School, Ham-mersmith Hospital, Ducane Road, London W12 OHS.

*Present address: Department of Cardiology, Harefield Hospital, Harefield,Uxbridge, Middlesex.

Accepted for publication 23 October 1986

coronary angiography, and cross sectional echo-cardiography. Three patients shared several clinicalcharacteristics. None of these three had clinical evi-dence of heart failure. All had normal physical ex-amination, normal laboratory indices of bonemarrow, renal, and hepatic function. All had left an-terior hemiblock and right bundle branch block.Left ventricular end diastolic and pulmonary arterypressures were normal and there was no disease ofthe major epicardial coronary arteries. The tablesummarises the investigations that were performedto assess disease activity and distribution.

In patient 1 systemic sarcoidosis was not diag-nosed during life. He presented with a two year his-tory of palpitation and ventricular tachycardiaassociated with syncope and evidence of aprogressive conduction system disturbance. Duringcross sectional echocardiography from the para-sternal long axis view (fig la) the basal part of theventricular septum was thin and akinetic with in-creased echo reflectivity and paradoxical systolicmotion. The same abnormality was seen in serialshort axis views at the level of mitral valve and papil-lary muscle (fig 2). The apical third of the ventricu-lar septum, the posterior wall of the ventricle, andthe right ventricular free wall were normal. Left

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Table Investigations to assess activity and extent of sarcoidosis

Patient I Patient 2 Patient 3 Patient 4 Patient 5

ESR 4 10 8 70 10SACE ND 33 88 58 NDGallium uptake ND Normal Matched uptake in left ND ND

lung hilum, andparatracheal area

Thallium uptake* Septum and ND Septum Anteroapicaland NDfree wall free wall

Chest x ray Recurrent Normal Hilar Hilar Hilarpulmonary lymphadenopathy, lymphadenopathy lymphadenopathyinfiltrates pulmonary infiltrates

Cardiothoracicratio 19/30 15/30 14/28 20/30 18/30

Pulmonary ND Normalt Decreased lung volumes Decreased lung volumes Normalfunction tests and gas transfer and gas transfer

*Thallium scans showed decreased uptake during exercise without recovery in the designated areas.tAt diagnosis chest x ray showed right hilar lymphadenopathy and a right apical infiltrate.SACE, serum angiotensin I converting enzyme (normal range = 16-53 units/ml); ND, not done; ESR, erythrocyte sedimentation rate.

ventricular angiography in the right anterior obliqueprojection (fig 3a) showed poor contraction of theanterobasal and posterobasal segments whereas theapical- segments contracted normally. Coronaryangiography was normal. Endocardial resection for

Fig 1 Echocardiographic appearances in the parasternallong axis views in patients I (a) and 3(b) showing thinning ofthe basal portion of the ventricular septum, which was

pronounced in patient 1.

resistant ventricular tachycardia was complicated bya low output state and the patient died during oper-ation.At necropsy the heart weighed 583 g. The basal

ventricular septum was thick and replaced byfibrous tissue (fig 4) that extended into the basal partof the posterior wall. This mirrored the echo-cardiographic and angiographic appearances. Histo-logical examination confirmed replacement of thispart of the septum by dense fibrous tissue. The re-mainder of the myocardium showed focal scarringwith an occasional giant cell but no granulomas.Typical sarcoid granulomas were, however, presentin the lungs, spleen, mediastinal lymph nodes, andliver.

In patient 2 sarcoidosis of the heart had been diag-nosed 10 years earlier when he presented withsupraventricular and ventricular arrhythmia,progressive conduction disturbance, and pulmonarysarcoidosis (table). He was referred for control ofventricular arrhythmias that had failed to improveon increasing doses of steroids. Cross sectional echo-cardiography in the parasternal long axis view (fig 5)showed that the basal portion of the ventricular sep-tum was thin, akinetic, and aneurysmal, and clearlyprotruded into the right ventricle in systole, whilethe apical part was of normal thickness and con-tracted normally. This focal ventricular abnormalitywas also seen in short axis views at the level of mitralvalve and papillary muscle (fig 6). The cardiac apexwas seen to be contracting normally. Angiographicexamination showed that the basal part of the leftventricle was dilated and aneurysmal and the apicalportion contracted normally (fig 3b). He was treatedwith mexiletine and amiodarone. Ventricular ar-rhythmia was inadequately controlled and he diedsuddenly. At necropsy the heart weighed 500 g. Thebasal two thirds of the ventricular septum was thin

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Valantine, McKenna, Nihoyannopoulos, Mitchell, Foale, Davies, Oakley

and extensively replaced by fibrous tissue that ex-tended into the basal part of the posterior wall. Else-where the myocardium appeared to be normal andno granulomas were found in histological sections ofthe heart. Examination of the lungs, mediastinum,liver, and spleen showed extensive replacement ofthe normal tissue by the typical non-caseating gran-uloma of sarcoidosis.

Patient 3 was known to have had pulmonary sar-coidosis for 14 years before his presentation with

Fig 2 Echocardiographic appearances in the short axisviews in patient 1 at the level of mitral valve (a), papillarymuscle (b), and apex (c). There was no systolic thickening ofthe septum at the mitral and papillary muscle level. Incontrast apical contraction was normal.

syncope, complete heart block, and a soft systolicmurmur at the apex. Echocardiography from theparasternal long axis view (fig lb) showed that theventricular septal dimension was within normal lim-its, but in its basal portion the septum was akineticand showed increased echo reflectivity. The apicalthird of the ventricular septum, posterior wall, andright ventricular free wall were normal. The shortaxis views (fig 7) at the level of the mitral valve alsoshowed the same akinetic and echo-dense ventricu-lar septum which was of normal dimensions at thelevel of the mitral valve, but at the papillary musclelevel the septum was thin and akinetic. Appearanceswere normal at the level of the apex. Left ventricularangiography showed mild impairment of con-traction of the basal portion of the left ventricle withmild mitral regurgitation (fig 3c). A biopsy specimenof the right ventricle contained epitheloid giant cellsand fibrous grFanulomas characteristic of sarcoidosis.The patient has been symptom free after the in-sertion of a permanent pacemaker.The clinical features and mode of presentation

were different 'i the remaining two patients. Patient4 presented with an acute systemic illness character-ised by fever, high erythrocyte sedimentation rate(70ml/h), hilar lymphadenopathy, and congestivecardiac failure. There were Qwaves on the electro-cardiogram that simulated anterior myocardial in-farction. Echocardiography showed septal hyper-trophy and mild global hypokinesia and there was afixed thallium perfusion defect of the anteroapicalregion of the left ventricle. Angiographic exam-ination of the left ventricle showed a considerableincrease in end systolic volume with extensiveanteroapical akinesia, and hypokinesia of the re-mainder of the ventricle. The result of coronary ar-teriography was normal. A biopsy specimen of themyocardium showed diffuse interstitial fibrosis butno granulomas, and the diagnosis of sarcoidosis wasbased on a biopsy specimen of the mediastinallymph nodes.

Patient 5 presented with ventricular tachycardiaand no evidence of congestive cardiac failure. Anelectrocardiogram showed T wave inversion in theinferior and lateral leads and voltage criteria thatwere characteristic of hypertrophy of the left ventri-cle but no conduction abnormality. Cross sectionalechocardiography showed global hypokinesia,which was confirmed by angiography, with akinesiaand calcification of the apex. The haemodynamicfunction of the right and left heart and the results ofcoronary arteriography were normal. A biopsyspecimen of the myocardium showed diffuse inter-stitital fibrosis only. Systemic sarcoidosis was diag-nosed on the basis of bilateral hilar lymph-adenopathy and a positive Kviem test.

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Sarcoidosis: a pattern of clinical and morphological presentation

Fig 3 Left ventricular angiograms ofpatients 1, 2, and 3 (a, b, and c respectively) in systole (right) and diastole(left) in the right anterior oblique projection, showing impaired contraction of the base of the heart, which is mostpronounced in patient 2.

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Fig 4 Echocardiuvgraphic andnecropsy appearances of the heart in7patient I as seen from the short axisviews at the level of the papillarymuscles, showing the thitn and akizneticseptuim, which is replaced by fibroustissue.

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261Sarcoidosis: a pattern of clinical and morphological presentation

Fig 5 Long axis views of systolic and diastolicframes in patient 2.

Discussion

Sarcoidosis is a multisystem granulomatous disorderofunknown cause. The frequency of clinical cardiacinvolvement in patients with systemic sarcoidosis is

low ( 5%). 2 Most (80%) patients with cardiac sar-

coidosis have conduction disturbance or

arrhythmia3-8 and/or impaired cardiac function(31 %).5-9 Patients have also presented with mitralstenosis caused by leaflet granuloma10 or with mitralregurgitation caused by infiltration of the papillarymuscle. 1 In patients with cardiac sarcoid the risk ofsudden death is considerable.3 An additional 23% of

patients with systemic sarcoidosis will have isolatedsarcoid granulomas that are detectable only by histo-logical examination of the heart1 but the proportionof positive cases probably varies withthe extent to which the myocardium is sampled at

necropsy.The wide range of clinical manifestations of car-

diac sarcoidosis evident from this report of five cases

is consistent with the varied distribution and mor-phological features of the abnormalities. In patientswho die in the active phase of myocardial sarcoidosisgranulomas may either be distributed evenlythroughout the myocardium or occur as a localisedmass, commonly in the basal portion of the ventricu-lar septum.3 512 The frequency of sudden deathreflects the high risk that the conduction system willbe affected in both the focal and diffuse forms.3This acute phase of myocardial sarcoidosis will re-

solve either as diffuse interstitial fibrosis of the myo-cardium and a generalised hypokinesia of theventricle or as a localised fibrous scar with focal con-traction abnormalities. Diffuse fibrosis is difficult todistinguish from dilated cardiomyopathy. Focallesions may also be difficult to distinguish in lifefrom ischaemic heart disease but the lesion in thebasal portion of the septum in cases 1-3 is in an un-usual site for old infarction and is typical of sarcoid-osis. For these reasons and because of the presenceofnormal coronary arteriograms the scars in patients



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tort axis views tn patzent 2. Legena as for fig 2.

1-3 were taken to indicate healed sarcoidosisthough no active granulomas were found in themyocardium.The acute and more chronic forms of myocardial

sarcoid have been linked to four histological pat-terns.`3 An exudative type (lymphocytic infiltrationwith oedema) and a granulomatous type (granu-lomata with epithelial cells) are associated with sys-temic disease and characterised by a subacute course

Fig 7 Short axis views in patient 3. Legend as for;fig 2.

with clear clinical evidence of multi-organ in-volvement. The chronic fibrous types (with andwithout giant cells) are associated with the chronicinsidious course seen in cases 1-3. The papillarymuscles and right ventricle are also commonly foundto contain granulomas at necropsy. Case 3 had clin-ical and echocardiographic evidence of papillarymuscle dysfunction as well as right ventricular in-volvement and typical granulomas were found in

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Sarcoidosis: a pattern of clinical and morphological presentation 263biopsy specimens of the right ventricle.The use of steroids in cardiac sarcoid has not been

systematically evaluated. Retrospective analysis,however, suggests that steroids promote healing ofgranulomas but the concomitant development offibrous tissue may be complicated by aneurysmformation5; this is an otherwise rare complication.Patients 2 and 3 received long term corticosteroidtreatment. Both showed thinning of myocardial seg-ments. In patient 2 there was an intracardiac an-eurysm of the basal septum that bulged into theoutflow tract of the right ventricle; at necropsy thissegment was found to be replaced with fibrous tis-sue. Though granulomas were detected in other or-gans they were not found in the heart. Patient 1 alsohad myocardial thinning caused by fibrous tissue re-placement and multiple organ granulomas but nocardiac ones. He had not been given steroids, how-ever. These findings are consistent with publishedreports which suggest that steroids promote healing,which may be complicated by the development of ananeurysm. They also indicate that steroids are not aprerequisite for such a course and they raise thequestion of the usefulness of steroids once myo-cardial thinning and aneurysm have developed.

Patient 2 had refractory ventricular arrhythmiaand died suddenly. Patients are usually only referredfor transplantation when poor and deteriorating leftventricular function and the ensuing shortness ofbreath, fatigue, and oedema indicate that they willdie soon. Referral for transplantation is much moredifficult and therefore less often acted upon whenlife threatening arrhythmia cannot be controlled.The argument for transplantation is more cogent ifthe arrhythmia is caused by a process which itselfmay be advancing, such as cardiac sarcoidosis. Weconsidered transplantation in patient 2 but did notact upon it immediately. His death was sudden butpredictable. Hearts have been successfully trans-planted into patients with cardiac sarcoidosis"4 butwe delayed too long.Our index patient, patient 1, had conduction dis-

turbance and ventricular tachycardia in the absenceof recognised systemic sarcoidosis. The diagnosis ofcardiac sarcoid is seldom missed when this constel-lation of changes coexists with systemic sarcoidosis.In the absence of systemic sarcoid these cardiac ab-normalities are not specific and are more likely to

have other causes. The focal abnormality of wallmotion localised to the basal portion of the ventricu-lar septum that we described is unusual in coronaryartery disease and should suggest the diagnosis ofcardiac sarcoid even when there are no systemicchanges.We are grateful to Professor John F Goodwin forpermission to publish details of case 1.

References

1 Silverman KJ, Hutchins GM, Buckley BH. Cardiacsarcoid: a clinicopathological study of 84 unselectedpatients with systemic sarcoidosis. Circulation1978;S8: 1204-11.

2 Fleming HA. Sarcoid heart disease. Br Heart J1974;36:54-68.

3 Lie JT, Hunt D, Valantine PA. Sudden death fromcardiac sarcoidosis with involvement of the conduc-tion system. Am J Med Sci 1974;267:123-8.

4 Lull RJ, Dunn BE, Gregoratus G, Cox WA, FisherGW. Ventricular aneurysm due to cardiac sarcoid-osis with surgical cure of refractory ventriculartachycardia. Am J Cardiol 1972;30:282-7.

5 Roberts WC, McAllister HA, Ferrans VJ. Sarcoidosisof the heart. A clinicopathologic study of 35 necropsypatients (group I) and review of 78 previously de-scribed necropsy patients (group II). Am J Med1977;63:86-108.

6 James TN. De Subitaneis Mortibus. XXV. Sarcoidheart disease. Circulation 1977;56:320-6.

7 McTaggart DR. Sarcoidosis with cardiac involvement.Med J Aust 1973;ii:689-90.

8 Miller A, Jackler I, Chuang M. Onset of sarcoidosiswith left ventricular failure and multisystem in-volvement. Chest 1976;70:302-4.

9 Ahmed SS, Rozefort R, Taclob LT, Brancato RW. De-velopment of ventricular aneurysm in cardiac sar-coidosis. Angiology 1977;28:323-9.

10 Fitchett DH, Oakley CM. Granulomatous mitral valveobstruction. Br Heart J 1976;38:112-6.

11 Raftery EB, Oakley CM, Goodwin JF. Acute subvalvarmitral incompetence. Lancet 1966;li:360-5.

12 Ghosh P, Fleming HA, Gresham GA, Stovin PGI.Myocardial sarcoidosis. Br Heart J 1972;34:769-73.

13 Matsui Y, Iwai K, Tachibana T, et al. Clin-icopathological study of fatal myocardial sarcoidosis.Ann NY Acad Sci 1976;278:455-69.

14 Gokel JM, Reichart B, Struck E. Human cardiactransplantation-evaluation of morphologicalchanges in serial endomyocardial biopsies. Pathol ResPract 1985;17:354-64.



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