EXEMPLAR - Heart

BrHeart J 1995;73:110-115

EXEMPLAR

Cardiac involvement in Wegener's granulomatosisN E R Goodfield, S Bhandari, W D Plant, A Morley-Davies, G R Sutherland

AbstractWegener's granulomatosis is a systemicinflammatory disorder of unknown aeti-ology. The protean clinical presentationsdepend on the organ(s) involved and thedegree of progression from a local to asystemic arteritis. The development ofserological tests (antineutrophil cytoplas-mic antibodies) allows easier diagnosis ofa disease whose incidence is increasing.This is particularly helpful where thepresentation is not classic-for example"overlap syndromes"-or where the dis-ease presents early in a more localisedform. This is true ofcardiac involvement,which is traditionally believed to be rare,but may not be as uncommon as hashitherto been thought (< 44%). Thisinvolvement may be subclinical or theprincipal source of symptoms either inthe form oflocalised disease or as part ofasystemic illness. Pericarditis, arteritis,myocarditis, valvulitis, and arrhythmiasare all recognised. Wegener's granulo-matosis should therefore be considered inthe differential diagnosis of any non-spe-cific illness with cardiac involvement.This includes culture negative endocardi-tis, because Wegener's granulomatosiscan produce systemic upset with masslesions and vasculitis. Echocardiographyand particularly transoesophageal echo-cardiography can easily identify anddelineate cardiac and proximal aorticinvolvement and may also be used toassess response to treatment.

(Br Heart _' 1995;73:1 10-115)

Department ofCardiology, RoyalInfirmary, EdinburghN E R GoodfieldS BhandariA Morley-DaviesDepartment ofRenalMedicine, RoyalInfirmary, EdinburghW D PlantDepartment ofCardiology, WesternGeneral Hospital,EdinburghG R SutherlandCorrespondence to:Dr N E R Goodfield,Department of Cardiology,Royal Infirmary,1 Lauriston Place,Edinburgh EH9 9YW.

Accepted for publication31 August 1994

Keywords: Wegener's granulomatosis; myocarditisand aortitis; transoesophageal echocardiography

The incidence of Wegener's granulomatosis, a

systemic disorder of unknown aetiology,appears to have increased.' 2 This finding maybe the result of an increased awareness andeasier, earlier diagnosis allowing less severe,more localised forms of the disease to berecognised. There has also been a trueincrease in incidence due to an expandingelderly population which is at greater risk.2AThe mode of presentation is protean5-7depending in part on which organs are

affected. Cardiac involvement can vary fromsubclinical to the primary organ affected,although this is thought to be rare.8" Using a

case from our institution, we describe for the

first time the transoesophageal echocardio-graphic features of Wegener's myocarditis andaortitis and give an illustrated review of theheart in Wegener's granulomatosis.

Case reportA 25 year old man was admitted with a twoweek history of intermittent palpitation afterupper respiratory tract symptoms. There wasno past history of note other than coinciden-tally found "aortic and mitral systolic bruits"some five years previously.On admission the patient was apyrexial

with no rash or splinter haemorrhage; hispulse was 77/min; blood pressure 100/70 mmHg; and he had a 3/6 ejection systolic murmurand a 2/4 early diastolic murmur. There wasno evidence of neuropathy.

Initial investigations showed normal urineanalysis, chest radiograph, full blood count,plasma chemistry, thyroid function tests, Creactive protein, erythrocyte sedimentationrate, and autoantibodies (antimitochondrial,smooth muscle, double stranded DNA,intrinsic factor, anticardiolipin, rheumatoidfactor, thyroid microglobulin and thyroglobu-lin, antinuclear factor and gastric parietalcell). Immune complex ratio at 0 75 andcomplement levels were normal. Four setsof blood cultures showed no growth.Antistreptolysin 0 titres were not raised andthroat swabs were negative to bacterial cul-ture. The electrocardiogram showed a normalPR interval and right bundle branch block.Transthoracic echocardiography showed anormal sized left ventricle with good contrac-tion. The aortic valve appeared bicuspid withwhat was initially thought to be a subvalvarmembrane in the left ventricular outflow tract.There was moderate aortic incompetence onDoppler echocardiography. A 24 h electrocar-diograph showed intermittent supraventricu-lar tachycardia for which the patient was givenmetoprolol. The symptoms recurred and hismedication was converted to verapamil. Thepatient was intolerant of this drug and hisantiarrhythmic treatment was changed to fle-cainide.The patient remained unwell and was

admitted elsewhere with severe malaise, weak-ness, weight loss, and recurrent palpitation.On examination he had multiple splinterhaemorrhages. The previously noted mur-murs were unchanged. The erythrocyte sedi-mentation rate was 45 mm in the first hourand the C reactive protein concentration wasmore than four times that of normal. The

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Cardiac involvement in Wegener's granulomatosis

electrocardiogram showed first degree heartblock in addition to the right bundle branchblock. Six sets of blood cultures were negativefor bacterial growth. Serological analysis foratypical organisms (coxiella, chlamydia,mycoplasma, psittacosis) and fungal precip-itins were also negative. A clinical diagnosis ofculture negative infective endocarditis wasmade and intravenous triple antibiotic treat-ment started.

Transoesophageal echocardiography wasperformed after transfer to our hospital, in anattempt to confirm the clinical diagnosis.Aortic incompetence with no evidence of veg-etations was confirmed but in additionmarked thickening and echodense reflectionwere seen circumferentially from the wall ofthe aortic root in the first 2-3 cm and from

Figure1 Initial pretreatment transoesophageal echocardiograms showing the features ofaortic root and left ventricular outflow tract involvement in the patient described in thetext. Upper left panel: transverse plane transoesophageal view at the level of the pulmonaryartery. Note that walls of the ascending aorta above the aortic sinuses, the superior venacava and the right pulmonary artery are ofnormal thickness. Upper right panel: thetransverse plane transoesophageal probe has been advanced to the level of the upper aorticsinuses. The aortic wall thickened in a concentric manner with a ground glass appearance.The anterior wall of the right ventricular outflow tract and the right atrial medial wall arealso thickened. Middle left panel: the probe has been advanced slightly further andincreased thickening of the aortic root and atrial wall is seen. Middle right panel: the probehas been advanced to the level of the aortic valve, where maximal aortic root involvementis seen. Lower left panel: advancing the probe further a large mass lesion in the area of themembranous interventricular septum is seen, (arrows), which produced a pressure gradientwithin the outflow tract of35-40 mm Hg as assessed by continuous wave Doppler. Lowerright panel: retraction of the probe and angulation towards the atrial septum demonstratedinvolvement by Wegener's tissue of the anterior portion of the interatrial septum. The tissueof the foramen ovale and superior rim of the atrial septum was normal in thickness andappearance. SVC, superior vena cava; RPA, right pulmonary artery; ASC AO,ascending aorta; MPA, main pulmonary artery; LA, left atrium; RA, right atrium;RVOT, right ventricular outflow tract; AO, aorta; IVS, interventricular septum; RV,right ventricle; LV, left ventricle.

the atrial and ventricular septa, with a fibro-muscular mass obstructing the left ventricularoutflow tract, producing a pressure gradientof 36-40 mm Hg as assessed by continuouswave Doppler examination (fig 1). Thepatient continued to receive triple antibiotictreatment without improvement while otherpossible causes of aortitis were excluded.No evidence was found to suggest ankylos-

ing spondylitis (HIA B27 negative), Reiter'ssyndrome or syphilis (antitreponemal anti-body negative). Antineutrophil cytoplasmicantibodies were not seen with indirectimmunofluorescence of ethanol fixed neu-trophils exposed to the patient's serum. Thepatient did, however, give a vague history ofrhinorrhoea and nose bleeds, raising the sus-picion of Wegener's granulomatosis. He wasreviewed by an otolaryngologist and a septalbiopsy specimen was taken which showedacute inflammation without granuloma orvasculitis. The patient then developedhaemoptysis with an ill defined opacity at theright base in the chest radiograph. This wasthought to be beyond the reach of percuta-neous or transbronchial biopsy. In a furtherattempt to gain histological proof ofWegener's granulomatosis, transoesophagealechocardiography was repeated, showing pro-gression of the aortitis with marked thickeningof the aortic wall. Guided myocardial biopsywas performed. Biopsy specimens taken fromthe interatrial septum, right ventricular apex,and right atrial side of the posterior aortic wallshowed only non-specific inflammation.Repeat indirect immunofluorescence for anti-neutrophil cytoplasmic antibody, two weeksafter it was initially performed, was stronglypositive with a diffuse granular staining pat-tern. This was subsequently confirmed, bothon repeat indirect immunofluorescence andafter solid phase radioimmunoassay, on asample sent to the University of CambridgeLaboratory at Addenbrookes Hospital. Theyreported antibody levels as 73% of a knownpositive serum (normal < 16%).The patient showed no improvement with

intravenous antibiotics but treatment withcyclophosphamide and prednisolone pro-duced an excellent symptomatic response.The erythrocyte sedimentation rate, C reac-tive protein concentration and, chest radiography and electrocardiogram findingsnormalised. Antineutrophil cytoplasmic anti-body became undetectable but aortic incom-petence remained. Repeat transoesophagealechocardiography showed marked improve-ment of aortitis (fig 2). Unfortunately, thepatient became increasingly short of breath,without any serological evidence of reactiva-tion of Wegener's granulomatosis as assessedby C reactive protein concentration andrepeat indirect immunofluorescence.Diastolic blood pressure was unrecordable,echocardiography showed progressive dilata-tion of the left ventricle and he was referredfor aortic valve surgery. The aortic valve atsurgery showed a shrunken right coronarycusp. Pathological examination showedlocalised inflammation but no evidence of

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Figure 2 Transverse plane transoesophageal echocardiograms 6 weeks after startingtreatment with cyclophosphamide and prednisolone. Upper left panel: the aortic root is cutin transverse section at the level of the left coronary artery. Note that the previousthickening seen in fig 1 is largely absent. Upper right, middle left and middle right panels:sequential sections are demonstrated by introducing the probe further through the aorticvalve and into the left ventricular outflow tract. Note that gross thickening of the aorticroot and hyperechogenicity are now mostly absent. The mass lesion in the left ventricularoutflow tract has resolved. Continuous wave Doppler examination from the apexconfirmed normalflow velocities in the left ventricular tract after treatment. Lower left andright panels: the probe was retracted to examine the atrial septum; the previous thickeninghas largely resolved. These features were considered to indicate resolution of Wegener'sgranulomatosis from the aortic root and the upper left ventricular outflow tract. LA, leftatrium; RA, right atrium; RVOT, right ventricular outflow tract; AO, aorta; RV, rightventricle; LV, left ventricle; LVOT, left ventricular outflow tract.

vasculitis. Symptoms of breathlessness were

greatly improved after surgery.A subglottal stenosis, which required resec-

tion, was subsequently discovered in thepatient. Pathological analysis of the tracheal

biopsy specimens showed organising granula-tion tissue with areas of acute superficialinflammation compatible with Wegener'sgranulomatosis.The patient continued to feel well while

receiving cyclophosphamide and pred-nisolone. Initial attempts to reduce the steroiddosage, however, produced a symptomaticrelapse requiring reintroduction of higherdoses. Currently three years after diagnosis,steroid medication has been reduced andcyclophosphamide has been converted to aza-

thioprine.

DiscussionWegener's granulomatosis is typically charac-terised by granulomatous inflammation of therespiratory tract and internal organs with a

generalised necrotising vasculitis andglomerulonephritis.12 It was first defined as a

distinct clinical syndrome in 1936,1314 but hadpreviously been described by Klinger in1931'5 and McBride in 1897.16 17 The onset isoften insidious, the mode of presentationdepending on the organs affected and theextent to which the disease has progressedfrom local involvement to a truly systemicarteritis.'2 18 This means the clinical manifesta-tions are protean and the condition should beconsidered in the differential diagnosis of anymultisystem disorder.'7 The diagnosis is pri-marily based on characteristic clinical featurescombined with specific organ involvementand histological findings (table 1). These tra-ditional classification systems,'9 20 however,may discriminate poorly between related dis-eases.2 21 This difficulty in classificationaccounts for the existence of the so called"overlap syndromes" where the clinical char-acteristics are mixed and the pathological fea-tures disparate or non-specific (table 2).18 InWegener's granulomatosis the characteristicgranulomata may be absent or difficult toidentify in the biopsy material obtained in anyone case. This difficulty in obtaininghistopathological confirmation5 18 leads to adelay in diagnosis; in a series of 158 patientsreported by Hoffman et al22 the mean time

Table 1 Systemic vasculitides

Vessel involvement Classical organ involvement Granuloma Comments

Wegener's Small-medium sized vessels Upper and lower respiratory tract, necrotising Present c-ANCA classically presentgranulomatosis vasculitis and glomerulonephritis

Microscopic Small vessels and/or small-medium Necrotising glomerulonephritis, necrotising Absent p-ANCA classically presentpolyarteritis sized arteries vasculitis (respiratory tract)

Classic polyarteritis Small-medium sized arteries No glomerulonephritis-renal involvement Absent Microaneurysm formation;nodosa via arteritis ANCA very infrequently positive

Takayasu's Aorta and major branches Present Common in young orientalarteritis females; ANCA very infrequently

positiveANCA very infrequently positive

Kawasali Small, medium and large arteries, Absent Children; associated mucocutaneoussyndrome including coronary arteries lymph node syndrome;

ANCA sometimes positiveanticathepsin G

Giant cell Aorta and major branches, Absent < 50 years of age; associatedarteritis especially extracranial branches polymyalgia rheumatica; ANCA

of carotid artery very infrequently positiveChurg-Strauss Small-medium sized vessels Respiratory tract, necrotising vasculitis Present Eosinophilia and asthma/allergic

syndrome rhinitis; ANCA infrequently positiveHenoch-Schoenlein Small vessels Skin, gut, glomerulonephritis, joints Absent IgA immune deposits, adults or

purpura children; ANCA very infrequentlypositive

ANCA, antineutrophil cytoplasmic antibody; c-ANCA, cytoplasmic ANCA; p-ANCA, perinuclear ANCA.

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Table 2 "Overlapsyndromes"-systemicvasculitides manifestingmixed clinicopathologicalfeatures

Overlap syndrome

Polyarteritis/Wegener'sgranulomatosis

Giant cell arteritis/Churg-Strausssyndrome/Wegener'sgranulomatosis

Polyarteritis/Churg-Strausssyndrome

Temporalarteritis/polyarteritis

Takayasu'sarteritis/polyarteritis

Polyarteritis/cutaneousvasculitis

Henoch-Schoenleinpurpura/polyarteritis

Systemic necrotisingvasculitis

from onset of symptoms to diagnosis was 15months with a range of immediate to 15 years.

Diagnosis is now facilitated, however, follow-

ing the development of both indirectimmunofluorescence and solid phase radio-immunoassay for antineutrophil cytoplasmicantibodies.23

Wegener's granulomatosis is classicallyassociated with a detectable antineutrophilcytoplasmic antibody which shows a cytoplas-mic distribution, as opposed to a perinuclear.This former pattern (fig 3) is associated withcirculating antineutrophil cytoplasmic anti-body against the proteinase-3 antigen, a com-

ponent of neutrophil primary granules.24These serological tests are both sensitive (>95%) and specific (> 80%)21 25 and not onlysimplify diagnosis but also allow an immuno-logical component to be included in classi-fication systems.32326 Realisation of theimportance of the underlying immunologicalmechanism as opposed to the clinicopatholog-ical syndrome it produces helps to reduce theproblems inherent within the old classificationsystems with their confusing taxonomy. Thisuse of serological testing rather than relianceonly on clinicopathological features means

that less severe more localised forms of thedisease can be recognised and the reportedrange of organ involvement may well alter.

Cardiac manifestations, previously said tobe uncommon6 8-11 may not be so rare27 (table3). In reviewing these and other series35-38 andKeifer Lehmann39 and Grant et al27 identified a

wide discrepancy in the reported incidence ofcardiac involvement. These variations mayreflect the variable natural history of the dis-ease,39 the source of patients,2734 the specialtyof the group investigating the patients,29 thesize of the population studied,'2-'4 or the avail-ability of techniques such as echocardiogra-phy to diagnose subclinical cardiacinvolvement before death.

Forstot et a140 retrospectively analysedreported cases of patients with cardiacinvolvement: about 50% had pericarditis,50% coronary arteritis, 25% focal myocardi-tis, and 21% valvulitis or endocarditis, withthe conduction system involved in 17% andmyocardial infarction in 1 1%.

PERICARDITISPericarditis and effusion have been reportedalone"334 and in conjunction with other car-

diac abnormalities42-45 and may be unexpect-edly found at postmortem examination,4647present acutely as tamponade,48 or as chronicconstriction.274950 In a few cases pericarditismay be secondary to myocardial infarction or

uraemia due to renal involvement.'2

Figure 3 Indirect immunofluorescence of ethanolfixed neutrophils exposed to the serum ofpatients with systemic vasculitis. Fluorescein labelled antihuman antibodies identify twoclassical patterns. (A) Diffuse cytoplasmic pattern of antineutrophil cytoplasmic antibodywhich tends to be associated with Wegener's granulomatosis and a circulating antibodyagainst proteinase-3. (B) Localised pattern ofperinuclear antineutrophil cytoplasmicantibody which tends to be associated with microscopic polyarteritis and a circulatingantibody against myeloperoxidase.

ARTERITISGeneralised arteritis may produce a systemicillness with fever, malaise, and weight loss,42'which may mimic infective endocarditis.More localised arteritis is recognised, affectingthe coronary arteries producing coronaryartery stenoses,5' myocardial infarction,8 4 anddeath.4647525' Inflammation may also involvethe aorta both proximally, causing dilata-tion,27 and distally, causing retroperitonealinflammation.54 Proximal aortic involvementhas previously been noted at postmortemexamination 9 124455 and in our case this was

demonstrated by transoesophageal echocar-diography. The transoesophageal characteris-tics of aortic and cardiac involvement inWegener's granulomatosis have never previ-ously been described and in our case thistechnique also proved useful in following theresponse to treatment.

MYOCARDITISMyocarditis withnised3052 and can

failure."1 41 44 45 56 It

granulomata is recog-produce acute cardiacmay later progress to

Table 3 Organ involvement in Wegener's granulomatosisOrgan involvement (%)

Reference No ofpatients Heart Respiratory Renal Joints Skin Eye Ear, nose and throat Nervous system

McDonald and DeRemee 28 108 69 42 14 22 95 11Anderson, et al12 265 <4 63 60 20 25 14 75DeRemee, et al"9 50 4 70 46 16 12 74 22Hoffman, et al22 158 <8 85 77 67 46 52 92 23Fauci, et al30 85 12 94 85 67 45 58 91 22Garrett et al3' 30 17 86 33 40 33 37 10Walton' 56 27 48 25 34 46 23 89Fauci and Wolff32 18 28 100 83 56 44 39 94 22Wolff, et al33 21 29 100 81 57 48 43 95 24Pinching, et al 18 44 100 94 77 66 77 94 44

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cardiomyopathy.8 30 The carditis may alsoaffect the atria'2 45 or produce mass lesionswithin the ventricles. These in turn may resultin arrhythmia42 or obstruction, as in ourpatient who had both tachyarrhythmia and adetectable gradient across the left ventricularoutflow tract. The single previous patientreported with a cardiac mass in Wegener'sgranulomatosis42 underwent surgical resec-tion, although appropriate chemotherapyinduced regression of the mass in our case.

VALVULITISValve abnormalities may occur secondary todilatation of the aortic root27 or left ventricle,but primary valvulitis is also recognised.9 10 Itoccurs both alone'05758 and as part of eitherwidespread endocarditis or pancarditis.41445'This may result in a mistaken diagnosis of cul-ture negative infective endocarditis which failsto respond to antibiotic therapy6 and delay inthe initiation of appropriate and potentiallylife saving treatment.

ARRHYTHMIAConduction abnormalities occur, possiblybecause of granuloma of the conduction sys-tem or arteritis of the atrioventricular nodalartery.43 All degrees of conduction defect arerecognised, from intraventricular conductiondefects'440 (as in our case) through first2749and second degree to complete heartblock.'4 40 49 59 60 These may require permanentpacing but will occasionally correct withtreatment.40 49 60The most common arrhythmias are atrial

tachycardia and atrial fibrillation orflutter.32 34 43 47 49 Ventricular arrhythmia hasbeen noted40 in association with dilated car-diomyopathy,30 ischaemia334647 and secondaryto cardiac masses.42

Cardiac involvement in Wegener's granulo-matosis is not as uncommon as generallythought, ranging from 6 to 44% of patients. Itmay take many forms and varies from theprincipal clinical feature to mild or subclinicaldisease. Involvement should be activelysought in patients with Wegener's granulo-matosis and should be considered in patientswith non-specific illness. In view of its proteanclinical manifestations it should be consideredearly in the course of any apparent multisys-tem disorder including culture negative endo-carditis, as it can similarly produce systemicupset with mass lesions and vasculitis. Therisks of blind and potentially inappropriateantibiotic treatment for "culture negativeendocarditis" are obvious. The possible differ-ential diagnosis of Wegener's granulomatosis,now easily confirmed immunologically,should therefore be excluded early in the ill-ness to reduce serious, long-term renal andpulmonary damage which may be fatal.

Echocardiography and particularly trans-oesophageal echocardiography can easilyidentify and delineate cardiac and proximalaortic involvement in Wegener's granulo-matosis and may also have a potentiallyimportant role in following the response totreatment.

1 Plant WD, O'Donoghue DJ, Lewis MJ, Vettriano MD,McLoughlin KJ, Craig KJ, et al. Treatment and outcomeof ANCA associated renal disease; a retrospective crite-rion based audit. Nephrol Dial Transplant 1992;7:1144-5.

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IN CARDIOLOGY

Gingival hyperplasia with nifedipine

David R Ramsdale, John L Morris, Phillip Hardy

A 57 year old man underwent coronary arterybypass surgery in 1981 and 1987, percuta-neous transluminal coronary angioplasty andthrombolytic therapy to reopen an occludedsaphenous vein graft to the right coronary

artery on two occasions in 1993, and direc-tional coronary atherectomy to a proximalstenosis in the same graft. He had been takingnifedipine capsules between 1982 and 1987and from February 1993 to January 1994when he presented with a three month historyof painful, swollen, and bleeding gums.Physical examination showed pronouncedinflammatory gingival hyperplasia involvingseveral papillae on the labial side of the loweranterior teeth (figure). The bulbous gingivawere red, shiny, and bled easily. There was

CardiothoracicCentre, LiverpoolD R RamsdaleJ L MorrisP HardyCorrespondence to:Dr D R Ramsdale,Department of Cardiology,The Cardiothoracic Centre,Thomas Drive, LiverpoolL14 3PE.Accepted for publication19 October 1994

Severe inflammatory gingival hyperplasia causing pain,swelling, and bleeding. Plaque and calculus are alsovisible.

periodontitis with plaque and calculusdeposits. Treatment with nifedipine was

stopped and he was advised to go for descal-ing and instructions on oral hygiene. Sixmonths later the gingival hyperplasia had dis-appeared.

Although gingival hyperplasia is a well-known side effect of treatment with pheny-toin, valproic acid, and cyclosporin, many

physicians and cardiologists may not be aware

that nifedipine,' diltiazem,2 verapamil,'3 andamlodipine4 have been similarly implicated.The nodular hyperplasia occurs mainly in

the labial gingiva of the lower anterior teeth,around the maxillary molars or the interdentalgingiva or both. Edentulous gums are unaf-fected. Histological examination shows hyper-plasia, epithelial acanthosis with proliferation,reticulation, and elongation of the rete pegs.Drug induced gingival hyperplasia usually

regresses after nifedipine is stopped.Regression may take a few months. Rigorousoral hygiene including scaling, gingival mas-

sage, and antiseptic washings to controlplaque are thought to be an essential part ofthe management to prevent recurrence.

Gingivectomy is sometimes required.

1 Ramon Y, Behar S, Kishon Y, Engelberg IS. Gingivalhyperplasia caused by nifedipine-a preliminary report.IntJ Cardiol 1984;5:195-206.

2 Colvard MD, Bishop J, Weissman D, Bargiulo AV.Cardizem-induced gingival hyperplasia. Periodontal CaseReports 1986;8:67-8.

3 Cucchi G, Giustiniani S, Robustelli F. Gingival hyperplasiainduced by verapamil. G Ital Cardiol 1985;15:556-7.

4 Smith RG. Gingival enlargement in a patient medicatedwith amlodipine. BrDentj 1993;175:279.

SHORT CASES

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