Journal of the American College of Cardiology Vol. 58, No. 1, 2011© 2011 by the American College of Cardiology Foundation ISSN 0735-1097/$36.00

Monomorphic Ventricular Tachycardia andMediastinal Adenopathy Due to Granulomatous Infiltrationin Patients With Preserved Ventricular Function

Ajit Thachil, MD, DM,* Johann Christopher, MD, DNB,* B. K. S. Sastry, MD, DM,*Kavitha Nallapa Reddy, DNB, DRM,† Vijaya K. Tourani, MD,* Ashfaq Hassan, MD,*Bhupathiraju Soma Raju, MD, DM,* Calambur Narasimhan, MD, DM*

Hyderabad, India

Objectives This report characterizes a syndrome of granulomatous infiltration presenting as sustained monomorphic ven-tricular tachycardia (SMVT) with mediastinal adenopathy in patients with preserved ventricular function.

Background Unlike truly idiopathic ventricular tachycardia, SMVT due to granulomatous infiltration responds poorly to radio-frequency ablation and has a poor prognosis.

Methods Patients without obstructive coronary artery disease and with normal ventricular function presenting with SMVTother than posterior fascicular morphology were evaluated. Computed chest tomograms, cardiac magneticresonance imaging, and 18-fluorodeoxyglucose positron emission tomographic scans (18FDG PET-CT) wereperformed. Significant lymph nodes were evaluated for tuberculosis and sarcoidosis. Initial treatment includedantiarrhythmic drugs � radiofrequency ablation. Additionally, patients with evidence of tuberculosis receivedanti-tuberculosis therapy; the rest were treated as sarcoidosis.

Results Mediastinal adenopathy with mid-myocardial scar and/or focal myocardial inflammation was observed in 14patients; lymph nodes revealed noncaseating granulomas in all. Evidence of tuberculosis was present in 79%.During follow-up (median duration 25 months), SMVT recurred despite initial treatment in 92%. Addition ofdisease-specific therapy abolished further recurrences in 64% of them. Decrease in SMVT correlated with resolu-tion of myocardial inflammation on serial 18FDG PET-CTs. Appropriate therapies occurred in 67% of patients re-ceiving implantable cardioverter-defibrillators.

Conclusions A subset of patients with SMVT with preserved ventricular function has a syndrome of arrhythmogenic myocardi-tis with granulomatous mediastinal adenopathy due to myocardial tuberculosis or cardiac sarcoidosis. This entityis optimally managed with a combination of disease-specific therapy and antiarrhythmic measures. (J Am CollCardiol 2011;58:48–55) © 2011 by the American College of Cardiology Foundation

Published by Elsevier Inc. doi:10.1016/j.jacc.2011.02.044

thot

Sustained monomorphic ventricular tachycardia (SMVT)with preserved ejection fraction (EF) typically has a benigncourse and responds well to antiarrhythmic drugs (AADs)and radiofrequency ablation (RFA) (1). We describe theclinical features, diagnostic and therapeutic strategies, andfollow-up results of a cohort of patients who presented withSMVT with preserved EF who were found to have tuber-culosis or sarcoidosis on evaluation; this patient subsetresponded poorly to AADs and RFA.

From the *Care Hospital, Banjara Hills, Hyderabad, India; and the †ApolloGleneagles PET-CT Center, Jubilee Hills, Hyderabad, India. The authors havereported that they have no relationships to disclose.

oManuscript received August 31, 2010; revised manuscript received January 31,

2011, accepted February 15, 2011.

Methods

Patient population. Between January 2008 and June 2009,of the 29 patients referred to our center with SMVT and thefeatures listed in Table 1, 19 consented to further evalua-tion. Sustained monomorphic ventricular tachycardia withgranulomatous mediastinal lymphadenopathy was diag-nosed in 11 of them (58%). This report describes the courseof these 11 patients and an additional 3 patients diagnosedbetween May 2006 and December 2007.Diagnostic evaluation. Figure 1 summarizes the diagnos-ic and therapeutic strategy adopted in patients suspected ofaving SMVT due to granulomatous infiltration. The sitef the index ventricular tachycardia (VT) was localized onhe basis of 12-lead electrocardiography as interpreted by 2

bservers. Three or more episodes of sustained VT/day or a

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49JACC Vol. 58, No. 1, 2011 Thachil et al.June 28, 2011:48–55 VT in Granulomatous Disease

single episode lasting more than 1 h despite treatment wasdefined as a VT storm (2).

IMAGING. All patients underwent contrast-enhanced 64-slice computed tomograms (Siemens, Erlangen, Germany).Delayed gadolinium enhancement-cardiac magnetic reso-nance imaging (DE-CMR) was done with a 1.5-T scanner(Siemens) in the 11 patients without prior implanteddevices. “Late” enhancement denoting myocardial scar wassought as previously described (3). A resting positronemission tomographic study after administration of 18-fluorodeoxyglucose in conjunction with a computed tomo-gram (18FDG PET-CT) and a 13N-ammonia cardiac per-fusion scan was performed on 12 patients, including the 3who did not undergo a DE-CMR, with a 16-slice scanner(Siemens) as per a standard protocol (4). High 18FDGptake was interpreted as inflammation; matched perfusionnd metabolism defects were interpreted as scar.

ETIOLOGICAL EVALUATION. The tuberculin skin test for.tuberculosis was performed with 5 tuberculin units of

urified protein derivative. Horizontal induration of �10m at 48 h was considered positive. Lymph nodes were

ampled in all, as per the described protocol (Fig. 1).ndomyocardial biopsy was performed in 4. All tissue

amples were subjected to histopathology, Gram’s stain, andtaining and culture for mycobacteria and fungi. A deoxy-ibonucleic acid polymerase chain reaction (PCR) detectinghe IS6110 sequence of M.tuberculosis was performed on 9

of the tissue samples.Treatment. INITIAL THERAPY. All patients received AADsbeta-blockers and amiodarone) as initial therapy, withdditional intravenous lidocaine/oral Mexiletine being usedo control breakthrough episodes of arrhythmia. RFA waserformed in 5 as part of initial therapy, predominantlymong the earlier patients. Mapping was performed with anlectroanatomic system (CARTO, Biosense Webster, Dia-ond Bar, California); a Stockert RF generator (StockertmBh, Freiburg, Germany) and an 8-F 3.5-mm tip irri-

ated catheter (NAVISTAR, Biosense Webster) were usedor ablation. Successful RFA was defined as noninducibilityf SMVT on ventricular stimulation from 2 sites includingextrastimuli; stimulation was performed without drugs

nd during continuous infusion of isoprenaline to a maximumose of 6 �g/min. Implantable cardioverter-defibrillatorsICDs) were recommended in all; however, owing tonancial constraints, only 9 received ICDs.

DISEASE-SPECIFIC THERAPY. Disease-specific therapy for tu-berculosis or sarcoidosis was added to initial therapy in allpatients as per the protocol in Figure 1. Individualized titrationof disease-specific therapy was guided by clinical response andserial 18FDG PET-CTs. Treatment duration ranged from 12o 30 months. A 3-month period was allowed for disease-pecific therapy to take effect, after which its effect was

nalyzed. Specific therapy was delayed due to late diagnosis in

of the initial patients; this helpedo assess the impact of disease-pecific therapy.ollow-up. Patients were evalu-ted at 3 monthly intervals anduring symptomatic recurrence.nterrogation of ICD and 12-ead electrocardiograms were per-ormed at each evaluation. Oneatient was lost to follow-up af-er 1 month.tatistical methods. Continu-us variables were reported asean � SD or medians (with

nterquartile range), as appropri-te. Significance of differencesas estimated with a Wilcoxonatched-pairs signed-rank test.he Pearson’s test was used to

orrelate post-treatment changen VT frequency with resolution ofnflammation on 18FDG PET-

CT. The patient who was lost tofollow-up was excluded from alloutcome analyses.

Results

Baseline characteristics. Baseline and follow-up featuresare summarized in Table 2. The mean age at presentationwas 44 � 11 years; mean left ventricular EF was 58 � 6%.None of the patients had symptoms of extracardiac disease.No patient had atrioventricular conduction block. Medianfollow-up was 25 months (interquartile range: 15 to 58months).VT morphology. All of the patients presented withSMVT. Morphologies of the index and subsequent VTs didnot conform to any particular pattern (Table 2). Themajority of the recurrent VTs (78%, or 7 of 9 recurrenceswhere 12-lead electrocardiograms were available) had adifferent morphology, as compared with the index VT.VT recurrence. Sustained monomorphic ventricular tachy-cardia recurred at a median follow-up of 4 months (range0.6 to 9 months) in 12 of 13 patients. Eleven of thesepatients had recurrence of VT before effective disease-

Features of Patients Evaluated for Monomorphic VTWith Mediastinal Adenopathy Due to GranulomatousInfiltrationTable 1

Features of Patients Evaluated for Monomorphic VTWith Mediastinal Adenopathy Due toGranulomatous Infiltration

Normal biventricular systolic function (ejection fraction �50%)

Absence of obstructive coronary artery disease

Absence of known ion channelopathies causing VT

Absence of transient, reversible causes of VT like electrolyte abnormalities

�1 episode of sustained monomorphic VT of any morphology other than typicalleft ventricular posteroseptal fascicular morphology, defined as VT of rightbundle branch block morphology, superior axis, and QRS duration �140 ms

Abbreviationsand Acronyms

18FDG PET-CT � 18-fluorodeoxyglucose positronemission tomography withcomputed tomogram

AAD � antiarrhythmic drug

ATT � anti-tuberculosistherapy

CS � cardiac sarcoidosis

DE-CMR � delayedgadolinium-enhancementcardiac magneticresonance imaging

EF � ejection fraction

ICD � implantablecardioverter-defibrillator

PCR � polymerase chainreaction

RFA � radiofrequencyablation

SMVT � sustainedmonomorphic ventriculartachycardia

VT � ventriculartachycardia

VT � ventricular tachycardia.

50 Thachil et al. JACC Vol. 58, No. 1, 2011VT in Granulomatous Disease June 28, 2011:48–55

Figure 1 Diagnostic and Therapeutic Strategy in Patients Suspected of Having SMVT Due to Granulomatous Disease

AFB � acid fast bacilli; CAD � coronary artery disease; DE-CMR � delayed gadolinium enhancement-cardiac magnetic resonance imaging; DNA-PCR � DNA-based poly-merase chain reaction; 18FDG PET-CT � 18fluorodeoxyglucose positron emission tomography with computed tomogram; FNAC � fine needle aspiration cytology; HRCT �

contrast-enhanced high resolution computed tomogram of the chest; ICD � implantable cardioverter-defibrillator; LV � left ventricular; MMVT � monomorphic ventriculartachycardia; PCR � polymerase chain reaction; RFA � radiofrequency ablation; SMVT � sustained monomorphic ventricular tachycardia; USG � ultrasonography;VATS � video-assisted thoracoscopic surgery; VT � ventricular tachycardia.

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51JACC Vol. 58, No. 1, 2011 Thachil et al.June 28, 2011:48–55 VT in Granulomatous Disease

specific therapy. Overall, there were 117 recurrences during58.2 patient years of follow-up, including 18 VT storms.Myocardial scarring and inflammation. Myocardial scar-ring or focal myocardial hypermetabolism was present in all(Fig. 2). DE-CMR revealed mid-myocardial scars in 9 of 11patients (82%) (Fig. 3A); overall, when defined by eitherDE-CMR or single-photon emission computed tomography–PET, scar was present in 10 (71%). 18FDG PET-CT revealedmyocardial inflammation in 11 of 12 (92%) (Fig. 3B). The onlypatient without myocardial uptake on 18FDG PET-CT had aiffuse matched perfusion-metabolism defect; etiological eval-ation was delayed by several years in this patient. Myocardialcar in the absence of inflammation was the cause of VT in thisatient. In contrast, 2 patients with normal DE-CMRs hadyocardial inflammation in the absence of scar.xtracardiac involvement. 18FDG avid mediastinal nodesere present in all, including the patient without myocardial

nflammation. Six patients had additional extramediastinaldenopathy (Table 2). Computed tomography scan showedsymptomatic pulmonary parenchymal abnormalities con-istent with sarcoidosis in 2 patients.

istopathologic analysis. Multiple noncaseating epitheli-id granulomas consistent with either sarcoidosis or tuber-ulosis were present in 13 of the 14 lymph node samples1 sample was inadequate). Endomyocardial biopsy wasormal in 3 patients and showed nongranulomatous, non-

Figure 2 Sites of Myocardial Scar and/or Inflammation Among

Scar was defined as delayed gadolinium enhancement on cardiac magnetic resonaemission tomographic computed tomography scan (PET) metabolism defect. Increascar and/or focal myocardial inflammation. *Matched metabolism - perfusion defeventricle; LV-AW � anterior wall of the left ventricle; LV-IW � inferior wall of the leventricle; RV � right ventricle; RVOT � right ventricular outflow tract; sl. no. � ser

aseating myocardial necrosis in the fourth.

uberculosis as an underlying etiology. Skin test foruberculosis was positive in 11 of 14 patients (79%). Threeatients showed an exuberant, necrotic local reaction to theurified tubercular protein derivative. Lymph node biopsyas positive for M.tuberculosis deoxyribonucleic acid PCR inof 9 patients. M.tuberculosis was cultured from the lymph

ode in 2 patients (Table 2).lectrophysiological study and RFA. Sustained mono-orphic ventricular tachycardia was inducible in 4 of 5

atients. Two morphologies of SMVT were inducible in 2f them. Induced VTs were consistent with a re-entrantechanism in 2 and focal mechanism in 2; the mechanism

ould not be determined in 2 of the VTs. Low voltage areasbipolar voltage �1.5 mV) on substrate map and sites ofFA corresponded to the sites of scar in DE-CMR or to

he site of inflammation in 18FDG PET-CT (Table 3).Response to treatment. RFA was successful in 3 of the 5patients who received it as part of initial therapy. Beforeeffective disease-specific therapy, VT recurred in 100% of thepatients who received AADs with RFA as initial therapy andin 75% of patients who received AADs only. Among the 11patients who experienced recurrence while receiving initialtherapy, disease-specific therapy controlled the VT in 9 (82%).This included 7 patients (64%) in whom further VT wasabolished and 2 others (18%) in whom VT frequency de-creased. Overall, disease-specific therapy reduced the VT

nts With Granulomatous Myocarditis

aging (MRI) or matched 13N-ammonia perfusion/18fluorodeoxyglucose positron8FDG uptake on PET-CT indicated inflammation. All patients had mid-myocardialgestive of scar was present on PET. IVS � interventricular septum; LV � leftricle; LV-LW � lateral wall of the left ventricle; LV-PW � posterior wall of the left

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frequency from 6.5 VTs/patient-year to 0.6 VTs/patient-year

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52 Thachil et al. JACC Vol. 58, No. 1, 2011VT in Granulomatous Disease June 28, 2011:48–55

(p � 0.016) (Fig. 4); 16 VT storms occurred before effectivedisease-specific therapy, compared with 2 after. Reduction inVT burden correlated with resolution of myocardial inflam-mation on post-treatment 18FDG PET-CTs (r � 0.87). Thisesponse was observed among all disease-specific therapy pro-ocols (Fig. 5). Appropriate ICD therapies occurred in 6 of 9CD recipients (67%). One patient who was diagnosed lateeveloped biventricular dysfunction before etiological diagnosisnd succumbed to progressive heart failure.

iscussion

his report describes a cohort of patients wherein a granu-omatous disease presented as SMVT with preserved EF.

Figure 3 Demonstrations of Myocardial Scar and Inflammation

(A) Demonstration of myocardial scar. Delayed gadolinium enhanced cardiac magncharacteristic mid-myocardial scar (arrows) in the interventricular septum. Owing t(B) Demonstration of myocardial inflammation. The 18fluorodeoxyglucose (FDG) poA showing myocardial hypermetabolism in the anterior and lateral walls, basal sep

ecurrent VT of morphology different from the index

resentation should arouse suspicion of an underlying infil-rative disorder among such patients.

iagnosis of cardiac sarcoidosis. Some of our patientsannot be diagnosed to have cardiac sarcoidosis (CS) on theasis of the Japanese Ministry of Health criteria (5,6). How-ver, patchy mid-myocardial scar, focal intense myocardial

18FDG uptake, noncaseating granulomas in lymph nodes, andthe observed treatment response are all consistent with CS(4,6). We recommend a protocol of routine contrast-enhancedchest computed tomography scans followed by sampling of theinvolved nodes as the preferred strategy for histological diag-nosis. Over-reliance on endomyocardial biopsies might have

esonance imaging (from patient number 7 in Table 2 and Figure 2) showing theatchy nature, the scar does not enhance as intensely as an ischemic scar.emission tomographic computed tomography scan of the same patient as innd a mediastinal lymph node.

etic ro its psitrontum, a

underdiagnosed this entity in the past (7).

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53JACC Vol. 58, No. 1, 2011 Thachil et al.June 28, 2011:48–55 VT in Granulomatous Disease

Unlike Banba et al. (8), who described VT as a latemanifestation of CS, we found that both the early inflam-matory and late scar phases of this disease could causeSMVT, as evidenced by: 1) myocardial inflammation with-out scar in 2 patients, and scar without inflammationcausing SMVT in another; and 2) resolution of inflamma-tion on 18FDG PET-CT correlating with reduction in VTburden.CS versus myocardial tuberculosis. Isolation of M.tuber-ulosis in 2 of our patients and their response to ATTonfirms isolated myocardial tuberculosis presenting asMVT, a rare but described entity (9). Whether M.tuber-

ulosis PCR positivity in sarcoid granulomas has an etiolog-cal implication is a matter of debate (10). Tuberculin skinest positivity has been used to differentiate tuberculosisrom sarcoidosis; whether this observation can be extendedo isolated CS is unexplored (11). From a therapeuticerspective, administering immunosuppressants withoutoncomitant ATT to such patients could result in flare-upf tuberculosis. This underscores the importance of evalu-tion for tuberculosis among these patients.reatment considerations. Unlike usual forms of SMVTith preserved EF, those due to granulomatous myocarditis

esponded poorly to RFA and had a 100% recurrence rate,finding similar to that reported by Koplan et al. (12).ppropriate therapies occurred in 67% of ICD recipients.ddition of disease-specific therapy significantly decreasedT burden and nearly eliminated VT storms. We recom-end a combination of disease-specific therapy, AADs, and

CD rather than RFA as the first line of treatment forMVT with preserved EF due to granulomatous

Figure 4 Change in VT Frequency After Addition of Disease-Specific Therapy to Antiarrhythmic Drugs/RFA

In the 13 patients available to follow-up, the effect of disease-specific therapywas measured starting from 3 months after its initiation. Mean follow-upbefore effective disease-specific therapy was 37 � 53 months and after effec-tive therapy was 16 � 13 months. Effective disease-specific therapy caused asignificant (p � 0.05) decrease in ventricular tachycardia (VT) burden. RFA �

radiofrequency ablation.

myocarditis.Ba T P S

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emission tomographic computed tomography scan; IVS � interventricular septum; IW � inferior wall of the left ventricle; LV � left ventricle; LW � lateral wall of the left ventricle; RFA � radiofrequencyablation; RVOT � right ventricular outflow tract.

54 Thachil et al. JACC Vol. 58, No. 1, 2011VT in Granulomatous Disease June 28, 2011:48–55

Figure 5 Pre- and Post-Treatment 18FDG PET-CT Scans Showing Resolution of Inflammation With Treatment

(A) 18Fluorodeoxyglucose positron emission tomographic computed tomography scan (18FDG PET-CT) images showing high myocardial and mediastinal node (whitearrows) uptake at baseline which resolved after treatment with anti-tuberculosis therapy in a patient with a positive M. tuberculosis culture from the mediastinal node.(B) 18FDG PET-CT images showing high myocardial, mediastinal, and splenic (white arrows) uptake at baseline which resolved after treatment with corticosteriods andmethotrexate in a patient with a negative acid fast bacilli stain, culture, M. tuberculosis DNA-polymerase chain reaction, and a negative tuberculin skin test.

EPS/RFA Findings of Patients Undergoing RFA, Correlated With DE-CMR and 18FDG PET-CT FindingsTable 3 EPS/RFA Findings of Patients Undergoing RFA, Correlated With DE-CMR and 18FDG PET-CT Findings

Patient Serial #

1 7 8 10 12

Site of scar in DE-CMR None IVS IVS, AW, IW, LW IVS, RVOT RVOT

Site of inflammation in 18FDG PET-CT IVS IVS, AW, LW Not done IVS, LW AW, IW, LW, LV apex

Site of low voltage None IVS IVS LW RVOT

Site of RFA IVS/RVOT septum IVS IVS LW RVOT

Patient serial # correspond to Table 2 and Figure 2.AW � anterior wall of the left ventricle; DE-CMR � delayed gadolinium enhanced cardiac magnetic resonance imaging; EPS � electrophysiological study; 18FDG PET-CT � 18fluorodeoxyglucose positron

1

1

1

55JACC Vol. 58, No. 1, 2011 Thachil et al.June 28, 2011:48–55 VT in Granulomatous Disease

Study limitations. This is a predominantly retrospectiveanalysis performed on a small number of patients from anarea endemic to tuberculosis. The report highlights theeffect of specific therapy in myocardial tuberculosis anddescribes only a limited number of patients with CS.Etiological factors might vary in different areas; however,work-up for various granulomatous disorders is warranted inthis entity. Larger, prospective studies are required to clarifythe relative diagnostic importance of the various findings wehave observed.

ConclusionsA subset of patients with SMVT and preserved EF hasunderlying granulomatous inflammation, due to CS or myo-cardial tuberculosis. Mediastinal adenopathy with mid-myocardial scar and/or focal myocardial hypermetabolismcharacterize this subset. Histopathology of the involved nodesreveals granulomas. Recurrent arrhythmia is frequent in them,despite AADs and RFA. Disease-specific therapy tailored tothe underlying disease can reduce and often abolish recurrentVT. Late recurrences of VT seem to justify ICD insertion.

AcknowledgmentsThe authors wish to thank Professor Hein J. Wellens(University of Maastricht, Maastricht, the Netherlands),Professor S. Jaishankar (CARE Hospitals, Hyderabad,India), and Dr. Andre d’Avila (Mount Sinai Hospital,New York, New York) for reviewing this report.

Reprint requests and correspondence: Dr. Calambur Narasimhan,Cardiac Arrhythmia Services, CARE Hospital, Road Number 1,Banjara Hills, Hyderabad, Andhra Pradesh 500034, India. E-mail:

calambur@hotmail.com.

m

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Key Words: cardiac sarcoidosis y granulomatous myocarditis y

yocardial tuberculosis y ventricular tachycardia.