Author + information
- Received August 31, 2010
- Revision received January 31, 2011
- Accepted February 15, 2011
- Published online June 28, 2011.
- 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⁎ and
- Calambur Narasimhan, MD, DM⁎,⁎ ()
- ↵⁎Reprint requests and correspondence:
Dr. Calambur Narasimhan, Cardiac Arrhythmia Services, CARE Hospital, Road Number 1, Banjara Hills, Hyderabad, Andhra Pradesh 500034, India
Objectives This report characterizes a syndrome of granulomatous infiltration presenting as sustained monomorphic ventricular 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 radiofrequency ablation and has a poor prognosis.
Methods Patients without obstructive coronary artery disease and with normal ventricular function presenting with SMVT other than posterior fascicular morphology were evaluated. Computed chest tomograms, cardiac magnetic resonance imaging, and 18-fluorodeoxyglucose positron emission tomographic scans (18FDG PET-CT) were performed. Significant lymph nodes were evaluated for tuberculosis and sarcoidosis. Initial treatment included antiarrhythmic drugs ± radiofrequency ablation. Additionally, patients with evidence of tuberculosis received anti-tuberculosis therapy; the rest were treated as sarcoidosis.
Results Mediastinal adenopathy with mid-myocardial scar and/or focal myocardial inflammation was observed in 14 patients; 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 of disease-specific therapy abolished further recurrences in 64% of them. Decrease in SMVT correlated with resolution of myocardial inflammation on serial 18FDG PET-CTs. Appropriate therapies occurred in 67% of patients receiving implantable cardioverter-defibrillators.
Conclusions A subset of patients with SMVT with preserved ventricular function has a syndrome of arrhythmogenic myocarditis with granulomatous mediastinal adenopathy due to myocardial tuberculosis or cardiac sarcoidosis. This entity is optimally managed with a combination of disease-specific therapy and antiarrhythmic measures.
Sustained monomorphic ventricular tachycardia (SMVT) with preserved ejection fraction (EF) typically has a benign course and responds well to antiarrhythmic drugs (AADs) and radiofrequency ablation (RFA) (1). We describe the clinical features, diagnostic and therapeutic strategies, and follow-up results of a cohort of patients who presented with SMVT with preserved EF who were found to have tuberculosis or sarcoidosis on evaluation; this patient subset responded poorly to AADs and RFA.
Between January 2008 and June 2009, of the 29 patients referred to our center with SMVT and the features listed in Table 1, 19 consented to further evaluation. Sustained monomorphic ventricular tachycardia with granulomatous mediastinal lymphadenopathy was diagnosed in 11 of them (58%). This report describes the course of these 11 patients and an additional 3 patients diagnosed between May 2006 and December 2007.
Figure 1 summarizes the diagnostic and therapeutic strategy adopted in patients suspected of having SMVT due to granulomatous infiltration. The site of the index ventricular tachycardia (VT) was localized on the basis of 12-lead electrocardiography as interpreted by 2 observers. Three or more episodes of sustained VT/day or a single episode lasting more than 1 h despite treatment was defined as a VT storm (2).
All patients underwent contrast-enhanced 64-slice computed tomograms (Siemens, Erlangen, Germany). Delayed gadolinium enhancement-cardiac magnetic resonance imaging (DE-CMR) was done with a 1.5-T scanner (Siemens) in the 11 patients without prior implanted devices. “Late” enhancement denoting myocardial scar was sought as previously described (3). A resting positron emission tomographic study after administration of 18-fluorodeoxyglucose in conjunction with a computed tomogram (18FDG PET-CT) and a 13N-ammonia cardiac perfusion scan was performed on 12 patients, including the 3 who did not undergo a DE-CMR, with a 16-slice scanner (Siemens) as per a standard protocol (4). High 18FDG uptake was interpreted as inflammation; matched perfusion and metabolism defects were interpreted as scar.
The tuberculin skin test for M.tuberculosis was performed with 5 tuberculin units of purified protein derivative. Horizontal induration of ≥10 mm at 48 h was considered positive. Lymph nodes were sampled in all, as per the described protocol (Fig. 1). Endomyocardial biopsy was performed in 4. All tissue samples were subjected to histopathology, Gram's stain, and staining and culture for mycobacteria and fungi. A deoxyribonucleic acid polymerase chain reaction (PCR) detecting the IS6110 sequence of M.tuberculosis was performed on 9 of the tissue samples.
All patients received AADs (beta-blockers and amiodarone) as initial therapy, with additional intravenous lidocaine/oral Mexiletine being used to control breakthrough episodes of arrhythmia. RFA was performed in 5 as part of initial therapy, predominantly among the earlier patients. Mapping was performed with an electroanatomic system (CARTO, Biosense Webster, Diamond Bar, California); a Stockert RF generator (Stockert GmBh, Freiburg, Germany) and an 8-F 3.5-mm tip irrigated catheter (NAVISTAR, Biosense Webster) were used for ablation. Successful RFA was defined as noninducibility of SMVT on ventricular stimulation from 2 sites including 2 extrastimuli; stimulation was performed without drugs and during continuous infusion of isoprenaline to a maximum dose of 6 μg/min. Implantable cardioverter-defibrillators (ICDs) were recommended in all; however, owing to financial constraints, only 9 received ICDs.
Disease-specific therapy for tuberculosis or sarcoidosis was added to initial therapy in all patients as per the protocol in Figure 1. Individualized titration of disease-specific therapy was guided by clinical response and serial 18FDG PET-CTs. Treatment duration ranged from 12 to 30 months. A 3-month period was allowed for disease-specific therapy to take effect, after which its effect was analyzed. Specific therapy was delayed due to late diagnosis in 8 of the initial patients; this helped to assess the impact of disease-specific therapy.
Patients were evaluated at 3 monthly intervals and during symptomatic recurrence. Interrogation of ICD and 12-lead electrocardiograms were performed at each evaluation. One patient was lost to follow-up after 1 month.
Continuous variables were reported as mean ± SD or medians (with interquartile range), as appropriate. Significance of differences was estimated with a Wilcoxon matched-pairs signed-rank test. The Pearson's test was used to correlate post-treatment change in VT frequency with resolution of inflammation on 18FDG PET-CT. The patient who was lost to follow-up was excluded from all outcome analyses.
Baseline and follow-up features are summarized in Table 2. The mean age at presentation was 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. Median follow-up was 25 months (interquartile range: 15 to 58 months).
All of the patients presented with SMVT. Morphologies of the index and subsequent VTs did not conform to any particular pattern (Table 2). The majority of the recurrent VTs (78%, or 7 of 9 recurrences where 12-lead electrocardiograms were available) had a different morphology, as compared with the index VT.
Sustained monomorphic ventricular tachycardia recurred at a median follow-up of 4 months (range 0.6 to 9 months) in 12 of 13 patients. Eleven of these patients had recurrence of VT before effective disease-specific therapy. Overall, there were 117 recurrences during 58.2 patient years of follow-up, including 18 VT storms.
Myocardial scarring and inflammation
Myocardial scarring or focal myocardial hypermetabolism was present in all (Fig. 2). DE-CMR revealed mid-myocardial scars in 9 of 11 patients (82%) (Fig. 3A); overall, when defined by either DE-CMR or single-photon emission computed tomography–PET, scar was present in 10 (71%). 18FDG PET-CT revealed myocardial inflammation in 11 of 12 (92%) (Fig. 3B). The only patient without myocardial uptake on 18FDG PET-CT had a diffuse matched perfusion-metabolism defect; etiological evaluation was delayed by several years in this patient. Myocardial scar in the absence of inflammation was the cause of VT in this patient. In contrast, 2 patients with normal DE-CMRs had myocardial inflammation in the absence of scar.
18FDG avid mediastinal nodes were present in all, including the patient without myocardial inflammation. Six patients had additional extramediastinal adenopathy (Table 2). Computed tomography scan showed asymptomatic pulmonary parenchymal abnormalities consistent with sarcoidosis in 2 patients.
Multiple noncaseating epithelioid granulomas consistent with either sarcoidosis or tuberculosis were present in 13 of the 14 lymph node samples (1 sample was inadequate). Endomyocardial biopsy was normal in 3 patients and showed nongranulomatous, noncaseating myocardial necrosis in the fourth.
Tuberculosis as an underlying etiology
Skin test for tuberculosis was positive in 11 of 14 patients (79%). Three patients showed an exuberant, necrotic local reaction to the purified tubercular protein derivative. Lymph node biopsy was positive for M.tuberculosis deoxyribonucleic acid PCR in 4 of 9 patients. M.tuberculosis was cultured from the lymph node in 2 patients (Table 2).
Electrophysiological study and RFA
Sustained monomorphic ventricular tachycardia was inducible in 4 of 5 patients. Two morphologies of SMVT were inducible in 2 of them. Induced VTs were consistent with a re-entrant mechanism in 2 and focal mechanism in 2; the mechanism could not be determined in 2 of the VTs. Low voltage areas (bipolar voltage <1.5 mV) on substrate map and sites of RFA corresponded to the sites of scar in DE-CMR or to the site of inflammation in 18FDG PET-CT (Table 3).
Response to treatment
RFA was successful in 3 of the 5 patients who received it as part of initial therapy. Before effective disease-specific therapy, VT recurred in 100% of the patients who received AADs with RFA as initial therapy and in 75% of patients who received AADs only. Among the 11 patients who experienced recurrence while receiving initial therapy, disease-specific therapy controlled the VT in 9 (82%). This included 7 patients (64%) in whom further VT was abolished and 2 others (18%) in whom VT frequency decreased. Overall, disease-specific therapy reduced the VT frequency from 6.5 VTs/patient-year to 0.6 VTs/patient-year (p = 0.016) (Fig. 4); 16 VT storms occurred before effective disease-specific therapy, compared with 2 after. Reduction in VT burden correlated with resolution of myocardial inflammation on post-treatment 18FDG PET-CTs (r = 0.87). This response was observed among all disease-specific therapy protocols (Fig. 5). Appropriate ICD therapies occurred in 6 of 9 ICD recipients (67%). One patient who was diagnosed late developed biventricular dysfunction before etiological diagnosis and succumbed to progressive heart failure.
This report describes a cohort of patients wherein a granulomatous disease presented as SMVT with preserved EF. Recurrent VT of morphology different from the index presentation should arouse suspicion of an underlying infiltrative disorder among such patients.
Diagnosis of cardiac sarcoidosis
Some of our patients cannot be diagnosed to have cardiac sarcoidosis (CS) on the basis of the Japanese Ministry of Health criteria (5,6). However, patchy mid-myocardial scar, focal intense myocardial 18FDG uptake, noncaseating granulomas in lymph nodes, and the observed treatment response are all consistent with CS (4,6). We recommend a protocol of routine contrast-enhanced chest computed tomography scans followed by sampling of the involved nodes as the preferred strategy for histological diagnosis. Over-reliance on endomyocardial biopsies might have underdiagnosed this entity in the past (7).
Unlike Banba et al. (8), who described VT as a late manifestation of CS, we found that both the early inflammatory and late scar phases of this disease could cause SMVT, as evidenced by: 1) myocardial inflammation without scar in 2 patients, and scar without inflammation causing SMVT in another; and 2) resolution of inflammation on 18FDG PET-CT correlating with reduction in VT burden.
CS versus myocardial tuberculosis
Isolation of M.tuberculosis in 2 of our patients and their response to ATT confirms isolated myocardial tuberculosis presenting as SMVT, a rare but described entity (9). Whether M.tuberculosis PCR positivity in sarcoid granulomas has an etiological implication is a matter of debate (10). Tuberculin skin test positivity has been used to differentiate tuberculosis from sarcoidosis; whether this observation can be extended to isolated CS is unexplored (11). From a therapeutic perspective, administering immunosuppressants without concomitant ATT to such patients could result in flare-up of tuberculosis. This underscores the importance of evaluation for tuberculosis among these patients.
Unlike usual forms of SMVT with preserved EF, those due to granulomatous myocarditis responded poorly to RFA and had a 100% recurrence rate, a finding similar to that reported by Koplan et al. (12). Appropriate therapies occurred in 67% of ICD recipients. Addition of disease-specific therapy significantly decreased VT burden and nearly eliminated VT storms. We recommend a combination of disease-specific therapy, AADs, and ICD rather than RFA as the first line of treatment for SMVT with preserved EF due to granulomatous myocarditis.
This is a predominantly retrospective analysis performed on a small number of patients from an area endemic to tuberculosis. The report highlights the effect of specific therapy in myocardial tuberculosis and describes only a limited number of patients with CS. Etiological factors might vary in different areas; however, work-up for various granulomatous disorders is warranted in this entity. Larger, prospective studies are required to clarify the relative diagnostic importance of the various findings we have observed.
A subset of patients with SMVT and preserved EF has underlying granulomatous inflammation, due to CS or myocardial tuberculosis. Mediastinal adenopathy with mid-myocardial scar and/or focal myocardial hypermetabolism characterize this subset. Histopathology of the involved nodes reveals granulomas. Recurrent arrhythmia is frequent in them, despite AADs and RFA. Disease-specific therapy tailored to the underlying disease can reduce and often abolish recurrent VT. Late recurrences of VT seem to justify ICD insertion.
The 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.
The authors have reported that they have no relationships to disclose.
- Abbreviations and Acronyms
- 18FDG PET-CT
- 18-fluorodeoxyglucose positron emission tomography with computed tomogram
- antiarrhythmic drug
- anti-tuberculosis therapy
- cardiac sarcoidosis
- delayed gadolinium-enhancement cardiac magnetic resonance imaging
- ejection fraction
- implantable cardioverter-defibrillator
- polymerase chain reaction
- radiofrequency ablation
- sustained monomorphic ventricular tachycardia
- ventricular tachycardia
- Received August 31, 2010.
- Revision received January 31, 2011.
- Accepted February 15, 2011.
- American College of Cardiology Foundation
- Aliot E.M.,
- Stevenson W.G.,
- Almendral-Garrote J.M.,
- et al.
- Okumura W.,
- Iwasaki T.,
- Toyama T.,
- et al.
- Hiraga H.,
- Hiroe M.,
- Iwai K.
- Uusimaa P.,
- Ylitalo K.,
- Anttonen O.,
- et al.
- Gupta D.,
- Agarwal R.,
- Aggarwal A.N.,
- Jindal S.K.