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Catheter Ablation of Atrial Arrhythmias in Cardiac Sarcoidosis JONATHAN M. WILLNER, M.D.,∗ JUAN F. VILES-GONZALEZ, M.D.,† JAMES O. COFFEY, M.D.,† ADAM S. MORGENTHAU, M.D.,∗ and DAVENDRA MEHTA, M.D.∗ From the ∗ Divisions of Cardiology and Pulmonary Medicine, Mount Sinai Medical Center and Icahn School of Medicine at Mount Sinai, New York, New York, USA; and the †Division of Cardiology, University of Miami Medical Center and Miami School of Medicine, Miami, Florida
Ablation of Atrial Arrhythmias in Cardiac Sarcoidosis. Background: We previously reported on the incidence and clinical implications of supraventricular arrhythmia in patients with cardiac sarcoidosis (CS). The role of catheter ablation for the management of atrial arrhythmia (AA) in this patient population is unknown. Methods and Results: One hundred consecutive patients with CS were monitored for the incidence of supraventricular arrhythmias. Those with persistent symptoms despite optimal medical therapy proceeded to catheter ablation. Following ablation, all patients were followed serially with Holter monitoring or device interrogation. Thirty-two (32%) patients had symptomatic supraventricular arrhythmias. Nine (28%) patients had symptomatic AA requiring catheter ablation for clinical indications. Mean age was 55 ± 11.6 years. Five (56%) patients had atrial fibrillation (AF), of whom 2 also had cavotricuspid isthmus ablation. Four patients had isolated atrial flutter: 2 patients with left atrial flutter, and 2 patients with cavotricuspid flutter. All other arrhythmias were ablated in the left atrium. Mean duration of follow-up was 1.8 ± 1.9 years. One patient with atypical atrial flutter, and one patient with AF have had recurrence; the remaining patients remain in sinus rhythm. Conclusions: Our study suggests that AA in CS is frequently left atrial in origin. Catheter ablation appears to be effective and safe for the maintenance of sinus rhythm in patients with CS. (J Cardiovasc Electrophysiol, Vol. 25, pp. 958-963, September 2014) atrial fibrillation, atrial flutter, cardiac sarcoid, catheter ablation, sarcoidosis, tachyarrhythmias Introduction Sarcoidosis is a chronic granulomatous disease of uncertain origin. Over 80% of cases present in patients between the ages of 20 and 40, and it is slightly more common in women than men.1 A total 40–50% of patients with systemic sarcoidosis will develop cardiac involvement.2,3 Clinical manifestations of cardiac sarcoidosis (CS), including conduction system disease, arrhythmia, heart failure, and sudden cardiac death, manifest in 2–5% of patients.4,5 While ventricular arrhythmia and sudden cardiac death remain the most feared complications of CS, atrial arrhythmia (AA) occurs in upwards of one-quarter of patients, the majority of whom are clinically symptomatic.6-10 The pathogenesis of AA in sarcoidosis remains uncertain, but is thought to have 2 potential etiologies: (1) elevated atrial pressure due to progressive ventricular dysfunction and/or pulmonary hypertension, or (2) sarcoid granulomatous deposition causing inflammation, scarring, and substrate heterogeneity.11 In the general population, catheter ablation of AA has become a mainstay of therapy. However, the safety and efficacy of catheter ablation in the management of CS have No disclosures. Address for correspondence: Davendra Mehta, M.D., Mount Sinai Medical Center, 1 Gustave L. Levy Place, Guggenheim Pavilion 2W, New York, NY 10029, USA. Fax: 212-241-9701; E-mail: [email protected] Manuscript received 24 January 2014; Revised manuscript received 18 March 2014; Accepted for publication 25 March 2014. doi: 10.1111/jce.12424 [The copyright line has been changed on 9 June 2014, after first online publication on 2 May 2014.]
not been investigated. This study sought to examine the outcomes of catheter ablation in the management of AA in patients with CS. Methods Patient Selection The Institutional Review Board of the Mount Sinai Medical Center approved the study (GCO 08-0673). Consecutive patients with an established diagnosis of CS referred to the Mount Sinai Electrophysiology Clinic were retrospectively evaluated. We identified 32 patients with AA from our database of 100 patients, of whom 9 underwent catheter ablation and were included in this study. All patients had biopsy-proven systemic sarcoidosis and evidence of CS as defined by biopsy (patient no. 8) or typical imaging findings on either cardiac magnetic resonance imaging (MRI) or positron emission tomography (PET). MRI findings diagnostic of CS included localized intramyocardial increased signal intensity on T2-weighted sequence indicative of edema, and delayed contrast enhancement suggestive of infiltration and scarring. PET imaging was considered positive when perfusion images showed no evidence of ischemia and fluorodeoxyglucose uptake images showed either increased or mismatched metabolic activity suggestive of infiltration, or matched decrease in metabolic activity indicative of scarring. All patients underwent echocardiography as a part of their cardiac workup. Medical Record Review Standardized data forms were used to extract pertinent data from the medical record regarding details of demographics and medical history. The presence of prednisone,
Willner et al. Ablation of Atrial Arrhythmias in Cardiac Sarcoidosis
methylprednisolone, hydrocortisone, and/or other immunosuppressants on the patient’s medication list was considered positive for corticosteroid/immunosuppressant usage, regardless of dosage or duration. History of use of an antiarrhythmic drug (AAD) was considered positive if a Class IC or III agent had been prescribed prior to the AA ablation. Coronary artery disease (CAD) was considered present if the patient had a history of either prior myocardial infarction or left heart catheterization documenting CAD. Echocardiographic Parameters For each patient, left ventricular ejection fraction (LVEF) was evaluated by 2D transthoracic echocardiography. Additional echocardiographic parameters including right and left atrial size, assessment of LV diastolic and systolic function, valvular disease, and pulmonary hypertension were recorded. Any degree of atrial enlargement (area >20 cm2 ) was considered abnormal. Any mitral regurgitation that was more than physiologic was considered positive. Pulmonary hypertension was determined by conventional transthoracic echocardiography and calculated using tricuspid regurgitation jet velocity and the modified Bernoulli equation (mild 35–50 mmHg, moderate 51–65 mmHg, severe >65 mmHg). Electrophysiologic Study and Ablation Standard electrophysiological procedures were used for diagnosis and catheter ablation. In patients with atrial flutter, catheters were placed in the coronary sinus and right atrium. Entrainment and 3-dimensional (3D) activation mapping were undertaken. If necessary, a transseptal approach was used for left atrial mapping and ablation. Mapping was performed using multielectrode mapping catheters. In patients with atrial fibrillation (AF), pulmonary vein isolation (PVI) was undertaken. A double transseptal technique was used. All patients had CT of the heart to determine left atrial and pulmonary vein anatomy. Three-dimensional maps were made using an electroanatomical mapping system (NAVX/CARTO). Thermocool ablation catheters were used for ablation of atrial tachycardias, atrial flutter, and AF. All patients underwent PVI in pairs (wide antral circumferential ablation) followed by mapping and ablation of complex fractionated atrial electrograms as previously described. PVI was confirmed by administration of intravenous adenosine (18 mg) to reveal dormant conduction, and if present, further lesions were given to confirm persistent isolation. Ablation lesion sets were stimulated (i.e., paced) with 10 mA using the ablation catheter. If electrical capture was present additional radiofrequency applications were delivered. After ablation, all patients were monitored for AA recurrence by either 2 weeks of event monitor or pacemaker/implantable cardioverter defibrillator (ICD) interrogation at 3 and 6 months postprocedure. Results Clinical Characteristics Out of 100 consecutive patients with an established diagnosis of CS, 32 (32%) were documented to have AA. Ten of these 32 patients (31%) ultimately required catheter ablation for arrhythmias resistant to medical therapy. One patient had SVT related to AVNRT and was excluded from the analysis
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as this was thought to be unrelated to CS. Of the 9 patients included, 5 (56%) had AF, 2 (22%) had typical atrial flutter, and 2 (22%) had a left-sided atrial tachycardia (AT)/atrial flutter. Table 1 shows the baseline clinical and echocardiographic characteristics of the patients undergoing ablation. Patients ranged in age from 35 to 74 years (mean age 55 ± 11.6 years), and 7 of 9 patients were male. All patients received AV nodal blocking agents, and 8 of 9 patients received a trial of AAD therapy prior to ablation. Five of 9 patients received a course of immunosuppressive therapy for active sarcoidosis. Five of 9 patients had evidence of LV systolic dysfunction, 7 of 9 patients had diastolic dysfunction, and 7 of 9 patients had pulmonary hypertension. Four of 9 patients had an ICD that was implanted at the discretion of each patient’s electrophysiologist: 1 device was implanted for primary prevention and the remaining 3 for secondary prevention following episodes of ventricular tachycardia. One patient underwent ablation for recurrent inappropriate ICD shocks; the remaining patients had symptomatic supraventricular arrhythmias refractory to medical therapy. Structural and Electrophysiologic Characteristics Table 2 shows the structural and electrophysiologic characteristics of the patients undergoing AA ablation. Patients 8 and 9 had isolated typical atrial flutter. Both of these patients had evidence of pulmonary hypertension and right atrial enlargement. Right atrial and coronary sinus mapping, and entrainment mapping from the cavotricuspid isthmus, confirmed the diagnosis of counterclockwise isthmus-dependent right atrial flutter. Ablation of the isthmus led to termination of atrial flutter and bidirectional block. Two patients (patient nos. 2 and 3) presented with EKG features consistent with atypical atrial flutter. Electroanatomical activation mapping showed features consistent with microreentry in patient 2. The earliest atrial activation and fractionated electrograms were recorded at the posteroinferior part of interatrial septum in close proximity to the coronary sinus ostium. Ablation at this site led to termination and noninducibility of atrial flutter. The patient remained free of arrhythmia for over 7 years, but subsequently had recurrent atypical atrial flutter with P-wave morphology identical to the one preceding the initial ablation. During the second procedure, mapping of both atria was performed. Features were again consistent with microreentry atrial flutter, with a small area of fractionated atrial electrograms recorded on the left posteroinferior part of interatrial septum (Fig. 1A). This area also showed entrainment with concealed fusion (Fig. 1B). Most of the left and right atrium showed normal voltage with a small area of left atrial scar (Fig. 1C). Catheter ablation at the site of fractionated electrograms led to termination of atrial flutter and noninducibility (Fig. 1D). Three dimensional mapping of the right atrium showed features consistent with a left atrial origin in patient 3. Activation and voltage mapping of the left atrium were undertaken. Voltage mapping showed extensive scarring in the septum and anterior wall, and activation and entrainment mapping also showed features consistent with a macroreentrant circuit with an area of slow conduction on the anterior wall of the left atrium (Fig. 2). Catheter ablation at this site led to
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TABLE 1 Patient Characteristics Patient No. 1 2 3 4 5 6 7 8 9
ImmunoICD InappLA RA DiasMitral Pulsuppressive AAD Indicropriate LVEF Enlarge- Enlarge- tolic Dys- Valve monary Age Gender HTN CAD Therapy Therapy ICD ation ICD Therapy (%) ment ment function Disease HTN 35 49 62 62 74 61 58 46 48
M M F M F M M M M
− − − + + + − − −
− − − − − + − − −
+ − + − − + + − −
− + + + + + + + +
− + − − − + − + +
10
+
20
−
20 20
− −
49 57 35 57 60 26 57 35 45
− − + − + + − − +
+ + + − + + + + +
− + + − − + + + +
− + + − + + − − −
− − + + + ++ ++ +++ +
AAD = antiarrhythmic drug; CAD = coronary artery disease; HTN = hypertension; ICD = implantable cardioverter defibrillator; LA = left atrium; LVEF = left ventricular ejection fraction; RA = right atrium; 10 = primary prevention; 20 = secondary prevention. For pulmonary HTN, + indicates mild, ++ indicates moderate, and +++ indicates severe. TABLE 2 Cardiac Function and Electrophysiologic Characteristics Patient No.
Clinical Arrhythmia
1 2
pAF Atypical AFl Atypical AFl Atypical AFl pAF Persistent AF Persistent AF Persistent AF Typical AFl Typical AFl pAF
3 4 5 6 7 8 9
Ablation
Follow-Up (Years)
Recurrence
PVI, CTI, + pace capture site RFA. RFA superior to coronary sinus RFA on left atrial septum LA anterior wall RFA, CTI PVI, CTI, + pace capture site RFA PVI, CTI CTI, PVI, CFE ablation PVI CTI CTI PVI, CFE ablation
1.6
− + − − − − − +† − − −
2.0 0.4 0.4 1.0 0 0.8 5.8 4.2 0.3
†Patient has had no subsequent recurrence on antiarrhythmic therapy. AFl = atrial flutter; CFE = complex fractionated electrograms; CTI = cavotricuspid isthmus; pAF = paroxymal atrial fibrillation; PVI = pulmonary vein isolation; RFA = radiofrequency ablation.
change in the atrial activation sequence. Repeat activation and entrainment mapping confirmed macroreentry from the anterior wall of the left atrium. Further ablation in the area led to termination and noninducibility of atrial flutter. Two patients (patient nos. 1 and 4) had paroxysmal AF, and 3 patients (patient nos. 5, 6, and 7) had persistent AF. Programmed stimulation with and without isoprenaline infusion failed to identify atrial triggers in the patients with paroxysmal AF. All underwent CT-guided circumferential PVI. Two patients had no evidence of left atrial scar, and 1 had only a small area of low voltage in the septal area. Patient 9 had extensive left atrial scar. For patient 6, ablation of areas of complex fractionated electrograms was undertaken in addition to PVI. Follow-Up Mean duration of follow-up was 1.8 ± 1.9 years. All 9 patients were noninducible with programmed stimulation at the completion of their procedure. Two patients had recurrent AA. As discussed above, patient 2 developed recurrent atypical atrial flutter and underwent a successful repeat ablation. He is now free from recurrence at 2 years. Patient 7 developed recurrent paroxysmal AF. He was started on dofetilide and continued on immunosuppressive therapy, and remains free of recurrence at 10 months. Patient 9, who initially presented with CTI-dependent atrial flutter, subsequently developed persistent AF and underwent successful PVI and complex
fractionated electrogram ablation; he is now arrhythmia-free at 4 months. Discussion Clinical Characteristics of CS Patients with AA CS is a well-known cause of cardiac conduction abnormality, progressive LV dysfunction, ventricular arrhythmias, and sudden cardiac death. While AA is not a lethal condition, patients are frequently symptomatic despite optimal medical therapy and will require catheter ablation for further management. This is the first study to describe the outcome of catheter ablation in CS patients with AA. In this study, patients with AA were relatively young and often with well-preserved LV function. Diastolic dysfunction and pulmonary hypertension were common—and often coexistent—diagnoses in these patients. These findings are consistent with the natural history of sarcoidosis, a disease that presents typically before the fourth decade of life and may thus be associated with the onset of premature cardiopulmonary disease and AA. AF was the most common AA requiring catheter ablation, followed by left atrial flutters and typical CVI atrial flutter. In our prior study examining the risk factors for arrhythmia in CS patients, left atrial size was the only variable that significantly increased the risk of having an AA (RR = 6.12; 95% CI 2.19–17.11; P = 0.0005).10 This finding was
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Figure 1. Patient 2 with atypical atrial flutter. A: The top 3 tracings are surface EKGs; P waves were positive in lead AVF. The coronary sinus catheter was in the proximal coronary sinus (CS 1–2 is distal and CS 9–12 proximal). Fractionated mid-diastolic, low-amplitude atrial electrograms were recorded by the ablation catheter from the inferior aspect of the interatrial septum. B: Tachycardia cycle length was 240 milliseconds. Post pacing cycle length at this site of fractionation was 250 milliseconds. C: Right lateral and caudal view of the electroanatomical map (NAVX) of the left atrium during atrial tachycardia showing early atrial activation in the inferior left atrium. White dots indicate the site of successful catheter ablation. There was a small area of atrial scar in the inferior left atrium, shown in gray. D: Termination of atrial flutter with radiofrequency application at the site with diastolic fractionated atrial electrogram.
confirmed in the current analysis, in which left-sided arrhythmias and left atrial enlargement were frequently coexistent. Our initial study also found the incidence of AA in patients with CS to be upwards of 19–32%. By contrast, the incidence of AF in the general population is approximately 3% in age-matched groups.12 We hypothesize that this is due both to the higher rates of comorbidities (heart failure and pulmonary hypertension) in patients with CS and to the direct proarrhythmic effect of myocardial granulomatous deposition. Mechanism of AA and Role of Catheter Ablation in CS We speculate that the mechanism of AA in CS is multifactorial. Right atrial flutter is related to pulmonary hypertension and remodeling of the tricuspid annulus from elevated ventricular diastolic pressures. Unique, however, is the potential contribution of inflammation, myocardial granulomatous deposition, and scarring to the development of AA.6 Findings in this patient population suggest that (1) deposition of sarcoid granuloma may occur more commonly and with greater density in the left atrium than in the right atrium, and/or (2) the left atrium is more predisposed to AA in the setting of granulomatous changes. Atrial scar (the result of granulomatous involvement of the atria) and areas of slow conduction probably lead to macroreentrant atrial flutter. The AF could be related to microreentry or triggered activity. A prospective study involving detailed left- and right-sided electroanatomic mapping and/or pathologic specimens to define the extent of atrial in-
volvement would help further define the role of infiltration in the pathophysiology of AA in CS. Additionally, delayed gadolinium cardiac MRI has recently been shown to accurately identify atrial scar and predict recurrence in patients with AF undergoing catheter ablation.13 While its applicability to AAs in CS is not yet known, it shows promise as a means to better understand the disease process in these patients. The results of this study suggest that catheter ablation of both AF and atrial flutter in CS has a high immediate and short-term procedural success rate. While these results are promising, recurrence when it does occur is unsurprising given the progressive nature of CS. PVI in those patients with AF was successful in treating the arrhythmia, suggesting a causal role of the pulmonary veins in these patients despite the diffuse nature of cardiac sarcoid. Role of Immunosuppressive Therapy in CS There are very limited data to guide therapeutic management in CS. Indeed, a recent physician survey revealed that current clinical practice for treatment of CS varies widely.14 It is likely, however, that therapy with immunosuppressive agents might reduce the recurrence rate after catheter ablation, as has been reported in the ablation of CS patients with ventricular tachycardia.15 Most experts agree that a combination of antiarrhythmic and anti-inflammatory therapies is indicated for the majority of patients who experience progressive conduction disease. In a systematic review of 57 patients, 27 (47.4%) with AV conduction disease improved
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Figure 2. Antero-posterior and postero-anterior views of electro-anatomical activation (NAVX) map of left atrium in patient 3 with left atrial flutter prior to ablation. A large area of atrial scar (gray color) extended from the roof anteriorly to the septum. Radiofrequency lesions (white dot) were given at the septal site where early activation met late. The site also showed fractionated electrograms, and pacing maneuvers showed entrainment with concealed fusion. Ablation at this site led to termination of atrial flutter and noninducibility.
after treatment with corticosteroids.16 While these data suggest that there is a role for corticosteroids with a reasonable change of AV nodal conduction recovery in this subgroup, it is unclear whether the improvements were secondary to corticosteroid therapy or simply the natural history of the disease. The role of steroid therapy in the management of AA is even less defined. Study Limitations This is a retrospective, single-center study with short to intermediate-term patient follow-up. As such, conclusions regarding the long-term procedural success rates and the likelihood of AA recurrence cannot be made. In addition, our hospital is a regional referral center for sarcoidosis, and since all patients were routinely evaluated by the Cardiac Arrhythmia Service there is the potential for a selection bias. This study was not designed to investigate the mechanisms involved in the genesis of AA in patients with CS; therefore, our statements in this regard are speculative. Conclusion AA is a common occurrence among patients with CS, even in relatively young patients. We hypothesize that AA can be due either to elevated atrial pressure in the setting of diastolic dysfunction or to progressive atrial disease (presumed from granulomatous deposition) leading to an atrial scar. Left AAs are more common. Catheter ablation appears to have high immediate and short-term success rates. However, given the progressive nature of CS, longer follow-up
for recurrence rates after ablation need to be validated in a long-term prospective study. References 1. Statement on sarcoidosis. Joint Statement of the American Thoracic Society (ATS), the European Respiratory Society (ERS) and the World Association of Sarcoidosis and Other Granulomatous Disorders (WASOG) adopted by the ATS Board of Directors and by the ERS Executive Committee, February 1999. Am J Respir Crit Care Med 1999;160:736755. 2. Silverman KJ, Hutchins GM, Bulkley BH: Cardiac sarcoid: A clinicopathologic study of 84 unselected patients with systemic sarcoidosis. Circulation 1978;58:1204-1211. 3. Roberts WC, McAllister HA Jr, Ferrans VJ: Sarcoidosis of the heart. A clinicopathologic study of 35 necropsy patients (group 1) and review of 78 previously described necropsy patients (group 11). Am J Med 1977;63:86-108. 4. Baughman RP, Teirstein AS, Judson MA, Rossman MD, Yeager H Jr, Bresnitz EA, DePalo L, Hunninghake G, Iannuzzi MC, Johns CJ, McLennan G, Moller DR, Newman LS, Rabin DL, Rose C, Rybicki B, Weinberger SE, Terrin ML, Knatterud GL, Cherniak R; Case Control Etiologic Study of Sarcoidosis (ACCESS) Research Group: Clinical characteristics of patients in a case control study of sarcoidosis. Am J Respir Crit Care Med 2001;164:1885-1889. 5. Mohsen A, Jimenez A, Hood RE, Dickfeld T, Saliaris A, Shorofsky S, Saba MM: Cardiac Sarcoidosis: Electrophysiological outcomes on long-term follow-up and the role of the implantable cardioverterdefibrillator. J Cardiovasc Electrophysiol 2014;25:171-176. 6. Sekhri V, Sanal S, Delorenzo LJ, Aronow WS, Maguire GP: Cardiac sarcoidosis: A comprehensive review. Arch Med Sci 2011;7:546554. 7. Nery PB, Leung E, Birnie DH: Arrhythmias in cardiac sarcoidosis: Diagnosis and treatment. Curr Opin Cardiol 2012;27:181-189. 8. Biviano AB, Bain W, Whang W, Leitner J, Dizon J, Hickey K, Garan H: Focal left atrial tachycardias not associated with prior catheter ablation
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9. 10.
11.
12.
for atrial fibrillation: Clinical and electrophysiological characteristics. Pacing Clin Electrophysiol 2012;35:17-27. Fleming HA: Sarcoidosis of the heart. Am J Med 1978;64:915916. Viles-Gonzalez JF, Pastori L, Fischer A, Wisnivesky JP, Goldman MG, Mehta D: Supraventricular arrhythmias in patients with cardiac sarcoidosis: Prevalence, predictors and clinical implications. Chest 2013;143:1085-1089. Latcu DG, Duparc A, Chabbert V, Labarre D, Mondoly P, Maury P, Delay M: Systemic sarcoidosis revealed by ventricular tachycardia: Electrocardiography and MRI correspondence. Pacing Clin Electrophysiol 2007;30:1566-1570. Heeringa J, van der Kuip DA, Hofman A, Kors JA, van Herpen G, Stricker BH, Stijnen T, Lip GY, Witteman JC: Prevalence, incidence and lifetime risk of atrial fibrillation: The Rotterdam study. Eur Heart J 2006;27:949-953.
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13. Malcolme-Lawes LC, Juli C, Karim R, Bai W, Quest R, Lim PB, JamilCopley S, Kojodjojo P, Ariff B, Davies DW, Rueckert D, Francis DP, Hunter R, Jones D, Boubertakh R, Petersen SE, Schilling R, Kanagaratnam P, Peters NS: Automated analysis of atrial late gadolinium enhancement imaging that correlates with endocardial voltage and clinical outcomes: A 2-center study. Heart Rhythm 2013;10:1184-1191. 14. Koplan BA, Soejima K, Baughman K, Epstein LM, Stevenson WG: Refractory ventricular tachycardia secondary to cardiac sarcoid: Electrophysiologic characteristics, mapping, and ablation. Heart Rhythm 2006;3:924-929. 15. Hamzeh NY, Wamboldt FS, Weinberger HD: Management of cardiac sarcoidosis in the United States: A Delphi study. Chest 2012;141:154162. 16. Sadek MM, Yung D, Birnie DH, Beanlands RS, Nery PB: Corticosteroid therapy for cardiac sarcoidosis: A systematic review. Can J Cardiol 2013;29:1034-1041.
Catheter Ablation of Atrial Arrhythmias in Cardiac Sarcoidosis JONATHAN M. WILLNER, M.D.,∗ JUAN F. VILES-GONZALEZ, M.D.,† JAMES O. COFFEY, M.D.,† ADAM S. MORGENTHAU, M.D.,∗ and DAVENDRA MEHTA, M.D.∗ From the ∗ Divisions of Cardiology and Pulmonary Medicine, Mount Sinai Medical Center and Icahn School of Medicine at Mount Sinai, New York, New York, USA; and the †Division of Cardiology, University of Miami Medical Center and Miami School of Medicine, Miami, Florida
Ablation of Atrial Arrhythmias in Cardiac Sarcoidosis. Background: We previously reported on the incidence and clinical implications of supraventricular arrhythmia in patients with cardiac sarcoidosis (CS). The role of catheter ablation for the management of atrial arrhythmia (AA) in this patient population is unknown. Methods and Results: One hundred consecutive patients with CS were monitored for the incidence of supraventricular arrhythmias. Those with persistent symptoms despite optimal medical therapy proceeded to catheter ablation. Following ablation, all patients were followed serially with Holter monitoring or device interrogation. Thirty-two (32%) patients had symptomatic supraventricular arrhythmias. Nine (28%) patients had symptomatic AA requiring catheter ablation for clinical indications. Mean age was 55 ± 11.6 years. Five (56%) patients had atrial fibrillation (AF), of whom 2 also had cavotricuspid isthmus ablation. Four patients had isolated atrial flutter: 2 patients with left atrial flutter, and 2 patients with cavotricuspid flutter. All other arrhythmias were ablated in the left atrium. Mean duration of follow-up was 1.8 ± 1.9 years. One patient with atypical atrial flutter, and one patient with AF have had recurrence; the remaining patients remain in sinus rhythm. Conclusions: Our study suggests that AA in CS is frequently left atrial in origin. Catheter ablation appears to be effective and safe for the maintenance of sinus rhythm in patients with CS. (J Cardiovasc Electrophysiol, Vol. 25, pp. 958-963, September 2014) atrial fibrillation, atrial flutter, cardiac sarcoid, catheter ablation, sarcoidosis, tachyarrhythmias Introduction Sarcoidosis is a chronic granulomatous disease of uncertain origin. Over 80% of cases present in patients between the ages of 20 and 40, and it is slightly more common in women than men.1 A total 40–50% of patients with systemic sarcoidosis will develop cardiac involvement.2,3 Clinical manifestations of cardiac sarcoidosis (CS), including conduction system disease, arrhythmia, heart failure, and sudden cardiac death, manifest in 2–5% of patients.4,5 While ventricular arrhythmia and sudden cardiac death remain the most feared complications of CS, atrial arrhythmia (AA) occurs in upwards of one-quarter of patients, the majority of whom are clinically symptomatic.6-10 The pathogenesis of AA in sarcoidosis remains uncertain, but is thought to have 2 potential etiologies: (1) elevated atrial pressure due to progressive ventricular dysfunction and/or pulmonary hypertension, or (2) sarcoid granulomatous deposition causing inflammation, scarring, and substrate heterogeneity.11 In the general population, catheter ablation of AA has become a mainstay of therapy. However, the safety and efficacy of catheter ablation in the management of CS have No disclosures. Address for correspondence: Davendra Mehta, M.D., Mount Sinai Medical Center, 1 Gustave L. Levy Place, Guggenheim Pavilion 2W, New York, NY 10029, USA. Fax: 212-241-9701; E-mail: [email protected] Manuscript received 24 January 2014; Revised manuscript received 18 March 2014; Accepted for publication 25 March 2014. doi: 10.1111/jce.12424 [The copyright line has been changed on 9 June 2014, after first online publication on 2 May 2014.]
not been investigated. This study sought to examine the outcomes of catheter ablation in the management of AA in patients with CS. Methods Patient Selection The Institutional Review Board of the Mount Sinai Medical Center approved the study (GCO 08-0673). Consecutive patients with an established diagnosis of CS referred to the Mount Sinai Electrophysiology Clinic were retrospectively evaluated. We identified 32 patients with AA from our database of 100 patients, of whom 9 underwent catheter ablation and were included in this study. All patients had biopsy-proven systemic sarcoidosis and evidence of CS as defined by biopsy (patient no. 8) or typical imaging findings on either cardiac magnetic resonance imaging (MRI) or positron emission tomography (PET). MRI findings diagnostic of CS included localized intramyocardial increased signal intensity on T2-weighted sequence indicative of edema, and delayed contrast enhancement suggestive of infiltration and scarring. PET imaging was considered positive when perfusion images showed no evidence of ischemia and fluorodeoxyglucose uptake images showed either increased or mismatched metabolic activity suggestive of infiltration, or matched decrease in metabolic activity indicative of scarring. All patients underwent echocardiography as a part of their cardiac workup. Medical Record Review Standardized data forms were used to extract pertinent data from the medical record regarding details of demographics and medical history. The presence of prednisone,
Willner et al. Ablation of Atrial Arrhythmias in Cardiac Sarcoidosis
methylprednisolone, hydrocortisone, and/or other immunosuppressants on the patient’s medication list was considered positive for corticosteroid/immunosuppressant usage, regardless of dosage or duration. History of use of an antiarrhythmic drug (AAD) was considered positive if a Class IC or III agent had been prescribed prior to the AA ablation. Coronary artery disease (CAD) was considered present if the patient had a history of either prior myocardial infarction or left heart catheterization documenting CAD. Echocardiographic Parameters For each patient, left ventricular ejection fraction (LVEF) was evaluated by 2D transthoracic echocardiography. Additional echocardiographic parameters including right and left atrial size, assessment of LV diastolic and systolic function, valvular disease, and pulmonary hypertension were recorded. Any degree of atrial enlargement (area >20 cm2 ) was considered abnormal. Any mitral regurgitation that was more than physiologic was considered positive. Pulmonary hypertension was determined by conventional transthoracic echocardiography and calculated using tricuspid regurgitation jet velocity and the modified Bernoulli equation (mild 35–50 mmHg, moderate 51–65 mmHg, severe >65 mmHg). Electrophysiologic Study and Ablation Standard electrophysiological procedures were used for diagnosis and catheter ablation. In patients with atrial flutter, catheters were placed in the coronary sinus and right atrium. Entrainment and 3-dimensional (3D) activation mapping were undertaken. If necessary, a transseptal approach was used for left atrial mapping and ablation. Mapping was performed using multielectrode mapping catheters. In patients with atrial fibrillation (AF), pulmonary vein isolation (PVI) was undertaken. A double transseptal technique was used. All patients had CT of the heart to determine left atrial and pulmonary vein anatomy. Three-dimensional maps were made using an electroanatomical mapping system (NAVX/CARTO). Thermocool ablation catheters were used for ablation of atrial tachycardias, atrial flutter, and AF. All patients underwent PVI in pairs (wide antral circumferential ablation) followed by mapping and ablation of complex fractionated atrial electrograms as previously described. PVI was confirmed by administration of intravenous adenosine (18 mg) to reveal dormant conduction, and if present, further lesions were given to confirm persistent isolation. Ablation lesion sets were stimulated (i.e., paced) with 10 mA using the ablation catheter. If electrical capture was present additional radiofrequency applications were delivered. After ablation, all patients were monitored for AA recurrence by either 2 weeks of event monitor or pacemaker/implantable cardioverter defibrillator (ICD) interrogation at 3 and 6 months postprocedure. Results Clinical Characteristics Out of 100 consecutive patients with an established diagnosis of CS, 32 (32%) were documented to have AA. Ten of these 32 patients (31%) ultimately required catheter ablation for arrhythmias resistant to medical therapy. One patient had SVT related to AVNRT and was excluded from the analysis
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as this was thought to be unrelated to CS. Of the 9 patients included, 5 (56%) had AF, 2 (22%) had typical atrial flutter, and 2 (22%) had a left-sided atrial tachycardia (AT)/atrial flutter. Table 1 shows the baseline clinical and echocardiographic characteristics of the patients undergoing ablation. Patients ranged in age from 35 to 74 years (mean age 55 ± 11.6 years), and 7 of 9 patients were male. All patients received AV nodal blocking agents, and 8 of 9 patients received a trial of AAD therapy prior to ablation. Five of 9 patients received a course of immunosuppressive therapy for active sarcoidosis. Five of 9 patients had evidence of LV systolic dysfunction, 7 of 9 patients had diastolic dysfunction, and 7 of 9 patients had pulmonary hypertension. Four of 9 patients had an ICD that was implanted at the discretion of each patient’s electrophysiologist: 1 device was implanted for primary prevention and the remaining 3 for secondary prevention following episodes of ventricular tachycardia. One patient underwent ablation for recurrent inappropriate ICD shocks; the remaining patients had symptomatic supraventricular arrhythmias refractory to medical therapy. Structural and Electrophysiologic Characteristics Table 2 shows the structural and electrophysiologic characteristics of the patients undergoing AA ablation. Patients 8 and 9 had isolated typical atrial flutter. Both of these patients had evidence of pulmonary hypertension and right atrial enlargement. Right atrial and coronary sinus mapping, and entrainment mapping from the cavotricuspid isthmus, confirmed the diagnosis of counterclockwise isthmus-dependent right atrial flutter. Ablation of the isthmus led to termination of atrial flutter and bidirectional block. Two patients (patient nos. 2 and 3) presented with EKG features consistent with atypical atrial flutter. Electroanatomical activation mapping showed features consistent with microreentry in patient 2. The earliest atrial activation and fractionated electrograms were recorded at the posteroinferior part of interatrial septum in close proximity to the coronary sinus ostium. Ablation at this site led to termination and noninducibility of atrial flutter. The patient remained free of arrhythmia for over 7 years, but subsequently had recurrent atypical atrial flutter with P-wave morphology identical to the one preceding the initial ablation. During the second procedure, mapping of both atria was performed. Features were again consistent with microreentry atrial flutter, with a small area of fractionated atrial electrograms recorded on the left posteroinferior part of interatrial septum (Fig. 1A). This area also showed entrainment with concealed fusion (Fig. 1B). Most of the left and right atrium showed normal voltage with a small area of left atrial scar (Fig. 1C). Catheter ablation at the site of fractionated electrograms led to termination of atrial flutter and noninducibility (Fig. 1D). Three dimensional mapping of the right atrium showed features consistent with a left atrial origin in patient 3. Activation and voltage mapping of the left atrium were undertaken. Voltage mapping showed extensive scarring in the septum and anterior wall, and activation and entrainment mapping also showed features consistent with a macroreentrant circuit with an area of slow conduction on the anterior wall of the left atrium (Fig. 2). Catheter ablation at this site led to
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TABLE 1 Patient Characteristics Patient No. 1 2 3 4 5 6 7 8 9
ImmunoICD InappLA RA DiasMitral Pulsuppressive AAD Indicropriate LVEF Enlarge- Enlarge- tolic Dys- Valve monary Age Gender HTN CAD Therapy Therapy ICD ation ICD Therapy (%) ment ment function Disease HTN 35 49 62 62 74 61 58 46 48
M M F M F M M M M
− − − + + + − − −
− − − − − + − − −
+ − + − − + + − −
− + + + + + + + +
− + − − − + − + +
10
+
20
−
20 20
− −
49 57 35 57 60 26 57 35 45
− − + − + + − − +
+ + + − + + + + +
− + + − − + + + +
− + + − + + − − −
− − + + + ++ ++ +++ +
AAD = antiarrhythmic drug; CAD = coronary artery disease; HTN = hypertension; ICD = implantable cardioverter defibrillator; LA = left atrium; LVEF = left ventricular ejection fraction; RA = right atrium; 10 = primary prevention; 20 = secondary prevention. For pulmonary HTN, + indicates mild, ++ indicates moderate, and +++ indicates severe. TABLE 2 Cardiac Function and Electrophysiologic Characteristics Patient No.
Clinical Arrhythmia
1 2
pAF Atypical AFl Atypical AFl Atypical AFl pAF Persistent AF Persistent AF Persistent AF Typical AFl Typical AFl pAF
3 4 5 6 7 8 9
Ablation
Follow-Up (Years)
Recurrence
PVI, CTI, + pace capture site RFA. RFA superior to coronary sinus RFA on left atrial septum LA anterior wall RFA, CTI PVI, CTI, + pace capture site RFA PVI, CTI CTI, PVI, CFE ablation PVI CTI CTI PVI, CFE ablation
1.6
− + − − − − − +† − − −
2.0 0.4 0.4 1.0 0 0.8 5.8 4.2 0.3
†Patient has had no subsequent recurrence on antiarrhythmic therapy. AFl = atrial flutter; CFE = complex fractionated electrograms; CTI = cavotricuspid isthmus; pAF = paroxymal atrial fibrillation; PVI = pulmonary vein isolation; RFA = radiofrequency ablation.
change in the atrial activation sequence. Repeat activation and entrainment mapping confirmed macroreentry from the anterior wall of the left atrium. Further ablation in the area led to termination and noninducibility of atrial flutter. Two patients (patient nos. 1 and 4) had paroxysmal AF, and 3 patients (patient nos. 5, 6, and 7) had persistent AF. Programmed stimulation with and without isoprenaline infusion failed to identify atrial triggers in the patients with paroxysmal AF. All underwent CT-guided circumferential PVI. Two patients had no evidence of left atrial scar, and 1 had only a small area of low voltage in the septal area. Patient 9 had extensive left atrial scar. For patient 6, ablation of areas of complex fractionated electrograms was undertaken in addition to PVI. Follow-Up Mean duration of follow-up was 1.8 ± 1.9 years. All 9 patients were noninducible with programmed stimulation at the completion of their procedure. Two patients had recurrent AA. As discussed above, patient 2 developed recurrent atypical atrial flutter and underwent a successful repeat ablation. He is now free from recurrence at 2 years. Patient 7 developed recurrent paroxysmal AF. He was started on dofetilide and continued on immunosuppressive therapy, and remains free of recurrence at 10 months. Patient 9, who initially presented with CTI-dependent atrial flutter, subsequently developed persistent AF and underwent successful PVI and complex
fractionated electrogram ablation; he is now arrhythmia-free at 4 months. Discussion Clinical Characteristics of CS Patients with AA CS is a well-known cause of cardiac conduction abnormality, progressive LV dysfunction, ventricular arrhythmias, and sudden cardiac death. While AA is not a lethal condition, patients are frequently symptomatic despite optimal medical therapy and will require catheter ablation for further management. This is the first study to describe the outcome of catheter ablation in CS patients with AA. In this study, patients with AA were relatively young and often with well-preserved LV function. Diastolic dysfunction and pulmonary hypertension were common—and often coexistent—diagnoses in these patients. These findings are consistent with the natural history of sarcoidosis, a disease that presents typically before the fourth decade of life and may thus be associated with the onset of premature cardiopulmonary disease and AA. AF was the most common AA requiring catheter ablation, followed by left atrial flutters and typical CVI atrial flutter. In our prior study examining the risk factors for arrhythmia in CS patients, left atrial size was the only variable that significantly increased the risk of having an AA (RR = 6.12; 95% CI 2.19–17.11; P = 0.0005).10 This finding was
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Figure 1. Patient 2 with atypical atrial flutter. A: The top 3 tracings are surface EKGs; P waves were positive in lead AVF. The coronary sinus catheter was in the proximal coronary sinus (CS 1–2 is distal and CS 9–12 proximal). Fractionated mid-diastolic, low-amplitude atrial electrograms were recorded by the ablation catheter from the inferior aspect of the interatrial septum. B: Tachycardia cycle length was 240 milliseconds. Post pacing cycle length at this site of fractionation was 250 milliseconds. C: Right lateral and caudal view of the electroanatomical map (NAVX) of the left atrium during atrial tachycardia showing early atrial activation in the inferior left atrium. White dots indicate the site of successful catheter ablation. There was a small area of atrial scar in the inferior left atrium, shown in gray. D: Termination of atrial flutter with radiofrequency application at the site with diastolic fractionated atrial electrogram.
confirmed in the current analysis, in which left-sided arrhythmias and left atrial enlargement were frequently coexistent. Our initial study also found the incidence of AA in patients with CS to be upwards of 19–32%. By contrast, the incidence of AF in the general population is approximately 3% in age-matched groups.12 We hypothesize that this is due both to the higher rates of comorbidities (heart failure and pulmonary hypertension) in patients with CS and to the direct proarrhythmic effect of myocardial granulomatous deposition. Mechanism of AA and Role of Catheter Ablation in CS We speculate that the mechanism of AA in CS is multifactorial. Right atrial flutter is related to pulmonary hypertension and remodeling of the tricuspid annulus from elevated ventricular diastolic pressures. Unique, however, is the potential contribution of inflammation, myocardial granulomatous deposition, and scarring to the development of AA.6 Findings in this patient population suggest that (1) deposition of sarcoid granuloma may occur more commonly and with greater density in the left atrium than in the right atrium, and/or (2) the left atrium is more predisposed to AA in the setting of granulomatous changes. Atrial scar (the result of granulomatous involvement of the atria) and areas of slow conduction probably lead to macroreentrant atrial flutter. The AF could be related to microreentry or triggered activity. A prospective study involving detailed left- and right-sided electroanatomic mapping and/or pathologic specimens to define the extent of atrial in-
volvement would help further define the role of infiltration in the pathophysiology of AA in CS. Additionally, delayed gadolinium cardiac MRI has recently been shown to accurately identify atrial scar and predict recurrence in patients with AF undergoing catheter ablation.13 While its applicability to AAs in CS is not yet known, it shows promise as a means to better understand the disease process in these patients. The results of this study suggest that catheter ablation of both AF and atrial flutter in CS has a high immediate and short-term procedural success rate. While these results are promising, recurrence when it does occur is unsurprising given the progressive nature of CS. PVI in those patients with AF was successful in treating the arrhythmia, suggesting a causal role of the pulmonary veins in these patients despite the diffuse nature of cardiac sarcoid. Role of Immunosuppressive Therapy in CS There are very limited data to guide therapeutic management in CS. Indeed, a recent physician survey revealed that current clinical practice for treatment of CS varies widely.14 It is likely, however, that therapy with immunosuppressive agents might reduce the recurrence rate after catheter ablation, as has been reported in the ablation of CS patients with ventricular tachycardia.15 Most experts agree that a combination of antiarrhythmic and anti-inflammatory therapies is indicated for the majority of patients who experience progressive conduction disease. In a systematic review of 57 patients, 27 (47.4%) with AV conduction disease improved
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Figure 2. Antero-posterior and postero-anterior views of electro-anatomical activation (NAVX) map of left atrium in patient 3 with left atrial flutter prior to ablation. A large area of atrial scar (gray color) extended from the roof anteriorly to the septum. Radiofrequency lesions (white dot) were given at the septal site where early activation met late. The site also showed fractionated electrograms, and pacing maneuvers showed entrainment with concealed fusion. Ablation at this site led to termination of atrial flutter and noninducibility.
after treatment with corticosteroids.16 While these data suggest that there is a role for corticosteroids with a reasonable change of AV nodal conduction recovery in this subgroup, it is unclear whether the improvements were secondary to corticosteroid therapy or simply the natural history of the disease. The role of steroid therapy in the management of AA is even less defined. Study Limitations This is a retrospective, single-center study with short to intermediate-term patient follow-up. As such, conclusions regarding the long-term procedural success rates and the likelihood of AA recurrence cannot be made. In addition, our hospital is a regional referral center for sarcoidosis, and since all patients were routinely evaluated by the Cardiac Arrhythmia Service there is the potential for a selection bias. This study was not designed to investigate the mechanisms involved in the genesis of AA in patients with CS; therefore, our statements in this regard are speculative. Conclusion AA is a common occurrence among patients with CS, even in relatively young patients. We hypothesize that AA can be due either to elevated atrial pressure in the setting of diastolic dysfunction or to progressive atrial disease (presumed from granulomatous deposition) leading to an atrial scar. Left AAs are more common. Catheter ablation appears to have high immediate and short-term success rates. However, given the progressive nature of CS, longer follow-up
for recurrence rates after ablation need to be validated in a long-term prospective study. References 1. Statement on sarcoidosis. Joint Statement of the American Thoracic Society (ATS), the European Respiratory Society (ERS) and the World Association of Sarcoidosis and Other Granulomatous Disorders (WASOG) adopted by the ATS Board of Directors and by the ERS Executive Committee, February 1999. Am J Respir Crit Care Med 1999;160:736755. 2. Silverman KJ, Hutchins GM, Bulkley BH: Cardiac sarcoid: A clinicopathologic study of 84 unselected patients with systemic sarcoidosis. Circulation 1978;58:1204-1211. 3. Roberts WC, McAllister HA Jr, Ferrans VJ: Sarcoidosis of the heart. A clinicopathologic study of 35 necropsy patients (group 1) and review of 78 previously described necropsy patients (group 11). Am J Med 1977;63:86-108. 4. Baughman RP, Teirstein AS, Judson MA, Rossman MD, Yeager H Jr, Bresnitz EA, DePalo L, Hunninghake G, Iannuzzi MC, Johns CJ, McLennan G, Moller DR, Newman LS, Rabin DL, Rose C, Rybicki B, Weinberger SE, Terrin ML, Knatterud GL, Cherniak R; Case Control Etiologic Study of Sarcoidosis (ACCESS) Research Group: Clinical characteristics of patients in a case control study of sarcoidosis. Am J Respir Crit Care Med 2001;164:1885-1889. 5. Mohsen A, Jimenez A, Hood RE, Dickfeld T, Saliaris A, Shorofsky S, Saba MM: Cardiac Sarcoidosis: Electrophysiological outcomes on long-term follow-up and the role of the implantable cardioverterdefibrillator. J Cardiovasc Electrophysiol 2014;25:171-176. 6. Sekhri V, Sanal S, Delorenzo LJ, Aronow WS, Maguire GP: Cardiac sarcoidosis: A comprehensive review. Arch Med Sci 2011;7:546554. 7. Nery PB, Leung E, Birnie DH: Arrhythmias in cardiac sarcoidosis: Diagnosis and treatment. Curr Opin Cardiol 2012;27:181-189. 8. Biviano AB, Bain W, Whang W, Leitner J, Dizon J, Hickey K, Garan H: Focal left atrial tachycardias not associated with prior catheter ablation
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for atrial fibrillation: Clinical and electrophysiological characteristics. Pacing Clin Electrophysiol 2012;35:17-27. Fleming HA: Sarcoidosis of the heart. Am J Med 1978;64:915916. Viles-Gonzalez JF, Pastori L, Fischer A, Wisnivesky JP, Goldman MG, Mehta D: Supraventricular arrhythmias in patients with cardiac sarcoidosis: Prevalence, predictors and clinical implications. Chest 2013;143:1085-1089. Latcu DG, Duparc A, Chabbert V, Labarre D, Mondoly P, Maury P, Delay M: Systemic sarcoidosis revealed by ventricular tachycardia: Electrocardiography and MRI correspondence. Pacing Clin Electrophysiol 2007;30:1566-1570. Heeringa J, van der Kuip DA, Hofman A, Kors JA, van Herpen G, Stricker BH, Stijnen T, Lip GY, Witteman JC: Prevalence, incidence and lifetime risk of atrial fibrillation: The Rotterdam study. Eur Heart J 2006;27:949-953.
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13. Malcolme-Lawes LC, Juli C, Karim R, Bai W, Quest R, Lim PB, JamilCopley S, Kojodjojo P, Ariff B, Davies DW, Rueckert D, Francis DP, Hunter R, Jones D, Boubertakh R, Petersen SE, Schilling R, Kanagaratnam P, Peters NS: Automated analysis of atrial late gadolinium enhancement imaging that correlates with endocardial voltage and clinical outcomes: A 2-center study. Heart Rhythm 2013;10:1184-1191. 14. Koplan BA, Soejima K, Baughman K, Epstein LM, Stevenson WG: Refractory ventricular tachycardia secondary to cardiac sarcoid: Electrophysiologic characteristics, mapping, and ablation. Heart Rhythm 2006;3:924-929. 15. Hamzeh NY, Wamboldt FS, Weinberger HD: Management of cardiac sarcoidosis in the United States: A Delphi study. Chest 2012;141:154162. 16. Sadek MM, Yung D, Birnie DH, Beanlands RS, Nery PB: Corticosteroid therapy for cardiac sarcoidosis: A systematic review. Can J Cardiol 2013;29:1034-1041.
