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Brugada Phenocopy: Redefinition and Updated Classification
READERS’ COMMENTS Brugada Phenocopy: Redefinition and Updated Classification We read the recent Readers’ Comment by García-Niebla et al1 demonstrating that applying a nonstandard high-pass filter of 0.5 Hz can artificially distort the ST-segment and terminal portion of the T wave, resulting in Brugada type 2 morphology in the right precordial leads. The presented patient was a 55-year-old woman receiving an angiotensin II receptor antagonist for hypertension. No comment was made with regard to known structural heart disease. It seems possible that artificial (or inadvertent) modulation of the electrocardiographic (ECG) highpass filter can reproduce the Brugada ECG pattern. This adds 1 additional category to our recent extensive review of Brugada phenocopies,2 in which we categorized them according to their pathogenesis. As such, we provide an update of the current Brugada phenocopy categories with the inclusion of the appropriate ECG highpass filter (Table 1). Brugada phenocopies are continuing to emerge as interesting clinical entities because their ECG patterns are indistinguishable from true congenital Brugada syndrome (BrS).2,3 BrS is a congenital cardiac channelopathy associated with malignant ventricular arrhythmias and sudden cardiac death in otherwise healthy adults, and less frequently in children and infants. BrS demonstrates a familial autosomal dominant pattern of inheritance with >80 mutations in the SCN5A gene, which encodes a subunit of the cardiac voltagegated sodium channel.4 It is characterized by 2 dynamic ECG patterns that can often be concealed on routine testing.3 Brugada
type 1 morphology has a distinct coved ST-segment elevation (0.2 mV) with an inverted T wave in the right precordial leads, while Brugada type 2 morphology has a saddleback appearance.3 The true congenital Brugada ECG patterns can often be unmasked by sodium channel blockers and febrile states.4,5 Brugada phenocopies, however, have various other causes, such as metabolic disturbances, cardiac mechanical compression, and ischemia.2 The criteria for defining a Brugada phenocopy have been revised since the publication of our report2 and could be summarized as follows: (1) the ECG pattern has a Brugada type 1 or type 2 morphology; (2) the patient has an underlying condition that is identifiable; (3) the ECG pattern resolves after resolution of the underlying condition; (4) there is a low clinical pretest probability of true BrS determined by lack of symptoms, medical history, and family history; (5) the results of provocative testing with flecainide, procainamide, ajmaline, or other sodium channel blockers are negative; and (6) the results of genetic testing are negative (not a mandatory criterion, because the SCN5A mutation is identified in only 20% to 30% of probands affected by true BrS6). It is possible that new underlying conditions that reproduce the Brugada ECG pattern will be described in the future. We are working to create an international registry database accessible through a Web site, similar to Postema et al’s7 Web site for drugs associated with BrS. These data will be compiled and analyzed with the hope of providing insight into the long-term follow-up of Brugada phenocopy cases and its distinct clinical evolution from true BrS.
Daniel D. Anselm, MD Adrian Baranchuk, MD Kingston, Ontario, Canada 7 September 2012
1. García-Niebla J, Serra-Autonell G, Bayés de Luna A. Brugada syndrome electrocardiographic pattern as a result of improper application of a high pass filter. Am J Cardiol 2012;110:318e320. 2. Baranchuk A, Nguyen T, Ryu MH, Femenía F, Zareba W, Wilde AAM, Shimizu W, Brugada P, Pérez-Riera AR. Brugada phenocopy: new terminology and proposed classification. Ann Noninvasive Electrocardiol 2012;17:299e314. 3. Bayés de Luna A, Brugada J, Baranchuk A, Borggrefe M, Breithardt G, Goldwasser D, Lambiase P, Riera AP, Garcia-Niebla J, Pastore C, Oreto G, McKenna W, Zareba W, Brugada R, Brugada P. Current electrocardiographic criteria for diagnosis of Brugada pattern: a consensus report. J Electrocardiol 2012;45:433e442. 4. Antzelevitch C, Brugada P, Borggrefe M, Brugada J, Brugada R, Corrado D, Gussak I, LeMarec H, Nademanee K, Perez Riera AR, Shimizu W, Schulze-Bahr E, Tan H, Wilde A. Brugada syndrome: report of the second consensus conference: endorsed by the Heart Rhythm Society and the European Heart Rhythm Association. Circulation 2005;111:659e670. 5. Dumaine R, Towbin JA, Brugada P, Vatta M, Nesterenko DV, Nesterenko VV, Brugada J, Brugada R, Antzelevitch C. Ionic mechanisms responsible for the electrocardiographic phenotype of the Brugada syndrome are temperature dependent. Circ Res 1999;85:803e809. 6. Probst V, Wilde AA, Barc J, Sacher F, Babuty D, Mabo P, Mansourati J, Le Scouarnec S, Kyndt F, Le Caignec C, Guicheney P, Gouas L, Albuisson J, Meregalli PG, Le Marec H, Tan HL, Schott JJ. SCN5A mutations and the role of genetic background in the pathophysiology of Brugada syndrome. Circ Cardiovasc Genet 2009;2:552e557. 7. Postema PG, Wolpert C, Amin AS, Probst V, Borggrefe M, Roden DM, Priori SG, Tan HL, Hiraoka M, Brugada J, Wilde AA. Drugs and Brugada syndrome patients: review of the literature, recommendations, and an up-to-date website, (www.brugadadrugs.org); 2009. Heart Rhythm 2009;6:1335e1341. http://dx.doi.org/10.1016/j.amjcard.2012.09.005
Table 1 Updated summary of Brugada phenocopies* Category Metabolic conditions Mechanical Compression Ischemia Myocardial and pericardial disease ECG modulation† Miscellaneous
Number of Patients (Number of Case Reports) 14 6 4 8 1 2
(14) (5) (4) (6) (1) (2)
Age (years), Mean (Range) 51.9 17.8 45.7 18.5 60.0 6.7 46.2 13.9 55 22.5 0.7
(28e89) (19e66) (55e68) (28e72) (55) (22e23)
Men/Women
ECG Type
Presence of Structural Heart Disease
13/1 3/3 2/2 5/3 0/1 1/1
13 type 1, 5 type 2, 4 variable 6 type 1, 0 type 2, 0 variable 4 type 1, 1 type 2, 1 variable 5 type 1, 4 type 2, 2 variable 0 type 1, 1 type 2, 0 variable 2 type 1, 1 type 2, 1 variable
0 yes, 14 no 3 yes, 3 no 1 yes, 3 no 2 yes, 6 no 0 yes, 1 no 1 yes, 1 no
* Adapted from Baranchuk et al.2 † Updated category of Brugada phenocopy on the basis of inappropriate ECG high-pass filtering.1 Am J Cardiol 2013;111:453e456 0002-9149/12/$ - see front matter Ó 2013 Elsevier Inc. All rights reserved.
www.ajconline.org
type 1 morphology has a distinct coved ST-segment elevation (0.2 mV) with an inverted T wave in the right precordial leads, while Brugada type 2 morphology has a saddleback appearance.3 The true congenital Brugada ECG patterns can often be unmasked by sodium channel blockers and febrile states.4,5 Brugada phenocopies, however, have various other causes, such as metabolic disturbances, cardiac mechanical compression, and ischemia.2 The criteria for defining a Brugada phenocopy have been revised since the publication of our report2 and could be summarized as follows: (1) the ECG pattern has a Brugada type 1 or type 2 morphology; (2) the patient has an underlying condition that is identifiable; (3) the ECG pattern resolves after resolution of the underlying condition; (4) there is a low clinical pretest probability of true BrS determined by lack of symptoms, medical history, and family history; (5) the results of provocative testing with flecainide, procainamide, ajmaline, or other sodium channel blockers are negative; and (6) the results of genetic testing are negative (not a mandatory criterion, because the SCN5A mutation is identified in only 20% to 30% of probands affected by true BrS6). It is possible that new underlying conditions that reproduce the Brugada ECG pattern will be described in the future. We are working to create an international registry database accessible through a Web site, similar to Postema et al’s7 Web site for drugs associated with BrS. These data will be compiled and analyzed with the hope of providing insight into the long-term follow-up of Brugada phenocopy cases and its distinct clinical evolution from true BrS.
Daniel D. Anselm, MD Adrian Baranchuk, MD Kingston, Ontario, Canada 7 September 2012
1. García-Niebla J, Serra-Autonell G, Bayés de Luna A. Brugada syndrome electrocardiographic pattern as a result of improper application of a high pass filter. Am J Cardiol 2012;110:318e320. 2. Baranchuk A, Nguyen T, Ryu MH, Femenía F, Zareba W, Wilde AAM, Shimizu W, Brugada P, Pérez-Riera AR. Brugada phenocopy: new terminology and proposed classification. Ann Noninvasive Electrocardiol 2012;17:299e314. 3. Bayés de Luna A, Brugada J, Baranchuk A, Borggrefe M, Breithardt G, Goldwasser D, Lambiase P, Riera AP, Garcia-Niebla J, Pastore C, Oreto G, McKenna W, Zareba W, Brugada R, Brugada P. Current electrocardiographic criteria for diagnosis of Brugada pattern: a consensus report. J Electrocardiol 2012;45:433e442. 4. Antzelevitch C, Brugada P, Borggrefe M, Brugada J, Brugada R, Corrado D, Gussak I, LeMarec H, Nademanee K, Perez Riera AR, Shimizu W, Schulze-Bahr E, Tan H, Wilde A. Brugada syndrome: report of the second consensus conference: endorsed by the Heart Rhythm Society and the European Heart Rhythm Association. Circulation 2005;111:659e670. 5. Dumaine R, Towbin JA, Brugada P, Vatta M, Nesterenko DV, Nesterenko VV, Brugada J, Brugada R, Antzelevitch C. Ionic mechanisms responsible for the electrocardiographic phenotype of the Brugada syndrome are temperature dependent. Circ Res 1999;85:803e809. 6. Probst V, Wilde AA, Barc J, Sacher F, Babuty D, Mabo P, Mansourati J, Le Scouarnec S, Kyndt F, Le Caignec C, Guicheney P, Gouas L, Albuisson J, Meregalli PG, Le Marec H, Tan HL, Schott JJ. SCN5A mutations and the role of genetic background in the pathophysiology of Brugada syndrome. Circ Cardiovasc Genet 2009;2:552e557. 7. Postema PG, Wolpert C, Amin AS, Probst V, Borggrefe M, Roden DM, Priori SG, Tan HL, Hiraoka M, Brugada J, Wilde AA. Drugs and Brugada syndrome patients: review of the literature, recommendations, and an up-to-date website, (www.brugadadrugs.org); 2009. Heart Rhythm 2009;6:1335e1341. http://dx.doi.org/10.1016/j.amjcard.2012.09.005
Table 1 Updated summary of Brugada phenocopies* Category Metabolic conditions Mechanical Compression Ischemia Myocardial and pericardial disease ECG modulation† Miscellaneous
Number of Patients (Number of Case Reports) 14 6 4 8 1 2
(14) (5) (4) (6) (1) (2)
Age (years), Mean (Range) 51.9 17.8 45.7 18.5 60.0 6.7 46.2 13.9 55 22.5 0.7
(28e89) (19e66) (55e68) (28e72) (55) (22e23)
Men/Women
ECG Type
Presence of Structural Heart Disease
13/1 3/3 2/2 5/3 0/1 1/1
13 type 1, 5 type 2, 4 variable 6 type 1, 0 type 2, 0 variable 4 type 1, 1 type 2, 1 variable 5 type 1, 4 type 2, 2 variable 0 type 1, 1 type 2, 0 variable 2 type 1, 1 type 2, 1 variable
0 yes, 14 no 3 yes, 3 no 1 yes, 3 no 2 yes, 6 no 0 yes, 1 no 1 yes, 1 no
* Adapted from Baranchuk et al.2 † Updated category of Brugada phenocopy on the basis of inappropriate ECG high-pass filtering.1 Am J Cardiol 2013;111:453e456 0002-9149/12/$ - see front matter Ó 2013 Elsevier Inc. All rights reserved.
www.ajconline.org