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The Brugada Syndrome: Can We Predict the Risk?

PETER OTT, M.D. and FRANK MARCUS, M.D.

From the Sarver Heart Center, University of Arizona Health Sciences Center, Tucson, Arizona, USA

Editorial Comment

The Brugada syndrome (BS) is now recognized as an im-portant condition predisposing individuals with a seeminglynormal heart to sudden death due to ventricular fibrillation(VF).1 Mutations in the gene encoding the cardiac sodiumchannel (SCN5A) have been found in 18–30% of patientswith BS.2 It is believed that abnormalities in regional repo-larization and/or depolarization provide the electrophysio-logical milieu for VF.3,4

In a recent consensus statement,5 the electrocardiographicfeatures have been categorized as follows: type 1 (diagnosticfor BS): coved ST segment elevation of ≥2 mm followed bya negative T wave in more than one of leads V1–3; type 2 (notdiagnostic for BS) saddleback shaped ST segment elevationwith ST elevation of ≥2 mm and a trough ≥1 mm ST eleva-tion; or type 3 (not diagnostic for BS) coved or SaddlebackST segment elevation of <1 mm. However, type 2 and 3 pat-tern are considered diagnostic, if the ST segment elevationconverts to a type 1 pattern after administration of a cardiacsodium channel blocking drug.

Data from the largest patient series6 have shown that thehighest risk for clinical events (sudden death, syncope) oc-curs in those patients who have a prior aborted sudden death(62% at 54 ± 54 months follow-up), followed by those withsyncope and spontaneously abnormal, type 1 pattern ECG(19% at 26 ± 36 months follow-up). However, the event rateamong asymptomatic patients was still 8% (27 ± 29 monthsfollow-up). Data from this series suggest that among theseasymptomatic patients, the risk is highest in those with spon-taneously diagnostic type 1 ECG pattern and lower if they de-velop this ECG pattern only after administration of a sodiumchannel blocking drug. The risk was also high in those withinducible VT/VF at electrophysiologic study. Other studies,however, report a much lower event risk in asymptomaticpatients and found that VT/VF inducibility was not predic-tive of future events.7 This difference may in part relate topatient selection including only patients with type 1 patternECG versus including also those with type 2 and 3 ECG pat-tern as well as the electrophysiologic stimulation protocolused.8 Thus, risk stratification in asymptomatic individualswith the Brugada ECG is still a challenge. The diagnosticclassification as well as risk stratification based on the threeECG patterns may be questionable since the ECG may spon-taneously change from one pattern to another in the sameindividual.9

J Cardiovasc Electrophysiol, Vol. 17, pp. 608-609, June 2006.

Address for correspondence: Peter Ott, M.D., Sarver Heart Center, Univer-sity of Arizona Health Sciences Center, 1501 N Campbell Avenue, TucsonAZ 85724. Fax: 520-626-4333; E-mail: ottp@email.arizona.edu

doi: 10.1111/j.1540-8167.2006.00495.x

In 1990, the Thai Ministry of Public Health Report foundan association between a large meal of glutinous rice (“stickyrice”) or carbohydrate ingested on the night of death in sud-den unexpected death syndrome (SUNDS).10 In this Jour-nal,11 Ikeda et al. report the effect of a large meal on theECG in 35 Japanese patients with proven or suspected BS.Patients enrolled had persistent or transient coved ST seg-ment elevation of ≥2 mm in leads V1-V3. Patients treatedwith cardiac sodium channel blocking drugs at the time ofdiagnosis were included. Patients with only saddle back STelevation were excluded. Seventeen patients were defined as“high risk” based on either a history of clinical events (syn-cope in 8, aborted sudden death in 5) or a family history ofsudden death in 15. Eighteen patients had neither a historyof clinical events nor a family history of sudden death andwere defined as “indeterminate risk.” After a large meal test,ingested over 20 minutes, this test was defined as positive if itelicited (a) an increase in the baseline ST segment elevationby >1 mm in leads V1-V3; (b) a change from saddle backto coved ST segment elevation; or (c) visible T wave ampli-tude alternans. This test was positive in 14 of 17 (82%) ofthe “high-risk” patients and only 3 of 18 (17%) of the “inde-terminate patients.” The authors conclude that ECG changescharacteristic for the BS are augmented after a large meal, andthis effect is seen primarily in patients with clinical markersfor “high risk.”

The data by Ikeda et al.11 appear to be consistent withthe proposed mechanism—that gastric distension followinga large meal has the effect of enhancing vagal tone with resul-tant ST elevation in patients with the BS. Metabolic effectssuch as a shift in insulin/glucose levels or electrolyte shiftsseem less probable mechanisms since the ECG changes wereobserved very soon after a meal at a time when significantmetabolic changes would not be expected.

In BS, clinical events often occur at rest or during sleep,suggesting a possible role of the autonomic nervous sys-tem. The role of enhanced vagal tone in BS is suggestedby the following: muscarinic stimulation augments ST el-evation typical of BS12; and increased vagal activity, as-sessed by heart rate variability analysis, can be seen prior tospontaneous ST segment elevation13 and prior to episodes ofVF.14

The high incidence of a positive large meal test in patientswith prior clinical events (“high risk”) and low incidence ofa positive large meal test in patients without prior clinicalevents (“indeterminate risk”) raises the possibility that thistest could be used for risk stratification. Does the large mealtest uncover a heightened vagal tone, common to “high-risk”patients, that differentiates them from “indeterminate-risk”patients? Or, if one assumes a similar increase in vagal tonebetween “high-risk” and “indeterminate-risk” patients, doesthe large meal test expose differences in trigger (enhanced va-gal tone) substrate (repolarization/depolarization abnormali-ties) interaction?

Ott and Marcus Editorial Comment 609

In a prospective study of 124 patients with coved or sad-dle back ST segment elevation of ≥1 mm in leads V1-V3 (24with a history of syncope, 11 with a family history of suddendeath), the same investigator15 identified a spontaneouschange in ST segment elevation on multiple ECG record-ings as the most significant factor in predicting sudden deathof VT/VF during a mean follow-up of 40 ± 19 months (haz-ard ratio: 9). Of interest, in this study the spontaneous STsegment change was seen most often after meals, and thepredictive value increased when a spontaneous ST segmentchange was combined with a family history of sudden deathor a history of syncope.

Thus, it appears that in addition to the spontaneous covedST segment elevation (type 1 ECG pattern) a spontaneouslychanging ST segment pattern (i.e., after large meal) predictsan increased event rate during follow-up. This would be incontrast to the benign prognosis of coved ST segment eleva-tion if seen only after administration of class I antiarrhythmicdrug use.6

Given the uncertainty in risk stratification in asymptomaticindividuals with the BS ECG pattern, a prospective evaluationof the diagnostic and prognostic clinical utility of the largemeal test or other measures enhancing vagal tone, alone orin combination with other clinical parameters, may be a pro-ductive avenue of investigation.

References

1. Brugada P, Brugada J: Right bundle branch block, persistent ST seg-ment elevation and sudden cardiac death: A distinct clinical and elec-trocardiographic syndrome: A multicenter report. J Am Coll Cardiol1992;20:1391-1396.

2. Schulze-Bahr E, Eckhardt L, Breithardt G, Seidl K, Wichter T, WolpertC, Borggrefe M: Sodium channel gene (SCN5A) mutations in 44 indexpatients with Brugada syndrome: Different incidences in familial andsporadic disease. Hum Mutat 2003;21:651-652.

3. Tukkie R, Sogaard P, Vleugels J, De Groot IK, Wilde AA, Tan HL:Delay in right ventricular activation contributes to Brugada Syndrome.Circulation 2004;1272-1277.

4. Antzelevitch C: The Brugada syndrome: Ionic basis and arrhythmiamechanisms. J Cardiovasc Electrophysiol 2001;12:268-272.

5. Antzelevitch C, Brugada P Borggrefe M, Brugada J, Brugada R, Cor-rado D, Gussak I, LeMarec H, Nademanee K, Riera ARP, Shimizu W,Schulze-Bahr E, Tan H, Wilde AA: Brugada syndrome. Report of thesecond consensus conference. Circulation 2005;111:659-670.

6. Brugada J, Brugada R, Antzelevitch C, Towbin J, Nademanee K, Bru-gada P: Long term follow up of individuals with the electrocardiographicpattern of right bundle branch block and ST segment elevation in pre-cordial leads V1 to V3. Circulation 2002;105:73-78.

7. Priori SG, Napolitano C, Gasparini M, Pappone C, Della Bella P, Gior-dano U, Bloise R, Giustetto C, De Nardis R, Grillo M, Ronchetti E,Faggiano G, Nastoli J: Natural history of Brugada syndrome: Insightsfor risk stratification and management. Circulation 2002;105:1342-1347.

8. Eckhardt L, Kirchhof P, Schulze-Bahr E, Ribbing M, Loh P, Bruns HJ,Witte A, Milberg P, Borggrefe M, Breithardt G, Wichter T, HaverkampW: Electrophysiologic evaluation in Brugada syndrome: Yield of pro-grammed ventricular stimulation at two ventricular sites with up to threepremature beats. Eur Heart J 2002;23:1394-1401.

9. Veltmann C, Schimpf R, Echternach C, Kuschyk J, Spehl S, StreitnerF, Borggrefe M, Wolpert C: High prevalence of fluctuation betweendiagnostic and non diagnostic ECGs in Brugada syndrome: Implicationsfor correct phenotyping and risk stratification (abstract). Circulation2004;110:2346.

10. Nimmannit S, Malasit P, Chaovakul V, Susaengrat W, Vasuvattakul S,Nilwarangkur S: Pathogenesis of sudden unexplained nocturnal death(lai tai) and endemic distal renal tubular acidosis. Lancet 1991;338:930-932.

11. Ikeda T, Abe A, Yusu S, Nakamura K, Ishiguro H, Mera H, YotsukuraM, Yoshino H: The full stomach test as a novel diagnostic technique foridentifying patients at risk of Brugada syndrome. J Cardiovasc Electro-physiol 2006;17:602-607.

12. Miyazaki T, Mitamura H, Miyoshi S, Soejima K, Aizawa Y, OgawaS: Autonomic and antiarrhythmic drug modulation of ST segmentelevation in patients with Brugada syndrome. J Am Coll Cardiol1996;27:1061-1070.

13. Mizumaki K, Fujiki A, Tsuneda T, Sakabe M, Sukabe M, Nishida K,Sugao M, Inoue H: Vagal activity modulates spontaneous augmentationof ST elevation in the daily life of patients with Brugada syndrome. JCardiovasc Electrophysiol 2004;15:667-673.

14. Kasanuki H, Ohnishi S, Ohtuka M, Matsuda N, Nirei T, Isogai R, ShodaM, Toyoshima Y, Hosoda S: Idiopathic ventricular fibrillation inducedwith vagal activity in patients without obvious heart disease. Circulation1997;95:2277-2285.

15. Ikeda T, Takami M, Sugi K, Mizusawa Y, Sakurada H, Yoshino H: Non-invasive risk stratification of subjects with a Brugada type electrocardio-gram and no history of cardiac arrest. Ann Noninvasive Electrocardiol2005;10:396-403.