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1 Fragmentation of the QRS Complex as a Prognostic Sign in Brugada Syndrome DOUGLAS P. ZIPES, MDDISTINGUISHED PROFESSORKRANNERT INSTITUTE OF CARDIOLOGYINDIANA UNIVERSITY SCHOOL OF MEDICINEEDITOR-IN-CHIEF HEARTRHYTHMSEPTEMBER 5, 2013
5 Fragmented QRS (fQRS) in Brugada syndrome Male (55 y.o.), aborted sudden deathIIIIIIaVRaVLaVFV1V2V3V4V5V6V1V2An case of resuscitated from VF. Multiple spikes existed at lead V1. This patient had frequent VF attacks.VF initiation (ICD monitoring)
8 ECG Epi Mid Epi Endo Endo ECG Epi Epi Endo Endo Morita, Zipes, et al 1 2EndoEpiAPD map270(ms)20012EpiMidEndoECG100 msPVC activation mapEpiEndo130150801234(ms)70140101234EpiECGEndo100 msThis figure shows 3-dimentional distribution of AP heterogeneity in a RVOT tissue.The epicardium had large AP heterogeneity but mid and endocardium had little heterogeneity of AP. This epicardial heterogeneity made complex intraepicardial and transmural APD dispersion.PVC initiated at short APD area in epicardium and propagated according to APD gradient.Morita, Zipes, et al8
10 ST elevation and QT dispersion in body surface mapping 61 M VFPost pilsicainideST elevation and QT dispersion in body surface mappingA. ST MapB. QT MapPilsicainide0.80.4(mV)- 0.2abcd500450400(ms)abcdC. ECG(A and C) ST voltage maps. High ST elevation is located in RVOT region and enhanced by pilsicainide.(B and D) QT interval map shows long QT area in RVOT region in control (dark area) and pilsicainide induced QT interval heterogeneity in RVOT area.(E) Lead (a) and (b) are located at RVOT area. Pilsicainide prolonged QT interval in lead (a) but abbreviated QT interval in lead (b).RVOTRVAILVacb445497401462dc(ms)Modified from Morita, Zipes et al. Heart Rhythm 2008;5:72510
14 Examples of f-QRS in Brugada syndrome. Figure 2. Example of f-QRS in Brugada syndrome. Dotted lines show onset and termination of the QRS complex. A, Multiple spikes between the R wave and the end of the QRS complex in leads V2 and V3. B, Multiple spikes were observed at the upstroke of the S wave in leads V1 and V2. C, Multiple spikes existed around the late r′ in leads V1 and V2. D, No sign of f-QRS. Right precordial lead showed rSr′ pattern without multiple spikes in the QRS complex.Morita Zipes et al. Circulation 2008;118:
17 Incidence of fQRS Incidence of f-QRS p<0.01 Incidence of fQRS in Brugada syndorme: 50/115 pts (43%)fQRS can be recorded within 1.5 months of their initial visit to hospitalIncidence of f-QRS(%)p<0.01f-QRS was observed in 43% of patients and it often observed in patients with VF (85%) and syncope (50%). f-QRS was also observed in asymptomatic patients (34%). Spontaneous variation of f-QRS occurred frequently.Morita, Zipes et al. Circulation 2009; 118:1697
18 Fragmented QRS f-QRS (+) Recurrent syncope due to VF f-QRS (-) (%) 100 51010050(yrs.)(%)f-QRS (-)Morita, Zipes et al. Circulation 2009; 118:1697
19 Fatty infiltration at RV in Brugada syndrome KH 50y.o. MaleIIIIIIaVRaVLaVFV1V2V3V4V5V6TVARVRVOTIIHRARVARVOTMAP
20 Depolarization abnormality in Brugada syndrome Decrease in Na+ currentMyocardial injury ( fatty infiltration, fibrosis, myocarditis）PQ、QRS、HV prolongation、fragmented QRS、delayed potential、late potentialIndex of poor prognosis?Depolarization abnormality can be associated with onset of VF.
21 Examples of electrocardiographic (ECG) traces ECG Presentation in Brugada Syndrome in the PRELUDE trial:Examples of electrocardiographic (ECG) tracesFigure 1 ECG Presentation in Brugada Syndrome Examples of electrocardiographic (ECG) traces (A to C) . (A) A 35-year-old male patient with presenting spontaneous type I ECG; (B) 30-year-old male patient presenting with type III ECG (left panel) con...Silvia G. Priori , Maurizio Gasparini , Carlo Napolitano , Paolo Della Bella , Andrea Ghidini Ottonelli , Biagio S...Risk Stratification in Brugada Syndrome : Results of the PRELUDE (PRogrammed ELectrical stimUlation preDictive valuE) RegistryJournal of the American College of Cardiology Volume 59, Issue
22 Survival According to Refractory Period and QRS-f Kaplan-Meier survivorship analysis of arrhythmic event-free survivalSilvia G. Priori , Maurizio Gasparini , Carlo Napolitano , Paolo Della Bella , Andrea Ghidini Ottonelli , Biagio S...Risk Stratification in Brugada Syndrome : Results of the PRELUDE (PRogrammed ELectrical stimUlation preDictive valuE) RegistryJournal of the American College of Cardiology Volume 59, Issue
31 Reduced sodium channel function unmasks residual embryonic slow conduction in the adult right ventricular outflow tract Circ Res 113:137Adult mice heterozygous for a mutation associated with Brugada syndrome (Scn5a1798insD/+).In embryonic heart, conduction velocity was lower in the RVOT than in the right ventricular free wall.In hearts of Scn5a1798insD/+ mice and in normal hearts treated with ajmaline, conduction was slower in the RVOT than in the right ventricular wall.The slowly conducting embryonic phenotype is maintained in the fetal and adult RVOT and is unmasked when cardiac sodium channel function is reduced.
32 In summary, it is likely that both depolarization and repolarization abnormalities can be present, and when both occur, they create the “perfect storm” for VF. However, many mysteries about sudden death remain to be written and explained.
33 Presidents Need to Know about Sudden Death THANK YOU FOR YOUR ATTENTIONIsraeli President Shimon PeresReads “Ripples in Opperman’s Pond”US Past President Bill Clinton“The Black Widows.”
35 Figure 5. T wave alternans (TWA) and random T wave changes in BS. A Figure 5. T wave alternans (TWA) and random T wave changes in BS. A. Patients with BS and TWAs (A-a, 75-year-old male) or random T wave changes (A-b, 45 year-old-male). Arrows indicate the deep T waves. B. A canine RVOT model of BS (in mM, pinacidil 5.0, pilsicainide 8.0, terfenadine 2.0) having TWA (alternating ST level and T wave depth). Alternating appearance and disappearance (white arrow) of the phase 2 dome occurred only in the epicardium. C. APs with and without blocked premature ventricular complexes (PVCs) produced TWA-like ECG activity, in a RVOT model of BS (in mM, pinacidil 3.75, pilsicainide 7.5).Morita et al
36 SUMMARY OF CHANGES Morita et al Figure 7. Pathophysiology of BS. Ion channel mutations (e.g., in SCN5A) deepen the phase 1 notch of the AP, especially in the epicardium of RVOT. The phase 1 notch modulates the phases 2 and 3 of the AP. Transmural difference in APs elevates J-ST and generates a negative T wave in ECG. Epicardial co-existence of APs with and without a dome produces QT dispersion. Instability in the dome exaggerates AP heterogeneity and causes TWAs. Conduction of the phase 2 dome generates PVCs, which can lead to VT and degenerate into VF.Morita et al
44 “FRAGMENTATION OF THE QRS COMPLEX AS A PROGNOSTIC SIGN IN BRUGADA SYNDROME” BRUDAGA SYNDROME: 20 YEARS OF SCIENTIFIC PROGRESSDOUGLAS P. ZIPES, MDDISTINGUISHED PROFESSORKRANNERT INSTITUTE OF CARDIOLOGY INDIANA UNIVERSITY SCHOOL OF MEDICINEEDITOR-IN-CHIEF HEARTRHYTHMSEPTEMBER 5, 2013
45 Brugada syndrome 71 y.o. Male SCN5A (-); Syncope at 8:30 a.m. I II III aVRaVLaVFV1V2V3V4V5V6V1V2Brugada syndrome45
46 Brugada SyndromeBrugada P, Brugada J. J Am Coll Cardiol 1992;20:in Discussion: The mechanism of the conduction disturbances, the abnormal repolarization and the ventricular arrhythmia can only be speculative at present.
49 Brugada syndrome model EpiEndTransDelayBrugada syndrome modelSynchronizedEpi Delay (46ms)AT = 76 msAT = 30 msPatient’s ECGECGEpi 1Epi 2EndAT = 28 msAT = 30 msDrug induced Brugada model. (left) ST elevation with negative T wave was observed when epicardial activation was synchronized. (right) local epicardial delay made multple spikes at the late phase of QRS complex, and it was followed by ST elevation and negative T wave. This multiple spikes resembles the ECG of patients with f-QRS (right, upper).Morita et al. Circulation 2009; 118:1697