1. Fragmentation of the QRS Complex as a Prognostic Sign in Brugada Syndrome
DOUGLAS P. ZIPES, MD
DISTINGUISHED PROFESSOR
KRANNERT INSTITUTE OF CARDIOLOGY
INDIANA UNIVERSITY SCHOOL OF MEDICINE
EDITOR-IN-CHIEF HEARTRHYTHM
SEPTEMBER 5, 2013

2. Figure 1. Different morphologies of an fQRS on a 12-lead ECG.
Das M K et al. Circulation 2006;113:
Copyright © American Heart Association

3. Figure 2. Twelve-lead ECG, showing an fQRS (various RSR′ patterns; QRS duration <120 ms) in inferior leads that is correlated with an inferior wall MI on a myocardial perfusion study (QRS complexes are enlarged in the lower row).
Figure 2. Twelve-lead ECG, showing an fQRS (various RSR′ patterns; QRS duration <120 ms) in inferior leads that is correlated with an inferior wall MI on a myocardial perfusion study (QRS complexes are enlarged in the lower row). The fQRS (a variant of the RSR′ pattern) is present in lead aVF. There is no Q wave. Nuclear imaging revealed a fixed inferior defect. Stre indicates during stress.
Das M K et al. Circulation 2006;113:
Copyright © American Heart Association

4. Kaplan-Meier analysis: all-cause mortality in patients with
Figure 3
Kaplan-Meier analysis: all-cause mortality in patients with
fragmented (fQRS group) and without fragmented QRS (non-fQRS group)
Kaplan-Meier analysis showing all-cause mortality in patients with fragmented QRS (fQRS group) and without fragmented QRS (non-fQRS group). Reprinted with permission.7
Source: Heart Rhythm 2009; 6:S8-S14 (DOI: /j.hrthm )
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5. Fragmented QRS (fQRS) in Brugada syndrome
Male (55 y.o.), aborted sudden death I II
III
aVR
aVL
aVF V1 V2 V3 V4 V5 V6 V1 V2
An case of resuscitated from VF. Multiple spikes existed at lead V1. This patient had frequent VF attacks.
VF initiation (ICD monitoring)

6. ELECTROPHYSIOLOGIC BASIS OF EP AND ECG CHANGES
Ion channel mutation and BrS. A: A reduced Na+ current (SCN5A, GPD1-L, or SCN1B mutations) slows conduction and enables the transient outward current (Ito) to deepen the phase 1 notch of the AP. A prominent phase 1 notch delays activation of the calcium current (ICa) and causes a delayed but prominent phase 2 dome. Excessively deepened phase 1 notch eliminates the phase 2 dome. Ito enhancement can be produced by mutation of KCNE3, which encodes the β-subunit of the Ito channel. ICa reduction can be caused by a mutated calcium channel gene. These AP changes occur predominantly in the epicardium of the RVOT. B: Transmural gradient of AP causes ST elevation and deep negative T waves in the ECG.
Source: Heart Rhythm 2009; 6:S34-S43 (DOI: /j.hrthm )
Copyright © 2009 Heart Rhythm Society Terms and Conditions

7. REPOLARIZATION HYPOTHESIS OF ECG CHANGES
ECGs and APs in a canine RVOT tissue model of BrS (top and middle) and clinical ECGs with similar features in a patient with BrS (bottom). In the tissue model, a Brugada-type ECG was induced with pilsicainide (5.0 μM), pinacidil (A: 2.5 μM; B and C: 5.0 μM), and terfenadine (A: 2.0 μM; B and C: 2.5 μM). A: A lower dose of pinacidil mildly deepened the phase 1 notch of the epicardial AP and elevated J-ST with positive T waves, similar to the saddle-back-type clinical ECG. B: Initial perfusion of higher doses of pinacidil and terfenadine deepened the phase 1 notch (large hollow arrow); delayed the phase 2 dome; resulted in later repolarization in the epicardium (Epi) than in the endocardium (Endo); and caused J-ST elevation, deep negative T wave, and long QT interval, similar to the coved-type ECG with deep negative T wave in the clinical ECG. C: Further perfusion of the higher doses of pinacidil and terfenadine abbreviated the epicardial AP, steepened the transmural gradient of repolarization, elevated J-ST, and generated small and shallow negative T waves. Arrows indicate repolarization. Clinical ECGs were recorded in a 45-year-old male with BrS who was resuscitated from cardiac arrest.
Source: Heart Rhythm 2009; 6:S34-S43 (DOI: /j.hrthm )
Copyright © 2009 Heart Rhythm Society Terms and Conditions

8. ECG Epi Mid Epi Endo Endo ECG Epi Epi Endo Endo Morita, Zipes, et al 12
Endo
Epi
APD map
270
(ms)
200 1 2
Epi
Mid
Endo
ECG
100 ms
PVC activation map
Epi
Endo
130
150 80 1 2 3 4
(ms) 70
140 10 1 2 3 4
Epi
ECG
Endo
100 ms
This 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 al 8

9. HETEROGENEITY IS CRITICAL
Electrophysiological heterogeneity in a canine tissue model of BrS (A: intraventricular; B: intraepicardial) and in a clinical patient with BrS (C). A: Compared with the RVAI preparation (small J wave and positive T wave), the RVOT preparation (from the same heart and treated identically with pilsicainide 7.5 μM, pinacidil 5.0 μM, and terfenadine 2.0 μM) had large J-ST elevation, negative T wave, and longer QT in ECG and more prominent phase 1 notch and phase 2 dome in the epicardial AP. B: Significant heterogeneity of APD within the epicardium (in the map) of an RVOT model of BrS (pilsicainide 10.0, pinacidil 7.5, and terfenadine 2.0). Compared with site b, site a had a prominent dome, longer APD, and corresponding negative T wave and longer QT in ECG. C: Unipolar ECG leads in a patient. The RVOT (the upper three leads) had prominent J-ST elevation (arrows) with negative T wave, and the RVOT (the lower 2 leads) had saddle-back-type ECG with small J wave.
Morita, Zipes, et al. Heart Rhythm 2009; 6:S34-S43 (DOI: /j.hrthm )
Copyright © 2009 Heart Rhythm Society Terms and Conditions

10. ST elevation and QT dispersion in body surface mapping
61 M VF
Post pilsicainide
ST elevation and QT dispersion in body surface mapping
A. ST Map
B. QT Map
Pilsicainide
0.8
0.4
(mV)
- 0.2 a b c d
500
450
400
(ms) a b c d
C. 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).
RVOT
RVAI LV a c b
445
497
401
462 d c
(ms)
Modified from Morita, Zipes et al. Heart Rhythm 2008;5:725 10

11. DEPOLARIZATION BASIS OF ECG CHANGES
Conduction disturbance enhances Brugada-type ECG. A: Epicardial conduction delay (from 27 ms [a] to 54 ms [b] after the endocardial stimulation) exaggerated J-ST elevation in a RVOT model of BrS (pinacidil 7.5 μM; terfenadine 2.0 μM; pilsicainide 7.5 μM). B: ECG and local electrograms in the RVOT in a patient with BrS-type ECG. Prominent J-ST elevation in ECG associated with a delayed repolarization time and delayed potential in the epicardium but not in the endocardium of RVOT. Numbers show local QT intervals.
Source: Heart Rhythm 2009; 6:S34-S43 (DOI: /j.hrthm )
Copyright © 2009 Heart Rhythm Society Terms and Conditions

12. Epicardial mapping in Brugada syndrome
ECG (V2)
HRA
His CS
RVA
Conus branch (Epi)
RVOT
(Endo)
RVOT-Epi
RVOT-Endo
Filter : Hz
delayed potential
RVOT-Epi
RVOT-Endo
Filter : Hz
Local QT
433 ms
350 ms
200 ms
Nagase et al. JACC 2008; 51:1154
Nagase et al. JACC 2002; 39:1992 12

13. Depolarization hypothesis: Wilde, Postema JMCC 2010

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:

15. f-QRS and LP. Upper panel shows ECGs in lead V2
Figure 6. f-QRS and LP. Upper panel shows ECGs in lead V2, with f-QRS circled. Bottom panel shows signal-averaged ECG (SAE) with the LP indicated by arrows. Patient A had both f-QRS and LPs. Patient B had only f-QRS. Patient C had only LPs. Patient D had neither f-QRS nor LP.
Morita Zipes et al. Circulation 2008;118:
Copyright © American Heart Association

16. Spontaneous variations of f-QRS and ST elevation
SUDDEN DEATH 6 MONTHS AFTER LAST ECG
Figure 3. Spontaneous variations of f-QRS and ST elevation. These ECGs were recorded in a patient who experienced cardiac arrest. A, ECG when patient was 55 years old (y.o.). Lead V2 had f-QRS at the late phase of the QRS complex (arrows). Leads V1 and V2 showed coved-type ST elevation. B, ECG at age 56 years. ST elevation decreased and changed to the saddle-back type. f-QRS was not observed. C, ECG at age 57 years. Coved-type ST elevation reappeared, but f-QRS did not appear. D, ECG at age 58 years. ECG converted to normal pattern. This patient died suddenly 6 months after the last ECG recording.
Morita Zipes et al. Circulation 2008;118:
Copyright © American Heart Association

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 hospital
Incidence of f-QRS
(%)
p<0.01
f-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 (-) (%) 1005 10
100 50
(yrs.)
(%)
f-QRS (-)
Morita, Zipes et al. Circulation 2009; 118:1697

19. Fatty infiltration at RV in Brugada syndrome
KH　50y.o. Male I II
III
aVR
aVL
aVF V1 V2 V3 V4 V5 V6
TVA RV
RVOT II
HRA
RVA
RVOT
MAP

20. Depolarization abnormality in Brugada syndrome
Decrease in Na+ current
Myocardial injury ( fatty infiltration, fibrosis, myocarditis）
PQ、QRS、HV prolongation、fragmented QRS、delayed potential、late potential
Index 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) traces
Figure 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) Registry
Journal 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 survival
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) Registry
Journal of the American College of Cardiology Volume 59, Issue

23. EPICARDIAL ABLATION IN CANINES
Examples of epicardial and transmural tissue preparations (A) and phase 2 reentry and site of ablation (B). (A) Tissues were perfused arterially at 36.5°C. Electrical activities were mapped on the epicardium or on a cut-exposed transmural surface. (B) After induction of Brugada syndrome model, the phase 2 dome of AP conducted from the region having a prominent dome (Epi1) to the region without a dome (Epi2) initiated arrhythmia. The Epi2 site had the earliest activation of PVC and received RFCAs. Coupling interval of PVC in transmural ECG was 335 ms. Epi2 activated 51 ms before the onset of QRS complex in transmural ECG. The earliest activation produced a small notch in the T wave in the transmural ECG (arrowhead). Arrows show phase 2 reentry. ECG = electrocardiogram; AP = action potential; Endo = endocardial; Epi = epicardial; PVC = premature ventricular complex; RFCA = radiofrequency catheter ablation.
Morita, Zipes Heart Rhythm 2009; 6: (DOI: /j.hrthm )
Copyright © 2009 Heart Rhythm Society Terms and Conditions

24. Arrhythmias before (A) and after (B) RFCA in the epicardial tissues
Arrhythmias before (A) and after (B) RFCA in the epicardial tissues. Spontaneous PVCs and polymorphic tachycardia occurred frequently in the epicardium after inducing the Brugada model (A). RFCAs at the earliest epicardial activation site eliminated arrhythmias, although both epicardial AP heterogeneity and ST-segment elevation in the transmural ECG remained (B). Abbreviations as in Figure 1.
Source: Heart Rhythm 2009; 6: (DOI: /j.hrthm )
Copyright © 2009 Heart Rhythm Society Terms and Conditions

25. Transmural APD distribution before and after RFCA in the Brugada model
Transmural APD distribution before and after RFCA in the Brugada model. Before RFCA, the Brugada model had both long (Epi1) and short (Epi3) APD regions simultaneously in the epicardium (A, transmural distribution of APD), resulting in frequent PVC (B, activation time of PVC). RFCA disconnected the long (Epi1) and short (Epi3) AP regions (C, transmural APD distribution after RFCA), and eliminated PVC. The black epicardial regions (circled by dotted line) in C indicate the area injured by RFCA. (D) The transmural ECG and APs at Epi1, Epi2, Epi3 and in the endocardium in correspondence to A-C. RFCA eliminated electrical activity at Epi2. Arrows represent propagation of PVC within the transmural tissue. ABL = ablation site; APD = action potential duration; PVC = premature ventricular complex.
Source: Heart Rhythm 2009; 6: (DOI: /j.hrthm )
Copyright © 2009 Heart Rhythm Society Terms and Conditions

26. Figure 7
Transmural sections of RFCA lesions. RFCA applied to the epicardium (Epi) resulted in a 3-mm-deep lesion in a tissue (arrows, A). In another tissue (B), the epicardial focus of arrhythmia was not affected by a RFCA lesion in the endocardium (Endo, white arrows), but eliminated by an epicardial ablation. Abbreviations as in Figure 4.
Source: Heart Rhythm 2009; 6: (DOI: /j.hrthm )
Copyright © 2009 Heart Rhythm Society Terms and Conditions

27. Left lateral view of the right ventricular outflow tract (RVOT) displays the difference in ventricular electrograms between the endocardial (ENDO) and epicardial (EPI) site of the anterior RVOT of the same patient (patient 4) as Figure 2.
Left lateral view of the right ventricular outflow tract (RVOT) displays the difference in ventricular electrograms between the endocardial (ENDO) and epicardial (EPI) site of the anterior RVOT of the same patient (patient 4) as Figure 2. The left and right insets display bipolar and unipolar electrograms recorded from the epicardium and endocardium from the same site of the RVOT, respectively. Bi-DIST indicates bipolar distal; Bi-PROX, bipolar proximal; Uni-DIST, unipolar distal; and Uni-PROX, unipolar proximal.
Nademanee K et al. Circulation 2011;123:
Copyright © American Heart Association

28. A scattered plot of all electrograms (n=827 points) recorded from the 9 patients from the 4 major areas: right ventricular (RV) epicardium, anterior right ventricular outflow tract (RVOT) epicardium, left ventricular (LV) epicardium, and RV endocardium.
A scattered plot of all electrograms (n=827 points) recorded from the 9 patients from the 4 major areas: right ventricular (RV) epicardium, anterior right ventricular outflow tract (RVOT) epicardium, left ventricular (LV) epicardium, and RV endocardium. A, scattered plots of late potential (LP) versus electrogram bipolar voltage (BimV) clearly demonstrate that low-voltage signals (<1 mV) with LP (>100 ms of the end of QRS complex) are exclusively from those recorded from anterior RVOT epicardium. B, Scattered plots of LP versus electrogram duration show similarly that the quadrant of LPs >100 ms and electrogram width >100 ms are almost entirely housed by the signals recorded from the anterior RVOT epicardium.
Nademanee K et al. Circulation 2011;123:
Copyright © American Heart Association

29. Figure 1 SACHER ET AL. Heart Rhythm (DOI:10.1016/j.hrthm.2013.05.023 )
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30. Source: Heart Rhythm (DOI:10.1016/j.hrthm.2013.05.023 )
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31. Reduced sodium channel function unmasks residual embryonic slow conduction in the adult right ventricular outflow tract Circ Res 113:137
Adult 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 ATTENTION
Israeli President Shimon Peres
Reads “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

37. Figure 7
Pathophysiology of BrS. 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 phases 2 and 3 of the AP. Transmural difference in APs elevates J-ST and generates a negative T wave in ECG. Epicardial coexistence 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.
Source: Heart Rhythm 2009; 6:S34-S43 (DOI: /j.hrthm )
Copyright © 2009 Heart Rhythm Society Terms and Conditions

38. Figure 4. Effects of recording site and filtering on f-QRS.
Figure 4. Effects of recording site and filtering on f-QRS. A, ECGs recorded by 0- to 150-Hz filtering. f-QRS appeared in the 3rd intercostal space (ics) and were manifested in the 2nd intercostal space (arrows). f-QRS was not observed at the regular ECG recording (in the 4th intercostal space). B, Reducing the cutoff frequency of the low-pass filter from 150 to 25 Hz diminished f-QRS in the same 2nd intercostal space ECG as in A.
Morita H et al. Circulation 2008;118:
Copyright © American Heart Association

39. Figure 5. Differences in ECG parameters between patients with and without f-QRS.
Figure 5. Differences in ECG parameters between patients with and without f-QRS. A, QRS width; B, QTc interval; C, ST level; and D, number of spikes within QRS complex. Patients with f-QRS had longer QRS interval, longer QTc interval, and multiple spikes within QRS compared with patients without f-QRS. There was no difference of ST level between the 2 groups. Sum indicates sum of spikes in all V1 through V3. **P<0.01.
Morita H et al. Circulation 2008;118:
Copyright © American Heart Association

40. Figure 8. Experimental model of Brugada syndrome.
Figure 8. Experimental model of Brugada syndrome. Transmural ECG, APs (filter 0 to 100 Hz), and unipolar potential (filter 30 to 100 Hz) before (A; control) and after (B) administration of drugs that induced the Brugada model. A, Control; left panel shows the transmural ECG and APs when epicardial (Epi) activation was synchronized in both tissues. QRS duration was not prolonged, and a small J wave and positive T wave were observed. Right, Activation of the epicardium was delayed at Epi 1, and the transmural ECG had the RsR′ pattern of the QRS complex, but without Brugada ECG characteristics in the transmural ECG. Arrows show delayed epicardial activation in the epicardial tissue. B, Brugada model. The phase 1 notch of the AP was larger and deeper than the control in A. There was no activation deflection at the upstroke of the phase 2 dome in the unipolar potential (30 to 100 Hz filtering). When epicardial activation was synchronized, the transmural ECG showed ST elevation with a negative T wave but without f-QRS (left). Local epicardial delay caused multiple spikes at the late phase of the QRS complex (thick arrow), followed by ST elevation and a negative T wave (right). Endo indicates endocardium.
Morita H et al. Circulation 2008;118:
Copyright © American Heart Association

41. Figure 2
Action potential duration (APD) and depth of phase 1 notch (P1N) in transmural tissues. (Column 1) At baseline (control), APs were shorter in the epicardium than in the endocardium and without heterogeneity within the epicardium (A). Phase 1 notch of AP was deeper in the epicardium than in the endocardium (D). (Column 2) After induction of Brugada type ECG, epicardium had both the longest (Epi1) and shortest (Epi2) APDs simultaneously, resulting in epicardial AP heterogeneity. Transmural APD distribution became complex (B). Phase 1 notch of AP was largest in the epicardium region having short APD (Epi 2) (E). (Column 3) After RFCA in the Brugada model, AP heterogeneity (both APD and depth of phase 1 notch of AP) still presented in the epicardium (C, F). However, RFCA disconnected the long and short AP regions, and eliminated arrhythmia. **P < .01. Abbreviations as in Figure 1.
Source: Heart Rhythm 2009; 6: (DOI: /j.hrthm )
Copyright © 2009 Heart Rhythm Society Terms and Conditions

42. Figure 6
Example of epicardial activity before and after a linear lesion of RFCA. (A and D) Epicardial distributions of APD before (A) and after (D) the RFCA linear lesion. (B and C) Maps of PVC activation before (B) and after (C) the first spot lesion of RFCA. (E) Transmural ECGs and APs at Epi1-3 before and after RFCA. Before RFCA, the tissue had short (right side) and long (left side) APD areas (A) and PVC initiated in the upper right area having short APDs (B). After a spot lesion that eliminated the initial focal site (identified in B), a new focus appeared next to the RFCA region (C). A linear lesion, which separated the short and long APD areas, was required to eliminate arrhythmias (E). Epicardial AP heterogeneity still presented after RFCA (D, E). Arrows in B and C show propagation of PVCs. Abbreviations as in Figure 4.
Source: Heart Rhythm 2009; 6: (DOI: /j.hrthm )
Copyright © 2009 Heart Rhythm Society Terms and Conditions

43. T wave changes
TWA and random T-wave changes in BrS. A: Patients with BrS 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 BrS (pinacidil 5.0 μM, pilsicainide 8.0 μM, terfenadine 2.0 μM) 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 PVCs produced TWA-like ECG activity in an RVOT model of BrS (pinacidil 3.75 μM, pilsicainide 7.5 μM).
Source: Heart Rhythm 2009; 6:S34-S43 (DOI: /j.hrthm )
Copyright © 2009 Heart Rhythm Society Terms and Conditions

44. “FRAGMENTATION OF THE QRS COMPLEX AS A PROGNOSTIC SIGN IN BRUGADA SYNDROME” BRUDAGA SYNDROME: 20 YEARS OF SCIENTIFIC PROGRESS
DOUGLAS P. ZIPES, MD
DISTINGUISHED PROFESSOR
KRANNERT INSTITUTE OF CARDIOLOGY INDIANA UNIVERSITY SCHOOL OF MEDICINE
EDITOR-IN-CHIEF HEARTRHYTHM
SEPTEMBER 5, 2013

45. Brugada syndrome 71 y.o. Male SCN5A (-); Syncope at 8:30 a.m. I II III
aVR
aVL
aVF V1 V2 V3 V4 V5 V6 V1 V2
Brugada syndrome 45

46. Brugada Syndrome
Brugada 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.

47. Ventricular arrhythmias induced by epicardial heterogeneity of AP in a canine RVOT model (A–C) and in a 48-year-old male with BrS (D–F). Experiment (A: APD map; B: activation isochronal map; C: local ECGs and APs from the sites indicated in A and B): Large phase 2 dome conducted (along the arrows) from the long APD region (site a, black color in A) to the short APD region (sites b and c, light color), then reentered the long APD region (site d), and was finally blocked by refractoriness (B and C). Local transmural ECGs (C) showed ST elevation with negative T wave in the long APD region (site d) and large ST elevation in the short APD region (site b). BrS was induced by pinacidil (10.0 μM), terfenadine (2.0 μM), and pilsicainide (12.5 μM). Patient (87-lead body surface map): The distribution of QT intervals in the anterior chest (D) shows that the upper chest (the RVOT region) had simultaneous presences of both short and long QT intervals (a and b), resembling the APD heterogeneity in the epicardium of canine RVOT model of BrS (A). The isochronal map (E) shows the RVOT origin of PVC. J-ST elevation occurred in the local ECGs at both sites a and b (F). Site a had a short QT interval without a negative T wave.
Source: Heart Rhythm 2009; 6:S34-S43 (DOI: /j.hrthm )
Copyright © 2009 Heart Rhythm Society Terms and Conditions

48. Recurrence of syncope due to ventricular arrhythmia
Figure 7. Recurrence of syncope due to ventricular arrhythmia. A, Freedom from events for patients with and without f-QRS. Patients with f-QRS often experienced recurrent syncope due to VF within 4 years from the first episode. The existence of LPs (B), mutation of SCN5A (C), and VF induced by programmed electrical stimulation (PES; D) did not predict the recurrence of syncope.
Morita H et al. Circulation 2008;118:
Copyright © American Heart Association

49. Brugada syndrome model
Epi
End
Trans
Delay
Brugada syndrome model
Synchronized
Epi Delay (46ms)
AT = 76 ms
AT = 30 ms
Patient’s ECG
ECG
Epi 1
Epi 2
End
AT = 28 ms
AT = 30 ms
Drug 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

50. Figure 5
Example of epicardial AP activity before and after a spot RFCA. (A-C) Epicardial distributions of APD before RFCA (A), after the first application of RFCA (B), and after the second application of RFCA (C). (D and E) Isochronal maps of PVC activations from 2 foci. (F) Transmural ECGs and APs at Epi1-3 before and after RFCA. Before RFCA, epicardium had AP heterogeneity (A, F) and PVC (PVC1) initiated at the upper right corner and propagated within epicardium after the APD gradient (D). RFCA at the earliest activation site (PVC1) injured the upper right corner (B). A second PVC (PVC2) initiated at the lower right corner where AP heterogeneity presented (E). RFCA at the earliest activation site of PVC2 separated the long and short AP regions, eliminated arrhythmia, but did not eliminate AP heterogeneity (C, F). Arrows in D and E show propagation of PVCs. Abbreviations as in Figure 4.
Source: Heart Rhythm 2009; 6: (DOI: /j.hrthm )
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51. A. BrS ECG（repolarization abnormality)
B. BrS ECG（depolarization abnormality)
Conduction delay
C. BrS ECG（repolarization + depolarization abnormalities
Conduction delay
ECG
Action potential
D. BrS ECG（saddle-back)
E. BrS ECG(Type 0 ECG)
Epicardial action potentials
Endocardial action potentials
Voltage gradient: epi→endo
Voltage gradient: endo→epi

52. F. BrS ECG（repolarization heterogeneity)
Ｇ. BrS ECG (phase 2 reentry)