**4. Electrocardiographic analysis**

#### **4.1. Size of substrate and ST-segment elevation**

In the BrS the mechanism of ST segment elevation has been explained by the repolarization theory (decreased of Na + and/or Ca++ channel function with a prominent Ito current in epicardium of RVOT generates a transmural voltage gradient), or the depolarization theory (disturbances in depolarization of RVOT can be cause of delayed conduction and ST segment elevation) [18, 20]. Nevertheless, the ECG changes are actually explained by the theorem of solid angle, where a substrate larger increases the magnitude of the ST segment elevation [31]. In 13 patients of high risk we have analyzed QRS complex duration, R wave amplitude in aVR lead, presence of fragmented QRS (f-QRS) and end-QRS slur or notch in DI, aVL, DII, DIII and aVF leads with J point peak ≥0.2 mv with descending ST segment, corresponding to an early repolarization or "J wave" [19]. Before of endocardial mapping the patients were underwent flecainide testing (400 mg, orally) with the purpose of measuring the greatest ST-segment elevation. The partial greatest ST-segment elevation in millimeters (ST-segment elevation in V1 + V2 leads in the third ICS and ST-segment elevation in V1 + V2 + V3 leads in fourth ICS), and total sum of greatest ST-segment elevation (ST segment elevation in V1 + V2 leads in the third ICS plus ST-segment elevation in V1 + V2 + V3 leads in fourth ICS) were measured. (**Figure 4-A**). Correlation between size and location of substrate in the electro-anatomic map and the ST-segment elevation were analyzed. As shown in **Figure 4** and **Table 2**, with a cut-off ≥13 mm in the total sum of ST segment elevation two variants were found: (1) A total sum of ST-segment elevation <13 mm (n = 8, 61.5%, mean 9.6 ± 1.3 mm) corresponded to a central area of substrate of 7.7 ± 1.8 mm2 ; (2) A total sum of ST segment elevation ≥13 mm (n = 5, 38.5%, mean 15 ± 1.1 mm) corresponded to a central area of substrate of 28.2 ± 9.2 mm2 (p < 0.001 for correlation of ST segment elevation and correlation of central area of substrate, with a value >0.90 of ROC curve).

inferolateral early repolarization and complete RBBB were associated with occurrence of ventricular tachyarrhythmia in the symptomatic patients [34]. Our population show in three patients

**Figure 4.** Correlation between ST segment elevation and substrate localization. A. With the administration of sodium channel blocker, a greater magnitude of total sum of ST segment elevation corresponds to a greater very low voltage area of substrate, and allows its location in the longitudinal plane of RVOT. (a) The location of the substrate in the bottom zone of RVOT correspond to a greater sum of ST segment elevation in fourth ICS vs. third ICS (5 vs. 3 mm). (b) The location of the substrate in the top zone of RVOT correspond to a greater sum of ST segment elevation in third ICS vs. 4th ICS (8 vs. 3 mm). (c) The location of the substrate in the intermediate zone of RVOT corresponds to a sum of ST segment elevation of equal magnitude in third ICS and fourth ICS (8 mm and 8 mm). B. The graph shows the correlation between linear increase of total sum of ST segment elevation and substrate size. The blue bars indicate each patient [19].

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Nademanee et al. found functional substrate in the anterior zone of epicardium of RVOT [17]. Brugada et al. in 14 inducible patients reported a functional substrate in epicardium of RVOT

In our study a high-density endocardial electroanatomical mapping of right ventricle and RVOT was performed [19]. Taking the pulmonary valve as upper limit and the supraventricular crest as lower limit in the longitudinal plane the RVOT was divided in top and bottom. As shown in **Figure 4-A** and Table II, we have found three variants: (1) When the substrate was located in the top region of RVOT, it corresponded with the greater sum of ST-segment elevation in V1-V2 leads in the 3rd ICS (n = 5, 38.5%); (2) When the substrate was located in the bottom region of RVOT (n = 5, 38.5%), it corresponded with the greater sum of ST-segment elevation in V1-V2-V3 leads in the 4th ICS; (3) When the substrate was located in

a QRS fragmentation (23%) and in two patients a J wave (15.4%) [19].

**4.2. Location of substrate in the longitudinal plane**

and anterior free wall of right ventricle [18].

Brugada et al. during electro-anatomic mapping with administration of a sodium channel blocker showed an increase in the size of the low voltage [18]. In concordance, our observations suggest that the total sum of ST segment elevation during flecainide testing would approximately determine the substrate size. In addition, the ECG leads with greater ST segment elevation would locate the substrate in the RVOT [19].

Morita et al. (145 patients who experienced syncope or had VF events) proposes ECG risk markers for the initial and recurrent episodes of VF in symptomatic patients with BrS. The f-QRS,

**Figure 4.** Correlation between ST segment elevation and substrate localization. A. With the administration of sodium channel blocker, a greater magnitude of total sum of ST segment elevation corresponds to a greater very low voltage area of substrate, and allows its location in the longitudinal plane of RVOT. (a) The location of the substrate in the bottom zone of RVOT correspond to a greater sum of ST segment elevation in fourth ICS vs. third ICS (5 vs. 3 mm). (b) The location of the substrate in the top zone of RVOT correspond to a greater sum of ST segment elevation in third ICS vs. 4th ICS (8 vs. 3 mm). (c) The location of the substrate in the intermediate zone of RVOT corresponds to a sum of ST segment elevation of equal magnitude in third ICS and fourth ICS (8 mm and 8 mm). B. The graph shows the correlation between linear increase of total sum of ST segment elevation and substrate size. The blue bars indicate each patient [19].

inferolateral early repolarization and complete RBBB were associated with occurrence of ventricular tachyarrhythmia in the symptomatic patients [34]. Our population show in three patients a QRS fragmentation (23%) and in two patients a J wave (15.4%) [19].

#### **4.2. Location of substrate in the longitudinal plane**

Although the results of mapping and RFA were good, we do not perform epicardial mapping and do not ignore the possibility that a portion of the substrate can remain present after

In addition, we found pre-systolic potentials as was previously reported by Haissaguerre et al. [15]. We showed with TEM Purkinje fibers in RVOT (**Figures 2** and **3**) [19]. These could be involved in the origin of pre-systolic potentials and genesis of early-onset PVCs that can trigger VT or VF, by spontaneous depolarization or micro-reentry circuit in the Purkinje network [30].

In the BrS the mechanism of ST segment elevation has been explained by the repolarization theory (decreased of Na + and/or Ca++ channel function with a prominent Ito current in epicardium of RVOT generates a transmural voltage gradient), or the depolarization theory (disturbances in depolarization of RVOT can be cause of delayed conduction and ST segment elevation) [18, 20]. Nevertheless, the ECG changes are actually explained by the theorem of solid angle, where a substrate larger increases the magnitude of the ST segment elevation [31]. In 13 patients of high risk we have analyzed QRS complex duration, R wave amplitude in aVR lead, presence of fragmented QRS (f-QRS) and end-QRS slur or notch in DI, aVL, DII, DIII and aVF leads with J point peak ≥0.2 mv with descending ST segment, corresponding to an early repolarization or "J wave" [19]. Before of endocardial mapping the patients were underwent flecainide testing (400 mg, orally) with the purpose of measuring the greatest ST-segment elevation. The partial greatest ST-segment elevation in millimeters (ST-segment elevation in V1 + V2 leads in the third ICS and ST-segment elevation in V1 + V2 + V3 leads in fourth ICS), and total sum of greatest ST-segment elevation (ST segment elevation in V1 + V2 leads in the third ICS plus ST-segment elevation in V1 + V2 + V3 leads in fourth ICS) were measured. (**Figure 4-A**). Correlation between size and location of substrate in the electro-anatomic map and the ST-segment elevation were analyzed. As shown in **Figure 4** and **Table 2**, with a cut-off ≥13 mm in the total sum of ST segment elevation two variants were found: (1) A total sum of ST-segment elevation <13 mm (n = 8, 61.5%, mean

9.6 ± 1.3 mm) corresponded to a central area of substrate of 7.7 ± 1.8 mm2

central area of substrate, with a value >0.90 of ROC curve).

ment elevation would locate the substrate in the RVOT [19].

segment elevation ≥13 mm (n = 5, 38.5%, mean 15 ± 1.1 mm) corresponded to a central area of

Brugada et al. during electro-anatomic mapping with administration of a sodium channel blocker showed an increase in the size of the low voltage [18]. In concordance, our observations suggest that the total sum of ST segment elevation during flecainide testing would approximately determine the substrate size. In addition, the ECG leads with greater ST seg-

Morita et al. (145 patients who experienced syncope or had VF events) proposes ECG risk markers for the initial and recurrent episodes of VF in symptomatic patients with BrS. The f-QRS,

(p < 0.001 for correlation of ST segment elevation and correlation of

; (2) A total sum of ST

ablation.

128 Cardiac Arrhythmias

**4. Electrocardiographic analysis**

substrate of 28.2 ± 9.2 mm2

**4.1. Size of substrate and ST-segment elevation**

Nademanee et al. found functional substrate in the anterior zone of epicardium of RVOT [17]. Brugada et al. in 14 inducible patients reported a functional substrate in epicardium of RVOT and anterior free wall of right ventricle [18].

In our study a high-density endocardial electroanatomical mapping of right ventricle and RVOT was performed [19]. Taking the pulmonary valve as upper limit and the supraventricular crest as lower limit in the longitudinal plane the RVOT was divided in top and bottom. As shown in **Figure 4-A** and Table II, we have found three variants: (1) When the substrate was located in the top region of RVOT, it corresponded with the greater sum of ST-segment elevation in V1-V2 leads in the 3rd ICS (n = 5, 38.5%); (2) When the substrate was located in the bottom region of RVOT (n = 5, 38.5%), it corresponded with the greater sum of ST-segment elevation in V1-V2-V3 leads in the 4th ICS; (3) When the substrate was located in


the intermediate region of RVOT (n = 3, 23%), the sum of ST-segment elevation was of equal

In our study during endocardial electroanatomical mapping, in the transverse plane an anterior, lateral, posterior and septal areas were identified [19]. During endocardial bipolar mapping, the regional depolarization time (RDT) from the endocardial EGM of right ventricular inflow tract (RVIT) recorder by the catheter located at the site of His, until the beginning of endocardial EGM of RVOT, recorded by the catheter located in the RVOT was measured. A value from 0 to 10 ms was considered normal. Moreover, the trans-mural depolarization time (TDT) of RVOT from the beginning of endocardial EGM of RVOT until the end of QRS complex in V2 lead was measured. The TDT measured at DI was considered as normal value. As shown in **Figure 5**, we have found two variants were found: (1) When the substrate was located in the anterior lateral region of RVOT (n = 5, 38.5%), the HV interval measured to DI lead (mean 70.6 ± 24 ms) was longer than the HV interval to V2 lead (mean 50 ± 15 ms). This was accompanied with widening of the QRS complex in its initial and final parts (widening of QRS left and right) in V1 and V2 lead. We defined this as "mixed delay of depolarization of RVOT".

magnitude in the 3rd and 4th ICS (n = 3, 23%).

**Patient ST-segment with Total sum of** 

**V1-V2 leads V1-V2-V3** 

**Third ICS 4TH ICS**

V1 = 2 V1 = 1

V1 = 2 V1 = 1

V1 = 3 V1 = 3

Source: [19].

**leads**

**ST-segment**

>elevation (mm) Elevation (mm) Area (mm2

**11** V2 = 6 V2 = 2 11 8 Top

**12** V2 = 3 V2 = 2 8 8 Top

**13** V2 = 4 V2 = 5 15 25 Intermediate

9.6 ± 1.3

**Table 2.** Correlation between sum of ST-segment elevation, location and size of low voltage area.

V3 = 0 Septal

V3 = 0 Anterior-septal

≥13 (n = 5, 38.5%) 15 ± 1.1 28.2 ± 9.2

V3 = 0 Anterior

**Size of low voltage**

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7.7 ± 1.8

**Location of substrate**

131

) In the longitudinal and

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**Transverse plane**

**4.3. Location of substrate in the transverse plane**

**Mean and SD** 3 ± 1.3 2.3 ± 1.5 <13 (n = 8, 61.5%)

*p* **value** <0.001 <0.001


**Table 2.** Correlation between sum of ST-segment elevation, location and size of low voltage area.

the intermediate region of RVOT (n = 3, 23%), the sum of ST-segment elevation was of equal magnitude in the 3rd and 4th ICS (n = 3, 23%).

#### **4.3. Location of substrate in the transverse plane**

**Patient ST-segment with Total sum of** 

**V1-V2 leads V1-V2-V3** 

**Third ICS 4TH ICS**

V1 = 2 V1 = 2

V1 = 3 V1 = 1

V1 = 2 V1 = 3

V1 = 2 V1 = 1

V1 = 2 V1 = 2

V1 = 2 V1 = 0

V1 = 1 V1 = 1

V1 = 3 V1 = 1

V1 = 2 V1 = 3

V1 = 5 V1 = 1

**leads**

130 Cardiac Arrhythmias

**ST-segment**

>elevation (mm) Elevation (mm) Area (mm2

**1** V2 = 4 V2 = 7 16 36 Bottom

**2** V2 = 4 V2 = 2 10 8 Top

**3** V2 = 3 V2 = 5 14 19 Bottom

**4** V2 = 6 V2 = 5 16 42 Intermediate

**5** V2 = 1 V2 = 2 8 5 Bottom

**6** V2 = 2 V2 = 2 8 5 Intermediate

**7** V2 = 3 V2 = 4 10 8 Bottom

**8** V2 = 5 V2 = 2 11 10 Top

**9** V2 = 3 V2 = 4 13 19 Bottom

**10** V2 = 3 V2 = 2 11 10 Top

V3 = 1 Anterior-lateral

V3 = 0 Anterior-lateral

V3 = 1 Anterior-lateral

V3 = 2 Anterior-lateral

V3 = 1 Anterior-lateral

V3 = 2 Anterior

V3 = 1 Septal

V3 = 0 Anterior

V3 = 0 Anterior

V3 = 1 Anterior-septal

**Size of low voltage**

**Location of substrate**

) In the longitudinal and

**Transverse plane**

In our study during endocardial electroanatomical mapping, in the transverse plane an anterior, lateral, posterior and septal areas were identified [19]. During endocardial bipolar mapping, the regional depolarization time (RDT) from the endocardial EGM of right ventricular inflow tract (RVIT) recorder by the catheter located at the site of His, until the beginning of endocardial EGM of RVOT, recorded by the catheter located in the RVOT was measured. A value from 0 to 10 ms was considered normal. Moreover, the trans-mural depolarization time (TDT) of RVOT from the beginning of endocardial EGM of RVOT until the end of QRS complex in V2 lead was measured. The TDT measured at DI was considered as normal value. As shown in **Figure 5**, we have found two variants were found: (1) When the substrate was located in the anterior lateral region of RVOT (n = 5, 38.5%), the HV interval measured to DI lead (mean 70.6 ± 24 ms) was longer than the HV interval to V2 lead (mean 50 ± 15 ms). This was accompanied with widening of the QRS complex in its initial and final parts (widening of QRS left and right) in V1 and V2 lead. We defined this as "mixed delay of depolarization of RVOT".

**Figure 5.** Location of substrate in transverse plane of RVOT. A. The N°4 patient displays a substrate located in the anterior-lateral zone of RVOT which corresponds to a widening of QRS complex to left and right. The HV interval to DI lead is longer (120 ms) that the HV interval to V2 lead (80 ms), while RDT and TDT are prolonged. B. The N°11 patient displays a substrate located in the septal zone of RVOT which correspond only to a widening of end QRS complex. The HV interval to DI and V2 leads is equal (55 ms) and only TDT is prolonged [19].

Simultaneously, TDT and RDT were prolonged, because early depolarization of RVOT occurs. (2) When the substrate was located only in the anterior part (30.8%), or anterior-septal (15.4%) or exclusively in the septal region (15.4%) of RVOT, the HV interval measured to DI and V2 leads showed no increase in its duration (mean 42.6 ± 6 ms and 41 ± 6.5 ms, respectively) and the widening of QRS was only rightward (widening QRS rightward). Moreover, the endocardial EGM of RVIT and RVOT, and beginning of QRS complex in DI-V1-V2 lead they were activated simultaneously, indicating that there is no RDT delay, while TDT of RVOT was prolonged of dynamic manner. We defined this as "end delay depolarization of RVOT".

endocardium correlated with the presence of end-QRS notching or slurring pattern in inferior or/and lateral leads by slow conduction. As shown in **Figure 6 A** and **B** the endocardial RFA of substrate produced their disappearance [19]. Normally the epicardium is electropositive with respect to electronegative endocardium creating a current flow of endocardium to epicardium. When activation spreads from endocardium to epicardium, in a context of slow conduction, the J wave coincides with the notch in the epicardial AP mediated by the Ito current and it is recorded by ECG. Conversely, when the activation begins in the epicardium, the J wave disappears hidden by the QRS complex [33]. Consequently, our observations lead us to think that the J wave depends more of late depolarization that early repolarization as was suggested by other authors.

**Figure 6.** RFA effects on the ECG. A. The N°7 patient displays a substrate located in bottom septal zone of RVOT. Before RFA a type 2 ECG BrS pattern, end-QRS notch in aVL lead and slurred S wave in DII, DIII and aVF leads are present. It disappears after RFA (red arrows). B. The N°11 patient displays a substrate in the top septal zone of RVOT. Before RFA a type 1 ECG BrS pattern and end-QRS slur in DI and aVL leads are present. It disappears after RFA (red arrows). C. Before RFA the flecainide test showed a type 1 ECG BrS pattern. The QRS complex duration in V1 and V2 leads was 180 ms, while in DI was 90 ms (red lines). Immediately after ablation, the duration of QRS complex in V2 lead decreased to 90 ms and ECG BrS pattern disappears (red arrows). After RFA the flecainide test not induced type 1 ECG BrS pattern.

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Endocardial and epicardial RFA has been proposed as a new strategy to prevent SCD and VT/VF in BrS patients of high risk. Nademanee et al. found what RFA on prolonged and

**5. Effects of RFA on the ECG BrS pattern and substrate**

The ECG at 3.8 years follow-up persist normal [19].

Was report that 11% of patients with BrS have early repolarization pattern in the inferior-lateral leads and a more severe phenotype [32]. Interestingly, as shown in **Figure 6** we found in two patients who had a substrate of exclusively septal location, showed end-QRS notching or slurring pattern. When the substrate was located in the bottom-septal zone of RVOT (patient N°7) only end-QRS notch in aVL lead and slurred S-wave in DII, DIII and a VF leads was observed (**Figure 6-A**). Whereas, when the substrate was located in the top-septal zone of RVOT (patient N°11) an end-QRS slur in DI and aVL leads was observed (**Figure 6-B**). Our observations suggest that a location of substrate in septal region of RVOT, with beginning of the depolarization at the

**Figure 6.** RFA effects on the ECG. A. The N°7 patient displays a substrate located in bottom septal zone of RVOT. Before RFA a type 2 ECG BrS pattern, end-QRS notch in aVL lead and slurred S wave in DII, DIII and aVF leads are present. It disappears after RFA (red arrows). B. The N°11 patient displays a substrate in the top septal zone of RVOT. Before RFA a type 1 ECG BrS pattern and end-QRS slur in DI and aVL leads are present. It disappears after RFA (red arrows). C. Before RFA the flecainide test showed a type 1 ECG BrS pattern. The QRS complex duration in V1 and V2 leads was 180 ms, while in DI was 90 ms (red lines). Immediately after ablation, the duration of QRS complex in V2 lead decreased to 90 ms and ECG BrS pattern disappears (red arrows). After RFA the flecainide test not induced type 1 ECG BrS pattern. The ECG at 3.8 years follow-up persist normal [19].

endocardium correlated with the presence of end-QRS notching or slurring pattern in inferior or/and lateral leads by slow conduction. As shown in **Figure 6 A** and **B** the endocardial RFA of substrate produced their disappearance [19]. Normally the epicardium is electropositive with respect to electronegative endocardium creating a current flow of endocardium to epicardium. When activation spreads from endocardium to epicardium, in a context of slow conduction, the J wave coincides with the notch in the epicardial AP mediated by the Ito current and it is recorded by ECG. Conversely, when the activation begins in the epicardium, the J wave disappears hidden by the QRS complex [33]. Consequently, our observations lead us to think that the J wave depends more of late depolarization that early repolarization as was suggested by other authors.
