Heart Rhythm



SUPPLEMENTARY MATERIALNew Electro-Mechanical Substrate Abnormalities in High-Risk Patients with Brugada SyndromeSupplementary MethodsInvestigational protocolPatients were included if they fulfilled the following criteria: age > 18 years; spontaneous or Ajmaline-induced type 1 ECG pattern; ICD implantation. Patients with any sign of arrhythmogenic RV cardiomyopathy by clinical history, physical examination and non-invasive testing, including 2D and Doppler transthoracic echocardiography, ergometric testing and cardiac magnetic resonance, were excluded. Likewise, those with abnormal LV function or with frequent atrial/ventricular premature beats or poor apical acoustic windows, complicating the echocardiographic imaging acquisition, were also excluded. The investigational protocol also included ajmaline administration (1 mg/kg in 5 minutes) to induce a stable type 1 ECG pattern in all patients. After enrollment, all patients underwent a standardized multimodality myocardial imaging protocol before and after Ajmaline provocation. We stopped Ajmaline administration if patients had significant QRS widening (≥ 130%), second- or third-degree AV block, or occurrence of frequent PVCs. The protocol included 3D echocardiography with 3D motion/deformation quantification imaging, 3D electroanatomical substrate mapping, and epicardial ablation. Fifty age- and sex-matched non-affected healthy individuals recruited during a family screening of individuals with a family history of BrS, but not sudden cardiac death, with a normal ECG, and negative genetic and Ajmaline testing, served as controls to obtain normal 3D RV motion/deformation patterns. Two experienced operators blinded for clinical data examined echocardiographic parameters and three-dimensional deformation patterns. Patients and controls were managed in accordance with the Declaration of Helsinki and provided informed consent for anonymous publication of scientific data. The institutional Ethics Committee approved the study protocol. All authors had full access to all the data in the study and take responsibility for its integrity and the data analysis.Transthoracic echocardiography Three-dimensional transthoracic acquisition was performed while the patient was awake using VIVID E9 ultrasound system and a 4V-D transducer (GE Healthcare, Norway) in the standard apical positions, with the patient in lateral left decubitus. Full volume acquisition of the right ventricle was performed using a multi-slice (twelve) ECG-gated acquisition over 4 cardiac cycles, during a breath-hold from an apical 4-chamber view focused on the RV. 3D data sets were stored, and then offline post-processed using a commercial dedicated software for the analysis of RV function (4D RV Function 2.0, TOMTEC Imaging Systems GmbH, Unterschleissheim, Germany) which, tracking the endocardial borders of the right ventricle, enables a complete assessment of its geometry, volumes and ejection fraction displaying the entire right ventricle including the inflow, the apex, and the outflow tracts. A wide angle of acquisition was taken to include the full RV volume and frame rate was optimized to > 25 Hz as required for adequate tracking of the endocardial borders and quantification of RV function by using a dedicated RV software (4D RV Function 2.0, TOMTEC Imaging Systems GmbH, Unterschleissheim, Germany). The 3D RV motion and deformation patterns were assessed over 4 cardiac cycles, before and after Ajmaline testing. The triangulated RV surface, provided by speckle tracking over time, consisted of a fixed number of triangles and vertexes arranged according to the same scheme. The following 3D wall motion/deformation parameters were defined according to Haddad et al (1), and regionally evaluated (Supplementary Figure 1) with respect to the initial end-diastolic RV configuration (t=0): i) areal strain (εA), the percentage change in the corresponding surface area of every triangle (Supplementary Figure 2); ii) normal displacement (U, expressed in mm), the component of each 3D vertex displacement aligned with the local outward normal to the RV endocardial surface (U < 0 and U > 0 represented inward and outward motion of the wall, respectively, Supplementary Figure 3); and iii) percentage minimum principal strain (εII), providing the maximum local RV myocardial shortening for every element of the RV endocardial surface (Supplementary Figures 4 and 5). For the normal displacement, baseline to post-Ajmaline changes (ΔU) lower than 2 mm were considered irrelevant, consistent with the millimetric space-resolution of ultrasound data. ΔU<-2 mm and ΔU>2 mm were associated with a relevant increase and decrease, respectively, of the inward systolic RV wall motion (Supplementary Figure 6). The extent of the area affected by worsening of the inward systolic motion of the wall (i.e., by ΔU >2mm) was quantified focusing on the regions of the anterior, lateral and outflow tract regions of the RV free wall.The echocardiographic measurements were repeated by the same echocardiographer to assess intraobserver reproducibility. Inter-observer reproducibility was assessed by a second observer who was blind to the first observer’s measurements. Substrate mappingElectroanatomic endocardial and epicardial 3D mapping was performed under general anesthesia. An invasive arterial pressure line was obtained through radial artery access. ECG was continuously recorded during the procedure. After femoral venous access, a multipolar diagnostic catheter was positioned at the RV apex. High-density color-coded endocardial and epicardial electroanatomical maps (EAM) were performed. Data were recorded and analyzed simultaneously as regard to amplitude, duration, relation to surface QRS, and presence of multiple components. The catheter was placed at multiple sites on the endocardial surface to record bipolar electrograms from RV inflow, anterior free wall, apex, and outflow. Epicardial mapping was performed after endocardial mapping, in order to adequately define the RV boundaries when mapping the epicardium. Epicardial RV mapping and ablation catheter manipulation were performed during sinus rhythm and were facilitated by a steerable sheath (Agilis St Jude Medical, St Paul, MN, USA). Details and definition of abnormal electrograms are reported in the Supplementary Appendix. Supplementary Figure 5 shows an example of the identification of an arrhythmic substrate and the corresponding motion/deformation patterns before and after Ajmaline provocation. Abnormal electrograms were annotated before and after Ajmaline and defined as those with amplitude ranging from 0.05 to 1.5 mV and/or associated wide duration (>110 ms), multiple (>2) or delayed components extending beyond the end of the QRS complex >200 ms. Bipolar EGMs were filtered from 16 to 500 Hz with 0.32- to 0.39-mV gain and displayed at 200 mm/s speed. Electrograms with <0.5 mV and without delayed components were considered as low-voltage and with <0.1mV as scar tissue after ablation. EGMs were acquired only from the electrode pairs of the decapolar catheter DECANAV (Biosense Webster). All electrodes have a 1-mm dimension, except for the tip, which is 2 mm, with the smallest interelectrode distance (2 mm) limiting the possibility to consider noise as late activity. All acquisitions have been performed only if the multipolar catheter was stable in each epicardial position, in the setting of a dry epicardium (all liquid manually drained). EGM morphology, evaluated by expert operators, was considered only if consistent and repetitive for at least 5 consecutive beats, thus avoiding artifacts. Acquisition was excluded if the technical quality was insufficient or if catheter-induced extrasystoles occurred.DefinitionsSyncope, aborted cardiac arrest and/or nocturnal agonal respiration due to sustained VT/VF were considered as BrS-related symptoms. Typical BrS ECG pattern was considered a spontaneous or ajmaline-induced coved-type ST elevation of ≥2 mm as documented in >1 lead from V1 to V3 positioned in the second, third, or fourth intercostal space. Because of the variable nature of the BrS-ECG pattern, BrS patients were classified according to their ECG at the time of the presentation and included a spontaneous type 1 BrS-ECG pattern or a concealed BrS-ECG pattern. Major complications were defined as those life-threatening or requiring a prolonged hospitalization.Intra-Observer and Inter-Observer ReproducibilityFor intra-observer and inter-observer reproducibility, Pearson’s correlations for RV ejection fraction were r=0.95 (P<0.001) and r=0.84 (P<0.001), respectively. The limits of agreement for intra-observer and inter-observer reproducibility were -1.5% to 3.7% and -3.7% to 5.9%, respectively.Statistical AnalysisMultivariate analysis: the model was estimated using the stepwise backward method (Wald’s test). A variable was entered into the model if the probability of its score was statistically less significant than the entry value (P<0.05), and a variable was removed if the probability was not significant (P=0.10). For the selection of the variables to be included in the multivariate model, we chose P=0.2 (which is a lax criterion) because variables may contribute to a multiple regression model in unforeseen ways, due to complex interrelationships among variables. Covariates included in the analysis were age, type 1 BrS ECG pattern, syncope, and the total area of RV dysfunction. The coefficients obtained from the logistic regression analyses were also expressed in terms of odds of occurrence of an event.Supplementary Reference1. Haddad F, Hunt SA, Rosenthal DN, Murphy DJ. Right Ventricular Function in Cardiovascular Disease, Part I. Anatomy, Physiology, Aging, and Functional Assessment of the Right Ventricle. Circulation. 2008; 117:1436-48.Supplementary TableSupplementary Table 1. Characteristics of BrS patients according to the spontaneous baseline ECG pattern, as compared to controlsCharacteristicsBrS patients (N=50)Controls (N=50)P-valueaP-valuebAllType 1 BrS-ECG patternYes (N=20)No (N=30)Mean age (±SD) – yr42±7.239±5.643±7.741±8.90.6060.034Male sex – no. (%)42 (84)18 (90)24 (80)42 (84)1.0000.450Family history for SCD – no. (%)13 (26)8 (40)7 (23)--0.228Positive genetic testing – no. (%)9 (18)6 (30)3 (10)--0.130Secondary prevention35 (70)16 (80)19 (63.3)--0.208Nocturnal agonal respiration – no. (%)4 (8)4 (20)0 (0)--0.021Dyspnea – no. (%)12 (24)2 (10)10 (33.3)--0.058Palpitations – no. (%)15 (30)4 (20)11 (36.7)--0.208Dizziness – no. (%)9 (18)4 (20)5 (16.7)--0.764Pre-syncope – no. (%)4 (8)2 (10)2 (6.7)--1.000Syncope – no. (%)23 (46)16 (80)7 (23.3)--<0.001Inducible VT/VF – no. (%)50 (100)20 (100)30 (100)---ICD – no. (%)50 (100)20 (100)30 (100)---SCD=sudden cardiac deatha BrS patients vs. controls; b Between BrS patients with and without type 1 spontaneous ECG patternSupplementary Table 2. SCN5A gene mutations in 9 patients with and without spontaneous BrS ECG patternMutations have been identified with NGS technique (TruSight panel by Illumina, kit by Agilent company with a medium coverage of 102x). Each mutation has been confirmed with Sanger sequencing.MutationGeneZygosityPhenotypeECG patternPublishedc.1140+2T>CSCN5AHeterozygousAborted cardiac arrestSpontaneous type 1Noc.1144C>T SCN5AHeterozygousAsymptomaticVT/VF inducibilityInduced by AjmalineNoc.4867C>GSCN5AHeterozygousAsymptomaticVT/VF inducibilitySpontaneous type 1Noc.2678G>T SCN5AHeterozygousSyncopeSpontaneous type 1Noc.3946C>TSCN5AHeterozygousSyncopeSpontaneous type 1Noc.4285G>A SCN5AHeterozygousAsymptomaticVT/VF inducibilitySpontaneous type 1Noc.4700_4701delSCN5AHeterozygousSyncope Induced by AjmalinePMID 32131430c.86_87delinsTGSCN5AHeterozygousSyncopeInduced by AjmalineNoc.3840+1G>ASCN5AHeterozygousAborted cardiac arrestSpontaneous type 1NoSupplementary Table 3. Electrocardiographic and echocardiographic changes before and after Ajmaline, as compared to control subjectsBrS Patients (N=50)Control subjects (N=50)BaselineAjmalineP-valueaBaselineAjmalineP-valueaP-valuebP-valuecHR, (bpm)73.8±14.180.3±16.2<0.00172.5±16.881.0±15.1<0.0010.6950.823PR, ms)192.4±35.4216.7±43.4<0.001181.9±30.3214.4±28.4<0.0010.1140.759QRS, (ms)98.1±16.5110.8±16.6<0.00187.4±14.7104.9±18.1<0.0010.0010.097QTc, (ms)394.4±46.4432.2±58.2<0.001388.6±25.9421.1±34.3<00010.4420.250ST, (mV)0.165±0.0650.318±0.072<0.0010.029±0.0020.029±0.0030.879<0.001<0.001RV EDV80.5±14.682.0±13.90.28372.9±15.672.6±17.00.8220.0140.003RV ESV35.1±8.144.9±9.1<0.00132.2±8.433.0±8.60.2710.081<0.001RV Sv45.4±8.836.9±6.8<0.00140.8±7.940.2±9.20.3790.0070.045RV EF 3D55.8±4.545.3±3.4<0.00156.5±4.155.7±3.20.1190.456<0.001RV EDD basal24.7±2.7?-24.1±3.4?-0.360?RV EDD medium34.2±4.0?-34.2±5.1?-0.969?RV LD76.9±6.4?-73.4±9.5?-0.037?TAPSE18.8±3.417.9±3.10.00117.9±3.117.5±2.10.1480.1830.462FAC45.4±5.441.6±5.5<0.00146.6±4.446.3±5.20.6500.235<0.001LV EDV80.4±12.979.8±12.60.28877.0±14.376.6±14.10.7120.2070.232LV ESV31.4±7.132.0±7.10.16030.9±7.131.5±6.50.1450.7040.716LV SV50.2±9.149.3±8.60.16847.0±10.046.3±9.60.2110.1010.103LV EF 2D59.7±4.659.5±5.00.66258.1±5.258.4±4.40.6520.1050.212HR, heart rate; RV, right ventricle; EDV, end-diastolic volume; ESV, end-systolic volume; SV, stroke volume; EF, ejection fraction; EDD, end-diastolic diameter; LD, longitudinal diameter; TAPSE, tricuspid annular plane systolic excursion; FAC, fractional area change; LV, left ventricle. a Baseline vs. Ajmaline; b Between baseline values of the two groups; c Between Ajmaline values of the two groups.Supplementary Table 4. ECG, echocardiographic and electrophysiological changes before and after Ajmaline, according to spontaneous BrS ECG patternType 1 BrS-ECG patternYes (N=20)No (N=30)BaselineAjmalineP-valueaBaselineAjmalineP-valueaP-valuebP-valuecHR (bpm)72.9±12.683.7±18.8<0.00174.3±15.278.1±14.00.0020.7280.231PR (ms)200.4±35.3219.6±39.8<0.001187.1±35.0214.8±46.2<0.0010.1960.704QRS (ms)104.4±18.9116.3±20.8<0.00194.0±13.3107.1±12.2<0.0010.0270.054QTc (ms)406.0±34.5442.3±60.20.003386.6±51.9425.5±56.8<0.0010.1490.322ST (mV)0.226±0.0250.295±0.038<0.0010.124±0.0480.334±0.085<0.001<0.0010.058RV EDV83.0±13.085.3±10.30.31478.8±15.579.7±15.70.5940.3180.167RV ESV36.9±7.347.5±7.9<0.00133.9±8.543.1±9.5<0.0010.1980.094RV Sv46.3±9.736.9±4.3<0.00144.9±8.236.9±8.1<0.0010.5810.965RV EF 3D53.7±4.844.6±3.6<0.00157.2±3.745.8±3.2<0.0010.0050.218Substrate Area (cm2) 15.0±1.325.6±1.7<0.0012.3±1.117.0±5.7<0.001<0.001<0.001HR, heart rate; RV, right ventricle; EDV, end-diastolic volume; ESV, end-systolic volume; SV, stroke volume; EF, ejection fraction. a Baseline vs. Ajmaline; b Between baseline values of the two groups; c Between Ajmaline values of the two groups.Supplementary Table 5. Right ventricle mechanical changes after substrate ablationBrS Patients (N=50)BaselineAjmalineP-valueNormal displacement Anterior Absolute values, mm Time to peak, ms-3.61±1.2539±5-3.56±1.1839±50.2700.112 Lateral Absolute values, mm Time to peak, ms-9.55±1.4338±5-9.44±1.3538±40.1520.216 RVOT Absolute values, mm Time to peak, ms-6.55±1.4740±5-6.50±1.4140±30.3540.197 Inferior Absolute values, mm Time to peak, ms-6.45±0.9139±4-6.30±0.7939±40.1050.096Areal strain Anterior Absolute values, % Time to peak, ms-40.36±7.0139±5-39.74±5.8839±40.1590.160 Lateral Absolute values, % Time to peak, ms-48.60±5.3039±5-47.44±4.5540±50.1640.140 RVOT Absolute values, % Time to peak, ms-27.51±5.9940±5-26.85±5.2640±30.0860.670 Inferior Absolute values, % Time to peak, ms-42.32±6.7938±4-41.32±5.5839±40.0900.190Minimum principal strain Anterior Absolute values, % Time to peak, ms-34.24±5.9939±5-33.68±4.4740±40.3490.108 Lateral Absolute values, % Time to peak, ms-40.02±3.9938±4-39.72±3.69 39±40.1600.200 RVOT Absolute values, % Time to peak, ms-24.47±2.7839±5-24.22±2.5240±40.1820.186 Inferior Absolute values, % Time to peak, ms-34.05±4.3737±4-34.97±2.4638±50.1070.094RVOT, right ventricular outflow tract.Supplementary FiguresSupplementary Figure 1. Anatomical clustering of the RV endocardial free wall. A triangulated surface of the RV anatomy was extracted over time from 4D RV Function analysis (TOMTEC Imaging Systems GmbH, Unterschleissheim, Germany); it consists of a fixed number of triangles (1872) and vertexes (938) arranged according to the same scheme for each subject and every time-point throughout the cardiac cycle. Anatomical clustering into RV regions was performed according to Haddad et al (1).Supplementary Figure 2. Regional quantification of RV area strain.Area strain (εA) was computed as the percentage change in the surface of RV regions (i.e., current frame i) with respect to their initial end- diastolic configuration (frame 0).Supplementary Figure 3. Definition of inward/outward displacement (U).For each vertex, U is updated through time computing the component un,i of the current 3D displacement (ui) aligned with the local outward normal (ni-1) to the RV endocardial surface. Thus, the time course of U is obtained with respect to the initial end-diastolic RV configuration (frame 0) from the summation of all the un,i contributions. By definition, inward and outward wall displacement correspond to negative (U<0) and positive (U<0) values, respectively.Supplementary Figure 4. Definition of minimum principal strain (εII).For each triangular element, the strain tensor ε is numerically computed in the cartesian coordinate system of the element and the principal strain tensor is computed as eigenvalues of ε. The second component εII is the minimum principal strain and represents a geometry-independent measure of tissue contraction, established from the dominant (i.e., principal) directions of local tissue deformationSupplementary Figure 5. Minimum principal strain distribution.Minimum Principal strain (εII) distribution over the RV endocardial wall computed at baseline (top) and after ajmaline (bottom) in a control subject (left panel) and a BrS patient (right panel), respectively. Strain data, expressed as percentage values, were complemented by ECG while substrate 3D mapping is reported for BrS only. εII, Minimum principal strain.Supplementary Figure 6. Analysis of the inward/outward displacement (U) along the local outward normal to the RV endocardial surface.a) Baseline to post-ajmaline changes (ΔU) computed at peak systole in a BrS (top) and a control (bottom) patient with ΔU<0 and ΔU>0 corresponding to an increase and decrease, respectively, of the inward systolic motion of the RV wall. b) Clustering of ΔU baseline to post-ajmaline changes: ΔU was irrelevant in the range of tolerance ± 2 mm while ΔU > 2 mm resulted in relevant decrease of the inward systolic motion of the RV wall. U, inward/outward displacement; ΔU, baseline to post-ajmaline inward/outward displacement change.Supplementary Figure 7. Pre- and post-ablation epicardial voltage maps of the arrhythmic substrate.Epicardial potential duration maps at baseline (left), after ajmaline (middle) and after RF ablation (right). The area of abnormally prolonged fractioned electrograms was 15.2 cm2 at baseline and increased to 21.1 cm2 after ajmaline (middle panel). The bottom panels show epicardial voltage maps before/after ablation. Before ablation (left), there were no low voltage areas in the epicardium (1.55±0.98 mV). After ablation, voltage maps showed only 2 small low voltage areas (6.8 cm2 and 1 cm2; middle and right panels, respectively), the redo color representing the smaller area with the lowest voltage (< 0.5mV).Supplementary Figure 8. Pre- and post-ablation voltage maps as in Figure S7.Before ablation the size of the arrhythmic substrate was 20.6 cm2 (middle) corresponding to a normal voltage area (1.21±0.74 mV). After ablation, the voltage map showed only 2 small areas of low voltage. The first area (green color in CARTO bipolar voltage map) was 6.6 cm2 in size (<0.8mV) while the second area (<0.5mV) was even smaller (1.4 cm2 in red color in CARTO bipolar map). ................
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