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The role of clinical assessment and electrophysiology study in Brugada syndrome patients with syncope
Journal Pre-proof The role of clinical assessment and electrophysiology study in Brugada Syndrome patients with syncope
Jaime Hernandez-Ojeda, Elena Arbelo, Paloma Jorda, Roger Borras, Oscar Campuzano, Georgia Sarquella-Brugada, Anna Iglesias, Lluis Mont, Ramon Brugada, Josep Brugada PII:
S0002-8703(19)30298-4
DOI:
https://doi.org/10.1016/j.ahj.2019.10.016
Reference:
YMHJ 6007
To appear in:
American Heart Journal
Received date:
12 April 2019
Accepted date:
12 October 2019
Please cite this article as: J. Hernandez-Ojeda, E. Arbelo, P. Jorda, et al., The role of clinical assessment and electrophysiology study in Brugada Syndrome patients with syncope, American Heart Journal(2019), https://doi.org/10.1016/j.ahj.2019.10.016
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© 2019 Published by Elsevier.
Journal Pre-proof The role of clinical assessment and electrophysiology study in Brugada Syndrome patients with syncope Jaime Hernandez-Ojeda MD PhDa,b*, Elena Arbelo MD PhDa,b,c*, Paloma Jorda MDa,b, Roger Borras MSca,b, Oscar Campuzano BSc PhDc,d,e, Georgia Sarquella-Brugada MD PhDe,f, Anna Iglesias PhDc,d,e, Lluis Mont MD PhDa,b,c, Ramon Brugada MD PhD c,d,e,g, Josep Brugada MD PhDa,b,c,f *Both authors contributed equally to this work
Arrhythmia Section, Cardiology Department, Hospital Clínic, Universitat de Barcelona.
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Barcelona (Spain). b
IDIBAPS, Institut d’Investigació August Pi i Sunyer (IDIBAPS). Barcelona (Spain).
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Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV),
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Madrid (Spain) d
Cardiovascular Genetics Center, University of Girona-IDIBGI, Girona (Spain)
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Medical Science Department, School of Medicine, University of Girona, Girona (Spain)
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Arrhythmia Unit, Hospital Sant Joan de Déu, University of Barcelona, Barcelona (Spain)
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Cardiology Service, Hospital Josep Trueta, Girona (Spain)
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Funding: This work was supported by Instituto de Salud Carlos III (FIS PI16/01203 and PI17/01690) co-funded by the European Regional Development Fund (ERDF) and the European Social Found (ESF) “Investing in Your Future”. The CERCA Programme (Centres de Recerca de Catalunya) of the Generalitat de Catalunya; Daniel Bravo Andreu Foundation; and Obra Social "La Caixa".
Diclosures: none
Corresponding author: Jaime Hernandez-Ojeda, MD, PhD Hospital Clínic de Barcelona C/ Villarroel 170, 6º, escala 3 08036 Barcelona Ph: (+34) 93 227 5551; Fax: (+34) 93 4513045 1
Journal Pre-proof Email: [email protected] ABSTRACT Background: Cardiogenic syncope in Brugada syndrome (BrS) increases the risk of major events. Nevertheless, clinical differentiation between cardiogenic and vasovagal syncope can be challenging. We characterized the long-term incidence of major events in a large cohort of BrS patients presented with syncope.
Methods: From a total of 474 patients, syncope was the initial manifestation in 135 (28.5%) individuals (43.9±13.9 years, 71.1% male). The syncope was classified prospectively in
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cardiogenic, vasovagal or undefined if unclear characteristics were present. Clinical, electrocardiographic, genetic and electrophysiologic features were analyzed. Cardiogenic
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syncope, sustained ventricular arrhythmias and sudden death were considered major events in
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follow-up.
Results: In 66 patients (48.9%) the syncope was cardiogenic, in 51 (37.8%) vasovagal and in
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18 (13.3%) undefined. The electrophysiology study (EPS) inducibility was more frequent in patients with cardiogenic syncope and absent in all patients with undefined syncope
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(28[53.8%] vs. 5[12.2%] vs 0[0%]; p<0.01). During follow-up (7.7±5.6 years), only patients with cardiogenic syncope presented major events (16 [11.9%]). Among patients with
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inducible EPS, 7 (21.2%) presented major events (p=0.04). The negative predictive value of
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the EPS for major events was 92.4%. The incidence rate of major events was 2.6% personyear. Parameters associated with major events included cardiogenic syncope (HR 6.3;95% IC 1.1-10.4;p=0.05); spontaneous type 1 ECG (HR 3.7;95% IC 1.3-10.5;p=0.01); and inducible EPS (HR 2.8;95% IC 1.1-8.8;p=0.05).
Conclusions: An accurate syncope classification is crucial in BrS patients for risk stratification. In patients with syncope of unclear characteristics the EPS may be helpful to prevent unnecessary implantable cardioverter defibrillators.
KEYWORDS: risk stratification, electrophysiology study, implantable cardioverter defibrillator, sudden death, ventricular arrhythmias.
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HIGHLIGHTS
This is a cohort with the longest follow-up of BrS patients presented with syncope.
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Major events occurred only in patients with cardiogenic syncope.
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An accurate classification of the syncope allowed an appropriate risk stratification.
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No major events were present in patients with undefined syncope and non-inducible EPS.
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EPS may be helpful to prevent unnecessary ICDs in patients with undefined syncope.
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ABBREVIATIONS
BrS = Brugada syndrome ECG = electrocardiogram SD = sudden death VT = ventricular tachycardia VF = ventricular fibrillation
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EPS = electrophysiology study ICD = implantable cardioverter defibrillator
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VA = ventricular arrhythmias
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TTT = tilt-table test
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AF = atrial fibrillation
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ATP = antitachycardia pacing
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Journal Pre-proof BACKGROUND
Brugada syndrome (BrS) is a cardiac disease characterized by a ST-segment elevation in the right precordial electrocardiogram (ECG) leads, which predisposes to sudden death (SD) due to polymorphic ventricular tachycardia (VT) or ventricular fibrillation (VF) in the absence of structural heart disease (1). In BrS patients presented with cardiogenic syncope the major event rate per year has been estimated to be 0–1.9% (2-4). This rate increases to 4.9-6.4% in the presence of spontaneous type 1 ECG (5); and to 27.2% in the presence of both spontaneous type 1 ECG and inducible
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electrophysiology study (EPS) (4). On the other hand, a higher susceptibility to vasovagal syncope has been reported in BrS patients, probably due to an associated autonomic dysfunction(6).
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The treatment of choice in BrS patients who have experienced a prior cardiac arrest or
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syncopal events secondary to ventricular arrhythmias (VA) is an implantable cardioverter defibrillator (ICD) (7, 8). The therapeutic strategy is of major importance in these patients as
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there may be device-related complications during the course of decades of expected use, including inappropriate shocks and lead-related problems, which subsequently might lead to
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morbidity and reduced quality of life (4, 5, 9-12).
The aim of the study was to characterize the prevalence of cardiogenic and vasovagal syncope
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of BrS patients over 20 years of experience in our centre, to evaluate the therapeutic strategy
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performed and to analyse the long-term follow-up of these patients.
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Journal Pre-proof METHODS
Study population From January 1994 to December 2017, all >18 year-old patients with syncope diagnosed of BrS in our center were included consecutively and followed-up prospectively. Data collection was done after approval from the medical ethics committee in our institution. All patients signed the informed consent. BrS was diagnosed in the presence of a type 1 Brugada pattern on the ECG (coved-type), either at baseline or after the administration of a sodium channel-blocking agent, in the
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absence of any structural cardiomyopathy (2). A type 1 ECG pattern was defined as the
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presence of a terminal r’ wave with a J-point elevation of ≥0.2 mV, with a slowly descending ST segment followed by a negative T wave in ≥1 right precordial lead (V1-V3), placed in the
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4th, 3rd or 2nd intercostal space. Flecainide (2 mg/kg) or ajmaline (1 mg/kg) were administered
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intravenously over a 10-minute period to unmask the diagnostic ECG pattern of BrS in case of a non-diagnostic baseline ECG. All ECGs were registered in a paper velocity of 25 mm/s
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and 10 mm/mV of amplitude, with right precordial leads in both sternal edges positioned at 4 th and 3rd intercostal spaces (from 2012 onwards, the 2nd intercostal space was also recorded).
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All ECGs were independently analysed by 2 experienced electrophysiologists; in case of disagreement another experienced faculty was consulted. In all patients, significant structural
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cardiomyopathy was ruled out by transthoracic echocardiogram and, in case of suspicious
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findings, by cardiac magnetic resonance.
Initial work-up and management All patients diagnosed of BrS who had experienced syncope by the time of diagnosis underwent to a detailed medical history interview consisted of a standardized systematic history taking including age at diagnosis, gender, race and family history of SD or BrS. A family history of SD was defined as a SD ≤55 years in ≥1 family members of 1 st or 2nd degree. A specific questionnaire of the event was performed by the time of diagnosis in each patient to determine the type of syncope which included: number of previous syncope events; specific triggers; presence of prodromes characterized by diaphoresis, epigastric discomfort, extreme fatigue, weakness, yawning, nausea, dizziness, and vertigo lasting seconds to several minutes; duration of the loss of conscience; presence of fever and/or palpitations preceding the episodes; activity during the syncope; associated trauma; and current medications. 6
Journal Pre-proof Syncopal episodes were independently classified in a prospective manner by 2 experienced electrophysiologists specialized in Genetic Arrhythmias in cardiogenic or vasovagal. In case of disagreement another expert faculty was consulted. A cardiogenic syncope was defined in case of absent or brief prodrome (<10 seconds), absence of specific triggering circumstance, brief loss of consciousness (<1 minute), and fast return to consciousness. If the event did not accomplish all these criteria was defined as vasovagal. If >1 of these characteristics were not possible to obtain and/or the event could not be well defined, the syncope was classified as undefined. Patients with multiple events were classified according to the event of highest severity after an exhaustive analysis of each event occurred.
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Genetic test was recommended to all patients; following the guidelines, SCN5A (Nav1.5) was analyzed in all samples (until 2012 using Sanger technology and from 2012 to date, through NGS technology). An EPS was performed in all BrS patients with syncope before 2005,
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unless patient’s rejection. From 2005 onwards, according to the second Brugada consensus
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conference recommendations (13), the EPS was not performed in some patients with clearly cardiogenic syncope who underwent to an ICD implant with no EPS. The EPS included basal
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measurements of conduction intervals and programmed ventricular stimulation. The protocol recommended used a single site of stimulation (right ventricular apex), three basic pacing
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cycle lengths (600, 500, and 430 ms), and induction of 1, 2, and 3 ventricular premature beats down to a minimum of 200 ms. A patient was considered inducible if sustained VA (VF,
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polymorphic VT or monomorphic VT lasting more than 30 seconds or requiring emergency intervention) were induced.
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A tilt-table test (TTT) was performed according to medical criteria in patients with a likely vasovagal syncope if the classification remained doubtful after obtaining the clinical information of the event. The protocol involved 2 phases placing the patient on a flat table with foot support then tilting the table upward at 70-degree angle: a first passive unmedicated phase of 20 minutes and an additional phase of 20 minutes after application 400 µg of sublingual nitroglycerine. During the test, blood pressure, heart rate, oxygen saturation, and cardiac rhythms were recorded and monitored for the end point of fainting, which indicated a positive TTT result. A positive test with a cardioinhibitory response was defined when syncope was related to a decrease of heart rate. A positive test with a vasodilator response was defined when syncope occurred due to reduce of blood pressure. From 2005 onwards, ICD therapy indications were determined according to the second Brugada consensus conference recommendations (13). Single or dual-chamber devices were indicated based on the presence of sinus node dysfunction or AV conduction abnormalities. 7
Journal Pre-proof The detection of all ICDs was standardized with a single VF zone programmed to 18 out of 24 events at an interval shorter ≤300 ms, or a ventricular rate ≥200 bpm, treated with 1 rapid burst of antitachycardia pacing (ATP) in the VF zone while charging (if available) and 3 shocks with maximum output. Subcutaneous ICDs were implanted (if available) after a correct basal ECG screening test in the absence of pacing requirements. Loop-recorder implant was decided individually according with clinical presentation, family history and consensual decision with the patient.
Follow-up
and,
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The follow-up assessment included a careful analysis of the patient’s history, 12-lead ECG complementary
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echocardiography and 24h-holter monitoring. Patients were seen in the dedicated
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Cardiogenetic Outpatient Clinic annually or earlier depending on the clinical evolution; in
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case of having an ICD implanted, they were also evaluated every 6-12 months in the ICD Clinic (unless shorter periods of follow-up were required). Patients with ICD remote
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monitoring capabilities were interrogated transtelephonically every 3 months and in the event of any device alert. In case of a loop- recorder implant, patients were followed every 3
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months. Patients with a follow-up of less than 6 months were excluded. The occurrence of device-related complications was also registered. A major event was defined as the presence
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of SD, cardiogenic syncope in patients without ICD and/or documented sustained VA (monomorphic VT, polymorphic VT and/or VF). In patients with ICD, sustained VA were
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defined as VA that completed the standardized ICD detection criteria, verified by an electrophysiologist, that were either appropriated detected by the ICD requiring termination to prevent hemodynamic compromise or that lasted for ≥30 seconds in case of ICD disfunction.
Statistical analysis Continuous variables presented as the mean value ± standard deviation. To compare means of two variables we used the Student’s t test or ANOVA as appropriate. Categorical variables were expressed as total number (percentages) and compared between groups using Chi-square test. The (event-free) survival of patients was evaluated with the Kaplan–Meier method. The effect of different variables on (event-free) survival was investigated using the Cox proportional hazards model. Variables that showed a statistically significant effect on (eventfree) survival in univariate analyses were entered in a multivariate Cox proportional hazards model using a backward stepwise selection to obtain the final model. At each step, the least 8
Journal Pre-proof significant variable was discarded from the model, until all variables in the model reached a P-value below 0.10. The number of variables that could enter the multivariate was limited using the P,m/10 rule to prevent over-fitting the model. For all tests, a P-value <0.05 was considered significant. Statistical analysis was performed using R software for Windows version 3.3.0 (R project for statistical computing; Vienna, Austria).
Founding sources This work was supported by Instituto de Salud Carlos III (FIS PI16/01203 and PI17/01690) co-funded by the European Regional Development Fund (ERDF) and the European Social
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Found (ESF) “Investing in Your Future”. The CERCA Programme (Centres de Recerca de Catalunya) of the Generalitat de Catalunya; Daniel Bravo Andreu Foundation; and Obra Social "La Caixa". The authors are solely responsible for the design and conduct of this study,
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all study analyses, the drafting and editing of the paper and its final contents.
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Journal Pre-proof RESULTS
Baseline characteristics From a total of 474 patients with BrS, 135 (28.5%) patients with syncope as the first clinical manifestation of BrS were included. Syncope was classified as cardiogenic in 66 patients (48.9%), vasovagal in 51 (37.8%) and undefined in 18 (13.3%). Six patients with cardiogenic syncope (9.1%) also had episodes of vasovagal syncope. Baseline characteristics according to the type of syncope are shown in Table 1. Mean age was 43.9±13.9 years and 108 (80.0%) were index cases. Ninety-six patients (71.1%) were male with significant differences in
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gender prevalence according to the type of syncope: 56 (84.8%) male patients with
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cardiogenic syncope; 29 (56.9%) male patients with vasovagal syncope; and 11 (61.1%) with undefined syncope (p<0.01). Family history of SD was present in 35 patients (25.9%) with no
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significant differences among groups.
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Table 1. Baseline characteristics of Brugada syndrome patients with syncope Cardioge Vasovag nic al All syncope syncope syncope (n=135) (n=66) (n=51) 43.9 ± 46.5 ± 42.6 ± Mean age, y 13.9 13.8 12.2
Undefin ed
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p syncope value (n=18) 37.8 ± 16.6 0.05 <0.0 96 (71.1) 56 (84.8) 29 (56.9) 11 (61.1) 1 108 (80.0) 59 (89.4) 37 (72.5) 12 (66.7) 0.03 35 (25.9) 18 (27.3) 13 (25.5) 4 (22.2) 0.90
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Male, n (%)
Proband, n (%) Family history of sudden death, n (%) Syncope characteristics Number of syncope Fever, n (%) Prodromes, n (%) Preceding palpitations, n (%) Exertional syncope, n (%) Associated trauma, n (%) VA with syncope, n (%) Baseline ECG PR, ms QRS in V1-V2, ms
2.4 ± 2.3 2.5 ± 2.2 2.1 ± 1.7 2.7 ± 3.6 10 (7.4) 4 (6.2) 5 (9.6) 1 (5.6) 52 65 (48.1) 4 (6.2) (100.0) 10 (55.6) 9 (6.7) 4 (6.2) 3 (5.8) 2 (11.1) 10 (7.4) 4 (6.2) 3 (5.8) 3 (16.7) 16 (11.9) 10 (15.4) 3 (5.8) 3 (16.7) 2 (1.5) 2 (3.1) 0 (0.0) 0 (0.0) 163.0 ± 34.4 120.5 ± 25.5
168.8 ± 37.5 127.1 ± 29.5
155.9 ± 32.0 115.1 ± 20.4
162.3 ± 26.1 112.4 ± 16.4
0.54 0.77 <0.0 1 0.64 0.21 0.19 0.34
0.14 0.02 10
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QTc in DII, ms Spontaneous type 1 ECG, n (%) Positive sodium channel blocker test, n (%) Genetic test performed, n (%) SCN5A mutation, n (%)* HCN4 mutation, n (%)* SCN4B mutation, n (%)* Tilt-table test, n (%) Positive tilt-table test, n (%) Positive cardioinhibitory tilt-table test, n (%) Positive vasodilator tilt-table test, n (%)
87 (64.4) 81 (60.0) 26 (32.1) 1 (1.2) 1 (1.2) 20 (14.8) 14 (70.0)
38 (57.6) 43 (65.2) 11 (25.6) 0 (0.0) 1 (2.4) 10 (15.2) 6 (60.0)
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0.77 0.83 0.96 0.12
34 (66.7) 15 (83.3) 0.12 28 (54.9) 10 (55.6) 0.80 10 (35.7) 5 (50.0) 0.18 1 (3.6) 0 (0.0) 0.54 0 (0.0) 0 (0.0) 0.44 8 (15.7) 2 (11.1) 0.89 8 (100.0) 0 (0.0) 0.01
5 (25.0) 2 (20.0) 3 (37.5) 13 (65.0) 5 (50.0) 8 (100.0) 111 Electrophysiology study, n (%) (82.2) 52 (78.8) 41 (80.4) 375.4 ± 383.2 ± 373.4 ± Corrected sinus node recovery time, ms 48.9 50.2 52.1 85.1 ± 94.6 ± 83.9 ± A-H interval, ms 30.2 32.8 28.3 49.1 48.5 ± 49.0 ± H-V interval, ms ±10.4 9.5 10.3
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94.1 ± 15.0 410.4 ± 45.0 395.3 ± 36.0 3 (16.7)
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QTc in V1-V2, ms
97.1 ± 98.2 ± 96.8 ± 19.0 19.3 20.0 415.6 ± 417.7 ± 414.6 ± 39.2 41.1 35.0 392.3 ± 392.4 ± 391.1 ± 47.4 37.4 61.0 45 (33.3) 27 (40.9) 15 (29.4)
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QRS in DII, ms
0 (0.0) 0 (0.0) 18 (100.0) 392.3 ± 51.4 76.6 ± 30.0 51.0 ± 13.6
0.18 0.01 0.10 0.87 0.36 0.73 <0.0 1
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Inducible sustained VA, n (%) 33 (29.7) 28 (53.8) 5 (12.2) 0 (0.0) VA induced with 1 premature ventricular beat, n (%) 6 (5.4) 5 (9.6) 1 (2.4) 0 (0.0) 0.15 VA induced with 2 premature ventricular beats, n (%) 11 (9.9) 9 (17.3) 2 (4.9) 0 (0.0) 0.03 VA induced with 3 premature 16 <0.0 ventricular beats, n (%) (14.4) 14 (26.9) 2 (4.9) 0 (0.0) 1 Values are mean ± SD or n (%). ECG = electrocardiogram. VA = ventricular arrhythmias *% expressed for the population in whom the genetic test was done. The mean number of syncopal episodes before BrS diagnosis was 2.4±2.3 per patient. Ten patients (7.4%) had fever during the syncope episode; 9 patients (6.7%) presented preceding palpitations; 10 (7.4%) had exertional syncope; and 16 (11.9%) presented associated trauma with no significant differences among groups. Prodromes occurred in all patients with vasovagal syncope; 4 patients (6.2%) with cardiogenic syncope; and 10 (55.6%) with undefined syncope (p<0.01). VA were documented in 2 patients (3.1%) with cardiogenic syncope and in no patient with either vasovagal or undefined syncope (p=0.34).
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Journal Pre-proof Spontaneous type 1 ECG pattern was documented in 45 patients (33.3%). The diagnosis was induced by sodium channel blocker test in 87 patients (64.4%). The remaining 3 patients (2.2%) were carriers of pathogenic rare variants in the SCN5A gene (relatives of probands with identified variant). Two of these patients had a non-diagnostic basal ECG with a PR interval of 230 and 250 ms respectively, who did not undergo to sodium-channel blocker test due to a prolonged HV in the EPS (65 and 88 ms, respectively). The third patient rejected a sodium-channel blocker test and EPS; however, a loop-recorder was implanted. Patients with cardiogenic syncope presented a baseline ECG with a wider QRS complex in right precordial leads: 127.1±29.5 ms in patients with cardiogenic syncope versus 115.1±20.4
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ms in patients with vasovagal syncope and 112.4±16.4 ms in patients with undefined syncope
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(p=0.02).
A total of 81 patients underwent genetic testing (60.0%): 69 probands (85.2%) and 12 non-
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index cases (14.8%). A pathogenic mutation was found in 28 (34.5%): 26 (32.1%) were
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positive for pathogenic rare variants in the SCN5A gene; 1 (1.2%) was positive for a pathogenic rare variant in the HCN4 gene; and 1 (1.2%) had a pathogenic rare variant in the
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SCN4B gene. Of these, 19 were probands (67.9%) and 9 were non-index cases (32.1%) (p<0.01). There were no differences between groups according to the type of syncope.
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A TTT was performed in 20 patients (14.8%) and it was positive in 14: 6 patients (60.0%) with cardiogenic syncope, 8 patients (100.0%) with vasovagal syncope; and no patient with
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undefined syncope (p=0.01). A positive vasodilator response was significantly more frequent in patients with vasovagal syncope compared to patients with cardiogenic syncope (50.0% vs.
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100.0%; p=0.01). A positive cardioinhibitory TTT presented in 2 patients with cardiogenic syncope (20.0%) and 3 (37.5%) with vasovagal syncope (p=0.18). EPS was performed in 111 individuals (82.2%). The corrected sinus node recovery time and the A-H interval were within normal limits in all patients. Nineteen patients (17.1%) shown a H-V interval >55 ms: 8 patients (15.4%) with cardiogenic syncope, 7 (17.1%) with vasovagal syncope and 4 (22.2%) with undefined syncope (p=0.80). No supraventricular arrhythmias were induced in any patient. Sustained VA were induced in 33 patients (29.7%): 6 patients (5.4%) with 1 ventricular premature beat, 11 patients (9.9%) with 2 ventricular premature beats and 16 patients (14.4%) with 3 ventricular premature beats. EPS inducibility was more frequent in patients with cardiogenic syncope: 28 (53.8%) patients vs. 5 patients (12.2%) with vasovagal syncope (p<0.01). No patient with undefined syncope presented inducible VA in EPS. Of the 19 patients with a H-V interval >55 ms, 6 patients (31.6%) presented inducible VA: 4 (7.7%) with cardiogenic syncope and 2 (4.9%) with vasovagal syncope. 12
Journal Pre-proof Figure 1 shows the incidence of BrS patients with syncope stratified by type, the number of
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EPS performed and ICDs implanted per year.
Figure 1. Incidence of Brugada syndrome patients with syncope. New Brugada syndrome
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patients per year according to the type of syncope. Electrophysiology studies performed and
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implantable cardioverter defibrillators implanted per year in Brugada syndrome patients with syncope. Of note, the difference in proportion of the types of syncope through the years and consequently the number of implantable defibrillators, which reflects more awareness in the
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Brugada syndrome diagnosis and the progressive inclusion of family studies. BrS = Brugada
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Management
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syndrome. EPS = electrophysiology study. ICD = implantable cardioverter defibrillator.
All patients were provided with lifestyle recommendations in order to avoid fever and other precipitating factors such as drugs and electrolyte disturbances. An ICD was implanted in 64 patients (47.4%). ICD implantation was recommended to all 66 patients with cardiogenic syncope, regardless EPS inducibility or H-V interval; however, 7 patients (10.6%) rejected this therapy. In patients with vasovagal syncope, 5 patients (9.8%) underwent an ICD implantation due to inducible VA during the EPS. A loop-recorder implantation was decided in 3 patients (5.9%) with vasovagal syncope due to recurrent episodes, 1 of these patients with a H-V interval >55 ms. Clinical follow-up with lifestyle recommendations as an only therapy was decided in the rest of patients. All patients with undefined syncope underwent an EPS and no patient had an ICD due to lack of inducible VA. A loop-recorder implantation was decided in 5 of these patients (27.8%), 4 of them presented a H-V interval > 55 ms. (Figure 2).
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Figure 2. Therapeutic strategy and major events in follow-up in Brugada syndrome patients with cardiogenic (A), vasovagal (B) and undefined (C) syncope. Three patients (1 with cardiogenic syncope and 2 with vasovagal syncope) had no spontaneous neither inducible type 1 ECG pattern. Two of these patients had a basal ECG with a PR interval of 230 and 250 ms respectively, who did not undergo to sodium-channel blocker test due to a prolonged HV in the EPS (65 and 88 ms respectively). The third patient rejected a sodium channel blocker test and an EPS; however, a loop-recorder was implanted. BrS = Brugada syndrome. EPS = electrophysiology study. ICD = implantable cardioverter defibrillator. VA = ventricular arrhythmias. SD = sudden death. 14
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Follow-up All patients included had ≥6 months of follow-up. Six patients (4.6%) were lost due to migration. After a follow-up of 7.7±5.6 years (range 1-22 years), 16 patients (11.9%) presented at least 1 major event. All major events occurred only in patients with cardiogenic syncope, 12 of these patients (75.0%) had an ICD and 7 (43.8%) presented inducible VA (Figure 3). Of the total of patients with inducible VA in the EPS, 7 individuals (21.2%) presented major events in follow-up (p=0.04): 2 patients (6.1%) with 1 ventricular premature beat, 3 patients (9.1%) with 2 ventricular premature beats and 2 patients (6.1%) with 3
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ventricular premature beats. The negative predictive value of the EPS for major events was
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92.4%.
Figure 3. Freedom from major events in Brugada syndrome patients with syncope. Kaplan-Meier curve analyzing freedom from major events according to syncope classification. P-value calculated with a long-rank test. Two (1.5%) patients with cardiogenic syncope presented SD during follow-up. One male patient with spontaneous type 1 ECG who rejected ICD implantation, presented SD 7 years after diagnosis. Another male patient with non-spontaneous type 1 ECG and an inducible EPS who rejected an ICD implantation, experienced SD 4 years after diagnosis (Figure 2A). Two male patients with non-spontaneous type 1 ECG who rejected any invasive procedure experienced a cardiogenic syncope with fever 5 and 7 years after diagnosis, respectively. No
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Table 2. Clinical outcomes in Brugada syndrome patients with syncope Cardiogen Vasovag Undefine ic al d All p syncope syncope syncope syncope value (n=135) (n=66) (n=51) (n=18) Mean follow-up duration, y 7.7 ± 5.6 9.3 ± 6.0 6.1 ± 4.8 6.7 ± 4.9 0.05 Syncope in follow-up, n (%) 6 (4.4) 3 (4.5) 3 (5.9) 0 (0.0) 0.75 Cardiogenic syncope, n (%) 2 (1.5) 2 (3.0) 0 (0.0) 0 (0.0) 0.86 Vasovagal syncope, n (%) 4 (3.0) 1 (1.5) 3 (5.9) 0 (0.0) 0.57 Atrial fibrillation, n (%) 12 (8.9) 9 (13.6) 2 (3.9) 1 (5.6) 0.16 Ventricular arrhythmias, n (%) 22 (16.3) 21 (31.8) 1 (2.0) 0 (0.0) <0.01 Sustained monomorphic VT, n (%) 2 (1.5) 2 (3.0) 0 (0.0) 0 (0.0) 0.34 Sustained polymorphic VT / VF, n (%) 10 (7.4) 10 (15.2) 0 (0.0) 0 (0.0) <0.01 Non-sustained VT, n (%) 15 (11.1) 14 (21.2) 1 (2.0) 0 (0.0) <0.01 Deaths, n (%) 4 (3.0) 4 (6.1) 0 (0.0) 0 (0.0) 0.12 Sudden death, n (%) 2 (1.5) 2 (3.0) 0 (0.0) 0 (0.0) 0.35 Cardiovascular, n (%) 3 (2.2) 3 (4.5) 0 (0.0) 0 (0.0) 0.62 Non-cardiovascular, n (%) 1 (0.7) 1 (1.5) 0 (0.0) 0 (0.0) 0.56 Inappropriate ICD therapies, n (%) 6 (4.4) 5 (7.8) 1 (2.0) 0 (0.0) 0.46 Atrial fibrillation, n (%) 3 (2.2) 2 (3.0) 1 (2.0) 0 (0.0) 0.26 Lead noise, n (%) 3 (2.2) 3 (4.5) 0 (0.0) 0 (0.0) 0.74 Other complications, n (%) 14 (10.4) 13 (19.7) 1 (2.0) 0 (0.0) 0.61 Cardiac tamponade, n (%) 1 (0.7) 1 (1.5) 0 (0.0) 0 (0.0) 0.92 Lead dysfunction, n (%) 9 (6.7) 8 (12.2) 1 (2.0) 0 (0.0) 0.61 Device migration, n (%) 1 (0.7) 1 (1.5) 0 (0.0) 0 (0.0) 0.92 Infection, n (%) 4 (3.0) 4 (6.1) 0 (0.0) 0 (0.0) 0.67 Pneumothorax, n (%) 3 (2.2) 3 (4.5) 0 (0.0) 0 (0.0) 0.74 Values are mean ± SD or n (%). SD = sudden death. VT = ventricular tachycardia. VF = ventricular fibrillation. ICD = implantable cardioverter defibrillator A total of 58 appropriate ICD shocks due to sustained VA occurred in 12 patients (18.2%) with cardiogenic syncope. No patient was successfully treated only with ATP. The mean was 5.2±3.8 shocks per patient (range 1–12). The mean time to the first ICD therapy was 2.6±2.8 years since diagnosis. All patients were male (p=0.02); and 4 patients (33.3%) were <40 years old (p=0.76). Five patients (41.7%) had family history of SD (p=0.30). Nine patients had a genetic test done (75.0%) and 3 of them (33.3%) carried pathogenic rare variants in the
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Journal Pre-proof SCN5A gene (p=0.61). Seven patients (58.3%) presented spontaneous type 1 ECG (p=0.06); and 6 (50.0%) had an inducible EPS (p=0.08). Four of these patients (33.3%) received oral quinidine as part of their treatment. No ablation was attempted. The incidence rate of major cardiac events in patients with cardiogenic syncope was 2.6 per 100 person-years; 3.7 per 100 person-years in patients with both cardiogenic syncope and spontaneous type 1 ECG; and 3.8 per 100 person-years in patients with cardiogenic syncope, spontaneous type 1 ECG and inducible EPS. In the univariate analysis, parameters associated with major events during follow-up included cardiogenic syncope before diagnosis (HR 6.3; 95% IC 1.1-10.4; p=0.05); spontaneous type 1
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ECG (HR 3.7; 95% IC 1.3-10.5; p=0.01); and inducible EPS (HR 2.8; 95% IC 1.1-8.8;
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p=0.05). No parameter remained as independent predictor of major events in multivariate
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analysis (Table 3).
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Table 3. Parameters associated with major events in follow-up in Brugada Syndrome patients with syncope Major Multivariate events Univariate analysis analysis H p H 95% p Variable n (%) R 95% IC value R IC value Age at diagnosis ≤ 40 y 7 (12.1) 1.1 0.4 - 3.4 0.81 Male 16 (16.7) 4.5 0.5 - 4.7 0.16 Proband 14 (12.9) 1.0 0.2 - 4.5 0.98 Family history of sudden death 5 (14.3) 1.6 0.5 - 4.7 0.39 Cardiogenic syncope before 1.1 0.8 diagnosis 15 (18.1) 6.3 10.4 0.05 2.0 9.4 0.08 1.3 0.8 Spontaneous type 1 ECG 8 (20.0) 3.7 10.5 0.01 2.7 9.2 0.09 QRS length in V1-V2 ≥ 150 ms 6 (16.5) 2.4 0.8 - 6.9 0.10 QTc duration in V1-V2 ≥ 450 ms 2 (7.4) 1.9 0.4 - 8.4 0.42 R wave voltage in aVR ≥ 3 mV 4 (13.7) 1.6 0.4 - 5.8 0.48 0.4 R/Q ratio in aVR ≥ 0.75 5 (12.7) 4.5 14.9 0.12 QRS fragmentation 4 (18.0) 2.3 0.6 - 8.3 0.21 Early repolarization 1 (20.0) 2.2 0.6 - 8.3 0.32 0.5 Atrial fibrillation before diagnosis 2 (18.2) 2.3 10.6 0.27 0.3 Inducible EPS 7 (21.2) 2.8 1.1 - 8.8 0.05 1.0 3.4 0.09 H-V interval >55 ms 3 (15.7) 1.3 0.4 - 4.9 0.68 17
Journal Pre-proof SCN5A mutation carrier 3 (11.5) 1.1 0.3 - 4.6 0.86 Major events refer to the actual incidence and percentage in each category. Results obtained by Cox regression analysis. EPS = electrophysiology study. HR = hazard ratio. CI = confidence interval Fifteen patients (11.1%) presented a total of 33 episodes of non-sustained VT during followup. The mean was 2.5±2.9 episodes of non-sustained VT per patient (range 1–10). Fourteen of these (93.3%) were patients with cardiogenic syncope who also experienced sustained VA
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with appropriate ICD therapies.
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Journal Pre-proof One male patient with cardiogenic syncope, a non-spontaneous type 1 ECG, an inducible EPS and ICD implanted, experienced 1 episode of vasovagal syncope in follow-up. The rate of ventricular pacing was <1% and no ventricular arrhythmias were detected during the episode. Of the total of patients with vasovagal syncope, 3 patients (5.9%) experienced 3 episodes of vasovagal syncope during follow-up (1 episode per patient). Two of these patients, were female with non-spontaneous type 1 ECG and non-inducible EPS. In both patients, a looprecorder was implanted due to recurrent episodes of syncope before diagnosis. No heart rhythm abnormalities were observed during follow-up. The third patient was a male patient
syncope episode in follow-up after a blood extraction test.
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with non-spontaneous type 1 ECG and non-inducible EPS who experienced a clearly reflex
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Twelve patients (8.9%) presented ≥1 episode of atrial fibrillation (AF) during follow-up with no significant differences among groups according with the type of syncope (p=0.15).
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Treatment for AF included oral quinidine in 6 patients (50.0%) and pulmonary vein ablation
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in 5 patients (41.7%).
Two patients (3.0%) with cardiogenic syncope and ICD presented signs of sinus node
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dysfunction during follow-up. Three patients (4.5%) with cardiogenic syncope and ICD presented atrio-ventricular block during follow-up, 1 of them had a baseline H-V interval of
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88 ms. Five patients (7.6%) with cardiogenic syncope required >1% of pacing during follow-
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Four male patients (3.0%) died after 5.9±2.3 years of follow-up. The mean age at death was 58.0±23.3 years. One patient died of septic shock due to pneumonia with a concomitant chronic obstructive pulmonary disease. Two patients, who rejected an ICD implantation, presented SD 4 and 7 years after diagnosis, respectively (see Follow-up section). Finally, a 34-year-old male presented electrical storm during a surgical lead extraction procedure 42 months after ICD implantation (Table 2).
Inappropriate ICD therapies and complications Thirty-one inappropriate ICD therapies were documented in 6 patients (4.4%) during followup. Five (83.3%) were patients with cardiogenic syncope; and 1 (16.7%) with vasovagal syncope (p=0.46). The mean number of inappropriate ICD therapies per patient was 3.3±2.9 19
Journal Pre-proof (range 1–13). The causes of inappropriate therapies were: AF (3 patients); and lead dysfunction (3 patients). The 3 patients with lead dysfunction underwent lead replacement; 1 of them experienced a pocket infection and subsequently had a subcutaneous ICD. Two patients with inappropriate therapies due to AF underwent pulmonary vein ablation, remaining asymptomatic after the procedure. The third patient was treated successfully with oral quinidine. Fourteen patients (10.4%) had ICD-related complications. Seven patients (5.2%) had periprocedural complications: cardiac tamponade (1 patient); pneumothorax (3 patients); and device infection (4 patients, 1 of them complicated with infective endocarditis). Non-peri-
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procedural complications were documented in 9 patients (6.7%): lead dysfunction (9 patients);
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and device migration requiring ICD reimplantation (1 patient) (Table 2).
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Journal Pre-proof DISCUSSION
The main and foremost finding of this long-term prospective registry is that an appropriate classification of syncope through a thorough clinical history allows an appropriate risk stratification in patients with BrS. To date, this is the cohort with the longest follow-up to report the natural history of patients with BrS and syncope. Syncope is the first clinical manifestation of BrS in 25-35% (28.5% in the present cohort) (35). Of those, approximately half can be classified as clearly cardiogenic (48.9% in this cohort) (14); these patients, show an unfavourable prognosis and should be protected with an ICD (7,
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8). The event rate in our population was 2.6 per 100 person-years. All major events occurred
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in patients with syncope clinically classified as cardiogenic, while no events occurred in patients with vasovagal or undefined syncope, findings that are in line with previously
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published data (14).
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The importance of an accurate classification of the syncope event lies not only in the different prognosis that patients have according to the type of syncope (4, 5, 14, 15), but also in the
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relatively high incidence of non-arrhythmic syncope of BrS patients (2, 14). In this study, 37.8% of patients presented a syncope event classified as vasovagal and none of these patients
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presented major cardiac events in follow-up. A detailed medical history interview is crucial for a correct syncope classification (16, 17) and each syncopal event should be methodically
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evaluated, as mixed mechanisms may be present in up to 13% of patients. All related information, including triggers like fever, prodromes, palpitations and activity during syncope
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and medication should be obtained.
The 2017 ACC/AHA/HRS and 2018 ESC guidelines for the diagnosis and management of patients with syncope recommend ICD implantation in patients with syncope of suspected arrhythmogenic origin and to avoid it in individuals with suspected reflex-mediated syncope (16, 17). Unfortunately, an accurate classification of a syncope episode in BrS patients may be frequently challenging especially in the presence of multiple episodes or family history of SD. In these cases, an EPS might be a helpful tool to establish a therapeutic strategy (class IIb) (7, 8, 16-18), although the evidence to support this practice is lacking. In this study, VA inducibility in EPS was significantly higher in patients with cardiogenic syncope, and 21.2% patients with inducible EPS presented major events in follow-up (p=0.04). This outcome supports, in a cohort with a longer follow-up, previously published data in BrS patients with syncope (19), in which the highest risk of ventricular events corresponds to patients with cardiogenic syncope and inducible EPS. 21
Journal Pre-proof Programmed stimulation may identify patients with BrS at increased risk for cardiac arrest, but the association appears most apparent in individuals induced with single or double extrastimuli (18). In this study, 71.4% of patients with inducible VA and arrhythmic events in follow-up, presented positive inducibility EPS with ≤2 ventricular extrastimuli. However, the most helpful characteristic of the EPS is its negative predictive value for major events (92.4% in this study); especially in patients with syncope with unclear characteristics and noninducible EPS in which no events were shown in follow-up.
Therefore, an EPS could
represent a helpful tool in patients with syncope episodes after clinical risk stratification, when the clinical classification is challenging due to unclear characteristics of the syncope
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event. According to this study, clinical features effectively stratify individuals at highest and
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lowest risk of VA. Thus, programmed stimulation may be most useful for predicting arrhythmia in undefined clinical stratification to prevent unnecessary ICD implantations,
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syncope in this cohort presented a positive TTT).
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especially due to the TTT showed to be highly unspecific (60% of patients with cardiogenic
Preventing unnecessary ICD implantations is crucial especially due to the ICD-related
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complications (8). In this study, 10.4% patients had complications and 4.4% experienced inappropriate shocks, of these patients 42.9% and 33.3% respectively also received
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appropriate shocks. Therefore, an accurate patient selection is highly recommendable. In this study, a loop-recorder implant was decided individually according with clinical
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presentation, family history and consensual decision with the patient. Five patients with undefined syncope underwent a loop-recorder implant. However, none of these patients had
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another syncope event during follow-up. Conversely, in the vasovagal syncope group, 3 patients received a loop-recorder due to recurrent episodes. Two of these patients had another syncope during follow-up. Therefore, a loop-recorder could help in recurrent vasovagal syncope to rule out arrhythmic events. One final important findings to highlight in this study is that patients with cardiogenic syncope presented a baseline ECG with a wider QRS complex in right precordial leads: 127.1±29.5 ms in patients with cardiogenic syncope versus 115.1±20.4 ms in patients with vasovagal syncope and 112.4±16.4 ms in patients with undefined syncope (p=0.02). Some studies have reported a wide QRS complex in right precordial leads as an important indicator to prevent cardiac events in BrS patients (20, 21). This aspect, that should be further validated in larger studies, may be a useful tool the syncope classification in episodes of unclear characteristics.
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Study limitations The present study has several strengths. It is a prospective registry of a relatively large cohort of consecutive BrS patients with syncope from a single centre and very few patients were lost after a long follow-up. However, there are limitations to acknowledge. Although this is a prospectively-design registry the nature of this specific analysis was retrospective. The type of syncope, presence of a baseline type 1 pattern and an inducibility of ventricular arrhythmias, were predictors of major events in follow-up in the univariate analysis but not in the
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multivariate. This is possibly due to the low number of events and consequently lack of
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statistical power. Even though this is the longest follow-up reported in the literature, 7.7±5.6 years may not be sufficient time to fully understand the true outcome of BrS patients with
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syncope.
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CONCLUSIONS
An accurate syncope classification is crucial in BrS patients and allows a correct stratification of future arrhythmic risk. When the clinical syncope characteristics are unclear and the classification is challenging, an EPS may be helpful to prevent unnecessary ICD
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implantations in case of no inducibility.
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REFERENCES
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Jaime Hernandez-Ojeda, Elena Arbelo, Paloma Jorda, Roger Borras, Oscar Campuzano, Georgia Sarquella-Brugada, Anna Iglesias, Lluis Mont, Ramon Brugada, Josep Brugada PII:
S0002-8703(19)30298-4
DOI:
https://doi.org/10.1016/j.ahj.2019.10.016
Reference:
YMHJ 6007
To appear in:
American Heart Journal
Received date:
12 April 2019
Accepted date:
12 October 2019
Please cite this article as: J. Hernandez-Ojeda, E. Arbelo, P. Jorda, et al., The role of clinical assessment and electrophysiology study in Brugada Syndrome patients with syncope, American Heart Journal(2019), https://doi.org/10.1016/j.ahj.2019.10.016
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© 2019 Published by Elsevier.
Journal Pre-proof The role of clinical assessment and electrophysiology study in Brugada Syndrome patients with syncope Jaime Hernandez-Ojeda MD PhDa,b*, Elena Arbelo MD PhDa,b,c*, Paloma Jorda MDa,b, Roger Borras MSca,b, Oscar Campuzano BSc PhDc,d,e, Georgia Sarquella-Brugada MD PhDe,f, Anna Iglesias PhDc,d,e, Lluis Mont MD PhDa,b,c, Ramon Brugada MD PhD c,d,e,g, Josep Brugada MD PhDa,b,c,f *Both authors contributed equally to this work
Arrhythmia Section, Cardiology Department, Hospital Clínic, Universitat de Barcelona.
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Barcelona (Spain). b
IDIBAPS, Institut d’Investigació August Pi i Sunyer (IDIBAPS). Barcelona (Spain).
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Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV),
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Madrid (Spain) d
Cardiovascular Genetics Center, University of Girona-IDIBGI, Girona (Spain)
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Medical Science Department, School of Medicine, University of Girona, Girona (Spain)
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Arrhythmia Unit, Hospital Sant Joan de Déu, University of Barcelona, Barcelona (Spain)
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Word count: 4417
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Cardiology Service, Hospital Josep Trueta, Girona (Spain)
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Funding: This work was supported by Instituto de Salud Carlos III (FIS PI16/01203 and PI17/01690) co-funded by the European Regional Development Fund (ERDF) and the European Social Found (ESF) “Investing in Your Future”. The CERCA Programme (Centres de Recerca de Catalunya) of the Generalitat de Catalunya; Daniel Bravo Andreu Foundation; and Obra Social "La Caixa".
Diclosures: none
Corresponding author: Jaime Hernandez-Ojeda, MD, PhD Hospital Clínic de Barcelona C/ Villarroel 170, 6º, escala 3 08036 Barcelona Ph: (+34) 93 227 5551; Fax: (+34) 93 4513045 1
Journal Pre-proof Email: [email protected] ABSTRACT Background: Cardiogenic syncope in Brugada syndrome (BrS) increases the risk of major events. Nevertheless, clinical differentiation between cardiogenic and vasovagal syncope can be challenging. We characterized the long-term incidence of major events in a large cohort of BrS patients presented with syncope.
Methods: From a total of 474 patients, syncope was the initial manifestation in 135 (28.5%) individuals (43.9±13.9 years, 71.1% male). The syncope was classified prospectively in
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cardiogenic, vasovagal or undefined if unclear characteristics were present. Clinical, electrocardiographic, genetic and electrophysiologic features were analyzed. Cardiogenic
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syncope, sustained ventricular arrhythmias and sudden death were considered major events in
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follow-up.
Results: In 66 patients (48.9%) the syncope was cardiogenic, in 51 (37.8%) vasovagal and in
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18 (13.3%) undefined. The electrophysiology study (EPS) inducibility was more frequent in patients with cardiogenic syncope and absent in all patients with undefined syncope
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(28[53.8%] vs. 5[12.2%] vs 0[0%]; p<0.01). During follow-up (7.7±5.6 years), only patients with cardiogenic syncope presented major events (16 [11.9%]). Among patients with
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inducible EPS, 7 (21.2%) presented major events (p=0.04). The negative predictive value of
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the EPS for major events was 92.4%. The incidence rate of major events was 2.6% personyear. Parameters associated with major events included cardiogenic syncope (HR 6.3;95% IC 1.1-10.4;p=0.05); spontaneous type 1 ECG (HR 3.7;95% IC 1.3-10.5;p=0.01); and inducible EPS (HR 2.8;95% IC 1.1-8.8;p=0.05).
Conclusions: An accurate syncope classification is crucial in BrS patients for risk stratification. In patients with syncope of unclear characteristics the EPS may be helpful to prevent unnecessary implantable cardioverter defibrillators.
KEYWORDS: risk stratification, electrophysiology study, implantable cardioverter defibrillator, sudden death, ventricular arrhythmias.
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HIGHLIGHTS
This is a cohort with the longest follow-up of BrS patients presented with syncope.
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Major events occurred only in patients with cardiogenic syncope.
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An accurate classification of the syncope allowed an appropriate risk stratification.
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No major events were present in patients with undefined syncope and non-inducible EPS.
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EPS may be helpful to prevent unnecessary ICDs in patients with undefined syncope.
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ABBREVIATIONS
BrS = Brugada syndrome ECG = electrocardiogram SD = sudden death VT = ventricular tachycardia VF = ventricular fibrillation
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EPS = electrophysiology study ICD = implantable cardioverter defibrillator
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VA = ventricular arrhythmias
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TTT = tilt-table test
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AF = atrial fibrillation
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ATP = antitachycardia pacing
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Journal Pre-proof BACKGROUND
Brugada syndrome (BrS) is a cardiac disease characterized by a ST-segment elevation in the right precordial electrocardiogram (ECG) leads, which predisposes to sudden death (SD) due to polymorphic ventricular tachycardia (VT) or ventricular fibrillation (VF) in the absence of structural heart disease (1). In BrS patients presented with cardiogenic syncope the major event rate per year has been estimated to be 0–1.9% (2-4). This rate increases to 4.9-6.4% in the presence of spontaneous type 1 ECG (5); and to 27.2% in the presence of both spontaneous type 1 ECG and inducible
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electrophysiology study (EPS) (4). On the other hand, a higher susceptibility to vasovagal syncope has been reported in BrS patients, probably due to an associated autonomic dysfunction(6).
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The treatment of choice in BrS patients who have experienced a prior cardiac arrest or
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syncopal events secondary to ventricular arrhythmias (VA) is an implantable cardioverter defibrillator (ICD) (7, 8). The therapeutic strategy is of major importance in these patients as
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there may be device-related complications during the course of decades of expected use, including inappropriate shocks and lead-related problems, which subsequently might lead to
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morbidity and reduced quality of life (4, 5, 9-12).
The aim of the study was to characterize the prevalence of cardiogenic and vasovagal syncope
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of BrS patients over 20 years of experience in our centre, to evaluate the therapeutic strategy
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performed and to analyse the long-term follow-up of these patients.
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Journal Pre-proof METHODS
Study population From January 1994 to December 2017, all >18 year-old patients with syncope diagnosed of BrS in our center were included consecutively and followed-up prospectively. Data collection was done after approval from the medical ethics committee in our institution. All patients signed the informed consent. BrS was diagnosed in the presence of a type 1 Brugada pattern on the ECG (coved-type), either at baseline or after the administration of a sodium channel-blocking agent, in the
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absence of any structural cardiomyopathy (2). A type 1 ECG pattern was defined as the
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presence of a terminal r’ wave with a J-point elevation of ≥0.2 mV, with a slowly descending ST segment followed by a negative T wave in ≥1 right precordial lead (V1-V3), placed in the
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4th, 3rd or 2nd intercostal space. Flecainide (2 mg/kg) or ajmaline (1 mg/kg) were administered
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intravenously over a 10-minute period to unmask the diagnostic ECG pattern of BrS in case of a non-diagnostic baseline ECG. All ECGs were registered in a paper velocity of 25 mm/s
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and 10 mm/mV of amplitude, with right precordial leads in both sternal edges positioned at 4 th and 3rd intercostal spaces (from 2012 onwards, the 2nd intercostal space was also recorded).
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All ECGs were independently analysed by 2 experienced electrophysiologists; in case of disagreement another experienced faculty was consulted. In all patients, significant structural
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cardiomyopathy was ruled out by transthoracic echocardiogram and, in case of suspicious
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findings, by cardiac magnetic resonance.
Initial work-up and management All patients diagnosed of BrS who had experienced syncope by the time of diagnosis underwent to a detailed medical history interview consisted of a standardized systematic history taking including age at diagnosis, gender, race and family history of SD or BrS. A family history of SD was defined as a SD ≤55 years in ≥1 family members of 1 st or 2nd degree. A specific questionnaire of the event was performed by the time of diagnosis in each patient to determine the type of syncope which included: number of previous syncope events; specific triggers; presence of prodromes characterized by diaphoresis, epigastric discomfort, extreme fatigue, weakness, yawning, nausea, dizziness, and vertigo lasting seconds to several minutes; duration of the loss of conscience; presence of fever and/or palpitations preceding the episodes; activity during the syncope; associated trauma; and current medications. 6
Journal Pre-proof Syncopal episodes were independently classified in a prospective manner by 2 experienced electrophysiologists specialized in Genetic Arrhythmias in cardiogenic or vasovagal. In case of disagreement another expert faculty was consulted. A cardiogenic syncope was defined in case of absent or brief prodrome (<10 seconds), absence of specific triggering circumstance, brief loss of consciousness (<1 minute), and fast return to consciousness. If the event did not accomplish all these criteria was defined as vasovagal. If >1 of these characteristics were not possible to obtain and/or the event could not be well defined, the syncope was classified as undefined. Patients with multiple events were classified according to the event of highest severity after an exhaustive analysis of each event occurred.
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Genetic test was recommended to all patients; following the guidelines, SCN5A (Nav1.5) was analyzed in all samples (until 2012 using Sanger technology and from 2012 to date, through NGS technology). An EPS was performed in all BrS patients with syncope before 2005,
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unless patient’s rejection. From 2005 onwards, according to the second Brugada consensus
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conference recommendations (13), the EPS was not performed in some patients with clearly cardiogenic syncope who underwent to an ICD implant with no EPS. The EPS included basal
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measurements of conduction intervals and programmed ventricular stimulation. The protocol recommended used a single site of stimulation (right ventricular apex), three basic pacing
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cycle lengths (600, 500, and 430 ms), and induction of 1, 2, and 3 ventricular premature beats down to a minimum of 200 ms. A patient was considered inducible if sustained VA (VF,
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polymorphic VT or monomorphic VT lasting more than 30 seconds or requiring emergency intervention) were induced.
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A tilt-table test (TTT) was performed according to medical criteria in patients with a likely vasovagal syncope if the classification remained doubtful after obtaining the clinical information of the event. The protocol involved 2 phases placing the patient on a flat table with foot support then tilting the table upward at 70-degree angle: a first passive unmedicated phase of 20 minutes and an additional phase of 20 minutes after application 400 µg of sublingual nitroglycerine. During the test, blood pressure, heart rate, oxygen saturation, and cardiac rhythms were recorded and monitored for the end point of fainting, which indicated a positive TTT result. A positive test with a cardioinhibitory response was defined when syncope was related to a decrease of heart rate. A positive test with a vasodilator response was defined when syncope occurred due to reduce of blood pressure. From 2005 onwards, ICD therapy indications were determined according to the second Brugada consensus conference recommendations (13). Single or dual-chamber devices were indicated based on the presence of sinus node dysfunction or AV conduction abnormalities. 7
Journal Pre-proof The detection of all ICDs was standardized with a single VF zone programmed to 18 out of 24 events at an interval shorter ≤300 ms, or a ventricular rate ≥200 bpm, treated with 1 rapid burst of antitachycardia pacing (ATP) in the VF zone while charging (if available) and 3 shocks with maximum output. Subcutaneous ICDs were implanted (if available) after a correct basal ECG screening test in the absence of pacing requirements. Loop-recorder implant was decided individually according with clinical presentation, family history and consensual decision with the patient.
Follow-up
and,
depending
on
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symptoms,
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The follow-up assessment included a careful analysis of the patient’s history, 12-lead ECG complementary
tests
such
as
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echocardiography and 24h-holter monitoring. Patients were seen in the dedicated
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Cardiogenetic Outpatient Clinic annually or earlier depending on the clinical evolution; in
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case of having an ICD implanted, they were also evaluated every 6-12 months in the ICD Clinic (unless shorter periods of follow-up were required). Patients with ICD remote
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monitoring capabilities were interrogated transtelephonically every 3 months and in the event of any device alert. In case of a loop- recorder implant, patients were followed every 3
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months. Patients with a follow-up of less than 6 months were excluded. The occurrence of device-related complications was also registered. A major event was defined as the presence
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of SD, cardiogenic syncope in patients without ICD and/or documented sustained VA (monomorphic VT, polymorphic VT and/or VF). In patients with ICD, sustained VA were
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defined as VA that completed the standardized ICD detection criteria, verified by an electrophysiologist, that were either appropriated detected by the ICD requiring termination to prevent hemodynamic compromise or that lasted for ≥30 seconds in case of ICD disfunction.
Statistical analysis Continuous variables presented as the mean value ± standard deviation. To compare means of two variables we used the Student’s t test or ANOVA as appropriate. Categorical variables were expressed as total number (percentages) and compared between groups using Chi-square test. The (event-free) survival of patients was evaluated with the Kaplan–Meier method. The effect of different variables on (event-free) survival was investigated using the Cox proportional hazards model. Variables that showed a statistically significant effect on (eventfree) survival in univariate analyses were entered in a multivariate Cox proportional hazards model using a backward stepwise selection to obtain the final model. At each step, the least 8
Journal Pre-proof significant variable was discarded from the model, until all variables in the model reached a P-value below 0.10. The number of variables that could enter the multivariate was limited using the P,m/10 rule to prevent over-fitting the model. For all tests, a P-value <0.05 was considered significant. Statistical analysis was performed using R software for Windows version 3.3.0 (R project for statistical computing; Vienna, Austria).
Founding sources This work was supported by Instituto de Salud Carlos III (FIS PI16/01203 and PI17/01690) co-funded by the European Regional Development Fund (ERDF) and the European Social
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Found (ESF) “Investing in Your Future”. The CERCA Programme (Centres de Recerca de Catalunya) of the Generalitat de Catalunya; Daniel Bravo Andreu Foundation; and Obra Social "La Caixa". The authors are solely responsible for the design and conduct of this study,
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all study analyses, the drafting and editing of the paper and its final contents.
9
Journal Pre-proof RESULTS
Baseline characteristics From a total of 474 patients with BrS, 135 (28.5%) patients with syncope as the first clinical manifestation of BrS were included. Syncope was classified as cardiogenic in 66 patients (48.9%), vasovagal in 51 (37.8%) and undefined in 18 (13.3%). Six patients with cardiogenic syncope (9.1%) also had episodes of vasovagal syncope. Baseline characteristics according to the type of syncope are shown in Table 1. Mean age was 43.9±13.9 years and 108 (80.0%) were index cases. Ninety-six patients (71.1%) were male with significant differences in
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gender prevalence according to the type of syncope: 56 (84.8%) male patients with
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cardiogenic syncope; 29 (56.9%) male patients with vasovagal syncope; and 11 (61.1%) with undefined syncope (p<0.01). Family history of SD was present in 35 patients (25.9%) with no
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significant differences among groups.
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Table 1. Baseline characteristics of Brugada syndrome patients with syncope Cardioge Vasovag nic al All syncope syncope syncope (n=135) (n=66) (n=51) 43.9 ± 46.5 ± 42.6 ± Mean age, y 13.9 13.8 12.2
Undefin ed
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p syncope value (n=18) 37.8 ± 16.6 0.05 <0.0 96 (71.1) 56 (84.8) 29 (56.9) 11 (61.1) 1 108 (80.0) 59 (89.4) 37 (72.5) 12 (66.7) 0.03 35 (25.9) 18 (27.3) 13 (25.5) 4 (22.2) 0.90
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Male, n (%)
Proband, n (%) Family history of sudden death, n (%) Syncope characteristics Number of syncope Fever, n (%) Prodromes, n (%) Preceding palpitations, n (%) Exertional syncope, n (%) Associated trauma, n (%) VA with syncope, n (%) Baseline ECG PR, ms QRS in V1-V2, ms
2.4 ± 2.3 2.5 ± 2.2 2.1 ± 1.7 2.7 ± 3.6 10 (7.4) 4 (6.2) 5 (9.6) 1 (5.6) 52 65 (48.1) 4 (6.2) (100.0) 10 (55.6) 9 (6.7) 4 (6.2) 3 (5.8) 2 (11.1) 10 (7.4) 4 (6.2) 3 (5.8) 3 (16.7) 16 (11.9) 10 (15.4) 3 (5.8) 3 (16.7) 2 (1.5) 2 (3.1) 0 (0.0) 0 (0.0) 163.0 ± 34.4 120.5 ± 25.5
168.8 ± 37.5 127.1 ± 29.5
155.9 ± 32.0 115.1 ± 20.4
162.3 ± 26.1 112.4 ± 16.4
0.54 0.77 <0.0 1 0.64 0.21 0.19 0.34
0.14 0.02 10
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QTc in DII, ms Spontaneous type 1 ECG, n (%) Positive sodium channel blocker test, n (%) Genetic test performed, n (%) SCN5A mutation, n (%)* HCN4 mutation, n (%)* SCN4B mutation, n (%)* Tilt-table test, n (%) Positive tilt-table test, n (%) Positive cardioinhibitory tilt-table test, n (%) Positive vasodilator tilt-table test, n (%)
87 (64.4) 81 (60.0) 26 (32.1) 1 (1.2) 1 (1.2) 20 (14.8) 14 (70.0)
38 (57.6) 43 (65.2) 11 (25.6) 0 (0.0) 1 (2.4) 10 (15.2) 6 (60.0)
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0.77 0.83 0.96 0.12
34 (66.7) 15 (83.3) 0.12 28 (54.9) 10 (55.6) 0.80 10 (35.7) 5 (50.0) 0.18 1 (3.6) 0 (0.0) 0.54 0 (0.0) 0 (0.0) 0.44 8 (15.7) 2 (11.1) 0.89 8 (100.0) 0 (0.0) 0.01
5 (25.0) 2 (20.0) 3 (37.5) 13 (65.0) 5 (50.0) 8 (100.0) 111 Electrophysiology study, n (%) (82.2) 52 (78.8) 41 (80.4) 375.4 ± 383.2 ± 373.4 ± Corrected sinus node recovery time, ms 48.9 50.2 52.1 85.1 ± 94.6 ± 83.9 ± A-H interval, ms 30.2 32.8 28.3 49.1 48.5 ± 49.0 ± H-V interval, ms ±10.4 9.5 10.3
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94.1 ± 15.0 410.4 ± 45.0 395.3 ± 36.0 3 (16.7)
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QTc in V1-V2, ms
97.1 ± 98.2 ± 96.8 ± 19.0 19.3 20.0 415.6 ± 417.7 ± 414.6 ± 39.2 41.1 35.0 392.3 ± 392.4 ± 391.1 ± 47.4 37.4 61.0 45 (33.3) 27 (40.9) 15 (29.4)
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QRS in DII, ms
0 (0.0) 0 (0.0) 18 (100.0) 392.3 ± 51.4 76.6 ± 30.0 51.0 ± 13.6
0.18 0.01 0.10 0.87 0.36 0.73 <0.0 1
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Inducible sustained VA, n (%) 33 (29.7) 28 (53.8) 5 (12.2) 0 (0.0) VA induced with 1 premature ventricular beat, n (%) 6 (5.4) 5 (9.6) 1 (2.4) 0 (0.0) 0.15 VA induced with 2 premature ventricular beats, n (%) 11 (9.9) 9 (17.3) 2 (4.9) 0 (0.0) 0.03 VA induced with 3 premature 16 <0.0 ventricular beats, n (%) (14.4) 14 (26.9) 2 (4.9) 0 (0.0) 1 Values are mean ± SD or n (%). ECG = electrocardiogram. VA = ventricular arrhythmias *% expressed for the population in whom the genetic test was done. The mean number of syncopal episodes before BrS diagnosis was 2.4±2.3 per patient. Ten patients (7.4%) had fever during the syncope episode; 9 patients (6.7%) presented preceding palpitations; 10 (7.4%) had exertional syncope; and 16 (11.9%) presented associated trauma with no significant differences among groups. Prodromes occurred in all patients with vasovagal syncope; 4 patients (6.2%) with cardiogenic syncope; and 10 (55.6%) with undefined syncope (p<0.01). VA were documented in 2 patients (3.1%) with cardiogenic syncope and in no patient with either vasovagal or undefined syncope (p=0.34).
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Journal Pre-proof Spontaneous type 1 ECG pattern was documented in 45 patients (33.3%). The diagnosis was induced by sodium channel blocker test in 87 patients (64.4%). The remaining 3 patients (2.2%) were carriers of pathogenic rare variants in the SCN5A gene (relatives of probands with identified variant). Two of these patients had a non-diagnostic basal ECG with a PR interval of 230 and 250 ms respectively, who did not undergo to sodium-channel blocker test due to a prolonged HV in the EPS (65 and 88 ms, respectively). The third patient rejected a sodium-channel blocker test and EPS; however, a loop-recorder was implanted. Patients with cardiogenic syncope presented a baseline ECG with a wider QRS complex in right precordial leads: 127.1±29.5 ms in patients with cardiogenic syncope versus 115.1±20.4
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ms in patients with vasovagal syncope and 112.4±16.4 ms in patients with undefined syncope
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(p=0.02).
A total of 81 patients underwent genetic testing (60.0%): 69 probands (85.2%) and 12 non-
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index cases (14.8%). A pathogenic mutation was found in 28 (34.5%): 26 (32.1%) were
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positive for pathogenic rare variants in the SCN5A gene; 1 (1.2%) was positive for a pathogenic rare variant in the HCN4 gene; and 1 (1.2%) had a pathogenic rare variant in the
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SCN4B gene. Of these, 19 were probands (67.9%) and 9 were non-index cases (32.1%) (p<0.01). There were no differences between groups according to the type of syncope.
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A TTT was performed in 20 patients (14.8%) and it was positive in 14: 6 patients (60.0%) with cardiogenic syncope, 8 patients (100.0%) with vasovagal syncope; and no patient with
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undefined syncope (p=0.01). A positive vasodilator response was significantly more frequent in patients with vasovagal syncope compared to patients with cardiogenic syncope (50.0% vs.
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100.0%; p=0.01). A positive cardioinhibitory TTT presented in 2 patients with cardiogenic syncope (20.0%) and 3 (37.5%) with vasovagal syncope (p=0.18). EPS was performed in 111 individuals (82.2%). The corrected sinus node recovery time and the A-H interval were within normal limits in all patients. Nineteen patients (17.1%) shown a H-V interval >55 ms: 8 patients (15.4%) with cardiogenic syncope, 7 (17.1%) with vasovagal syncope and 4 (22.2%) with undefined syncope (p=0.80). No supraventricular arrhythmias were induced in any patient. Sustained VA were induced in 33 patients (29.7%): 6 patients (5.4%) with 1 ventricular premature beat, 11 patients (9.9%) with 2 ventricular premature beats and 16 patients (14.4%) with 3 ventricular premature beats. EPS inducibility was more frequent in patients with cardiogenic syncope: 28 (53.8%) patients vs. 5 patients (12.2%) with vasovagal syncope (p<0.01). No patient with undefined syncope presented inducible VA in EPS. Of the 19 patients with a H-V interval >55 ms, 6 patients (31.6%) presented inducible VA: 4 (7.7%) with cardiogenic syncope and 2 (4.9%) with vasovagal syncope. 12
Journal Pre-proof Figure 1 shows the incidence of BrS patients with syncope stratified by type, the number of
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EPS performed and ICDs implanted per year.
Figure 1. Incidence of Brugada syndrome patients with syncope. New Brugada syndrome
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patients per year according to the type of syncope. Electrophysiology studies performed and
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implantable cardioverter defibrillators implanted per year in Brugada syndrome patients with syncope. Of note, the difference in proportion of the types of syncope through the years and consequently the number of implantable defibrillators, which reflects more awareness in the
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Brugada syndrome diagnosis and the progressive inclusion of family studies. BrS = Brugada
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Management
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syndrome. EPS = electrophysiology study. ICD = implantable cardioverter defibrillator.
All patients were provided with lifestyle recommendations in order to avoid fever and other precipitating factors such as drugs and electrolyte disturbances. An ICD was implanted in 64 patients (47.4%). ICD implantation was recommended to all 66 patients with cardiogenic syncope, regardless EPS inducibility or H-V interval; however, 7 patients (10.6%) rejected this therapy. In patients with vasovagal syncope, 5 patients (9.8%) underwent an ICD implantation due to inducible VA during the EPS. A loop-recorder implantation was decided in 3 patients (5.9%) with vasovagal syncope due to recurrent episodes, 1 of these patients with a H-V interval >55 ms. Clinical follow-up with lifestyle recommendations as an only therapy was decided in the rest of patients. All patients with undefined syncope underwent an EPS and no patient had an ICD due to lack of inducible VA. A loop-recorder implantation was decided in 5 of these patients (27.8%), 4 of them presented a H-V interval > 55 ms. (Figure 2).
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Figure 2. Therapeutic strategy and major events in follow-up in Brugada syndrome patients with cardiogenic (A), vasovagal (B) and undefined (C) syncope. Three patients (1 with cardiogenic syncope and 2 with vasovagal syncope) had no spontaneous neither inducible type 1 ECG pattern. Two of these patients had a basal ECG with a PR interval of 230 and 250 ms respectively, who did not undergo to sodium-channel blocker test due to a prolonged HV in the EPS (65 and 88 ms respectively). The third patient rejected a sodium channel blocker test and an EPS; however, a loop-recorder was implanted. BrS = Brugada syndrome. EPS = electrophysiology study. ICD = implantable cardioverter defibrillator. VA = ventricular arrhythmias. SD = sudden death. 14
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Follow-up All patients included had ≥6 months of follow-up. Six patients (4.6%) were lost due to migration. After a follow-up of 7.7±5.6 years (range 1-22 years), 16 patients (11.9%) presented at least 1 major event. All major events occurred only in patients with cardiogenic syncope, 12 of these patients (75.0%) had an ICD and 7 (43.8%) presented inducible VA (Figure 3). Of the total of patients with inducible VA in the EPS, 7 individuals (21.2%) presented major events in follow-up (p=0.04): 2 patients (6.1%) with 1 ventricular premature beat, 3 patients (9.1%) with 2 ventricular premature beats and 2 patients (6.1%) with 3
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ventricular premature beats. The negative predictive value of the EPS for major events was
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92.4%.
Figure 3. Freedom from major events in Brugada syndrome patients with syncope. Kaplan-Meier curve analyzing freedom from major events according to syncope classification. P-value calculated with a long-rank test. Two (1.5%) patients with cardiogenic syncope presented SD during follow-up. One male patient with spontaneous type 1 ECG who rejected ICD implantation, presented SD 7 years after diagnosis. Another male patient with non-spontaneous type 1 ECG and an inducible EPS who rejected an ICD implantation, experienced SD 4 years after diagnosis (Figure 2A). Two male patients with non-spontaneous type 1 ECG who rejected any invasive procedure experienced a cardiogenic syncope with fever 5 and 7 years after diagnosis, respectively. No
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Journal Pre-proof more episodes of syncope occurred afterwards thanks to preventive measures (early fever control) (Table 2).
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Table 2. Clinical outcomes in Brugada syndrome patients with syncope Cardiogen Vasovag Undefine ic al d All p syncope syncope syncope syncope value (n=135) (n=66) (n=51) (n=18) Mean follow-up duration, y 7.7 ± 5.6 9.3 ± 6.0 6.1 ± 4.8 6.7 ± 4.9 0.05 Syncope in follow-up, n (%) 6 (4.4) 3 (4.5) 3 (5.9) 0 (0.0) 0.75 Cardiogenic syncope, n (%) 2 (1.5) 2 (3.0) 0 (0.0) 0 (0.0) 0.86 Vasovagal syncope, n (%) 4 (3.0) 1 (1.5) 3 (5.9) 0 (0.0) 0.57 Atrial fibrillation, n (%) 12 (8.9) 9 (13.6) 2 (3.9) 1 (5.6) 0.16 Ventricular arrhythmias, n (%) 22 (16.3) 21 (31.8) 1 (2.0) 0 (0.0) <0.01 Sustained monomorphic VT, n (%) 2 (1.5) 2 (3.0) 0 (0.0) 0 (0.0) 0.34 Sustained polymorphic VT / VF, n (%) 10 (7.4) 10 (15.2) 0 (0.0) 0 (0.0) <0.01 Non-sustained VT, n (%) 15 (11.1) 14 (21.2) 1 (2.0) 0 (0.0) <0.01 Deaths, n (%) 4 (3.0) 4 (6.1) 0 (0.0) 0 (0.0) 0.12 Sudden death, n (%) 2 (1.5) 2 (3.0) 0 (0.0) 0 (0.0) 0.35 Cardiovascular, n (%) 3 (2.2) 3 (4.5) 0 (0.0) 0 (0.0) 0.62 Non-cardiovascular, n (%) 1 (0.7) 1 (1.5) 0 (0.0) 0 (0.0) 0.56 Inappropriate ICD therapies, n (%) 6 (4.4) 5 (7.8) 1 (2.0) 0 (0.0) 0.46 Atrial fibrillation, n (%) 3 (2.2) 2 (3.0) 1 (2.0) 0 (0.0) 0.26 Lead noise, n (%) 3 (2.2) 3 (4.5) 0 (0.0) 0 (0.0) 0.74 Other complications, n (%) 14 (10.4) 13 (19.7) 1 (2.0) 0 (0.0) 0.61 Cardiac tamponade, n (%) 1 (0.7) 1 (1.5) 0 (0.0) 0 (0.0) 0.92 Lead dysfunction, n (%) 9 (6.7) 8 (12.2) 1 (2.0) 0 (0.0) 0.61 Device migration, n (%) 1 (0.7) 1 (1.5) 0 (0.0) 0 (0.0) 0.92 Infection, n (%) 4 (3.0) 4 (6.1) 0 (0.0) 0 (0.0) 0.67 Pneumothorax, n (%) 3 (2.2) 3 (4.5) 0 (0.0) 0 (0.0) 0.74 Values are mean ± SD or n (%). SD = sudden death. VT = ventricular tachycardia. VF = ventricular fibrillation. ICD = implantable cardioverter defibrillator A total of 58 appropriate ICD shocks due to sustained VA occurred in 12 patients (18.2%) with cardiogenic syncope. No patient was successfully treated only with ATP. The mean was 5.2±3.8 shocks per patient (range 1–12). The mean time to the first ICD therapy was 2.6±2.8 years since diagnosis. All patients were male (p=0.02); and 4 patients (33.3%) were <40 years old (p=0.76). Five patients (41.7%) had family history of SD (p=0.30). Nine patients had a genetic test done (75.0%) and 3 of them (33.3%) carried pathogenic rare variants in the
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Journal Pre-proof SCN5A gene (p=0.61). Seven patients (58.3%) presented spontaneous type 1 ECG (p=0.06); and 6 (50.0%) had an inducible EPS (p=0.08). Four of these patients (33.3%) received oral quinidine as part of their treatment. No ablation was attempted. The incidence rate of major cardiac events in patients with cardiogenic syncope was 2.6 per 100 person-years; 3.7 per 100 person-years in patients with both cardiogenic syncope and spontaneous type 1 ECG; and 3.8 per 100 person-years in patients with cardiogenic syncope, spontaneous type 1 ECG and inducible EPS. In the univariate analysis, parameters associated with major events during follow-up included cardiogenic syncope before diagnosis (HR 6.3; 95% IC 1.1-10.4; p=0.05); spontaneous type 1
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ECG (HR 3.7; 95% IC 1.3-10.5; p=0.01); and inducible EPS (HR 2.8; 95% IC 1.1-8.8;
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p=0.05). No parameter remained as independent predictor of major events in multivariate
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analysis (Table 3).
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Table 3. Parameters associated with major events in follow-up in Brugada Syndrome patients with syncope Major Multivariate events Univariate analysis analysis H p H 95% p Variable n (%) R 95% IC value R IC value Age at diagnosis ≤ 40 y 7 (12.1) 1.1 0.4 - 3.4 0.81 Male 16 (16.7) 4.5 0.5 - 4.7 0.16 Proband 14 (12.9) 1.0 0.2 - 4.5 0.98 Family history of sudden death 5 (14.3) 1.6 0.5 - 4.7 0.39 Cardiogenic syncope before 1.1 0.8 diagnosis 15 (18.1) 6.3 10.4 0.05 2.0 9.4 0.08 1.3 0.8 Spontaneous type 1 ECG 8 (20.0) 3.7 10.5 0.01 2.7 9.2 0.09 QRS length in V1-V2 ≥ 150 ms 6 (16.5) 2.4 0.8 - 6.9 0.10 QTc duration in V1-V2 ≥ 450 ms 2 (7.4) 1.9 0.4 - 8.4 0.42 R wave voltage in aVR ≥ 3 mV 4 (13.7) 1.6 0.4 - 5.8 0.48 0.4 R/Q ratio in aVR ≥ 0.75 5 (12.7) 4.5 14.9 0.12 QRS fragmentation 4 (18.0) 2.3 0.6 - 8.3 0.21 Early repolarization 1 (20.0) 2.2 0.6 - 8.3 0.32 0.5 Atrial fibrillation before diagnosis 2 (18.2) 2.3 10.6 0.27 0.3 Inducible EPS 7 (21.2) 2.8 1.1 - 8.8 0.05 1.0 3.4 0.09 H-V interval >55 ms 3 (15.7) 1.3 0.4 - 4.9 0.68 17
Journal Pre-proof SCN5A mutation carrier 3 (11.5) 1.1 0.3 - 4.6 0.86 Major events refer to the actual incidence and percentage in each category. Results obtained by Cox regression analysis. EPS = electrophysiology study. HR = hazard ratio. CI = confidence interval Fifteen patients (11.1%) presented a total of 33 episodes of non-sustained VT during followup. The mean was 2.5±2.9 episodes of non-sustained VT per patient (range 1–10). Fourteen of these (93.3%) were patients with cardiogenic syncope who also experienced sustained VA
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with appropriate ICD therapies.
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Journal Pre-proof One male patient with cardiogenic syncope, a non-spontaneous type 1 ECG, an inducible EPS and ICD implanted, experienced 1 episode of vasovagal syncope in follow-up. The rate of ventricular pacing was <1% and no ventricular arrhythmias were detected during the episode. Of the total of patients with vasovagal syncope, 3 patients (5.9%) experienced 3 episodes of vasovagal syncope during follow-up (1 episode per patient). Two of these patients, were female with non-spontaneous type 1 ECG and non-inducible EPS. In both patients, a looprecorder was implanted due to recurrent episodes of syncope before diagnosis. No heart rhythm abnormalities were observed during follow-up. The third patient was a male patient
syncope episode in follow-up after a blood extraction test.
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with non-spontaneous type 1 ECG and non-inducible EPS who experienced a clearly reflex
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Twelve patients (8.9%) presented ≥1 episode of atrial fibrillation (AF) during follow-up with no significant differences among groups according with the type of syncope (p=0.15).
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Treatment for AF included oral quinidine in 6 patients (50.0%) and pulmonary vein ablation
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in 5 patients (41.7%).
Two patients (3.0%) with cardiogenic syncope and ICD presented signs of sinus node
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dysfunction during follow-up. Three patients (4.5%) with cardiogenic syncope and ICD presented atrio-ventricular block during follow-up, 1 of them had a baseline H-V interval of
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88 ms. Five patients (7.6%) with cardiogenic syncope required >1% of pacing during follow-
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Four male patients (3.0%) died after 5.9±2.3 years of follow-up. The mean age at death was 58.0±23.3 years. One patient died of septic shock due to pneumonia with a concomitant chronic obstructive pulmonary disease. Two patients, who rejected an ICD implantation, presented SD 4 and 7 years after diagnosis, respectively (see Follow-up section). Finally, a 34-year-old male presented electrical storm during a surgical lead extraction procedure 42 months after ICD implantation (Table 2).
Inappropriate ICD therapies and complications Thirty-one inappropriate ICD therapies were documented in 6 patients (4.4%) during followup. Five (83.3%) were patients with cardiogenic syncope; and 1 (16.7%) with vasovagal syncope (p=0.46). The mean number of inappropriate ICD therapies per patient was 3.3±2.9 19
Journal Pre-proof (range 1–13). The causes of inappropriate therapies were: AF (3 patients); and lead dysfunction (3 patients). The 3 patients with lead dysfunction underwent lead replacement; 1 of them experienced a pocket infection and subsequently had a subcutaneous ICD. Two patients with inappropriate therapies due to AF underwent pulmonary vein ablation, remaining asymptomatic after the procedure. The third patient was treated successfully with oral quinidine. Fourteen patients (10.4%) had ICD-related complications. Seven patients (5.2%) had periprocedural complications: cardiac tamponade (1 patient); pneumothorax (3 patients); and device infection (4 patients, 1 of them complicated with infective endocarditis). Non-peri-
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procedural complications were documented in 9 patients (6.7%): lead dysfunction (9 patients);
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and device migration requiring ICD reimplantation (1 patient) (Table 2).
20
Journal Pre-proof DISCUSSION
The main and foremost finding of this long-term prospective registry is that an appropriate classification of syncope through a thorough clinical history allows an appropriate risk stratification in patients with BrS. To date, this is the cohort with the longest follow-up to report the natural history of patients with BrS and syncope. Syncope is the first clinical manifestation of BrS in 25-35% (28.5% in the present cohort) (35). Of those, approximately half can be classified as clearly cardiogenic (48.9% in this cohort) (14); these patients, show an unfavourable prognosis and should be protected with an ICD (7,
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8). The event rate in our population was 2.6 per 100 person-years. All major events occurred
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in patients with syncope clinically classified as cardiogenic, while no events occurred in patients with vasovagal or undefined syncope, findings that are in line with previously
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published data (14).
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The importance of an accurate classification of the syncope event lies not only in the different prognosis that patients have according to the type of syncope (4, 5, 14, 15), but also in the
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relatively high incidence of non-arrhythmic syncope of BrS patients (2, 14). In this study, 37.8% of patients presented a syncope event classified as vasovagal and none of these patients
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presented major cardiac events in follow-up. A detailed medical history interview is crucial for a correct syncope classification (16, 17) and each syncopal event should be methodically
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evaluated, as mixed mechanisms may be present in up to 13% of patients. All related information, including triggers like fever, prodromes, palpitations and activity during syncope
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and medication should be obtained.
The 2017 ACC/AHA/HRS and 2018 ESC guidelines for the diagnosis and management of patients with syncope recommend ICD implantation in patients with syncope of suspected arrhythmogenic origin and to avoid it in individuals with suspected reflex-mediated syncope (16, 17). Unfortunately, an accurate classification of a syncope episode in BrS patients may be frequently challenging especially in the presence of multiple episodes or family history of SD. In these cases, an EPS might be a helpful tool to establish a therapeutic strategy (class IIb) (7, 8, 16-18), although the evidence to support this practice is lacking. In this study, VA inducibility in EPS was significantly higher in patients with cardiogenic syncope, and 21.2% patients with inducible EPS presented major events in follow-up (p=0.04). This outcome supports, in a cohort with a longer follow-up, previously published data in BrS patients with syncope (19), in which the highest risk of ventricular events corresponds to patients with cardiogenic syncope and inducible EPS. 21
Journal Pre-proof Programmed stimulation may identify patients with BrS at increased risk for cardiac arrest, but the association appears most apparent in individuals induced with single or double extrastimuli (18). In this study, 71.4% of patients with inducible VA and arrhythmic events in follow-up, presented positive inducibility EPS with ≤2 ventricular extrastimuli. However, the most helpful characteristic of the EPS is its negative predictive value for major events (92.4% in this study); especially in patients with syncope with unclear characteristics and noninducible EPS in which no events were shown in follow-up.
Therefore, an EPS could
represent a helpful tool in patients with syncope episodes after clinical risk stratification, when the clinical classification is challenging due to unclear characteristics of the syncope
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event. According to this study, clinical features effectively stratify individuals at highest and
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lowest risk of VA. Thus, programmed stimulation may be most useful for predicting arrhythmia in undefined clinical stratification to prevent unnecessary ICD implantations,
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syncope in this cohort presented a positive TTT).
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especially due to the TTT showed to be highly unspecific (60% of patients with cardiogenic
Preventing unnecessary ICD implantations is crucial especially due to the ICD-related
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complications (8). In this study, 10.4% patients had complications and 4.4% experienced inappropriate shocks, of these patients 42.9% and 33.3% respectively also received
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appropriate shocks. Therefore, an accurate patient selection is highly recommendable. In this study, a loop-recorder implant was decided individually according with clinical
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presentation, family history and consensual decision with the patient. Five patients with undefined syncope underwent a loop-recorder implant. However, none of these patients had
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another syncope event during follow-up. Conversely, in the vasovagal syncope group, 3 patients received a loop-recorder due to recurrent episodes. Two of these patients had another syncope during follow-up. Therefore, a loop-recorder could help in recurrent vasovagal syncope to rule out arrhythmic events. One final important findings to highlight in this study is that patients with cardiogenic syncope presented a baseline ECG with a wider QRS complex in right precordial leads: 127.1±29.5 ms in patients with cardiogenic syncope versus 115.1±20.4 ms in patients with vasovagal syncope and 112.4±16.4 ms in patients with undefined syncope (p=0.02). Some studies have reported a wide QRS complex in right precordial leads as an important indicator to prevent cardiac events in BrS patients (20, 21). This aspect, that should be further validated in larger studies, may be a useful tool the syncope classification in episodes of unclear characteristics.
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Study limitations The present study has several strengths. It is a prospective registry of a relatively large cohort of consecutive BrS patients with syncope from a single centre and very few patients were lost after a long follow-up. However, there are limitations to acknowledge. Although this is a prospectively-design registry the nature of this specific analysis was retrospective. The type of syncope, presence of a baseline type 1 pattern and an inducibility of ventricular arrhythmias, were predictors of major events in follow-up in the univariate analysis but not in the
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multivariate. This is possibly due to the low number of events and consequently lack of
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statistical power. Even though this is the longest follow-up reported in the literature, 7.7±5.6 years may not be sufficient time to fully understand the true outcome of BrS patients with
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syncope.
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CONCLUSIONS
An accurate syncope classification is crucial in BrS patients and allows a correct stratification of future arrhythmic risk. When the clinical syncope characteristics are unclear and the classification is challenging, an EPS may be helpful to prevent unnecessary ICD
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implantations in case of no inducibility.
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