Author + information
- Esther Scheirlynck, MDa,
- Monica Chivulescu, MDb,
- Øyvind H. Lie, MD, PhDb,
- Andreea Motoc, MDa,
- Jorgos Koulalisa,
- Carlo de Asmundis, MD, PhDc,
- Juan Sieira, MD, PhDc,
- Gian-Battista Chierchia, MD, PhDc,
- Pedro Brugada, MD, PhDc,
- Bernard Cosyns, MD, PhDa,
- Thor Edvardsen, MD, PhDc,
- Steven Droogmans, MD, PhDa and
- Kristina H. Haugaa, MD, PhDb,∗ ()
- aCentrum voor Hart-en Vaatziekten, Universitair Ziekenhuis Brussel- Vrije Universiteit Brussel, Brussels, Belgium
- bDepartment of Cardiology, Oslo University Hospital, Rikshospitalet-Institute for Clinical Medicine, University of Oslo, Oslo, Norway
- cHeart Rhythm Management Center, Centrum voor Hart- en Vaatziekten Universitair Ziekenhuis Brussel -Vrije Universiteit Brussel, Postgraduate program in Cardiac Electrophysiology and Pacing, European Reference Network GUARD-Heart, Brussels, Belgium
- ↵∗Address for correspondence:
Dr. Kristina H. Haugaa, Department of Cardiology, Oslo University Hospital, Rikshospitalet, PO Box 4950 Nydalen, 0424 Oslo, Norway.
Objectives This study aimed to assess the presence of echocardiographic and electrocardiographic similarities in patients with Brugada syndrome (BrS) and arrhythmogenic cardiomyopathy (AC) and the prevalence and prognostic value of AC structural/electrical features in patients with BrS.
Background BrS and AC are genetic cardiac diseases with high risk for sudden cardiac death. Although BrS and AC display different features, previous reports suggest a phenotypic overlap.
Methods We acquired clinical data, electrocardiogram, and transthoracic echocardiography in patients with BrS and AC. We assessed the presence of AC diagnostic criteria according to the 2010 AC task force criteria for right ventricular outflow tract (RVOT), fractional area change, depolarization, and repolarization in the patients with BrS. We compared arrhythmic outcome in BrS patients with and without AC structural/electrical criteria.
Results A total of 116 BrS and 141 AC patients were included. AC electrical features were present in 28 (24%) BrS patients and structural features in 97 (84%) BrS patients. BrS patients with an RVOT or depolarization AC criterion showed a trend towards worse severe arrhythmia-free survival compared to BrS patients without (p = 0.05). The criterion for RVOT dilation showed high sensitivity and improved detection of arrhythmic BrS patients when added to type 1 electrocardiogram pattern and syncope (area under the curve 0.73 [95% confidence interval: 0.59 to 0.87] vs. area under the curve 0.79 [95% confidence interval: 0.69 to 0.90]); p = 0.009).
Conclusions In this large cohort comparison, Brugada syndrome (BrS) and arrhythmogenic cardiomyopathy patients had phenotypic overlap. The presence of arrhythmogenic cardiomyopathy diagnostic criteria in BrS patients was associated with a trend towards higher arrhythmic risk. The right ventricular outflow tract dilation criterion improved detection of arrhythmic BrS patients.
Brugada syndrome (BrS) and arrhythmogenic cardiomyopathy (AC) are both characterized by high risk for sudden cardiac death (1). BrS has been categorized as a primary electrical heart disease without structural abnormalities (2). In AC on the other hand, myocardial dysfunction caused by desmosomal alterations and ultimately fibrofatty replacement is a hallmark (3). Although BrS and AC have different features, pre-clinical research and clinical cases suggest the existence of a phenotypic overlap between these 2 diseases (4,5). Studies directly comparing clinical, electrocardiogram (ECG), and imaging features of BrS and AC patients are scarce.
We aimed to assess the presence of electrical and structural overlap in BrS and AC patients. We hypothesized that BrS patients with AC features have worse prognosis than those without these electrical or structural changes.
In this multicenter study, patients with BrS were included at University Hospital Brussels, Universitair Ziekenhuis Brussel, Belgium, and patients with AC were included at Oslo University Hospital, Rikshospitalet, Norway. BrS patients from a previous study (6) were contacted to perform a new study visit between May 2018 and September 2018 with increased focus on right ventricular outflow tract (RVOT) acquisitions. AC patients were consecutively recruited when visiting the outpatient clinic between July 2006 and February 2018 (7).
BrS patients had been diagnosed based either on a spontaneous or drug-induced ST segment elevation with a type 1 morphology of ≥2 mm in 1 or more leads among the right precordial leads (V1-V2) positioned in the second, third, or fourth intercostal space (1). AC patients were diagnosed according to task force criteria (TFC) (3). Patients included before 2010 were re-evaluated accordingly. Family members with AC, diagnosed by cascade genetic screening, were included only if they were mutation positive as described previously (8). AC family members diagnosed by cascade genetic screening without previous symptoms were defined as having early-phase AC compared to overt disease in probands.
All patients were minimum 16 years of age with no history of ischemic disease or more than mild valvular heart disease. We excluded patients with atrial fibrillation or pacing during transthoracic echocardiography.
Written informed consent was obtained from all individuals. This study was performed in accordance with the Declaration of Helsinki and was approved by the Ethics Committee of UZ Brussel and the Regional Committee for Medical Research Ethics in South Eastern Norway.
Clinical characteristics, initial presentation, and the occurrence of syncope of suspected arrhythmic origin were collected through anamnesis and a thorough search of the medical records. Severe ventricular arrhythmia was defined as a history of sustained ventricular tachycardia or ventricular fibrillation documented on 12-lead ECG, Holter monitor, implantable cardioverter-defibrillator (ICD) monitoring, appropriate ICD shock, or aborted cardiac arrest. The proband was defined as the first patient in a family to be diagnosed. We reported genetic test results and likely pathogenic or pathogenic variants were referred to as mutations (9).
Standard 12-lead ECG was acquired the same day as the echocardiography. Parameters assessed on the ECG were: PQ interval, QRS duration, QTc interval, and the presence of a type 1 BrS pattern or right bundle branch block (Supplemental Figure 1) (2). The presence of depolarization abnormalities (major: epsilon waves; minor: terminal activation duration [TAD] ≥55 ms) and repolarization abnormalities (major or minor T-wave inversions) according to AC TFC was assessed in all patients (3). Negative T-waves as part of a type 1 BrS pattern were not considered for repolarization criteria. ECG evaluation was performed blinded to other patient data.
Transthoracic echocardiography was performed using a commercial cardiac ultrasound system (Vivid 7, Vivid E9 or Vivid E95, GE Vingmed Ultrasound, Horten, Norway). We acquired standard parasternal long- and short-axis (PSAX) images, apical 4-, 2- and 3-chamber views, and a right ventricle (RV)–focused 4-chamber view in all patients (10). Analysis was performed offline blinded for arrhythmic outcome (EchoPac, version 202, GE Vingmed Ultrasound).
The left ventricle end-diastolic and end-systolic volume were measured and left ventricular function was assessed by ejection fraction (modified Simpson’s biplane method) and global longitudinal strain defined as the mean of the peak systolic strain in the 16 left ventricular segments (10). Tricuspid annular plane systolic excursion (TAPSE) was obtained by M-mode through the tricuspid annulus on the 4-chamber view. We measured RVOT proximal diameter from the PSAX view and RV basal diameter, end-diastolic and end-systolic area from the RV-focused 4-chamber view. Fractional area change (FAC) (11) and RV longitudinal strain from the 3 RV free wall segments were calculated.
The presence of right sided structural abnormalities according to AC TFC (majorly increased RVOT diameter: PSAX RVOT ≥36 mm or PSAX RVOT indexed ≥21 mm/m2; minorly increased RVOT diameter: PSAX RVOT ≥32 mm to <36 mm or PSAX RVOT indexed ≥18 mm/m2 to <21 mm/m2; majorly decreased FAC: FAC ≤33%; minorly decreased FAC: FAC >33% to ≤40%) was assessed in all patients (3).
Continuous data was presented as mean ± SD or median (interquartile range). Categorical data was presented as number (%). Comparisons were performed using T-test, Mann-Whitney U test, chi Square or Fischer exact test as appropriate. We reported incidence rate of arrhythmias. Survival free of severe arrhythmia of BrS patients with and without predefined AC features was presented with Kaplan-Meier plots and the log rank test.
We sought to build risk models associated with severe ventricular arrhythmias. New risk factors were identified by comparing the prevalence of AC diagnostic TFC between arrhythmic and non-arrhythmic BrS patients. Significant parameters were included in the risk models, on top of previously confirmed risk factors type 1 ECG and syncope (1). Odds ratio with 95% confidence interval (CI) for severe ventricular arrhythmia was calculated by univariate logistic regression for newly identified and pre-specified risk factors. The area under the curve of the receiver operator characteristics curve, chi Square statistics and the Akaike information criterion were used to compare the discriminating capacity of the models.
Intra- and interobserver agreement of RVOT measurements were assessed using intraclass correlation coefficient for absolute agreement in 20 randomly selected subjects, analyzed by the same operator minimum 2 months apart, and by a second operator. Statistical analysis was performed using SPSS version 25.0 (SPSS Inc., Chicago, Illinois) and risk model comparisons by Stata/SE 15.1 (StataCorp LLC, College Station, Texas).
We included 116 BrS patients (51 ± 14 years old, 62 [53%] females) and 141 AC patients (age 47 ± 17 years, 69 [49%] females) (Supplemental Figure 2). BrS patients consisted of mostly low-risk patients with 61 (53%) individuals diagnosed after cascade family screening and 90 (78%) patients who never presented a spontaneous type 1 ECG. The AC patients consisted of 100 (71%) with definite diagnosis, 22 (16%) with borderline diagnosis, and 19 (13%) with possible diagnosis according to TFC. Among AC family members (early-phase) 17 (23%) had major and 13 (18%) had minor structural criteria.
BrS and AC: ECG
QRS duration was longer in BrS than in AC (104 [IQR: 95 to 122] ms vs. 94 [IQR: 86 to 102] ms, p < 0.001) (Table 1) as a result of prolonged QRS duration in BrS patients with severe ventricular arrhythmias (Figure 1). PR intervals were longer in both arrhythmic BrS and AC than in the non-arrhythmic patients, whereas QTc was mainly prolonged in arrhythmic AC. The ECGs showed minor depolarization and repolarization abnormalities according to AC diagnostic criteria in 28 (24%) of the BrS patients, but no epsilon waves or major T-wave inversions were observed (Central Illustration, Table 2). Two BrS patients had a possible and 1 patient had a borderline AC diagnosis according to the TFC, as a result of a minor arrhythmic AC criterion (i.e., ventricular tachycardia) and 1 or 2 electrical criteria (Figure 2). BrS patients with severe ventricular arrhythmia more frequently had presented a spontaneous type 1 pattern than those without arrhythmias (7 [54%] vs. 19 [18%], p = 0.004). None of the AC patients presented a spontaneous type 1 pattern.
BrS and AC: echocardiography
AC patients had worse left and right ventricular function and larger RVOT/RV diameters than BrS patients (Table 1). BrS patients with ventricular arrhythmias and mutation positive early-phase AC patients had similar echocardiographic characteristics (Supplemental Table 1). Consequently, the differences between BrS and AC patients were mainly driven by worse function and increased cavities in AC patients with ventricular arrhythmias (Figure 1, Supplemental Table 2).
The majority of BrS patients had an RVOT diameter and/or FAC compatible with minor or major AC TFC (n = 97, 84%) (Table 2). All BrS patients who had experienced a severe ventricular arrhythmia (n = 13, 100%) had minor or major RVOT diameter dilation as defined by the AC TFC (Figure 3). No BrS patient fulfilled structural AC criteria due to the requirement of RV akinesia, dyskinesia, or aneurysm in addition to RVOT dilation.
There was excellent intraobserver and interobserver agreement for RVOT diameter (intraclass correlation coefficient 0.98 [95% CI: 0.96 to 0.99, p < 0.001] and 0.96 [95% CI: 0.90 to 0.98, p < 0.001]).
Outcome in BrS with AC features
Thirteen BrS patients experienced a severe ventricular arrhythmia (Table 1). Six patients were asymptomatic at diagnosis, whereas 7 had ventricular arrhythmia before diagnosis. Of the 7 patients with prior ventricular arrhythmias, 2 had recurrent arrhythmias during follow-up.
BrS patients with a spontaneous type 1 ECG had a 5-fold increased odds of severe ventricular arrhythmias compared to BrS patients with a drug-induced type 1 pattern (OR: 5.2; 95% CI: 1.6 to 17.1; p = 0.007). A history of syncope tended to be more frequent among arrhythmic compared to non-arrhythmic BrS patients (9 [69%] vs. 45 [44%], p = 0.09).
BrS patients with dilated RVOT diameter or prolonged TAD had more frequently severe arrhythmias compared to BrS patients without these AC features (p = 0.05) (Figure 3). The presence of dilated RVOT was associated with a higher incidence rate of severe ventricular arrhythmia (0.3% [95% CI: 0.2 to 0.5%] vs. 0.0% per patient-year; p = 0.03). Adding RVOT ≥32 mm or RVOT indexed ≥18 mm to a risk model comprising type 1 ECG pattern and syncope improved detection of arrhythmic BrS patients (area under the curve from 0.73 [95% CI: 0.59 to 0.87) to 0.79 [95% CI: 0.69 to 0.90], p = 0.009; chi square from 8.6 to 14.4, p < 0.05; Akaike information criterion from 74.6 to 72.3) (Figure 4⇓).
None of the BrS patients with normal RVOT according to the AC criteria had experienced severe ventricular arrhythmias, irrespective of the presence of a spontaneous type 1 ECG pattern or history of syncope. Thus, the absence of an RVOT minor or major criterion had a 100% negative predictive value for the occurrence of severe ventricular arrhythmias.
This is the first study combining clinical, ECG, and echocardiography data in a large cohort of BrS and AC patients showing a substantial overlap in electrical and structural changes. BrS patients with electrical and/or echocardiographic features of AC had worse prognosis regarding severe arrhythmias. Detection of BrS patients with severe arrhythmias improved when adding dilated RVOT to known risk markers spontaneous type 1 ECG and previous syncope. Furthermore, a normal RVOT diameter (<32 mm or indexed RVOT diameter <18 mm) in BrS was associated with the absence of arrhythmic events, also in patients with a spontaneous type 1 ECG and previous syncope. These findings indicate a possible clinical value of repeated echocardiographic assessments in risk stratification for ventricular arrhythmias.
Pathophysiologic basis for a BrS-AC continuum
Our study has shown a continuum between BrS and AC both in electrical and structural changes showing 24% of BrS patients with electrical and as many as 84% with structural changes associated with AC. We found similar slightly pathologic left- and right-sided function and dimensions in BrS patients and early-phase AC patients, highlighting the overlap between the diseases and in line with previous studies challenging the earlier concept of BrS as a purely electrical disease (12,13). Previous cardiac magnetic resonance imaging studies have shown structural and functional abnormalities in BrS including RVOT dilation, fat infiltration, wall motion abnormalities (14,15), and reduced RV and left ventricular function (12,13).
A genetic overlap between BrS and AC in a subset of patients has previously been suggested (4,16). Experimental research suggested the connexome as a common molecular origin for both diseases (17). Desmosomes (assuring mechanical connection of cardiomyocytes) and sodium channels (important for electrical conduction) are closely related and part of the connexome. Therefore, defective desmosomal proteins can alter electrical conduction associated with a BrS phenotype (18,19), whereas sodium channel dysfunction may cause myocardial fibrosis and worse cardiac function (20,21). Connexome disease would therefore suggest a continuum of BrS- and AC-associated features rather than 2 completely distinct syndromes.
AC structural alterations in BrS and the association with ventricular arrhythmias
As expected, AC patients had more ventricular arrhythmias, worse contractile function, and larger RVOT dimensions compared to BrS patients. However, the majority of BrS patients met the requirements for FAC or RVOT diameter as described in the TFC for diagnosis of AC. Importantly, AC-related changes were associated with worse arrhythmic outcome in BrS. All BrS patients who had experienced an arrhythmic event fulfilled the RVOT criterion for dilation. Adding RVOT dilation increased the detection of severe events in BrS on top of the known risk factors spontaneous type 1 ECG and previous syncope. Consequently, changes in the RVOT structure seemed to be a very sensitive marker for arrhythmic risk, indicating potential usefulness as a negative predictive marker for ventricular arrhythmias. However, the number of patients with a normal RVOT was limited, and this finding should be confirmed in a larger cohort. RVOT size has previously been associated with the presence of a spontaneous type 1 ECG pattern, indicating a link between structural alterations and conduction disorders in BrS (22). Also, our group’s previous findings supported that subtle structural and functional changes are present and associated with ventricular arrhythmias in both early AC and BrS (6,23,24), making differential diagnosis challenging. Previous imaging studies comparing AC and BrS showed lower right ventricle strain in AC, similar to our findings, but did not report arrhythmic outcome (25,26).
ECG overlap in BrS and AC
Presence of AC electrical criteria in BrS was less evident compared to structural changes. Only minor T-wave inversions were observed in the BrS patients, without an association with outcome, and none of the BrS patients presented epsilon waves. Nevertheless, TAD prolongation was observed in 17 of 116 BrS patients and these patients tended to have a poorer arrhythmia-free survival. A previous study found epsilon-like waves in 2 of 47 subjects at baseline ECG and in 4 more patients after sodium channel blocker administration, as well as prolonged TAD in 40% of their BrS patients, but no outcome data were available (27). A prolonged TAD might represent abnormal depolarization in the epicardial RVOT and therefore be associated with an increased vulnerability for ventricular arrhythmias (28). We did not observe spontaneous BrS type 1 ECG patterns in the AC patients, yet previous reports have shown both spontaneous and sodium channel blocker–induced ST segment elevations in patients diagnosed with AC (5,29).
Risk stratification for ventricular arrhythmias in BrS is challenging and the decision to implant a primary prevention ICD is difficult. Our study showed that echocardiographic assessment of patients with BrS may improve risk stratification for ventricular arrhythmias. The presence of RVOT dilation significantly increased detection of arrhythmic events, whereas a normal RVOT diameter was associated with excellent prognosis. In particular, risk stratification for asymptomatic BrS patients with type 1 ECG is challenging and current guidelines do not recommend ICD implantation in these cases (1). Repeated echocardiographic assessments of RVOT dimensions could potentially increase confidence in decisions to implant or not implant a primary prevention ICD. Given the variability inherent to echocardiographic parameters and the subtlety of structural changes in BrS, RVOT diameter has presumably more potential as part of a multifactorial risk score than as a stand-alone parameter. These preliminary findings must be confirmed in larger prospective studies.
Furthermore, the concept of a continuous clinical spectrum rather than delineated diseases underlines the importance of patient specific management.
This was an observational study with retrospective event adjudication and inclusion of the 2 patient groups at 2 different sites. Our study included a higher proportion of BrS women compared to other studies. This may be explained by the extensive family screening performed in our center. Accordingly, the number of events in BrS patients was limited.
Cardiac arrest is a strong predictor of recurrent arrhythmias during follow-up in BrS patients and previous arrhythmia may have biased our findings. However, only 2 of 7 patients with arrhythmic events before diagnosis had a recurrent arrhythmia during follow-up. Therefore, prior ventricular arrhythmia is unlikely to have affected the results of prognostic factors in this study cohort.
Holter monitoring and cardiac magnetic resonance was not available for the majority of the BrS patients, and was therefore not included in this study. We did not perform sodium channel blocker provocation tests in the AC patients.
In this large cohort comparison, BrS and AC patients had phenotypic overlap. The presence of AC diagnostic criteria including RVOT dilation was associated with a higher arrhythmic risk in BrS patients. No severe ventricular arrhythmias occurred in BrS patients without RVOT dilation, irrespective of the presence of syncope or a type 1 ECG pattern, indicating a potential added value in risk stratification in BrS patients.
COMPETENCY IN MEDICAL KNOWLEDGE: Some BrS patients present electrical and echocardiographic features associated with AC. These were associated with more ventricular arrhythmias.
TRANSLATION OUTLOOK: Phenotypic overlap between BrS and AC indicates a clinical continuum rather than delineated diseases. Big data might help to elucidate the genetic background of hereditary cardiac disease and to understand the overlap between different types of cardiomyopathies and/or primary arrhythmia disorders.
This work was supported by a public grant (203489/030) from the Norwegian Research Council, Norway. Dr. Scheirlynck has received grants from the European Society of Cardiology in the form of an ESC Research Grant. Dr. de Asmundis has received honoraria for teaching purposes and proctoring from AF solutions and Medtronic; is a steering committee member with ETNA-AF-Europe Daiichi Sankyo Europe; and has received grants on behalf of the center from Biotronik, Medtronic, St. Jude Medical, Abbot, Livanova, and Boston Scientific. Dr. Chierchia has received honoraria for teaching and proctoring from AF solutions and Medtronic. Dr. Brugada has received honoraria for speaking from Biotronik and Medtronic. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
The authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’ institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information, visit the JACC: Clinical Electrophysiology author instructions page.
- Abbreviations and Acronyms
- arrhythmogenic cardiomyopathy
- Brugada syndrome
- fractional area change
- implantable cardioverter-defibrillator
- parasternal short-axis view
- right ventricular outflow tract
- terminal activation duration
- tricuspid annular plane systolic excursion
- task force criteria
- Received November 4, 2019.
- Revision received April 27, 2020.
- Accepted May 20, 2020.
- 2020 The Authors
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