Author + information
- Received October 10, 2017
- Revision received December 17, 2017
- Accepted January 8, 2018
- Published online March 12, 2018.
- Michael Papadakis, MBBS, MDa,b,
- Efstathios Papatheodorou, MDa,b,
- Greg Mellor, MBChB, MDa,b,
- Hariharan Raju, MBChB, PhDa,b,
- Rachel Bastiaenen, PhDa,
- Yanushi Wijeyeratne, BMBSa,
- Sara Wasim, BSca,
- Bode Ensam, MBChBa,b,
- Gherardo Finocchiaro, MDa,b,
- Belinda Gray, BSc(Med), MBBS, PhDa,
- Aneil Malhotra, MBBChir, MA, MSC, PhDa,b,
- Andrew D’Silva, MBBSa,b,
- Nina Edwards, BSca,
- Della Cole, RGN BSca,
- Virginia Attard, MSca,
- Velislav N. Batchvarov, MD, PhDa,
- Maria Tome-Esteban, MD, PhDa,
- Tessa Homfray, MBBSa,
- Mary N. Sheppard, MB, BCh, BAO, MDa,
- Sanjay Sharma, MBChB, MDa,b,∗ ( and )
- Elijah R. Behr, MBBS, MDa
- aCardiology Clinical Academic Group, St. George's, University of London and St. George's University Hospitals NHS Foundation Trust, London, United Kingdom, European Reference Network for rare and low prevalence diseases of the heart, Guard-Heart
- bUniversity Hospital Lewisham, Lewisham, United Kingdom
- ↵∗Address for correspondence:
Dr. Sanjay Sharma, Cardiology Clinical Academic Group, St George’s, University of London, Cranmer Terrace, London SW17 0QT, United Kingdom.
Background Familial evaluation after a sudden death with negative autopsy (sudden arrhythmic death syndrome; SADS) may identify relatives at risk of fatal arrhythmias.
Objectives This study aimed to assess the impact of systematic ajmaline provocation testing using high right precordial leads (RPLs) on the diagnostic yield of Brugada syndrome (BrS) in a large cohort of SADS families.
Methods Three hundred three SADS families (911 relatives) underwent evaluation with resting electrocardiogram using conventional and high RPLs, echocardiography, exercise, and 24-h electrocardiogram monitor. An ajmaline test with conventional and high RPLs was undertaken in 670 (74%) relatives without a familial diagnosis after initial evaluation. Further investigations were guided by clinical suspicion.
Results An inherited cardiac disease was diagnosed in 128 (42%) families and 201 (22%) relatives. BrS was the most prevalent diagnosis (n = 85, 28% of families; n = 140, 15% of relatives). Ajmaline testing was required to unmask the BrS in 97% of diagnosed individuals. The use of high RPLs showed a 16% incremental diagnostic yield of ajmaline testing by diagnosing BrS in an additional 49 families. There were no differences of the characteristics between individuals and families with a diagnostic pattern in the conventional and the high RPLs. On follow-up, a spontaneous type 1 Brugada pattern and/or clinically significant arrhythmic events developed in 17% (n = 25) of the concealed BrS cohort.
Conclusions Systematic use of ajmaline testing with high RPLs increases substantially the yield of BrS in SADS families. Assessment should be performed in expert centers where patients are counseled appropriately for the potential implications of provocation testing.
Sudden arrhythmic death syndrome (SADS) refers to a sudden cardiac death with negative toxicology, where no structural pathology is identified despite detailed postmortem histopathologic examination (1–3). During the past decade, SADS has emerged as an important subset of sudden death in young individuals, including athletes, and is reported in up to 40% of cases (4–6). Studies in relatives of SADS victims detect an inherited cardiac disease in 22% to 53% of the families, identifying asymptomatic individuals at potential risk of fatal arrhythmias. Ion channelopathies are consistently the predominant diagnosis, although the exact diagnostic yield and the individual conditions identified are dependent on the clinicogenetic protocols used (2,3,5,7–12).
Brugada syndrome (BrS) accounts for a small proportion of diagnoses in most SADS series (2,3,5,7–11). Its prevalence, however, may have been underestimated by selective use of sodium channel blocker provocation testing, the main diagnostic tool for concealed BrS. In addition, studies in patients with established diagnoses of BrS suggest that assessment with higher right precordial leads (RPLs) on electrocardiogram (ECG) increases the detection rate of the Brugada phenotype by up to 40% (13–15). Consequently, placement of leads V1 and V2 in the third and second intercostal space (IS), is advocated in the 2013 diagnostic criteria for BrS and a recent expert consensus report endorsed by the international scientific communities (1,16).
Contemporary studies in relatives of SADS victims but also in individuals with low a priori risk of BrS suggest that systematic use of sodium channel blocker provocation testing with higher RPLs significantly increases the yield of the Brugada phenotype in both populations, raising concerns about its specificity (17,18). We report on the diagnostic yield of a large consecutive cohort of SADS families who underwent standardized comprehensive clinical evaluation including systematic ajmaline provocation testing with higher RPLs as part of the investigative protocol.
We prospectively studied 303 consecutive, unselected SADS families referred to our dedicated inherited cardiac diseases clinics between 2006 and 2015. The authors established a “one-stop-shop” model at St. George's, University Hospitals, and University Hospital Lewisham in London, where relatives of the deceased from throughout the United Kingdom undergo comprehensive evaluation during a single visit.
SADS was defined as a sudden unexpected death in an individual age 1 to 64 years who was last seen alive and well within 12 h of being found dead, had no prior recorded cardiac disease, and who underwent a normal full coroner’s postmortem examination with a negative toxicology screen.
Our investigation protocol included routine use of clinical history and noninvasive evaluation with baseline ECG with conventional (fourth IS) and high (third and second IS) RPLs, echocardiography, and ECG monitoring. Exercise testing was performed in relatives aged above 16 years. An ajmaline provocation test was offered to all first-degree relatives who were older than 16 years, and in younger relatives with cardiac symptoms in whom the aforementioned investigations were normal, or in the presence of the type 2 Brugada ECG pattern. Ajmaline provocation tests were performed using conventional and high RPLs, as per established protocol (13,19). A MAC 5000 or a Cardiosoft recorder (GE Medical, Milwaukee, Wisconsin; 500 samples/s, 4.88 mcV) was used for digital ECG acquisition. All ECGs were subsequently exported to a customized software program where tracings could be magnified to measure basic intervals accurately with on-screen calipers. Further investigations, including signal-averaged ECG, cardiac magnetic resonance imaging (MRI) and epinephrine provocation testing were performed in accordance with clinical findings. Standard diagnostic criteria for inherited cardiac disease were used (1,20–22). The diagnosis of BrS required the presence of a type 1 Brugada pattern in ≥1 of the RPLs (1,16).
This study places emphasis on the comprehensive clinical evaluation of SADS families. Because of a historic limitation of funds and the poor yield in conditions such as BrS (23), genetic testing was not offered in a systematic manner and performed in a limited number of family members with a positive clinical phenotype. Similarly, because of historic limitations on blood and tissue retention, “molecular autopsy” was only available in a small number of cases. Pathogenicity was assessed using the American College of Medical Genetics guidelines (24).
Individuals diagnosed with a cardiac condition were followed-up at our institute or their local cardiology department on an annual basis or more regularly if clinically indicated. Repeat evaluation during follow-up included as a minimum a 12-lead ECG, using high RPLs and 12-lead 24-h ambulatory monitoring in cases of BrS. Further, repeat investigations were at the discretion of the assessing physician. The follow-up period was estimated from time of first assessment to last clinic appointment.
The Student's t-test and the Mann-Whitney U test ware used for analysis of continuous variables, as appropriate. The chi-square test was used for analysis of categorical variables. Two-sided p values <0.05 were considered statistically significant. Univariate and multivariate logistic-regression models were used to assess predictors associated with a positive diagnosis of an inherited cardiac condition and a diagnosis of BrS at familial and individual relative levels. The variables included were the proband’s sex, age of death, ethnicity, circumstances of death, and presence of symptoms before death, the use of an expert cardiac pathology, family history of sudden cardiac death in relatives younger than 50 years of age and the evaluation of more than 1 relatives per family. Stata version 13.0 was used (StataCorp, LP, College, Station, Texas).
The 303 consecutive families comprised 911 relatives (37.9 ± 15.7 years [range, 2 to 83 years], 46% male, 82% first-degree relatives of the deceased) (Figure 1). The characteristics of the deceased are reported in Table 1. Relatives underwent basic noninvasive investigations (Central Illustration). An ajmaline provocation test was performed in 670 individuals (74%). Of the 241 relatives who did not undergo an ajmaline provocation test, 90 were from families with an alternate diagnosis; 86 were younger than 16 years, including 30 relatives of families diagnosed with BrS; 44 had contraindications; 27 refused consent; and 4 had a spontaneous type 1 Brugada pattern on the resting ECG. None of the individuals experienced sustained ventricular tachycardia during the ajmaline test.
An inherited cardiac disease was diagnosed in 128 families (42%) and 201 relatives (22%) (Figure 2). Channelopathies accounted for 92% (n = 118) of the diagnoses with BrS being the predominant condition (n = 85), followed by long QT syndrome (LQTS) (n = 22), catecholaminergic polymorphic ventricular tachycardia (CPVT) (n = 5), and 1 case of progressive cardiac conduction defect (PCCD). Five families showed an overlap syndrome: BrS/LQTS-3 (n = 1), BrS/PCCD (n = 2), BrS/dilated cardiomyopathy (DCM) (n = 1), and CPVT/left ventricular noncompaction (LVNC) (n = 1). Despite a normal postmortem in the proband, a cardiomyopathy was identified in 10 (3.3%) families (Figure 2). In multivariate analysis, evaluation of more than 1 relative in a family (odds ratio: 2.94; 95% confidence interval: 1.64 to 5.24; p < 0.001) was the only predictor of a positive diagnosis as well as the sole predictor of BrS diagnosis (odds ratio: 4.61; 95% confidence interval: 1.68 to 12.60; p < 0.001).
At initial evaluation, 4 (0.4%) individuals showed a spontaneous type 1 Brugada pattern on the resting ECG, of which 2 were seen only on the high RPLs. In 145 (15.9%) individuals, BrS or a Brugada overlap syndrome was diagnosed following a positive ajmaline provocation test. Of those, only 53 (37%) exhibited the type 1 Brugada pattern in the conventional RPLs. The majority (n = 140, 97%) showed the type 1 Brugada pattern in at least 1 of the higher RPLs (Figure 3). At the familial level, of the 87 families with a diagnosis of BrS or Brugada overlap syndrome, 37 (43%) families had at least 1 relative who exhibited the diagnostic Brugada phenotype in the fourth IS. All 87 families had at least 1 relative with the Brugada phenotype in the higher RPLs. There were no differences in the baseline characteristics of individuals or families exhibiting the type 1 Brugada phenotype in the higher RPLs alone, compared with those who exhibited the diagnostic phenotype in the conventional RPLs (Table 2). In 46 families with a diagnosis of BrS, we had the opportunity to perform comprehensive evaluation of both parents of the deceased. In 2 families (4.3%), both parents exhibited a positive ajmaline test.
In 10 (3.3%) families, 1 or more relatives (n = 17) were diagnosed with a definite or possible cardiomyopathy. Seven families were diagnosed with DCM based on the identification of the phenotype in 10 relatives. In 3 families, 4 relatives fulfilled 2010 task force criteria for possible (n = 2) and borderline (n = 1) arrhythmogenic right ventricular cardiomyopathy (ARVC) (20).
Genetic testing was performed in 47 families (36% of affected index relatives and 16% of the total families evaluated), including 36 BrS index cases. Nine (19%) families were genotype positive for a rare pathogenic or likely pathogenic variant (Online Table 1). Of the 36 BrS index cases, 6 (16%) carried a pathogenic or likely pathogenic variant in SCN5A. Cascade testing was undertaken in 32 relatives, of whom 18 (56%) were positive.
Thirty-three SADS cases (11%) underwent molecular autopsy and 2 pathogenic de novo RYR2 mutations (6%) were found in 2 SADS victims with no clinical phenotype in the family (Figure 1, Online Table 2).
Management and follow-up
Appropriate lifestyle modification advice was administered to all relatives with a diagnosis including avoidance of exacerbating medications and treatment of fever in those with BrS. Medical therapy was initiated in 35 relatives for the following: LQTS (n = 15); CPVT (n = 4); cardiomyopathy (n = 11); and overlap syndrome (n = 5). An implantable cardioverter-defibrillator (ICD) was implanted for primary prevention in 19 relatives for cases of BrS (n = 8), CPVT (n = 3), LQTS (n = 1), DCM (n = 1); and overlap syndrome (n = 6). One relative with a diagnosis of PCCD and trifascicular block was implanted with a permanent pacemaker.
During a mean follow-up of 4.31 ± 1.74 years, 9 relatives (6%) with a drug-induced type 1 Brugada pattern developed a spontaneous pattern, 11 (8%) relatives with BrS experienced documented (n = 3) or presumed (n = 8) arrhythmic syncope, and 4 relatives with BrS experienced nonsustained ventricular tachycardia. An ICD was implanted in 9 additional relatives with BrS due to documented or presumed arrhythmic syncope and a relative with PCCD who developed complete heart block. Of the 18 relatives with BrS and an ICD, only 1 experienced an inappropriate shock due to supraventricular tachycardia. One relative diagnosed with BrS and deemed low risk due to the absence of symptoms or the spontaneous type 1 Brugada pattern died suddenly 7 years after initial diagnosis.
During the same follow-up period, 1 patient with an LVNC/CPVT overlap phenotype experienced 1 appropriate and 1 inappropriate shock. One patient with LQTS and 1 patient with cardiomyopathy experienced arrhythmic syncope and were implanted with an ICD.
As far as the authors are aware, this study reports on the largest prospective series of families investigated comprehensively following a SADS death in the literature. The results show a familial diagnostic yield of 42% based on the identification of an inherited cardiac condition in 22% of evaluated relatives. Previous studies evaluating families with SADS have reported diagnostic yields ranging from 13% to 53% due to differing populations and investigative protocols. Consistent with existing literature, channelopathies accounted for the majority of the diagnoses in our series, whereas cardiomyopathies contributed a modest 3% of the cases (2,3,5,7–11,19,25,26). In contrast with previous series in which the diagnosis of LQTS has predominated, our investigation revealed that BrS accounted for the majority of diagnoses and was identified in 28% of the families. Cohort-specific characteristics may partly account for diagnostic disparities as the great majority (71%) of SADS victims in our cohort died at rest or during sleep, which is the predominant mode of death in BrS. Our SADS cohort, however, was very similar to a recent population-based study in New Zealand and Australia, which failed to make any clinical diagnosis of BrS in 91 SADS families (5). This is not surprising as the diagnostic yield of that study was predominantly based on molecular autopsy, which coupled with a low genetic yield in BrS would significantly underestimate its significance. Similar findings have been reported in previous molecular autopsy series in which a diagnosis of LQTS and CPVT predominated (18,27,28).
Impact of ajmaline provocation testing
It is well established that the baseline ECG in the majority of BrS patients may be normal or fluctuate between a normal ECG pattern and the type 1 Brugada pattern (29–32). In our study only 4 of 149 (2.7%) individuals diagnosed with BrS or a Brugada overlap syndrome revealed a spontaneous type 1 Brugada pattern on the baseline ECG, with a further 9 (6%) developing the diagnostic pattern during follow-up. Provocation testing with a sodium channel blocker is therefore recommended to establish the diagnosis. Hong et al. (33) showed the value of provocation testing in BrS families with pathogenic SCN5A mutations. They showed a sensitivity of 80% and specificity of 94%, increasing disease penetrance from 32.7% to 78.6%. Previous studies of SADS families have performed provocation tests in a limited proportion of relatives (11% to 28%) using as criterion the presence of a type 2 or type 3 Brugada ECG pattern and/or when the circumstances of death were suggestive of BrS and achieved yields of 5.0% to 8.7% (Figure 4) (7–11). One fundamental difference in our methodology was the routine use of ajmaline provocation testing which was offered to any individual with initial negative screening and was undertaken in 670 (74%) relatives from 258 (85%) families (Figure 4). Almost one-third (n = 40; 28%) of individuals diagnosed with BrS after ajmaline testing had a normal baseline ECG and the SADS proband’s circumstances of death would not have been considered immediately suggestive of a BrS-related death (16).
Impact of high RPLs
The use of the high RPLs increased the diagnostic yield of ajmaline provocation testing from 14% (53 of 378) to 38% (145 of 378), and unmasked the Brugada phenotype in an additional 92 relatives. Omission of the high RPLs would have failed to reveal the type 1 pattern in 49 families and reduced the overall cohort diagnostic yield from 42% to 26%. Several studies have previously shown an up to a 3-fold increase in the diagnostic yield of BrS using high RPLs at baseline ECG and during provocation testing, raising the possibility of more false positive tests (13–15). Imaging studies indicate that the location of the right ventricular outflow tract relative to the precordium dictates the leads which are likely to display the type 1 pattern. In the majority of patients, the right ventricular outflow tract location corresponds to the high RPLs (34,35). Further, indirect evidence that the positive ajmaline tests in the higher RPLs represent true positive results come from the study of Miyamoto et al. (36), which showed that men with a spontaneous type 1 Brugada pattern had similar prognosis, irrespective of whether the Brugada phenotype was identified in the conventional or the higher RPLs. In addition, Meregalli et al. (14) and Savastano et al. (35) reported a similar proportion of mutation carriers in individuals with a positive flecainide test who underwent provocation testing in both the conventional and higher RPLs.
The absence of a gold standard diagnostic test for BrS renders identification of false positive and false negative results challenging. Ajmaline testing may provoke the type 1 Brugada pattern in a considerable proportion of patients with other conditions, such as myotonic dystrophy (37) and ARVC (38). Furthermore, recent reports have challenged the specificity of the ajmaline test suggesting that cautious interpretation of positive tests is necessary. Hasdemir et al. (39) showed that 4.5% of apparently healthy controls and 27% of patients with symptomatic atrioventricular nodal re-entrant tachycardia had a positive ajmaline provocation test. It is not surprising, however, that otherwise healthy subjects may show a positive response to ajmaline. BrS is not a monogenic disorder and genome-wide association studies has uncovered common genetic variation at 3 loci that contribute significantly to the risk of carrying BrS (40). It is our hypothesis that a positive ajmaline reveals an underlying predisposition to the development of the BrS that is very much dependent on a priori risk. Thus, in the setting of a SADS death in an immediate blood relative and thorough exclusion of other etiologies by expert autopsy and systematic familial evaluation, the implication of a positive test is much greater. However, careful counseling on the benefits and disadvantages of a positive test should be addressed in an expert setting.
Recently, Tadros et al. (17) reported on the yield of ajmaline testing in the context of sudden unexplained death and unexplained cardiac arrest. The authors identified a positive ajmaline test in 88 of 482 (14%) families tested. In 7 (8%) of those cases they concluded that the positive ajmaline response was a confounder, either in the presence of an alternative genetic diagnosis (5 cases) or due to failure of segregation of positive ajmaline response and arrhythmia (2 cases). In contrast with our study, however, where no patient received more than the target dose of 1 mg/kg, Tadros et al. (17) infused higher doses of ajmaline in cases with coved ST-segment elevation that did not reach diagnostic criteria (2 mm). This is particularly relevant as all confounding responses were observed at ajmaline doses >1 mg/kg.
Although we cannot exclude the possibility of false positive results, supporting evidence that our findings are representative of the yield of BrS in SADS families include that there were no significant differences of the characteristics between individuals and families with a diagnostic pattern in the conventional leads and the high RPLs (Table 2); genetic testing in our families revealed similar yields (16%) to those previously reported (41,42); more than 1 relative was identified with a type 1 Brugada ECG pattern in 38% of the families; and a spontaneous type 1 Brugada pattern and/or clinically significant arrhythmic events developed in 17% (n = 25) of the concealed BrS cohort. Although we did not enroll a control group in the study, there were only 2 situations from 46 families with a diagnosis of BrS in which both parents of the deceased exhibited a positive ajmaline test. If it is assumed that there is an autosomal dominant inheritance pattern, this would suggest a “worst-case scenario” false positive rate of 4.3%, which is substantially less than our overall diagnostic yield. If, however, it is assumed that there is an oligogenic inheritance pattern, this would suggest inheritance of risk for BrS from both parents.
Finally, ajmaline is not universally accessible and our results should not be generalized to other sodium channel blockers. However, we believe that based on our data, investigative protocols of SADS families should include provocation testing with a sodium channel blocker and the use of high intercostal leads in all relatives without an alternate diagnosis, after appropriate counseling.
Implications of diagnostic criteria
The value of provocation testing and higher RPLs is acknowledged in the revision of the diagnostic criteria for BrS in both the 2013 and 2016 Shanghai expert consensus documents (1,16). The proposed Shanghai scoring system offers a novel probabilistic approach for the diagnosis of the BrS, similar to the Schwartz score used in LQTS (43). The authors propose a probable/definite diagnosis of BrS (score ≥3.5) in individuals with a spontaneous type 1 pattern in any lead, even in the absence of symptoms or family history. On the contrary, a drug-induced type 1 Brugada pattern even in the context of SADS is considered nondiagnostic (0.5 points) in the absence of symptoms or documented arrhythmia and without a baseline type 2 or 3 Brugada ECG pattern. This is the case even when a drug-induced Brugada pattern is identified in multiple relatives. Although a probabilistic approach is prudent, we are concerned that the proposed scoring system does not address the true likelihood of BrS in relatives of SADS victims as it would label 35% of our BrS cohort as nondiagnostic (Figure 5). Our results support that a type 1 Brugada pattern should be considered diagnostic of the BrS in the presence of a family history of premature sudden death (<45 years of age) or a SADS death.
Comprehensive clinical evaluation of families after a SADS death has the potential to identify an inherited cardiac condition in one-quarter of previously unsuspected relatives. The use of high RPLs during ajmaline testing substantially increased the yield of BrS, emphasizing the importance of applying the test systematically to ensure susceptible individuals receive appropriate advice on specific lifestyle modification and suitable follow-up. Further large prospective studies in individuals with low a priori risk are necessary to define the exact specificity of different sodium channel blockers and their implication for risk. Until then, it is prudent for assessment of SADS families to be performed in expert centers where the potential implications of sodium channel blocker provocation testing are fully evaluated and patients can be counseled accordingly.
COMPETENCY IN MEDICAL KNOWLEDGE: Evaluation of families in which a sudden arrhythmic death has occurred can identify an inherited cardiac condition in one-quarter of previously unsuspected relatives. Systematic use of ajmaline testing with high right precordial ECG leads increases the yield of cases with BrS.
TRANSLATIONAL OUTLOOK: Prospective clinical and genetic studies are necessary to define the sensitivity and specificity of provocative testing with sodium channel blockers and establish the implications of the findings for risk stratification.
The authors thank the charitable organization Cardiac Risk in the Young (CRY) for providing funding and equipment to support the specialist inherited cardiac diseases clinics and the CRY center for cardiac pathology.
Dr. Behr has received consulting fees from Medtronic; has received research funding from Biotronik; and has received a research grant from McColl's Ltd. Retail Group and the British Heart Foundation. Drs. Papadakis, Papatheodorou, Mellor, Raju, Ensam, Finocchiaro, Malhotra, and D'Silva were funded by research fellowship grants from a charitable organization called Cardiac Risk in the Young (CRY). Drs. Papadakis, Sheppard, Sharma, and Behr have received research grants from CRY. Dr. Wijeyeratne has received a research fellowship grant from McColl's Ltd. Retail Group. Dr. Raju has received a research fellowship grant from the British Heart Foundation. Drs. Edwards and Batchvarov have received support from the British Heart Foundation. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. Drs. Papadakis and Papatheodorou contributed equally to this work and are joint first authors. Drs. Sharma and Behr contributed equally to this work and are joint senior authors.
- Abbreviations and Acronyms
- Brugada syndrome
- catecholaminergic polymorphic ventricular tachycardia
- dilated cardiomyopathy
- arrhythmogenic right ventricular cardiomyopathy
- implantable cardioverter-defibrillator
- long QT syndrome
- left ventricular noncompaction
- right precordial leads
- sudden arrhythmic death syndrome
- Received October 10, 2017.
- Revision received December 17, 2017.
- Accepted January 8, 2018.
- 2018 American College of Cardiology Foundation
- Finocchiaro G.,
- Papadakis M.,
- Robertus J.-L.,
- et al.
- Harmon K.G.,
- Asif I.M.,
- Maleszewski J.J.,
- et al.
- Tan H.L.,
- Hofman N.,
- van Langen I.M.,
- van der Wal A.C.,
- Wilde A.A.M.
- Van Der Werf C.,
- Hofman N.,
- Tan H.L.,
- et al.
- Caldwell J.,
- Moreton N.,
- Khan N.,
- et al.
- Govindan M.,
- Batchvarov V.N.,
- Raju H.,
- et al.
- Sangwatanaroj S.,
- Prechawat S.,
- Sunsaneewitayakul B.,
- Sitthisook S.,
- Tosukhowong P.,
- Tungsanga K.
- Antzelevitch C.,
- Yan G.-X.,
- Ackerman M.J.,
- et al.
- Tadros R.,
- Nannenberg E.A.,
- Lieve K.V.,
- et al.
- Lahrouchi N.,
- Raju H.,
- Lodder E.M.,
- et al.
- Wong L.C.H.,
- Roses-Noguer F.,
- Till J.A.,
- Behr E.R.
- Marcus F.I.,
- McKenna W.J.,
- Sherrill D.,
- et al.
- Ackerman M.J.,
- Priori S.G.,
- Willems S.,
- et al.
- Papadakis M.,
- Raju H.,
- Behr E.R.,
- et al.
- Hofman N.,
- Tan H.L.,
- Alders M.,
- et al.
- Nunn L.M.L.,
- Lopes L.R.,
- Syrris P.,
- et al.
- Hong K.,
- Brugada J.,
- Oliva A.,
- et al.
- Maury P.,
- Audoubert M.,
- Cintas P.,
- et al.
- Crotti L.,
- Marcou C.A.,
- Tester D.J.,
- et al.
- Schwartz P.J.,
- Crotti L.