Y. Wijeyeratne - Academia.edu (original) (raw)
Papers by Y. Wijeyeratne
Circulation: Genomic and Precision Medicine
Background: Brugada syndrome (BrS) is characterized by the type 1 Brugada ECG pattern. Pathogenic... more Background: Brugada syndrome (BrS) is characterized by the type 1 Brugada ECG pattern. Pathogenic rare variants in SCN5A (mutations) are identified in 20% of BrS families in whom incomplete penetrance and genotype-negative phenotype-positive individuals are observed. E1784K- SCN5A is the most common SCN5A mutation identified. We determined the association of a BrS genetic risk score (BrS-GRS) and SCN5A mutation type on BrS phenotype in BrS families with SCN5A mutations. Methods: Subjects with a spontaneous type 1 pattern or positive/negative drug challenge from cohorts harboring SCN5A mutations were recruited from 16 centers (n=312). Single nucleotide polymorphisms previously associated with BrS at genome-wide significance were studied in both cohorts: rs11708996, rs10428132, and rs9388451. An additive linear genetic model for the BrS-GRS was assumed (6 single nucleotide polymorphism risk alleles). Results: In the total population (n=312), BrS-GRS ≥4 risk alleles yielded an odds rat...
Circulation
Background: Long QT syndrome (LQTS) is a rare genetic disorder and a major preventable cause of s... more Background: Long QT syndrome (LQTS) is a rare genetic disorder and a major preventable cause of sudden cardiac death in the young. A causal rare genetic variant with large effect size is identified in up to 80% of probands (genotype positive) and cascade family screening shows incomplete penetrance of genetic variants. Furthermore, a proportion of cases meeting diagnostic criteria for LQTS remain genetically elusive despite genetic testing of established genes (genotype negative). These observations raise the possibility that common genetic variants with small effect size contribute to the clinical picture of LQTS. This study aimed to characterize and quantify the contribution of common genetic variation to LQTS disease susceptibility. Methods: We conducted genome-wide association studies followed by transethnic meta-analysis in 1656 unrelated patients with LQTS of European or Japanese ancestry and 9890 controls to identify susceptibility single nucleotide polymorphisms. We estimate...
European Heart Journal
Doxorubicin (DOX) is a highly effective antineoplastic anthracycline drug; however, the adverse e... more Doxorubicin (DOX) is a highly effective antineoplastic anthracycline drug; however, the adverse effect of the cardiotoxicity has limited its widespread application. Melatonin, a highly conserved molecule that is mainly produced by the pineal gland, is well known for its free radical scavenging and anti-oxidative roles. The aim of this study was to investigate the possible protective effects of melatonin against DOX-induced cardiomyopathy. We preliminarily established DOX-induced cardiotoxicity models in H9c2 cells, and C57 mice, which clearly showed cardiac dysfunction and injury, oxidative stress, and apoptotic damage. Treatment with melatonin obviously attenuated the DOX-induced cardiac dysfunction and pathological changes. The anti-oxidative stress activity of melatonin was achieved via reduced generation of reactive oxygen species through regulation of AMPK and PGC1α signaling. Its anti-apoptotic activity was shown by reductions in the number of TUNEL-positive cells and DNA fragments along with a decreased ratio of Bax/Bcl-2 expression. In a further mechanistic study, melatonin exerted improvement on the cardiac function, oxidative stress, and apoptosis were inhibited by Compound C treatment or AMPK/PGC1α siRNA. The present work demonstrates for the first time that melatonin obviously prevented DOX-induced cardiotoxicity via the suppression of oxidative stress and apoptosis through the AMPK/PGC1α signaling pathway. P3813 Beneficial effect of landiolol on adiponectin and high-molecular weight adiponectin level in patients with stable coronary artery disease performed percutaneous coronary intervention
European Heart Journal
Hypertension pathophysiology / Non-invasive diagnostic methods in cardiac arrhythmias 433 systoli... more Hypertension pathophysiology / Non-invasive diagnostic methods in cardiac arrhythmias 433 systolic, PP and pulse pressure amplification by gender and age deciles. Results were analysed with JMP, version 7.1 (SAS for Windows), p<0.05 considered significant. Results: The mean age of the population was 59±11 years, 23% female. Central systolic BP increased while central diastolic BP decreased with age resulting in a linear age-related increase in central PP (p<0.0001). There was a significant linear relationship between age and central aortic systolic (r=0.29, p<0.0001), diastolic (r=-0.30, p<0.0001) and central aortic PP (r=0.45, p<0.0001) with weaker correlations observed with brachial pressures. Furthermore, there was a significantly higher increment in central compared with brachial PP with age (p<0.0001). The mean PP amplification was-5±18 mm Hg with significantly lower values observed in women than men (-10±22 vs.-3±15, p<0.0001). PP amplification decreased linearly with age in both genders (p<0.0001). Furthermore, the increase in central PP and reduction in PP amplification with age was steeper for women than for men (p<0.001). Conclusions: This is the first large study describing invasive central aortic pulsatile haemodynamic patterns in an Arab cohort. While these data are derived from a coronary artery disease cohort and cannot be generalized to the general population, they provide us for the first time reference ranges for central aortic parameters in the Arab population, hitherto not studied.
European Journal of Human Genetics
Sudden cardiac death (SCD) is often associated with structural abnormalities of the heart during ... more Sudden cardiac death (SCD) is often associated with structural abnormalities of the heart during autopsy. This study sought to compare the diagnostic yield of postmortem genetic testing in (1) cases with structural findings of uncertain significance at autopsy to (2) cases with autopsy findings diagnostic of cardiomyopathy. We evaluated 57 SCD cases with structural findings at cardiac autopsy. Next-generation sequencing using a panel of 77 primary electrical disorder and cardiomyopathy genes was performed. Pathogenic and likely pathogenic variants were classified using American College of Medical Genetics (ACMG) consensus guidelines. In 29 cases (51%) autopsy findings of uncertain significance were identified whereas in 28 cases (49%) a diagnosis of cardiomyopathy was established. We identified a pathogenic or likely pathogenic variant in 10 cases (18%); in 1 (3%) case with non-specific autopsy findings compared with 9 (32%) cases with autopsy findings diagnostic of cardiomyopathy (p = 0.0054). The yield of genetic testing in SCD cases with autopsy findings consistent with cardiomyopathy is comparable with the yield in cardiomyopathy patients that are alive. Genetic testing in cases with findings of uncertain significance offers lower clinical utility than in cardiomyopathy, with lower yields than detected previously. This highlights the need for stringent evaluation of variant pathogenicity.
Heart Rhythm
BACKGROUND There is limited information on ethnic differences between patients with Brugada syndr... more BACKGROUND There is limited information on ethnic differences between patients with Brugada syndrome (BrS) with arrhythmic events (AEs). OBJECTIVES To compare clinical, electrocardiographic (ECG), electrophysiologic (EP) and genetic characteristics between White and Asian BrS-patients with AE. METHODS SABRUS is a multicenter survey from Western and Asian countries, gathering 678 BrS-patients with first documented AE. After excluding patients with other (n=14; 2.1%) or unknown (n=30; 4.4%) ethnicity, 364 (53.7%) Whites and 270 (39.8%) Asians comprised the study group. RESULTS There was no difference in AE age onset (41.3±16.1 years in Whites vs. 43.3±12.3 years in Asians, P=0.285). Higher proportions of Whites were observed in pediatric and elderly populations. Asians were predominantly males (98.1% vs. 85.7% in Whites, P<0.001) and frequently presented with aborted cardiac arrest (ACA) (71.1% vs. 56%, P<0.001). Asians tended to display more spontaneous type 1 BrS-ECG (71.5% vs. 64.3%, P=0.068). Family history of sudden cardiac death (FHSCD) was noted more in Whites (29.1% vs. 11.5%, P<0.001), with higher rate of SCN5A mutation carriers (40.1% vs. 13.2% in Asians, P<0.001), as well as more fever-related AEs (8.5% vs. 2.9%, 0.011). No difference was observed between the two groups regarding prior history of syncope and ventricular arrhythmia inducibility. CONCLUSIONS There are important differences between Asian and White BrS-patients. Asian patients present almost exclusively as male adults, more often with ACA and spontaneous type 1 BrS-ECG. However, they have less FHSCD and markedly lower SCN5A mutation rates. The striking difference in SCN5A mutation rates should be tested in future studies.
Journal of the American College of Cardiology
A multi-center study on young Brugada syndrome patients with an arrhythmic event demonstrates hig... more A multi-center study on young Brugada syndrome patients with an arrhythmic event demonstrates high recurrence rates and defined risk factors for arrhythmia recurrence.
European heart journal, Jan 27, 2018
To clarify the clinical characteristics and outcomes of children with SCN5A-mediated disease and ... more To clarify the clinical characteristics and outcomes of children with SCN5A-mediated disease and to improve their risk stratification. A multicentre, international, retrospective cohort study was conducted in 25 tertiary hospitals in 13 countries between 1990 and 2015. All patients ≤16 years of age diagnosed with a genetically confirmed SCN5A mutation were included in the analysis. There was no restriction made based on their clinical diagnosis. A total of 442 children {55.7% boys, 40.3% probands, median age: 8.0 [interquartile range (IQR) 9.5] years} from 350 families were included; 67.9% were asymptomatic at diagnosis. Four main phenotypes were identified: isolated progressive cardiac conduction disorders (25.6%), overlap phenotype (15.6%), isolated long QT syndrome type 3 (10.6%), and isolated Brugada syndrome type 1 (1.8%); 44.3% had a negative electrocardiogram phenotype. During a median follow-up of 5.9 (IQR 5.9) years, 272 cardiac events (CEs) occurred in 139 (31.5%) patients...
Heart rhythm, Jan 13, 2018
There is limited information on gender differences in patients with Brugada syndrome (BrS) who ex... more There is limited information on gender differences in patients with Brugada syndrome (BrS) who experienced arrhythmic events (AEs). To compare clinical, electrocardiographic (ECG), electrophysiologic (EP) and genetic characteristics between males and females in BrS-patients with their first AE. The multicenter Survey on AE in BrS (SABRUS) collected data on first AE in 678 BrS-patients including 619 (91.3%) males and 59 (8.7%) females aged 0.27 to 84 (mean 42.5±14.1) years at the time of AE. After excluding pediatric patients, females were older than males (49.5±14.4 vs. 43±12.7 years, respectively, P=0.001). Higher proportions of females were observed in the pediatric and elderly populations. In Asians, male/female ratio of AE was ≈9-fold higher compared to Caucasians. Spontaneous type 1 BrS-ECG was associated with earlier onset of AE in pediatric females. A similar prevalence (≈65%) of spontaneous type 1 BrS-ECG was present in males and females above age of 60 years. Females less f...
Journal of the American College of Cardiology, Jan 20, 2018
Familial evaluation after a sudden death with negative autopsy (sudden arrhythmic death syndrome;... more Familial evaluation after a sudden death with negative autopsy (sudden arrhythmic death syndrome; SADS) may identify relatives at risk of fatal arrhythmias. 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. 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. 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 ...
Circulation. Arrhythmia and electrophysiology, 2017
Data on the age at first arrhythmic event (AE) in Brugada syndrome are from limited patient cohor... more Data on the age at first arrhythmic event (AE) in Brugada syndrome are from limited patient cohorts. The aim of this study is 2-fold: (1) to define the age at first AE in a large cohort of patients with Brugada syndrome, and (2) to assess the influence of the mode of AE documentation, sex, and ethnicity on the age at first AE. A survey of 23 centers from 10 Western and 4 Asian countries gathered data from 678 patients with Brugada syndrome (91.3% men) with first AE documented at time of aborted cardiac arrest (group A, n=426) or after prophylactic implantable cardioverter-defibrillator implantation (group B, n=252). The vast majority (94.2%) of the patients were 16 to 70 years old at the time of AE, whereas pediatric (<16 years) and elderly patients (>70 years) comprised 4.3% and 1.5%, respectively. Peak AE rate occurred between 38 and 48 years (mean, 41.9±14.8; range, 0.27-84 years). Group A patients were younger than in Group B by a mean of 6.7 years (46.1±13.2 versus 39.4±1...
Heart rhythm, 2018
Detailed information on the profile of patients with Brugada syndrome (BrS) presenting their firs... more Detailed information on the profile of patients with Brugada syndrome (BrS) presenting their first arrhythmic event (AE) after prophylactic implantation of an implantable cardioverter-defibrillator (ICD) is limited. The objectives of this study were (1) to compare clinical, electrocardiographic, electrophysiologic, and genetic profiles of patients who exhibited their first documented AE as aborted cardiac arrest (group A) with profiles of those in whom the AE was documented after prophylactic ICD implantation (group B) and (2) to characterize group B patients' profile using the class II indications for ICD implantation established by HRS/EHRA/APHRS expert consensus statement in 2013. A survey of 23 centers from 10 Western and 4 Asian countries enabled data collection of 678 patients with BrS who exhibited their AE (group A, n = 426; group B, n = 252). The first AE occurred in group B patients 6.7 years later than in group A (mean age 46.1 ± 13.3 years vs 39.4 ± 15.1 years; P <...
Heart rhythm, Jan 9, 2018
The literature on fever related arrhythmic events (AE) in Brugada syndrome (BrS) is currently lim... more The literature on fever related arrhythmic events (AE) in Brugada syndrome (BrS) is currently limited to few case reports and small series. The current study aims to describe the characteristics of fever-related AE in a large cohort of BrS patients. SABRUS is a multicenter study on 678 BrS patients with first AE documented at time of aborted cardiac arrest (ACA) (n=426) or after prophylactic ICD implantation (n=252). In 35(6%) of the 588 patients with available information, the AE occurred during a febrile illness. Most of the 35 patients were male (80%), Caucasian (83%) and proband (70%). Age at time of AE was 29±24 (range 0.3-76) years. Most patients (80%) presented with ACA and 6 (17%) with arrhythmic storm. Family history of sudden death, history of syncope and spontaneous type 1 Brugada-ECG were noted in 17%, 40% and 66% of patients, respectively. VF was induced at EPS in 9/19(47%) patients. An SCN5A mutation was found in 14/28(50%) patients. The highest proportion of fever-rel...
Trends in Cardiovascular Medicine
Approximately 4% of sudden cardiac deaths are unexplained (the sudden arrhythmic death syndrome: ... more Approximately 4% of sudden cardiac deaths are unexplained (the sudden arrhythmic death syndrome: SADS), and up to 6-10% of survivors of cardiac arrest do not have an identifiable cardiac abnormality after comprehensive clinical evaluation (idiopathic ventricular fibrillation: IVF). Genetic testing may be able to play a role in diagnostics and can be targeted to an underlying phenotype present in family members following clinical evaluation. Alternatively post-mortem genetic testing (the 'molecular autopsy') may diagnose the underlying cause if a clearly pathogenic rare variant is found. Limitations include a modest yield, and the high probability of finding a variant of unknown significance (VUS) leading to a low signal-to-noise ratio. Next generation sequencing enables costefficient high throughput screening of a larger number of genes but at the expense of increased genetic noise. The yield from genetic testing is even lower in IVF in the absence of any suggestion of another phenotype in the index case or his/her family, and should be actively discouraged at this time. Future improvements in diagnostic utility include optimisation of the use of variant-calling pipelines and shared databases as well as patient-specific models of disease to more accurately assign pathogenicity of variants. Studying 'trios' of parents and the index case may better assess the yield of sporadic and recessive disease.
Circulation. Arrhythmia and electrophysiology, 2017
Insight into type 6 long-QT syndrome (LQT6), stemming from mutations in the KCNE2-encoded voltage... more Insight into type 6 long-QT syndrome (LQT6), stemming from mutations in the KCNE2-encoded voltage-gated channel β-subunit, is limited. We sought to further characterize its clinical phenotype. Individuals with reported pathogenic KCNE2 mutations identified during arrhythmia evaluation were collected from inherited arrhythmia clinics and the Rochester long-QT syndrome (LQTS) registry. Previously reported LQT6 cases were identified through a search of the MEDLINE database. Clinical features were assessed, while reported KCNE2 mutations were evaluated for genotype-phenotype segregation and classified according to the contemporary American College of Medical Genetics guidelines. Twenty-seven probands possessed reported pathogenic KCNE2 mutations, while a MEDLINE search identified 17 additional LQT6 cases providing clinical and genetic data. Sixteen probands had normal resting QTc values and only developed QT prolongation and malignant arrhythmias after exposure to QT-prolonging stressor...
Journal of the American College of Cardiology, Jan 2, 2017
Sudden arrhythmic death syndrome (SADS) describes a sudden death with negative autopsy and toxico... more Sudden arrhythmic death syndrome (SADS) describes a sudden death with negative autopsy and toxicological analysis. Cardiac genetic disease is a likely etiology. This study investigated the clinical utility and combined yield of post-mortem genetic testing (molecular autopsy) in cases of SADS and comprehensive clinical evaluation of surviving relatives. We evaluated 302 expertly validated SADS cases with suitable DNA (median age: 24 years; 65% males) who underwent next-generation sequencing using an extended panel of 77 primary electrical disorder and cardiomyopathy genes. Pathogenic and likely pathogenic variants were classified using American College of Medical Genetics (ACMG) consensus guidelines. The yield of combined molecular autopsy and clinical evaluation in 82 surviving families was evaluated. A gene-level rare variant association analysis was conducted in SADS cases versus controls. A clinically actionable pathogenic or likely pathogenic variant was identified in 40 of 302 ...
Clinical Cardiogenetics, 2016
Heart rhythm, Apr 2, 2016
There is increasing evidence that the Brugada ECG pattern is a marker of subtle structural heart ... more There is increasing evidence that the Brugada ECG pattern is a marker of subtle structural heart disease. We characterised Brugada syndrome (BrS) patients using cardiovascular magnetic resonance (CMR) with late gadolinium enhancement (LGE). BrS was diagnosed according to international guidelines. 26% BrS patients carried SCN5A mutations. CMR data from 78 BrS patients were compared with 78 healthy controls (44±15 vs 42±14 years; p=0.434 and 64% vs 64% male; p=1.000). Right ventricular (RV) ejection fraction was slightly lower (61±8% vs 64±5%; p=0.004) and RV end-systolic volume slightly greater (31±10mL/m(2) vs 28±6mL/m(2); p=0.038) in BrS compared with controls. These values remained within the normal range. LGE was demonstrated in 8% BrS patients (left ventricular (LV) midwall LGE in 5%) but not in controls (p=0.028). In BrS patients with midwall LGE there were no other features of cardiomyopathy at the time of CMR but genetic testing and follow-up has revealed a desmoplakin mutati...
Heart, 2014
ABSTRACT Long QT syndrome (LQTS) and Brugada syndrome (BrS) are inherited arrhythmia syndromes ch... more ABSTRACT Long QT syndrome (LQTS) and Brugada syndrome (BrS) are inherited arrhythmia syndromes characterised by sudden death and highly variable penetrance. The E1784K mutation in SCN5A, which encodes the α-subunit of the cardiac sodium channel Nav1.5, is the most commonly identified SCN5A mutation in both conditions. It causes a LQTS/BrS overlap disease with variable phenotype. The aim of this project was to identify potential genetic modifiers that may influence the E1784K phenotypic expression in an international cohort of carriers of this mutation.
Circulation: Genomic and Precision Medicine
Background: Brugada syndrome (BrS) is characterized by the type 1 Brugada ECG pattern. Pathogenic... more Background: Brugada syndrome (BrS) is characterized by the type 1 Brugada ECG pattern. Pathogenic rare variants in SCN5A (mutations) are identified in 20% of BrS families in whom incomplete penetrance and genotype-negative phenotype-positive individuals are observed. E1784K- SCN5A is the most common SCN5A mutation identified. We determined the association of a BrS genetic risk score (BrS-GRS) and SCN5A mutation type on BrS phenotype in BrS families with SCN5A mutations. Methods: Subjects with a spontaneous type 1 pattern or positive/negative drug challenge from cohorts harboring SCN5A mutations were recruited from 16 centers (n=312). Single nucleotide polymorphisms previously associated with BrS at genome-wide significance were studied in both cohorts: rs11708996, rs10428132, and rs9388451. An additive linear genetic model for the BrS-GRS was assumed (6 single nucleotide polymorphism risk alleles). Results: In the total population (n=312), BrS-GRS ≥4 risk alleles yielded an odds rat...
Circulation
Background: Long QT syndrome (LQTS) is a rare genetic disorder and a major preventable cause of s... more Background: Long QT syndrome (LQTS) is a rare genetic disorder and a major preventable cause of sudden cardiac death in the young. A causal rare genetic variant with large effect size is identified in up to 80% of probands (genotype positive) and cascade family screening shows incomplete penetrance of genetic variants. Furthermore, a proportion of cases meeting diagnostic criteria for LQTS remain genetically elusive despite genetic testing of established genes (genotype negative). These observations raise the possibility that common genetic variants with small effect size contribute to the clinical picture of LQTS. This study aimed to characterize and quantify the contribution of common genetic variation to LQTS disease susceptibility. Methods: We conducted genome-wide association studies followed by transethnic meta-analysis in 1656 unrelated patients with LQTS of European or Japanese ancestry and 9890 controls to identify susceptibility single nucleotide polymorphisms. We estimate...
European Heart Journal
Doxorubicin (DOX) is a highly effective antineoplastic anthracycline drug; however, the adverse e... more Doxorubicin (DOX) is a highly effective antineoplastic anthracycline drug; however, the adverse effect of the cardiotoxicity has limited its widespread application. Melatonin, a highly conserved molecule that is mainly produced by the pineal gland, is well known for its free radical scavenging and anti-oxidative roles. The aim of this study was to investigate the possible protective effects of melatonin against DOX-induced cardiomyopathy. We preliminarily established DOX-induced cardiotoxicity models in H9c2 cells, and C57 mice, which clearly showed cardiac dysfunction and injury, oxidative stress, and apoptotic damage. Treatment with melatonin obviously attenuated the DOX-induced cardiac dysfunction and pathological changes. The anti-oxidative stress activity of melatonin was achieved via reduced generation of reactive oxygen species through regulation of AMPK and PGC1α signaling. Its anti-apoptotic activity was shown by reductions in the number of TUNEL-positive cells and DNA fragments along with a decreased ratio of Bax/Bcl-2 expression. In a further mechanistic study, melatonin exerted improvement on the cardiac function, oxidative stress, and apoptosis were inhibited by Compound C treatment or AMPK/PGC1α siRNA. The present work demonstrates for the first time that melatonin obviously prevented DOX-induced cardiotoxicity via the suppression of oxidative stress and apoptosis through the AMPK/PGC1α signaling pathway. P3813 Beneficial effect of landiolol on adiponectin and high-molecular weight adiponectin level in patients with stable coronary artery disease performed percutaneous coronary intervention
European Heart Journal
Hypertension pathophysiology / Non-invasive diagnostic methods in cardiac arrhythmias 433 systoli... more Hypertension pathophysiology / Non-invasive diagnostic methods in cardiac arrhythmias 433 systolic, PP and pulse pressure amplification by gender and age deciles. Results were analysed with JMP, version 7.1 (SAS for Windows), p<0.05 considered significant. Results: The mean age of the population was 59±11 years, 23% female. Central systolic BP increased while central diastolic BP decreased with age resulting in a linear age-related increase in central PP (p<0.0001). There was a significant linear relationship between age and central aortic systolic (r=0.29, p<0.0001), diastolic (r=-0.30, p<0.0001) and central aortic PP (r=0.45, p<0.0001) with weaker correlations observed with brachial pressures. Furthermore, there was a significantly higher increment in central compared with brachial PP with age (p<0.0001). The mean PP amplification was-5±18 mm Hg with significantly lower values observed in women than men (-10±22 vs.-3±15, p<0.0001). PP amplification decreased linearly with age in both genders (p<0.0001). Furthermore, the increase in central PP and reduction in PP amplification with age was steeper for women than for men (p<0.001). Conclusions: This is the first large study describing invasive central aortic pulsatile haemodynamic patterns in an Arab cohort. While these data are derived from a coronary artery disease cohort and cannot be generalized to the general population, they provide us for the first time reference ranges for central aortic parameters in the Arab population, hitherto not studied.
European Journal of Human Genetics
Sudden cardiac death (SCD) is often associated with structural abnormalities of the heart during ... more Sudden cardiac death (SCD) is often associated with structural abnormalities of the heart during autopsy. This study sought to compare the diagnostic yield of postmortem genetic testing in (1) cases with structural findings of uncertain significance at autopsy to (2) cases with autopsy findings diagnostic of cardiomyopathy. We evaluated 57 SCD cases with structural findings at cardiac autopsy. Next-generation sequencing using a panel of 77 primary electrical disorder and cardiomyopathy genes was performed. Pathogenic and likely pathogenic variants were classified using American College of Medical Genetics (ACMG) consensus guidelines. In 29 cases (51%) autopsy findings of uncertain significance were identified whereas in 28 cases (49%) a diagnosis of cardiomyopathy was established. We identified a pathogenic or likely pathogenic variant in 10 cases (18%); in 1 (3%) case with non-specific autopsy findings compared with 9 (32%) cases with autopsy findings diagnostic of cardiomyopathy (p = 0.0054). The yield of genetic testing in SCD cases with autopsy findings consistent with cardiomyopathy is comparable with the yield in cardiomyopathy patients that are alive. Genetic testing in cases with findings of uncertain significance offers lower clinical utility than in cardiomyopathy, with lower yields than detected previously. This highlights the need for stringent evaluation of variant pathogenicity.
Heart Rhythm
BACKGROUND There is limited information on ethnic differences between patients with Brugada syndr... more BACKGROUND There is limited information on ethnic differences between patients with Brugada syndrome (BrS) with arrhythmic events (AEs). OBJECTIVES To compare clinical, electrocardiographic (ECG), electrophysiologic (EP) and genetic characteristics between White and Asian BrS-patients with AE. METHODS SABRUS is a multicenter survey from Western and Asian countries, gathering 678 BrS-patients with first documented AE. After excluding patients with other (n=14; 2.1%) or unknown (n=30; 4.4%) ethnicity, 364 (53.7%) Whites and 270 (39.8%) Asians comprised the study group. RESULTS There was no difference in AE age onset (41.3±16.1 years in Whites vs. 43.3±12.3 years in Asians, P=0.285). Higher proportions of Whites were observed in pediatric and elderly populations. Asians were predominantly males (98.1% vs. 85.7% in Whites, P<0.001) and frequently presented with aborted cardiac arrest (ACA) (71.1% vs. 56%, P<0.001). Asians tended to display more spontaneous type 1 BrS-ECG (71.5% vs. 64.3%, P=0.068). Family history of sudden cardiac death (FHSCD) was noted more in Whites (29.1% vs. 11.5%, P<0.001), with higher rate of SCN5A mutation carriers (40.1% vs. 13.2% in Asians, P<0.001), as well as more fever-related AEs (8.5% vs. 2.9%, 0.011). No difference was observed between the two groups regarding prior history of syncope and ventricular arrhythmia inducibility. CONCLUSIONS There are important differences between Asian and White BrS-patients. Asian patients present almost exclusively as male adults, more often with ACA and spontaneous type 1 BrS-ECG. However, they have less FHSCD and markedly lower SCN5A mutation rates. The striking difference in SCN5A mutation rates should be tested in future studies.
Journal of the American College of Cardiology
A multi-center study on young Brugada syndrome patients with an arrhythmic event demonstrates hig... more A multi-center study on young Brugada syndrome patients with an arrhythmic event demonstrates high recurrence rates and defined risk factors for arrhythmia recurrence.
European heart journal, Jan 27, 2018
To clarify the clinical characteristics and outcomes of children with SCN5A-mediated disease and ... more To clarify the clinical characteristics and outcomes of children with SCN5A-mediated disease and to improve their risk stratification. A multicentre, international, retrospective cohort study was conducted in 25 tertiary hospitals in 13 countries between 1990 and 2015. All patients ≤16 years of age diagnosed with a genetically confirmed SCN5A mutation were included in the analysis. There was no restriction made based on their clinical diagnosis. A total of 442 children {55.7% boys, 40.3% probands, median age: 8.0 [interquartile range (IQR) 9.5] years} from 350 families were included; 67.9% were asymptomatic at diagnosis. Four main phenotypes were identified: isolated progressive cardiac conduction disorders (25.6%), overlap phenotype (15.6%), isolated long QT syndrome type 3 (10.6%), and isolated Brugada syndrome type 1 (1.8%); 44.3% had a negative electrocardiogram phenotype. During a median follow-up of 5.9 (IQR 5.9) years, 272 cardiac events (CEs) occurred in 139 (31.5%) patients...
Heart rhythm, Jan 13, 2018
There is limited information on gender differences in patients with Brugada syndrome (BrS) who ex... more There is limited information on gender differences in patients with Brugada syndrome (BrS) who experienced arrhythmic events (AEs). To compare clinical, electrocardiographic (ECG), electrophysiologic (EP) and genetic characteristics between males and females in BrS-patients with their first AE. The multicenter Survey on AE in BrS (SABRUS) collected data on first AE in 678 BrS-patients including 619 (91.3%) males and 59 (8.7%) females aged 0.27 to 84 (mean 42.5±14.1) years at the time of AE. After excluding pediatric patients, females were older than males (49.5±14.4 vs. 43±12.7 years, respectively, P=0.001). Higher proportions of females were observed in the pediatric and elderly populations. In Asians, male/female ratio of AE was ≈9-fold higher compared to Caucasians. Spontaneous type 1 BrS-ECG was associated with earlier onset of AE in pediatric females. A similar prevalence (≈65%) of spontaneous type 1 BrS-ECG was present in males and females above age of 60 years. Females less f...
Journal of the American College of Cardiology, Jan 20, 2018
Familial evaluation after a sudden death with negative autopsy (sudden arrhythmic death syndrome;... more Familial evaluation after a sudden death with negative autopsy (sudden arrhythmic death syndrome; SADS) may identify relatives at risk of fatal arrhythmias. 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. 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. 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 ...
Circulation. Arrhythmia and electrophysiology, 2017
Data on the age at first arrhythmic event (AE) in Brugada syndrome are from limited patient cohor... more Data on the age at first arrhythmic event (AE) in Brugada syndrome are from limited patient cohorts. The aim of this study is 2-fold: (1) to define the age at first AE in a large cohort of patients with Brugada syndrome, and (2) to assess the influence of the mode of AE documentation, sex, and ethnicity on the age at first AE. A survey of 23 centers from 10 Western and 4 Asian countries gathered data from 678 patients with Brugada syndrome (91.3% men) with first AE documented at time of aborted cardiac arrest (group A, n=426) or after prophylactic implantable cardioverter-defibrillator implantation (group B, n=252). The vast majority (94.2%) of the patients were 16 to 70 years old at the time of AE, whereas pediatric (<16 years) and elderly patients (>70 years) comprised 4.3% and 1.5%, respectively. Peak AE rate occurred between 38 and 48 years (mean, 41.9±14.8; range, 0.27-84 years). Group A patients were younger than in Group B by a mean of 6.7 years (46.1±13.2 versus 39.4±1...
Heart rhythm, 2018
Detailed information on the profile of patients with Brugada syndrome (BrS) presenting their firs... more Detailed information on the profile of patients with Brugada syndrome (BrS) presenting their first arrhythmic event (AE) after prophylactic implantation of an implantable cardioverter-defibrillator (ICD) is limited. The objectives of this study were (1) to compare clinical, electrocardiographic, electrophysiologic, and genetic profiles of patients who exhibited their first documented AE as aborted cardiac arrest (group A) with profiles of those in whom the AE was documented after prophylactic ICD implantation (group B) and (2) to characterize group B patients' profile using the class II indications for ICD implantation established by HRS/EHRA/APHRS expert consensus statement in 2013. A survey of 23 centers from 10 Western and 4 Asian countries enabled data collection of 678 patients with BrS who exhibited their AE (group A, n = 426; group B, n = 252). The first AE occurred in group B patients 6.7 years later than in group A (mean age 46.1 ± 13.3 years vs 39.4 ± 15.1 years; P <...
Heart rhythm, Jan 9, 2018
The literature on fever related arrhythmic events (AE) in Brugada syndrome (BrS) is currently lim... more The literature on fever related arrhythmic events (AE) in Brugada syndrome (BrS) is currently limited to few case reports and small series. The current study aims to describe the characteristics of fever-related AE in a large cohort of BrS patients. SABRUS is a multicenter study on 678 BrS patients with first AE documented at time of aborted cardiac arrest (ACA) (n=426) or after prophylactic ICD implantation (n=252). In 35(6%) of the 588 patients with available information, the AE occurred during a febrile illness. Most of the 35 patients were male (80%), Caucasian (83%) and proband (70%). Age at time of AE was 29±24 (range 0.3-76) years. Most patients (80%) presented with ACA and 6 (17%) with arrhythmic storm. Family history of sudden death, history of syncope and spontaneous type 1 Brugada-ECG were noted in 17%, 40% and 66% of patients, respectively. VF was induced at EPS in 9/19(47%) patients. An SCN5A mutation was found in 14/28(50%) patients. The highest proportion of fever-rel...
Trends in Cardiovascular Medicine
Approximately 4% of sudden cardiac deaths are unexplained (the sudden arrhythmic death syndrome: ... more Approximately 4% of sudden cardiac deaths are unexplained (the sudden arrhythmic death syndrome: SADS), and up to 6-10% of survivors of cardiac arrest do not have an identifiable cardiac abnormality after comprehensive clinical evaluation (idiopathic ventricular fibrillation: IVF). Genetic testing may be able to play a role in diagnostics and can be targeted to an underlying phenotype present in family members following clinical evaluation. Alternatively post-mortem genetic testing (the 'molecular autopsy') may diagnose the underlying cause if a clearly pathogenic rare variant is found. Limitations include a modest yield, and the high probability of finding a variant of unknown significance (VUS) leading to a low signal-to-noise ratio. Next generation sequencing enables costefficient high throughput screening of a larger number of genes but at the expense of increased genetic noise. The yield from genetic testing is even lower in IVF in the absence of any suggestion of another phenotype in the index case or his/her family, and should be actively discouraged at this time. Future improvements in diagnostic utility include optimisation of the use of variant-calling pipelines and shared databases as well as patient-specific models of disease to more accurately assign pathogenicity of variants. Studying 'trios' of parents and the index case may better assess the yield of sporadic and recessive disease.
Circulation. Arrhythmia and electrophysiology, 2017
Insight into type 6 long-QT syndrome (LQT6), stemming from mutations in the KCNE2-encoded voltage... more Insight into type 6 long-QT syndrome (LQT6), stemming from mutations in the KCNE2-encoded voltage-gated channel β-subunit, is limited. We sought to further characterize its clinical phenotype. Individuals with reported pathogenic KCNE2 mutations identified during arrhythmia evaluation were collected from inherited arrhythmia clinics and the Rochester long-QT syndrome (LQTS) registry. Previously reported LQT6 cases were identified through a search of the MEDLINE database. Clinical features were assessed, while reported KCNE2 mutations were evaluated for genotype-phenotype segregation and classified according to the contemporary American College of Medical Genetics guidelines. Twenty-seven probands possessed reported pathogenic KCNE2 mutations, while a MEDLINE search identified 17 additional LQT6 cases providing clinical and genetic data. Sixteen probands had normal resting QTc values and only developed QT prolongation and malignant arrhythmias after exposure to QT-prolonging stressor...
Journal of the American College of Cardiology, Jan 2, 2017
Sudden arrhythmic death syndrome (SADS) describes a sudden death with negative autopsy and toxico... more Sudden arrhythmic death syndrome (SADS) describes a sudden death with negative autopsy and toxicological analysis. Cardiac genetic disease is a likely etiology. This study investigated the clinical utility and combined yield of post-mortem genetic testing (molecular autopsy) in cases of SADS and comprehensive clinical evaluation of surviving relatives. We evaluated 302 expertly validated SADS cases with suitable DNA (median age: 24 years; 65% males) who underwent next-generation sequencing using an extended panel of 77 primary electrical disorder and cardiomyopathy genes. Pathogenic and likely pathogenic variants were classified using American College of Medical Genetics (ACMG) consensus guidelines. The yield of combined molecular autopsy and clinical evaluation in 82 surviving families was evaluated. A gene-level rare variant association analysis was conducted in SADS cases versus controls. A clinically actionable pathogenic or likely pathogenic variant was identified in 40 of 302 ...
Clinical Cardiogenetics, 2016
Heart rhythm, Apr 2, 2016
There is increasing evidence that the Brugada ECG pattern is a marker of subtle structural heart ... more There is increasing evidence that the Brugada ECG pattern is a marker of subtle structural heart disease. We characterised Brugada syndrome (BrS) patients using cardiovascular magnetic resonance (CMR) with late gadolinium enhancement (LGE). BrS was diagnosed according to international guidelines. 26% BrS patients carried SCN5A mutations. CMR data from 78 BrS patients were compared with 78 healthy controls (44±15 vs 42±14 years; p=0.434 and 64% vs 64% male; p=1.000). Right ventricular (RV) ejection fraction was slightly lower (61±8% vs 64±5%; p=0.004) and RV end-systolic volume slightly greater (31±10mL/m(2) vs 28±6mL/m(2); p=0.038) in BrS compared with controls. These values remained within the normal range. LGE was demonstrated in 8% BrS patients (left ventricular (LV) midwall LGE in 5%) but not in controls (p=0.028). In BrS patients with midwall LGE there were no other features of cardiomyopathy at the time of CMR but genetic testing and follow-up has revealed a desmoplakin mutati...
Heart, 2014
ABSTRACT Long QT syndrome (LQTS) and Brugada syndrome (BrS) are inherited arrhythmia syndromes ch... more ABSTRACT Long QT syndrome (LQTS) and Brugada syndrome (BrS) are inherited arrhythmia syndromes characterised by sudden death and highly variable penetrance. The E1784K mutation in SCN5A, which encodes the α-subunit of the cardiac sodium channel Nav1.5, is the most commonly identified SCN5A mutation in both conditions. It causes a LQTS/BrS overlap disease with variable phenotype. The aim of this project was to identify potential genetic modifiers that may influence the E1784K phenotypic expression in an international cohort of carriers of this mutation.