Showing papers by "Elijah R. Behr published in 2014"

Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization

Abstract: The QT interval, an electrocardiographic measure reflecting myocardial repolarization, is a heritable trait. QT prolongation is a risk factor for ventricular arrhythmias and sudden cardiac death (SCD) and could indicate the presence of the potentially lethal mendelian long-QT syndrome (LQTS). Using a genome-wide association and replication study in up to 100,000 individuals, we identified 35 common variant loci associated with QT interval that collectively explain ∼8-10% of QT-interval variation and highlight the importance of calcium regulation in myocardial repolarization. Rare variant analysis of 6 new QT interval-associated loci in 298 unrelated probands with LQTS identified coding variants not found in controls but of uncertain causality and therefore requiring validation. Several newly identified loci encode proteins that physically interact with other recognized repolarization proteins. Our integration of common variant association, expression and orthogonal protein-protein interaction screens provides new insights into cardiac electrophysiology and identifies new candidate genes for ventricular arrhythmias, LQTS and SCD.

Novel calmodulin mutations associated with congenital arrhythmia susceptibility.

Abstract: Background—Genetic predisposition to life-threatening cardiac arrhythmias such as congenital long-QT syndrome (LQTS) and catecholaminergic polymorphic ventricular tachycardia (CPVT) represent treatable causes of sudden cardiac death in young adults and children. Recently, mutations in calmodulin (CALM1, CALM2) have been associated with severe forms of LQTS and CPVT, with life-threatening arrhythmias occurring very early in life. Additional mutation-positive cases are needed to discern genotype–phenotype correlations associated with calmodulin mutations. Methods and Results—We used conventional and next-generation sequencing approaches, including exome analysis, in genotypenegative LQTS probands. We identified 5 novel de novo missense mutations in CALM2 in 3 subjects with LQTS (p.N98S, p.N98I, p.D134H) and 2 subjects with clinical features of both LQTS and CPVT (p.D132E, p.Q136P). Age of onset of major symptoms (syncope or cardiac arrest) ranged from 1 to 9 years. Three of 5 probands had cardiac arrest and 1 of these subjects did not survive. The clinical severity among subjects in this series was generally less than that originally reported for CALM1 and CALM2 associated with recurrent cardiac arrest during infancy. Four of 5 probands responded to β-blocker therapy, whereas 1 subject with mutation p.Q136P died suddenly during exertion despite this treatment. Mutations affect conserved residues located within Ca 2+ -binding loops III (p.N98S, p.N98I) or IV (p.D132E, p.D134H, p.Q136P) and caused reduced Ca 2+ -binding affinity. Conclusions—CALM2 mutations can be associated with LQTS and with overlapping features of LQTS and CPVT. (Circ Cardiovasc Genet. 2014;7:466-474.)

Burden of Sudden Cardiac Death in Persons Aged 1 to 49 Years Nationwide Study in Denmark

Abstract: Background— Knowledge of the burden and causes of sudden cardiac death (SCD) is sparse in persons aged <50 years; better understanding is needed to lower the risk of SCD. The aim of this study was to report SCD incidence rates and autopsy findings in persons aged 1 to 49 years. Methods and Results— All deaths in persons aged 1 to 49 years were included in 2007 to 2009. Death certificates were reviewed by 2 physicians. History of previous admissions to hospital was assessed, and discharge summaries were read. Sudden unexpected death cases were identified and autopsy reports were collected. In the 3-year study period, there were 7849 deaths of which we identified 893 (11%) SCD cases. The annual incidence rate per 100 000 persons increased from 2.3 (95% confidence interval, 2.0–2.7) to 21.7 (95% confidence interval, 20.2–23.4) in persons aged 1 to 35 and 36 to 49 years, respectively. Coronary artery disease was the most common cause of death and was found in 158 (36%) autopsied cases, followed by 135 (31%) cases of sudden unexplained death. Conclusions— In a nationwide cohort of persons aged <50 years, the annual incidence rate of SCD was ≈10× higher in persons aged 36 to 49 years than in persons aged 1 to 35 years. Notably, coronary artery disease was the most common cause of SCD, followed by unexplained deaths. These findings may help in developing strategies to prevent SCD in the future.

The importance of specialist cardiac histopathological examination in the investigation of young sudden cardiac deaths

Abstract: Aims Post-mortem examination of the heart in young sudden cardiac death (SCD) is vital as the underlying aetiology is often an inherited cardiac disease with implications for surviving relatives. Our aim is to demonstrate the improvement in diagnostic quality offered by a specialist cardiac pathology service established to investigate SCD with fast-track reporting on hearts sent by pathologists in cases of SCD. Methods and results A tertiary centre prospective observational study was conducted. Detailed histopathological examination was performed in a tertiary centre specialized in the investigation of cardiac pathology in SCD. Hearts from 720 consecutive cases of SCD referred by coroners and pathologists from 2007 to 2009 were included. A comparison was drawn with diagnoses from referring pathologists. Most SCDs occurred in males (66%), with the median age being 32 years. The majority (57%) of deaths occurred at home. The main diagnoses were a morphologically normal heart ( n = 321; 45%), cardiomyopathy ( n = 207, 29%), and coronary artery pathology ( n = 71; 10%). In 158 out of a sample of 200 consecutive cases, a cardiac examination was also performed by the referring pathologist with a disparity in diagnosis in 41% of the cases ( κ = 0.48). Referring pathologists were more inclined to diagnose cardiomyopathy than normality with only 50 out of 80 (63%) normal hearts being described correctly. Conclusion Expert cardiac pathology improves the accuracy of coronial post-mortem diagnoses in young SCD. This is important as the majority of cases may be due to inherited cardiac diseases and the autopsy guides the appropriate cardiological evaluation of blood relatives for their risk of sudden death.

Clinical characteristics and circumstances of death in the sudden arrhythmic death syndrome.

Abstract: Background— Sudden cardiac death (SCD) is a devastating event in the young. Referral to a specialist cardiac pathologist is recommended. Age, sex, and circumstances of death may reflect underlying diagnoses. We aim to describe the demographics of victims and circumstances surrounding sudden cardiac death with a normal heart (ie, sudden arrhythmic death syndrome). Methods and Results— There were 2156 cases of sudden cardiac death from across the United Kingdom referred to a tertiary cardiac pathology service from 1994 to 2010. We analyzed 967 consecutive cases (61% male; median age 29 years) with a normal heart at postmortem. Information from referring coroners’ reports was used to ascertain clinical information. Familial evaluation was performed in 5% of cases. Information from these cases was used to determine the likely accuracy of coronial reports. Deaths during sleep or at rest were more common than deaths during exercise or with emotional stress: 82% versus 16%. Death with exercise/stress was more common in males (relative risk, 2.33; 95% confidence interval, 1.56–3.47; P <0.001) and those under 18 years of age: males, relative risk, 2.41 (95% confidence interval, 1.69–3.13; P <0.001) and females, relative risk, 2.91 (95% confidence interval, 1.80–4.01; P <0.001)). Prior syncope (4.1%), documented arrhythmia (3.4%), and family history of sudden death (4.2%) were uncommon. Epilepsy had been diagnosed in 6.6%. Conclusions— Death caused by sudden arrhythmic death syndrome is more common at rest or during sleep. Death with exercise/stress is more common in males and those aged below 18 years. Up to 90% of SADS victims have no preceding symptoms or recognized risk factors for sudden death. Epilepsy may be considered a risk factor for SADS.

Sudden unexplained death in infants and children: the role of undiagnosed inherited cardiac conditions.

Abstract: Sudden unexplained death in childhood is a traumatic event for both the immediate family and medical professionals. This is termed sudden unexplained or arrhythmic death syndrome (SUDS/SADS) for children over 1 year of age while sudden unexplained death in infancy or sudden infant death syndrome (SUDI/SIDS) refers to unexplained deaths in the first year of life. There is increasing evidence for the role of undiagnosed inherited cardiac conditions, particularly channelopathies, as the cause of these deaths. This has far-reaching implications for the family regarding the potential risk to other family members and future pregnancies, providing a challenge not only in the counselling but also in the structured assessment and management of immediate relatives. This review will discuss the cardiac risk involved in sudden unexplained deaths of infants and children, the role of molecular autopsy, family cardiological screening, current management strategies, and future directions in this area.

Cardiac Evaluation of Pediatric Relatives in Sudden Arrhythmic Death Syndrome A 2-Center Experience

Abstract: Background— Sudden arrhythmic death syndrome defines a sudden unexpected and unexplained death despite comprehensive pathological and toxicological investigation. Previous studies have focused on evaluation of adult relatives. There is, however, a lack of data in children, leading to highly variable management. We sought to determine the clinical utility of cardiac evaluation in pediatric relatives of sudden arrhythmic death syndrome probands. Methods and Results— Retrospective review was undertaken of pediatric patients with a family history of sudden arrhythmic death syndrome assessed from 2010 to 2013 in 2 centers. Clinical history, cardiac, and genetic investigations were assessed, including diagnoses made after evaluation of adult relatives. A total of 112 pediatric relatives from 61 families were evaluated (median age at presentation, 8 years; range, 0.5–16 years). A probable diagnosis was made in 18 (29.5%) families: Brugada syndrome, 13/18 (72%); long QT syndrome, 3/18 (17%); and catecholaminergic polymorphic ventricular tachycardia, 2/18 (11%). Genetic testing identified mutations in 20% of Brugada syndrome (2/10) and 50% of long QT syndrome (1/2) and catecholaminergic polymorphic ventricular tachycardia families (1/2) who were tested. Pediatric evaluation diagnosed 6/112 relatives (5.4%), increasing to 7% (6/85) if only first-degree relatives were assessed. The only useful diagnostic tests were the 12-lead and exercise electrocardiograms and ajmaline provocation test. The median duration of follow-up was 2.1 years (range, 0.2–8.2 years) with no cardiac events. Conclusions— The yield of evaluating pediatric relatives is significant and higher when focused on first-degree relatives and on conditions usually expressed in childhood. We propose a management pathway for these children.

Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization

Abstract: The QT interval, an electrocardiographic measure reflecting myocardial repolarization, is a heritable trait. QT prolongation is a risk factor for ventricular arrhythmias and sudden cardiac death (SCD) and could indicate the presence of the potentially lethal mendelian long-QT syndrome (LQTS). Using a genome-wide association and replication study in up to 100,000 individuals, we identified 35 common variant loci associated with QT interval that collectively explain ∼8–10% of QT-interval variation and highlight the importance of calcium regulation in myocardial repolarization. Rare variant analysis of 6 new QT interval–associated loci in 298 unrelated probands with LQTS identified coding variants not found in controls but of uncertain causality and therefore requiring validation. Several newly identified loci encode proteins that physically interact with other recognized repolarization proteins. Our integration of common variant association, expression and orthogonal protein-protein interaction screens provides new insights into cardiac electrophysiology and identifies new candidate genes for ventricular arrhythmias, LQTS and SCD.

MicroRNAs in cardiac arrhythmia: DNA sequence variation of MiR-1 and MiR-133A in long QT syndrome.

Abstract: Long QT syndrome (LQTS) is a genetic cardiac condition associated with prolonged ventricular repolarization, primarily a result of perturbations in cardiac ion channels, which predisposes individuals to life-threatening arrhythmias Using DNA screening and sequencing methods, over 700 different LQTS-causing mutations have been identified in 13 genes worldwide Despite this, the genetic cause of 30-50% of LQTS is presently unknown MicroRNAs (miRNAs) are small (∼ 22 nucleotides) noncoding RNAs which post-transcriptionally regulate gene expression by binding complementary sequences within messenger RNAs (mRNAs) The human genome encodes over 1800 miRNAs, which target about 60% of human genes Consequently, miRNAs are likely to regulate many complex processes in the body, indeed aberrant expression of various miRNA species has been implicated in numerous disease states, including cardiovascular diseases MiR-1 and MiR-133A are the most abundant miRNAs in the heart and have both been reported to regulate cardiac ion channels We hypothesized that, as a consequence of their role in regulating cardiac ion channels, genetic variation in the genes which encode MiR-1 and MiR-133A might explain some cases of LQTS Four miRNA genes (miR-1-1, miR-1-2, miR-133a-1 and miR-133a-2), which encode MiR-1 and MiR-133A, were sequenced in 125 LQTS probands No genetic variants were identified in miR-1-1 or miR-133a-1; but in miR-1-2 we identified a single substitution (n100A> G) and in miR-133a-2 we identified two substitutions (n-19G> A and n98C> T) None of the variants affect the mature miRNA products Our findings indicate that sequence variants of miR-1-1, miR-1-2, miR-133a-1 and miR-133a-2 are not a cause of LQTS in this cohort

Sudden Unexplained Death - Treating the Family.

Abstract: Sudden unexplained death in the context of a normal heart at post-mortem and negative toxicological analysis is termed sudden arrhythmic death syndrome (SADS). SADS is often due to cardiac genetic disease, particularly channelopathies. Assessment of family members of SADS victims will reveal at least one affected individual in up to half of families. Specialist evaluation begins with an expert cardiac autopsy that improves diagnostic accuracy and minimises erroneous interpretation of minor pathological findings. Retention of appropriate material for post-mortem genetic testing, 'the molecular autopsy', is recommended as this may provide a genetic diagnosis in up to a third of cases. Clinical assessment of families initially comprises 12-lead ECG with high right ventricular leads, echocardiogram and exercise testing. Additional investigations include sodium channel blocker and epinephrine provocation tests. Families with a diagnosis should be managed as per guidelines. Those with negative investigations can generally be discharged unless they are young and/or symptomatic.

The genetics of pro‐arrhythmic adverse drug reactions

Abstract: Ventricular arrhythmia induced by drugs (pro-arrythmia) is an uncommon event, whose occurrence is unpredictable but potentially fatal The ability of a variety of medications to induce these arrhythmias is a significant problem facing the pharmaceutical industry Genetic variants have been shown to play a role in adverse events and are also known to influence an individual's optimal drug dose This review provides an overview of the current understanding of the role of genetic variants in modulating the risk of drug induced arrhythmias

17The brugada syndrome and cardiomyopathy: altered collagen and gap junction expression

Abstract: Background: Brugada syndrome (BrS) is considered an inherited arrhythmia syndrome, though it may represent a concealed cardiomyopathy confined to the right ventricular outflow tract (RVOT). We aimed to ascertain fibrosis and gap junction expression in ventricular myocardium following sudden cardiac death (SCD) due to BrS. Methods: The BrS cohort consisted of 6 cases of unexplained SCD referred for specialist whole heart autopsy whose family were diagnosed with BrS. Comparisons were made to matched homograft control hearts (n=6) and cases of arrhythmogenic right ventricular cardiomyopathy (ARVC, n=5). Morphometric evaluation of collagen and fat content of left (LV) and right (RV) ventricles and RVOT by picrosirius red-staining was undertaken. Gap junction expression was assessed by Connexin43 (Cx43) immunostaining in the RVOT. Results: Collagen in controls was predominantly perivascular in long fine fibres and diffuse reticular interstitial networks. Interstitial long collagen strands were thickened in BrS, with evidence of epicardial patchy replacement fibrosis. ARVC was characterised by both interstitial and dense patchy replacement fibrosis. Maximal collagen content, indicative of fibrosis, was present in the RVOT (p=0.003) and epicardium (p=0.001) in all three disease groups, with RV more fibrosed than LV (p=0.020). ARVC cases exhibited the most fibrosis (p=0.001), while BrS cases were significantly more fibrosed than controls (OR 1.42; p=0.024). No significant difference in fat content was observed between BrS and controls (p=0.133). BrS cases showed a reduced Cx43 signal in comparison to controls (OR 0.59; p=0.001), which remained significant after adjusting for collagen content (Figure). However, lateralisation and dispersion of Cx43 over the cellular surface was seen in both control and BrS sections. In ARVC, Cx43 signal was severely reduced in comparison to BrS (OR 0.61; p=0.002). Discussion: BrS associates with generalised ventricular myocardial fibrosis and reduced RVOT gap junction expression in comparison with controls, with ARVC demonstrating similar but more severe abnormalities. Thus, BrS may represent a disease of myocardial architecture, with baseline properties of the RVOT predisposing it to more severe fibrosis. We speculate that myocyte electrical uncoupling indicated by gap junction abnormalities and changes in conduction related to fibrosis confer arrhythmic risk. ![Graphic][1] Figure Scatterplot of Cx43:collagen ratio in RVOT by myocardial zone (filled data points=mean) demonstrating significant differences between ARVC, BrS and Control cohorts, but no difference from epi- to endo-cardium. [1]: /embed/inline-graphic-1.gif

16Ethnicity and phenotype in the SCN5A E1784K mutation

Abstract: Background: Long QT (LQTS) and Brugada syndromes (BrS) are inherited arrhythmia syndromes characterised by risk of sudden cardiac death (SCD) and highly variable penetrance. Mutations in SCN5A, which encodes the Nav1.5 cardiac ion channel responsible for the inward cardiac sodium current, are responsible for 5-10% of LQTS and associated with 20% of BrS. The E1784K mutation in SCN5A is the most commonly identified SCN5A mutation in both LQTS and BrS, and causes the Long QT type 3 (LQT3)/BrS overlap disease with variable phenotypic expression. Carriers within the same pedigree may exhibit LQT3 phenotype, BrS phenotype or both. The aim of this international project was to determine if there are any associations between phenotype and ethnicity within a unique cohort of E1784K mutation carriers. Methods: 93 E1784K mutation carriers belonging to 33 families from 6 different countries including Japan were included. Data was collected on age, gender, symptoms, family history and the ECG. Non-digital and digital ECG data were analysed using proprietary software. Automatic readings and measurements from 2 observers were taken. A 3rd observer reviewed the ECGs where there was inter-observer discrepancy between the measurements. Statistical significance was determined using either the 2-tailed t-test or Chi-squared test as appropriate. Results: QTc intervals were significantly longer amongst Japanese E1784K mutation carriers, who were more symptomatic albeit with a lower incidence of SCD. Results are summarised in Table [1][1]. The spontaneous type 1 BrS ECG pattern also appeared to be more prevalent in the Japanese compared to Caucasian mutation carriers although the numbers were small. Mean QRS duration was longer amongst Caucasian mutation carriers. Drug-induced BrS phenotype was unmasked in 63% of Caucasians (34/54) who underwent a test. A family history of SCD was present in 50% of Caucasian families compared to only 13.6% of Japanese families (p=0.015). | | Total (n=93) | Caucasian (n=64) | Japanese (n=29) | p-value | | ------------------------- | ------------ | ---------------- | --------------- | ------- | | Age (years, mean, range) | 28, 1-67 | 30, 1-67 | 23, 6-62 | 0.0826 | | Sex-male (n,%) | 47, 51 | 32, 50 | 15, 52 | 0.8776 | | Spontaneous BrS (n,%) | 4, 4 | 1, 2 | 3, 10 | 0.0531 | | QTc (ms, mean, range) | 480, 404-579 | 472, 404-533 | 499, 430-579 | 0.0001 | | PR (ms, mean, range) | 167, 116-302 | 167, 116-302 | 166, 149-180 | 0.8952 | | QRS (ms, mean, range) | 96, 60-139 | 99, 68-139 | 90, 60-120 | 0.0145 | | Pre-syncope/syncope (n,%) | 17, 18 | 8, 13 | 9, 31 | 0.0741 | | Aborted SCD (n,%) | 6, 6 | 6, 9 | 0, 0 | 0.0882 | Table 1 Clinical characteristics Conclusions: There is variation in expression of E1784K between ethnicities with ethnic differences in severity and risk of sudden death. These results support a strong role for genetic modifiers of phenotype and risk which deserves further study. [1]: #T1

56Linear relationship between distance and ECG similarity during endocardial and epicardial pacing: application in a novel mapping algorithm for the real-time prediciton of the site of origin of ventricular arrhythmias

Abstract: Introduction: Pacemapping (PM) is an established method for localising the site of origin (SO) of ventricular arrhythmias (VA). Currently, there is no system to indicate where subsequent PM will result in a better match to the clinical VA. We investigated the relationship between the change in ECG and distance between PM points and developed a novel navigation algorithm which was tested prospectively. Methods: Digitised ECGs and Cartesian catheter coordinates were extracted from prospectively collected PM points across the endocardial (endo) surface of both ventricles and epicardial (epi) where possible, along with geometry from a 3D mapping system used in patients who underwent ablation of VA. Using custom software, a similarity metric was calculated using the root mean square error sum (RMSE) for each ECG between pairs of PM points (myocardial voltage > 0.5 mV) and plotted against Euclidian distance and linear regression through origin performed to examine the distance similarity relationship (DSR). For the navigation concept, custom 3D mapping software was developed to run in parallel with the EnSite Velocity System (St Jude Medical, MN). For each study, a patient specific DSR was created initially from 3 widely spaced PM points and RMSE calculated between the VA and PM points. Using the DSR, the distance between VA and each PM point was extrapolated and visualised as 3 overlapping circles converging on a target superimposed on the 3D geometry (Figure). If the target was large, the PM point furthest away was substituted with a PM point predicted to be closest to the VA and this process repeated iteratively until the target area reduced to a minimum. Results: From Oct 11-Jun 14, we enrolled 64 patients, 43 Male, median age 56 (IQR 26) who underwent 70 procedures (40 VE, 30 VT, 65 Endo, 5 Epi approach). 30 had normal hearts (NH), 19 ICM and 15 NICM. Median LVEF was 55% (IQR 22). A total of 861 PM points were analysed (mean 12.3±4.4 PM points per patient). Distance and ECG similarity were strongly correlated, median correlation coefficient R 0.937 (IQR .044). There was no difference in strength of correlation or gradient of the slope between scarred vs NH or between NH vs ICM vs NICM. We performed real time SO prediction on 25 prospectively enrolled patients (18 male; age 52±15 yrs; median LVEF 57% (IQR 15); 15 VE, 10 VT; 11 NH, 4 IHD, 10 NICM; Epi approach in 3). SO prediction was performed on 32 distinct VA (12 LV, 4 LVOT, 3 RV, 11 RVOT, 2 Epi LV). The system correctly identified the SO (as identified by conventional means) in 31/32 instances with a mean target area of 208±185mm2 range (40-708mm2) requiring 7±3 PM to build the relationship. In one case, the system correctly identified the area of best PM match but was discordant with activation mapping. Conclusion: There is a strong linear relationship between change in ECG morphology and distance using PM points from myocardium >0.5 mV that does not appear to be significantly different between scar and non-scar aetiologies. Using this novel system, it is possible to correctly identify a clinically useful target area in real time to identify the SO of VA in patients with structural heart disease and normal hearts. Further work is needed to confirm its usefulness in VA of epicardial origin. ![Graphic][1] [1]: /embed/inline-graphic-1.gif

Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization

Abstract: The QT interval, an electrocardiographic measure reflecting myocardial repolarization, is a heritable trait. QT prolongation is a risk factor for ventricular arrhythmias and sudden cardiac death (SCD) and could indicate the presence of the potentially lethal mendelian long-QT syndrome (LQTS). Using a genome-wide association and replication study in up to 100,000 individuals, we identified 35 common variant loci associated with QT interval that collectively explain ∼8-10% of QT-interval variation and highlight the importance of calcium regulation in myocardial repolarization. Rare variant analysis of 6 new QT interval-associated loci in 298 unrelated probands with LQTS identified coding variants not found in controls but of uncertain causality and therefore requiring validation. Several newly identified loci encode proteins that physically interact with other recognized repolarization proteins. Our integration of common variant association, expression and orthogonal protein-protein interaction screens provides new insights into cardiac electrophysiology and identifies new candidate genes for ventricular arrhythmias, LQTS and SCD.

163 Genetic Modifiers in Carriers of the SCN5A E1784K Mutation with Variable Phenotypic Expression - Long QT3 / Brugada Syndrome Overlap Disease

Abstract: Introduction 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. Methods 88 E1784K mutation carriers from 14 families were genotyped for 48 single nucleotide polymorphisms (SNPs). The chosen SNPs associate with different electrocardiographic (ECG) traits in the general population in large genome wide association studies. Association with PR interval, QRS duration, QTc interval, BrS phenotype (spontaneous and drug-induced type 1 ECG pattern) and time to occurrence of symptoms/arrhythmic events were tested using either mixed effects Cox models or generalised estimating equation logistic regression tests as appropriate, with adjustment for age and sex. P-values were uncorrected for multiple testing as the aim of this study was to identify potential genetic modifiers with existing evidence for biological plausibility that could be subsequently confirmed or refuted through replication in larger patient cohorts. Results Eight SNPs showed significant association (p Four SNPs were significantly associated (p Two SNPs (rs11047543, Chr 12 and rs17020136, Chr 2) were associated with the occurrence of events (cardiac syncope, ventricular tachycardia or aborted cardiac arrest) with p-values of 0.0467 and 0.0154, and odds ratios of 3.35 and 2.61 respectively. Conclusions Several SNPs showed significant and highly significant association with different ECG traits and occurrence of symptoms in this cohort of E1784K carriers. These results provide promising initial evidence for the presence of potential genetic modifiers in LQT3 and BrS. Further supporting evidence will be required through replication in larger cohorts and functional studies. These may provide evidence for new pathways that modulate phenotype and risk and provide clinical risk stratifiers.

Comparative study of signal decomposition methods for enhancement of the accuracy of T-wave end localisation

Abstract: The goal of this study was to compare several ECG signal decomposition methods in order to enhance the accuracy of T wave end localisation. PTB Diagnostic ECG Database comprising 549 recordings was used. The idea was to combine the 8 independent leads (I, II, V1,…, V6) of the standard 12-leads ECG into a single lead.