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Biomedical subjects

Koonlawee Nademanee

Publications and source records attributed to Koonlawee Nademanee.

18 recordsLinked to original sources
PubMed2026

Whole-genome sequencing implicates rare, low-frequency and structural non-coding variation at the SCN5A locus in Brugada syndrome.

Brugada syndrome (BrS) is an inherited cardiac condition characterized by a hallmark ECG pattern and an increased risk of sudden cardiac death. Central to the aetiology of BrS, the SCN5A region harbours both common non-coding risk variants and rare coding variants that are causative in approximately 20% of patients. However, rare non-coding genetic variation in this region remains largely unexplored. Here, we used whole-genome sequencing (WGS) of 752 European-ancestry BrS cases and 1,827 ancestry-matched controls to identify BrS-associated rare non-coding genetic variation at the SCN5A locus. Sliding-window and cis-regulatory element (CRE)-based rare-variant aggregate testing implicated three conserved CREs, including a dense aggregation of case singleton variants within a 178 bp enhancer in intron 17 of SCN5A which replicated in an independent BrS cohort. Prioritised BrS-associated rare and low-frequency non-coding variants within these elements were predicted to alter cardiac transcription factor motifs, and altered CRE activity in hiPSC-CM luciferase assays or were associated with BrS-relevant ECG endophenotypes in the UK Biobank. Single-variant analysis across the region identified a Bonferroni-significant five-fold case-enriched low-frequency variant within a known CRE in intron 1 of SCN5A, which replicated, was associated with slower cardiac conduction in the UK Biobank and accounted for part of the BrS GWAS signal at this locus. Structural variant analyses identified a 10.5 kb deletion upstream of SCN5A in a BrS case that encompassed a cardiac CRE and reduced sodium current density in a hiPSC-CM model, as well as a 6 kb BrS-enriched retrotransposon insertion in SCN5A that appeared to underlie part of the GWAS signal in this region. Together, these findings implicate rare and low-frequency non-coding variation at the SCN5A locus in BrS susceptibility and demonstrate the value of targeted WGS analysis of key disease loci.

Journal Article↗
PubMed2026

Clinical Profile and Mode of Initiation of Spontaneous Ventricular Tachyarrhythmias in Patients With Brugada Syndrome (START-BrS).

BACKGROUND: Data on the spontaneous onset of ventricular tachyarrhythmias (VTAs) in Brugada syndrome (BrS), including polymorphic ventricular tachycardia (PVT) and monomorphic ventricular tachycardia (MVT), remain limited. OBJECTIVES: The goal of this study was to compare the clinical profile and mode of initiation of PVT and MVT in BrS. METHODS: This retrospective multicenter registry included 154 patients with BrS from 29 centers with documented VTA initiation captured by implantable cardioverter-defibrillator (94.9%) or electrocardiogram (5.1%). A total of 234 VTAs were analyzed, and initiation patterns were classified by using predefined electrocardiographic criteria. RESULTS: PVT was observed in 80.5% of patients, MVT in 16.9%, and both in 2.6%. Patients with MVT tended to be older, exhibit drug-induced Brugada electrocardiogram, and were more frequently White. Pause-dependent initiation occurred in approximately 25% of PVT and approximately 33% of MVT episodes. Coupling intervals initiating PVT were nonsignificantly shorter than for MVT (median 368 milliseconds vs 395 milliseconds), with a significantly lower prematurity index and faster early arrhythmia cycle length. Antecedent premature ventricular complexes were present in approximately 43% of both VTA types, commonly sharing morphology with the initiating premature ventricular complex. The prevalence of pathogenic/likely pathogenic SCN5A mutation did not differ between groups. CONCLUSIONS: In this largest analysis to date of spontaneous VTA onset in BrS, MVT occurred in a substantial minority and was associated with older age, White ethnicity, drug-induced electrocardiogram pattern, and a preceding tachycardia. Initiation patterns were broadly similar across arrhythmia types, although PVT exhibited a significantly lower prematurity index and faster early cycle length despite only nonsignificant shorter coupling intervals. These findings refine the clinical and electrophysiological characterization of BrS-related arrhythmias and delineate distinct features of PVT and MVT initiation.

Adult↗
PubMed2006

Nonexcitatory, cardiac contractility modulation electrical impulses: feasibility study for advanced heart failure in patients with normal QRS duration.

BACKGROUND: Cardiac contractility modulation signals are associated with acutely improved hemodynamics, but chronic clinical impact is not defined. OBJECTIVES: The purpose of this randomized, double-blind, pilot study was to determine the feasibility of safely and effectively delivering cardiac contractility modulation signals in patients with heart failure. METHODS: Forty-nine subjects with ejection fraction <35%, normal QRS duration (105 +/- 15 ms), and New York Heart Association (NYHA) class III or IV heart failure despite medical therapy received a cardiac contractility modulation pulse generator. Patients were randomized to have their devices programmed to deliver cardiac contractility modulation signals (n = 25, treatment group) or to remain off (n = 24, control group) for 6 months. Evaluations included NYHA class, 6-minute walk, cardiopulmonary stress test, Minnesota Living with Heart Failure Questionnaire, and Holter monitoring. RESULTS: Although most baseline features were balanced between groups, ejection fraction (31.4% +/- 7.4% vs 24.9% +/- 6.5%, P = .003), end-diastolic dimension (52.1 +/- 21.4 mm vs 62.5 +/- 6.2 mm, P = .01), peak VO(2) (16.0 +/- 2.9 mL O(2)/kg/min vs 14.3 +/- 2.8 mL O(2)/kg/min, P = .02), and anaerobic threshold (12.3 +/- 2.5 mL O(2)/kg/min vs 10.6 +/- 2.4 mL O(2)/kg/min, P = .01) were worse in the treatment group than in the control group. Nevertheless, one death occurred in the control group, and more patients in the treatment group were free of hospitalization for any cause at 6 months (84% vs 62%). No change in ectopy was observed. Compared with baseline, 6-minute walk (13.4 m), peak VO(2) (0.2 mL O(2)/kg/min), and anaerobic threshold (0.8 mL O(2)/kg/min) increased more in the treatment group than in control. None of these differences were statistically significant (small sample size). NYHA and Minnesota Living with Heart Failure Questionnaire changed similarly in the two groups. CONCLUSION: Despite a sicker population in the treatment group, no specific safety concerns emerged with chronic cardiac contractility modulation signal administration. Further study is required to definitively define the safety and efficacy of cardiac contractility modulation signals.

Aged↗
PubMed2006

Clinical experience with tiered atrial therapies and atrial arrhythmia prevention algorithms in a dual chamber cardioverter defibrillator.

INTRODUCTION: The acceptance of atrial arrhythmia features in implantable cardioverter defibrillators (ICDs) will depend on their ability to appropriately discriminate atrial tachyarrhythmias/atrial fibrillation (AT/AF). This study tested the effectiveness of an atrial/ventricular ICD with advanced atrial detection and new algorithms designed to prevent atrial arrhythmias. METHODS AND RESULTS: Ninety-five patients were implanted with a dual chamber ICD (Model 1900, Guidant Corporation, MN, USA) at 25 US centers. Ten patients received a coronary sinus (CS) lead allowing a defibrillation vector for AT/AF cardioversion. Follow-up was 12.2 months. The addition of new atrial features designed for detection, discrimination, and prevention of AT/AF had no adverse effect upon detection of induced ventricular fibrillation (VF) (mean detection time with new features ON was 2.22 seconds vs 2.19 seconds with features OFF). A total of 100% of the induced and spontaneous ventricular and atrial arrhythmias receiving shock therapy were reviewed as appropriate detection. Atrial shock conversion efficacy for spontaneous and induced AT/AF episodes was 83% and 96%, respectively (144 spontaneous, 162 induced episodes). A 3-month randomized crossover trial of atrial preventative pacing features did not result in adverse effects, but there was no clinical efficacy for prevention of AT/AF. CONCLUSION: Enhanced atrial detection and discrimination features combined with tiered atrial therapies did not adversely impact the ability of the ICD (Model 1900) to appropriately detect and treat ventricular tachyarrhythmias.

Aged↗
PubMed2005

Brugada syndrome: report of the second consensus conference: endorsed by the Heart Rhythm Society and the European Heart Rhythm Association.

Since its introduction as a clinical entity in 1992, the Brugada syndrome has progressed from being a rare disease to one that is second only to automobile accidents as a cause of death among young adults in some countries. Electrocardiographically characterized by a distinct ST-segment elevation in the right precordial leads, the syndrome is associated with a high risk for sudden cardiac death in young and otherwise healthy adults, and less frequently in infants and children. Patients with a spontaneously appearing Brugada ECG have a high risk for sudden arrhythmic death secondary to ventricular tachycardia/fibrillation. The ECG manifestations of Brugada syndrome are often dynamic or concealed and may be unmasked or modulated by sodium channel blockers, a febrile state, vagotonic agents, alpha-adrenergic agonists, beta-adrenergic blockers, tricyclic or tetracyclic antidepressants, a combination of glucose and insulin, hypo- and hyperkalemia, hypercalcemia, and alcohol and cocaine toxicity. In recent years, an exponential rise in the number of reported cases and a striking proliferation of articles defining the clinical, genetic, cellular, ionic, and molecular aspects of the disease have occurred. The report of the first consensus conference, published in 2002, focused on diagnostic criteria. The present report, which emanated from the second consensus conference held in September 2003, elaborates further on the diagnostic criteria and examines risk stratification schemes and device and pharmacological approaches to therapy on the basis of the available clinical and basic science data.

Arrhythmogenic Right Ventricular Dysplasia↗
PubMed2005

Brugada syndrome: report of the second consensus conference.

Since its introduction as a clinical entity in 1992, the Brugada syndrome has progressed from being a rare disease to one that is second only to automobile accidents as a cause of death among young adults in some countries. Electrocardiographically characterized by a distinct ST-segment elevation in the right precordial leads, the syndrome is associated with a high risk for sudden cardiac death in young and otherwise healthy adults, and less frequently in infants and children. Patients with a spontaneously appearing Brugada ECG have a high risk for sudden arrhythmic death secondary to ventricular tachycardia/fibrillation. The ECG manifestations of Brugada syndrome are often dynamic or concealed and may be unmasked or modulated by sodium channel blockers, a febrile state, vagotonic agents, alpha-adrenergic agonists, beta-adrenergic blockers, tricyclic or tetracyclic antidepressants, a combination of glucose and insulin, hypo- and hyperkalemia, hypercalcemia, and alcohol and cocaine toxicity. In recent years, an exponential rise in the number of reported cases and a striking proliferation of articles defining the clinical, genetic, cellular, ionic, and molecular aspects of the disease have occurred. The report of the first consensus conference, published in 2002, focused on diagnostic criteria. The present report, which emanated from the second consensus conference held in September 2003, elaborates further on the diagnostic criteria and examines risk stratification schemes and device and pharmacological approaches to therapy on the basis of the available clinical and basic science data.

Arrhythmogenic Right Ventricular Dysplasia↗
PubMed2004

A new approach for catheter ablation of atrial fibrillation: mapping of the electrophysiologic substrate.

OBJECTIVES: We sought to test the hypothesis that complex fractionated electrograms (CFAEs) recorded during atrial fibrillation (AF) could be used as target sites for catheter ablation of AF. BACKGROUND: Mapping of AF in humans has shown that areas of CFAEs correlate with areas of slowed conduction and pivot points of reentrant wavelets. We hypothesized that such areas of CFAEs could be identified in patients with AF and might serve as target sites for catheter ablation to maintain sinus rhythm. METHODS: The study population included 121 patients (29 females; mean age, 63 years) with refractory AF (57 paroxysmal, 64 chronic). All patients underwent nonfluoroscopic electroanatomic mapping (CARTO) during AF. Using CARTO, the biatrial replica, displayed in a three-dimensional color-coded voltage map, was created during AF, and areas associated with CFAEs were identified. Radiofrequency ablation of the area with CFAEs was performed, aiming to eliminate CFAE and/or convert to sinus rhythm. RESULTS: Complex fractionated atrial electrograms were found in seven of nine regions of both atria, but were mainly confined to the interatrial septum, pulmonary veins, roof of left atrium, and left posteroseptal mitral annulus and coronary sinus ostium. Ablations of the areas associated with CFAEs resulted in termination of AF without external cardioversion in 115 of the 121 patients (95%); 32 (28%) required concomitant ibutilide treatment. At the one-year follow-up, 110 (91%) patients were free of arrhythmia and symptoms, 92 after one ablation and 18 after two. CONCLUSIONS: Areas with CFAEs represent a defined electrophysiologic substrate and are ideal target sites for ablations to eliminate AF and maintain normal sinus rhythm.

Atrial Fibrillation↗
PubMed2003

Defibrillator Versus beta-Blockers for Unexplained Death in Thailand (DEBUT): a randomized clinical trial.

BACKGROUND: Sudden Unexplained Death Syndrome (SUDS) is the leading cause of death in young, healthy, Southeast Asian men. The role of an implantable cardioverter defibrillator (ICD) for mortality reduction in these patients remains unclear. METHODS AND RESULTS: The Defibrillator Versus beta-Blockers for Unexplained Death in Thailand (DEBUT) study is a randomized, clinical trial conducted in 2 phases (pilot study followed by the main trial) to compare the annual all-cause mortality rates among SUDS patients treated with beta-blockers versus that among those treated with an ICD. A total of 86 patients who were SUDS survivors and probable SUDS survivors were randomized to receive an ICD or propranolol (20 patients were in the pilot study and 66 were in the main trial). The primary end point was death from all causes. The secondary end point was recurrent ventricular tachycardia/ventricular fibrillation (VF) or cardiac arrest. During the 3-year follow-up period of the main trial, there were 4 deaths; all occurred in the beta-blocker group (P=0.02). Seven subjects in the ICD arm had recurrent VF, and all were effectively treated by the ICD. On the basis of the main trial results, the Data Safety Monitoring Board stopped the study. In total (both from the Pilot study and the main trial), there were 7 deaths (18%) in the beta-blocker group and no deaths in the ICD group, but there were a total of 12 ICD patients receiving ICD discharges due to recurrent VF. CONCLUSIONS: ICD treatment provides full protection from death related to primary VF in a SUDS population and is superior to beta-blockade treatment.

Adrenergic beta-Antagonists↗
PubMed2003

Heart rate variability in patients with Brugada syndrome in Thailand.

AIMS: Since patients with Brugada syndrome usually have symptoms at nighttime, we hypothesize that changes in autonomic modulation have an important role in the occurrence of the ventricular fibrillation episodes. The objective of this study was to determine the changes in heart rate variability (HRV) in patients with Brugada syndrome compared to asymptomatic subjects with Brugada ECG and controls. METHODS AND RESULTS: We studied 17 patients with Brugada syndrome, 10 asymptomatic subjects with Brugada ECG and 45 controls. Patients with Brugada syndrome and asymptomatic subjects with Brugada ECG underwent echocardiography, exercise stress testing, 24-h Holter monitoring, signal-averaged ECG. Patients with Brugada syndrome also underwent coronary angiography and electrophysiologic study. Time domain and frequency domain HRV analysis were performed at daytime and nighttime. The results of this study showed that patients with Brugada syndrome had lower HRV or lower vagal tone at night compared to the controls. They also had lower heart rate during the day and higher during the night compared to asymptomatic subjects and the controls. CONCLUSION: Patients with Brugada syndrome had low heart rate variability at night which may predispose to the occurrence of VF episodes.

Adult↗
PubMed2002

Genetic and biophysical basis of sudden unexplained nocturnal death syndrome (SUNDS), a disease allelic to Brugada syndrome.

Sudden unexplained nocturnal death syndrome (SUNDS), a disorder found in southeast Asia, is characterized by an abnormal electrocardiogram with ST-segment elevation in leads V1-V3 and sudden death due to ventricular fibrillation, identical to that seen in Brugada syndrome. We screened patients with SUNDS for mutations in SCN5A, the gene known to cause Brugada syndrome, as well as genes encoding ion channels associated with the long-QT syndrome. Ten families were enrolled, and screened for mutations using single-strand DNA conformation polymorphism analysis, denaturing high-performance liquid chromatography and DNA sequencing. Mutations were identified in SCN5A in three families. One mutation, R367H, lies in the first P segment of the pore-lining region between the DIS5 and DIS6 transmembrane segments of SCN5A. A second mutation, A735V, lies in the first transmembrane segment of domain II (DIIS1) close to the first extracellular loop between DIIS1 and DIIS2, whereas the third mutation, R1192Q, lies in domain III. Analysis of these mutations in Xenopus oocytes showed that the R367H mutant channel did not express any current and the likely effect of this mutation is to depress peak current due to the loss of one functional allele. The A735V mutant expressed currents with steady state activation voltage shifted to more positive potentials. The R1192Q mutation accelerated the inactivation of the sodium channel current. Both mutations resulted in reduced sodium channel current (I(Na)) at a time corresponding to the end of phase 1 of the action potential, as described previously in the Brugada syndrome. Based upon these observations we suggest that SUNDS and Brugada syndrome are phenotypically, genetically and functionally the same disorder.

Alleles↗
PubMed2002

Long-term follow-up of individuals with the electrocardiographic pattern of right bundle-branch block and ST-segment elevation in precordial leads V1 to V3.

BACKGROUND: The electrocardiographic pattern of right bundle-branch block with ST-segment elevation in leads V1 to V3 is increasingly recognized among patients who have aborted sudden cardiac death, but also in asymptomatic individuals, raising questions about its prognostic significance. METHODS AND RESULTS: The clinical, electrophysiological, and follow-up data of 334 patients with the Brugada phenotype were analyzed. A total of 79 women and 255 men with a mean age at diagnosis of 42+/-16 years were studied. The abnormal ECG was recognized after a resuscitated cardiac arrest in 71 patients (group A), after a syncopal episode in 73 patients (group B), and in 190 asymptomatic individuals (group C). Sustained ventricular arrhythmias were inducible in 83%, 63%, and 33% of patients in group A, group B, and group C, respectively. During 54+/-54 and 26+/-36 months of follow-up, respectively, 62% of patients in group A and 19% of group B patients had a new arrhythmic event. Inducibility of ventricular arrhythmias was the only predictor of arrhythmia occurrence in both groups. During a mean follow-up of 27+/-29 months, 8% of group C individuals had a first arrhythmic event. In these individuals, inducibility of ventricular arrhythmias and a basal abnormal ECG were predictors of arrhythmia occurrence. CONCLUSIONS: An ECG showing right bundle-branch block and ST-segment elevation in the right precordial leads is a marker of malignant ventricular arrhythmias and sudden death. Recurrence of malignant arrhythmias is high after the occurrence of symptoms. Among asymptomatic individuals, those with a spontaneously abnormal ECG and inducible to ventricular arrhythmias have the poorer prognosis.

Adult↗
PubMed2002

Novel mutations in domain I of SCN5A cause Brugada syndrome.

Brugada syndrome, an autosomal dominantly inherited form of ventricular fibrillation characterized by ST-segment elevation in leads V1-V3 and right bundle-branch block on surface electrocardiogram, is caused by mutations in the cardiac sodium channel gene SCN5A. Patients with Brugada syndrome were studied using single-strand conformation polymorphism analysis, denaturing high-performance liquid chromatography, and DNA sequencing of SCN5A. Mutations were identified in SCN5A in two families and one sporadic case. In one family, a missense mutation leading to a glycine to valine substitution (G351V) in the pore region between the DIS5 and DIS6 transmembrane segments was detected. Biophysical analysis demonstrated that this mutation caused significant current reduction. In the other family, a 20-bp deletion of the exon 5 splice acceptor site was identified; as exon 5 encodes part of the intracellular loop between DIS2 and DIS3, this portion of the channel is disrupted. In the sporadic patient, a missense mutation resulting in the substitution of lysine by glutamic acid (K126E) in the intracellular loop at the boundary with DIS1 was identified. These three new SCN5A mutations in Brugada syndrome patients are all located within domain I of SCN5A, a region not previously considered important in the development of ventricular arrhythmias.

Animals↗