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1.  Management of patients with implantable cardioverter defibrillators at emergency departments 
Emergency Medicine Journal : EMJ  2007;24(2):106-109.
With rapid improvements in technology and accumulation of clinical evidence, the implantable cardioverter defibrillator (ICD) has become a standard treatment for either primary or secondary prevention of sudden cardiac death. However, no analysis based on the perspective of emergency department has been reported, and managing patients with ICD remains a challenge to the emergency department doctors.
This study reviewed the emergency department visits of patients who received ICD implantation in a single university hospital from 1995 to 2004. The baseline demographic and laboratory data were compared between groups with the non‐parametric method of the Mann–Whitney U test for continuous data and the χ2 test for categorical data; p<0.05 was considered significant.
81 patients (56 men and 25 women) were included in this study. 43% of patients had at least one emergency department visit during the follow‐up period, and a total of 86 emergency department visits were recorded. The most frequent aetiology of emergency department visits was ICD discharge (37 episodes; 43.1%) and the most frequent presenting symptom was electric shock sensation (25 episodes; 29.1%). Only 11 (12.8%) emergency department visits were because of non‐cardiac aetiologies. Patients with emergency department visits had significant lower left ventricular ejection fraction (mean (SD) 41.5 (19.8) v 55.2 (18.4) ejection fraction units; p = 0.005) and more use of warfarin (8.6% v 0%; p<0.05). Although most emergency department visits were device or arrhythmia related, the acute coronary syndrome and congestive heart failure still accounted for 27.9% of hospital returns in combination.
Defibrillator discharge, acute coronary syndrome and heart failure constitute most aetiologies of emergency department visits of patients with ICD. The risk factors include lower left ventricular ejection fraction and use of warfarin.
PMCID: PMC2658183  PMID: 17251615
2.  Disease-Targeted Sequencing of Ion Channel Genes identifies de novo mutations in Patients with Non-Familial Brugada Syndrome 
Scientific Reports  2014;4:6733.
Brugada syndrome (BrS) is one of the ion channelopathies associated with sudden cardiac death (SCD). The most common BrS-associated gene (SCN5A) only accounts for approximately 20–25% of BrS patients. This study aims to identify novel mutations across human ion channels in non-familial BrS patients without SCN5A variants through disease-targeted sequencing. We performed disease-targeted multi-gene sequencing across 133 human ion channel genes and 12 reported BrS-associated genes in 15 unrelated, non-familial BrS patients without SCN5A variants. Candidate variants were validated by mass spectrometry and Sanger sequencing. Five de novo mutations were identified in four genes (SCNN1A, KCNJ16, KCNB2, and KCNT1) in three BrS patients (20%). Two of the three patients presented SCD and one had syncope. Interestingly, the two patients presented with SCD had compound mutations (SCNN1A:Arg350Gln and KCNB2:Glu522Lys; SCNN1A:Arg597* and KCNJ16:Ser261Gly). Importantly, two SCNN1A mutations were identified from different families. The KCNT1:Arg1106Gln mutation was identified in a patient with syncope. Bioinformatics algorithms predicted severe functional interruptions in these four mutation loci, suggesting their pivotal roles in BrS. This study identified four novel BrS-associated genes and indicated the effectiveness of this disease-targeted sequencing across ion channel genes for non-familial BrS patients without SCN5A variants.
PMCID: PMC4206841  PMID: 25339316
3.  Utilizing Multiple in Silico Analyses to Identify Putative Causal SCN5A Variants in Brugada Syndrome 
Scientific Reports  2014;4:3850.
Brugada syndrome (BrS) is an inheritable sudden cardiac death disease mainly caused by SCN5A mutations. Traditional approaches can be costly and time-consuming if all candidate variants need to be validated through in vitro studies. Therefore, we developed a new approach by combining multiple in silico analyses to predict functional and structural changes of candidate SCN5A variants in BrS before conducting in vitro studies. Five SCN5A non-synonymous variants (1651G>A, 1776C>G, 1673A>G, 3269C>T and 3578G>A) were identified in 14 BrS patients using direct DNA sequencing. Several bioinformatics algorithms were applied and predicted that 1651G>A (A551T) and 1776C>G (N592K) were high-risk SCN5A variants (odds ratio 59.59 and 23.93). The results were validated by Mass spectrometry and in vitro electrophysiological assays. We concluded that integrating sequence-based information and secondary protein structures elements may help select highly potential variants in BrS before conducting time-consuming electrophysiological studies and two novel SCN5A mutations were validated.
PMCID: PMC3902491  PMID: 24463578
4.  Spatial Repolarization Heterogeneity Detected by Magnetocardiography Correlates with Cardiac Iron Overload and Adverse Cardiac Events in Beta-Thalassemia Major 
PLoS ONE  2014;9(1):e86524.
Patients with transfusion-dependent beta-thalassemia major (TM) are at risk for myocardial iron overload and cardiac complications. Spatial repolarization heterogeneity is known to be elevated in patients with certain cardiac diseases, but little is known in TM patients. The purpose of this study was to evaluate spatial repolarization heterogeneity in patients with TM, and to investigate the relationships between spatial repolarization heterogeneity, cardiac iron load, and adverse cardiac events.
Methods and Results
Fifty patients with TM and 55 control subjects received 64-channel magnetocardiography (MCG) to determine spatial repolarization heterogeneity, which was evaluated by a smoothness index of QTc (SI-QTc), a standard deviation of QTc (SD-QTc), and a QTc dispersion. Left ventricular function and myocardial T2* values were assessed by cardiac magnetic resonance. Patients with TM had significantly greater SI-QTc, SD-QTc, and QTc dispersion compared to the control subjects (all p values<0.001). Spatial repolarization heterogeneity was even more pronounced in patients with significant iron overload (T2*<20 ms, n = 20) compared to those with normal T2* (all p values<0.001). Loge cardiac T2* correlated with SI-QTc (r = −0.609, p<0.001), SD-QTc (r = −0.572, p<0.001), and QTc dispersion (r = −0.622, p<0.001), while all these indices had no relationship with measurements of the left ventricular geometry or function. At the time of study, 10 patients had either heart failure or arrhythmia. All 3 indices of repolarization heterogeneity were related to the presence of adverse cardiac events, with areas under the receiver operating characteristic curves (ranged between 0.79 and 0.86), similar to that of cardiac T2*.
Multichannel MCG demonstrated that patients with TM had increased spatial repolarization heterogeneity, which is related to myocardial iron load and adverse cardiac events.
PMCID: PMC3903540  PMID: 24475137
5.  Effects of simvastatin on cardiac neural and electrophysiologic remodeling in rabbits with hypercholesterolemia 
Significant cardiac neural and electrophysiologic remodeling occurs with hypercholesterolemia (HC). Whether simvastatin can reverse HC-induced remodeling is unclear.
The purpose of this study was to determine the mechanisms underlying the antiarrhythmic effects of statins.
Rabbits (N = 38) were fed HC chow (HC), standard chow (Control), HC chow followed by standard chow (Withdrawal), or HC chow and simvastatin (Statin) for 8 weeks. The hearts then were Langendorff-perfused for electrophysiologic studies. Nerves were identified by immunostaining of growth-associated protein-43 (GAP43) and tyrosine hydroxylase (TH). Action potential duration (APD) restitution in normal hearts with (N = 5) and without (N = 5) simvastatin therapy also was studied.
Serum cholesterol levels (mg/dL) were 1,855 ± 533 in HC, 50 ± 21 in Control, 570 ± 115 in Withdrawal, and 873 ± 112 in Statin groups (P <.001). Compared with HC (16,700 ± 5,342; 12,200 ± 3,878 µm2/mm2), the Statin group had significantly reduced GAP43-positive (10,289 ± 3,393 µm2/mm2, P = .03) and TH-positive (7,685 ± 2,959 µm2/mm2, P = .04) nerve density, respectively. APD was longer in HC rabbits than in controls (192 ± 20 ms vs 174 ± 17 ms; P <.03). Withdrawal and Statin groups had less APD prolongation than HC group. Statin group has less repolarization heterogeneity than HC group (P <.01). Statin therapy flattened the slope of APD restitution in normal hearts. Ventricular fibrillation was either induced or occurred spontaneously in 79% of hearts in HC, 20% in Control, and 66% in Withdrawal groups. However, there was no VF in hearts of Statin group (P <.001).
Simvastatin significantly reduced vulnerability to ventricular fibrillation via the mechanism of reduction of HC-induced neural and electrophysiologic remodeling.
PMCID: PMC2757294  PMID: 19121803
Arrhythmia; Statin; Lipids; Nervous system; Pathology
6.  Distinct functional defect of three novel Brugada syndrome related cardiac sodium channel mutations 
The Brugada syndrome is characterized by ST segment elevation in the right precodial leads V1-V3 on surface ECG accompanied by episodes of ventricular fibrillation causing syncope or even sudden death. The molecular and cellular mechanisms that lead to Brugada syndrome are not yet completely understood. However, SCN5A is the most well known responsible gene that causes Brugada syndrome. Until now, more than a hundred mutations in SCN5A responsible for Brugada syndrome have been described. Functional studies of some of the mutations have been performed and show that a reduction of human cardiac sodium current accounts for the pathogenesis of Brugada syndrome. Here we reported three novel SCN5A mutations identified in patients with Brugada syndrome in Taiwan (p.I848fs, p.R965C, and p.1876insM). Their electrophysiological properties were altered by patch clamp analysis. The p.I848fs mutant generated no sodium current. The p.R965C and p.1876insM mutants produced channels with steady state inactivation shifted to a more negative potential (9.4 mV and 8.5 mV respectively), and slower recovery from inactivation. Besides, the steady state activation of p.1876insM was altered and was shifted to a more positive potential (7.69 mV). In conclusion, the SCN5A channel defect related to Brugada syndrome might be diverse but all resulted in a decrease of sodium current.
PMCID: PMC2653527  PMID: 19272188

Results 1-6 (6)