Prophylactic Cavotricuspid Isthmus Ablation in Atrial Fibrillation without Documented Typical Atrial Flutter: A Systematic Review and Meta-analysis

Background: The advantage of prophylactic cavotricuspid isthmus (CTI) ablation for AF patients without documented atrial flutter is still unclear. The present study aimed to evaluate the role of prophylactic CTI ablation in this population. Methods: A systematic review and meta-analysis study was conducted. The overall effects estimation was conducted using random effects models. The pooled effects were presented as the risk difference and standardised mean difference for dichotomous and continuous outcomes, respectively. Results: A total of 1,476 patients from four studies were included. The risk of atrial tachyarrhythmias following a successful catheter ablation procedure was greater in the pulmonary vein isolation + CTI ablation group than pulmonary vein isolation alone group (34.8% versus 28.2%; risk difference 0.08; 95% CI [0.00–0.17]; p=0.04). Prophylactic CTI ablation was associated with a higher recurrent AF rate (33.8% versus 27.1%; risk difference 0.07; 95% CI [0.01–0.13]; p=0.02). Additional prophylactic CTI ablation to pulmonary vein isolation significantly increased the radio frequency application time (standardised mean difference 0.52; 95% CI [0.04–1.01]; p=0.03). Conclusion: This study suggested that prophylactic CTI ablation was an ineffective and inefficient approach in AF without documented typical atrial flutter patients

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

KCNN2 polymorphisms and cardiac tachyarrhythmias

Potassium calcium-activated channel subfamily N member 2 (KCNN2) encodes an integral membrane protein that forms small-conductance calcium-activated potassium (SK) channels. Recent studies in animal models show that SK channels are important in atrial and ventricular repolarization and arrhythmogenesis. However, the importance of SK channels in human arrhythmia remains unclear. The purpose of the present study was to test the association between genetic polymorphism of the SK2 channel and the occurrence of cardiac tachyarrhythmias in humans. We enrolled 327 Han Chinese, including 72 with clinically significant ventricular tachyarrhythmias (VTa) who had a history of aborted sudden cardiac death (SCD) or unexplained syncope, 98 with a history of atrial fibrillation (AF), and 144 normal controls. We genotyped 12 representative tag single nucleotide polymorphisms (SNPs) across a 141-kb genetic region containing the KCNN2 gene; these captured the full haplotype information. The rs13184658 and rs10076582 variants of KCNN2 were associated with VTa in both the additive and dominant models (odds ratio [OR] 2.89, 95% confidence interval [CI] = 1.505-5.545, P = 0.001; and OR 2.55, 95% CI = 1.428-4.566, P = 0.002, respectively). After adjustment for potential risk factors, the association remained significant. The population attributable risks of these 2 variants of VTa were 17.3% and 10.6%, respectively. One variant (rs13184658) showed weak but significant association with AF in a dominant model (OR 1.91, CI = 1.025-3.570], P = 0.042). There was a significant association between the KCNN2 variants and clinically significant VTa. These findings suggest an association between KCNN2 and VTa; it also appears that KCNN2 variants may be adjunctive markers for risk stratification in patients susceptible to SCD

Cardiac Myosin Binding Protein C and MAP-Kinase Activating Death Domain-Containing Gene Polymorphisms and Diastolic Heart Failure

OBJECTIVE: Myosin binding protein C (MYBPC3) plays a role in ventricular relaxation. The aim of the study was to investigate the association between cardiac myosin binding protein C (MYBPC3) gene polymorphisms and diastolic heart failure (DHF) in a human case-control study. METHODS: A total of 352 participants of 1752 consecutive patients from the National Taiwan University Hospital and its affiliated hospital were enrolled. 176 patients diagnosed with DHF confirmed by echocardiography were recruited. Controls were matched 1-to-1 by age, sex, hypertension, diabetes, renal function and medication use. We genotyped 12 single nucleotide polymorphisms (SNPs) according to HapMap Han Chinese Beijing databank across a 40 kb genetic region containing the MYBPC3 gene and the neighboring DNA sequences to capture 100% of haplotype variance in all SNPs with minor allele frequencies ≥ 5%. We also analyzed associations of these tagging SNPs and haplotypes with DHF and linkage disequilibrium (LD) structure of the MYBPC3 gene. RESULTS: In a single locus analysis, SNP rs2290149 was associated with DHF (allele-specific p = 0.004; permuted p = 0.031). The SNP with a minor allele frequency of 9.4%, had an odds ratio 2.14 (95% CI 1.25-3.66; p = 0.004) for the additive model and 2.06 for the autosomal dominant model (GG+GA : AA, 95% CI 1.17-3.63; p = 0.013), corresponding to a population attributable risk fraction of 12.02%. The haplotypes in a LD block of rs2290149 (C-C-G-C) was also significantly associated with DHF (odds ratio 2.10 (1.53-2.89); permuted p = 0.029). CONCLUSIONS: We identified a SNP (rs2290149) among the tagging SNP set that was significantly associated with early DHF in a Chinese population

A Flexible Computational Framework for Detecting, Characterizing, and Interpreting Statistical Patterns of Epistasis in Genetic Studies of Human Disease Susceptibility

Detecting, characterizing, and interpreting gene-gene interactions or epistasis in studies of human disease susceptibility is both a mathematical and a computational challenge. To address this problem, we have previously developed a multifactor dimensionality reduction (MDR) method for collapsing high-dimensional genetic data into a single dimension (i.e. constructive induction) thus permitting interactions to be detected in relatively small sample sizes. In this paper, we describe a comprehensive and flexible framework for detecting and interpreting gene- gene interactions that utilizes advances in information theory for selecting interesting single-nucleotide polymorphisms ( SNPs), MDR for constructive induction, machine learning methods for classification, and finally graphical models for interpretation. We illustrate the usefulness of this strategy using artificial datasets simulated from several different two-locus and three-locus epistasis models. We show that the accuracy, sensitivity, specificity, and precision of a naive Bayes classifier are significantly improved when SNPs are selected based on their information gain (i.e. class entropy removed) and reduced to a single attribute using MDR. We then apply this strategy to detecting, characterizing, and interpreting epistatic models in a genetic study (n = 500) of atrial fibrillation and show that both classification and model interpretation are significantly improved. (c) 2005 Elsevier Ltd. All rights reserved

Evolution of Left Atrial Systolic and Diastolic Functions in Different Stages of Hypertension: Distinct Effects of Blood Pressure Control

Background: To evaluate the left atrial (LA) volume, and LA systolic ( contractile) and diastolic (expansion) functions in different stages of hypertension with or without atrial fibrillation (AF), as well as the effects of good blood pressure control. Methods: A prospective observational study . Individuals including 22 normotensive controls, 23 patients with mild hypertension, 20 with severe hypertension , and 17 with hypertension and paroxysmal AF were recruited for paired echocardiography studies at baseline and 6 months after control of hypertension. Results: With increasing severity of hypertension, left ventricular (LV) diastolic function deteriorated with decreasing LV septal E'/A' and increasing E/E' ratios. LA expansion index was reduced in parallel. LA expansion index was correlated positively with LV E'/A' (r = 0.43, p = 0.022) and inversely with LV E/E' (r = 0.49, p = 0.009). Significant improvement of LV diastolic function and LA expansion index preceded the reduction of LA volume after blood pressure control. In patients with paroxysmal AF, LA volume reduction was more evident in patients receiving angiotensin- converting enzyme inhibitors or angiotensin II type 1 receptor blockers. Conclusions: With progressive LV diastolic dysfunction in hypertension, there was a corresponding deterioration in LA diastolic function. Effective blood pressure control for 6 months improved LA diastolic function

Next-generation sequencing of nine atrial fibrillation candidate genes identified novel de novo mutations in patients with extreme trait of atrial fibrillation

Background Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia. Genome-wide association studies (GWAS) have identified common variants in nine genomic regions associated with AF (KCNN3, PRRX1, PITX2, WNT8A, CAV1, C9orf3, SYNE2, HCN4 and ZFHX3 genes); however, the genetic variability of these risk variants does not explain the entire genetic susceptibility to AF. Rare variants missed by GWAS may also contribute to genetic risk of AF. ;Methods We used an extreme trait design to sequence carefully selected probands with extreme phenotypes and their unaffected parents to identify rare de novo variants or mutations. Based on the hypothesis that common and rare variants may colocate in the same disease susceptibility gene, we used next-generation sequencing to sequence these nine published AF susceptibility genes identified by GWAS (a total of 179 exons) in 20 trios, 200 unrelated patients with AF and 200 non-AF controls. ;Results We identified a novel mutation in the 50 untranslated region of the PITX2 gene, which localised in the transcriptionally active enhancer region. We also identified one missense exon mutation in KCNN3, two in ZFHX3 and one in SYNE2. None of these mutations were present in other unrelated patients with AF, healthy controls, unaffected parents and are thus novel and de novo (p<10(-4)). Functional study showed that the mutation in the 50 untranslated region of the PITX2 gene significantly downregulated PITX2 expression in atrial myocytes, either in basal condition or during rapid pacing. In silico analysis showed that the missense mutation in ZFHX3 results in damage of the ZFHX3 protein structure. ;Conclusions The genetic architecture of subjects with extreme phenotypes of AF is similar to that of rare or Mendelian diseases, and mutations may be the underlying cause