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Background: Little is known about genome-wide changes in the atrial transcriptome as a cause or consequence of atrial fibrillation (AF), and the effect of its common and clinically relevant comorbidity-heart failure (HF)., Objective: The purpose of this study was to explore candidate disease processes for AF by investigating gene expression changes in atrial tissue samples from patients with and without AF, stratified by HF., Methods: RNA sequencing was performed in right and left atrial appendage tissue in 195 patients undergoing open heart surgery from centers participating in the CATCH-ME consortium (no history of AF, n = 91; paroxysmal AF, n = 53; persistent/permanent AF, n = 51). Analyses were stratified into patients with/without HF (n = 75/120) and adjusted for age, sex, atrial side, and a combination of clinical characteristics., Results: We identified 35 genes associated with persistent AF compared to patients without a history of AF, both in the presence or absence of HF (false discovery rate <0.05). These were mostly novel associations, including 13 long noncoding RNAs. Genes were involved in regulation of cardiomyocyte structure, conduction properties, fibrosis, inflammation, and endothelial dysfunction. Gene set enrichment analysis identified mainly inflammatory gene sets to be enriched in AF patients without HF, and gene sets involved in cellular respiration in AF patients with HF., Conclusion: Analysis of atrial gene expression profiles identified numerous novel genes associated with persistent AF, in the presence or absence of HF. Interestingly, no consistent transcriptional changes were associated with paroxysmal AF, suggesting that AF-induced changes in gene expression predominate other changes., (Crown Copyright © 2022. Published by Elsevier Inc. All rights reserved.)

Aims: Catheter ablation is recommended for symptomatic WPW-syndrome. Commonly perceived low recurrence rates were challenged recently. We sought to identify patient strata at increased risk., Method: Of 12,566 patients enrolled at 52 German Ablation Registry sites from 2007 to 2010, 789 were treated for WPW-syndrome. Patients were included for symptomatic palpitations and tachycardia documentation. Follow-up duration was one year. Overall complications were defined as serious, access-related, and ablation-related. We adjudicated WPW-recurrence for re-ablation during follow-up. Risk strata included: admission for repeat ablation at registry entry; accessory pathway localization; antiarrhythmic medical treatment before the ablation., Results: WPW-syndrome patients were 42.8 ± 16.2 years on average; 39.9% were women. A majority of 95.9% was symptomatic; in 84.4%, a tachycardia was documented. Seventy-six (9.6%) patients presented for repeat procedures. Accessory pathways were located in the left atrium (71.4%), right atrium (21.1%), septum (4.4%), or coronary sinus diverticula (2.1%). Prior antiarrhythmic medication was used in 43.7% of patients. No serious events occurred. The overall complication rate was 2.5% (ablation related 1.2%, access-related 1.3%). Major determinants for complications were presentation for re-ablation as registry index procedure (6.9% vs 2.2%; p = 0.016) and septal pathway location (left 2.0% vs septal 9.1%, p = 0.014). The overall re-ablation rate was 9.7%. Usage of prior antiarrhythmic medication was associated with higher recurrence rates (12.2% vs. 7.6%; p = 0.035)., Conclusions: Patients at higher complication risk may be identified by repeat procedure and septal pathway location. Prior antiarrhythmic medication was associated with higher recurrence rates. Our findings may help improving peri-procedural patient management and information., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: A novel, automatically annotating ultra-high density mapping system (Rhythmia©, Boston Scientific) collects a high number and quality of electrograms (EGMs). So far, data on general use in the electrophysiological laboratory are sparse., Methods: We retrospectively analyzed all our ablations using Rhythmia and recorded patient clinical data, procedural parameters, and mapping parameters including the count of EGMs, mapping time, and mapping volume. Where appropriate, procedural parameters were compared over time to assess a learning curve., Results: 400 patients underwent ablation of atrial fibrillation (n = 202), typical (n = 16) or atypical atrial flutter (n = 49), VT (n = 48), PVC (n = 35), accessory pathways (n = 14), AVNRT (n = 4), and focal atrial tachycardia (n = 32). System use was feasible, as no procedure had to be stopped for technical reasons and no ablation had to be withheld because of mapping failure, and safe, with an overall complication rate of 2.25%. Initial restrictions in manoeuvrability of the mapping catheter were overcome rapidly, as indicated by a significant decrease of fluoroscopy time (20 vs. 14 min, p = 0.02), use of contrast agent (50 vs. 40 ml; p < 0.01), and (not significant) lower procedure times (194 vs. 170 min; p = 0.12; comparing the first with the last third of patients undergoing pulmonary vein isolation only procedure). Ablation of complex left atrial, focal and ventricular tachycardias benefited from the reliable automatic annotation of a high number of EGMs., Conclusion: The use of the Rhythmia is feasible and safe. Initial restrictions in manoeuvrability of the Orion mapping catheter were overcome rapidly. The procedures that benefit the most from ultra-high density mapping are complex left atrial tachycardias, focal tachycardias, and ventricular tachycardias., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Objectives: To compare complication rates, length of hospital stay, and resulting costs between the use of manual compression and a vascular closing device (VCD) in both diagnostic and interventional catheterization in a German university hospital setting., Methods: A stratified analysis according to risk profiles was used to compare the risk of complications in a retrospective cross-sectional single-center study. Differences in costs and length of hospital stay were calculated using the recycled predictions method, based on regression coefficients from generalized linear models with gamma distribution. All models were adjusted for propensity score and possible confounders, such as age, sex, and comorbidities. The analysis was performed separately for diagnostic and interventional catheterization., Results: The unadjusted relative risk (RR) of complications was not significantly different in diagnostic catheterization when a VCD was used (RR = 0.70; 95% confidence interval [CI] 0.22-2.16) but significantly lower in interventional catheterization (RR = 0.44; 95% CI 0.21-0.93). Costs were on average €275 lower in the diagnostic group (95% CI -€478.0 to -€64.9; P = 0.006) and around €373 lower in the interventional group (95% CI -€630.0 to -€104.2; P = 0.014) when a VCD was used. The adjusted estimated average length of stay did not differ significantly between the use of a VCD and manual compression in both types of catheterization., Conclusions: In interventional catheterization, VCDs significantly reduced unadjusted complication rates, as well as costs. A significant reduction in costs also supports their usage in diagnostic catheterization on a larger scale., (Copyright © 2017 International Society for Pharmacoeconomics and Outcomes Research (ISPOR). Published by Elsevier Inc. All rights reserved.)

Background: Results on the association between P-wave duration and the risk of atrial fibrillation (AF) are conflicting., Objective: The purpose of this study was to obtain a detailed description of the relationship between P-wave duration and the risk of AF., Methods: Using computerized analysis of electrocardiograms from a large primary care population, we evaluated the association between P-wave duration and the risk of AF. Secondary end-points were death from cardiovascular causes and putative ischemic stroke. Data on drug use, comorbidity, and outcomes were collected from administrative registries., Results: A total of 285,933 individuals were included. During median follow-up period of 6.7 years, 9550 developed AF, 9371 died of a cardiovascular cause, and 8980 had a stroke. Compared with the reference group (100-105 ms), individuals with very short (≤89 ms; hazard ratio [HR] 1.60, 95% confidence interval [CI] 1.41-1.81), intermediate (112-119 ms; HR 1.22, 95% CI 1.13-1.31), long (120-129 ms; HR 1.50, 95% CI 1.39-1.62), and very long P-wave duration (≥130 ms; HR 2.06, 95% CI 1.89-2.23) had an increased risk of incident AF. With respect to death from cardiovascular causes, we found an increased risk for very short (≤89 ms; HR 1.20, 95% CI 1.06-1.34), long (120-129 ms; HR 1.11, 95% CI 1.04-1.19), and very long P-wave duration (≥130 ms; HR 1.30, 95% CI 1.21-1.40) compared with the reference group (106-111 ms). Similar but weaker associations were found between P-wave duration and the risk of putative ischemic stroke., Conclusion: In a large primary care population we found both short and long P-wave duration to be robustly associated with an increased risk of AF., (Copyright © 2015 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Background: Atrial fibrillation (AF) is the most common arrhythmia, and a recent genome-wide association study identified the hyperpolarization-activated cyclic nucleotide-gated channel 4 (HCN4) as a novel AF susceptibility locus. HCN4 encodes for the cardiac pacemaker channel, and HCN4 mutations are associated with familial sinus bradycardia and AF., Objective: The purpose of this study was to determine whether novel variants in the coding region of HCN4 contribute to the susceptibility for AF., Methods: We sequenced the coding region of HCN4 for novel variants from 527 cases with early-onset AF from the Massachusetts General Hospital AF Study and 443 referents from the Framingham Heart Study. We used site-directed mutagenesis, cellular electrophysiology, immunocytochemistry, and confocal microscopy to functionally characterize novel variants., Results: We found the frequency of novel coding HCN4 variants was 2-fold greater for individuals with AF (7 variants) compared to the referents (3 variants). We determined that of the 7 novel HCN4 variants in our AF cases, 1 (p.Pro257Ser, located in the amino-terminus adjacent to the first transmembrane spanning domain) did not traffic to cell membrane, whereas the remaining 6 were not functionally different from wild type. In addition, the 3 novel variants in our referents did not alter function compared to wild-type. Coexpression studies showed that the p.Pro257Ser mutant channel failed to colocalize with the wild-type HCN4 channel on the cell membrane., Conclusion: Our findings are consistent with HCN4 haploinsufficiency as the likely mechanism for early-onset AF in the p.Pro257Ser carrier., (Copyright © 2014 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Background: Genome-wide association studies (GWAS) have identified common genetic variants that predispose to atrial fibrillation (AF). It is unclear whether rare and low-frequency variants in genes implicated by such GWAS confer additional risk of AF., Objective: To study the association of genetic variants with AF at GWAS top loci., Methods: In the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Targeted Sequencing Study, we selected and sequenced 77 target gene regions from GWAS loci of complex diseases or traits, including 4 genes hypothesized to be related to AF (PRRX1, CAV1, CAV2, and ZFHX3). Sequencing was performed in participants with (n = 948) and without (n = 3330) AF from the Atherosclerosis Risk in Communities Study, the Cardiovascular Health Study, the Framingham Heart Study, and the Massachusetts General Hospital., Results: One common variant (rs11265611; P = 1.70 × 10(-6)) intronic to IL6R (interleukin-6 receptor gene) was significantly associated with AF after Bonferroni correction (odds ratio 0.70; 95% confidence interval 0.58-0.85). The variant was not genotyped or imputed by prior GWAS, but it is in linkage disequilibrium (r(2) = .69) with the single-nucleotide polymorphism, with the strongest association with AF so far at this locus (rs4845625). In the rare variant joint analysis, damaging variants within the PRRX1 region showed significant association with AF after Bonferroni correction (P = .01)., Conclusions: We identified 1 common single-nucleotide polymorphism and 1 gene region that were significantly associated with AF. Future sequencing efforts with larger sample sizes and more comprehensive genome coverage are anticipated to identify additional AF-related variants., (© 2013 Heart Rhythm Society Published by Heart Rhythm Society All rights reserved.)

Background: The early repolarization pattern (ERP) is common and associated with risk of sudden cardiac death. ERP is heritable, and mutations have been described in syndromatic cases., Objective: To conduct a meta-analysis of genome-wide association studies to identify common genetic variants influencing ERP., Methods: We ascertained ERP on the basis of electrocardiograms in 3 large community-based cohorts from Europe and the United States: the Framingham Heart Study, the Health 2000 Study, and the KORA F4 Study. We analyzed genome-wide association studies in participants with and without ERP by logistic regression assuming an additive genetic model and meta-analyzed individual cohort results. We then sought to strengthen support for findings that reached P ≤ 1 × 10(-5) in independent individuals by direct genotyping or in-silico analysis of genome-wide data. We meta-analyzed the results from both stages., Results: Of 7482 individuals in the discovery stage, 452 showed ERP (ERP positive: mean age 46.9 ± 8.9 years, 30.3% women; ERP negative: 47.5 ± 9.4 years, 54.2% women). After meta-analysis, 8 single nucleotide polymorphisms reached P ≤ 1 × 10(-5): The most significant finding was intergenic rs11653989 (odds ratio 0.47; 95% confidence interval 0.36-0.61; P = 6.9 × 10(-9)). The most biologically relevant finding was intronic to KCND3: rs17029069 (odds ratio 1.46; 95% confidence interval 1.25-1.69; P = 8.5 × 10(-7)). In the replication step (7151 individuals), none of the 8 variants replicated, and combined meta-analysis results failed to reach genome-wide significance., Conclusions: In a genome-wide association study, we were not able to reliably identify genetic variants predisposing to ERP, presumably due to insufficient statistical power and phenotype heterogeneity. The reported heritability of ERP warrants continued investigation in larger well-phenotyped populations., (Copyright © 2012 Heart Rhythm Society. All rights reserved.)

Background: Atrial fibrillation (AF) is the most common sustained arrhythmia and has a substantial heritable component. Numerous associations between single nucleotide polymorphisms (SNPs) and AF have been described, but few have been replicated., Objective: We sought to systematically replicate SNPs that are reported to be associated with AF in two large study samples of European descent., Methods: We searched PubMed for studies reporting associations between SNPs and AF published before July 1, 2007. SNPs were genotyped in two independent case-control samples from Germany and the United States. Associations between SNPs and AF were assessed using logistic regression models adjusting for age, sex, and hypertension. A meta-analysis of the results from the two studies was performed., Results: We identified 21 SNPs and the angiotensin-converting enzyme insertion/deletion polymorphism that were reported to be associated with AF in the literature. Nine of these genetic variants were not represented on common genome-wide SNP arrays. We successfully genotyped 21 of these 22 variants in 2,145 cases with AF from the German Competence Network for Atrial Fibrillation and 4,073 controls from the KORA S4 study and 16 variants in 790 cases and 1,330 controls from the Massachusetts General Hospital. None of the SNPs replicated in independent populations with AF., Conclusion: Our results suggest that previously reported associations to AF were likely false positives and highlight the need for systematic replication of genetic associations in large, independent cohorts to accurately detect variants associated with disease., (Copyright © 2011 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)