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Funding Acknowledgements Type of funding sources: Public grant(s) – EU funding. Main funding source(s): TRAIN-HEART Innovative Training Network, funded by the European Union’s Horizon 2020 research and innovation program (under the Marie Sklodowska-Curie grant agreement no. 813716) Characterizing Atrial fibrillation by Translating its Causes into Health Modifiers in the Elderly (CATCH ME), funded by the European Union’s Horizon 2020 research and innovation program (under the grant agreement no. 633196) Background Atrial fibrillation (AF) is the most common cardiac arrhythmia and is associated with heart failure (HF) and stroke. Clinical and experimental data from previous studies suggest gender differences in mechanisms and phenotypes of AF: women may have more atrial fibrosis, worse outcomes after catheter ablation, and some women carry a higher risk for thromboembolic complications than men. The molecular mechanisms underlying these differences are still poorly understood. Methods Gender-based transcriptional patterns were assessed using paired-end, directional RNA sequencing data generated from atrial tissue biopsies in 199 patients either in sinus rhythm or with paroxysmal or persistent AF as part of the CATCH-ME project. Transcript counts were compared between genders separately in the left and right atria using the DESeq2 package in R. The models were adjusted for potential sources of confounding (age, atrial fibrillation status, heart failure status and sequencing batch). Interaction models were implemented using DESeq2 to compare gender*morbidity interactions for persistent AF and HF. Significance was assessed using likelihood ratio tests comparing models with and without the interaction terms. Results with an adjusted P-value 0.05 were considered significant and utilized for subsequent downstream assessments. Differentially expressed (DE) genes were tested for enrichment of gene ontology (GO) terms and KEGG pathways using the WebGestalt toolkit. Results Transcriptome-wide profiling across the cohort identified 33 sex-differentiated genes in the left atria and 51 in the right atrial samples, with 21 of these showing bilateral differences. Interestingly, 36 (44%) of the results from these analyses were comprised of non-coding transcripts, including long non-coding RNAs (lncRNAs), antisense RNAs and pseudogenes. GO and pathway enrichment analyses for these genes revealed their involvement in critical pathways such as the complement and coagulation cascades and RNA transport. Interaction analyses between gender and AF identified two genes (MPP2 & GNAS-AS1) that were differentially transcribed in the right atria and one gene (MYL2) that was DE in the left atria by gender in persistent AF samples. A similar analysis comparing gender*HF morbidity also revealed evidence of DE. Four transcripts (HLA-DQB1-AS1, EIF1AY, UTY and ZFY-AS1) showed gender-specific differences in expression by HF status in left atria, while HLA-DQB1-AS1 was differentially regulated by gender and HF status in right atrial samples. Conclusions These RNA-seq analyses provide novel insights into gender-related differences in the transcriptional landscape of right and left adult human atrial appendages. Moreover, interaction analyses identified three genes DE in female atria in persistent AF and four DE genes in female atria in heart failure, providing a molecular anchor for the observed differences in atrial diseases phenotypes between men and women.

Background Atrial Fibrillation (AF) is common and is caused and predisposed to by a complex pathophysiology. Aging is among the most important risk factors for AF. Yet, some individuals develop AF in early years, whereas elderly individuals may remain free of AF. Aside from measurable concomitant risks, we hypothesized that a pathophysiologically relevant biological age exists, which outweighs a patient's calendar age. Telomere length is a measurable marker of age, which might reflect biological age. AF and telomere length have previously been associated, but results remained controversial. Here, we tested the relation between AF and telomere length in a well-characterized and so far largest cohort. Methods Since 2005, we enrolled 2475 patients with AF from the prospective AFLMU cohort, preferentially if they developed AF before age 65 years, and 3077 control individuals free of AF from the community-based KORA Study between 2006–08. All participants received a detailed clinical characterization, an electrocardiogram, and a blood draw for biomarker analyses. In all participants, we determined telomere length using a qPCR-based method. In a 384 well format, we employed a multiplex TaqMan assay to determine both telomere length and the single copy gene 36B4. Telomere length was expressed by the delta-CT method and was reformatted to have lower CT values indicate shorter telomere length. We compared telomere length between cases and controls using multi-variably corrected logistic regression models. Results Our cohort's mean age was 58 years in AFLMU and 56 years in KORA F4. Men were enrolled more commonly, with 72.3% in AFLMU and 51.7% in KORA F4. For consistency with available information, we confirmed that telomere length is continuously decreasing with age and that men have shorter telomere length compared to women. As a main result we found that AF patients have significantly shorter telomere length compared to controls (controls: telomere length 13,10 [12.60, 13.63] versus AF: 9.81 [5.98, 13.1], p Conclusion AF is significantly associated with telomere length in one of the largest cohorts to date. Assessment of telomere length may adjudicate patients with AF due to premature biological aging. The underlying reasons for such premature aging remain to be identified. Funding Acknowledgement Type of funding source: Public grant(s) – EU funding. Main funding source(s): European Commission - Horizon 2020

Aims Risks of catheter ablation for atrial fibrillation and flutter assessed in retrospective studies, registries, and controlled trials may underestimate ‘real world’ conditions. Methods and results To assess complications in a nationwide approach, we included all cases undergoing catheter ablation for atrial fibrillation and atrial flutter in Germany in 2014, using ICD-10-GM-based German Diagnosis Related Group (G-DRG) codes and the well differentiated German Operation and Procedure Classification (OPS) analysing 33 353 in-hospital cases. For left atrial ablations (19 514 cases), the overall complication rate ranged from a mean of 11.7% to 13.8% depending on type and site of applied energy, including major complications ranging from 3.8% to 7.2%. Whereas overall complication rates were lower for atrial flutter ablations (13 871 cases, 10.5%; P 100 vs. ≤100 left atrial ablations annually (12.7% vs. 16.4%; P

Background/Introduction Atrial fibrillation (AF) can be challenging to diagnose due to asymptomatic and paroxysmal presentation. Identifying prognostic factors of AF would elucidate potential mechanisms causing AF and refine screening for at risk patients. Purpose To identify the main predictors of AF and to develop a prognostic model for prevalent AF. Methods Data of 120 potential predictors were harmonised in individual patient data from 4 independent European studies. A three stage Delphi expert consensus process identified predictors based on clinical knowledge. The predictors were further reduced using statistical selection (backward elimination), and a logistic regression model was fitted. We calculated odds ratios (OR) for each of the selected predictors and evaluated model performance using the C-statistic. Results Overall, 2420 patients (mean [standard deviation] age = 62.7 [14.5] years, 35.6% female, 43.1% with AF) were included in the analysis. Thirty-one potential predictors identified from the Delphi process which had sufficient data across all datasets were modelled. Of these 14 were deemed prognostic in predicting AF (age, sex, BMI, height, hypertension, diabetes, history of coronary artery disease, left atrial volume, left ventricular end systolic diameter, abnormality on echo, tricuspid valve disease of at least moderate intensity, aldosterone-antagonists, beta-blockers and P2Y12 blockers; see Figure 1). There was a clear interaction between age and sex indicating that males are at higher risk than females early in life, while females are at increased risk of AF at older age (Figure 1). The risk prediction model combining these prognostic factors performed well (C-statistic 0.79; 95% CI 0.77–0.81). Figure 1. (a) Forest plot; (b) Interaction Conclusion(s) Our preliminary analysis identified important prognostic factors and a complex relationship between age and sex, which predicts prevalent AF, highlighting the different potential causes of AF in different patients. There is a clear need to validate these factors in external datasets and for further investigation into the molecular mechanism underlying these factors. Acknowledgement/Funding European Commission H2020 framework

Aims To test the value of Periodic Repolarization Dynamics (PRD), a recently validated electrocardiographic marker of sympathetic activity, as a novel approach to predict sudden cardiac death (SCD) and non-sudden cardiac death (N-SCD) and to improve identification of patients that profit from ICD-implantation. Methods and results We included 856 post-infarction patients with left-ventricular ejection fraction (LVEF) ≤30% of the MADIT-II trial in sinus rhythm. Of these, 507 and 348 patients were randomized to ICD or conventional treatment. PRD was assessed from multipolar 10-min baseline ECGs. Primary and secondary endpoints were total mortality, SCD and N-SCD. Multivariable analyses included treatment group, QRS-duration, New York Heart Association classification, blood-urea nitrogen, diabetes mellitus, beta-blocker therapy and LVEF. During follow-up of 20.4 months, 119 patients died (53 SCD and 36 N-SCD). On multivariable analyses, increased PRD was a significant predictor of mortality (standardized coefficient 1.37[1.19–1.59]; P Conclusion In post-infarction patients with impaired LVEF, PRD is a significant predictor of SCD and N-SCD. Assessment of PRD is a promising tool to identify post-MI patients with reduced LVEF who might benefit from intensified treatment.

Aims The early repolarization pattern (ERP) has been shown to be associated with arrhythmias in patients with short QT syndrome, Brugada syndrome, and ischaemic heart disease. Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited arrhythmia syndrome and related to malignant ventricular tachyarrhythmias in a structurally normal heart. The aim of this study was to evaluate the prevalence of ERP and clinical events in patients with CPVT. Methods and results Digitalized resting 12-lead ECGs of patients were analysed for ERP and for repolarization markers (QT and T peak– T end interval). The ERP was diagnosed as ‘notching’ or ‘slurring’ at the terminal portion of QRS with ≥0.1 mV elevation in at least two consecutive inferior (II, III, aVF) and/or lateral leads (V4–V6, I, aVL). Among 51 CPVT patients (mean age 36 ± 15 years, 11 males), the ERP was present in 23 (45%): strictly in the inferior leads in 9 (18%) patients, in the lateral leads in 9 (18%) patients, and in infero-lateral leads in 5 (10%) patients. All patients with ERP were symptomatic at presentation (23 of 23 patients with ERP vs. 19 of 28 patients without ERP, P = 0.003). Syncope was also more frequent in patients with ERP (18 of 23 patients with ERP vs. 11 of 28 patients without ERP, P = 0.005). Conclusion A pathologic ERP is present in an unexpected large proportion (45%) of patients and is associated with an increased frequency of syncope. In patients with unexplained syncope and ERP at baseline, exercise testing should be performed to detect CPVT.

Aims Sudden cardiac death (SCD) is among the most common causes of death in western countries including Germany. Whereas risk stratification and primary prevention is still insufficient, we also lack accurate incidence estimates. Current estimates vary widely (18.6–128/100 000/year), but data on SCD incidence in Germany are missing. Depending on SCD definitions, death needs to occur between 1 and 24 h after the onset of symptoms. Methods and results In the district of Aurich (190 000 inhabitants, Lower Saxony, Germany), emergency medical service (EMS) is provided by a district government operated single carrier and two hospitals. To evaluate all EMS calls in this district from 2002 to 2009, we obtained EMS protocols, medical records, and death certificates for data analysis and adjudication of SCD. We defined SCD according to the definition of the World Health Organization, considering patients with cardiac arrest within ≤1 h after the onset of symptoms. We also required cardiopulmonary resuscitation being performed by EMS personnel. The overall mortality rate in the district of Aurich (1060/100 000/year) corresponded well with the average mortality rate in Germany (1030/100 000/year). During the observation period, we adjudicated 1212 SCD cases, equivalent to an annual rate of 151 SCD cases (81 cases/100 000/year). Rates remained remarkably stable over time, and affected a considerable number of individuals of working age (32/100 000/year). Conclusion Consistent with prior reports, the SCD incidence in a district of Germany is substantial. Despite an elaborate EMS system and advanced medical care, SCD rates remain stable and necessitate improved, individualized risk stratification.

Sudden cardiac death (SCD) remains a daunting problem. It is a major public health issue for several reasons: from its prevalence (20% of total mortality in the industrialized world) to the devastating psycho-social impact on society and on the families of victims often still in their prime, and it represents a challenge for medicine, and especially for cardiology. This text summarizes the discussions and opinions of a group of investigators with a long-standing interest in this field. We addressed the occurrence of SCD in individuals apparently healthy, in patients with heart disease and mild or severe cardiac dysfunction, and in those with genetically based arrhythmic diseases. Recognizing the need for more accurate registries of the global and regional distribution of SCD in these different categories, we focused on the assessment of risk for SCD in these four groups, looking at the significance of alterations in cardiac function, of signs of electrical instability identified by ECG abnormalities or by autonomic tests, and of the progressive impact of genetic screening. Special attention was given to the identification of areas of research more or less likely to provide useful information, and thereby more or less suitable for the investment of time and of research funds. ? The Author 2014. Published by Oxford University Press on behalf of the European Society of Cardiology.

AIMS: The Brugada syndrome is a rare, potentially fatal primary cardiomyopathy. Patients are identified by symptoms and typical electrocardiogram (ECG) patterns. Prevalence of spontaneous Brugada ECG patterns in the general population is unknown. METHODS AND RESULTS: We analysed 12-lead resting ECGs of 4149 men and women aged 25-74 years from the population-based KORA Study. Computer-assisted analysis identified ECGs with J-point elevation in leads V1-V3 and QRS duration

Aims Atrial fibrillation (AF) is the most frequent arrhythmia in humans. Rare familial forms exist. Recent evidence indicates a genetic susceptibility to common forms of AF. The α-subunit of the myocardial IKr-channel, encoded by the KCNH2 gene, is crucial to ventricular and atrial repolarization. Patients with mutations in KCNH2 present with higher incidence of AF. Common variants in KCNH2 have been shown to modify ventricular repolarization. We intended to investigate, whether such variants may also modulate atrial repolarization and predispose to AF. Methods and results In a two-stage association study we analysed 1207 AF-cases and 2475 controls. In stage I 40 tagSNPs (single nucleotide polymorphisms) from the KCNH2 genomic region were genotyped in 671 AF-cases and 694 controls. Of five associated variants, the common K897-allele of the KCNH2 -K897T variant was replicated in n = 536 independent AF cases and n = 1781 controls in stage II [overall odds ratio 1.25, 95% confidence interval 1.11–1.41, P = 0.00033]. This association remained significant after adjustment for gender and age. Conclusion We report a genetic association finding including positive replication between the K897-allele and higher incidence of AF. This provides a molecular correlate for complex genetic predispositions to AF. The consequences of the K897T variant at the atrial level will require further functional investigations.

AIMS: Torsades de pointes arrhythmias (TdP) occur by definition in the setting of prolonged QT intervals. Animal models of drug induced Long-QT syndrome (dLQTS) have shown higher predictive value for proarrhythmia with beat-to-beat variability of repolarization duration (BVR) when compared with QT intervals. Here, we evaluate variability of QT intervals in patients with a history of drug-induced long QT syndrome (dLQTS) and TdP in absence of a mutation in any of the major LQTS genes. METHODS AND RESULTS: Twenty patients with documented TdP under drugs with QT-prolonging potential were compared with 20 matched control individuals. An observer blinded to diagnosis manually measured lead-II, RR, and QT intervals from 30 consecutive beats. BVR was determined from Poincare plots of QT intervals as short-term variability (STV(QT) = Sigma|QT(n)(+1) - QT(n)|/[30 x radical2]). QRS interval and cycle length was comparable between study groups and controls. No difference was found in QTc between dLQTS and controls (428 +/- 25 vs. 421 +/- 34 ms, P = 0.26), whereas STV(QT) was significantly higher in dLQTS when compared with controls (8.1 +/- 3.7 vs. 3.6 +/- 1.3 ms, P = 0.001). Proarrhythmic predictive power of STV(QT) was superior to that of the QTc interval (AUC: 0.89 vs. 0.57, 95% CI: 0.79-0.99 vs. 0.39-0.75). CONCLUSION: In the absence of QTc prolongation, baseline STV(QT) characterized patients with documented drug-induced proarrhythmia. STV(QT) could prove to be a useful non-invasive, easily obtainable parameter aiding the identification of the patient at risk for potentially life threatening arrhythmia in the context of drugs with QT prolonging potential.

Aims The QT interval in the general population is a complex trait with 30–50% heritability. QT prolongation is associated with an increased risk of sudden death. A recent family-based study found an association between QT interval and the common non-synonymous Glycin 38 Serine variant (G38S, rs1805127) of the KCNE1 gene coding for the minK-potassium channel subunit. We intended to replicate this finding in a large population sample of central European Caucasian ancestry as part of our ongoing search for genetic variants predisposing to arrhythmias. Methods and results We studied 3966 unrelated individuals from the KORA S4 population-based study without atrial fibrillation, pacemaker implant, or pregnancy. Individuals were genotyped by MALDI-TOF mass spectrometry. We did not detect any significant association between the genotypes of the G38S variant and the QT interval in the entire population or in any gender. Conclusion Unlike the common Lysine 897 Threonine variant of KCNH2 (K897T, rs1805123) the G38S variant of KCNE1 does not appear to have a strong modifying effect on QT interval. However, we cannot rule out an effect of G38S on QT in other ethnic groups, under exercise or medications or on the risk for arrhythmias and sudden death.

Prolongation of action potential duration is the most consistent electrophysiological abnormality in myocardium and myocytes from hypertrophied and failing hearts. Measurements of currents in myocytes from hypertrophied and failing hearts indicate that, in most cases, this is due to a decrease in outward potassium currents. If present, a calcium-independent transient outward current is usually substantially reduced, but delayed rectifier and inward rectifier currents have also been found to be diminished. There is increasing evidence that potassium current down-regulation contributes significantly to the enhanced lability of the repolarization process in heart failure, predisposing to early after-depolarizations, dispersion of repolarization and ventricular arrhythmias. The reduction of outward potassium currents may also be involved in the enhanced sensitivity of failing myocardium to triggering factors like hypokalemia, ischemia, and antiarrhythmic agents with Class III effects. A thorough understanding of the mechanisms of cardiac excitability and arrhythmogenesis at the cellular and molecular level under normal and pathological conditions will be essential for the development of new pharmacological strategies to prevent sudden cardiac death in heart failure.

A 36-year-old patient was admitted after successful resuscitation due to ventricular fibrillation. The patient recovered without neurological sequelae. Cardiological examination including QTc interval, ajmaline testing, echocardiography, coronary angiography, and cardiac magnetic resonance imaging revealed no abnormal findings. The patient received a dual-chamber ICD …