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Objective: Approximately 20% of strokes are embolic strokes of undetermined source (ESUS). Undetected atrial fibrillation (AF) remains an important cause. Yet, oral anticoagulation in unselected ESUS patients failed in secondary stroke prevention. Guidance on effective AF detection is lacking. Here, we introduce a novel, non-invasive AF risk assessment after ESUS. Methods: Catch-Up ESUS is an investigator-initiated, observational cohort study conducted between 2018 and 2019 at the Munich University Hospital. Besides clinical characteristics, patients received & GE;72 h digital electrocardiogram recordings to generate the rhythm irregularity burden. Uni- and multivariable regression models predicted the primary endpoint of incident AF, ascertained by standardized follow-up including implantable cardiac monitors. Predictors included the novel rhythm irregularity burden constructed from digital electrocardiogram recordings. We independently validated our model in ESUS patients from the University Hospital Tubingen, Germany. Results: A total of 297 ESUS patients were followed for 15.6 +/- 7.6 months. Incident AF (46 patients, 15.4%) occurred after a median of 105 days (25th to 75th percentile 31-33 days). Secondary outcomes were recurrent stroke in 7.7% and death in 6.1%. Multivariable-adjusted analyses identified the rhythm irregularity burden as the strongest AF-predictor (hazard ratio 3.12, 95% confidence interval 1.62-5.80, p < 0001) while accounting for the known risk factors age, CHA(2)DS(2)-VASc-Score, and NT-proBNP. Independent validation confirmed the rhythm irregularity burden as the most significant AF-predictor (hazard ratio 2.20, 95% confidence interval 1.45-3.33, p < 0001). Interpretation: The novel, non-invasive, electrocardiogram-based rhythm irregularity burden may help adjudicating AF risk after ESUS, and subsequently guide AF-detection after ESUS. Clinical trials need to clarify if high-AF risk patients benefit from tailored secondary stroke prevention.

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: To explore candidate disease processes for atrial fibrillation, we investigated 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) and persistent/permanent AF (n=51)). Analyses were stratified into patients with and 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 rateCONCLUSIONS: Analysis of atrial gene expression profiles identified numerous novel genes associated with persistent AF, in 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.

AIMS: Aging is accompanied by telomere shortening. Increased telomere shortening is considered a marker of premature aging. Cardiac aging results in the development of cardiac pathologies. Electrocardiogram (ECG) measures reflect cardiac excitation, conduction, and repolarization. ECG measures also prolong with aging and are associated with cardiac pathologies including atrial fibrillation. As premature prolongation of ECG measures is observed, we hypothesized that such prolongation may be associated with telomere length. METHODS AND RESULTS: We studied the large, community-based KORA F4 Study. Of 3,080 participants enrolled between 2006 and 2007 with detailed information on demographic, anthropometric, clinical, and ECG characteristics, 2,575 presented with available data on leukocyte telomere length. Telomere length was determined by real-time quantitative PCR and expressed relative to a single copy gene. We fitted multivariable adjusted linear regression models to associate the ECG measures RR-interval, PR-interval, QRS-duration, and heart rate corrected QTc with telomere length. In our cohort, the mean age was 54.9±12.9 years and 46.6% were men. Increased age was associated with shorter telomere length (p

The QT interval is a heritable electrocardiographic measure associated with arrhythmia risk when prolonged. Here, the authors used a series of genetic analyses to identify genetic loci, pathways, therapeutic targets, and relationships with cardiovascular disease. The QT interval is an electrocardiographic measure representing the sum of ventricular depolarization and repolarization, estimated by QRS duration and JT interval, respectively. QT interval abnormalities are associated with potentially fatal ventricular arrhythmia. Using genome-wide multi-ancestry analyses (>250,000 individuals) we identify 177, 156 and 121 independent loci for QT, JT and QRS, respectively, including a male-specific X-chromosome locus. Using gene-based rare-variant methods, we identify associations with Mendelian disease genes. Enrichments are observed in established pathways for QT and JT, and previously unreported genes indicated in insulin-receptor signalling and cardiac energy metabolism. In contrast for QRS, connective tissue components and processes for cell growth and extracellular matrix interactions are significantly enriched. We demonstrate polygenic risk score associations with atrial fibrillation, conduction disease and sudden cardiac death. Prioritization of druggable genes highlight potential therapeutic targets for arrhythmia. Together, these results substantially advance our understanding of the genetic architecture of ventricular depolarization and repolarization.

Background The metabolic syndrome (MetS), defined by the simultaneous clustering of cardio-metabolic risk factors, is a significant worldwide public health burden with an estimated 25% prevalence worldwide. The pathogenesis of MetS is not entirely clear and the use of molecular level data could help uncover common pathogenic pathways behind the observed clustering. Methods Using a highly multiplexed aptamer-based affinity proteomics platform, we examined associations between plasma proteins and prevalent and incident MetS in the KORA cohort (n = 998) and replicated our results for prevalent MetS in the HUNT3 study (n = 923). We applied logistic regression models adjusted for age, sex, smoking status, and physical activity. We used the bootstrap ranking algorithm of least absolute shrinkage and selection operator (LASSO) to select a predictive model from the incident MetS associated proteins and used area under the curve (AUC) to assess its performance. Finally, we investigated the causal effect of the replicated proteins on MetS using two-sample Mendelian randomization. Results Prevalent MetS was associated with 116 proteins, of which 53 replicated in HUNT. These included previously reported proteins like leptin, and new proteins like NTR domain-containing protein 2 and endoplasmic reticulum protein 29. Incident MetS was associated with 14 proteins in KORA, of which 13 overlap the prevalent MetS associated proteins with soluble advanced glycosylation end product-specific receptor (sRAGE) being unique to incident MetS. The LASSO selected an eight-protein predictive model with an (AUC = 0.75; 95% CI = 0.71–0.79) in KORA. Mendelian randomization suggested causal effects of three proteins on MetS, namely apolipoprotein E2 (APOE2) (Wald-Ratio = − 0.12, Wald-p = 3.63e−13), apolipoprotein B (APOB) (Wald-Ratio = − 0.09, Wald-p = 2.54e−04) and proto-oncogene tyrosine-protein kinase receptor (RET) (Wald-Ratio = 0.10, Wald-p = 5.40e−04). Conclusions Our findings offer new insights into the plasma proteome underlying MetS and identify new protein associations. We reveal possible casual effects of APOE2, APOB and RET on MetS. Our results highlight protein candidates that could potentially serve as targets for prevention and therapy.

Aims The risk of developing atrial fibrillation (AF) and its complications continues to increase, despite good progress in preventing AF-related strokes. Methods and results This article summarizes the outcomes of the 7th Consensus Conference of the Atrial Fibrillation NETwork (AFNET) and the European Heart Rhythm Association (EHRA) held in Lisbon in March 2019. Sixty-five international AF specialists met to present new data and find consensus on pressing issues in AF prevention, management and future research to improve care for patients with AF and prevent AF-related complications. This article is the main outcome of an interactive, iterative discussion between breakout specialist groups and the meeting plenary. AF patients have dynamic risk profiles requiring repeated assessment and risk-based therapy stratification to optimize quality of care. Interrogation of deeply phenotyped datasets with outcomes will lead to a better understanding of the cardiac and systemic effects of AF, interacting with comorbidities and predisposing factors, enabling stratified therapy. New proposals include an algorithm for the acute management of patients with AF and heart failure, a call for a refined, data-driven assessment of stroke risk, suggestions for anticoagulation use in special populations, and a call for rhythm control therapy selection based on risk of AF recurrence. Conclusion The remaining morbidity and mortality in patients with AF needs better characterization. Likely drivers of the remaining AF-related problems are AF burden, potentially treatable by rhythm control therapy, and concomitant conditions, potentially treatable by treating these conditions. Identifying the drivers of AF-related complications holds promise for stratified therapy.

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.

Cardiac rhythm monitoring plays an integral role in the diagnosis and treatment of various conditions. Technological developments of recent years have partly increased the ease of use and the availability of cardiac rhythm monitoring. Yet, the multitude of options has also added confusion. Various manufacturers offer devices for pulse wave and electrocardiogram analysis. Their use plays an important role in clinical routine, both for diagnostic purposes and for the need to interpret opportunistic findings. This article is intended to provide an overview of existing technologies and to highlight their advantages and disadvantages. It also is intended to introduce future technologies. In any case it is important to emphasize that numerous clinical trials will be required to evaluate the benefit of modern cardiac rhythm monitoring and foster its medical use.

Background: Catheter ablation for ventricular tachycardia (VT) reduces the recurrence of VT in patients with implantable cardioverter-defibrillators (ICDs). The appropriate timing of VT ablation and its effects on mortality and heart failure progression remain a matter of debate. In patients with life-threatening arrhythmias necessitating ICD implantation, we compared outcomes of preventive VT ablation (undertaken before ICD implantation to prevent ICD shocks for VT) and deferred ablation after 3 ICD shocks for VT. Methods: The BERLIN VT study (Preventive Ablation of Ventricular Tachycardia in Patients With Myocardial Infarction) was a prospective, open, parallel, randomized trial performed at 26 centers. Patients with stable ischemic cardiomyopathy, a left ventricular ejection fraction between 30% and 50%, and documented VT were randomly assigned 1:1 to a preventive or deferred ablation strategy. The primary outcome was a composite of all-cause death and unplanned hospitalization for either symptomatic ventricular arrhythmia or worsening heart failure. Secondary outcomes included sustained ventricular tachyarrhythmia and appropriate ICD therapy. We hypothesized that preventive ablation strategy would be superior to deferred ablation strategy in the intention-to-treat population. Results: During a mean follow-up of 396±284 days, the primary end point occurred in 25 (32.9%) of 76 patients in the preventive ablation group and 23 (27.7%) of 83 patients in the deferred ablation group (hazard ratio, 1.09 [95% CI, 0.62–1.92]; P =0.77). On the basis of prespecified criteria for interim analyses, the study was terminated early for futility. In the preventive versus deferred ablation group, 6 versus 2 patients died (7.9% versus 2.4%; P =0.18), 8 versus 2 patients were admitted for worsening heart failure (10.4% versus 2.3%; P =0.062), and 15 versus 21 patients were hospitalized for symptomatic ventricular arrhythmia (19.5% versus 25.3%; P =0.27). Among secondary outcomes, the proportions of patients with sustained ventricular tachyarrhythmia (39.7% versus 48.2%; P =0.050) and appropriate ICD therapy (34.2% versus 47.0%; P =0.020) were numerically reduced in the preventive ablation group. Conclusions: Preventive VT ablation before ICD implantation did not reduce mortality or hospitalization for arrhythmia or worsening heart failure during 1 year of follow-up compared with the deferred ablation strategy. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02501005.

Genetic studies on telomere length are important for understanding age-related diseases. Prior GWAS for leukocyte TL have been limited to European and Asian populations. Here, we report the first sequencing-based association study for TL across ancestrally-diverse individuals (European, African, Asian and Hispanic/Latino) from the NHLBI Trans-Omics for Precision Medicine (TOPMed) program. We used whole genome sequencing (WGS) of whole blood for variant genotype calling and the bioinformatic estimation of telomere length in n=109,122 individuals. We identified 59 sentinel variants (p-value

Background: Observational studies suggest an association of stroke with cardiac traits beyond atrial fibrillation, the leading source of cardioembolism. However, controversy remains regarding a causal role of these traits in stroke pathogenesis. Here, we leveraged genetic data to systematically assess associations between cardiac traits and stroke risk using a Mendelian Randomization framework. Methods: We studied 66 cardiac traits including cardiovascular diseases, magnetic resonance imaging–derived cardiac imaging, echocardiographic imaging, and electrocardiographic measures, as well as blood biomarkers in a 2-sample Mendelian Randomization approach. Genetic predisposition to each trait was explored for associations with risk of stroke and stroke subtypes in data from the MEGASTROKE consortium (40 585 cases/406 111 controls). Using multivariable Mendelian Randomization, we adjusted for potential pleiotropic or mediating effects relating to atrial fibrillation, coronary artery disease, and systolic blood pressure. Results: As expected, we observed strong independent associations between genetic predisposition to atrial fibrillation and cardioembolic stroke and between genetic predisposition to coronary artery disease as a proxy for atherosclerosis and large-artery stroke. Our data-driven analyses further indicated associations of genetic predisposition to both heart failure and lower resting heart rate with stroke. However, these associations were explained by atrial fibrillation, coronary artery disease, and systolic blood pressure in multivariable analyses. Genetically predicted P-wave terminal force in V1, an electrocardiographic marker for atrial cardiopathy, was inversely associated with large-artery stroke. Conclusions: Available genetic data do not support substantial effects of cardiac traits on the risk of stroke beyond known clinical risk factors. Our findings highlight the need to carefully control for confounding and other potential biases in studies examining candidate cardiac risk factors for stroke.

Europace : the European journal of pacing, arrhythmias and cardiac electrophysiology euac062 (2022). doi:10.1093/europace/euac062, Published by Oxford Univ. Press, Oxford

A diverse set of driver genes, such as regulators of DNA methylation, RNA splicing, and chromatin remodeling, have been associated with pre-malignant clonal expansion of hematopoietic stem cells (HSCs). The factors mediating expansion of these mutant clones remain largely unknown, partially due to a paucity of large cohorts with longitudinal blood sampling. To circumvent this limitation, we developed and validated a method to infer clonal expansion rate from single timepoint data called PACER (passenger-approximated clonal expansion rate). Applying PACER to 5,071 persons with clonal hematopoiesis accurately recapitulated the known fitness effects due to different driver mutations. A genome-wide association study of PACER revealed that a common inherited polymorphism in the TCL1A promoter was associated with slower clonal expansion. Those carrying two copies of this protective allele had up to 80% reduced odds of having driver mutations in TET2, ASXL1, SF3B1, SRSF2, and JAK2, but not DNMT3A. TCL1A was not expressed in normal or DNMT3A-mutated HSCs, but the introduction of mutations in TET2 or ASXL1 by CRISPR editing led to aberrant expression of TCL1A and expansion of HSCs in vitro. These effects were abrogated in HSCs from donors carrying the protective TCL1A allele. Our results indicate that the fitness advantage of multiple common driver genes in clonal hematopoiesis is mediated through TCL1A activation. PACER is an approach that can be widely applied to uncover genetic and environmental determinants of pre-malignant clonal expansion in blood and other tissues.

Introduction: Embolic stroke of undetermined source (ESUS) accounts for up to 20% of ischemic strokes. Undetected atrial fibrillation (AF) represents one important underlying cause. Once diagnosed, initiation of oral anticoagulation is recommended for secondary stroke prevention. Yet, detection of paroxysmal AF is tedious. Implantable loop recorders (ICM) have evolved as the diagnostic gold standard. Prior studies have indicated that ICM implantation and remote monitoring in particular result in a relevant financial and personnel burden in unselected patients. ESUS patients are considered at higher risk of an AF diagnosis. Hypothesis: We hypothesized that AF diagnosis by ICM and remote monitoring puts considerable strain on health care providers, even in patients at high risk for AF after ESUS. Methods: We investigated all patients of our hospital-based, prospective, single-center, observational ESUS cohort that were equipped with an ICM after ESUS between January 2018 and December 2019. Follow-up was performed through July 2020. Results: Overall, 179 patients were eligible for analysis. Of these, 38 patients (22,1%) were diagnosed with AF by ICM and remote monitoring. During the study period a total of 11,975 episodes were transmitted through remote monitoring, of which 3,766 were alarms for AF. Response to alarms resulted in 307 on site visits and 132 telephone calls to inquire about symptoms, to inform about the diagnosis of AF, and to initiate a change in antithrombotic regimen from antiplatelet therapy to oral anticoagulation. On average, a single ESUS patient generated 40.9 episodes per year for review, triggered one additional on-site visit, and every other patient required additional telephonic follow-up. The number needed to diagnose one ESUS patient with AF within one year was 5. Conclusions: ICM and remote monitoring can successfully diagnose AF in a high-risk cohort after ESUS. Yet, the number of alarms other than for AF, and alarms inappropriately suggesting AF by far exceed appropriate AF diagnoses. Even in a cohort at high risk for AF and with an immediate therapeutic consequence upon AF diagnosis, the resulting burden on personnel and health care resources is high. An optimization of diagnostic ICM algorithms is therefore desirable.

Background: Atrial Fibrillation (AF) is common pathophysiologically complex. Age is among the most important AF risk factors. However, some young patients develop early-onset AF, whereas many others do not despite an advanced age. Advanced biological aging as opposed to advanced calendar age may be an explanation. Telomere length is associated with age and may be considered a measurable marker of biological age. AF and telomere length have previously been associated, but results remained inconclusive. Hypothesis: AF is age-related and associates with telomere length in a large case-control cohort. Methods: Between 2005 and 2018, we enrolled 2475 early-onset AF patients into the prospective AFLMU cohort. 3077 AF-free individuals from the community-based KORA study (enrollment 2006-08) served as controls. Clinical characteristics, an electrocardiogram, and a blood sample was obtained in all participants. We determined telomere length by a qPCR-based method using a multiplex TaqMan assay. Telomere length was expressed as delta-CT referenced to the single copy gene 36B4 .Lower CT values indicate shorter telomere length. Telomere length in cases vs. controls was assessed using multi-variably adjusted logistic regression. Results: Mean age was 58 years in AFLMU and 56 years in KORA. Men accounted for 72.3% in AFLMU and for 51.7% in KORA. For quality control, we confirmed a reduction of telomere length with age and demonstrated shorter telomere length in men compared to women. Median telomere length was also significantly shorter in AF patients compared to controls (9.81 [5.98, 13.1] vs. 13,10 [12.60, 13.63], p Conclusion: In a large case-control cohort, AF significantly associates with telomere length. Information on telomere length may help to inform if a patient develops AF due to premature biological aging. The underlying pathomechanisms for premature aging remain to be elucidated.

lncRNAs are at the core of many regulatory processes and have also been recognized to be involved in various complex diseases. They affect gene regulation through direct interactions with RNA, DNA or proteins. Accordingly, lncRNAs structure is likely to be essential for their regulatory function. Point mutations, which manifest as SNPs (single nucleotide polymorphisms) in genome screens, can substantially alter their function and, subsequently, the expression of their down-stream regulated genes. To test the effect of SNPs on structure, we investigated lncRNAs associated with dilated cardiomyopathy. Among 322 human candidate lncRNAs we demonstrate first the significant association of a SNP located in lncRNA H19 using data from 1084 diseased and 751 control patients. H19 is generally highly expressed in the heart, with a complex expression pattern during heart development. Next, we used MFE (minimum free energy) folding to demonstrate a significant refolding in the secondary structure of this 861 nt long lncRNA. Since MFE folding may overlook the importance of sub-optimal structures, we showed that this refolding also manifests in the overall Boltzmann structure ensemble. There, the composition of structures is tremendously affected in their thermodynamic probabilities through the genetic variant. Finally, we confirmed these results experimentally, using SHAPE-Seq, corroborating that SNPs affecting such structures may explain hidden genetic variance not accounted for through genome wide association studies. Our results suggest that structural changes in lncRNAs, and lncRNA H19 in particular, affect regulatory processes and represent optimal targets for further in-depth studies probing their molecular interactions.

Catheter ablation is the treatment of choice for recurrent focal atrial tachycardia (FAT) as medical therapy is limited. Routinely, a three-dimensional mapping system is used. Whether or not optimized signal detection does improve ablation success rates has not yet been investigated. This retrospective cohort study compared ablation procedures using an ultra-high-density mapping system (UHDM, Rhythmia, Boston Scientific) with improved signal detection and automatic annotation with procedures using a conventional electroanatomic mapping system (CEAM, Biosense Webster, CARTO).All patients undergoing ablation for FAT using UHDM or CEAM from April 2015 to August 2018 were included. Endpoints comprised procedural parameters, acute success as well as freedom from arrhythmia 12 months after ablation.A total of 70 patients underwent ablation (48 with UHDM, 22 with CEAM). No significant differences were noted for parameters like procedural and radiation duration, area dose, and RF applications. Acute success was significantly higher in the UHDM cohort (89.6% vs. 68.2%, p = .03). Nevertheless, arrhythmia freedom 12 months after ablation was almost identical (56.8% vs. 60%, p = .87), as more patients with acute success of ablation presented with a relapse during follow-up (35.0 vs. 7.7%, p = .05).Acute success rate of FAT ablation might be improved by UHDM, without an adverse effect on procedural parameters. Nevertheless, further research is needed to understand the underlying mechanism for increased recurrence rates after acute successful ablation.

Background: The P-wave duration (PWD) is an electrocardiographic measurement that represents cardiac conduction in the atria. Shortened or prolonged PWD is associated with atrial fibrillation (AF). We used exome-chip data to examine the associations between common and rare variants with PWD. Methods: Fifteen studies comprising 64 440 individuals (56 943 European, 5681 African, 1186 Hispanic, 630 Asian) and ≈230 000 variants were used to examine associations with maximum PWD across the 12-lead ECG. Meta-analyses summarized association results for common variants; gene-based burden and sequence kernel association tests examined low-frequency variant-PWD associations. Additionally, we examined the associations between PWD loci and AF using previous AF genome-wide association studies. Results: We identified 21 common and low-frequency genetic loci (14 novel) associated with maximum PWD, including several AF loci ( TTN , CAND2 , SCN10A , PITX2 , CAV1 , SYNPO2L , SOX5 , TBX5, MYH6, RPL3L ). The top variants at known sarcomere genes ( TTN, MYH6 ) were associated with longer PWD and increased AF risk. However, top variants at other loci (eg, PITX2 and SCN10A ) were associated with longer PWD but lower AF risk. Conclusions: Our results highlight multiple novel genetic loci associated with PWD, and underscore the shared mechanisms of atrial conduction and AF. Prolonged PWD may be an endophenotype for several different genetic mechanisms of AF.

Cardiac thromboembolism attributed to atrial fibrillation (AF) is responsible for up to one-third of ischemic strokes. Stroke may be the first manifestation of previously undetected AF. Given the efficacy of oral anticoagulants in preventing AF-related ischemic strokes, strategies of searching for AF after a stroke using ECG monitoring followed by oral anticoagulation (OAC) treatment have been proposed to prevent recurrent cardioembolic strokes. This white paper by experts from the AF-SCREEN International Collaboration summarizes existing evidence and knowledge gaps on searching for AF after a stroke by using ECG monitoring. New AF can be detected by routine plus intensive ECG monitoring in approximately one-quarter of patients with ischemic stroke. It may be causal, a bystander, or neurogenically induced by the stroke. AF after a stroke is a risk factor for thromboembolism and a strong marker for atrial myopathy. After acute ischemic stroke, patients should undergo 72 hours of electrocardiographic monitoring to detect AF. The diagnosis requires an ECG of sufficient quality for confirmation by a health professional with ECG rhythm expertise. AF detection rate is a function of monitoring duration and quality of analysis, AF episode definition, interval from stroke to monitoring commencement, and patient characteristics including old age, certain ECG alterations, and stroke type. Markers of atrial myopathy (eg, imaging, atrial ectopy, natriuretic peptides) may increase AF yield from monitoring and could be used to guide patient selection for more intensive/prolonged poststroke ECG monitoring. Atrial myopathy without detected AF is not currently sufficient to initiate OAC. The concept of embolic stroke of unknown source is not proven to identify patients who have had a stroke benefitting from empiric OAC treatment. However, some embolic stroke of unknown source subgroups (eg, advanced age, atrial enlargement) might benefit more from non–vitamin K-dependent OAC therapy than aspirin. Fulfilling embolic stroke of unknown source criteria is an indication neither for empiric non–vitamin K-dependent OAC treatment nor for withholding prolonged ECG monitoring for AF. Clinically diagnosed AF after a stroke or a transient ischemic attack is associated with significantly increased risk of recurrent stroke or systemic embolism, in particular, with additional stroke risk factors, and requires OAC rather than antiplatelet therapy. The minimum subclinical AF duration required on ECG monitoring poststroke/transient ischemic attack to recommend OAC therapy is debated.

Funding Acknowledgements Type of funding sources: Public grant(s) – EU funding. Main funding source(s): CATCH ME Horizon 2020, EU-H2020-PHC-RIA (633196) CVON2014-09, RACE V: Reappraisal of Atrial Fibrillation: Interaction between hyperCoagulability, Electrical remodeling, and Vascular Destabilisation in the Progression of AF Background Atrial fibrosis is one of the most important aspects of structural remodeling in the atria and largely increases the inducibility and sustainability of AF. The main risk factors for recurrent AF, such as ageing, heart failure, and history of AF, partly enhance AF propensity by inducing atrial fibrosis. A distinction should be made between replacement fibrosis following myocyte death and reactive fibrosis, which often occurs in the absence of myocyte death. Endomysial fibrosis, a type of reactive fibrosis in between cardiomyocytes, is poorly studied as a result of limitations and labor intensiveness of traditional histochemical quantification. Purpose We examined the contributions of age, sex, AF and heart failure to the development of overall and endomysial fibrosis in the context of concurrent pathologies. Methods We developed an algorithm for automated quantification of multiple features of structural remodeling following myocardial staining with wheat germ agglutinin (WGA). We studied the type, quantity and distribution of fibrosis in left (LAA, n = 95) and right (RAA, n = 76) atrial appendage biopsies in a large European cohort of patients with varying indications for cardiac surgery. Linear mixed effect models were constructed to predict endomysial fibrosis quantity and clustering as a function of AF, heart failure, sex, age and 4 principle components that accounted for potential confounding due to other clinical characteristics. Results Persistent AF, heart failure and female sex were independently associated with endomysial fibrosis, age was not. AF and age were not associated with overall fibrosis. Clustering of endomysial fibrosis was observed in females (LAA), paroxysmal AF (RAA), persistent AF and heart failure (LAA) patients (table 1). Conclusions Female sex, AF, and heart failure are associated with the quantity and distribution of endomysial fibrosis, the effects of age are limited. summary of results Clinical parameter Overall fibrosis Endomysial fibrosis Clustering of endomysial fibrosis LAA RAA LAA RAA LAA RAA Paroxysmal AF +1.6%±1.5; p = 0.29 +2.1%±2.2; p = 0.34 -0.7μm ± 0.5; p = 0.19 +1.0μm ± 0.6; p = 0.10 -0.8%±3.6; p = 0.82 +7.4%±4.1; p = 0.04 Persistent AF +1.6%±1.5; p = 0.26 +2.2%±2.1; p = 0.30 +1.1μm ± 0.5; p = 0.04 +1.3μm ± 0.6; p = 0.03 +5.7%±0.03; p = 0.04 +6.9%±3.9, p = 0.04 Heart failure +4.8%±1.5; p = 0.01 +2.3%±2.0; p = 0.24 +2.5μm ± 0.5; p

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.

Aim. Cardiac arrhythmias comprise a major health and economic burden and are associated with significant morbidity and mortality, including cardiac failure, stroke and sudden cardiac death (SCD). Development of efficient preventive and therapeutic strategies is hampered by incomplete knowledge of disease mechanisms and pathways. Our aim is to identify novel mechanisms underlying cardiac arrhythmia and SCD using an unbiased approach. Methods and Results. We employed a phenotype-driven N-ethyl-N-nitrosourea (ENU) mutagenesis screen and identified a mouse line with a high incidence of sudden death at young age (6-9 weeks) in the absence of prior symptoms. Affected mice were found to be homozygous for the nonsense mutation Bcat2p.Q300*/p.Q300* in the Bcat2 gene encoding branched chain amino acid transaminase 2. At the age of 4-5 weeks, Bcat2p.Q300*/p.Q300* mice displayed drastic increase of plasma levels of branch chain amino acids (BCAAs – leucine, isoleucine, valine) due to the incomplete catabolism of BCAAs, in addition to inducible arrhythmias ex vivo as well as cardiac conduction and repolarization disturbances. In line with these findings, plasma BCAA levels were positively correlated to ECG indices of conduction and repolarization in the German community-based KORA F4 Study. Isolated cardiomyocytes from Bcat2p.Q300*/p.Q300* mice revealed action potential (AP) prolongation, pro-arrhythmic events (early and late afterdepolarizations, triggered APs) and dysregulated calcium homeostasis. Incubation of human pluripotent stem cell-derived cardiomyocytes with elevated concentration of BCAAs induced similar calcium dysregulation and pro-arrhythmic events which were prevented by rapamycin, demonstrating the crucial involvement of mTOR pathway activation. Conclusions. Our findings identify for the first time a causative link between elevated BCAAs and arrhythmia, which has implications for arrhythmogenesis in conditions associated with BCAA metabolism dysregulation such as diabetes, metabolic syndrome and heart failure. Translational perspectives. Development of efficient anti-arrhythmic strategies is hampered by incomplete knowledge of disease mechanisms. Using an unbiased approach, we here identified for the first time a pro-arrhythmic effect of increased levels of branched chain amino acids (BCAAs). This is of particular relevance for conditions associated with BCAA dysregulation and increased arrhythmia risk, including heart failure, obesity and diabetes, as well as for athletes supplementing their diet with BCAAs. Such metabolic dysregulation is potentially modifiable through dietary interventions, paving the way for novel preventive strategies. Our findings furthermore identify mTOR inhibition as a potential anti-arrhythmic strategy in patients with metabolic syndrome.

Highlights • Acute cardiac tamponade is a highly relevant complication in modern cardiology. • Continuous pericardial drainage is safe and does not increase total drainage volume. • Continuous drainage associates with lower rates of open-heart surgical interventions. • Continuous drainage associates with reduced re-tamponades and mortality on day 5., Background Acute cardiac tamponade is a life-threatening pathology in modern cardiology as catheter-based interventions become increasingly relevant. Pericardiocentesis is usually the primary treatment of choice. However, protocols for handling of draining pigtail catheters are very variable due to limit data and require further investigation. Methods We retrospectively analyzed 52 patients with acute cardiac tamponade requiring immediate pericardiocentesis from January 2017 to August 2020. Patients were treated with a classical approach of intermittent manual aspiration or continuous pericardial drainage using a redon drainage system. Results Mean age of patients was 74 years in both groups. Most common causes for cardiac tamponade were percutaneous coronary interventions in about 50% and transaortic valve implantations in 25% of all cases. 28 patients were treated with classic intermittent drainage from 2017 to 2020. 24 patients were treated with continuous drainage from December 2018–2020. Compared to classical intermittent drainage treatment, continuous drainage was associated with a lower rate of a surgical intervention or cardiac re-tamponade and a lower mortality at 5 days (HR 0.2, 95% CI 0.1–0.9, log-rank p = 0.03). Despite a longer total drainage time under continuous suction, drainage volumes were comparable in both groups. Conclusion Acute cardiac tamponade can be efficiently treated by pericardiocentesis with subsequent continuous negative pressure drainage via a pigtail catheter. Our retrospective analysis shows a significantly lower mortality, a decreased rate of interventions and lower rates of cardiac re-tamponade without any relevant side effects when compared to classical intermittent manual drainage. These findings require further investigations in larger, randomized trials.

Background: Early detection of atrial fibrillation (AF) and subsequent initiation of anticoagulation and rhythm control therapy markedly reduce stroke, cardiovascular death, and heart failure, but unselected ECG screening for AF is time- and resource-intensive. Combining biomarkers reflecting different biological processes may identify patients at high risk of AF, enabling targeted ECG screening. Methods: We systematically reviewed literature and patent information to define candidate biomarkers for AF detection. The top 12 biomarkers identified through this process were quantified on a high-precision, high-throughput platform in 1485 consecutive patients at risk for AF presenting acutely to hospital (median age 69 years [Q1, Q3 60,78]; 60% male). Patients had either known AF (45%) or AF ruled out by 7-day ECG-monitoring. A model simultaneously considering 7 key clinical characteristics and all biomarkers was developed in a randomly sampled discovery cohort (n=933) and validated in the remaining patients (n=552). Neural networks were also applied. Findings: Using backward elimination, a model using age, sex, body mass index (BMI), BMP10, ANG2, and FGF23 discriminated between patients with and without AF with an AUC of 0·743 [95% confidence interval (CI) 0·712-0·775]. The biomarkers represent distinct pathways relevant for atrial cardiomyopathy and AF, namely hypertrophy and fibrosis (FGF23), endothelial dysfunction (ANG2), and atrial oxidative stress and the genomic predisposition to AF (BMP10). The SHAP procedure for neural networks identified the same variables as the regression. The validation yielded an AUC of 0·719 (95%CI 0·677, 0·762), corroborated using deep neural networks (AUC 0·784 [95%CI 0·745, 0·822]). Interpretation: The combination of three simple characteristics (age, sex, BMI) and three biomarkers (BMP10, ANG2, and FGF23) robustly identifies patients with AF. Such an approach enables targeted screening for AF and provides a platform to develop personalised prevention and treatment in patients with AF. Funding Statement: This work was partially supported by the European Commission (grant agreements no. 633196 [CATCH ME]) to PKi, LF, BC, SH, SK, LM, MFS, US, and no. 116074 [BigData@Heart EU IMI] to PKi, British Heart Foundation (FS/13/43/30324 and (AA/18/2/34218) to PKi and LF), German Centre for Cardiovascular Research supported by the German Ministry of Education and Research (DZHK, via a grant to AFNET to PKi), and Leducq Foundation (14CVD01) to PKi. Declaration of Interests: LF has received institutional research grants and non-financial support from European Union, British Heart Foundation, Medical Research Council (UK), and DFG and Gilead. PKi has received additional support for research from the European Union, British Heart Foundation, Leducq Foundation, Medical Research Council (UK), and German Centre for Heart Research, from several drug and device companies active in atrial fibrillation, honoraria from several such companies. PKi and LF are listed as inventors on two patents held by University of Birmingham (Atrial Fibrillation Therapy WO 2015140571, Markers for Atrial Fibrillation WO 2016012783). PKa is an employee of Roche Diagnostics GmbH. AZ is an employee of Roche Diagnostics Intl. All other authors have reported no relationships relevant to the contents of this paper to disclose. Ethics Approval Statement: This study complied with the Declaration of Helsinki, was approved by the National Research Ethics Service Committee (IRAS ID 97753), and was sponsored by the University of Birmingham.

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

With an estimated prevalence of 463 million affected, type 2 diabetes represents a major challenge to health care systems worldwide. Analyzing the plasma proteomes of individuals with type 2 diabetes may illuminate hitherto unknown functional mechanisms underlying disease pathology. We assessed the associations between type 2 diabetes and >1000 plasma proteins in the KORA (Cooperative health research in the Region of Augsburg) F4 cohort (n=993, 110 cases), with subsequent replication in the HUNT3 (Third wave of the Nord-Trøndelag Health Study) cohort (n=940, 149 cases). We computed logistic regression models adjusted for age, sex, BMI, smoking status and hypertension. Additionally, we investigated associations with incident type 2 diabetes and performed two-sample bi-directional Mendelian randomization (MR) analysis to prioritize our results. Association analysis of prevalent type 2 diabetes revealed 24 replicated proteins, of which eight are novel. Proteins showing association with incident type 2 diabetes were aminoacylase-1, growth hormone receptor, and insulin-like growth factor binding protein-2. Aminoacylase-1 was associated with both prevalent and incident type 2 diabetes. MR analysis yielded nominally significant causal effects of type 2 diabetes on cathepsin Z and rennin, both known to have roles in the pathophysiological pathways of cardiovascular disease, and of sex hormone-binding globulin on type 2 diabetes. In conclusion, our high-throughput proteomics study replicated previously reported type 2 diabetes-protein associations, and identified new candidate proteins possibly involved in the pathogenesis of type 2 diabetes.

Background Biomarkers reflecting different biological pathways have been associated with atrial fibrillation (AF). These discoveries motivate the consideration of a multiple biomarker model in the context of AF screening to improve detection. Objective We assessed a selection of clinical characteristics and biomarkers known to be associated with AF as established in literature, to identify a mechanism-based combination of markers for simplifying patient selection for screening. Methods and Results 1485 patients presenting acutely to hospital (median age [Q1, Q3] 69 [60, 78] years; 60% male; 45% with AF) with either diagnosed AF or ≥2 CHA2DS2-VASc risk factors (silent AF ruled out by 7-day ECG monitoring) were analysed. From EDTA plasma, 12 known cardiovascular biomarkers selected from published literature were quantified at a single centre on a high-throughput platform (Roche Diagnostics GMBH, DE). After adjustment for known confounders (age, sex, BMI, eGFR, heart failure, stroke/TIA, hypertension status), 6 biomarkers remained univariately associated with increased odds of AF (BMP10, ANG2, NTproBNP, IGFBP7, FGF23, CA125; see Figure). A model which simultaneously considered clinical characteristics and biomarkers was developed in a discovery cohort (n = 933) randomly sampled from all included patients (60:40 discovery:validation) and subsequently validated on the remaining patients (n = 552) using both logistic regression and machine learning methodologies for comparison. Using regression with backward statistical selection, an optimism-adjusted model of Age, Sex, BMI, BMP10, ANG2, and FGF23 was found to discriminate between patients with and without AF with an area under the ROC curve, AUC, of 0.743 [95% confidence interval, 0.712, 0.775], corroborated by machine learning (AUC 0.760 [95%CI 0.746, 0.764]). Performance was similar in the validation cohort for regression (AUC 0.719 [0.677, 0.762]) and machine learning (AUC 0.733 [95%CI 0.691, 0.775]). In a sensitivity analysis using biomarker quartiles instead of absolute values, an additional biomarker was selected: NTproBNP. Conclusion In our analysis of known markers of AF, a combination of 3 simple clinical characteristics (Age, Sex, BMI) and 3 biomarkers (BMP10, ANG2, and FGF23) robustly discriminated between patients with diagnosed AF and sinus rhythm patients with cardiovascular risks in both discovery and validation cohorts. Biomarkers implicate pathways related to inflammation (BMP10), fibrosis (FGF23) and hypoxia (ANG2), known to be associated with AF. Prospective studies can examine if AF screening with multiple biomarkers has the potential of identifying patients who could benefit from further ECG monitoring. Conflict of Interest None.

Introduction: With an estimated prevalence of 425 million individuals, type 2 diabetes (T2D) is a major challenge to health care systems worldwide. It is a multifactorial complex disease characterized by insulin resistance and hyperinsulinemia, and involves widespread complications. We performed hypothesis-free association and Mendelian randomization (MR) based causal inference analyses of T2D, investigating 1,100 plasma proteins in cross-sectional and longitudinal settings. Methods: The population-based cohort studies KORA (Cooperative health research in the Region of Augsburg) and HUNT3 (Third wave of the Nord-Trøndelag Health Study) were used for discovery and replication, respectively. Proteins were quantified using the SOMAscan proteomics platform in 999 KORA and 1007 HUNT participants. After quality control, we log2-transformed and (0,1)-standardized the proteomics data. We validated T2D using clinical and oral glucose tolerance test data in KORA, and clinical data only in HUNT3. We computed logistic regression models adjusted for age, sex, body mass index, smoking status and hypertension status and accounted for multiple testing using the Benjamini-Hochberg false discovery rate (FDR) method (FDR Results: The cross-sectional analysis with prevalent T2D (KORA 110 cases and HUNT 149) yielded 24 replicated proteins, of which the three yielding the highest odds ratios were aminoacylase 1, complement C2 and plasma protease C1 inhibitor. Longitudinal analysis with incident T2D (KORA 74 cases and HUNT 103) yielded three replicated proteins namely aminoacylase-1, growth hormone receptor and insulin like growth factor binding protein 2. The MR analysis testing the causal effect of T2D on the replicated proteins, using 120 SNPs as instrumental variables (IV), yielded nominally significant p-values (p Conclusion: Using an aptamer-based technique, we replicated previously reported prevalent and incident T2D-protein associations, including SHBG, complement C2 and renin as well as identified novel ones, like aminoacylase-1. Causality analyses using MR identified SHBG as a potential protein directly involved in the pathogenesis of T2D, and suggested a causal effect of T2D on both cathepsin Z and renin, both known to have roles in the pathophysiological pathways of cardiovascular disease.

Background: Ablation is a widely used therapy for atrial fibrillation (AF); however, arrhythmia recurrence and repeat procedures are common. Studies examining surrogate markers of genetic susceptibility to AF, such as family history and individual AF susceptibility alleles, suggest these may be associated with recurrence outcomes. Accordingly, the aim of this study was to test the association between AF genetic susceptibility and recurrence after ablation using a comprehensive polygenic risk score for AF. Methods: Ten centers from the AF Genetics Consortium identified patients who had undergone de novo AF ablation. AF genetic susceptibility was measured using a previously described polygenic risk score (N=929 single-nucleotide polymorphisms) and tested for an association with clinical characteristics and time-to-recurrence with a 3 month blanking period. Recurrence was defined as >30 seconds of AF, atrial flutter, or atrial tachycardia. Multivariable analysis adjusted for age, sex, height, body mass index, persistent AF, hypertension, coronary disease, left atrial size, left ventricular ejection fraction, and year of ablation. Results: Four thousand two hundred seventy-six patients were eligible for analysis of baseline characteristics and 3259 for recurrence outcomes. The overall arrhythmia recurrence rate between 3 and 12 months was 44% (1443/3259). Patients with higher AF genetic susceptibility were younger ( P P =0.001). Persistent AF (hazard ratio [HR], 1.39 [95% CI, 1.22–1.58]; P P P =0.008) were associated with increased risk of recurrence. In univariate analysis, higher AF genetic susceptibility trended towards a higher risk of recurrence (HR, 1.08 [95% CI, 0.99–1.18]; P =0.07), which became less significant in multivariable analysis (HR, 1.06 [95% CI, 0.98–1.15]; P =0.13). Conclusions: Higher AF genetic susceptibility was associated with younger age and fewer clinical risk factors but not recurrence. Arrhythmia recurrence after AF ablation may represent a genetically different phenotype compared to AF susceptibility.

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

ZusammenfassungVorhofflimmern ist die häufigste Herzrhythmusstörung und betrifft mehrere Millionen Menschen weltweit. Nachdem in den letzten Jahren bereits ein starker genetischer Einfluss auf die Entstehung von Vorhofflimmern nachgewiesen worden war, konnte eine Studie kürzlich die Heritabilität von Vorhofflimmern mit 22,1% quantifizieren. Klinisch spiegelt sich dies in der Bedeutung der Familienanamnese für Vorhofflimmern wider. Neben seltenen Mutationen, etwa in Ionenkanalgenen, stellen insbesondere häufige genetische Varianten, sog. Single Nucleotide Polymorphisms, einen entscheidenden Faktor der Heritabilität von Vorhofflimmern dar. Mithilfe genomweiter Assoziationsstudien konnten mittlerweile 97 Genorte identifiziert werden, die mit einem erhöhten Risiko für das Auftreten von Vorhofflimmern assoziiert sind. Obwohl die meisten dieser Polymorphismen in der Nachbarschaft von elektrophysiologisch relevanten Genen, kardialen Strukturgenen oder entwicklungsbiologisch relevanten Genen liegen, sind die dem erhöhten Vorhofflimmerrisiko zugrunde liegenden zellulären und molekularen Mechanismen in vielen Fällen unbekannt. Um dies aufzuklären, sind umfangreiche Untersuchungen in zell- und tierexperimentellen Modellen notwendig.