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Background Evidence in non-ischaemic cardiogenic shock (CS), especially regarding prognostic markers and use of mechanical circulatory support (MCS), is scarce. Aim The aim of this study was to evaluate left ventricular ejection fraction (LVEF) as a prognostic marker as well as a factor to guide the use of MCS in non-ischaemic CS. Methods In this international observational study, patients with non-ischaemic CS (e.g. caused by severe de-novo or acute on chronic heart failure; but not by acute myocardial infarction) treated with or without MCS from 18 tertiary-care centers in five countries were enrolled. Cox regression models adjusted for age, sex, SCAI class, lactate, prior resuscitation, mechanical ventilation and pH were fitted to evaluate the association between LVEF and 30-day mortality as well as the interaction between MCS use, LVEF and 30-day mortality. Results A total of 807 patients were enrolled, of whom 387 (47,9%) were treated with and 418 (52.1%) without MCS; mean age was 63 [interquartile range (IQR) 51.5–72) years, 601 (74.5%) were male, 486 (60.2%) had acute on chronic heart failure, 221 (32.7%) had an ischaemic cardiomyopathy and 277 (34.5%) had prior cardiac arrest. The baseline LVEF was 20 (IQR 15–30) % and baseline lactate was 4.9 (IQR 2.6–8.5) mmol/l. There was no significant association between LVEF and 30-day mortality risk [hazard ratio (HR) 0.95, 95% confidence interval (CI) 0.74–1.22 if LVEF was considered as a continuous variable; HR 1.09, 95% CI 0.83–1.44 if LVEF was considered as a categorical variable with ≤20% vs. >20%]. However, there was a significant interaction between MCS use and LVEF, indicating a lower 30-day mortality risk with MCS use in patients with a depressed LVEF (HR 0.74, 95% CI 0.52–1.05, interaction-p = 0.04). Conclusion In this retrospective, multicenter, international study of patients with non-ischaemic CS, LVEF was not a predictor of 30-day mortality risk. However, we observed a significant interaction between MCS use and LVEF, indicating a lower morality risk with MCS use only in patients with a depressed LVEF. This provides rationale to use LVEF as a parameter to guide MCS therapy in non-ischaemic CS, and calls for a randomized trial on this topic. Funding Acknowledgement Type of funding sources: None.

Background Heart failure (HF) is an established risk factor for stroke and systemic embolic events (SEE) in subjects with atrial fibrillation (AF), but it is debated whether this risk varies according to left ventricular ejection fraction (LVEF). Methods We investigated the impact of HF in the ETNA-AF-Europe registry, a prospective, multi-centre, post-authorisation, observational study enrolling patients treated with edoxaban for AF in 825 sites from 10 European countries. This 2-year follow-up analysis is based on a data snapshot from 26 October 2020. HF was defined as a) history of HF or b) ischaemic cardiomyopathy or c) EF Results Of the 13,133 patients, 1,854 (14.1%) had HF; LVEF was available for 1,489 (80.3%), and was When patients with HF were categorized according to LVEF, ischaemic stroke/TIA/SEE was more frequent in those with LVEF ≥40% vs those with LVEF Univariable Cox regression analysis confirmed the association of HF with major bleeding (HR 2.01, 95% CI [1.49–2.71]) and all-cause death (2.62 [2.28–3.02]), but not with ischaemic stroke/TIA/SEE (1.06 [0.72–1.55]). The results were consistent when LVEF was taken into account: the HRs for LVEF Conclusions In this real-world, large cohort of patients with AF on edoxaban, those with HF at baseline faced more ischaemic, bleeding, and death events, and having HF increased the risk of major bleeding and death, with no differences according to LVEF. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): This research was funded by Daiichi Sankyo Europe.

Background Cardiac magnetic resonance imaging (MRI), a key method guiding medical diagnosis and therapy, is increasingly performed at 3 Tesla (T) field strength. Growing evidence suggests a relatively safe conductance of 1.5 T MRI in patients with cardiac implantable electronic devices (CIEDs), leading to conditional certification of some CIEDs for MRI. However, data on the safety of MRI imaging at 3 T in patients with CIEDs are scarce. Purpose We analysed the safety of clinically indicated 3 T MRI in patients with “3T MRI-conditional” and “3 T MRI-non-conditional” CIEDs. Methods We performed a retrospective single-center analysis of consecutive patients with CIEDs labelled by the manufacturer as “MRI non-conditional”, “1.5 T MRI-conditional” and “3 T MRI-conditional”. Patients underwent clinically indicated 3 T MRI of different thoracic and non-thoracic body regions from April 2020 to February 2022. Devices were interrogated and programmed appropriately before and after scanning. Statistics included median and interquartile range. Measurements of device and lead function and integrity before and after scanning were assessed. Adverse events included all-cause death, arrhythmias, loss of capture, inappropriate anti-tachycardia therapies, electrical reset and lead or generator failure during or shortly after MRI scan. Results One hundred twenty-eight 3 T MRI scans were performed in 94 patients (mean age 72±16 years, 36.2% female). 3T MRI scans were performed in patients with “non-MRI-conditional” devices (n=9), “1.5 T MRI-conditional” devices (n=22), and “3 T MRI-conditional” devices (n=97). Patients were pacemaker-dependent in 24 MRI scans. After MRI, lead impedance had changed by 100 Ohms or more in seven cases (4 atrial and 3 right ventricular leads). P-wave (−25%) reduction was noted in one, R-wave (−50%) reduction in two cases. Right atrial and ventricular threshold exceeded the limit of 0,5V in one case each only in “3 T MRI-conditional” devices. No clinically relevant adverse events occurred. Conclusion 3 T MRI was safely conducted in patients with “3 T MRI-conditional” and “non-MRI conditional” CIEDs in our single-center study. Pending verification in independent series, our data suggest that clinically indicated 3T MRI scans should not be withheld from patients with cardiac pacemakers or defibrillators. Funding Acknowledgement Type of funding sources: None.

Background/Introduction Concomitant diabetes mellitus (DM) in patients with atrial fibrillation (AF) has been associated with a higher risk of stroke/systemic embolic events (SEE), and higher mortality. Purpose To evaluate effectiveness and safety outcomes in AF patients with different types of concomitant DM vs those without concomitant DM after 2 years of edoxaban treatment in a sub-analysis of the prospective ETNA-AF-Europe registry. Methods Patients with AF who received edoxaban once daily were enrolled across 825 centres in 10 European countries. This sub-analysis is based on a data snapshot from 26th October 2020. Patients were grouped by DM status (with or without DM; insulin-treated or non-insulin-treated DM). Baseline characteristics are summarised descriptively. Kaplan-Meier (KM) survival curves of outcomes were constructed; annualised event rates (AERs; %/year) and comparisons between patients with or without DM by univariate analysis are presented. Comparisons of patients with insulin- vs non-insulin-treated DM were made by multivariate analysis adjusted for HbA1c. Results Patients' demographics and baseline characteristics are shown in Table 1. Of 13,133 patients with AF, 2885 (22.0%) had DM. Among patients with DM, 2756 (95.6%) received treatment: 605 (22.0%) with insulin and 2151 (78.0%) with non-insulin treatments. KM curves for effectiveness and safety outcomes are shown in Figure 1. AERs (%/year) of ischaemic stroke/transient ischaemic attack (TIA)/SEE were 0.86% in patients with AF and no DM, 0.87% with non-insulin-treated DM (p=0.9216 vs no DM) and 1.81% with insulin-treated DM (p=0.0022 vs no DM; p=0.0014 vs non-insulin-treated DM). AERs of myocardial infarction (MI) were 0.40%, 0.43% (p=0.7454 vs no DM), and 1.04% (p=0.0033 vs no DM) respectively; of major bleeding were 0.90%, 1.10% (p=0.2427 vs no DM), and 1.71% (p=0.0106 vs no DM), respectively; and of all-cause death were 3.36%, 5.02% (p Conclusion In patients with AF and DM, risk of stroke/TIA/SEE, MI and major bleeding was confined to insulin-treated DM patients only. These patients also had poorer survival rates vs those without DM and those with non-insulin-treated DM, reinforcing previously published data showing a strong association between insulin treatment and poorer outcomes, and a mild/absent association between non-insulin treatments and poorer outcomes in patients with AF and DM. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): This research was funded by Daiichi Sankyo Europe.

Aim To evaluate the impact of timing of active left ventricular (LV) unloading in relation to veno-arterial extracorporeal membrane oxygenation (VA-ECMO) implantation on outcomes of patients with cardiogenic shock (CS). Methods and results Data from 421 patients with CS treated with active LV unloading on top of VA-ECMO at 18 tertiary-care centers in 4 countries were collected. Only patients in whom both devices were implanted within 24 hours of each other were considered and patients were stratified by timing of device implantation in early vs. delayed active LV unloading (e.g. active LV unloading before vs. after VA-ECMO). Cox and logistic regression models (adjusted for age, sex, lactate, cardiopulmonary resuscitation (CPR), VA-ECMO assisted CPR and enrollment center) were fitted to evaluate the association between early active LV unloading and 30-day mortality as well as several safety outcomes. Overall, 310 (73.6%) patients were treated with early active LV unloading. Early active LV unloading was associated with a lower 30-day mortality risk (hazard ratio 0.63, 95% confidence interval 0.46–0.87) and a higher likelihood of weaning from mechanical ventilation (odds ratio 1.25, 95% confidence interval 1.03–1.52), but not with more complications. Importantly, postponing active LV unloading in these patients was associated with higher mortality risk (Figure 1), and lower likelihood of successful weaning from mechanical ventilation. Conclusion This exploratory study lends support to the use of early active LV unloading in CS patients on VA-ECMO as a primary treatment strategy, as opposed to a bail-out approach. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): Unrestricted research grant from Abiomed

Background Heart failure (HF) occurs in approximately 26% of patients with atrial fibrillation (AF). Real-world data of oral anticoagulation with edoxaban in AF patients with HF history are limited. Purpose To compare edoxaban effectiveness and safety in AF patients with or without HF history. Methods The Global ETNA-AF programme (EU: NCT02944019, Japan: UMIN000017011, South Korea/Taiwan: NCT02951039) integrates data from multiple prospective, observational, noninterventional regional studies of AF patients receiving edoxaban for stroke prevention. This snapshot analysis summarises baseline characteristics and 2-year annualised rates of all-cause death, cardiovascular (CV) death, stroke (haemorrhagic, ischaemic, any), and bleeding (major bleeding [MB], major gastrointestinal [GI] bleeding, intracranial haemorrhage [ICH], clinically relevant nonmajor bleeding [CRNMB], and any bleeding) in patients with or without HF history. Univariate Cox regression models assessed clinical outcomes. Results Data from 27,333 patients (5258 with HF history) from Europe, Japan, South Korea, and Taiwan were analysed. Patients with HF history were significantly older and had lower mean body weight and creatinine clearance (P Conclusions In AF patients receiving edoxaban, the rates of MB, major GI bleeding, and CV or all-cause death were higher when comparing those with versus without HF history. The higher incidence of MB and major GI bleeding in patients with HF history did not lead to proportionally higher fatal bleeding rates among all-cause deaths. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): Daiichi Sankyo

Background The aim of this study was to evaluate mechanical circulatory support (MCS) for the treatment of non-ischemic cardiogenic shock (CS). Methods Data from 1,030 consecutive patients with non-ischemic CS treated with or without MCS at 16 tertiary-care centers were retrospectively collected. The association between MCS and 30-day mortality was assessed in a 1:1 propensity score matched cohort. Results MCS was used in 406 (39%) patients. MCS treated patients presented with more severe CS (lactate 5.4 vs. 4.1 mmol/l, systolic blood pressure 80 vs. 83 mmHg, higher SCAI class) and with more disease modifiers (prior cardiac arrest 42.4 vs. 36.1%, mechanical ventilation 78.4 vs. 56.5%). After matching, 272 patients treated with were compared vs. 272 patients treated without MCS. MCS was associated with a lower 30-day mortality (hazard ratio 0.77, 95% confidence interval 0.60–0.98, Figure 1). This finding was consistent through all tested sub-groups except when ejection fraction was considered, indicating an association especially in patients with an ejection fraction ≤20%. Complications occurred more frequently in patients with MCS; e.g. severe bleedings (21.8 vs. 9.2%) and access-site related ischemia (6.6 vs. 0%). Conclusion In patients with non-ischemic CS, MCS use was associated with lower 30-day mortality as compared to medical therapy only, particularly in patients with a lower ejection fraction. This provides rationale for randomized trials to validate these findings. Funding Acknowledgement Type of funding sources: None.

Background Atrial fibrillation (AF) patients with a history of ischaemic stroke (IS) have a higher risk for recurrent IS events and were largely excluded from the pivotal, randomised, controlled phase 3 trials on oral anticoagulants. Thus, the effectiveness and safety of edoxaban in these patients need to be studied in a real-world setting. Purpose To compare edoxaban real-world effectiveness and safety in AF patients with or without an IS history. Methods The Global ETNA-AF programme (EU: NCT02944019, Japan: UMIN000017011, South Korea/Taiwan: NCT02951039) integrates data from multiple prospective, observational, noninterventional regional studies of AF patients receiving edoxaban for stroke prevention. This snapshot analysis summarises baseline characteristics with medical history and 2-year annualised rates of all-cause death, cardiovascular (CV) death, stroke (haemorrhagic, ischaemic, any), and bleeding (including major bleeding [MB], major gastrointestinal [GI] bleeding, intracranial haemorrhage [ICH], clinically relevant nonmajor bleeding [CRNMB], and any bleeding) in patients with or without IS history. Results Data from 27,333 patients (3215 with prior IS and 24,118 without) from Europe, Japan, South Korea, and Taiwan were analysed. Patients with IS history were significantly older, more likely ≥75 years of age, and had a lower mean body weight and creatinine clearance (P Conclusions Patients with AF who have a history of IS are more likely elderly; have histories of MB, ICH, and TIA; and have high baseline stroke and bleeding risk scores. Patients with IS history receiving edoxaban have a considerably higher likelihood of experiencing IS or TIA, whereas the risk of experiencing any bleeding event (with the exception of ICH) is only modestly higher than in those without IS history. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): Daiichi Sankyo

Background/Introduction Many clinicians estimate the frailty of patients solely using their clinical expertise instead of validated scores. Previous reports show that women are more often perceived as frail than men. It is uncertain whether the same trend is observed in patients with atrial fibrillation (AF) and if the association between perceived frailty and adverse clinical outcomes is affected by sex. Purpose To assess whether sex affects the association between frailty status and adverse clinical outcomes in patients with AF. Methods ETNA-AF-Europe is an ongoing, post-authorisation, prospective cohort study conducted in 825 centres enrolling patients with AF treated with edoxaban in 10 European countries. In this substudy on the first 2-years of follow-up, patients were categorised in four subgroups based on sex and clinician-perceived frailty at baseline. We calculated incidence rates (per 100 patient-years) of the composite endpoint of any stroke or systemic embolic event (SEE), of major bleeding, and of all-cause death for the four subgroups; and determined the unadjusted association between perceived frailty (frail vs non-frail) and each outcome, stratified by sex, using Cox proportional hazards models. To assess for consistency in our findings, we tested the same associations by sex category but using objective risk factors: age (>74 vs Results Information about frailty-status was recorded for 12,254 (93.3%) patients, of whom 8.5% of men and 15.4% of women were perceived as frail by their clinician (p Conclusion In our cohort, differences in the risks of clinical outcomes between those who were perceived as frail and those who were not is more pronounced for men than women. Because we did not observe similar trends in the associations between age or CHA2DS2-VASc score subgroups and clinical outcomes, our results indicate that clinicians perceive the extent of frailty differently in men than in women. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): This research was funded by Daiichi Sankyo Europe.

Background/Introduction In recent years, it has been proposed that a thrombogenic atrial substrate due to various alterations in (left) atrial morphology and function could contribute to atrial thromboembolism even in the absence of (clinically overt) atrial fibrillation. This so-called atrial cardiomyopathy may pose a risk of stroke and cognitive decline beyond the presence of atrial fibrillation. Purpose To define the association of echocardiographic parameters of left atrial cardiomyopathy and left ventricular diastolic dysfunction with cognitive function in individuals free of clinically overt atrial fibrillation or stroke. Methods Data from the first 10,000 participants of a large German population-based cohort study were analysed. Of these, 8264 individuals underwent standardized transthoracic echocardiography and cognitive function testing at baseline. Parameters of left ventricular systolic and diastolic function as well as left atrial function were systematically assessed, including left atrial global peak strain. Cognitive function was quantified using the Animal Naming Test and the Trail Making Test A and B. We performed linear regression analyses with incremental adjustment to examine the association of echocardiographic parameters with the performance on the neuropsychological tests. Results After exclusion of 463 individuals with known AF and 309 individuals with prior/known stroke or severe depression, 7492 individuals were analysed (mean age 61.9±8.4 years, 52.3% women, median left ventricular ejection fraction 59% [25th/75th percentile 56/62%], median left atrial volume index 25.0 ml/m2 [25th/75th percentile 20/30 ml/m2]). In multivariable-adjusted analyses, E/e'-ratio was significantly associated with a worse performance on the Animal Naming Test (−0.24 per one standard deviation [SD] increase, 95% confidence interval [CI] −0.42 to −0.06), the Trail Making Test A (0.76 per one SD increase, 95% CI 0.35–1.17) and B (1.1 per one SD increase, 95% CI 0.09–2.11). Left atrial strain was associated with worse performance on Trail Making Test B (−1.39 per one SD increase, 95% CI −2.46 to −0.32). Increased left atrial volume index was associated with worse performance on the ANT (0.2, 95% CI 0.03–0.37). Conclusions Subtle echocardiographic signs of atrial cardiomyopathy and left ventricular diastolic dysfunction are associated with worse performance on cognitive function tests in a German middle-aged population. Funding Acknowledgement Type of funding sources: Public hospital(s). Main funding source(s): The Hamburg City Health Study (HCHS) is supported by the University Medical Center Hamburg-Eppendorf and by various grants from different institutions/organizations.

Introduction The EAST-AFNET4 study found that early, systematic rhythm control reduced cardiovascular (CV) outcomes in patients with early atrial fibrillation/atrial flutter (AF) of ≤12 months compared to guideline-recommended usual care. Purpose This post-hoc analysis aimed to assess whether antiarrhythmic drug therapy alone (i.e. dronedarone 400 mg BID) improved CV outcomes compared to placebo in patients with early AF in the ATHENA trial (NCT00174785; Ref 2) applying the EAST-AFNET4 criteria. Methods All patients in the randomised, placebo-controlled ATHENA trial with ≥2 CV conditions as defined in the EAST-AFNET 4 inclusion criteria and known AF duration at baseline were identified. Patients were split into early AF (≤12 months duration) and late AF (>12 months duration) subgroups. Outcomes were collected over a mean follow-up of 21 months and included a composite of CV death, stroke, or hospitalisation with worsening of heart failure or acute coronary syndrome; nights spent in hospital per year; and a safety composite endpoint comprising death, stroke, or pre-specified serious adverse events. All analyses were conducted in the intention-to-treat population. Results Dronedarone treatment was associated with significantly (p=0.014) fewer CV events vs placebo in patients with early AF (Fig 1). There was no interaction with AF duration (p=0.64). Patients on dronedarone spent numerically fewer nights in hospital vs placebo in early (13.4 vs 14.0) and late AF (13.9 vs 16.3), with no treatment interaction between subgroups (p=NS). Dronedarone was associated with more sinus rhythm (SR) at 12 months vs placebo (early AF: 79.9% vs 70.3%; late AF: 60.6% vs 54.0%), and similar rates of SR at 24 months (early AF: 65.8% vs 65.7%; late AF: 54.7% vs 54.1%). For the safety composite endpoint, estimated events/patients were as follows for the early AF group (dronedarone: 153/135; placebo: 182/165) and the late AF group (dronedarone: 86/81; placebo: 95/89). Conclusions The clinical benefit of early rhythm control found in the EAST-AFNET4 trial can be replicated in this analysis of patients with early AF treated in the ATHENA trial comparing dronedarone to placebo. These data support the use of dronedarone as part of early rhythm control. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): Sanofi

Background Atrial fibrillation patients with a history of major bleeding (MB) are at high risk of future bleeding events; this history was an exclusion criterion in pivotal phase 3 trials of anticoagulation for stroke prevention. Real-world edoxaban effectiveness and safety in patients with a history of MB were analysed from the global ETNA programme. Purpose To compare edoxaban effectiveness and safety in AF patients with or without an MB history. Methods The Global ETNA-AF programme (EU: NCT02944019, Japan: UMIN000017011, South Korea/Taiwan: NCT02951039) integrates data from multiple prospective, observational, noninterventional regional studies of AF patients treated with edoxaban for stroke prevention. This snapshot analysis summarises global baseline characteristics and 2-year annualised rates of all-cause death, cardiovascular death, stroke (haemorrhagic, ischaemic, any), and bleeding (including MB, major gastrointestinal bleeding [MGIB], intracranial haemorrhage [ICH], clinically relevant nonmajor bleeding, and any bleeding) in patients with or without MB history. Results Data from 27,333 patients (479 with MB history and 26,854 without) from Europe, Japan, South Korea, and Taiwan were analysed. Patients with MB history were significantly older (P Conclusions Patients with AF receiving edoxaban and who have a history of MB are more likely elderly, male, and have comorbidities, including HF. These patients are also more susceptible to any adverse cardiovascular event. ICH event rates were not higher in patients with prior ICH than those with non-ICH major bleedings, whereas history of MGIB was associated with a high risk of MGIB recurrence. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): Daiichi Sankyo

Aims Atrial fibrillation (AF) is the most common cardiac arrhythmia. Pathogenic variants in genes encoding ion channels are associated with familial AF. The point mutation M1875T in the SCN5A gene, which encodes the α-subunit of the cardiac sodium channel Nav1.5, has been associated with increased atrial excitability and familial AF in patients. Methods and results We designed a new murine model carrying the Scn5a-M1875T mutation enabling us to study the effects of the Nav1.5 mutation in detail in vivo and in vitro using patch clamp and microelectrode recording of atrial cardiomyocytes, optical mapping, electrocardiogram, echocardiography, gravimetry, histology, and biochemistry. Atrial cardiomyocytes from newly generated adult Scn5a-M1875T+/− mice showed a selective increase in the early (peak) cardiac sodium current, larger action potential amplitude, and a faster peak upstroke velocity. Conduction slowing caused by the sodium channel blocker flecainide was less pronounced in Scn5a-M1875T+/− compared to wildtype atria. Overt hypertrophy or heart failure in Scn5a-M1875T+/− mice could be excluded. Conclusion The Scn5a-M1875T point mutation causes gain-of-function of the cardiac sodium channel. Our results suggest increased atrial peak sodium current as a potential trigger for increased atrial excitability.

Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): DZHK Ernst und Berta Grimmke Stiftung Background Myocarditis is an inflammatory disease of the myocardium indicated by mononuclear cell infiltration. It is predominantly caused by infectious agents such as coxsackievirus B3 (CVB3). Especially in young adults, myocarditis is a major source of sudden cardiac arrest. However, its clinical course has a broad spectrum of outcomes, ranging from mild symptoms and complete recovery to cardiac dysfunction and dilated cardiomyopathy. G protein-coupled receptor 15 (GPR15) was identified as a T cell homing receptor in the context of inflammatory intestine and skin diseases. We found Gpr15 to be highly upregulated in the left ventricle (LV) 7 days after CVB3 infection in wild type (WT) mice. Purpose GPR15 has not been described in a cardiac context, yet. Our aim was to investigate the role of GPR15 in recruiting immune cell subsets and later in virus elimination during viral myocarditis. Methods Gpr15 deficient (Gpr15gfp/gfp) and WT mice were infected intraperitoneal with CVB3 to investigate the acute (6 & 7 days post infection(p.i.)) and the subacute phase (16 days p.i.) of myocarditis. To study differentially expressed genes, LV tissue was used for TaqMan analysis and RNA-sequencing. Inflammation and fibrosis were evaluated on histological level. For functional characterization, healthy and diseased mice were hemodynamically characterized 16 days p.i.. Furthermore, in vitro migration assays were used to study the interaction between GPR15 and its ligands in vitro. Results Infected Gpr15gfp/gfp mice exhibited higher upregulation of immune response related genes on mRNA level in the acute phase of myocarditis 7 days p.i.. For instance, Cd8a, a cytotoxic T cell marker, and Foxp3, a regulatory T cell marker, were significantly higher in infected Gpr15gfp/gfp compared to infected WT mice. Bulk RNA-sequencing confirmed that the response to virus did not decline from day 6 to 7 in infected GPR15-deficient mice as observed in infected WT mice. Subsequent gene ontology (GO) term analyses reveled enhanced chemotaxis and cytotoxic T cell-related GO terms in GPR15-deficient mice on day 7. Among investigated T cell subsets, GPR15 was highest expressed on CD8+ T cell. Its deficiency abolished chemotaxis of T cells, especially of cytotoxic T cells, towards GPR15 ligand in vitro. In the subacute phase of myocarditis 16 days p.i., viral persistence was observed in more than 85 % of Gpr15gfp/gfp mice. In contrast, more than 70 % of WT mice with verified viremia cleared the virus successfully. Furthermore, Gpr15gfp/gfp mice demonstrated a decreased cardiac function accompanied by increased fibrosis in comparison to WT mice. Conclusion Our findings indicate that despite the prolonged inflammatory response, scant virus elimination was presumably caused by decelerated recruitment of cytotoxic T cells leading to impaired outcome in the GPR15-deficient mice.

Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): German Centre for Cardiovascular Research (DZHK) Background Cardiovascular diseases such as myocardial infarction (MI) are a leading cause of death worldwide. Since matrix metalloproteinases (MMPs) are essential for the cleavage of collagen as well as for the modification of inflammatory proteins and cytokines, they play a substantial role in remodelling processes after MI. Purpose Previous results of our group revealed, that Mmp13 expression is upregulated post-MI in mice, while it is downregulated after Ischemia/Reperfusion (I/R), indicating an involvement in remodelling processes. In humans, the functional homologue of Mmp13 is MMP1. Single nucleotide polymorphisms (SNPs) in the promotor of MMP1 can lead to alterations in its gene expression level. We analysed the genotype for 3 MMP1 SNPs in a human cohort containing ~2000 patients who presented to the emergency department with suspected MI to identify their associations with development of MI and outcome after MI. Methods The Mmp13 expression in different cardiac cell types was investigated at quiescent stage and under ischaemic conditions, to determine the cellular origin of Mmp13 expression. A MMP13-knockout (KO) mouse model was examined after induction of MI or I/R. Thus, gene expression analysis, histological staining and hemodynamic measurements were conducted to analyse differences between KO and WT as well as between MI and I/R. Out of the human cohort, 2 patient groups (non-MI and MI) were restricted, and Hazard ratios were calculated to evaluate risk for MI and risk for death after MI in dependency of the SNPs. Results The Mmp13 expression in macrophages (6.6-fold to control; p=0.0286) and fibroblasts (4.9-fold; p=0.0079) increased significantly after activation with ischaemic secretome of cardiomyocytes, while Mmp13 expression of leucocytes was unaltered. After stimulation with ischaemic secretome of fibroblasts, Mmp13 expression in macrophages (4.3-fold; p=0.0286) and leukocytes (2.3-fold; p=0.0260) was significantly elevated as well. Comparing MI and I/R, the immune cell infiltration revealed significant differences 1-day post-intervention. About 50% of WT mice but only few KO mice died (p=0.0107) after MI due to cardiac rupture. Moreover, KO mice showed an improved cardiac function compared to WT mice after MI. Risk for death was significantly altered between the investigated genotypes in 2 of 3 investigated SNPs in the BACC cohort. Conclusion Activated macrophages and leucocytes express high levels of Mmp13 in cell culture experiments. The infiltrating immune cell types are different between MI and I/R, which might lead to differences in Mmp13 expression in these models. MMP13 KO mice are protected from cardiac rupture after MI and unveiled improved cardiac function 28 days post-MI. SNPs of the human homologue of Mmp13 – MMP1 – showed an association of MMP1 with remodelling processes after MI.

Funding Acknowledgements Type of funding sources: None. Background Catheter ablation targeting isolation of the pulmonary veins (PVI) is the most effective treatment for atrial fibrillation (AF). Despite its high overall effectiveness, repeat AF ablations (re-do procedures, RDP) are often required to maintain sinus rhythm. Purpose Determine predictors for multiple and/or complex RDP, evaluate reference values for procedure duration and radiation exposure during index PVI (iPVI) and nth RDP in a large cohort. Methods and Results Data mining identified 934 (mean age 62.6 ± 12.3 years, 346 females) out of 6848 total AF ablation patients from a large German AF ablation center between 09/2008 and 09/2021 with an index PVI and at least one RDP. Analysis included 2152 procedures (out of 8750 total AF-related ablations). At iPVI, AF pattern was classified as paroxysmal AF (PAF) in 387 patients (41%). All others (59%) were classified as non-paroxysmal AF (Non-PAF). Non-PAF was significantly more frequent in males (64% vs. 49%, p iPVI was classified as PVI-only or PVI with additional substrate modification (SM). 724/934 patients (78%) received PVI-only as initial procedure. Of these, 572 (79%) had only 1 RDP, 116 (16%) had 2 RDP and 36 (5%) had 3 or more RDP. This distribution was 77%, 15% and 8% for 1, 2 and 3 or more RDP for patients with complex PVI as iPVI. An algorithm based on regular expressions classified all RDP as repeat PVI (Re-PVI) due to reconduction (PV reconduction), ablation of atrial tachycardia (AT) or SM, e. g. defragmentation of fractionated signals, or combinations. The results were manually quality-controlled. 798/934 (85%) patients required PV re-isolation due to PV reconduction, 298/934 (32%) required ablation for atrial tachycardia (AT) at least once during FU (Figure 1B). Comparing PVI-only iPVI patients with patients who received substrate modification during iPVI, significantly less patients with PVI-only iPVI had RDP for AT compared to those with SM during iPVI (27% vs. 50%, p Conclusion Redo AF ablations procedures are mainly required due to reconnected pulmonary veins or AT. Patients with PAF at iPVI are less likely to require more than one RDP which provides indirect support for early rhythm control in treatment of AF. SM at iPVI might be a predictor for occurrence of AT in the further course.

Funding Acknowledgements Type of funding sources: Public grant(s) – EU funding. Main funding source(s): European Union Horizon 2020 CATCH ME; Cardiovascular Research Netherlands RACE V Background Little is known about changes in the atrial transcriptome associated with paroxysmal and persistent atrial fibrillation (AF). Purpose To identify major molecular mechanisms in AF, we determined consistent differential expression (DE) between atrial tissue samples from well-characterized patients with paroxysmal or persistent AF and patients without a history of AF (no AF) in two independent patient cohorts. Methods Poly-A tailed RNA from left and right atrial appendage tissue samples from independent discovery and replication cohorts CATCH ME (n=192) and RACE V (n=122) was sequenced and analyzed according to patient AF history. Analyses were performed stratified by atrial side, adjusting for age, sex, heart failure and a combination of clinical characteristics determined by principal component analysis. Transcripts were considered DE in CATCH ME if their fold change reached transcriptome-wide significance (false discovery rate (FDR) < 0.05). DE transcripts in each rhythm comparison were replicated in RACE V if we observed a concordant direction of effect and a within-set FDR < 0.05 in the same comparison. Results Persistent AF compared to no AF was associated with 184 left atrial DE transcripts in CATCH ME of which 85 (46%) were replicated in RACE V, and with 208 right atrial DE transcripts in CATCH ME of which 86 (41%) were replicated in RACE V. Overall, 26 transcripts were discovered and replicated in both atria. Discovered but non-replicated transcripts often did exhibit concordant direction of effect (left: 78%, right: 83%). Replicated transcripts consisted of protein coding genes, antisense and non-coding RNAs. Protein coding genes showed involvement in pathways linking persistent AF to cardiomyocyte structure, conduction properties, fibrosis, inflammation, molecule trafficking, and endothelial dysfunction. Interestingly, paroxysmal AF was not consistently associated with DE transcripts in any comparison. Principal component analysis of the expression of the 26 transcripts strongly associated with persistent AF did however reveal a distinct paroxysmal AF expression profile in-between no AF and persistent AF patients in the first principal component scores (Figure 1). Conclusion RNA sequencing of human atrial tissue samples identified many transcripts associated with persistent AF in left and/or right atria, discovered and replicated using two independent cohorts. These consistent findings of AF-induced changes provide a starting point for targeted proteomic analysis and single-nucleus sequencing to further unravel the molecular mechanisms underlying AF progression to persistent AF, and biomarker development to quantify AF progression and enable precision medicine in individual patients.

Funding Acknowledgements Type of funding sources: None. Background Conventional mapping systems do not provide wall-thickness data, which is, however, known to be a determinant of radiofrequency ablation lesion transmurality. KODEX-EPD is a novel open-platform system, which uses dielectric tissue properties to provide real-time, high-resolution cardiac images, tissue characteristics and wall-thickness measurement to guide ablation procedures. Aim The aim of this case series was to report on our first experiences with KODEX-EPD regarding estimation of myocardial wall-thickness during catheter ablation of atrial fibrillation (AF). Methods We retrospectively analyzed consecutive patients undergoing radiofrequency AF-ablation in combination with KODEX-EPD. A high-resolution image from the left atrium (LA) and the pulmonary veins (PV) was obtained prior to ablation using a spiral mapping catheter in conjunction with KODEX-EPD. Wall-viewer points were collected within the LA, the PVs and the left atrial appendage (LAA) using a standard radiofrequency non-contact force ablation catheter and analyzed for wall-thickness applying the latest KODEX-EPD software version (1.5.0, not yet commercially released). Wall-viewer points were divided into a total of 10 segments (PV ostia, anterior wall, posterior wall, LA roof, LA floor, LAA and PV carina, details see Figure 1) in order to characterize wall-thickness in respective areas. Results A total of 570 wall-viewer points in 5 patients were analyzed. Most of the wall-viewer points were collected at the PV ostia as well as along the posterior and anterior wall (449/570, 79%). Actual myocardial atrial thickness ranged from 1.6 to 3.9 mm. Thickest myocardial LA-tissue was measured at the anterior wall (median 3.1 mm) and thinnest at the LA-roof (median 2.2 mm). Figure 2 gives a detailed distribution of wall-thickness measurements at different sites in the LA and PVs. Conclusion Atrial wall thickness can be estimated in patients during AF ablation procedures using dielectric tissue properties. Further evaluation and validation of the method are needed to study its reliability and utility for clinical practice.

Funding Acknowledgements Type of funding sources: Private company. Main funding source(s): FARAPULSE, Inc. Introduction Thermal energy sources damage the entire atrial tissue during pulmonary vein isolation (PVI) including cardiac nerves and ganglia. This induces a postinterventional increase in heart rate. Pulsed-field ablation (PFA), a new non-thermal energy source for PVI, primarily damages cardiomyocytes by electroporation. Whether use of PFA reduces damage to cardiac nerves and ganglia and influences postinterventional increase of heart rate is not known. Purpose We compared the acute effects of PFA with a pentaspline catheter and cryoballoon ablation (CBA) on secretion of circulating biomolecules reflecting cardiomyocyte and neuronal injury and postinterventional increase in heart rate to estimate damage to the cardiac autonomic nervous system and autonomic dysfunction after PVI. Methods Blood samples were taken before and after PVI in consecutive patients undergoing PFA and CBA. All patients participated in the TRUST registry. Serum concentrations of high-sensitive Troponin I (hsTropI, Immunoassay) and S100b (ELISA), a surrogate marker for neuronal injury, were quantified in blood samples taken prior to PVI and directly after PVI. Pre- and postinterventional heart rates were measured in ECGs and Holter-ECGs. Results Fifty-six patients underwent PVI, either by PFA (n=28, age 63 [54; 75] y, 64% males, 57% persistent AF) or CBA (n=28, age 71 [62; 78] y, 61% males, 54% persistent AF). All 112 blood samples were analyzable. Acute success of PVI was 100% in both groups without major complications, especially, no TIA and no stroke. After CBA, one patient suffered from phrenic palsy, which reversed after 3 months. HsTropI increased 3.3-fold more after PFA compared to CBA (625±138 vs. 185±42 pg/ml; p=0.004) suggesting more damage to cardiomyocytyes. S100b increased 2.9-fold less after PFA compared to CBA (21.1±3.7 vs. 61.2±8.1 pg/ml; p Conclusion This study in patients validates the experimental concept that PFA-based AF ablation leads to more specific damage to cardiomyocytes than to cardiac nerves and ganglia, reflected by lower S100B concentrations and no post-interventional heart rate increase compared to CBA.

Funding Acknowledgements Type of funding sources: Private company. Main funding source(s): Study grant by EPD Solutions, Philips, Netherlands Background The occlusion tool was recently introduced for KODEX-EPD which is a novel dielectric high-resolution cardiac imaging system. The occlusion tool provides information about level of pulmonary vein occlusion by the cryoballoon (CB) in CB-based pulmonary vein isolation (PVI) ablation procedures for atrial fibrillation (AF). Purpose Assess effects of the introduction of the occlusion tool on procedural parameters during CB-PVI such as feasibility, acute efficacy and periprocedural safety of KODEX-EPD in different software versions. Methods and Results 173 consecutive patients (60/173 (35%) paroxysmal AF, 64±12 years, 66/173 (38%) female) underwent CB-PVI with EPD imaging between 08/2019 and 10/2021. 38/173 (22%) of all patients were treated using software version 1.4.6, 33/173 (19%) patients with version 1.4.6a, 41/173 (24%) patients with version 1.4.7 and 61/173 (35%) patients with the latest version 1.4.8. Acute PVI was achieved in all patients. No major periprocedural complications were documented. Software version showed significant effects on procedure duration, fluoroscopy duration and dose area product in ANOVA testing (Figure 1A-C). The largest effect in post-hoc testing was observed for fluoroscopy duration (Figure 1B). Tobit regressions were fitted to model effects of software version on the censored variable contrast volume. All software versions predicted used contrast volume (p Conclusion CB-based PVI in combination with its PV-occlusion tool is feasible and safe. The present data strongly suggests a steady positive development of the novel wide-band dielectric imaging and mapping system towards a fluoroscopy- and dye-reduced CB-based AF-ablation. Software versions were introduced sequentially. Therefore time (procedure date) needs to be considered as the most relevant confounder of the described results (e.g. due to a learning curve using the system). However, differentiated statistical testing could show that the results are mainly explained by software version and only much weaker by procedure date.

Funding Acknowledgements Type of funding sources: None. Introduction Pulsed-field ablation (PFA) is a novel energy source to perform pulmonary vein isolation (PVI) in patients with atrial fibrillation or cavo-tricuspid isthmus ablation (CTI) in patients with atrial flutter. Whether strong electrical fields generated by PFA could change the function and integrity of cardiac implantable electronic devices (CIED) is not known. Aim To assess the function and integrity of implanted devices before and after pulsed-field ablation. Methods This study included consecutive patients with CIED undergoing PFA at a large single center. Real-time CIED electrograms were recorded during PFA applications. CIED were interrogated before and after PFA assessing function (threshold, sensing), integrity (impedance), and arrhythmia episodes. Results We performed PFA in six patients (age 69±12 years, 1/6 female, left atrial diameter was 44±3 mm, left-ventricular ejection fraction 40±14%) for PVI in five patients with atrial fibrillation and CTI ablation in one patient with atrial flutter. All patients had CIEDs (one cardiac resynchronization device, two implantable cardioverter-defibrillators, three two-chamber pacemakers). Each patient undergoing PVI received 32 PFA applications of 2.5 s. (4x basket configuration and 4x flower configuration at each pulmonary vein), amounting to a total ablation time of 80 s and resulting in complete PVI in all five patients. For CTI ablation we applied 8 PFA applications of 2.5 s (20 s total ablation time) resulting in CTI blockade. Real-time intracardiac electrograms (iEGM) during PFA applications revealed sensing of single PFA application impulses in three patients and blanking of the iEGM in three patients. Postinterventional device testing revealed no changes in impedance, stimulation threshold or sensing. No leads were dislocated or damaged. No other device malfunctions occurred during the procedure, as well as no other major periprocedural complications occurred. Conclusion The function and integrity of pacemakers and defibrillators is not affected by PFA in our patient sample. Larger series are needed to confirm the apparent safety of PFA in patients with CIED.

Funding Acknowledgements Type of funding sources: Public grant(s) – EU funding. Main funding source(s): Horizon 2020 Background Risk factors for atrial fibrillation (AF), such as ageing, heart failure and AF itself, enhance AF propensity partly by inducing atrial fibrosis. Atrial endomysial fibrosis, a type of reactive fibrosis occurring between cardiomyocytes, impairs transverse conduction in rapid atrial pacing animal models. The factors underlying transcriptional regulation of endomysial fibrosis are largely unknown. Objective To examine the contributions of age, sex, AF and heart failure to the development of endomysial fibrosis in the context of concurrent pathologies. To study genome-wide transcriptional changes associated with endomysial fibrosis in human left and right atrial appendage biopsies (LAA, n=95; RAA, n=76). Methods An algorithm for automated quantification of endomysial fibrosis following staining with wheat germ agglutinin (WGA) was employed. Linear mixed models were constructed to determine endomysial fibrosis quantity as a function of AF, heart failure, sex, age and four principal components that accounted for potential confounding effects of other clinical characteristics. RNA sequencing was used to study expression changes in the atrial transcriptome associated with endomysial fibrosis. Results Sex, persistent AF, heart failure and age were independently associated with endomysial fibrosis. We identified hundreds (LAA: 386, RAA: 311) of RNA transcripts associated with endomysial fibrosis. None of these associations were independent from the clinical phenotypes. However, explorative gene set enrichment analysis identified association of endomysial fibrosis with gene sets involved in extracellular matrix organization, immune response, cell motility, developmental processes, cardiac muscle contraction and proteostasis in LAA while in RAA only gene sets regulating contractile function were enriched. Conclusion Besides AF, female sex, age and heart failure are associated with endomysial fibrosis in the atria. While abundance of none of the differential genes were independently associated with endomysial fibrosis, gene set enrichment analysis suggests an involvement of extracellular matrix organization, immune response, cell motility, developmental processes and cardiac muscle contraction in endomysial fibrosis.

Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): BMBF Introduction Human induced pluripotent stem cell-derived cardiomyocytes (HiPSC-CM) are an emerging, powerful tool to study human cardiac physiology, pharmacology and toxicology, to model cardiovascular diseases or even to use for cardiac repair. Understanding the similarities and differences between hiPSC-CM and adult human cardiomyocytes is critical for their use. Here we focus on sodium calcium exchanger (NCX) who plays a crucial role in the Ca2+-homeostasis in the mammalian heart. Importantly, alterations in NCX expression in human heart are associated with various cardiac pathologies such as heart failure or arrhythmias. In order to investigate whether hiPSC-CM could serve as model for adult human heart NCX we measured the properties of NCX in hiPSC-CM and human ventricular tissue. Rat ventricular tissue was used for comparison. Methods HiPSC-CM were differentiated from a healthy iPSC line and dissociated from engineered heart tissue (EHT). Adult human and rat cardiomyocytes were digested from ventricular samples. We measured NCX current by the whole-cell patch clamp technique at 37 °C. Standard sharp microelectrodes were used to record action potentials (AP). Contractile force in human and rat ventricular samples was measured isometrically. A video-optical contractility test system was used to measure force in EHT. SEA0400 (10 µM) was used to block NCX. Results NCX currents could be measured in every hiPSC-CM. The NCX current densities in hiPSC-CM were larger than in human ventricular cardiomyocytes (3.2±0.2 pA/pF n=28 vs. 1.3±0.2 pA/pF n=15, p Conclusion HiPSC-CM possess NCX in the physiological range. HiPSC-CM show NCX-effects on APD and force as predicted from rat ventricle and in full accordance with cardiac physiology. Lack of NCX effect in human adult ventricles that had been already reported previously needs further investigations.

Funding Acknowledgements Type of funding sources: None. Introduction Pulsed-field ablation (PFA) and the multi-electrode radiofrequency balloon (RFB) are two novel ablation technologies to perform pulmonary vein isolation (PVI). It is currently unknown whether these technologies differ in lesion formation and lesion extent. Purpose We compared the acute lesion extent after PVI induced by PFA and RFB by measuring low-voltage area in high-density maps and the release of biomolecules reflecting cardiac injury. Methods PVI was performed with a pentaspline catheter (FARAPULSE) applying PFA or with the compliant multi-electrode radiofrequency balloon (HELIOSTAR). Before and after PVI high-density mapping with CARTO3 was performed. In addition, blood samples were taken before transseptal puncture and after post-PVI remapping. Serum concentrations of high-sensitive Troponin I (hsTropI) were quantified by Immunoassay. Results 50 patients undergoing PVI by PFA (n=26, age 71±10 y, 58% males, 58% persistent AF) or RFB (n=24; age 64±13 y, 54% males, 25% persistent AF) were evaluated. Acute PVI was achieved in all patients in both groups. Mean number of PFA pulses were n=34±5 and mean number RFB applications were n=8±3. Total posterior ablation area was bigger in PFA (19.0±6.2 cm²) than in RFB (9.0±2.2 cm²; p Conclusion Pulse-field ablation delivers larger acute lesion areas and higher troponin release upon successful pulmonary vein isolation than multi-electrode array balloon-based pulmonary vein isolation in this single-center series.

(1)AimsAtrial fibrillation (AF) is the most common cardiac arrhythmia. Pathogenic variants in genes encoding ion channels are associated with familial AF. The point mutation M1875T in the SCN5A gene, which encodes the α-subunit of the cardiac sodium channel Nav1.5, has been associated with increased atrial excitability and familial AF.(2)MethodsWe designed a new murine model carrying the Scn5a-M1875T mutation enabling us to study the effects of the Nav1.5 mutation in detail in vivo and in vitro using patch clamp and microelectrode recording of atrial cardiomyocytes, optical mapping, ECG, echocardiography, gravimetry, histology and biochemistry.(3)ResultsAtrial cardiomyocytes from newly generated adult Scn5a-M1875T+/- mice showed a selective increase in the early (peak) cardiac sodium current, larger action potential amplitude and a faster peak upstroke velocity. Conduction slowing caused by the sodium channel blocker flecainide was less pronounced in Scn5a-M1875T+/- compared to wildtype atria. Overt hypertrophy or heart failure in Scn5a-M1875T+/- mice could be excluded.(4)ConclusionThe Scn5a-M1875T point mutation causes gain-of-function of the cardiac sodium channel. Our results suggest increased atrial peak sodium current as a potential trigger for increased atrial excitability and thus AF.What’s newThe point mutation M1875T in the C-terminal domain of the cardiac sodium channel Nav1.5 causes an increase in early peak sodium current in left atria.The observed changes induced by this point mutation suggest an increase in peak sodium current as a cause of familial atrial fibrillation (AF).Our findings provide a possible explanation for the variable effectiveness of sodium channel blockers in patients with AF. Carriers of such sodium channel gain-of-function mutations may benefit more from tailored treatments.Graphical abstract

Introduction There is a substantial residual risk in patients with chronic coronary syndrome (CCS). Risk scores could be useful tools to allocate intensified secondary preventive medications to address this residual risk. Whether their predictive value can be improved by addition of angiographic scores of the extent of coronary artery disease (CAD) is unknown. Purpose To test and compare the predictive value of three externally developed risk scores for CAD and to investigate the effect of addition of SYNTAX and Gensini scores. Methods We tested the TIMI risk score for secondary prevention (TRS 2°P), a risk score derived from the INVEST study, and the ABC-CHD model (see references 1–3) in 1280 patients with CCS from a contemporary observational CAD cohort ongoing since 2015 with a median follow-up of 3.6 years. In a second step we added SYNTAX and Gensini scores to the models. The endpoints tested were cardiovascular death and major adverse cardiovascular events (MACE), consisting of cardiovascular death, myocardial infarction and ischemic stroke. Results All investigated scores yielded continuously increasing event rates for MACE and cardiovascular death with increasing score points obtained. As an example Figure 1 displays 3-year rates for cardiovascular death and MACE against the points obtained in the TRS 2°P, whilst also displaying the distribution of patients amongst the risk categories. The three scores showed modest predictive value for occurrence of cardiovascular death (c-indices 0.60, 0.64, 0.70 for TRS 2°P, INVEST score, ABC-CHD score, respectively). Addition of both SYNTAX and Gensini scores to the models yielded c-indices of 0.66, 0.69 and 0.70 respectively (Figure 2a). Similar predictive values were observed for the occurrence of MACE (c-indices 0.59, 0.60, 0.64 for TRS 2°P, INVEST score, ABC-CHD score, respectively) as well after addition of both SYNTAX and Gensini scores (c-indices 0.62, 0.63, 0.64, see Figure 2b). Conclusion (I) Currently available risk scores are modestly predictive for the occurence of cardiovascular events in patients with CCS. (II) Addition of Gensini and SYNTAX scores improves their predictive value particularly in weaker risk scores. Funding Acknowledgement Type of funding sources: None. Figure 1Figure 2a (left) and 2b (right)

Background Individual risk assessment in patients with pulmonary arterial hypertension (PAH) is fundamental to improve their outcome. Although right ventricular (RV) dysfunction is a major determinant of outcome in PAH, echocardiographic measures of RV function are poorly represented by current risk models. Objective The objective of this study was to identify echocardiographic measures of RV function, which are associated with adverse outcome and to develop a non-invasive, echocardiography-based risk score for PAH patients. Methods In 254 patients with PAH we analyzed functional status, laboratory results, pulmonary function and echocardiographic measures. Echocardiographic measures comprised RV chamber diameters, right atrial area, fractional area change (FAC), tricuspid annular plane systolic excursion (TAPSE), 2D RV strain and pericardial effusion. We used Cox regression models to assess the association with the composite endpoint of 5-year all-cause death or lung transplantation. The analyses included a conventional model using only guideline-recommended variables and a model adding significant echocardiographic measures. Based on the final multivariable model a point risk score was derived, indicating the association with the primary outcome. Results Median age was 65.5 years, 33.9% were females. During a median follow-up time of 4.18 years 74 patients died (n=63) or underwent lung transplantation (n=11). In univariable analyses low systolic blood pressure (Hazard ratio [HR] 0.99, 95% Confidence Interval [CI] 0.98,1.00), NYHA functional class IV (HR 3.23, 95% CI 1.48,7.07), 6-minute walk distance (HR 1.00, 95% CI 1.00,1.00), NT-proBNP concentrations (HR 1.00, 95% CI 1.00,1.00), renal impairment (HR 0.99, 95% CI 0.98,1.00), reduced diffusion capacity for carbon monoxide (HR 0.99, 95% CI 0.98,1.00), reduced TAPSE (HR 0.90, 95% CI 0.85,0.96) and reduced FAC (HR 0.97, 95% CI 0.94,1.00) were associated with the endpoint. A multivariable, conventional risk model, including NYHA functional class, 6-minute walk distance, NT-proBNP concentrations, pericardial effusion and right atrial area, resulted in a C-Index of 0.539. Adding TAPSE and FAC to this model improved the performance significantly (C-index 0.639, p-value 0.017). This model was translated to a 12-point score with the highest weighting assigned to TAPSE, FAC, pericardial effusion and 6-minute walk distance (Figure). Conclusion An easily applicable score integrating non-invasive, echocardiographic parameters of RV function improves prediction of adverse outcome in PAH patients. Funding Acknowledgement Type of funding sources: None. Risk prediction chart

Background The ESC atrial fibrillation management guidelines recommend a risk-based approach to oral anticoagulant (OAC) therapy. How clinical practice aligns with these recommendations is of interest. Purpose To analyse real world data from Global ETNA-AF program in patient groups stratified by stroke and bleeding risk scores according to ESC guidelines. Methods Global ETNA-AF is a multicentre, prospective, noninterventional program evaluating the safety and effectiveness of edoxaban in patients from European and Asian countries. Baseline characteristics and clinical event data at 2-year follow-up were analysed in 4 subgroups defined by CHA2DS2-VASc score (≥3 for female / ≥2 for male [OAC recommended] vs 2 for female / 1 for male [OAC should be considered]) and HAS-BLED score (≥3 [Bleeding risk high] vs Results Of 27,616 patients included in this analysis, 23,152 (83.8%) were in the “OAC recommended” category and 3,539 (12.8%) were in the “OAC should be considered” category. Only 3.3% of patients did not meet ESC guideline criteria for OAC initiation. Among patients with high bleeding risk, 98% were in the “OAC recommended” category. A similar distribution was observed across regions (Table 2). The recommended edoxaban dose was used in the vast majority (>80%) of patients across all risk stratification subgroups. In the “OAC recommended” category, patients with high bleeding risk had higher rates of thromboembolic, bleeding, and death events than those with low bleeding risk. Conclusion Data from routine clinical practice in Global ETNA-AF demonstrate high concordance of edoxaban treatment with ESC guidelines. Edoxaban dose is consistent with label recommendation in the vast majority (>80%) of patients. Clinical event rates were generally low across all risk groups, including acceptable bleeding rates in anticoagulated patients with high bleeding risk. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): Daiichi Sankyo Table 1. Subgroups as per ESC guidelinesTable 2. Patient characteristics & events