Showing papers by "Paulus Kirchhof published in 2019"

Searching for Atrial Fibrillation Poststroke: A White Paper of the AF-SCREEN International Collaboration

Abstract: 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.

Data-driven discovery and validation of circulating blood-based biomarkers associated with prevalent atrial fibrillation.

Abstract: AIMS Undetected atrial fibrillation (AF) is a major health concern. Blood biomarkers associated with AF could simplify patient selection for screening and further inform ongoing research towards stratified prevention and treatment of AF. METHODS AND RESULTS Forty common cardiovascular biomarkers were quantified in 638 consecutive patients referred to hospital [mean ± standard deviation age 70 ± 12 years, 398 (62%) male, 294 (46%) with AF] with known AF or ≥2 CHA2DS2-VASc risk factors. Paroxysmal or silent AF was ruled out by 7-day ECG monitoring. Logistic regression with forward selection and machine learning algorithms were used to determine clinical risk factors, imaging parameters, and biomarkers associated with AF. Atrial fibrillation was significantly associated with age [bootstrapped odds ratio (OR) per year = 1.060, 95% confidence interval (1.04-1.10); P = 0.001], male sex [OR = 2.022 (1.28-3.56); P = 0.008], body mass index [BMI, OR per unit = 1.060 (1.02-1.12); P = 0.003], elevated brain natriuretic peptide [BNP, OR per fold change = 1.293 (1.11-1.63); P = 0.002], elevated fibroblast growth factor-23 [FGF-23, OR = 1.667 (1.36-2.34); P = 0.001], and reduced TNF-related apoptosis-induced ligand-receptor 2 [TRAIL-R2, OR = 0.242 (0.14-0.32); P = 0.001], but not other biomarkers. Biomarkers improved the prediction of AF compared with clinical risk factors alone (net reclassification improvement = 0.178; P < 0.001). Both logistic regression and machine learning predicted AF well during validation [area under the receiver-operator curve = 0.684 (0.62-0.75) and 0.697 (0.63-0.76), respectively]. CONCLUSION Three simple clinical risk factors (age, sex, and BMI) and two biomarkers (elevated BNP and elevated FGF-23) identify patients with AF. Further research is warranted to elucidate FGF-23 dependent mechanisms of AF.

ElectroMap: High-throughput open-source software for analysis and mapping of cardiac electrophysiology

Abstract: The ability to record and analyse electrical behaviour across the heart using optical and electrode mapping has revolutionised cardiac research. However, wider uptake of these technologies is constrained by the lack of multi-functional and robustly characterised analysis and mapping software. We present ElectroMap, an adaptable, high-throughput, open-source software for processing, analysis and mapping of complex electrophysiology datasets from diverse experimental models and acquisition modalities. Key innovation is development of standalone module for quantification of conduction velocity, employing multiple methodologies, currently not widely available to researchers. ElectroMap has also been designed to support multiple methodologies for accurate calculation of activation, repolarisation, arrhythmia detection, calcium handling and beat-to-beat heterogeneity. ElectroMap implements automated signal segmentation, ensemble averaging and integrates optogenetic approaches. Here we employ ElectroMap for analysis, mapping and detection of pro-arrhythmic phenomena in silico, in cellulo, animal model and in vivo patient datasets. We anticipate that ElectroMap will accelerate innovative cardiac research and enhance the uptake, application and interpretation of mapping technologies leading to novel approaches for arrhythmia prevention.

Cabins, castles, and constant hearts: rhythm control therapy in patients with atrial fibrillation.

Abstract: Recent innovations have the potential to improve rhythm control therapy in patients with atrial fibrillation (AF). Controlled trials provide new evidence on the effectiveness and safety of rhythm control therapy, particularly in patients with AF and heart failure. This review summarizes evidence supporting the use of rhythm control therapy in patients with AF for different outcomes, discusses implications for indications, and highlights remaining clinical gaps in evidence. Rhythm control therapy improves symptoms and quality of life in patients with symptomatic AF and can be safely delivered in elderly patients with comorbidities (mean age 70 years, 3-7% complications at 1 year). Atrial fibrillation ablation maintains sinus rhythm more effectively than antiarrhythmic drug therapy, but recurrent AF remains common, highlighting the need for better patient selection (precision medicine). Antiarrhythmic drugs remain effective after AF ablation, underpinning the synergistic mechanisms of action of AF ablation and antiarrhythmic drugs. Atrial fibrillation ablation appears to improve left ventricular function in a subset of patients with AF and heart failure. Data on the prognostic effect of rhythm control therapy are heterogeneous without a clear signal for either benefit or harm. Rhythm control therapy has acceptable safety and improves quality of life in patients with symptomatic AF, including in elderly populations with stroke risk factors. There is a clinical need to better stratify patients for rhythm control therapy. Further studies are needed to determine whether rhythm control therapy, and particularly AF ablation, improves left ventricular function and reduces AF-related complications.

Risk factors for thromboembolic and bleeding events in anticoagulated patients with atrial fibrillation: the prospective, multicentre observational PREvention oF thromboembolic events - European Registry in Atrial Fibrillation (PREFER in AF)

Abstract: Objectives We identified factors associated with thromboembolic and bleeding events in two contemporary cohorts of anticoagulated patients with atrial fibrillation (AF), treated with either vitamin K antagonists (VKA) or non-VKA oral anticoagulants (NOACs). Design Prospective, multicentre observational study. Setting 461 centres in seven European countries. Participants 5310 patients receiving a VKA (PREvention oF thromboembolic events - European Registry in Atrial Fibrillation (PREFER in AF), derivation cohort) and 3156 patients receiving a NOAC (PREFER in AF Prolongation, validation cohort) for stroke prevention in AF. Outcome measures Risk factors for thromboembolic events (ischaemic stroke, systemic embolism) and major bleeding (gastrointestinal bleeding, intracerebral haemorrhage and other life-threatening bleeding). Results The mean age of patients enrolled in the PREFER in AF registry was 72±10 years, 40% were female and the mean CHA2DS2-VASc Score was 3.5±1.7. The incidence of thromboembolic and major bleeding events was 2.34% (95% CI 1.93% to 2.74%) and 2.84% (95% CI 2.41% to 3.33%) after 1-year of follow-up, respectively. Abnormal liver function, prior stroke or transient ischaemic attack, labile international normalised ratio (INR), concomitant therapy with antiplatelet or non-steroidal anti-inflammatory drugs, heart failure and older age (≥75 years) were independently associated with both thromboembolic and major bleeding events. With the exception of unstable INR values, these risk factors were validated in patients treated with NOACs (PREFER in AF Prolongation Study, 72±9 years, 40% female, CHA2DS2-VASc 3.3±1.6). For each single point decrease on a modifiable bleeding risk scale we observed a 30% lower risk for major bleeding events (OR 0.70, 95% CI 0.64 to 0.76, p Conclusion Attending to modifiable risk factors is an important treatment target in anticoagulated AF patients to reduce thromboembolic and bleeding events. Initiation of anticoagulation in those at risk of stroke should not be prevented by elevated bleeding risk scores.

Atrial high-rate episodes: prevalence, stroke risk, implications for management, and clinical gaps in evidence

Abstract: Self-terminating atrial arrhythmias are commonly detected on continuous rhythm monitoring, e.g. by pacemakers or defibrillators. It is unclear whether the presence of these arrhythmias has therapeutic consequences. We sought to summarize evidence on the prevalence of atrial high-rate episodes (AHREs) and their impact on risk of stroke. We performed a comprehensive, tabulated review of published literature on the prevalence of AHRE. In patients with AHRE, but without atrial fibrillation (AF), we reviewed the stroke risk and the potential risk/benefit of oral anticoagulation. Atrial high-rate episodes are found in 10-30% of AF-free patients. Presence of AHRE slightly increases stroke risk (0.8% to 1%/year) compared with patients without AHRE. Atrial high-rate episode of longer duration (e.g. those >24 h) could be associated with a higher stroke risk. Oral anticoagulation has the potential to reduce stroke risk in patients with AHRE but is associated with a rate of major bleeding of 2%/year. Oral anticoagulation is not effective in patients with heart failure or survivors of a stroke without AF. It remains unclear whether anticoagulation is effective and safe in patients with AHRE. Atrial high-rate episodes are common and confer a slight increase in stroke risk. There is true equipoise on the best way to reduce stroke risk in patients with AHRE. Two ongoing trials (NOAH-AFNET 6 and ARTESiA) will provide much-needed information on the effectiveness and safety of oral anticoagulation using non-vitamin K antagonist oral anticoagulants in patients with AHRE.

Development and validation of a score to detect paroxysmal atrial fibrillation after stroke.

Abstract: Objective Prolonged monitoring times (72 hours) are recommended to detect paroxysmal atrial fibrillation (pAF) after ischemic stroke but this is not yet clinical practice; therefore, an individual patient selection for prolonged ECG monitoring might increase the diagnostic yield of pAF in a resource-saving manner. Methods We used individual patient data from 3 prospective studies (n total = 1,556) performing prolonged Holter-ECG monitoring (at least 72 hours) and centralized data evaluation after TIA or stroke in patients with sinus rhythm. Based on the TRIPOD (Transparent Reporting of a Multivariable Prediction Model for Individual Prognosis or Diagnosis) guideline, a clinical score was developed on one cohort, internally validated by bootstrapping, and externally validated on 2 other studies. Results pAF was detected in 77 of 1,556 patients (4.9%) during 72 hours of Holter monitoring. After logistic regression analysis with variable selection, age and the qualifying stroke event (categorized as stroke severity with NIH Stroke Scale [NIHSS] score ≤5 [odds ratio 2.4 vs TIA; 95% confidence interval 0.8–6.9, p = 0.112] or stroke with NIHSS score >5 [odds ratio 7.2 vs TIA; 95% confidence interval 2.4–21.8, p 5 = 21 points; to Find AF [AS5F]). The high-risk group defined by AS5F is characterized by a predicted risk between 5.2% and 40.8% for detection of pAF with a number needed to screen of 3 for the highest observed AS5F points within the study population. Regarding the low number of outcomes before generalization of AS5F, the results need replication. Conclusion The AS5F score can select patients for prolonged ECG monitoring after ischemic stroke to detect pAF. Classification of evidence This study provides Class I evidence that the AS5F score accurately identifies patients with ischemic stroke at a higher risk of pAF.

Cardiac Optogenetics and Optical Mapping - Overcoming Spectral Congestion in All-Optical Cardiac Electrophysiology.

Abstract: Optogenetic control of the heart is an emergent technology that offers unparalleled spatio-temporal control of cardiac dynamics via light-sensitive ion pumps and channels (opsins). This fast-evolving technique holds broad scope in both clinical and basic research setting. Combination of optogenetics with optical mapping of voltage or calcium fluorescent probes facilitates 'all-optical' electrophysiology, allowing precise optogenetic actuation of cardiac tissue with high spatio-temporal resolution imaging of action potential and calcium transient morphology and conduction patterns. In this review, we provide a synopsis of optogenetics and discuss in detail its use and compatibility with optical interrogation of cardiac electrophysiology. We briefly discuss the benefits of all-optical cardiac control and electrophysiological interrogation compared to traditional techniques, and describe mechanisms, unique features and limitations of optically induced cardiac control. In particular, we focus on state-of-the-art setup design, challenges in light delivery and filtering, and compatibility of opsins with fluorescent reporters used in optical mapping. The interaction of cardiac tissue with light, and physical and computational approaches to overcome the 'spectral congestion' that arises from the combination of optogenetics and optical mapping are discussed. Finally, we summarize recent preclinical work applications of combined cardiac optogenetics and optical mapping approach.

Characteristics of patients initiated on edoxaban in Europe: baseline data from edoxaban treatment in routine clinical practice for patients with atrial fibrillation (AF) in Europe (ETNA-AF-Europe).

Abstract: Non-vitamin K antagonist (VKA) oral anticoagulants (NOACs) have substantially improved anticoagulation therapy for prevention of stroke and systemic embolism in patients with atrial fibrillation (AF) The available routine care data have demonstrated the safety of different NOACs; however, such data for edoxaban are scarce Here, we report baseline characteristics of 13,638 edoxaban-treated patients with AF enrolled between November 2016 and February 2018 ETNA-AF-Europe is a multinational, multi-centre, post-authorisation, observational study conducted in 825 sites in 10 European countries Patients will be followed up for four years Overall, 13,980 patients were enrolled of which 342 patients were excluded from the analysis Mean patient age was 736 years with an average creatinine clearance of 694 mL/min 566% were male The calculated CHA2DS2-VASc and HAS-BLED mean scores were 31 and 26, respectively Overall, 33, 146 and 820% of patients had low (CHA2DS2-VASc = 0), intermediate (CHA2DS2-VASc = 1) and high (CHA2DS2-VASc≥2) risks of stroke, respectively High-risk patients (those with prior stroke, prior major bleeding, prior intracranial bleed or CHA2DS2-VASc ≥4) comprised 384% of the overall population For 751% of patients edoxaban was their first anticoagulant prescription, whilst 169% switched from a VKA and 80% from another NOAC A total of 234% of patients in ETNA-AF-Europe received the reduced dose of edoxaban 30 mg Overall, 838% of patients received an edoxaban dose in line with the criteria outlined in the label Edoxaban was predominantly initiated in older, often anticoagulation-naive, unselected European patients with AF, with a good overall adherence to the approved label NCT02944019; Date of registration: October 24, 2016

Design and rationale of the Edoxaban Treatment in routiNe clinical prActice for patients with Atrial Fibrillation in Europe (ETNA-AF-Europe) study.

Abstract: AimEdoxaban, a nonvitamin K antagonist oral anticoagulant, is an oral factor Xa inhibitor approved for the prevention of stroke and systemic embolism in adult patients with atrial fibrillation and for the treatment and secondary prevention in adult patients with venous thromboembolism (VTE). This st

Outcomes associated with non-recommended dosing of rivaroxaban: results from the XANTUS study.

Abstract: Aims: In Europe, the approved rivaroxaban dose for stroke prevention in patients with atrial fibrillation is 20 mg once daily (od), with 15 mg od recommended in patients with creatinine clearance [CrCl] 15-49 mL/min. Non-recommended doses are prescribed in real-world practice. This analysis of the XANTUS study assessed outcomes associated with non-recommended dosing and patient characteristics that may have impacted dose choice. Methods and results: Baseline characteristics and 1-year outcomes were compared in 4464/6784 patients with known CrCl, receiving recommended or non-recommended rivaroxaban doses; 3608 (80.8%) patients received recommended doses (mean CHADS2 score 1.9) and 856 (19.2%) non-recommended doses (mean CHADS2 score 2.5). Incidence rate (events/100 patient-years) for the composite of treatment-emergent adjudicated major bleeding, stroke/systemic embolism and death was 7.5 (95% confidence interval [CI] 5.7-9.8) and 4.8 (95% CI 4.1-5.7) with non-recommended and recommended doses, respectively (hazard ratio 1.55; 95% CI 1.2-2.1; P = 0.004). Incidence rates for the components of the composite were 3.7 and 2.6, 1.4 and 0.9, and 3.5 and 1.9, respectively. Adjustment for baseline characteristics showed similar rates of the composite outcome (hazard ratio 1.06; 95% CI 0.77-1.45; P = 0.719). Multivariable analysis identified age, anaemia, congestive heart failure, diabetes mellitus, CrCl, lower body weight, atrial fibrillation type, and vascular disease as predictors of non-recommended dosing. Conclusion: Non-recommended rivaroxaban dosing was associated with less favourable outcomes, possibly due to baseline characteristics, in addition to renal function, that may also affect physicians' dosing decisions. Trial registration number: Clinicaltrials.gov: NCT01606995.

Evidence for Arrhythmogenic Effects of A2A-Adenosine Receptors.

Abstract: Adenosine can be released from the heart and may stimulate four different cardiac adenosine receptors. A receptor subtype that couples to the generation of cAMP is the A2A-adenosine receptor (A2A-AR). To better understand its role in cardiac function, we studied mechanical and electrophysiological effects in transgenic mice that overexpress the human A2A-AR in cardiomyocytes (A2A-TG). We used isolated preparations from the left atrium, the right atrium, isolated perfused hearts with surface ECG recording and surface body ECG recordings of living mice. The hypothesized arrhythmogenic effects of transgenicity per se and A2A-AR stimulation were studied. We noted an increase in the incidence of supraventricular and ventricular arrhythmias under these conditions in A2A-TG. Moreover, we noted that the A2A-AR agonist CGS 21680 exerted positive inotropic effect in isolated human electrically driven (1 Hz) right atrial trabeculae carneae. We conclude that A2A-adenosine receptors are functional not only in A2A-TG but also in isolated human atrial preparations. A2A-adenosine receptors in A2A-TG per se and their stimulation can lead to cardiac arrhythmias not only in isolated cardiac preparations from A2A-TG but also in living A2A-TG.

Cardiomyocyte functional screening: interrogating comparative electrophysiology of high-throughput model cell systems

Abstract: Cardiac arrhythmias of both atrial and ventricular origin are an important feature of cardiovascular disease. Novel antiarrhythmic therapies are required to overcome current drug limitations related to effectiveness and pro-arrhythmia risk in some contexts. Cardiomyocyte culture models provide a high-throughput platform for screening antiarrhythmic compounds, but comparative information about electrophysiological properties of commonly used types of cardiomyocyte preparations is lacking. Standardization of cultured cardiomyocyte microelectrode array (MEA) experimentation is required for its application as a high-throughput platform for antiarrhythmic drug development. The aim of this study was to directly compare the electrophysiological properties and responses to isoproterenol of three commonly used cardiac cultures. Neonatal rat ventricular myocytes (NRVMs), immortalized atrial HL-1 cells, and custom-generated human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) were cultured on microelectrode arrays for 48-120 h. Extracellular field potentials were recorded, and conduction velocity was mapped in the presence/absence of the β-adrenoceptor agonist isoproterenol (1 µM). Field potential amplitude and conduction velocity were greatest in NRVMs and did not differ in cardiomyocytes isolated from male/female hearts. Both NRVMs and hiPSC-CMs exhibited longer field potential durations with rate dependence and were responsive to isoproterenol. In contrast, HL-1 cells exhibited slower conduction and shorter field potential durations and did not respond to 1 µM isoproterenol. This is the first study to compare the intrinsic electrophysiologic properties of cultured cardiomyocyte preparations commonly used for in vitro electrophysiology assessment. These findings offer important comparative data to inform methodological approaches in the use of MEA and other techniques relating to cardiomyocyte functional screening investigations of particular relevance to arrhythmogenesis.

Digital learning and the future cardiologist.

Abstract: The European Society of Cardiology (ESC) is a leader in the field of cardiology education and has recently laid down its vision for how to improve education for trainees as well as certified cardiologists. Although the ESC has an action plan for how to integrate electronic health services into patient care, the rapidly evolving field of digital education has received less attention but has considerable impact on clinical practice. All cardiologists, and those in training, routinely use digital sources of learning and yet we lack an understanding of the challenges and limitations for integration of new technologies. There are also important opportunities to advance and stimulate a transformation in educational practice across the ESC. These topics were addressed at the 5th ESC Education Conference, held at the European Heart House in Sophia Antipolis (France) in January 2018. In this Cardiopulse article, we report a summary of the main conclusions of this meeting of National Directors of Training (representing 45 ESC countries), Young Cardiologists and patient representatives. The conference included workshops and plenaries on several key themes relating to digital learning and how we train the cardiologist of the future (Figure 1).

Effect of Concomitant Atrial Fibrillation on In-Hospital Outcomes of Non-ST-Elevation-Acute Coronary Syndrome-Related Hospitalizations in the United States.

Abstract: Atrial fibrillation (AF) is the most common arrhythmia in patients presenting with acute coronary syndrome (ACS). The present study examined the rates and trends of clinical outcomes and management strategies of non–ST-elevation ACS (NSTE-ACS) related hospitalizations in the United States, in patients with concomitant AF compared with those in sinus rhythm (SR). We analyzed the “Nationwide Inpatient Sample” database (2004 to 2014) for patients with a primary discharge diagnosis of NSTE-ACS, and further stratified the cohort on the basis of diagnoses into SR and AF groups. Multivariate analysis was performed to examine the association between AF and major adverse cardiovascular and cerebrovascular events (composite of mortality, stroke, and cardiac complications) and its components. Of 4,668,737 NSTE-ACS hospitalizations, the proportions of SR and AF groups were 82.4% (3,848,202) and 17.6% (820,535), respectively. The incidence of AF increased significantly over time from 16.5% (2004) to 19.3% (2014). The AF group was at a greater risk of adverse outcomes with higher rates and adjusted relative risk (RR) of major adverse cardiovascular and cerebrovascular events (12.9% vs 5.3%; RR 1.74 [1.72, 1.75]), mortality (6.5% vs 3.3%; RR 1.12 [1.11, 1.13]), stroke (2.7% vs 1.5%; RR 1.32 [1.30, 1.34]), and bleeding (14.7% vs 8.8%; RR 1.42 [1.41, 1.43]). Furthermore, the AF group was less likely to receive coronary angiography (47.1% vs 58%) and percutaneous coronary intervention (18.7% vs 32.6%) in comparison to SR (p

The global Edoxaban Treatment in routine cliNical prActice (ETNA) noninterventional study program: rationale and design

Abstract: Background Randomized controlled trials showed the nonvitamin K oral anticoagulant (NOAC) edoxaban was effective and safe for stroke and systemic embolism prevention in nonvalvular atrial fibrillation (AF) and for the prevention and treatment of venous thromboembolism (VTE; including pulmonary embolism and deep vein thrombosis). Additional research is needed to evaluate the effects of edoxaban in routine clinical practice. Therefore, the Edoxaban Treatment in routine cliNical prActice (ETNA) program is being conducted to provide routine clinical care data on characteristics and outcomes in patients with AF or VTE receiving edoxaban. Methods The Global ETNA program integrates prospectively collected data from edoxaban patients in regional ETNA noninterventional studies across Europe, Japan, and East and Southeast Asia into indication-specific databases for AF and VTE. Targeted enrollment is >31 000 patients (AF >26 000; VTE >4500), with a follow-up of 2 years for AF and 1 year for VTE. Data integration will be possible using consistent terminology, parameter definitions, and data collection across the regional noninterventional studies. Safety and effectiveness data will be assessed. Crude rates of outcomes including bleeding and thromboembolic events will be reported. Results Globally, enrollment began in early 2015 and is ongoing. Conclusions Global ETNA will generate the largest integrated prospective repository of routine clinical care data for a single NOAC in patients with AF or VTE. It will provide important information on the safety of edoxaban in routine clinical care and gather further information on its effectiveness.

Roadmap for cardiovascular education across the European Society of Cardiology : inspiring better knowledge and skills, now and for the future

Abstract: Aims The provision of high-quality education allows the European Society of Cardiology (ESC) to achieve its mission of better cardiovascular practice and provides an essential component of translating new evidence to improve outcomes. Methods and results The 4th ESC Education Conference, held in Sophia Antipolis (December 2016), brought together ESC education leaders, National Directors of Training of 43 ESC countries, and representatives of the ESC Young Community. Integrating national descriptions of education and cardiology training, we discussed innovative pathways to further improve knowledge and skills across different training programmes and health care systems. We developed an ESC roadmap supporting better cardiology training and continued medical education (CME), noting: (i) The ESC provides an excellent framework for unbiased and up-to-date cardiovascular education in close cooperation with its National Societies. (ii) The ESC should support the harmonization of cardiology training, curriculum development, and professional dialogue and mentorship. (iii) ESC congresses are an essential forum to learn and discuss the latest developments in cardiovascular medicine. (iv) The ESC should create a unified, interactive educational platform for cardiology training and continued cardiovascular education combining Webinars, eLearning Courses, Clinical Cases, and other educational programmes, along with ESC Congress content, Practice Guidelines and the next ESC Textbook of Cardiovascular Medicine. (v) ESC-delivered online education should be integrated into National and regional cardiology training and CME programmes. Conclusion These recommendations support the ESC to deliver excellent and comprehensive cardiovascular education for the next generation of specialists. Teamwork between international, national and local partners is essential to achieve this objective.

High-Throughput Analysis of Optical Mapping Data Using ElectroMap

Abstract: Optical mapping is an established technique for high spatio-temporal resolution study of cardiac electrophysiology in multi-cellular preparations. Here we present, in a step-by-step guide, the use of ElectroMap for analysis, quantification, and mapping of high-resolution voltage and calcium datasets acquired by optical mapping. ElectroMap analysis options cover a wide variety of key electrophysiological parameters, and the graphical user interface allows straightforward modification of pre-processing and parameter definitions, making ElectroMap applicable to a wide range of experimental models. We show how built-in pacing frequency detection and signal segmentation allows high-throughput analysis of entire experimental recordings, acute responses, and single beat-to-beat variability. Additionally, ElectroMap incorporates automated multi-beat averaging to improve signal quality of noisy datasets, and here we demonstrate how this feature can help elucidate electrophysiological changes that might otherwise go undetected when using single beat analysis. Custom modules are included within the software for detailed investigation of conduction, single file analysis, and alternans, as demonstrated here. This software platform can be used to enable and accelerate the processing, analysis, and mapping of complex cardiac electrophysiology.

Real-world vs. randomized trial outcomes in similar populations of rivaroxaban-treated patients with non-valvular atrial fibrillation in ROCKET AF and XANTUS.

Abstract: Aims Based on Phase III data, non-vitamin K antagonist oral anticoagulants are recommended for stroke prevention in patients with atrial fibrillation. To determine whether trial outcomes translate into similar event rates in unselected patients, this analysis compared outcomes from the real-world XANTUS study with those from the Phase III ROCKET AF study. Methods and results Individual patient data from 4020 XANTUS patients were re-weighted to match the proportion of selected baseline characteristics in 7061 rivaroxaban-treated patients from ROCKET AF, using the matching-adjusted indirect comparison (MAIC) method. For the primary analysis, CHADS2 scores and gender were selected as relevant variables. Adjusted annualized incidence rates for XANTUS were calculated and compared with incidence rates from ROCKET AF-the ratio of these rates ('MAIC ratio') was used as a relative effect estimate. Rates of major bleeding [3.10%/year vs. 3.60%/year; MAIC ratio 0.86; 95% confidence interval (CI) 0.67-1.12] and stroke/non-central nervous system systemic embolism (1.54%/year vs. 1.70%/year; MAIC ratio 0.91; 95% CI 0.62-1.32) were similar between XANTUS and ROCKET AF. The rate of all-cause death was higher in XANTUS (3.22%/year vs. 1.87%/year; MAIC ratio 1.72; 95% CI 1.31-2.27), but the rates of vascular death were similar (1.83%/year vs. 1.53%/year; MAIC ratio 1.19; 95% CI 0.84-1.70). Sensitivity analyses weighted by different baseline characteristics supported these results. Conclusion The low rates of major bleeding and stroke in XANTUS were consistent with results from ROCKET AF. All-cause death, but not vascular death, was higher in XANTUS, as expected in an unselected real-world population.

MRI-detected brain lesions in AF patients without further stroke risk factors undergoing ablation - a retrospective analysis of prospective studies

Abstract: Atrial fibrillation (AF) without other stroke risk factors is assumed to have a low annual stroke risk comparable to patients without AF. Therefore, current clinical guidelines do not recommend oral anticoagulation for stroke prevention of AF in patients without stroke risk factors. We analyzed brain magnetic resonance imaging (MRI) imaging to estimate the rate of clinically inapparent (“silent”) ischemic brain lesions in these patients. We pooled individual patient-level data from three prospective studies comprising stroke-free patients with symptomatic AF. All study patients underwent brain MRI within 24–48 h before planned left atrial catheter ablation. MRIs were analyzed by a neuroradiologist blinded to clinical data. In total, 175 patients (median age 60 (IQR 54–67) years, 32% female, median CHA2DS2-VASc = 1 (IQR 0–2), 33% persistent AF) were included. In AF patients without or with at least one stroke risk factor, at least one silent ischemic brain lesion was observed in 4 (8%) out of 48 and 10 (8%) out of 127 patients, respectively (p > 0.99). Presence of silent ischemic brain lesions was related to age (p = 0.03) but not to AF pattern (p = 0.77). At least one cerebral microbleed was detected in 5 (13%) out of 30 AF patients without stroke risk factors and 25 (25%) out of 108 AF patients with stroke risk factors (p = 0.2). Presence of cerebral microbleeds was related to male sex (p = 0.04) or peripheral artery occlusive disease (p = 0.03). In patients with symptomatic AF scheduled for ablation, brain MRI detected silent ischemic brain lesions in approximately one in 12 patients, and microbleeds in one in 5 patients. The prevalence of silent ischemic brain lesions did not differ in AF patients with or without further stroke risk factors.

Development and external validation of predictive models for prevalent and recurrent atrial fibrillation: a protocol for the analysis of the CATCH ME combined dataset

Abstract: Atrial fibrillation (AF) is caused by different mechanisms but current treatment strategies do not target these mechanisms. Stratified therapy based on mechanistic drivers and biomarkers of AF have the potential to improve AF prevention and management outcomes. We will integrate mechanistic insights with known pathophysiological drivers of AF in models predicting recurrent AF and prevalent AF to test hypotheses related to AF mechanisms and response to rhythm control therapy. We will harmonise and combine baseline and outcome data from 12 studies collected by six centres from the United Kingdom, Germany, France, Spain, and the Netherlands which assess prevalent AF or recurrent AF. A Delphi process and statistical selection will be used to identify candidate clinical predictors. Prediction models will be developed in patients with AF for AF recurrence and AF-related outcomes, and in patients with or without AF at baseline for prevalent AF. Models will be used to test mechanistic hypotheses and investigate the predictive value of plasma biomarkers. This retrospective, harmonised, individual patient data analysis will use information from 12 datasets collected in five European countries. It is envisioned that the outcome of this analysis would provide a greater understanding of the factors associated with recurrent and prevalent AF, potentially allowing development of stratified approaches to prevention and therapy management.

Prognostic models for predicting incident or recurrent atrial fibrillation: protocol for a systematic review

Abstract: Atrial fibrillation (AF) is the arrhythmia most commonly diagnosed in clinical practice. It is associated with significant morbidity and mortality. Prevalence of AF and complications of AF, estimated by hospitalisations, have increased dramatically in the last decade. Being able to predict AF would allow tailoring of management strategies and a focus on primary or secondary prevention. Models predicting recurrent AF would have particular clinical use for the selection of rhythm control therapy. There are existing prognostic models which combine several predictors or risk factors to generate an individualised estimate of risk of AF. The aim of this systematic review is to summarise and compare model performance measures and predictive accuracy across different models and populations at risk of developing incident or recurrent AF. Methods tailored to systematic reviews of prognostic models will be used for study identification, risk of bias assessment and synthesis. Studies will be eligible for inclusion where they report an internally or externally validated model. The quality of studies reporting a prognostic model will be assessed using the Prediction Study Risk Of Bias Assessment Tool (PROBAST). Studies will be narratively described and included variables and predictive accuracy compared across different models and populations. Meta-analysis of model performance measures for models validated in similar populations will be considered where possible. To the best of our knowledge, this will be the first systematic review to collate evidence from all studies reporting on validated prognostic models, or on the impact of such models, in any population at risk of incident or recurrent AF. The review may identify models which are suitable for impact assessment in clinical practice. Should gaps in the evidence be identified, research recommendations relating to model development, validation or impact assessment will be made. Findings will be considered in the context of any models already used in clinical practice, and the extent to which these have been validated. PROSPERO ( CRD42018111649 ).

Clinical characteristics of heart failure patients undergoing atrial fibrillation ablation today in Europe. Data from the atrial fibrillation registries of the European Society of Cardiology and the European Heart Rhythm Association

Abstract: Clinical characteristics of heart failure patients undergoing atrial fibrillation ablation today in Europe. Data from the atrial fibrillation registries of the European Society of Cardiology and the European Heart Rhythm Association.

Second look Holter ECG in neurorehabilitation.

Abstract: Many stroke survivors suffer recurrent stroke because paroxysmal atrial fibrillation (AF) was missed and no preventive anticoagulation initiated. This prospective cohort study determined the added diagnostic yield of second-look 24-h electrocardiographic recording (ECG) in a population at high risk for AF: patients who suffered a stroke of such severity that they require inpatient neurorehabilitation. We enrolled 508 patients with ischemic stroke admitted to post-acute inpatient neurorehabilitation and determined whether AF was detected during acute care at the referring hospital. Second-look baseline and 24-h Holter ECG were then conducted during neurorehabilitation. Primary outcome was number of newly detected AF with duration of > 30 s; secondary outcomes were number of newly detected absolute arrhythmia of 10–30 s and 30 s in 20 of these patients, i.e. 6.6% of the sample, and shorter absolute arrhythmia in 50 patients (i.e. 16.5%). Second-look 24-Hour ECG performed during post-acute inpatient neurorehabilitation has a high diagnostic yield and should become a standard component of recurrent stroke prevention.

Safety and efficacy of uninterrupted vs. minimally interrupted periprocedural direct oral anticoagulants for catheter ablation of atrial fibrillation: two sides of the same coin?

Abstract: Yet, though this procedure is considered to be relatively safe and it is widely performed, due to catheter manipulation and the creation of lesions in the left atrium, patients undergoing CA of AF have a considerable risk of peri-procedural clinical stroke, transient ischaemic attack (TIA), or systemic embolism. The periprocedural stroke risk associated with AF ablation is 1%. In addition, several studies and the COMPARE trial have shown that the incidence of this periprocedural complication is higher in patients with non-paroxysmal AF. Continuous anticoagulation with vitamin K antagonists (VKA) prevents periprocedural stroke better than interrupted anticoagulation. In the COMPARE study, patients were randomly assigned in a 1:1 ratio to be off-VKA or on-VKA. In the off-VKA group, 5% of patients experienced thrombo-embolic events compared with 0.25% of patients in the uninterrupted VKA group (P < 0.001). Importantly, these results were mostly driven by patients with long-standing persistent AF (LSPAF). With the advent of direct oral anticoagulants (DOACs), data on the safety of AF ablation on continuous DOAC therapy were needed. The VENTURE-AF trial was the first randomized controlled trial of uninterrupted rivaroxaban vs. warfarin in patients undergoing AF ablation. The number of any adjudicated events, any bleeding events, and any other procedure-attributable events were similar between both groups. This trial demonstrated that in patients undergoing ablation for AF, the use of uninterrupted oral rivaroxaban was feasible, and the event rates were similar to those for uninterrupted warfarin therapy. Likewise, the RE-CIRCUIT trial assigned patients scheduled for CA of AF to receive either dabigatran or warfarin. Uninterrupted dabigatran was associated with fewer bleeding and thrombo-embolic complications than uninterrupted warfarin. The efficacy and safety of periprocedural anticoagulation with apixaban was evaluated in the recently published AXAFA—AFNET 5 trial. The primary outcome was similar in patients randomized to apixaban compared to those randomized to warfarin (non-inferiority P = 0.0002). In this issue of EP-Europace, Nakamura et al. report a prospective, randomized, single-centre study that aimed to directly compare the safety and efficacy of uninterrupted and minimally interrupted periprocedural anticoagulation protocols with DOACs in patients undergoing AF ablation. A total of 846 AF patients were enrolled. The primary endpoint was a composite of symptomatic thromboembolism and major bleeding events within 30 days following CA. Secondary endpoints included symptomatic and silent thromboembolism and major and minor bleeding events. The primary endpoint occurred in 0.7% of the uninterrupted DOAC group (one TIA and two major bleeding events) and 1.2% of the interrupted DOAC group (one TIA and four major bleeding events); P = 0.365. The incidence of major and minor bleeding was comparable between the two groups (0.5% vs. 0.9%, P = 0.345; 5.9% vs. 5.4%, P = 0.753). Silent cerebral ischaemic lesions (SCI) occurred with a similar frequency in both study groups (19.8% vs. 22.0%, P = 0.484), and the percentage of SCIs that were resolved and disappeared on magnetic resonance