EU Funds Research Articles

Markers of imminent myocardial infarction

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – EU funding. Main funding source(s): AFA Insurance and the European Commission Seventh Framework Programme. Background and Purpose Myocardial infarction is a leading cause of death globally, but is notoriously difficult to predict. While most studies to date have considered long timeframes for etiological and prediction models, we aimed to identify biomarkers of an imminent first myocardial infarction and design relevant prediction models. Methods We used a novel case–cohort consortium of 2018 persons without prior cardiovascular disease (420 cases, 1598 subcohort representatives) from six European cohorts. We investigated associations of 817 proteins, 1025 metabolites, and 16 clinical variables at baseline with subsequent risk of a first myocardial infarction within 6 months after baseline. Associations in weighted, stratified Cox proportional hazards models that passed multiple testing bounds in the discovery sample were verified in an independent validation sample. We also developed a prediction model for clinical use. Results Forty-eight proteins, 43 metabolites, age, sex, and systolic blood pressure were associated with risk of an imminent first myocardial infarction in models adjusted for technical covariates only (Figure 1). Brain natriuretic peptide (BNP) was most consistently associated with imminent myocardial infarction risk, in models adjusting for additional covariates including age and sex. Using clinically readily available variables, we devised a prediction model (Figure 2) with good ability to discriminate between subsequent cases and non-cases (cross-validated C-index 0.78) to which the addition of BNP did not improve performance. Conclusion We found 94 biomarkers associated with risk of a first myocardial infarction within 6 months in persons without prior cardiovascular disease, and devised a prediction model with good discriminative ability for an imminent first myocardial infarction in the general population, with potential for motivating primary prevention efforts.

Hemodynamic optimization of cardiac resynchronization therapy by heart sound sensor in pulse generator

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – EU funding. Main funding source(s): EU-HORIZON 2020-International Training Network H2020-MSCA-ITN-2017. Background Continuous ambulatory AV-optimization for Cardiac Resynchronization Therapy (CRT) is mainly performed by electrical means. Objective Develop an estimation model of cardiac function that uses feedback from a piezoelectric transducer embedded in an internal pulse generator to guide CRT optimization. Methods During implantation procedures measurements were performed of left ventricular pressure (LVP) and heart sound waveforms, the latter using the piezoelectric alarm transducer of the device in 22 CRT patients at atrioventricular (AV)-delays of 60-330 ms. Post-hoc, machine learning (ML) was employed to produce models that use heart-sound based features to estimate cardiac function in terms of maximum LVP (LVPmax) and the maximum positive derivative of LVP (LVdP/dtmax). Polynomial curve fitting was used to compare estimated and measured AV-delays with highest LVPmax and LVdP/dtmax. Results The figure displays the concept of the study and an example of the measured and estimated optimization curve. With a dataset of ~30,000 beats, ML provided three most suitable features. Using LVPmax, ML-based estimated optimal AV-delays were not significantly different from measured ones (-5.6 ± 17.1ms for LVPmax and +5.1 ± 46.7ms for LVdP/dtmax). The difference in function between the estimated and measured optimal AV-delays was small and not statically significant (1 ± 3mmHg for LVPmax and 9 ± 57mmHg/s for LVdP/dtmax). Conclusion Heart sound sensors in devices in combination with ML provide a reliable assessment of absolute LVPmax and LVdP/dtmax and may be used for continuous optimization of AV-delays in CRT patients.

The risk of obesity and the association of body mass index on all-cause mortality after cardiac resynchronization therapy

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – EU funding. Main funding source(s): European Union. Background Overweight and obese people have a higher risk of acquiring heart failure, however these patients tend to have more favorable outcome, a phenomenon known as the obesity paradox. Purpose We aimed to investigate the risk of obesity and the association of body mass index (BMI) on all-cause mortality in heart failure CRT patients at long-term. Methods We examined retrospectively 1585 patients undergoing CRT implantation at our clinic between 2000-2020 with their BMI available at baseline. Patients were sorted into three groups: normal weight (BMI ‹25), overweight (BMI 25-29.9) and obese (BMI≥30). The composite primary endpoint was all-cause mortality, heart transplantation or implantation of a left ventricular assist device. Time-to-event data was studied by log-rank and multivariate Cox regression analysis. We studied peri-procedural complication rates, and reverse remodeling, defined as a ≥15% relative increase in left ventricular ejection fraction (LVEF) within 6 months after CRT implantation. Results During our mean follow-up time of 5.1 years, 973 (61%) reached our primary endpoint, 302 (66%) in the BMI ‹25 group, 389 (61%) in the BMI 25-29.9 group and 282 (58%) in the BMI≥30 group. Obese patients showed mortality benefit over normal-weighed patients (HR 0.78; 95%CI 0.66-0.92; p=0.003), with only a trend in overweight patients over normal-weighed patients (HR 0.86; 95%CI 0.74-1.00; p=0.05). At multivariate analysis, BMI ‹25 patients showed a 19% higher risk of all-cause mortality compared to overweight and obese patients (HR 1.19; 95%CI 1.03-1.38; p=0.02) after adjusting for age, sex, NYHA class, diabetes, hypertension, myocardial infarction and atrial fibrillation. Obese and overweight patients were younger than normal-weighed patients (68yrs. vs. 69yrs. vs. 70 yrs.; p‹0.0001), similar sex distribution can be seen. Diabetes (BMI ‹25 48% vs. BMI 25-29.9 37% vs. BMI≥30 26%; p‹0.0001) and hypertension (BMI ‹25 82% vs. BMI 25-29.9 74% vs. BMI≥30 71%; p‹0.001) occurred more frequently in obese and overweight patients. Obese and overweight patients had a higher LVEF than in the normal weight group (30% vs. 28% vs. 27%; p‹0.001), respectively. Peri-procedural complication rates did not differ in the three groups. In all patient groups, a significant improvement in LVEF at 6 months was seen (BMI ‹25 ∆-EF 7%, BMI 25-29.9 ∆-EF 7.5%, and BMI ≥30 ∆-EF 6; p<0.001). No difference was seen in the proportion of developing reverse remodeling (BMI ‹25 58% vs. BMI 25-29.9 61% vs. BMI≥30 57%; p=0.75). Conclusions Despite having more co-morbidities like diabetes or hypertension, obese patients showed mortality benefit over normal-weighed patients proving, that the obesity paradox was present in our CRT patient cohort at long-term. Peri-procedural complications did not occur more frequently in obese or overweight patients. Echocardiographic response did not vary, similar reverse remodeling was observed across the patient groups.

Combining atrial activation maps for the big picture of simulated atrial fibrillation mechanisms

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – EU funding. Main funding source(s): This work was supported by PersonalizeAF project. This project has received funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No 860974. Background Pulmonary vein isolation (PVI) alone is not sufficient for all persistent atrial fibrillation (AF) patients. Ablation of localized AF drivers might be a promising adjunctive ablation strategy but detecting such drivers is limited by the small field of view of current mapping catheters. Purpose We propose a technique to detect localized AF drivers that combines sequential mapping of repetitive activation patterns into a larger composite map. The performance of this technique was evaluated in several simulated scenarios of known mechanisms during AF. Methods Representative repetitive conduction patterns that may occur in AF were simulated in a detailed volumetric 3D model of the atria: a large peripheral wave, stable and meandering re-entries, and single and multiple ectopic foci. Endocardial electrograms were sequentially generated from overlapping regions in the left posterior wall (4x4 grid, 3mm spacing, 0.5-1.5 seconds), and repetitive activation patterns were detected. Overlapping areas between sequential maps were used to align the repetitive patterns. Local patterns were then combined into larger composite maps (Fig. 1A). Reconstruction performance was quantified by the average local activation time (LAT) difference between original and reconstructed activation patterns. The relation between electrode overlaps and the quality of reconstructions were assessed at different degrees of spatial overlap (approximately 10% to 25% of the grid area, corresponding to 1.6 ± 0.6 and 4.1 ± 1.2 overlapping electrodes, respectively). Results All simulated patterns could be reconstructed from sequential recordings (Fig. 1B). LAT errors in recordings with 25% overlap were low in all cases: 5±2 msec for the peripheral wave, 5±2 and 3±1 msec for focal and multifocal activities and 6±2 and 11±2 & 17±3 msec for stable, meandering and highly meandering re-entries respectively (Fig. 2). Composite maps of meandering and highly meandering re-entries presented significantly higher reconstruction errors than other more stable patterns (p<0.01). Reducing spatial overlap to 10% did not significantly increase the errors, except for the highly meandering re-entrant activity (p<0.05). Conclusion We developed a novel methodology to combine high-density sequential recordings with limited coverage into larger composite activation maps. Using this method, we reconstructed highly accurate activation maps for multiple simulated AF mechanism scenarios. Results were promising even with a small overlap between sequential recording sites and relatively unstable patterns, providing a proof of principle to apply this approach in clinical recordings of human AF.

Heart failure, female sex and atrial fibrillation are the main drivers of atrial cardiomyopathy in cardiac surgery patients: results from the CATCH ME consortium

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – EU funding. Main funding source(s): CATCH ME: Characterizing Atrial fibrillation by Translating its Causes into Health Modifiers in the Elderly Background Atrial cardiomyopathy is emerging as independent prognostic factor in cardiovascular disease. Fibrotic remodeling, cardiomyocyte hypertrophy and a reduction in capillary density are histological hallmarks of atrial cardiomyopathy. The contribution of etiological factors to atrial cardiomyopathy has not been robustly quantified. Purpose To quantify the relation between histological features of atrial cardiomyopathy and the clinical profile of patients. Methods We examined left (LA, n=91) and right (RA, n=75) atrial appendages sampled from a European cohort of patients undergoing cardiac surgery. Quantification of histological cardiomyopathy features was performed a recently developed and validated imaging analysis algorithm following myocardial triple staining with wheat germ agglutinin (WGA), CD31 and vimentin. The contributions of AF, heart failure (HF), sex, age, and 4 principal components accounting for confounding clinical characteristics to over-all and endomysial fibrosis were determined in a multivariate model. K-means clustering of 6 atrial histological features was performed to identify different types of remodeling. Results LA samples showed less fibrosis (p<0.001), a higher capillary density (p<0.05), a smaller capillary size (p<0.05), and larger cardiomyocytes (p<0.01) than RA samples. In both LA and RA, persistent AF was associated with endomysial fibrosis, while over-all fibrosis was not. Men had larger cardiomyocytes (LAA), while women had a higher degree of endomysial fibrosis (LA). Heart failure patients had more endomysial and over-all fibrosis (LA), a higher capillary density (LA) and capillary size (LA/RA). Samples clustered into 2 distinct clusters. One cluster showed fibrotic cardiomyopathy, with more endomysial (p<0.001) and overall fibrosis (p<0.001), more fibroblasts (p<0,001) and a higher capillary density (p<0.001). The other cluster showed hypertrophic cardiomyopathy, with hypertrophic cardiomyocytes (p<0.001). Patients with fibrotic cardiomyopathy were more often female (LA and RA, p<0.003) and had more often persistent AF (LA, p=0.031) or heart failure (LA, p<0.001). Patients with hypertrophic cardiomyopathy were more often male (LA and RA, p<0.003). Conclusions Fibrotic cardiomyopathy is associated with female sex, persistent AF and heart failure while hypertrophic cardiomyopathy more often occurs in men. More research is needed to establish whether treatment of AF and heart failure prevents the development of atrial cardiomyopathy.

A personalized real-time virtual model of whole heart electrophysiology

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – EU funding. Main funding source(s): This research has also received funding from the European Union’s Horizon 2020 research and innovation programme under the ERA-NET co-fund action No. 680969 (ERA-CVD SICVALVES) funded by the Austrian Science Fund (FWF), Grant I 4652-B to CMA. This project has also received funding MedalCare 18HLT07 from the EMPIR programme co-financed by the Participating States and from the European Union's Horizon 2020 research and innovation programme. Background Biophysics-based Cardiac Digital Twin (CDT) models strive to encode known physics and physiology in mathematical equations and tune these to represent individual patients. Owing to their mechanistic nature, when calibrated with high-fidelity CDTs show high potential to aide in clinical diagnostics, treatment planning, and prognostics. Challenges in building CDTs limit uptake and widespread in the clinics. Generation of CDT models and their personalisation based on measurable clinical data (i.e. the 12-lead electrocardiogram (ECG)) must be performed fast and automated, to be applicable at a clinical scale, and CDTs must replicate a patient’s electrophysiology (EP) with high fidelity to offer predictive capabilities for clinical use. Purpose We aimed to create the first personalized real-time in silico model of whole heart EP capable of both replicating the 12-lead ECG of a single subject under healthy sinus rhythm and subsequently capturing the complex mechanisms of various cardiac diseases. Method We constructed an automated pipeline for the generation of a ventricular-torso model personalised according to the 12-lead ECG during normal sinus rhythm (NSR), fitted with a physiologically-detailed cardiac conduction system facilitating retrograde activation, and included atrial and atrio-ventricular dynamics. Predictive capabilities of the mechanistic model were probed by interrupting conduction in the left and right bundle branches (LBBB, RBBB), by creating accessory paths, and by pacing at the right-ventricular (RV) apex. EP simulations were carried out with real-time performance. Goodness of fit was assessed for sinus rhythm in the 12 lead ECG. Computed pathological ECGs were evaluated with standard clinical diagnostic criteria. Results The computed 12-lead ECG of the personalised whole heart EP model under NSR showed close correspondence with the measured 12-lead ECG of the male subject. The 12 lead ECGs under the various pathologies manifested most morphological features in agreement with diagnostic criteria. Conclusions We report on a personalized real-time in silico model of whole heart EP for a single male subject that closely replicated the 12 lead ECG. Simulated pathological showed most known diagnostic features, but some features were less pronounced as not all factors of the underlying pathology were considered. The importance of dilation or slower cell-to-cell conduction in clinical LBBB aetiology, for example, was not considered. While the CDT shows promise for patient care in a single subject, broader validation with clinical and experimental data is needed to demonstrate agreement between models and physical reality. The pipeline must also be applied to additional subjects of both sexes.

QRS complex and T wave planarity for the prediction of death and appropriate shocks in recipients of prophylactic implantable defibrillators

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – EU funding. Main funding source(s): European Community’s 7th Framework Programme (HEALTH-F2-2009-602299) Ministry of Health, Czech Republic Background Three-dimensional (e.g., vectorcardiography) loops of normal physiologic QRS complex and T wave are known to be planar. Non-planarity of these electrocardiogram (ECG) loops was described in cardiac patients, mainly in relation to ischemic heart disease, but predictive values of the extent of non-planarity of the loops have not been systematically researched. Methods Pre-implantation digital ECGs were collected in 1948 cardiac patients (381 females, median age 65, inter-quartile range 56 – 72 years, 62% ischemic heart disease) who obtained an implantable cardioverter-defibrillator (ICD) for primary prophylactic reasons. In each ECG, QRS and T wave 3-dimensional loops were constructed using singular value decomposition and the non-planarity of the loops was measured as the relative power of the 3rd, least significant decomposition component. The non-planarity (i.e., the spatial twist) of the loops was related to all-cause mortality and to appropriate ICD shocks that occurred during the first 5 years after device implantation. This predictive power was compared to that of age, heart rate, left ventricular ejection fraction, QRS duration, spatial QRS-T angle, QTc interval, and T-peak to T-end interval. Results Non-planarity of the QRS loop was significantly associated with follow-up deaths despite ICD protection (p<0.001 both univariably and in multivariable Cox regression analysis) but was less powerfully associated with appropriate ICD shocks. Non-planarity of the T wave loop was significantly associated with appropriate ICD shocks during follow-up (p<0.001 both univariably and in multivariable Cox regression analysis) but was not associated with mortality during follow-up (Table). This was also seen in significant separation of Kaplan-Meier event probability curves (Figure). Conclusions The analysed data of recipients of prophylactic ICDs suggest that non-planarity of QRS complex and T wave loops offers distinction between patients who are at greater risk of death despite ICD protection and those who are likely to utilize the defibrillator protection.

The novel left atrial anterior 'seatbelt' line reduces sustained atrial arrhythmia by 72% compared to pulmonary vein isolation alone in a cohort of 400 virtual atria models

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – EU funding. Main funding source(s): European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No.860974. Background The success-rate of pulmonary vein isolation (PVI) is modest in persistent atrial fibrillation (AF), but additional empirical ablation, such as posterior wall isolation (PWI), has not been shown to reduce the rate of AF recurrence. The "seatbelt", an anterior linear ablation lesion connecting the right superior pulmonary vein to the mitral annulus, is a novel substrate modification approach that is yet to be tested in a large-scale randomised clinical trial. Purpose To use in-silico trials with human-based modelling and simulation to compare the efficacy of (i) PVI alone, (ii) PVI and PWI (PVI+PWI), or (iii) PVI and seatbelt (PVI+SB) for the prevention of atrial arrhythmia in large populations of virtual patient models. Methods AF was simulated in a cohort of 400 virtual atrial models with anatomical and electrophysiological variability, with AF persisting for >7 seconds defined as sustained. Models which sustained AF were each independently subjected to all three ablation approaches before repeating the AF induction protocol. Results Three hundred forty-four (86%) atrial models developed sustained AF at baseline. After applying the ablation lesions, substantially fewer models sustained atrial arrhythmias in the PVI+SB group (50 [14%] vs. 134 [39%] with PVI+PWI vs. 172 [50%] with PVI). PVI+SB was more effective than PVI and PVI+PWI in preventing both AF and atrial flutter (i.e., presence of a single rotor), since PVI and PVI+PWI led to the formation of anatomical re-entries around the rings of the pulmonary veins and the posterior wall of the left atrium, respectively (Figure). Therefore, PVI+SB restricted atrial flutter mainly to the right atrium (either anatomical, around the inferior cava vein, or functional, meandering throughout the venous portion of the right atrium, Figure). Importantly, in all three ablation strategies, the likelihood of AF recurrence was directly proportional to the surface area of the right atrium (AF probability increased 0.95%/cm², 0.88%/cm² and 0.56%/cm² after PVI+SB, PVI+PWI and PVI, respectively). The role of the right atrial size was less accentuated for PVI alone, since after the ablation the entire left atrial body was still available for rotor anchoring. Moreover, an enlarged left atrium enabled the appearance of micro-re-entries in the anterior and inferior wall of the left atrium, even after applying floor and roof lines. One atrial model additionally presented a rotor in the posterior wall of the left atrium after completely isolating it from the left atrial body. Conclusion(s) In a cohort of 400 virtual atrial models, PVI+SB reduced sustained atrial arrhythmias by 72% compared to PVI alone and by 64% to PVI+PWI, but AF could still originate in an enlarged right atrium.

A smartphone-based intervention to support cardiovascular patients adhere to a healthy diet: a usability and feasibility study

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – EU funding. Main funding source(s): H2020 CoroPrevention. Background Dietary management is a vital component of lifestyle optimization in cardiac rehabilitation and secondary prevention, and face-to-face dietary consultation is the standard care in many clinical settings. The Mediterranean diet pattern is highly recommended to patients with cardiovascular disease. However, patients often have poor adherence to a healthy diet because of lack of motivation or knowledge about healthy diet, inaccurate dietary records, delayed response from a dietician and lack of follow up. Therefore, it is important for a patient to have access to clear information about the diet, and innovative interventions are needed to improve their motivation. Digital health solutions may have great potential for application in the field of nutrition and improve the adherence. Purpose The purpose of the study is to explore the usability and feasibility of a gamified smartphone application for diet management, as well as collect preliminary data of the effect on adherence to the mediterranean diet, knowledge about healthy nutrition and self-efficacy in patients with cardiovascular disease. Methods A six-week pilot intervention study was conducted with patients following a rehabilitation programme after a cardiac event, in which the patients were requested to use the smartphone application. Before and after the intervention, patients were given the MedDietScore questionnaire, "Nutrition Self-Efficacy Scale" and a nutrition knowledge questionnaire. At the end of the intervention, patients were asked to also finish the "Intrinsic Motivation Inventory (IMI)", "Self-reported Habit Index", an usability questionnaire and a semi-structured interview, which, alongside application logs, were used to determine usability and acceptance. Results 15 out of 21 patients (n=15, 80.0% (n=12) were male, mean age of 63.3 + 8.7) completed the full six-week trajectory. No significant improvements were found in the patients’ MedDietScore, knowledge and self-efficacy. Patients did respond positively on the Interest-Enjoyment (20.4/35 ,58.3%), Perceived competence (15.7/28, 56.2%) and Effort-Importance (17.0/28, 60.7%) dimensions of the IMI, while reporting relatively low on Tension-Pressure (11.8/28, 42.1%). An average total score of 44.1/84 (52.5%) was reported for the Self-Reported Habit Index. Furthermore, patients appreciated the application, specifically the logbook component and the dieticians feedback provided through this component, and reacted neutral to positive on the ability to search for products and track goals. Conclusion The results of the short intervention study reveal initial usability and feasibility evaluations of the app, and highlight preferred application features. A longer intervention is needed to evaluate possible medical and behavioural benefits. Considering patients' positive response to the interaction with the dieticians through the application, we suggest that future systems should facilitate similar interaction.

Left bundle branch area pacing produces more physiological ventricular activation than biventricular pacing in patients with heart failure and LBBB

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – EU funding. Main funding source(s): National Institute for Research of Metabolic and Cardiovascular Diseases, Programme EXCELES, Ministry of Health of the Czech Republic, grant number NU21-02-00584. Introduction Biventricular pacing (BiV) is an established treatment for patients with heart failure and dyssynchronous ventricular activation. Left bundle branch area pacing (LBBAP) appears to be a promising alternative to BiV-CRT. To date, there is insufficient data regarding their effect on the reduction of ventricular dyssynchrony. Purpose To compare ventricular synchrony during spontaneous rhythm, BiV and LBBAP in patients with heart failure, reduced left ventricular ejection fraction (LVEF), and LBBB using ultra-high-frequency ECG (UHF-ECG). Methods This was a retrospective analysis of consecutive patients with indication to CRT from two centers. It included patients with heart failure, QRS of LBBB morphology, and LVEF ≤ 40%, treated by BiV and/or LBBAP-CRT. UHF-ECG data were obtained during spontaneous and paced rhythms. These parameters were calculated: eDYS (time difference between the first and last activation), Vdmean (average of V1-V8 local depolarization durations) and QRSd (measured from pacing artifact). Results Analyzes were performed on 80 spontaneous rhythms, 39 biventricular captures and 64 LBBAP, obtained from 80 patients. Their mean age was 74±10 years, 61% were men, mean LV ejection fraction was 31±9 %, and 32% had ischemic cardiomyopathy. Both BiV and LBBAP-CRT significantly reduced QRSd compared to the spontaneous rhythm (from 172 ms, 95% CI [168;176] to 146 ms [141;152] during BiV and 143 ms [139;149] during LBBAP). Also, the eDYS and Vdmean were significantly reduced by both BiV and LBBAP-CRT, i.e., the eDYS from 82 ms [76;86] during LBBB to 33 ms [28;37], p<0.001 during biventricular pacing and to 24 ms [20;28], p<0.001, during LBBAP and Vdmean from 71 ms [68;73] to 59 ms [56;61], p<0.001 during BiV and to 53 ms [51;55], p<0.001 during LBBAP. Although the QRSd did not differ between LBBAP and biventricular pacing (143ms [139;148] vs 146ms [141;152], p=NS), LBBAP compared to BiV led to significantly shorter eDYS (24ms [20;28] vs 33ms [28;38]; p<0.008 and Vdmean (53ms [51;55] vs 59ms [56;61], respectively; p<0.003}. Conclusions In patients with heart failure, LBBB and reduced LVEF, both BiV and LBBAP CRT significantly reduce ventricular dyssynchrony compared to the spontaneous rhythm. Our results indicate that LBBAP is associated with more physiological ventricular activation than BiV-CRT.

Detection of the most dominant drivers of atrial fibrillation based on repetitive activity in sequential electro-anatomical mapping

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – EU funding. Main funding source(s): This work is part of Personalize AF. This project received funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No 860974, This work was also supported by the Swiss National Supercomputing Centre (CSCS), project s1074. Introduction Detecting and targeting the most dominant drivers of atrial fibrillation (AF) might improve the outcome of AF ablation procedures. We hypothesize that dominant drivers entrain their vicinity in a temporally and spatially stable manner resulting in local as well as adjacent repetitive activation patterns. Purpose We present a novel approach to detect the most dominant drivers of AF based on driver repetitiveness and the degree to which they entrain their vicinity. Methods We retrospectively analyzed a dataset of high-density bi-atrial sequential mapping in ablation-naive persistent AF patients (n=13, 30s recording per site). Candidate drivers (focal activity or re-entry) were detected based on local activation time analysis of unipolar electrograms. Focal activity was defined as radial spread of activation, re-entry as a circular activation sequence on at least 4 splines of the mapping catheter that covered >50% of the AF cycle length. As a measure of driver stability, we determined the driver's local repetitiveness (in % of recording). As a measure of driver-associated entrainment, we determined the directionally coherent repetitiveness of adjacent recordings within 30 mm (Figure 1). Following our hypothesis, most dominant drivers can be recognized by their high local and directional coherent adjacent repetitiveness. Results A total of 459 recordings were analyzed (35±5 per patient). We detected 130 focal activities (10±3 per patient) and 42 re-entries (4±2 per patient) in total. The spatial distribution of all drivers is shown in Figure 2 (blue bars). Focal activities were more repetitive than re-entries (Figure 2, median [IQR] 3.2% [1.9%, 5.6%] vs. 1.8% [1.8%, 2.2%], p<0.001 Mann-Whitney U-test). When applying a 90th percentile threshold (8.2%) to both the local and directional coherent adjacent repetitiveness to detect the most dominant drivers, we were able to detect 9 dominant drivers (all focal activities, 7 patients). Most dominant drivers were located in the upper right atrium or left pulmonary vein region (Figure 2). Interestingly, only 9 of the 130 initially detected drivers (7%) showed an activation pattern in line with a repetitive entrainment of their vicinity. Furthermore, in 6 patients (46%), no dominant drivers were detected. This might indicate that not all patients have temporally and spatially stable drivers. Conclusion In this abstract we present a novel methodology to detect the most dominant drivers of AF. Using this method, we found that some (but not all) patients have temporally and spatially stable drivers that are able to entrain their vicinity.

Atrial contractile and electrical remodeling is associated with more complex conduction patterns in patients without history of atrial fibrillation: a high-density epicardial mapping study

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – EU funding. Main funding source(s): This work was supported by the Netherlands Heart Foundation (CVON2014-09, RACE V Reappraisal of Atrial Fibrillation: Interaction between hyperCoagulability, Electrical remodelling, and Vascular Destabilisation in the Progression of AF), the European Union (ITN Network Personalized Therapies for Atrial Fibrillation: a translational network: PersonalizeAF, grant 860974, CATCH ME: Characterizing Atrial fibrillation by Translating its Causes into Health Modifiers in the Elderly, No. 633196). Background Early atrial remodeling refers to a concept where atrial structural, functional, and electrophysiological changes may be present without clinical manifestation of atrial arrhythmias. (1) However, it is currently unknown how electrophysiological and functional atrial properties are related, especially in the early stages of atrial remodeling. Purpose To investigate the relationship between electrophysiological properties of the atria, determined by intraoperative high-density epicardial mapping after AF-induction, and echocardiographic and electrocardiographic parameters in patients without a history of AF undergoing cardiac surgery. Methods All patients underwent functional and electrophysiological analysis of both atria using preoperative transthoracic echocardiography, electrocardiography, and intraoperative biatrial high-density epicardial mapping. Postoperatively, all patients were continuously monitored for occurrence of new-onset postoperative AF (POAF). In addition to univariable and multivariable analysis, cluster analysis was performed to identify distinct clusters of subjects for epicardial mapping parameters. Results The study population consisted of 38 patients undergoing coronary artery bypass grafting, isolated aortic valve replacement, or the combination of both. All patients completed 1-year continuous rhythm monitoring and 19 patients (50%) developed POAF. There was a greater number of waves/cycle (4.57±1.55 vs. 3.98±1.63, p=0.04) and breakthrough (BT) waves/cycle (1.16±0.58 vs. 0.88±0.60, p=0.01) in the RA compared to the LA (Figure 1). Also, there was a lower conduction velocity (CV) in the RA than in the LA (0.71±0.10m/s vs 1.19±0.36m/s, p<0.01) (Figure 1). Average waves/cycle were significantly correlated with reduced P-wave duration and P-wave amplitude (Spearman’s rho=-0.32, p=0.04, and Spearman’s rho=-0.32, p=0.04, respectively). Also, there was significant negative correlation between LA booster function and LA waves/cycle (Spearman’s rho=-0.55, p<0.01). Survival analysis revealed that older age, lower P-wave amplitude, reduced LA booster function, and increased RA waves/cycle were associated with increased occurrence of POAF (Figure 2). Cluster analysis was performed for RA and LA epicardial mapping parameters, which identified 2 distinct clusters: cluster 1 consisted of patients with more complex atrial electrical conduction patterns, and cluster 2 less complex atrial electrical conduction patterns. Multivariable analysis showed that reduced LA booster function was independently associated with a cluster representing more complex atrial electrical conduction patterns in the LA (OR=1.13, 95% CI: 1.02-1.25, p=0.02). Conclusion In patients without a history of AF, reduced LA contractile function and lower P-wave amplitude are associated with more complex electrical conduction patterns in acutely induced AF, potentially representing an early step in the atrial remodeling process.

The explanation of educational disparities in adiposity by lifestyle, socioeconomic and mental health mediators

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – EU funding. Main funding source(s): This work has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No 857487 (R-Exposome Chair) and National Institute for Research of Metabolic and Cardiovascular Diseases (Programme EXCELES, ID Project No. LX22NPO5104) - Funded by the European Union – Next Generation EU. Background The inverse association between education and obesity was previously found in numerous studies. However, education level per se is not directly related to obesity. Instead, other factors linked to educational disadvantage are likely to serve as mediators of the association. Lower educational levels are associated with poor lifestyle, economic disadvantage, and mental health problems, which all are risk factors of increased adiposity. Purpose We hypothesize the potential mediating role of lifestyle, socioeconomic and mental health factors in the association between education and increased adiposity, thus this study aims to assess diverse mediators in the educational disparities in adiposity. Methods Cross-sectional population-based sample from Czechia included 2154 25-64 years old subjects (2013-2014, 54.6% women). Educational attainment was classified as high, middle, and low. Adiposity was assessed as a latent variable constructed based on four main available adiposity biomarkers - body fat percentage, BMI, waist circumference, and visceral fat. The mediation potential of 8 factors (unhealthy dietary behaviour, alcohol intake, smoking, sedentary behaviours, income, stress, depression, and quality of life) was assessed in age-adjusted sex-specific simple and multiple mediation models. Results The negative direct effect of education on adiposity was significant in all investigated models. In a simple mediation model (each potential mediator tested separately), in men, the indirect effect significantly operated via sedentary behaviour, while in women via dietary risk, alcohol consumption, sedentary behaviour, income, and mental health. In multiple mediation models (all potential mediators tested in a one set), in men, the indirect effect was significant via sedentary behavior (β=0.041; 95% CI [0.025-0.062]) with a mediation ratio of 23.7%. In women, the indirect effect was significant via dietary risk (β=-0.023, 95% CI [-0.037, -0.013]), alcohol intake (β=-0.006; 95% CI [-0.014, -0.001]), sedentary behavior (β=0.012, 95% CI [0.004,0.023]), income (β=-0.022; 95% CI [-0.041, -0.004]), and mental health (β=-0.007; 95% CI [-0.019, -0.001]). The total mediation ratio in women was 30.5%. Conclusions Sedentary behaviours mediated the protective potential of higher educational levels on adiposity in both sexes, with a higher magnitude in men. In addition, unhealthy diet and lower income partially mediated the educational gradient in women. Reducing sedentary time should be targeted in public health strategies to reduce the burden of increased adiposity. Future studies should investigate a broader spectrum of potential mediators including knowledge-related factors and components of external environment.

Novel reconstruction technique of omnipolar signals in high density electrode arrays

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – EU funding. Main funding source(s): National Research Program, Ministerio de Ciencia e Innovación, Spanish Government; Instituto de Salud Carlos III. Background Novel multi-electrode array catheters with equidistant spacing between the electrodes, have emerged in recent years - e.g. Advisor™ HD Grid Mapping Catheter, Sensor Enabled™ (SE). These systems typically use unipolar signals, sensitive to low-frequency noise, and bipolar signals - highly dependent on the direction of propagation. Thus, the full potential of these new devices is not yet fully exploited. We hypothesise that, a new clique (4-electrode in a squared 2x2 matrix) configuration for the computation of omnipolar signals allows to take full advantage of novel multi-electrode catheters, more robust to the direction of propagation of the wavefront against the one currently proposed in literature – thus helpful in the clinic given the challenging positioning of the catheter in the heart cavity during electrophysiologic studies. Methods In the current 3-electrode clique, the centre of the signal obtained does not correspond to the centre of the area of the clique, being less robust to wavefront propagation direction (see fig. 1A). A new configuration, the cross clique, is proposed for calculating the electrogram to improve the robustness and reduce the errors in the estimation local activation time (LAT) and others – see figure 1. One thousand simulated signals with stratified propagation angles and variable parameters were implemented to emulate flat waves and homogeneous propagation over cardiac tissue. The methods used to calculate the signal with the proposed shape are: obtaining the bipoles, 45 degree correction of the signal, detection of the propagation angle, rotation of the detected angle and estimation of the LAT. Results The average amplitude of the bipolar loop increased from the old triangular clique configuration: 600.36 ± 116.40 mV; to the novel one cross-clique: 840.47 ± 160.09 mV. Regarding the local activation time estimation, a decrease in the error is observed from the current omnipolar reconstruction: 207.50 ± 256.91 μs, to the one proposed 22.75 ± 29.426 μs. When the bEGM propagation angle estimation is activated, the angle estimation error is 2.77 ± 25.26o for the current reconstruction method, in contrast to 1.09 ± 11.35o in the proposed one – see figure 1B. Conclusion Our novel configuration considerably reduces the LAT estimation error and, on average, captures a larger signal amplitude than the classic triangular clique method. Thus, it allows using the full potential of new catheters, improving the omnipolar analysis. hen applying automatic angle detection to the methods, in the case of the traditional method, it is influenced by the desynchronisation of the components of the traditional model as it widens the bipolar EGM loop – see figure 1.B. Thus, a novel omnipolar reconstruction method is proposed to better estimate intracardiac EGMs, more robustly against the direction of the wavefront propagation. Further studies are under consideration with clinical signals.

Characteristics of recurrent ventricular tachycardias after stereotactic body radiotherapy

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – EU funding. Main funding source(s): Grant project AZV NU20-02-00244 from the Ministry of Health of the Czech Republic and European Union's Horizon 2020 research and innovation program under grant agreement No 945119. Introduction Stereotactic body radiotherapy (SBRT) is a novel treatment for otherwise resistant ventricular tachycardias (VTs). Different mechanisms of SBRT for VT suppression were proposed that include radiation-induced fibrosis but also SBRT-triggered increase in myocardial conduction velocities without significant fibrotic changes. Purpose The study compared the morphologies and cycle lengths (CLs) of inducible VTs during re-do catheter ablation after SBRT with VTs before SBRT. Methods We investigated patients that underwent SBRT (a single session of 25 Gy) for refractory VT and subsequent electrophysiology study / reablation for recurrences of VTs. All inducible VTs were analysed concerning morphology and CL. Results A total of 9 patients (2 women, aged 60 ± 13 years) were included. Two patients had ischemic heart disease, six patients had nonischemic cardiomyopathy, and one had a cardiac fibroma. All patients were on chronic amiodarone treatment. The mean ejection fraction of the left ventricle was 35 ± 12%. The mean planning target volume for SBRT was 39 ± 21 ml. Electrophysiology study/reablation was performed at a mean interval of 8 months (interquartile range: 2-10months) after SBRT. A total of 23 and 27 distinct VT morphologies were inducible before and after SBRT, respectively. Twelve pairs of VTs (44%) were identified that had identical morphology before and after SBRT. The mean CL of these VT pairs decreased from 399 ± 98 ms to 472 ± 74 ms (P = 0.01) after SBRT. Overall, 15/27 of all VT morphologies induced after SBRT originated from the irradiated region. Conclusions Recurrent VTs after SBRT had commonly origin in the irradiated region. In pairwise comparison, the CL of VTs has prolonged after the SBRT. This suggests that SBRT results in radiation-induced fibrosis rather than an increase in conduction velocity.

Resting heart rate does not refine risk stratification of sudden cardiac death in the general population

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – EU funding. Main funding source(s): Horizon 2020 Background Sudden cardiac death (SCD) is a major public health issue in which most events occur in the general population. Although resting heart rate is associated with SCD, its added value regarding prediction is unknown. Methods for risk stratification and prediction are needed to help prevent future SCD. Purpose The aim of this study was to assess the association between resting heart rate (RHR) and SCD in the general population. Methods Participants from the Copenhagen City Heart Study in sinus rhythm with baseline RHR between 40 and 120 bpm were followed from 1993 to 2016. Deaths were adjudicated, by two cardiologists, using death certificates and autopsy reports. Associations between RHR and SCD was investigated using cause specific cox models. The added value of RHR in predicting SCD was investigated by adding RHR to an already published prediction model (including age, sex, cholesterol, statin use, hypertension, systolic and diastolic blood pressure, current smoking status, diabetes, and body mass index (Bogle 2018)). RHR was evaluated as a continuous covariate with a linear effect. Prediction performance measures were evaluated using bootstrap cross validation. Results The study included 10,099 participants of which 8,986 fulfilled inclusion criteria (median age 60 (25%-75%: 47-70), 57% female). During 24 years of follow-up 4,668 deaths including 656 SCD were observed. Mean RHR was 73 bpm (SD 12.4). Increasing HR was associated with incidence of SCD (HR 1.18 (95% CI: 1.12-1.26) per 10 bmp), however, almost to the same extend with death from other causes (HR 1.14 (1.11-1.17). History of AMI and baseline hypertension were differentially associated with the two outcomes, but not RHR (figure 1). We find no added value when including RHR in a prediction model (AUC at 10 years 80.6 vs 80.4 (figure 2), Brier score 3.1 vs 3.1). Allowing for a more flexible RHR-fit (non-linear effect and interaction) did not improve predictions. All results were consistent in sensitivity analyses (only individuals <70 years at entry, censoring after 10 years of follow up, only the most certain SCD diagnoses). Conclusion In the general population, even if RHR was associated with SCD, it did not refine risk stratification when added to a model previously published.

Overall fibrosis content rather than regional differences in extracellular volume alters ventricular conduction in aortic stenosis patients

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – EU funding. Main funding source(s): European Union's Horizon 2020 research and innovation program under the ERA-NET co-fund action No. 680969 with ANR (ERA-CVD SICVALVES) and Agence Nationale de la Recherche Background Extracellular volume (ECV) determined by magnetic resonance imaging (MRI) is considered a marker of myocardial fibrosis and a predictor of mortality. In addition to diffuse fibrosis, aortic stenosis (AS) patients present increased ECV. However, the impact of regional ECV differences on ventricular conduction in AS patients has not been assessed. Purpose To investigate regional ECV differences in AS patients and to determine their impact on ventricular conduction. Methods MRI was performed in 22 AS patients (11 males, 11 females) before and 3 months after aortic valve replacement (AVR). Regional differences in ECV were determined between mid-ventricular and basal planes. To investigate the impact of these differences on conduction, a computational model of ventricular tissue (9x1x1 cm) was developed with human fiber orientation and transmural/apicobasal electrophysiology. The model was divided in two regions (Fig 1A), each representing tissue with different ECV. Extracellular conductivities (GE) in each region were adjusted to the patient with the highest difference in ECV between the planes (male 75y, post-AVR, ECV mid 25.5%, ECV base 31.3%) so that GE was 26.4% less for ECV of 31.3% compared to 25.5%. A model with uniform ECV of 25.5% was used as a control. The models were paced from the apical face with a S1-S2 protocol (S1: 750 ms, n=10, S2: 700-350 ms, n=1). To compare the results to conduction slowing from diffuse myocardial fibrosis, the simulations were repeated with an additional GE reduction by 40% in both regions to mimic conduction delays observed in fibrotic hearts. Ventricular conduction was compared between the models by analyzing conduction velocity (CV) measured between two points at the endocardium (Fig 1A, blue dots) and the occurrence of abnormalities in the form of non-uniform conduction, and/or conduction block after S2 (Fig 1B). Results Significantly higher ECV was found in the basal plane of AS patients when compared to the mid-ventricular plane before and after AVR (Fig 2), with the largest ECV found after AVR (mid-ventricular: p=0.0021; basal: p=0.0048). No sex-specific differences were found. The model representing the patient with the largest regional ECV difference showed slightly lower CV than the model with uniform ECV (92.9 vs. 96.0 cm/s, S2=500 ms). By contrast, myocardial fibrosis had a larger impact on CV slowing (92.9 vs. 79.2 cm/s, S2=500 ms, patient model, Fig 1C). Conduction block and non-uniform conduction occurred at comparable cycle lengths for all models (Fig 1D). Conclusion Regional differences in ECV were found in the ventricles of AS patients, but computer simulations suggest that these differences have a minimal effect on ventricular conduction when compared to diffuse fibrosis. Although the results suggest a limited electrophysiological relevance, additional studies are necessary to investigate whether these ECV differences have a more significant impact on cardiac mechanics.

Fraud related to EU funds. The case of Romania

"According to the latest PIF report on the protection of the financial interests of the European Union, in 2021 Romania reported to the European Commission fraud related to European projects worth 1.4 billion euros. The reported amount is quite impressive as it represents over 80% of the total amounts reported as being fraudulently obtained in 2021 by all member states, making Romania a true performer in this regard at the European level. Starting from these values, using descriptive statistics, the study analyzes the data reported by Romania in the last ten years, compared to the other EU member states, data extracted from the PIF Reports (2012-2021), trying to verify if Romania's status as a champion in terms of fraud with European funds is fully deserved or circumstantial. Although the numbers show that Romania is indeed a performer in this regard, both in terms of value and the number of reported cases, these values must be viewed in context, as they are influenced by a wide series of factors, including reporting errors, the capacity and willingness of member states to detect irregularities, as well as the particularities of the awarding procedures and contracting periods. Also, in the end, the paper presents some recommendations for strengthening efforts to combat the phenomenon of fraud related to EU funds in Romania."

Convergence and economic integration of CEECs through EU regional policy system

In order to assess the effectiveness of individual management systems in the analysed EU countries (Croatia, Poland, Slovakia, Latvia, Lithuania, Estonia, Malta, Cyprus, Slovenia, Hungary), an econometric analysis of the interdependence between the quality of the institutional and regulatory framework and the absorption of EU funds and economic growth was conducted. Conceptually, the econometric analysis aims to identify two levels of interdependence between institutional and regulatory variables on the one hand and dependent variables on the other: (1) the effect of the quality of the institutional and regulatory environment on the absorption of EU funds; (2) the effect of the quality of the institutional and regulatory environment on economic growth. The results of the analysis confirm that EU funds have led to increased economic growth in EU countries which provides basis for economic convergence. However, the allocation of funds alone did not necessarily increase the quality of the institutional framework and competitiveness of the analysed countries. Thus, the paper confirms the importance of improvement of the institutional and regulatory framework of particular grant recipient country, as this not only increases the absorption of EU funds, but also improves the economic growth prospects.

Sanctions within the European Union

The article is devoted to the analysis of the practice of sanctions within the EU. Two groups of sanctions are identified — traditional ones, related to the country’s infringement of the main fiscal rules in the Economic and Monetary Union, and relatively new ones, related to non-compliance with the basic principles of the EU. This article’s attention is focused on the second group of measures, previously not studied in detail in the Russian scientific literature, which are aimed at resolving internal contradictions in the EU — between supranational structures and new Eastern European EU members. These are measures of financial nature in the form of freezing the EU funds payouts, although other measures are also envisaged. For these purposes, the conditionality mechanism has been fixed in 2020, providing for the dependence of payments from the EU funds on the respect of European norms and compliance with EU fundamental values. The ability to avoid blocking at the EU level decisions on sanctions against the violating country is also provided for. As a last resort, a sanction is fixed in the form of depriving the country of the voting rights in the EU Council. We conclude that it is possible to resolve problems without adoption of tough financial measures, by political will and by the institutional mechanisms for settling disagreements.