Atrial fibrillation screening: feasible approaches and implementation challenges across Europe

Background Atrial fibrillation (AF) screening has the potential to increase early detection and possibly reduce complications of AF. Guidelines recommend screening, but the most appropriate approaches are unknown. Purpose We aimed to explore the views of stakeholders across Europe about the opportunities and challenges of implementing four different AF screening scenarios. Method This qualitative study included 21 semi-structured interviews with healthcare professionals and regulators potentially involved in AF screening implementation in nine European countries. Data were analysed using thematic analysis. Results Three themes evolved. 1) Current approaches to screening: there are no national AF screening programmes, with most AF detected in symptomatic patients. Patient-led screening exists via personal devices, creating screening inequity by the reach of screening programmes being limited to those who access healthcare services. 2) Feasibility of screening approaches: single time point opportunistic screening in primary care using single lead ECG devices was considered the most feasible approach and AF screening may be possible in previously unexplored settings such as dentists and podiatrists. Software algorithms may aid identification of patients suitable for screening and telehealth services have the potential to support diagnosis. However, there is a need for advocacy to encourage the use of telehealth to aid AF diagnosis, and training for screening familiarisation and troubleshooting. 3) Implementation requirements: sufficient evidence of benefit is required. National rather than pan-European screening processes must be developed due to different payment mechanisms and health service regulations. There is concern that the rapid spread of wearable devices for heart rate monitoring may increase workload due to false positives in low risk populations for AF. Data security and inclusivity for those without access to primary care or personal devices must be addressed. Conclusions There is an overall awareness of AF screening. Opportunistic screening appears to be most feasible across Europe. Challenges that need to be addressed concern health inequalities, identification of best target groups for screening, streamlined processes, the need for evidence of benefit, and a tailored approach adapted to national realities. Funding Acknowledgement Type of funding sources: Public grant(s) – EU funding. Main funding source(s): H2020 Screening Scenarios Graphical abstract

Rotational activity presence and its impact in persistent atrial fibrillation follow-up

Introduction Treatment of atrial fibrillation (AF) remains sub-optimal, with low success in pulmonary vein isolation (PVI) ablation procedures in long-standing-persistent AF patients. The maintenance mechanisms of AF are still under debate. Rotational activity (RA) events, also known as rotors, may play a role in perpetuating AF. The characterisation of these drivers during electroanatomical (EA) guided ablation procedures in relationship with follow-up and recurrence ratios in AF patients is necessary to design new ablation strategies to improve the AF treatment success. Purpose We report an AF patient cohort of endocardial mapping and PVI ablation procedures with additional RA events detected during the EA study. We aim to study the presence and distribution of RA in AF patients and its impact on AF recurrence when only PVI ablation is performed. Methods 75 persistent consecutive AF patients (age 60.7±9.8, 74.7% men) underwent EA mapping and RA detection with an automatic algorithm. The presence of RA was annotated on the EA map based on the unipolar electrograms (EGMs) registered with a 20-pole catheter. RA presence was analysed at different left atrial locations (37.2±14.8 sites per patient). AF recurrence was evaluated in follow-up after treatment. Results At follow-up (9±5 months), 50% of the patients presented AF recurrence. Patients with RA had more dilated atria in terms of volumes (p=0.002) and areas (p=0.001). Patients with RA exhibited higher mean voltage EGMs 0.6±0.3 mV vs 0.5±0.2 mV (p=0.036), with shorter cycle lengths 169.1±26.0 ms vs. 188.4±44.2 ms (p=0.044). Finally, patients with RA presented more AF recurrence rates than patients with no RA events (p=0.007). No significant differences were found in terms of comorbidities, e.g., heart failure, hypertension, COPD, stroke, SHD, or diabetes mellitus. Conclusions The results show that patients with more RA events and those with RA outside the PVI ablated regions presented higher AF recurrence episodes than those with no RA or events inside the areas affected by radio-frequency ablation. The study suggests that further ablation treatment of the areas harboring RA might be necessary to reduce the recurrence ratio in AF patients. FUNDunding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Instituto de Salud Carlos III; Sociedad Española de Cardiología

Cardiovascular benefit of lowering LDL-C below 1 mmol/L (40 mg/dl)

Background The 2019 ESC/EAS Dyslipidemia Guidelines recommend an LDL-C goal of <1.4 mmol/L (∼55 mg/dl) for patients with very high-risk ASCVD, and <1 mmol/L (∼40 mg/dl) for those with recurrent events within 2 years despite taking maximally tolerated statin therapy. The addition of PCSK9 inhibitors to statin therapy can achieve LDL-C levels well below 1 mmol/L in many patients, yet the clinical benefit of LDL-C lowering beyond this level has recently been questioned. Methods FOURIER was a cardiovascular outcomes trial comparing evolocumab vs. placebo in patients with stable ASCVD on optimized statin therapy with a median follow-up of 2.2 years. We performed an exploratory analysis to determine the consistency of CV risk reduction with LDL-C lowering below ∼1 mmol/L (40 mg/dl) with evolocumab. We modeled the achieved LDL-C at 48 weeks in the two treatment arms as well as the percentage of LDL-C difference between the two arms that was due to LDL-C below ∼1 mmol/L (40 mg/dl) as a function of baseline LDL-C. We then modeled the hazard ratio (HR) for the composite of CV death, MI or stroke (per 1 mmol/L reduction in LDL-C) with evolocumab vs. placebo as a function of baseline LDL-C. Results All 27,564 patients from FOURIER were included in this analysis. Patients with lower baseline LDL-C achieved lower LDL-C levels following evolocumab therapy, with achieved LDL-C typically being below 1 mmol/L (40 mg/dl) once the baseline LDL-C was below 2.4 mmol/L (94 mg/dl) and reaching levels approaching 0.5 mmol/L (∼20 mg/dl). Accordingly, the further baseline LDL-C levels were below 2.4 mmol/L (94 mg/dl), the greater the proportion of the difference in achieved LDL-C between the evolocumab and placebo arms was due to LDL-C levels below ∼1 mmol/L (40 mg/dl), reaching nearly 40% of the difference in LDL-C between treatment arms (Upper Panel). Despite this, the clinical benefit of LDL-C lowering was not attenuated (p=0.78) (and even appeared greater), with robust reductions in risk of CV death, MI or stroke even when LDL-C was lowered to nearly 0.5 mmol/L (∼20 mg/dl) and having close to 40% of the LDL-C difference between treatment arms due to LDL-C lowering below ∼1 mmol/L (40 mg/dl) (Lower Panel). Conclusion PCSK9 inhibitors added to statin therapy can achieve LDL-C well below 1 mmol/L (40 mg/dl). There is no evidence for attenuation of the clinical benefit of lowering LDL-C below this threshold. These data support lowering LDL-C to below 1 mmol/L (40 mg/dl) in patients with ASCVD. FUNDunding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): National Institute of Health

The novel proteomic signature for the detection of cardiac allograft vasculopathy

Background Cardiac allograft vasculopathy (CAV) is the major long-term complications after heart transplantation, leading to mortality and re-transplantation. As available noninvasive biomarkers are scarce for CAV screening, we aimed to identify a proteomic signature for CAV detection. Methods Urinary proteome was measured by capillary electrophoresis coupled to mass spectrometry in 217 heart transplantation recipients. Participants were further randomly and evenly divided into the derivation cohort and validation cohort. The proteomic signature for CAV was identified by decision tree-based machine learning in the derivation cohort and further tested in the validation cohort. The pathway analysis was investigated with Reactome Pathway Database. Results We identified a proteomic signature with 27 urinary peptides, which yielded areas under the curve (AUC) of 0.83 and 0.71 in the derivation and validation cohort, respectively. In the validation cohort, it had a sensitivity of 68.4%, specificity of 73.2%, accuracy of 71.6%, negative predictive value of 81.3%. Including the proteomic signature into the basic model further improved the diagnostic accuracy with an relative integrated discrimination improvement of 25.9% and the continuous net reclassification improvement of 83.3% (p≤0.023). The pathways analysis on revealed that collagen turnover, platelet aggregation and coagulation, cell adhesion and motility might involve in the pathogenesis of CAV. Conclusions The proteomic signature might be valuable for the surveillance of CAV thereby reduce the frequency of invasive procedures after HTx. Moreover, the highlighted pathways might provide insights in the potential novel treatment targets for CAV. FUNDunding Acknowledgement Type of funding sources: Public grant(s) – EU funding. Main funding source(s): European Research Council Advanced Researcher Grant and Proof-of-Concept Grant ROC curves of the urinary proteomic The 25 highlighted enrichment pathways

Atrial chamber colocalization for multiple 3D imaging techniques in atrial fibrillation

Introduction There exist many imaging techniques and systems to reproduce atrial chambers in 3D. These technologies include electroanatomical (EA) mapping systems, noninvasive electrocardiographic imaging (ECGI), magnetic resonance imaging (MRI), or computed tomography (CT) scans. In the case of atrial fibrillation (AF), the most employed non-pharmacological treatment is catheter ablation to electrically isolate the pulmonary veins from the rest of the left atrium. Driver mechanisms such as focal or rotational activity have been proposed as possible initiating and maintaining mechanisms of AF. However, correspondence and validation of these sites when several systems are employed in the same patient remains a challenge, as they are mostly manually aligned based on visual inspection. Purpose To develop an automatic 3D alignment algorithm for cardiac 3D meshes to colocalize points between atrial maps generated with multiple EA mapping systems, ECGI, MRI, or CT scans. Methods A total of 25 left atrial meshes from persistent AF patients were exported from an EA mapping system. The total number of vertices for all the meshes was 2545444 points (101817.8±13593.3 points per map). A reference mesh was employed with minor modifications [1]. All meshes were manually segmented into 12 different left atrial regions, see Table for the region names. The method implements a non-rigid variant of the iterative closest point algorithm to transform the atrial mesh onto the reference one, see Figure. The geographical distance between the mean position of the 12 different segmented reference areas and the 12 transformed points was employed as the performance metric. Results The global error for all the fiducial points in all left atrial meshes was 11.57±2.55 mm. The average local errors for the 12 atrial areas are summarized in the Table. The best three aligned areas were the RSPV, atrial septum, and lateral wall. The areas with less alignment accuracy were the LAA, LSPV, and atrial roof. Conclusions The algorithm provides a promising solution to evaluate and validate site-related results from different systems, e.g., rotational activity presence between EA mapping and ECGI systems. The method works automatically for any given chamber anatomy or any number of points. No prior segmentation is needed since the transformation and co-localization are applied to the raw chamber mesh. Further analysis with a larger mesh database is needed. FUNDunding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Instituto de Salud Carlos III and Ministerio de Ciencia, Innovaciόn y Universidades

Sex differences in cardiovascular research

Background Women are underrepresented in cardiovascular publications. We sought to investigate sex-specific differences in cardiovascular research over the last decade. Methods and results All 387,463 cardiovascular publications between 2010–2019 were retrieved from Web-of-Science and analyzed regarding the authors' sex, the average impact factor (IF), the number of citations, co-authors per article, and international collaborations. The number of cardiovascular research articles increased between 2010–2019 from 19,960 to 29,604 articles per year. The number of articles written by female first authors increased by 48.3% (6434 articles in 2010 and 11,343 articles in 2019) and by 35.0% for male first authors (13,526 articles in 2010 and 18,261 articles in 2019). The last/senior author was more likely to be female in articles with female first authors compared with male first authors (28.2% vs. 14.1%; odds ratio 2.48, 95% confidence interval 2.43–2.53, p<0.001). The average IF for articles by female first authors was lower compared to male (3.1±3.8 vs. 3.5±4.9, p<0.001). Likewise, the H-Index was lower for female than male first authors (1.07±0.74 vs. 1.25±0.98, p<0.001), as was the number of citations per articles (14.0±31.1 vs. 18.0±68.8 citations, p<0.001). Female first authors had fewer co-authors per article than their male peers (7.4±19.6 vs. 8.2±35.2; p<0.001) and were less represented in articles with >15 co-authors (3,623 articles by female and 8,941 by male first authors; ratio female to male 0.41). Scientific advancement as the ratio between female to male first authorships was highest in publications from Latin America (ratio 0.92) and lowest in Asia (ratio 0.40). Female authorship articles reached the highest IF in North America (average IF 3.7), the lowest Africa (average IF 1.8). Conclusions Publications in cardiovascular research have increased over the last decade, particularly by female authors. Female researchers are cited less often compared with their male peers and publish with fewer co-authors. The IF remains lower for articles by female researchers. Efforts to further increase women-led research activities are needed FUNDunding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): German Cardiac SocietyGerman Research Foundation (DFG)

Muscle stretching induces twitch contractions without activation of stretch-activated channels in intact rat trabeculae

Introduction Mechano-electric coupling (MEC) means that muscle stretching can induce action potentials. Stretch-activated channels (SACs) have been believed to play important roles in their induction. Purpose To investigate what degree of muscle stretching can induce MEC-mediated action potentials and what roles SACs play in their induction. Methods Trabeculae were obtained from right ventricles of rat hearts. Force was measured with a strain gauge, sarcomere length (SL) with a laser diffraction technique, and [Ca2+]i with fura-2 (24°C). The SL was set at 2.0 μm at the resting condition. Trabeculae were stimulated electrically at 400-ms intervals for 7.5 s. Various degrees of muscle stretching were applied at 500 ms after the last stimulus of the electrical train to determine the minimal SL (SL-AP) at which an action potential or a twitch contraction was induced by the stretching (0.7 mM [Ca2+]o). Results The SL-AP was 2.34±0.02 μm (n=8) when trabeculae were stretched rapidly from a SL of 2.0 μm (400-ms stimulation intervals, 0.7 mM [Ca2+]o). The SL-AP was not changed by increasing the stimulation intervals from 400 to 2000 ms (n=7), by increasing [Ca2+]o from 0.7 to 2 mM (n=8), and by adding 1 μM isoproterenol (n=8), suggesting that Ca2+ loading within the myocardium has no effect on the SL-AP. Surprisingly, the SL-AP was not changed by adding 5 μM GsMTx4 (n=8), 10 mM Gd3+ (n=9), 100 μM (n=8) and 200 μM streptomycin (n=11), revealing that SACs play no roles in the determination of SL-AP. The SL-AP was not changed by adding 1 μM ryanodine (n=5) and 30 μM cyclopiazonic acid and was not changed by adding 3 μM diphenyleneiodonium chloride (n=8) and 10 μM colchicine, suggesting that Ca2+ leak from the SR and activation of NADPH oxidase has no effect on the SL-AP. In contrast, elevation of temperature from 23 to 36°C decreased the SL-AP from 2.35±0.01 to 2.34±0.02 μm (p<0.05, n=7). Elevation of extracellular K+ ([K+]o) from 5 to 10 mM increased the SL-AP from 2.35±0.01 to 2.38±0.01 μm (p<0.01, n=7), while reduction of [K+]o to 5 mM decreased it to 2.36±0.01 μm (p<0.05, n=7), suggesting that depolarization of membrane potential suppresses MEC-mediated twitch contractions. The SL-AP was increased from 2.34±0.01 to 2.36±0.01 μm (p<0.01, n=7) when stretching was applied at a shorter interval after the last stimulus, i.e., 200 ms. After electrical stimulation at 300-ms stimulation intervals for 30 s, arrhythmias were induced by a MEC-mediated twitch contraction in 6 out of 9 trabeculae when stretching was applied at 500 ms after the last stimulus, while they were induced only in 2 out of 9 trabeculae without the stretching (4 mM [Ca2+]o, 1 μM isoproterenol). Conclusions These results suggest that muscle stretching causes membrane excitation, which potentially induces arrhythmias and that activation of SACs, Ca2+ release from the SR, and activation of NADPH oxidase by muscle stretching are not involved in the excitation. FUNDunding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Grant-in-Aid for Scientific Research (C) from Japan Society for the Promotion of Science.

Applying the ESC 2016, the H2FPEF, and the HFA-PEFF diagnostic algorithms for heart failure with preserved ejection fraction to the general population – a comparative approach

Background Heart failure with preserved ejection fraction (HFpEF) is common in patients presenting with dyspnoea. Nevertheless, diagnosing HFpEF remains challenging. Recently, different algorithms were developed to predict the likelihood of HFpEF. Purpose Our objective was to provide an in-depth comparison of the ESC 2016 algorithm, the H2FPEF- and the HFA-PEFF algorithm for diagnosing and characterising HFpEF in the general population. Methods The study included 5,613 participants of the population-based H. City Health Study (HCHS), aged 62±8.7 years (51.1% women), that were enrolled between 2016 and 2019. Exclusion criteria were other common causes of dyspnea. We calculated the prevalence and compared characteristics of HFpEF according to the different diagnostic algorithms applying the ESC 2016 heart failure guidelines and the cut-off values suggested by the authors of the HFA-PEFF and H2FPEF score for defining HFpEF. Results Unexplained dyspnea was present in 407 (7.3%) subjects. In those, the estimated prevalence of HFpEF was 20.4% (ESC 2016), 12.3% (H2FPEF), and 7.6% (HFA-PEFF). The majority of subjects was classified as HFpEF not excludable according to the HFA-PEFF (57.7%) and the H2FPEF (59.2%) score. For all algorithms, subjects diagnosed with HFpEF showed elevated age and body mass index as well as a higher prevalence of atrial fibrillation, diabetes, and arterial hypertension compared to those without HFpEF or HFpEF not excludable. The distribution of those comorbidities and risk factors varied between the differently diagnosed HFpEF groups with the highest burden in the HFpEF group defined by the H2FPEF score. The overlap of subjects diagnosed with HFpEF according to the different algorithms was very limited. Conclusion Unexplained dyspnoea is common in the middle-aged general population. The ESC 2016 algorithm, the H2FPEF-, and the HFA-PEFF score detect different, discordant sub-populations of probands with breathlessness. Further classification of the HFpEF syndrome is desirable. FUNDunding Acknowledgement Type of funding sources: Public grant(s) – EU funding. Main funding source(s): Innovative medicine initiative Figure 1. Prevalence and concordance of the three HFpEF algorithms in subjects with unexplained dyspnea. Of the 407 subjects with unexplained dyspnea, the prevalence ranged from 20.4% (n=83, ESC 2016 guideline) to 12.3% (n=50, H2FPEF score) and 7.6% (n=31, HFA-PEFF score). The concordance was highest between the ESC 2016 guidelines and the HFA-PEFF score reflected by a kappa coefficient of 0.38 and a reclassification rate of 16%. RecR = reclassification rate.

Risk prediction of atrial fibrillation and its complications in the community using high-sensitivity cardiac troponin I: results from the BiomarCaRE Consortium

Aims Atrial fibrillation (AF) is becoming increasingly common and is associated with serious complications. Traditional cardiovascular risk factors (CVRF) do not explain all AF cases. Blood-based biomarkers reflecting cardiac injury may help close this gap. High-sensitivity troponin I (hsTnI) has emerged as a potential predictor. Methods We investigated the predictive ability of hsTnI for incident AF in 29,227 participants (median age 52.6 years, 51.2% men) across four different European community cohorts of the Biomarkers for Cardiovascular Risk Assessment in Europe (BiomarCaRE) consortium in comparison to CVRF and established biomarkers (high-sensitive C-reactive protein (hsCRP), N-terminal pro B-type natriuretic peptide (NT-proBNP)). Results During a median follow-up of 13.8 (lower and upper quartiles 4.5, 21.3) years, 1,509 (5.2%) participants developed AF. Those in the highest fourth of hsTnI values at baseline (≥5.1 ng/L) had a 2.71-fold (95% confidence interval (CI) 2.31, 3.17; P<0.01) risk for developing AF compared to those in the lowest fourth (≤2.1 ng/L). In multivariable-adjusted Cox proportional hazard models no statistically significant association was seen between hsTnI and AF, whereas NT-proBNP (hazard ratio (HR) per two-fold increase in NT-proBNP 1.64; 95% CI 1.56, 1.72; P<0.001) as well as hsCRP (HR ratio per two-fold increase in hsCRP 1.05; 95% CI 1.01, 1.10; P=0.01) were statistically significantly related to incident AF. Inclusion of hsTnI did not improve model discrimination over CVRFs (C-index CVRF 0.7914 vs. C-index CVRF, hsTnI 0.7927; 95% CI −0.0004, 0.0031; P=0.130). Higher hsTnI concentrations were associated with AF complications such as stroke (HR 1.25; 95% CI 1.03, 1.51; P=0.02), heart failure (HR 1.27; 95% CI 1.12, 1.44; P<0.001) and cardiovascular events (HR 1.24; 95% CI 1.08, 1.42; P<0.001) as well as overall mortality (HR 1.15; 95% CI 1.05, 1.25; P<0.001) in those who were diagnosed with AF. Conclusion hsTnI as a biomarker of myocardial injury does not improve prediction of AF incidence beyond classical CVRFs. However, it is associated with AF complications and mortality after AF onset probably reflecting underlying subclinical cardiovascular impairment. FUNDunding Acknowledgement Type of funding sources: Public grant(s) – EU funding. Main funding source(s): European Union Seventh Framework Programme (FP7/2007-2013