Publications associated with MAESTRIA

New pharmacological agents and novel cardiovascular pharmacotherapy strategies in 2023
Tamargo J, Agewall S, Borghi C, Ceconi C, Cerbai E, Dan GA, Ferdinandy P, Grove EL, Rocca B, Magavern E, Sulzgruber P, Semb AG, Sossalla S, Niessner A, Kaski JC and Dobrev D
Although cardiovascular diseases (CVDs) are the leading cause of death worldwide, their pharmacotherapy remains suboptimal. Thus, there is a clear unmet need to develop more effective and safer pharmacological strategies. In this review, we summarize the most relevant advances in cardiovascular pharmacology in 2023, including the approval of first-in-class drugs that open new avenues for the treatment of atherosclerotic CVD and heart failure (HF). The new indications of drugs already marketed (repurposing) for the treatment of obstructive hypertrophic cardiomyopathy, hypercholesterolaemia, type 2 diabetes, obesity, and HF; the impact of polypharmacy on guideline-directed drug use is highlighted as well as results from negative clinical trials. Finally, we end with a summary of the most important phase 2 and 3 clinical trials assessing the efficacy and safety of cardiovascular drugs under development for the prevention and treatment of CVDs.
Clinical Predictors of Device-Detected Atrial Fibrillation During 2.5 Years After Cardiac Surgery: Prospective RACE V Cohort
Gilbers MD, Kawczynski MJ, Bidar E, Maesen B, Isaacs A, Winters J, Linz D, Rienstra M, van Gelder I, Maessen JG and Schotten U
Postoperative atrial fibrillation (POAF) is a frequent complication after cardiac surgery that is associated with late atrial fibrillation (AF) recurrences (late-POAF) and increased morbidity and long-term mortality.
The Kir2.1E299V mutation increases atrial fibrillation vulnerability while protecting the ventricles against arrhythmias in a mouse model of short QT syndrome type 3
Moreno-Manuel AI, Macías Á, Cruz FM, Gutiérrez LK, Martínez F, González-Guerra A, Martínez Carrascoso I, Bermúdez-Jimenez FJ, Sánchez-Pérez P, Vera-Pedrosa ML, Ruiz-Robles JM, Bernal JA and Jalife J
Short QT syndrome type 3 (SQTS3) is a rare arrhythmogenic disease caused by gain-of-function mutations in KCNJ2, the gene coding the inward rectifier potassium channel Kir2.1. We used a multidisciplinary approach and investigated arrhythmogenic mechanisms in an in-vivo model of de-novo mutation Kir2.1E299V identified in a patient presenting an extremely abbreviated QT interval and paroxysmal atrial fibrillation.
Atrial fibrillation in the young: consider heritable conditions like short QT syndrome
Fabritz L and Lemoine MD
Heart failure pharmacotherapy and cancer: pathways and pre-clinical/clinical evidence
Sayour NV, Paál ÁM, Ameri P, Meijers WC, Minotti G, Andreadou I, Lombardo A, Camilli M, Drexel H, Grove EL, Dan GA, Ivanescu A, Semb AG, Savarese G, Dobrev D, Crea F, Kaski JC, de Boer RA, Ferdinandy P and Varga ZV
Heart failure (HF) patients have a significantly higher risk of new-onset cancer and cancer-associated mortality, compared to subjects free of HF. While both the prevention and treatment of new-onset HF in patients with cancer have been investigated extensively, less is known about the prevention and treatment of new-onset cancer in patients with HF, and whether and how guideline-directed medical therapy (GDMT) for HF should be modified when cancer is diagnosed in HF patients. The purpose of this review is to elaborate and discuss the effects of pillar HF pharmacotherapies, as well as digoxin and diuretics on cancer, and to identify areas for further research and novel therapeutic strategies. To this end, in this review, (i) proposed effects and mechanisms of action of guideline-directed HF drugs on cancer derived from pre-clinical data will be described, (ii) the evidence from both observational studies and randomized controlled trials on the effects of guideline-directed medical therapy on cancer incidence and cancer-related outcomes, as synthetized by meta-analyses will be reviewed, and (iii) considerations for future pre-clinical and clinical investigations will be provided.
Anticoagulation with edoxaban in patients with long atrial high-rate episodes ≥24 h
Becher N, Toennis T, Bertaglia E, Blomström-Lundqvist C, Brandes A, Cabanelas N, Calvert M, Camm AJ, Chlouverakis G, Dan GA, Dichtl W, Diener HC, Fierenz A, Goette A, de Groot JR, Hermans ANL, Lip GYH, Lubinski A, Marijon E, Merkely B, Mont L, Ozga AK, Rajappan K, Sarkozy A, Scherr D, Schnabel RB, Schotten U, Sehner S, Simantirakis E, Vardas P, Velchev V, Wichterle D, Zapf A and Kirchhof P
Patients with long atrial high-rate episodes (AHREs) ≥24 h and stroke risk factors are often treated with anticoagulation for stroke prevention. Anticoagulation has never been compared with no anticoagulation in these patients.
Reduced plakoglobin increases the risk of sodium current defects and atrial conduction abnormalities in response to androgenic anabolic steroid abuse
Sommerfeld LC, Holmes AP, Yu TY, O'Shea C, Kavanagh DM, Pike JM, Wright T, Syeda F, Aljehani A, Kew T, Cardoso VR, Kabir SN, Hepburn C, Menon PR, Broadway-Stringer S, O'Reilly M, Witten A, Fortmueller L, Lutz S, Kulle A, Gkoutos GV, Pavlovic D, Arlt W, Lavery GG, Steeds R, Gehmlich K, Stoll M, Kirchhof P and Fabritz L
Androgenic anabolic steroids (AAS) are commonly abused by young men. Male sex and increased AAS levels are associated with earlier and more severe manifestation of common cardiac conditions, such as atrial fibrillation, and rare ones, such as arrhythmogenic right ventricular cardiomyopathy (ARVC). Clinical observations suggest a potential atrial involvement in ARVC. Arrhythmogenic right ventricular cardiomyopathy is caused by desmosomal gene defects, including reduced plakoglobin expression. Here, we analysed clinical records from 146 ARVC patients to identify that ARVC is more common in males than females. Patients with ARVC also had an increased incidence of atrial arrhythmias and P wave changes. To study desmosomal vulnerability and the effects of AAS on the atria, young adult male mice, heterozygously deficient for plakoglobin (Plako ), and wild type (WT) littermates were chronically exposed to 5α-dihydrotestosterone (DHT) or placebo. The DHT increased atrial expression of pro-hypertrophic, fibrotic and inflammatory transcripts. In mice with reduced plakoglobin, DHT exaggerated P wave abnormalities, atrial conduction slowing, sodium current depletion, action potential amplitude reduction and the fall in action potential depolarization rate. Super-resolution microscopy revealed a decrease in Na 1.5 membrane clustering in Plako atrial cardiomyocytes after DHT exposure. In summary, AAS combined with plakoglobin deficiency cause pathological atrial electrical remodelling in young male hearts. Male sex is likely to increase the risk of atrial arrhythmia, particularly in those with desmosomal gene variants. This risk is likely to be exaggerated further by AAS use. KEY POINTS: Androgenic male sex hormones, such as testosterone, might increase the risk of atrial fibrillation in patients with arrhythmogenic right ventricular cardiomyopathy (ARVC), which is often caused by desmosomal gene defects (e.g. reduced plakoglobin expression). In this study, we observed a significantly higher proportion of males who had ARVC compared with females, and atrial arrhythmias and P wave changes represented a common observation in advanced ARVC stages. In mice with reduced plakoglobin expression, chronic administration of 5α-dihydrotestosterone led to P wave abnormalities, atrial conduction slowing, sodium current depletion and a decrease in membrane-localized Na 1.5 clusters. 5α-Dihydrotestosterone, therefore, represents a stimulus aggravating the pro-arrhythmic phenotype in carriers of desmosomal mutations and can affect atrial electrical function.
Adipose Tissue in Cardiovascular Disease: From Basic Science to Clinical Translation
Polkinghorne MD, West HW and Antoniades C
The perception of adipose tissue as a metabolically quiescent tissue, primarily responsible for lipid storage and energy balance (with some endocrine, thermogenic, and insulation functions), has changed. It is now accepted that adipose tissue is a crucial regulator of metabolic health, maintaining bidirectional communication with other organs including the cardiovascular system. Additionally, adipose tissue depots are functionally and morphologically heterogeneous, acting not only as sources of bioactive molecules that regulate the physiological functioning of the vasculature and myocardium but also as biosensors of the paracrine and endocrine signals arising from these tissues. In this way, adipose tissue undergoes phenotypic switching in response to vascular and/or myocardial signals (proinflammatory, profibrotic, prolipolytic), a process that novel imaging technologies are able to visualize and quantify with implications for clinical prognosis. Furthermore, a range of therapeutic modalities have emerged targeting adipose tissue metabolism and altering its secretome, potentially benefiting those at risk of cardiovascular disease.
Disturbed atrial metabolism, shear stress, and cardiac load contribute to atrial fibrillation after ablation: AXAFA biomolecule study
Chua W, Khashaba A, Canagarajah H, Nielsen JC, di Biase L, Haeusler KG, Hindricks G, Mont L, Piccini J, Schnabel RB, Schotten U, Wienhues-Thelen UH, Zeller T, Fabritz L and Kirchhof P
Different disease processes can combine to cause atrial fibrillation (AF). Their contribution to recurrent AF after ablation in patients is not known. Cardiovascular processes associated with recurrent AF after AF ablation were determined by quantifying biomolecules related to inflammation, metabolism, proliferation, fibrosis, shear stress, atrial pressure, and others in the AXAFA biomolecule study.
Triage in major incidents: development and external validation of novel machine learning-derived primary and secondary triage tools
Xu Y, Malik N, Chernbumroong S, Vassallo J, Keene D, Foster M, Lord J, Belli A, Hodgetts T, Bowley D and Gkoutos G
Major incidents (MIs) are an important cause of death and disability. Triage tools are crucial to identifying priority 1 (P1) patients-those needing time-critical, life-saving interventions. Existing expert opinion-derived tools have limited evidence supporting their use. This study employs machine learning (ML) to develop and validate models for novel primary and secondary triage tools.
Association of systemic inflammation with shock severity, 30-day mortality, and therapy response in patients with cardiogenic shock
Dettling A, Weimann J, Sundermeyer J, Beer BN, Besch L, Becher PM, Brunner FJ, Kluge S, Kirchhof P, Blankenberg S, Westermann D and Schrage B
Mortality in cardiogenic shock (CS) remains high even when mechanical circulatory support (MCS) restores adequate circulation. To detect a potential contribution of systemic inflammation to shock severity, this study determined associations between C-reactive protein (CRP) concentrations and outcomes in patients with CS.
Temporal trends in incidence, patient characteristics, microbiology and in-hospital mortality in patients with infective endocarditis: a contemporary analysis of 86,469 cases between 2007 and 2019
Becher PM, Goßling A, Fluschnik N, Schrage B, Seiffert M, Schofer N, Blankenberg S, Kirchhof P, Westermann D and Kalbacher D
Infective endocarditis (IE) is characterized by high morbidity and mortality rates, despite recent improvements in diagnostics and treatment. We aimed to investigate incidence, clinical characteristics, and in-hospital mortality in a large-scale nationwide cohort.
Structural Progression in Patients with Definite and Non-Definite Arrhythmogenic Right Ventricular Cardiomyopathy and Risk of Major Adverse Cardiac Events
Aljehani A, Baig S, Kew T, Kalla M, Sommerfeld LC, Murukutla VA, Fabritz L and Steeds RP
Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a rare inherited disease characterised by early arrhythmias and structural changes. Still, there are limited echocardiography data on its structural progression. We studied structural progression and its impact on the occurrence of major adverse cardiovascular events (MACE). In this single-centre observational cohort study, structural progression was defined as the development of new major or minor imaging 2010 Task Force Criteria during follow-up. Of 101 patients, a definite diagnosis of ARVC was made in 51 patients, while non-definite 'early' disease was diagnosed in 50 patients. During 4 years of follow-up (IQR: 2-6), 23 (45%) patients with a definite diagnosis developed structural progression while only 1 patient in the non-definite (early) group gained minor imaging Task Force Criteria. Male gender was strongly associated with structural progression (62% of males progressed structurally, while 88% of females remained stable). Patients with structural progression were at higher risk of MACE (64% of patients with MACE had structural progression). Therefore, the rate of structural progression is an essential factor to be considered in ARVC studies.
Deep learned representations of the resting 12-lead electrocardiogram to predict at peak exercise
Khurshid S, Churchill TW, Diamant N, Di Achille P, Reeder C, Singh P, Friedman SF, Wasfy MM, Alba GA, Maron BA, Systrom DM, Wertheim BM, Ellinor PT, Ho JE, Baggish AL, Batra P, Lubitz SA and Guseh JS
To leverage deep learning on the resting 12-lead electrocardiogram (ECG) to estimate peak oxygen consumption (V˙O2peak) without cardiopulmonary exercise testing (CPET).
A High-Protein Diet Promotes Atrial Arrhythmogenesis via Absent-in-Melanoma 2 Inflammasome
Song J, Wu J, Robichaux DJ, Li T, Wang S, Arredondo Sancristobal MJ, Dong B, Dobrev D, Karch J, Thomas SS and Li N
High-protein diets (HPDs) offer health benefits, such as weight management and improved metabolic profiles. The effects of HPD on cardiac arrhythmogenesis remain unclear. Atrial fibrillation (AF), the most common arrhythmia, is associated with inflammasome activation. The role of the Absent-in-Melanoma 2 (AIM2) inflammasome in AF pathogenesis remains unexplored. In this study, we discovered that HPD increased susceptibility to AF. To demonstrate the involvement of AIM2 signaling in the pathogenesis of HPD-induced AF, wildtype (WT) and mice were fed normal-chow (NC) and HPD, respectively. Four weeks later, inflammasome activity was upregulated in the atria of WT-HPD mice, but not in the -HPD mice. The increased AF vulnerability in WT-HPD mice was associated with abnormal sarcoplasmic reticulum (SR) Ca-release events in atrial myocytes. HPD increased the cytoplasmic double-strand (ds) DNA level, causing AIM2 activation. Genetic inhibition of AIM2 in mice reduced susceptibility to AF, cytoplasmic dsDNA level, mitochondrial ROS production, and abnormal SR Ca-release in atrial myocytes. These data suggest that HPD creates a substrate conducive to AF development by activating the AIM2-inflammasome, which is associated with mitochondrial oxidative stress along with proarrhythmic SR Ca-release. Our data imply that targeting the AIM2 inflammasome might constitute a novel anti-AF strategy in certain patient subpopulations.
Recent highlights on coronary artery disease from the
Tedeschi A, Ammirati E, Conti N and Dobrev D
Management of pericardial tamponade in the electrophysiology laboratory: results from a national survey
Metzner A, Reubold SD, Schönhofer S, Reißmann B, Ouyang F, Rottner L, Schleberger R, Dinshaw L, Moser J, Moser F, Lemoine M, Münkler P, Kany S, Steven D, Sommer P, Kirchhof P and Rillig A
Despite continued efforts to improve the safety of catheter ablation, pericardial tamponade remains one of its more frequent, potentially life-threatening complications. Management of cardiac tamponade is not standardized and uncertainties regarding acute treatment remain.
Coagulation Factor Xa Has No Effects on the Expression of PAR1, PAR2, and PAR4 and No Proinflammatory Effects on HL-1 Cells
Ruf L, Bukowska A, Gardemann A and Goette A
Atrial fibrillation (AF), characterised by irregular high-frequency contractions of the atria of the heart, is of increasing clinical importance. The reasons are the increasing prevalence and thromboembolic complications caused by AF. So-called atrial remodelling is characterised, among other things, by atrial dilatation and fibrotic remodelling. As a result, AF is self-sustaining and forms a procoagulant state. But hypercoagulation not only appears to be the consequence of AF. Coagulation factors can exert influence on cells via protease-activated receptors (PAR) and thereby the procoagulation state could contribute to the development and maintenance of AF. In this work, the influence of FXa on Heart Like-1 (HL-1) cells, which are murine adult atrial cardiomyocytes (immortalized), was investigated. PAR1, PAR2, and PAR4 expression was detected. After incubations with FXa (5-50 nM; 4-24 h) or PAR1- and PAR2-agonists (20 µM; 4-24 h), no changes occurred in PAR expression or in the inflammatory signalling cascade. There were no time- or concentration-dependent changes in the phosphorylation of the MAP kinases ERK1/2 or the p65 subunit of NF-κB. In addition, there was no change in the mRNA expression of the cell adhesion molecules (ICAM-1, VCAM-1, fibronectin). Thus, FXa has no direct PAR-dependent effects on HL-1 cells. Future studies should investigate the influence of FXa on human cardiomyocytes or on other cardiac cell types like fibroblasts.
Automatic search for photoacoustic marker using automated transrectal ultrasound
Wu Z, Moradi H, Yang S, Song H, Boctor EM and Salcudean SE
Real-time transrectal ultrasound (TRUS) image guidance during robot-assisted laparoscopic radical prostatectomy has the potential to enhance surgery outcomes. Whether conventional or photoacoustic TRUS is used, the robotic system and the TRUS must be registered to each other. Accurate registration can be performed using photoacoustic (PA markers). However, this requires a manual search by an assistant [IEEE Robot. Autom. Lett8, 1287 (2023).10.1109/LRA.2022.3191788]. This paper introduces the first automatic search for PA markers using a transrectal ultrasound robot. This effectively reduces the challenges associated with the da Vinci-TRUS registration. This paper investigated the performance of three search algorithms in simulation and experiment: Weighted Average (WA), Golden Section Search (GSS), and Ternary Search (TS). For validation, a surgical prostate scenario was mimicked and various tissues were tested. As a result, the WA algorithm can achieve 0.53°±0.30° average error after 9 data acquisitions, while the TS and GSS algorithm can achieve and 0.48°±0.32° average errors after 28 data acquisitions.
Preventative Imaging with Coronary Computed Tomography Angiography
Antonopoulos AS and Simantiris S
Coronary computed tomography angiography (CCTA) is the diagnostic modality of choice for patients with stable chest pain. In this review, we scrutinize the evidence on the use of CCTA for the screening of asymptomatic patients.
Heart Failure, Female Sex, and Atrial Fibrillation Are the Main Drivers of Human Atrial Cardiomyopathy: Results From the CATCH ME Consortium
Winters J, Isaacs A, Zeemering S, Kawczynski M, Maesen B, Maessen J, Bidar E, Boukens B, Hermans B, van Hunnik A, Casadei B, Fabritz L, Chua W, Sommerfeld L, Guasch E, Mont L, Batlle M, Hatem S, Kirchhof P, Wakili R, Sinner M, Stoll M, Goette A, Verheule S and Schotten U
Atrial cardiomyopathy (atCM) is an emerging prognostic factor in cardiovascular disease. Fibrotic remodeling, cardiomyocyte hypertrophy, and capillary density are hallmarks of atCM. The contribution of etiological factors and atrial fibrillation (AF) to the development of differential atCM phenotypes has not been quantified. This study aimed to evaluate the association between histological features of atCM and the clinical phenotype.
Deep Learning-Enabled Assessment of Left Heart Structure and Function Predicts Cardiovascular Outcomes
Lau ES, Di Achille P, Kopparapu K, Andrews CT, Singh P, Reeder C, Al-Alusi M, Khurshid S, Haimovich JS, Ellinor PT, Picard MH, Batra P, Lubitz SA and Ho JE
Deep learning interpretation of echocardiographic images may facilitate automated assessment of cardiac structure and function.
Heterogeneity of outcomes within diabetic patients with atrial fibrillation on edoxaban: a sub-analysis from the ETNA-AF Europe registry
Patti G, Pecen L, Casalnuovo G, Manu MC, Kirchhof P and De Caterina R
Recent data have suggested that insulin-requiring diabetes mostly contributes to the overall increase of thromboembolic risk in patients with atrial fibrillation (AF) on warfarin. We evaluated the prognostic role of a different diabetes status on clinical outcome in a large cohort of AF patients treated with edoxaban.
Recent highlights from the on challenges for adequate stroke prevention in patients with atrial fibrillation
Fender AC and Dobrev D
Edoxaban in patients with non-valvular atrial fibrillation after percutaneous coronary intervention: ENCOURAGE-AF design
Baldus S, Beyer-Westendorf J, Möllmann H, Rottbauer W, Beyerlein E and Goette A
Approximately one fifth of patients diagnosed with atrial fibrillation (AF) undergo a percutaneous coronary intervention (PCI). Current guidelines recommend different combinations and durations of triple or dual antithrombotic therapy for these patients but data on the implementation of these recommendations in clinical routine are scarce. ENCOURAGE-AF is a prospective, non-interventional, non-comparative, multicentre study. Approximately 720 patients will be consecutively enrolled from 70 participating sites across Germany. Patients with non-valvular AF treated with edoxaban, who have undergone successful PCI, have no planned elective cardiac intervention during the study period, have capability, availability, and willingness for follow-up by telephone interview during the study, are aged ≥ 18 years with life expectancy ≥ 1 year, and provide written informed consent, will be included. Eligible patients will be enrolled between 4- and 72-h after completing a successful PCI. Duration of exposure to and dosing regimens of edoxaban, antiplatelet agents and other concomitant medications of interest will be monitored in line with the clinical practice. Physician- and patient-reported clinical events, adverse drug reactions, patient quality of life (EQ-5D-5L) and health resource utilisation (HRU) parameters will be evaluated at 30 days and 1-year post-PCI. The ENCOURAGE-AF non-interventional study will provide insights into the patterns of edoxaban usage in combination with antiplatelet treatment and other concomitant medications in AF patients with a successful PCI over a 1-year time period during routine clinical practice in Germany. The effectiveness and safety of edoxaban in this patient population, as well as patients' quality of life and HRU will be evaluated.Trial registration: Clinicaltrial.gov NCT04519944, registered on 20 August 2020.
Dual effects of the small-conductance Ca-activated K current on human atrial electrophysiology and Ca-driven arrhythmogenesis: an in silico study
Herrera NT, Zhang X, Ni H, Maleckar MM, Heijman J, Dobrev D, Grandi E and Morotti S
By sensing changes in intracellular Ca, small-conductance Ca-activated K (SK) channels dynamically regulate the dynamics of the cardiac action potential (AP) on a beat-to-beat basis. Given their predominance in atria versus ventricles, SK channels are considered a promising atrial-selective pharmacological target against atrial fibrillation (AF), the most common cardiac arrhythmia. However, the precise contribution of SK current () to atrial arrhythmogenesis is poorly understood, and may potentially involve different mechanisms that depend on species, heart rates, and degree of AF-induced atrial remodeling. Both reduced and enhanced have been linked to AF. Similarly, both SK channel up- and downregulation have been reported in chronic AF (cAF) versus normal sinus rhythm (nSR) patient samples. Here, we use our multiscale modeling framework to obtain mechanistic insights into the contribution of in human atrial cardiomyocyte electrophysiology. We simulate several protocols to quantify how modulation affects the regulation of AP duration (APD), Ca transient, refractoriness, and occurrence of alternans and delayed afterdepolarizations (DADs). Our simulations show that activation shortens the APD and atrial effective refractory period, limits Ca cycling, and slightly increases the propensity for alternans in both nSR and cAF conditions. We also show that increasing counteracts DAD development by enhancing the repolarization force that opposes the Ca-dependent depolarization. Taken together, our results suggest that increasing in human atrial cardiomyocytes could promote reentry while protecting against triggered activity. Depending on the leading arrhythmogenic mechanism, inhibition may thus be a beneficial or detrimental anti-AF strategy. Using our established framework for human atrial myocyte simulations, we investigated the role of the small-conductance Ca-activated K current () in the regulation of cell function and the development of Ca-driven arrhythmias. We found that inhibition, a promising atrial-selective pharmacological strategy against atrial fibrillation, counteracts the reentry-promoting abbreviation of atrial refractoriness, but renders human atrial myocytes more vulnerable to delayed afterdepolarizations, thus potentially increasing the propensity for ectopic (triggered) activity.
An angiopoietin 2, FGF23, and BMP10 biomarker signature differentiates atrial fibrillation from other concomitant cardiovascular conditions
Chua W, Cardoso VR, Guasch E, Sinner MF, Al-Taie C, Brady P, Casadei B, Crijns HJGM, Dudink EAMP, Hatem SN, Kääb S, Kastner P, Mont L, Nehaj F, Purmah Y, Reyat JS, Schotten U, Sommerfeld LC, Zeemering S, Ziegler A, Gkoutos GV, Kirchhof P and Fabritz L
Early detection of atrial fibrillation (AF) enables initiation of anticoagulation and early rhythm control therapy to reduce stroke, cardiovascular death, and heart failure. In a cross-sectional, observational study, we aimed to identify a combination of circulating biomolecules reflecting different biological processes to detect prevalent AF in patients with cardiovascular conditions presenting to hospital. Twelve biomarkers identified by reviewing literature and patents were quantified on a high-precision, high-throughput platform in 1485 consecutive patients with cardiovascular conditions (median age 69 years [Q1, Q3 60, 78]; 60% male). Patients had either known AF (45%) or AF ruled out by 7-day ECG-monitoring. Logistic regression with backward elimination and a neural network approach considering 7 key clinical characteristics and 12 biomarker concentrations were applied to a randomly sampled discovery cohort (n = 933) and validated in the remaining patients (n = 552). In addition to age, sex, and body mass index (BMI), BMP10, ANGPT2, and FGF23 identified patients with prevalent AF (AUC 0.743 [95% CI 0.712, 0.775]). These circulating biomolecules represent distinct pathways associated with atrial cardiomyopathy and AF. Neural networks identified the same variables as the regression-based approach. The validation using regression yielded an AUC of 0.719 (95% CI 0.677, 0.762), corroborated using deep neural networks (AUC 0.784 [95% CI 0.745, 0.822]). Age, sex, BMI and three circulating biomolecules (BMP10, ANGPT2, FGF23) are associated with prevalent AF in unselected patients presenting to hospital. Findings should be externally validated. Results suggest that age and different disease processes approximated by these three biomolecules contribute to AF in patients. Our findings have the potential to improve screening programs for AF after external validation.
Recent highlights on specific aspects of oral anticoagulation in difficult clinical scenarios from the
Fender AC and Dobrev D
Chronic kidney disease promotes atrial fibrillation via inflammasome pathway activation
Song J, Navarro-Garcia JA, Wu J, Saljic A, Abu-Taha I, Li L, Lahiri SK, Keefe JA, Aguilar-Sanchez Y, Moore OM, Yuan Y, Wang X, Kamler M, Mitch WE, Ruiz-Hurtado G, Hu Z, Thomas SS, Dobrev D, Wehrens XH and Li N
Chronic kidney disease (CKD) is associated with a higher risk of atrial fibrillation (AF). The mechanistic link between CKD and AF remains elusive. IL-1β, a main effector of NLR family pyrin domain-containing 3 (NLRP3) inflammasome activation, is a key modulator of conditions associated with inflammation, such as AF and CKD. Circulating IL-1β levels were elevated in patients with CKD who had AF (versus patients with CKD in sinus rhythm). Moreover, NLRP3 activity was enhanced in atria of patients with CKD. To elucidate the role of NLRP3/IL-1β signaling in the pathogenesis of CKD-induced AF, Nlrp3-/- and WT mice were subjected to a 2-stage subtotal nephrectomy protocol to induce CKD. Four weeks after surgery, IL-1β levels in serum and atrial tissue were increased in WT CKD (WT-CKD) mice versus sham-operated WT (WT-sham) mice. The increased susceptibility to pacing-induced AF and the longer AF duration in WT-CKD mice were associated with an abbreviated atrial effective refractory period, enlarged atria, and atrial fibrosis. Genetic inhibition of NLRP3 in Nlrp3-/- mice or neutralizing anti-IL-1β antibodies effectively reduced IL-1β levels, normalized left atrial dimensions, and reduced fibrosis and the incidence of AF. These data suggest that CKD creates a substrate for AF development by activating the NLRP3 inflammasome in atria, which is associated with structural and electrical remodeling. Neutralizing IL-1β antibodies may be beneficial in preventing CKD-induced AF.
Epicardial Adipose Tissue in Myocardial Disease: From Physiology to Heart Failure Phenotypes
Antonopoulos AS, Papastamos C, Cokkinos DV, Tsioufis K and Tousoulis D
Epicardial adipose tissue (EAT) is increasingly being recognized as a determinant of myocardial biology. The EAT-heart crosstalk suggests causal links between dysfunctional EAT and cardiomyocyte impairment. Obesity promotes EAT dysfunction and shifts in secreted adipokines which adversely affect cardiac metabolism, induce cardiomyocyte inflammation, redox imbalance and myocardial fibrosis. Thus, EAT determines cardiac phenotype via effects on cardiac energetics, contractility, diastolic function, and atrial conduction. Vice-versa the EAT is altered in heart failure (HF), and such phenotypic changes can be detected by noninvasive imaging or incorporated in Artificial Intelligence-enhanced tools to aid the diagnosis, subtyping or risk prognostication of HF. In the present article, we summarize the links between EAT and the heart, explaining how the study of epicardial adiposity can improve the understanding of cardiac disease, serve as a source of diagnostic and prognostic biomarkers, and as a potential therapeutic target in HF to improve clinical outcomes.
Perivascular adipose tissue as a source of therapeutic targets and clinical biomarkers
Antoniades C, Tousoulis D, Vavlukis M, Fleming I, Duncker DJ, Eringa E, Manfrini O, Antonopoulos AS, Oikonomou E, Padró T, Trifunovic-Zamaklar D, De Luca G, Guzik T, Cenko E, Djordjevic-Dikic A and Crea F
Obesity is a modifiable cardiovascular risk factor, but adipose tissue (AT) depots in humans are anatomically, histologically, and functionally heterogeneous. For example, visceral AT is a pro-atherogenic secretory AT depot, while subcutaneous AT represents a more classical energy storage depot. Perivascular adipose tissue (PVAT) regulates vascular biology via paracrine cross-talk signals. In this position paper, the state-of-the-art knowledge of various AT depots is reviewed providing a consensus definition of PVAT around the coronary arteries, as the AT surrounding the artery up to a distance from its outer wall equal to the luminal diameter of the artery. Special focus is given to the interactions between PVAT and the vascular wall that render PVAT a potential therapeutic target in cardiovascular diseases. This Clinical Consensus Statement also discusses the role of PVAT as a clinically relevant source of diagnostic and prognostic biomarkers of vascular function, which may guide precision medicine in atherosclerosis, hypertension, heart failure, and other cardiovascular diseases. In this article, its role as a 'biosensor' of vascular inflammation is highlighted with description of recent imaging technologies that visualize PVAT in clinical practice, allowing non-invasive quantification of coronary inflammation and the related residual cardiovascular inflammatory risk, guiding deployment of therapeutic interventions. Finally, the current and future clinical applicability of artificial intelligence and machine learning technologies is reviewed that integrate PVAT information into prognostic models to provide clinically meaningful information in primary and secondary prevention.
Heart transplantation for refractory ventricular tachyarrhythmia: a too stormy approach?
Goette A
Anticoagulation with Edoxaban in Patients with Atrial High-Rate Episodes
Kirchhof P, Toennis T, Goette A, Camm AJ, Diener HC, Becher N, Bertaglia E, Blomstrom Lundqvist C, Borlich M, Brandes A, Cabanelas N, Calvert M, Chlouverakis G, Dan GA, de Groot JR, Dichtl W, Kravchuk B, Lubiński A, Marijon E, Merkely B, Mont L, Ozga AK, Rajappan K, Sarkozy A, Scherr D, Sznajder R, Velchev V, Wichterle D, Sehner S, Simantirakis E, Lip GYH, Vardas P, Schotten U, Zapf A, and
Device-detected atrial high-rate episodes (AHREs) are atrial arrhythmias detected by implanted cardiac devices. AHREs resemble atrial fibrillation but are rare and brief. Whether the occurrence of AHREs in patients without atrial fibrillation (as documented on a conventional electrocardiogram [ECG]) justifies the initiation of anticoagulants is not known.
Recent Advances in Antiarrhythmic Drug Therapy
Saljic A, Heijman J and Dobrev D
Cardiac arrhythmias remain a common cause of death and disability. Antiarrhythmic drugs (AADs) and antiarrhythmic agents remain a cornerstone of current cardiac arrhythmia management, despite moderate efficacy and the potential for significant adverse proarrhythmic effects. Due to conceptual, regulatory and financial considerations, the number of novel antiarrhythmic targets and agents in the development pipeline has decreased substantially during the last few decades. However, several promising candidates remain and there are exciting developments in repurposing and reformulating already existing drugs for indications related to cardiac arrhythmias. This review discusses the key conceptual considerations for the development of new antiarrhythmic agents, summarizes new compounds and formulations currently in clinical development for rhythm control of atrial fibrillation, and highlights the potential for drug repurposing. Finally, future directions in AAD development are discussed. Together with an ever-increasing understanding of the molecular mechanisms underlying cardiac arrhythmias, these components support a cautiously optimistic outlook towards improved pharmacological treatment opportunities for patients suffering from cardiac arrhythmias.
Clinical Pathway for Coronary Atherosclerosis in Patients Without Conventional Modifiable Risk Factors: JACC State-of-the-Art Review
Figtree GA, Vernon ST, Harmer JA, Gray MP, Arnott C, Bachour E, Barsha G, Brieger D, Brown A, Celermajer DS, Channon KM, Chew NWS, Chong JJH, Chow CK, Cistulli PA, Ellinor PT, Grieve SM, Guzik TJ, Hagström E, Jenkins A, Jennings G, Keech AC, Kott KA, Kritharides L, Mamas MA, Mehran R, Meikle PJ, Natarajan P, Negishi K, O'Sullivan J, Patel S, Psaltis PJ, Redfern J, Steg PG, Sullivan DR, Sundström J, Vogel B, Wilson A, Wong D, Bhatt DL, Kovacic JC, Nicholls SJ and
Reducing the incidence and prevalence of standard modifiable cardiovascular risk factors (SMuRFs) is critical to tackling the global burden of coronary artery disease (CAD). However, a substantial number of individuals develop coronary atherosclerosis despite no SMuRFs. SMuRFless patients presenting with myocardial infarction have been observed to have an unexpected higher early mortality compared to their counterparts with at least 1 SMuRF. Evidence for optimal management of these patients is lacking. We assembled an international, multidisciplinary team to develop an evidence-based clinical pathway for SMuRFless CAD patients. A modified Delphi method was applied. The resulting pathway confirms underlying atherosclerosis and true SMuRFless status, ensures evidence-based secondary prevention, and considers additional tests and interventions for less typical contributors. This dedicated pathway for a previously overlooked CAD population, with an accompanying registry, aims to improve outcomes through enhanced adherence to evidence-based secondary prevention and additional diagnosis of modifiable risk factors observed.
Association of genetic risk and outcomes in patients with atrial fibrillation: interactions with early rhythm control in the EAST-AFNET4 trial
Kany S, Al-Taie C, Roselli C, Pirruccello JP, Borof K, Reinbold C, Suling A, Krause L, Reissmann B, Schnabel RB, Zeller T, Zapf A, Wegscheider K, Fabritz L, Ellinor PT and Kirchhof P
The randomized Early Treatment of Atrial Fibrillation for Stroke Prevention Trial found that early rhythm control reduces cardiovascular events in patients with recently diagnosed atrial fibrillation (AF) compared with usual care. How genetic predisposition to AF and stroke interacts with early rhythm-control therapy is not known.
Atrial fibrillation and stroke prevention: 25 years of research at EP Europace journal
Lip GYH, Proietti M, Potpara T, Mansour M, Savelieva I, Tse HF, Goette A, Camm AJ, Blomstrom-Lundqvist C, Gupta D and Boriani G
Stroke prevention in patients with atrial fibrillation (AF) is one pillar of the management of this common arrhythmia. Substantial advances in the epidemiology and associated pathophysiology underlying AF-related stroke and thrombo-embolism are evident. Furthermore, the introduction of the non-vitamin K antagonist oral anticoagulants (also called direct oral anticoagulants) has clearly changed our approach to stroke prevention in AF, such that the default should be to offer oral anticoagulation for stroke prevention, unless the patient is at low risk. A strategy of early rhythm control is also beneficial in reducing strokes in selected patients with recent onset AF, when compared to rate control. Cardiovascular risk factor management, with optimization of comorbidities and attention to lifestyle factors, and the patient's psychological morbidity are also essential. Finally, in selected patients with absolute contraindications to long-term oral anticoagulation, left atrial appendage occlusion or exclusion may be considered. The aim of this state-of-the-art review article is to provide an overview of the current status of AF-related stroke and prevention strategies. A holistic or integrated care approach to AF management is recommended to minimize the risk of stroke in patients with AF, based on the evidence-based Atrial fibrillation Better Care (ABC) pathway, as follows: A: Avoid stroke with Anticoagulation; B: Better patient-centred, symptom-directed decisions on rate or rhythm control; C: Cardiovascular risk factor and comorbidity optimization, including lifestyle changes.
Does weight matter in cryoballoon ablation?
Gawałko M, Linz D and Dobrev D
Non-invasive electromechanical assessment during atrial fibrillation identifies underlying atrial myopathy alterations with early prognostic value
Enríquez-Vázquez D, Quintanilla JG, García-Escolano A, Couselo-Seijas M, Simón-Chica A, Lee P, Alfonso-Almazán JM, Mahía P, Redondo-Rodríguez A, Modrego J, Ortega-Hernández A, Marcos-Alberca P, Magni R, Calvo E, Gómez-Gordo R, Yan P, La Rosa G, Bustamante-Madrión J, Pérez-García CN, Martín-Sánchez FJ, Calvo D, de la Hera JM, García-Torrent MJ, García-Osuna Á, Ordonez-Llanos J, Vázquez J, Pérez-Villacastín J, Pérez-Castellano N, Loew LM, Sánchez-González J, Gómez-Garre D and Filgueiras-Rama D
Electromechanical characterization during atrial fibrillation (AF) remains a significant gap in the understanding of AF-related atrial myopathy. This study reports mechanistic insights into the electromechanical remodeling process associated with AF progression and further demonstrates its prognostic value in the clinic. In pigs, sequential electromechanical assessment during AF progression shows a progressive decrease in mechanical activity and early dissociation from its electrical counterpart. Atrial tissue samples from animals with AF reveal an abnormal increase in cardiomyocytes death and alterations in calcium handling proteins. High-throughput quantitative proteomics and immunoblotting analyses at different stages of AF progression identify downregulation of contractile proteins and progressive increase in atrial fibrosis. Moreover, advanced optical mapping techniques, applied to whole heart preparations during AF, demonstrate that AF-related remodeling decreases the frequency threshold for dissociation between transmembrane voltage signals and intracellular calcium transients compared to healthy controls. Single cell simulations of human atrial cardiomyocytes also confirm the experimental results. In patients, non-invasive assessment of the atrial electromechanical relationship further demonstrate that atrial electromechanical dissociation is an early prognostic indicator for acute and long-term rhythm control.
Determinants and therapeutic potential of calcium handling abnormalities in atrial fibrillation: what can we learn from computer models?
Heijman J and Dobrev D
Accelerometer-Derived "Weekend Warrior" Physical Activity and Incident Cardiovascular Disease
Khurshid S, Al-Alusi MA, Churchill TW, Guseh JS and Ellinor PT
Guidelines recommend 150 minutes or more of moderate to vigorous physical activity (MVPA) per week for overall health benefit, but the relative effects of concentrated vs more evenly distributed activity are unclear.
Early Rhythm Control Is Therapy of Choice to Treat Atrial Fibrillation After Cerebral Stroke
Goette A
In silico analysis of the dynamic regulation of cardiac electrophysiology by K 11.1 ion-channel trafficking
Meier S, Grundland A, Dobrev D, Volders PGA and Heijman J
Cardiac electrophysiology is regulated by continuous trafficking and internalization of ion channels occurring over minutes to hours. K 11.1 (also known as hERG) underlies the rapidly activating delayed-rectifier K current (I ), which plays a major role in cardiac ventricular repolarization. Experimental characterization of the distinct temporal effects of genetic and acquired modulators on channel trafficking and gating is challenging. Computer models are instrumental in elucidating these effects, but no currently available model incorporates ion-channel trafficking. Here, we present a novel computational model that reproduces the experimentally observed production, forward trafficking, internalization, recycling and degradation of K 11.1 channels, as well as their modulation by temperature, pentamidine, dofetilide and extracellular K . The acute effects of these modulators on channel gating were also incorporated and integrated with the trafficking model in the O'Hara-Rudy human ventricular cardiomyocyte model. Supraphysiological dofetilide concentrations substantially increased K 11.1 membrane levels while also producing a significant channel block. However, clinically relevant concentrations did not affect trafficking. Similarly, severe hypokalaemia reduced K 11.1 membrane levels based on long-term culture data, but had limited effect based on short-term data. By contrast, clinically relevant elevations in temperature acutely increased I due to faster kinetics, while after 24 h, I was decreased due to reduced K 11.1 membrane levels. The opposite was true for lower temperatures. Taken together, our model reveals a complex temporal regulation of cardiac electrophysiology by temperature, hypokalaemia, and dofetilide through competing effects on channel gating and trafficking, and provides a framework for future studies assessing the role of impaired trafficking in cardiac arrhythmias. KEY POINTS: K 11.1 channels underlying the rapidly activating delayed-rectifier K current are important for ventricular repolarization and are continuously shuttled from the cytoplasm to the plasma membrane and back over minutes to hours. K 11.1 gating and trafficking are modulated by temperature, drugs and extracellular K concentration but experimental characterization of their combined effects is challenging. Computer models may facilitate these analyses, but no currently available model incorporates ion-channel trafficking. We introduce a new two-state ion-channel trafficking model able to reproduce a wide range of experimental data, along with the effects of modulators of K 11.1 channel functioning and trafficking. The model reveals complex dynamic regulation of ventricular repolarization by temperature, extracellular K concentration and dofetilide through opposing acute (millisecond) effects on K 11.1 gating and long-term (hours) modulation of K 11.1 trafficking. This in silico trafficking framework provides a tool to investigate the roles of acute and long-term processes on arrhythmia promotion and maintenance.
Implementation of a screening and management pathway for chronic obstructive pulmonary disease in patients with atrial fibrillation
van der Velden RMJ, Hereijgers MJM, Arman N, van Middendorp N, Franssen FME, Gawalko M, Verhaert DVM, Habibi Z, Vernooy K, Koltowski L, Hendriks JM, Heidbuchel H, Desteghe L, Simons SO and Linz D
Chronic obstructive pulmonary disease (COPD) negatively impacts the efficacy of heart rhythm control treatments in patients with atrial fibrillation (AF). Although COPD is recognized as a risk factor for AF, practical guidance about how and when to screen for COPD is not available. Herein, we describe the implementation of an integrated screening and management pathway for COPD into the existing pre-ablation work-up in an AF outpatient clinic infrastructure.
Does epicardial fat modify the effect of catheter ablation in patients with atrial fibrillation?
Goette A
Phosphodiesterase 8 governs cAMP/PKA-dependent reduction of L-type calcium current in human atrial fibrillation: a novel arrhythmogenic mechanism
Grammatika Pavlidou N, Dobrev S, Beneke K, Reinhardt F, Pecha S, Jacquet E, Abu-Taha IH, Schmidt C, Voigt N, Kamler M, Schnabel RB, Baczkó I, Garnier A, Reichenspurner H, Nikolaev VO, Dobrev D and Molina CE
Atrial fibrillation (AF) is associated with altered cAMP/PKA signaling and an AF-promoting reduction of L-type Ca2+-current (ICa,L), the mechanisms of which are poorly understood. Cyclic-nucleotide phosphodiesterases (PDEs) degrade cAMP and regulate PKA-dependent phosphorylation of key calcium-handling proteins, including the ICa,L-carrying Cav1.2α1C subunit. The aim was to assess whether altered function of PDE type-8 (PDE8) isoforms contributes to the reduction of ICa,L in persistent (chronic) AF (cAF) patients.
Cardiac magnetic resonance imaging of pericardial diseases: a comprehensive guide
Antonopoulos AS, Vrettos A, Androulakis E, Kamperou C, Vlachopoulos C, Tsioufis K, Mohiaddin R and Lazaros G
Cardiac magnetic resonance (CMR) imaging has been established as a valuable diagnostic tool in the assessment of pericardial diseases by providing information on cardiac anatomy and function, surrounding extra-cardiac structures, pericardial thickening and effusion, characterization of pericardial effusion, and the presence of active pericardial inflammation from the same scan. In addition, CMR imaging has excellent diagnostic accuracy for the non-invasive detection of constrictive physiology evading the need for invasive catheterization in most instances. Growing evidence in the field suggests that pericardial enhancement on CMR is not only diagnostic of pericarditis but also has prognostic value for pericarditis recurrence, although such evidence is derived from small patient cohorts. CMR findings could also be used to guide treatment de-escalation or up-titration in recurrent pericarditis and selecting patients most likely to benefit from novel treatments such as anakinra and rilonacept. This article is an overview of the CMR applications in pericardial syndromes as a primer for reporting physicians. We sought to provide a summary of the clinical protocols used and an interpretation of the major CMR findings in the setting of pericardial diseases. We also discuss points that are less well clear and delineate the strengths and weak points of CMR in pericardial diseases.
Acute stress induces long-term metabolic, functional, and structural remodeling of the heart
Yoganathan T, Perez-Liva M, Balvay D, Le Gall M, Lallemand A, Certain A, Autret G, Mokrani Y, Guillonneau F, Bruce J, Nguyen V, Gencer U, Schmitt A, Lager F, Guilbert T, Bruneval P, Vilar J, Maissa N, Mousseaux E, Viel T, Renault G, Kachenoura N and Tavitian B
Takotsubo cardiomyopathy is a stress-induced cardiovascular disease with symptoms comparable to those of an acute coronary syndrome but without coronary obstruction. Takotsubo was initially considered spontaneously reversible, but epidemiological studies revealed significant long-term morbidity and mortality, the reason for which is unknown. Here, we show in a female rodent model that a single pharmacological challenge creates a stress-induced cardiomyopathy similar to Takotsubo. The acute response involves changes in blood and tissue biomarkers and in cardiac in vivo imaging acquired with ultrasound, magnetic resonance and positron emission tomography. Longitudinal follow up using in vivo imaging, histochemistry, protein and proteomics analyses evidences a continued metabolic reprogramming of the heart towards metabolic malfunction, eventually leading to irreversible damage in cardiac function and structure. The results combat the supposed reversibility of Takotsubo, point to dysregulation of glucose metabolic pathways as a main cause of long-term cardiac disease and support early therapeutic management of Takotsubo.
Pleiotropic effects of NOACs with focus on edoxaban: scientific findings and potential clinical implications
Goette A, Mollenhauer M, Rudolph V, Lamparter M, Meier M and Böhm M
Non-vitamin K antagonist oral anticoagulants (NOACs) are well-established as inhibitors of factor Xa (FXa) and thrombin in the treatment and prevention of thrombosis. However, there is growing evidence that beneficial outcomes might be based on additional pleiotropic effects beyond anticoagulation. FXa and thrombin are also known to activate protease-activated receptors (PARs), which can mediate pro-inflammatory and pro-fibrotic effects. Since PAR‑1 and PAR‑2 play an important role in the development of atherosclerosis, the inhibition of this pathway represents an interesting potential target for preventing the progression of atherosclerosis and fibrosis. This review focuses on potential pleiotropic effects of FXa inhibition with edoxaban seen in a variety of studies in different in vitro and in vivo test systems. As common findings from these experiments, edoxaban was able to attenuate FXa- and thrombin-induced pro-inflammatory and pro-fibrotic effects and decrease pro-inflammatory cytokine expression. In some, but not all experiments edoxaban was also shown to decrease the levels of PAR‑1 and PAR‑2 expression. Further studies are required to clarify the clinical implications of the pleiotropic effects mediated by NOACs.
High-density and high coverage composite mapping of repetitive atrial activation patterns
Özgül O, Hermans BJ, van Hunnik A, Verheule S, Schotten U, Bonizzi P and Zeemering S
Repetitive atrial activation patterns (RAAPs) during atrial fibrillation (AF) may be associated with localized mechanisms that maintain AF. Current electro-anatomical mapping systems are unsuitable for analyzing RAAPs due to the trade-off between spatial coverage and electrode density in clinical catheters. This work proposes a technique to overcome this trade-off by constructing composite maps from spatially overlapping sequential recordings.
Screening for undiagnosed atrial fibrillation using a single-lead electrocardiogram at primary care visits: patient uptake and practitioner perspectives from the VITAL-AF trial
Atlas SJ, Ashburner JM, Chang Y, Borowsky LH, Ellinor PT, McManus DD, Lubitz SA and Singer DE
Screening for atrial fibrillation (AF) is appealing because AF is common, when undiagnosed may increase stroke risk, and stroke is preventable with anticoagulants. This study assessed patient and primary care practitioner (PCP) acceptability of screening for AF using a 30-s single-lead electrocardiogram (SL-ECG) during outpatient visits.
Origin of SRS-induced beam quality distortion under TMI threshold
Wang L, Zhang H, Zhong P, Zeng L, Yang B, Xi X, Wang P, Wang X and Xu X
In high power fiber lasers, the degradation of beam quality caused by Raman effect has attracted more and more attention in recent years, but its physical mechanism is still unclear. We're going to differentiate between heat effect and nonlinear effect by duty cycle operation. The evolution of beam quality at different pump duty cycles has been studied based on a quasi-continuous wave (QCW) fiber laser. It is found that even if the Stokes intensity is only -6 dB (energy proportion: 26%) lower than that of the signal light intensity, the beam quality has no obvious change with the duty cycle of 5%; on the contrary, when the duty cycle gradually approaches 100% (CW-pumped scheme), the beam quality distortion changes faster and faster with the increase of Stokes intensity. The experimental results are contrary to core-pumped Raman effect theory [IEEE Photon. Technol. Lett.34, 215 (2022)10.1109/LPT.2022.3148999], and further analysis confirms that the heat accumulation in the process of Stokes frequency shift should be responsible for this phenomenon. That is the first time, to the best of our knowledge, for intuitive reveal of the origin of stimulated Raman scattering (SRS)-induced beam quality distortion under transverse mode instability (TMI) threshold in an experiment.
Deep-Learning for Epicardial Adipose Tissue Assessment With Computed Tomography: Implications for Cardiovascular Risk Prediction
West HW, Siddique M, Williams MC, Volpe L, Desai R, Lyasheva M, Thomas S, Dangas K, Kotanidis CP, Tomlins P, Mahon C, Kardos A, Adlam D, Graby J, Rodrigues JCL, Shirodaria C, Deanfield J, Mehta NN, Neubauer S, Channon KM, Desai MY, Nicol ED, Newby DE, Antoniades C and
Epicardial adipose tissue (EAT) volume is a marker of visceral obesity that can be measured in coronary computed tomography angiograms (CCTA). The clinical value of integrating this measurement in routine CCTA interpretation has not been documented.
Generic Nonadditivity of Quantum Capacity in Simple Channels
Leditzky F, Leung D, Siddhu V, Smith G and Smolin JA
Determining capacities of quantum channels is a fundamental question in quantum information theory. Despite having rigorous coding theorems quantifying the flow of information across quantum channels, their capacities are poorly understood due to superadditivity effects. Studying these phenomena is important for deepening our understanding of quantum information, yet simple and clean examples of superadditive channels are scarce. Here we study a family of channels called platypus channels. Its simplest member, a qutrit channel, is shown to display superadditivity of coherent information when used jointly with a variety of qubit channels. Higher-dimensional family members display superadditivity of quantum capacity together with an erasure channel. Subject to the "spin-alignment conjecture" introduced in our companion paper [F. Leditzky, D. Leung, V. Siddhu, G. Smith, and J. A. Smolin, The platypus of the quantum channel zoo, IEEE Transactions on Information Theory (IEEE, 2023), 10.1109/TIT.2023.3245985], our results on superadditivity of quantum capacity extend to lower-dimensional channels as well as larger parameter ranges. In particular, superadditivity occurs between two weakly additive channels each with large capacity on their own, in stark contrast to previous results. Remarkably, a single, novel transmission strategy achieves superadditivity in all examples. Our results show that superadditivity is much more prevalent than previously thought. It can occur across a wide variety of channels, even when both participating channels have large quantum capacity.
New pharmacological agents and novel cardiovascular pharmacotherapy strategies in 2022
Tamargo J, Agewall S, Borghi C, Ceconi C, Cerbai E, Dan GA, Ferdinandy P, Grove EL, Rocca B, Sulzgruber P, Semb AG, Sossalla S, Niessner A, Kaski JC and Dobrev D
Cardiovascular diseases (CVD) remain the leading cause of death worldwide and pharmacotherapy of most of them is suboptimal. Thus, there is a clear unmet clinical need to develop new pharmacological strategies with greater efficacy and better safety profiles. In this review, we summarize the most relevant advances in cardiovascular pharmacology in 2022 including the approval of first-in-class drugs that open new avenues for the treatment of obstructive hypertrophic cardiomyopathy (mavacamten), type 2 diabetes mellitus (tirzepatide), and heart failure (HF) independent of left ventricular ejection fraction (sodium-glucose cotransporter 2 inhibitors). We also dealt with fixed dose combination therapies repurposing different formulations of "old" drugs with well-known efficacy and safety for the treatment of patients with acute decompensated HF (acetazolamide plus loop diuretics), atherosclerotic cardiovascular disease (moderate-dose statin plus ezetimibe), Marfan syndrome (angiotensin receptor blockers plus β-blockers), and secondary cardiovascular prevention (i.e. low-dose aspirin, ramipril and atorvastatin), thereby filling existing gaps in knowledge, and opening new avenues for the treatment of CVD. Clinical trials confirming the role of dapagliflozin in patients with HF and mildly reduced or preserved ejection fraction, long-term evolocumab to reduce the risk of cardiovascular events, vitamin K antagonists for stroke prevention in patients with rheumatic heart disease-associated atrial fibrillation, antibiotic prophylaxis in patients at high risk for infective endocarditis before invasive dental procedures, and vutrisiran for the treatment of hereditary transthyretin-related amyloidosis with polyneuropathy were also reviewed. Finally, we briefly discuss recent clinical trials suggesting that FXIa inhibitors may have the potential to uncouple thrombosis from hemostasis and attenuate/prevent thromboembolic events with minimal disruption of hemostasis.
Adiposity-associated atrial fibrillation: molecular determinants, mechanisms, and clinical significance
Gawałko M, Saljic A, Li N, Abu-Taha I, Jespersen T, Linz D, Nattel S, Heijman J, Fender A and Dobrev D
Obesity is an important contributing factor to the pathophysiology of atrial fibrillation (AF) and its complications by causing systemic changes, such as altered haemodynamic, increased sympathetic tone, and low-grade chronic inflammatory state. In addition, adipose tissue is a metabolically active organ that comprises various types of fat deposits with discrete composition and localization that show distinct functions. Fatty tissue differentially affects the evolution of AF, with highly secretory active visceral fat surrounding the heart generally having a more potent influence than the rather inert subcutaneous fat. A variety of proinflammatory, profibrotic, and vasoconstrictive mediators are secreted by adipose tissue, particularly originating from cardiac fat, that promote atrial remodelling and increase the susceptibility to AF. In this review, we address the role of obesity-related factors and in particular specific adipose tissue depots in driving AF risk. We discuss the distinct effects of key secreted adipokines from different adipose tissue depots and their participation in cardiac remodelling. The possible mechanistic basis and molecular determinants of adiposity-related AF are discussed, and finally, we highlight important gaps in current knowledge, areas requiring future investigation, and implications for clinical management.
Quantifying a spectrum of clinical response in atrial tachyarrhythmias using spatiotemporal synchronization of electrograms
Ganesan P, Deb B, Feng R, Rodrigo M, Ruiperez-Campillo S, Rogers AJ, Clopton P, Wang PJ, Zeemering S, Schotten U, Rappel WJ and Narayan SM
There is a clinical spectrum for atrial tachyarrhythmias wherein most patients with atrial tachycardia (AT) and some with atrial fibrillation (AF) respond to ablation, while others do not. It is undefined if this clinical spectrum has pathophysiological signatures. This study aims to test the hypothesis that the size of spatial regions showing repetitive synchronized electrogram (EGM) shapes over time reveals a spectrum from AT, to AF patients who respond acutely to ablation, to AF patients without acute response.
Atrial Fibrillation in Patients With Cancer: A Persistent and Increasing Challenge
Suero-Abreu GA and Ellinor PT
The Genetic Determinants of Aortic Distention
Pirruccello JP, Rämö JT, Choi SH, Chaffin MD, Kany S, Nekoui M, Chou EL, Jurgens SJ, Friedman SF, Juric D, Stone JR, Batra P, Ng K, Philippakis AA, Lindsay ME and Ellinor PT
As the largest conduit vessel, the aorta is responsible for the conversion of phasic systolic inflow from ventricular ejection into more continuous peripheral blood delivery. Systolic distention and diastolic recoil conserve energy and are enabled by the specialized composition of the aortic extracellular matrix. Aortic distensibility decreases with age and vascular disease.
Current and Future Use of Artificial Intelligence in Electrocardiography
Martínez-Sellés M and Marina-Breysse M
Artificial intelligence (AI) is increasingly used in electrocardiography (ECG) to assist in diagnosis, stratification, and management. AI algorithms can help clinicians in the following areas: (1) interpretation and detection of arrhythmias, ST-segment changes, QT prolongation, and other ECG abnormalities; (2) risk prediction integrated with or without clinical variables (to predict arrhythmias, sudden cardiac death, stroke, and other cardiovascular events); (3) monitoring ECG signals from cardiac implantable electronic devices and wearable devices in real time and alerting clinicians or patients when significant changes occur according to timing, duration, and situation; (4) signal processing, improving ECG quality and accuracy by removing noise/artifacts/interference, and extracting features not visible to the human eye (heart rate variability, beat-to-beat intervals, wavelet transforms, sample-level resolution, etc.); (5) therapy guidance, assisting in patient selection, optimizing treatments, improving symptom-to-treatment times, and cost effectiveness (earlier activation of code infarction in patients with ST-segment elevation, predicting the response to antiarrhythmic drugs or cardiac implantable devices therapies, reducing the risk of cardiac toxicity, etc.); (6) facilitating the integration of ECG data with other modalities (imaging, genomics, proteomics, biomarkers, etc.). In the future, AI is expected to play an increasingly important role in ECG diagnosis and management, as more data become available and more sophisticated algorithms are developed.
Familial atrial fibrillation mutation M1875T-SCN5A increases early sodium current and dampens the effect of flecainide
O'Reilly M, Sommerfeld LC, O'Shea C, Broadway-Stringer S, Andaleeb S, Reyat JS, Kabir SN, Stastny D, Malinova A, Delbue D, Fortmueller L, Gehmlich K, Pavlovic D, Skryabin BV, Holmes AP, Kirchhof P and Fabritz L
Atrial fibrillation (AF) is the most common cardiac arrhythmia. Pathogenic variants in genes encoding ion channels are associated with familial AF. The point mutation M1875T in the SCN5A gene, which encodes the α-subunit of the cardiac sodium channel Nav1.5, has been associated with increased atrial excitability and familial AF in patients.
Clinical characteristics, causes and predictors of outcomes in patients with in-hospital cardiac arrest: results from the SURVIVE-ARREST study
Hannen LEM, Toprak B, Weimann J, Mahmoodi B, Fluschnik N, Schrage B, Roedl K, Söffker G, Kluge S, Issleib M, Blankenberg S, Kirchhof P, Clemmensen P, Sinning C, Zengin-Sahm E and Becher PM
In-hospital cardiac arrest (IHCA) is acutely life-threatening and remains associated with high mortality and morbidity. Identifying predictors of mortality after IHCA would help to guide acute therapy.
Early diagnosis and better rhythm management to improve outcomes in patients with atrial fibrillation: the 8th AFNET/EHRA consensus conference
Schnabel RB, Marinelli EA, Arbelo E, Boriani G, Boveda S, Buckley CM, Camm AJ, Casadei B, Chua W, Dagres N, de Melis M, Desteghe L, Diederichsen SZ, Duncker D, Eckardt L, Eisert C, Engler D, Fabritz L, Freedman B, Gillet L, Goette A, Guasch E, Svendsen JH, Hatem SN, Haeusler KG, Healey JS, Heidbuchel H, Hindricks G, Hobbs FDR, Hübner T, Kotecha D, Krekler M, Leclercq C, Lewalter T, Lin H, Linz D, Lip GYH, Løchen ML, Lucassen W, Malaczynska-Rajpold K, Massberg S, Merino JL, Meyer R, Mont L, Myers MC, Neubeck L, Niiranen T, Oeff M, Oldgren J, Potpara TS, Psaroudakis G, Pürerfellner H, Ravens U, Rienstra M, Rivard L, Scherr D, Schotten U, Shah D, Sinner MF, Smolnik R, Steinbeck G, Steven D, Svennberg E, Thomas D, True Hills M, van Gelder IC, Vardar B, Palà E, Wakili R, Wegscheider K, Wieloch M, Willems S, Witt H, Ziegler A, Daniel Zink M and Kirchhof P
Despite marked progress in the management of atrial fibrillation (AF), detecting AF remains difficult and AF-related complications cause unacceptable morbidity and mortality even on optimal current therapy. This document summarizes the key outcomes of the 8th AFNET/EHRA Consensus Conference of the Atrial Fibrillation NETwork (AFNET) and the European Heart Rhythm Association (EHRA). Eighty-three international experts met in Hamburg for 2 days in October 2021. Results of the interdisciplinary, hybrid discussions in breakout groups and the plenary based on recently published and unpublished observations are summarized in this consensus paper to support improved care for patients with AF by guiding prevention, individualized management, and research strategies. The main outcomes are (i) new evidence supports a simple, scalable, and pragmatic population-based AF screening pathway; (ii) rhythm management is evolving from therapy aimed at improving symptoms to an integrated domain in the prevention of AF-related outcomes, especially in patients with recently diagnosed AF; (iii) improved characterization of atrial cardiomyopathy may help to identify patients in need for therapy; (iv) standardized assessment of cognitive function in patients with AF could lead to improvement in patient outcomes; and (v) artificial intelligence (AI) can support all of the above aims, but requires advanced interdisciplinary knowledge and collaboration as well as a better medico-legal framework. Implementation of new evidence-based approaches to AF screening and rhythm management can improve outcomes in patients with AF. Additional benefits are possible with further efforts to identify and target atrial cardiomyopathy and cognitive impairment, which can be facilitated by AI.
Single-nucleus RNA sequencing in ischemic cardiomyopathy reveals common transcriptional profile underlying end-stage heart failure
Simonson B, Chaffin M, Hill MC, Atwa O, Guedira Y, Bhasin H, Hall AW, Hayat S, Baumgart S, Bedi KC, Margulies KB, Klattenhoff CA and Ellinor PT
Ischemic cardiomyopathy (ICM) is the leading cause of heart failure worldwide, yet the cellular and molecular signature of this disease is largely unclear. Using single-nucleus RNA sequencing (snRNA-seq) and integrated computational analyses, we profile the transcriptomes of over 99,000 human cardiac nuclei from the non-infarct region of the left ventricle of 7 ICM transplant recipients and 8 non-failing (NF) controls. We find the cellular composition of the ischemic heart is significantly altered, with decreased cardiomyocytes and increased proportions of lymphatic, angiogenic, and arterial endothelial cells in patients with ICM. We show that there is increased LAMININ signaling from endothelial cells to other cell types in ICM compared with NF. Finally, we find that the transcriptional changes that occur in ICM are similar to those in hypertrophic and dilated cardiomyopathies and that the mining of these combined datasets can identify druggable genes that could be used to target end-stage heart failure.
Early rhythm-control therapy for atrial fibrillation in patients with a history of stroke: a subgroup analysis of the EAST-AFNET 4 trial
Jensen M, Suling A, Metzner A, Schnabel RB, Borof K, Goette A, Haeusler KG, Zapf A, Wegscheider K, Fabritz L, Diener HC, Thomalla G and Kirchhof P
Patients with atrial fibrillation and a history of stroke are at high risk of recurrent stroke and cardiovascular complications. In the EAST-AFNET 4 trial we showed that a systematic strategy of early rhythm control was associated with a lower risk of cardiovascular outcomes than usual care in patients with atrial fibrillation diagnosed in the past 12 months. In this pre-specified subgroup analysis we aimed to assess whether a strategy of early rhythm control is safe and can prevent adverse cardiovascular outcomes compared with usual care in such patients.
Characterisation of patients referred to a tertiary-level inherited cardiac condition clinic with suspected arrhythmogenic right ventricular cardiomyopathy (ARVC)
Aljehani A, Kew T, Baig S, Cox H, Sommerfeld LC, Ensam B, Kalla M, Steeds RP and Fabritz L
Arrhythmogenic right ventricular cardiomyopathy (ARVC) or arrhythmogenic cardiomyopathy is a rare inherited disease with incomplete penetrance and an environmental component. Although a rare disease, ARVC is a common cause of sudden cardiac death in young adults. Data on the different stages of ARVC remains scarce. The purpose of this study is to describe the initial presentation and cardiac phenotype of definite and non-definite ARVC for patients seen at a tertiary service.
Is Periodontitis a Modifiable Risk Factor for Atrial Fibrillation Substrate?
Goette A
Genomic risk scores, biomolecules, and clinical conditions to predict atrial fibrillation: time to integrate what we can measure
Kääb S, Holm H and Kirchhof P
A Gut Feeling: Lipopolysaccharide Links Gut Dysbiosis With Inflammatory Atrial Cardiomyopathy, Obesity, and Atrial Fibrillation
Fender AC and Dobrev D
Impacts of a high-fat diet on the metabolic profile and the phenotype of atrial myocardium in mice
Suffee N, Baptista E, Piquereau J, Ponnaiah M, Doisne N, Ichou F, Lhomme M, Pichard C, Galand V, Mougenot N, Dilanian G, Lucats L, Balse E, Mericskay M, Le Goff W and Hatem SN
Obesity, diabetes, and metabolic syndromes are risk factors of atrial fibrillation (AF). We tested the hypothesis that metabolic disorders have a direct impact on the atria favouring the formation of the substrate of AF.
Animal models and animal-free innovations for cardiovascular research: current status and routes to be explored. Consensus document of the ESC Working Group on Myocardial Function and the ESC Working Group on Cellular Biology of the Heart
van der Velden J, Asselbergs FW, Bakkers J, Batkai S, Bertrand L, Bezzina CR, Bot I, Brundel BJJM, Carrier L, Chamuleau S, Ciccarelli M, Dawson D, Davidson SM, Dendorfer A, Duncker DJ, Eschenhagen T, Fabritz L, Falcão-Pires I, Ferdinandy P, Giacca M, Girao H, Gollmann-Tepeköylü C, Gyongyosi M, Guzik TJ, Hamdani N, Heymans S, Hilfiker A, Hilfiker-Kleiner D, Hoekstra AG, Hulot JS, Kuster DWD, van Laake LW, Lecour S, Leiner T, Linke WA, Lumens J, Lutgens E, Madonna R, Maegdefessel L, Mayr M, van der Meer P, Passier R, Perbellini F, Perrino C, Pesce M, Priori S, Remme CA, Rosenhahn B, Schotten U, Schulz R, Sipido KR, Sluijter JPG, van Steenbeek F, Steffens S, Terracciano CM, Tocchetti CG, Vlasman P, Yeung KK, Zacchigna S, Zwaagman D and Thum T
Cardiovascular diseases represent a major cause of morbidity and mortality, necessitating research to improve diagnostics, and to discover and test novel preventive and curative therapies, all of which warrant experimental models that recapitulate human disease. The translation of basic science results to clinical practice is a challenging task, in particular for complex conditions such as cardiovascular diseases, which often result from multiple risk factors and comorbidities. This difficulty might lead some individuals to question the value of animal research, citing the translational 'valley of death', which largely reflects the fact that studies in rodents are difficult to translate to humans. This is also influenced by the fact that new, human-derived in vitro models can recapitulate aspects of disease processes. However, it would be a mistake to think that animal models do not represent a vital step in the translational pathway as they do provide important pathophysiological insights into disease mechanisms particularly on an organ and systemic level. While stem cell-derived human models have the potential to become key in testing toxicity and effectiveness of new drugs, we need to be realistic, and carefully validate all new human-like disease models. In this position paper, we highlight recent advances in trying to reduce the number of animals for cardiovascular research ranging from stem cell-derived models to in situ modelling of heart properties, bioinformatic models based on large datasets, and state-of-the-art animal models, which show clinically relevant characteristics observed in patients with a cardiovascular disease. We aim to provide a guide to help researchers in their experimental design to translate bench findings to clinical routine taking the replacement, reduction, and refinement (3R) as a guiding concept.
Guidelines for assessment of cardiac electrophysiology and arrhythmias in small animals
Ripplinger CM, Glukhov AV, Kay MW, Boukens BJ, Chiamvimonvat N, Delisle BP, Fabritz L, Hund TJ, Knollmann BC, Li N, Murray KT, Poelzing S, Quinn TA, Remme CA, Rentschler SL, Rose RA and Posnack NG
Cardiac arrhythmias are a major cause of morbidity and mortality worldwide. Although recent advances in cell-based models, including human-induced pluripotent stem cell-derived cardiomyocytes (iPSC-CM), are contributing to our understanding of electrophysiology and arrhythmia mechanisms, preclinical animal studies of cardiovascular disease remain a mainstay. Over the past several decades, animal models of cardiovascular disease have advanced our understanding of pathological remodeling, arrhythmia mechanisms, and drug effects and have led to major improvements in pacing and defibrillation therapies. There exist a variety of methodological approaches for the assessment of cardiac electrophysiology and a plethora of parameters may be assessed with each approach. This guidelines article will provide an overview of the strengths and limitations of several common techniques used to assess electrophysiology and arrhythmia mechanisms at the whole animal, whole heart, and tissue level with a focus on small animal models. We also define key electrophysiological parameters that should be assessed, along with their physiological underpinnings, and the best methods with which to assess these parameters.
Smartphone and wearable detected atrial arrhythmias in Older Adults: Results of a fully digital European Case finding study
Fabritz L, Connolly DL, Czarnecki E, Dudek D, Guasch E, Haase D, Huebner T, Zlahoda-Huzior A, Jolly K, Kirchhof P, Obergassel J, Schotten U, Vettorazzi E, Winkelmann SJ, Zapf A, Schnabel RB and
Simplified detection of atrial arrhythmias via consumer-electronics would enable earlier therapy in at-risk populations. Whether this is feasible and effective in older populations is not known.
Persisting stroke risk in patients with atrial fibrillation despite proper anticoagulation - Unmet clinical needs
Bruns F, Dobrev D and Fender AC
Recent highlights on thrombosis and hemostasis from the International Journal of Cardiology: Heart & Vasculature
Fender AC and Dobrev D
Atrial fibrillation in the presence and absence of heart failure enhances expression of genes involved in cardiomyocyte structure, conduction properties, fibrosis, inflammation, and endothelial dysfunction
Zeemering S, Isaacs A, Winters J, Maesen B, Bidar E, Dimopoulou C, Guasch E, Batlle M, Haase D, Hatem SN, Kara M, Kääb S, Mont L, Sinner MF, Wakili R, Maessen J, Crijns HJGM, Fabritz L, Kirchhof P, Stoll M and Schotten U
Little is known about genome-wide changes in the atrial transcriptome as a cause or consequence of atrial fibrillation (AF), and the effect of its common and clinically relevant comorbidity-heart failure (HF).
Eligibility for early rhythm control in patients with atrial fibrillation in the UK Biobank
Kany S, Cardoso VR, Bravo L, Williams JA, Schnabel R, Fabritz L, Gkoutos GV and Kirchhof P
The Early Treatment of Atrial Fibrillation for Stroke Prevention (EAST-AFNET4) trial showed a clinical benefit of early rhythm-control therapy in patients with recently diagnosed atrial fibrillation (AF). The generalisability of the results in the general population is not known.
A State-of-the-Art Survey of Tasks for Tree Design and Evaluation With a Curated Task Dataset
Pandey A, Syeda UH, Shah C, Guerra-Gomez JA and Borkin MA
In the field of information visualization, the concept of "tasks" is an essential component of theories and methodologies for how a visualization researcher or a practitioner understands what tasks a user needs to perform and how to approach the creation of a new design. In this article, we focus on the collection of tasks for tree visualizations, a common visual encoding in many domains ranging from biology to computer science to geography. In spite of their commonality, no prior efforts exist to collect and abstractly define tree visualization tasks. We present a literature review of tree visualization articles and generate a curated dataset of over 200 tasks. To enable effective task abstraction for trees, we also contribute a novel extension of the Multi-Level Task Typology to include more specificity to support tree-specific tasks as well as a systematic procedure to conduct task abstractions for tree visualizations. All tasks in the dataset were abstracted with the novel typology extension and analyzed to gain a better understanding of the state of tree visualizations. These abstracted tasks can benefit visualization researchers and practitioners as they design evaluation studies or compare their analytical tasks with ones previously studied in the literature to make informed decisions about their design. We also reflect on our novel methodology and advocate more broadly for the creation of task-based knowledge repositories for different types of visualizations. The Supplemental Material, which can be found on the Computer Society Digital Library at http://doi.ieeecomputersociety.org/10.1109/TVCG.2021.3064037, will be maintained on OSF: https://osf.io/u5ehs/.
A Generative Deep Learning Approach to Stochastic Downscaling of Precipitation Forecasts
Harris L, McRae ATT, Chantry M, Dueben PD and Palmer TN
Despite continuous improvements, precipitation forecasts are still not as accurate and reliable as those of other meteorological variables. A major contributing factor to this is that several key processes affecting precipitation distribution and intensity occur below the resolved scale of global weather models. Generative adversarial networks (GANs) have been demonstrated by the computer vision community to be successful at super-resolution problems, that is, learning to add fine-scale structure to coarse images. Leinonen et al. (2020, https://doi.org/10.1109/TGRS.2020.3032790) previously applied a GAN to produce ensembles of reconstructed high-resolution atmospheric fields, given coarsened input data. In this paper, we demonstrate this approach can be extended to the more challenging problem of increasing the accuracy and resolution of comparatively low-resolution input from a weather forecasting model, using high-resolution radar measurements as a "ground truth." The neural network must learn to add resolution and structure whilst accounting for non-negligible forecast error. We show that GANs and VAE-GANs can match the statistical properties of state-of-the-art pointwise post-processing methods whilst creating high-resolution, spatially coherent precipitation maps. Our model compares favorably to the best existing downscaling methods in both pixel-wise and pooled CRPS scores, power spectrum information and rank histograms (used to assess calibration). We test our models and show that they perform in a range of scenarios, including heavy rainfall.
Genetic inhibition of serum glucocorticoid kinase 1 prevents obesity-related atrial fibrillation
Bapat A, Li G, Xiao L, Yeri A, Hulsmans M, Grune J, Yamazoe M, Schloss MJ, Iwamoto Y, Tedeschi J, Yang X, Nahrendorf M, Rosenzweig A, Ellinor PT, Das S and Milan D
Obesity is an important risk factor for atrial fibrillation (AF), but a better mechanistic understanding of obesity-related atrial fibrillation is required. Serum glucocorticoid kinase 1 (SGK1) is a kinase positioned within multiple obesity-related pathways, and prior work has shown a pathologic role of SGK1 signaling in ventricular arrhythmias. We validated a mouse model of obesity-related AF using wild-type mice fed a high-fat diet. RNA sequencing of atrial tissue demonstrated substantial differences in gene expression, with enrichment of multiple SGK1-related pathways, and we showed upregulated of SGK1 transcription, activation, and signaling in obese atria. Mice expressing a cardiac specific dominant-negative SGK1 were protected from obesity-related AF, through effects on atrial electrophysiology, action potential characteristics, structural remodeling, inflammation, and sodium current. Overall, this study demonstrates the promise of targeting SGK1 in a mouse model of obesity-related AF.
Attaining sinus rhythm mediates improved outcome with early rhythm control therapy of atrial fibrillation: the EAST-AFNET 4 trial
Eckardt L, Sehner S, Suling A, Borof K, Breithardt G, Crijns H, Goette A, Wegscheider K, Zapf A, Camm J, Metzner A and Kirchhof P
A strategy of systematic, early rhythm control (ERC) improves cardiovascular outcomes in patients with atrial fibrillation (AF). It is not known how this outcome-reducing effect is mediated.
The Complex Relation between Atrial Cardiomyopathy and Thrombogenesis
D'Alessandro E, Winters J, van Nieuwenhoven FA, Schotten U and Verheule S
Heart disease, as well as systemic metabolic alterations, can leave a 'fingerprint' of structural and functional changes in the atrial myocardium, leading to the onset of atrial cardiomyopathy. As demonstrated in various animal models, some of these changes, such as fibrosis, cardiomyocyte hypertrophy and fatty infiltration, can increase vulnerability to atrial fibrillation (AF), the most relevant manifestation of atrial cardiomyopathy in clinical practice. Atrial cardiomyopathy accompanying AF is associated with thromboembolic events, such as stroke. The interaction between AF and stroke appears to be far more complicated than initially believed. AF and stroke share many risk factors whose underlying pathological processes can reinforce the development and progression of both cardiovascular conditions. In this review, we summarize the main mechanisms by which atrial cardiomyopathy, preceding AF, supports thrombogenic events within the atrial cavity and myocardial interstitial space. Moreover, we report the pleiotropic effects of activated coagulation factors on atrial remodeling, which may aggravate atrial cardiomyopathy. Finally, we address the complex association between AF and stroke, which can be explained by a multidirectional causal relation between atrial cardiomyopathy and hypercoagulability.
Contactless medical equipment AI big data risk control and quasi thinking iterative planning
Rongrong Z
Research Background, the intelligent polymorphic system of heavy core clustering fitting iterative programming is constructed by using the edge lens of dual core heavy core. The tracking system of heavy core TANH equilibrium array is used to obtain the abnormal data range. The energy regular fluctuation of the edge lens with dual core and heavy core is used to obtain high-definition images. And build the complexity dependent parameter group from low-end equipment to high-end equipment. Heavy core clustering of hierarchical fuzzy clustering system based on differential incremental balance theory is applied to Contactless medical equipment AI big data risk control and quasi thinking iterative planning. At the same time, the mathematical model risk control is performed by fitting the TANH balance of the local nonlinear random regular micro-vibration diffusion curve. The CT/MR original data is subjected to hierarchical cross domain overlapping grid screening with the structure of fitting weakly nonlinear curve, which can capture the heavy core cluster analysis of the core layer of big data anomalies [1:10]. Successfully control the parameter group of CT/MR machine internal data, big data AI Mathematical model risk. The polar graph of high-dimensional heavy core clustering processing data is regular and scientific. The same time, it can prevent the dimension disaster caused by the construction of high-dimensional big data due to the partial loss of original data, and form a stable and predictable maintenance of CT/MR. Compared with the discrete characteristics of the polar graph of the original data. So as to correctly detect and control the dynamic change process of CT/MR in the entire life cycle. It provides help for predictive maintenance of early pre-inspection and orderly maintenance of the medical system, and developed standardized model software of automated unsupervised learning for medical big equipment big data AI Mathematical model risk control. Scientifically evaluated the exposure time and heat capacity MHU% of CT tubes, as well as the internal law of MR (nuclear magnetic resonance), and processed big data twice and three times in heavy nuclear clustering. After optimizing the algorithm, hundreds of thousands of nonlinear random vibrations are performed in the operation and maintenance database every second, and at least 30 concurrent operations are formed, which greatly improves and shortens the operation time (Yanwei et al. in J Complex 2017:1-9, 2017. https://doi.org/10.1155/2017/3437854 ). Finally, after adding micro-vibration quasi thinking iterative planning for the uncertain structure of AI operation, we can successfully obtain the scientific and correct results required by high-dimensional information and analyze images. This kind of AI big data risk control improves the intelligent management ability of medical institutions. Cross platform embedded web system for predictable maintenance of AI big data is established (Qi et al. in J IEEE Trans Ind Inf 99:1, 2020. https://doi.org/10.1109/tii.2020.3012157 ).
Assessment of atrial function by echocardiography: Can this be used to assess the arrhythmogenic atrial substrate?
Bruns F and Dobrev D
Symptoms and risk factors for long COVID in non-hospitalized adults
Subramanian A, Nirantharakumar K, Hughes S, Myles P, Williams T, Gokhale KM, Taverner T, Chandan JS, Brown K, Simms-Williams N, Shah AD, Singh M, Kidy F, Okoth K, Hotham R, Bashir N, Cockburn N, Lee SI, Turner GM, Gkoutos GV, Aiyegbusi OL, McMullan C, Denniston AK, Sapey E, Lord JM, Wraith DC, Leggett E, Iles C, Marshall T, Price MJ, Marwaha S, Davies EH, Jackson LJ, Matthews KL, Camaradou J, Calvert M and Haroon S
Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection is associated with a range of persistent symptoms impacting everyday functioning, known as post-COVID-19 condition or long COVID. We undertook a retrospective matched cohort study using a UK-based primary care database, Clinical Practice Research Datalink Aurum, to determine symptoms that are associated with confirmed SARS-CoV-2 infection beyond 12 weeks in non-hospitalized adults and the risk factors associated with developing persistent symptoms. We selected 486,149 adults with confirmed SARS-CoV-2 infection and 1,944,580 propensity score-matched adults with no recorded evidence of SARS-CoV-2 infection. Outcomes included 115 individual symptoms, as well as long COVID, defined as a composite outcome of 33 symptoms by the World Health Organization clinical case definition. Cox proportional hazards models were used to estimate adjusted hazard ratios (aHRs) for the outcomes. A total of 62 symptoms were significantly associated with SARS-CoV-2 infection after 12 weeks. The largest aHRs were for anosmia (aHR 6.49, 95% CI 5.02-8.39), hair loss (3.99, 3.63-4.39), sneezing (2.77, 1.40-5.50), ejaculation difficulty (2.63, 1.61-4.28) and reduced libido (2.36, 1.61-3.47). Among the cohort of patients infected with SARS-CoV-2, risk factors for long COVID included female sex, belonging to an ethnic minority, socioeconomic deprivation, smoking, obesity and a wide range of comorbidities. The risk of developing long COVID was also found to be increased along a gradient of decreasing age. SARS-CoV-2 infection is associated with a plethora of symptoms that are associated with a range of sociodemographic and clinical risk factors.
Gut microbiota, dysbiosis and atrial fibrillation. Arrhythmogenic mechanisms and potential clinical implications
Gawałko M, Agbaedeng TA, Saljic A, Müller DN, Wilck N, Schnabel R, Penders J, Rienstra M, van Gelder I, Jespersen T, Schotten U, Crijns HJGM, Kalman JM, Sanders P, Nattel S, Dobrev D and Linz D
Recent preclinical and observational cohort studies have implicated imbalances in gut microbiota composition as a contributor to atrial fibrillation (AF). The gut microbiota is a complex and dynamic ecosystem containing trillions of microorganisms, which produces bioactive metabolites influencing host health and disease development. In addition to host-specific determinants, lifestyle-related factors such as diet and drugs are important determinants of the gut microbiota composition. In this review, we discuss the evidence suggesting a potential bidirectional association between AF and gut microbiota, identifying gut microbiota-derived metabolites as possible regulators of the AF substrate. We summarize the effect of gut microbiota on the development and progression of AF risk factors, including heart failure, hypertension, obesity, and coronary artery disease. We also discuss the potential anti-arrhythmic effects of pharmacological and diet-induced modifications of gut microbiota composition, which may modulate and prevent the progression to AF. Finally, we highlight important gaps in knowledge and areas requiring future investigation. Although data supporting a direct relationship between gut microbiota and AF are very limited at the present time, emerging preclinical and clinical research dealing with mechanistic interactions between gut microbiota and AF is important as it may lead to new insights into AF pathophysiology and the discovery of novel therapeutic targets for AF.
Errata to "Parallax Free Registration for Augmented Reality Optical See-Through Displays in the Peripersonal Space" [1] (DOI: 10.1109/TVCG.2020.3021534)
Ferrari V, Cattari N, Fontana U and Cutolo F
In the original article, there was a mistake in the content of Table 2 page 8 column 1 as published. The values of the mean and standard deviation of the virtual-to-real overlay error in visual angles, which are reported for different checkerboard distances, are to be corrected. Due to a typing error within the data analysis code, we mistakenly considered an erroneous value of the average angular resolution for the eye-replacement camera. This scale factor is used to pass from the original registration errors (expressed in pixel) to the angular registration errors (in arcmin). The value of the average angular resolution is $\approx 2.67$≈2.67 arcmin/pixel. The corrected Table 2 appears below.
LMNA Variants and Risk of Adult-Onset Cardiac Disease
Lazarte J, Jurgens SJ, Choi SH, Khurshid S, Morrill VN, Weng LC, Nauffal V, Pirruccello JP, Halford JL, Hegele RA, Ellinor PT, Lunetta KL and Lubitz SA
Genetic variants in LMNA may cause cardiac disease, but population-level contributions of variants to cardiac disease burden are not well-characterized.
Presenting Pattern of Atrial Fibrillation and Outcomes of Early Rhythm Control Therapy
Goette A, Borof K, Breithardt G, Camm AJ, Crijns HJGM, Kuck KH, Wegscheider K, Kirchhof P and
Whether atrial fibrillation (AF) pattern or timing of AF therapy modifies the effectiveness of early rhythm control (ERC) is not known.
Endomysial fibrosis, rather than overall connective tissue content, is the main determinant of conduction disturbances in human atrial fibrillation
Maesen B, Verheule S, Zeemering S, La Meir M, Nijs J, Lumeij S, Lau DH, Granier M, Crijns HJ, Maessen JG, Dhein S and Schotten U
Although in persistent atrial fibrillation (AF) a complex AF substrate characterized by a high incidence of conduction block has been reported, relatively little is known about AF complexity in paroxysmal AF (pAF). Also, the relative contribution of various aspects of structural alterations to conduction disturbances is not clear. In particular, the contribution of endomysial fibrosis to conduction disturbances during progression of AF has not been studied yet.
The temporal context of oral anticoagulation outcome in atrial fibrillation
Fender AC and Dobrev D
gene rescues ion channel function and is antiarrhythmic in cardiomyocytes derived from induced pluripotent stem cells from muscular dystrophy patients
Jimenez-Vazquez EN, Arad M, Macías Á, Vera-Pedrosa ML, Cruz FM, Gutierrez LK, Cuttitta AJ, Monteiro da Rocha A, Herron TJ, Ponce-Balbuena D, Guerrero-Serna G, Binah O, Michele DE and Jalife J
Patients with cardiomyopathy of Duchenne Muscular Dystrophy (DMD) are at risk of developing life-threatening arrhythmias, but the mechanisms are unknown. We aimed to determine the role of ion channels controlling cardiac excitability in the mechanisms of arrhythmias in DMD patients.
Epicardial origin of cardiac arrhythmias: clinical evidences and pathophysiology
Chaumont C, Suffee N, Gandjbakhch E, Balse E, Anselme F and Hatem SN
Recent developments in imaging, mapping, and ablation techniques have shown that the epicardial region of the heart is a key player in the occurrence of ventricular arrhythmic events in several cardiac diseases, such as Brugada syndrome, arrhythmogenic cardiomyopathy, or dilated cardiomyopathy. At the atrial level as well, the epicardial region has emerged as an important determinant of the substrate of atrial fibrillation, pointing to common underlying pathophysiological mechanisms. Alteration in the gradient of repolarization between myocardial layers favouring the occurrence of re-entry circuits has largely been described. The fibro-fatty infiltration of the subepicardium is another shared substrate between ventricular and atrial arrhythmias. Recent data have emphasized the role of the epicardial reactivation in the formation of this arrhythmogenic substrate. There are new evidences supporting this structural remodelling process to be regulated by the recruitment of epicardial progenitor cells that can differentiate into adipocytes or fibroblasts under various stimuli. In addition, immune-inflammatory processes can also contribute to fibrosis of the subepicardial layer. A better understanding of such 'electrical fragility' of the epicardial area will open perspectives for novel biomarkers and therapeutic strategies. In this review article, a pathophysiological scheme of epicardial-driven arrhythmias will be proposed.
Increased atrial effectiveness of flecainide conferred by altered biophysical properties of sodium channels
O' Brien S, Holmes AP, Johnson DM, Kabir SN, O' Shea C, O' Reilly M, Avezzu A, Reyat JS, Hall AW, Apicella C, Ellinor PT, Niederer S, Tucker NR, Fabritz L, Kirchhof P and Pavlovic D
Atrial fibrillation (AF) affects over 1% of the population and is a leading cause of stroke and heart failure in the elderly. A feared side effect of sodium channel blocker therapy, ventricular pro-arrhythmia, appears to be relatively rare in patients with AF. The biophysical reasons for this relative safety of sodium blockers are not known. Our data demonstrates intrinsic differences between atrial and ventricular cardiac voltage-gated sodium currents (I), leading to reduced maximum upstroke velocity of action potential and slower conduction, in left atria compared to ventricle. Reduced atrial I is only detected at physiological membrane potentials and is driven by alterations in sodium channel biophysical properties and not by Na1.5 protein expression. Flecainide displayed greater inhibition of atrial I, greater reduction of maximum upstroke velocity of action potential, and slowed conduction in atrial cells and tissue. Our work highlights differences in biophysical properties of sodium channels in left atria and ventricles and their response to flecainide. These differences can explain the relative safety of sodium channel blocker therapy in patients with atrial fibrillation.
The Increasing Role of Rhythm Control in Patients With Atrial Fibrillation: JACC State-of-the-Art Review
Camm AJ, Naccarelli GV, Mittal S, Crijns HJGM, Hohnloser SH, Ma CS, Natale A, Turakhia MP and Kirchhof P
The considerable mortality and morbidity associated with atrial fibrillation (AF) pose a substantial burden on patients and health care services. Although the management of AF historically focused on decreasing AF recurrence, it evolved over time in favor of rate control. Recently, more emphasis has been placed on reducing adverse cardiovascular outcomes using rhythm control, generally by using safe and effective rhythm-control therapies (typically antiarrhythmic drugs and/or AF ablation). Evidence increasingly supports early rhythm control in patients with AF that has not become long-standing, but current clinical practice and guidelines do not yet fully reflect this change. Early rhythm control may effectively reduce irreversible atrial remodeling and prevent AF-related deaths, heart failure, and strokes in high-risk patients. It has the potential to halt progression and potentially save patients from years of symptomatic AF; therefore, it should be offered more widely.
Security enhancement for adaptive optics aided longitudinal orbital angular momentum multiplexed underwater wireless communications
Zhu L, Xin X, Chang H, Wang X, Tian Q, Zhang Q, Gao R and Liu B
The frozen-wave-based longitudinal orbital angular momentum multiplexing (LOAMM) system developed in [IEEE Photonics J.10, 7900416 (2018)10.1109/JPHOT.2017.2778238] has the potential to overcome the crosstalk effects induced by turbulence. In this paper, we propose a defocus measurement aided adaptive optics (DMA-AO) technique for turbulence compensation in a LOAMM underwater wireless optical communication (UWOC) system to investigate the enhancement of physical layer security. Relying on a phase retrieval algorithm and probe beam, three amplitude-only measurements obtained from different back focus planes can realize phase reconstruction of distorted OAM beams. Moreover, the so-called mixture generalized gamma-Johnson S (GJSB) distribution is proposed to characterize the probability density function (PDF) of reference-channel irradiance of OAM. The GJSB allows for obtaining closed-form and analytically tractable expression for the probability of strictly positive secrecy capacity (SPSC) in a single input single output (SISO) system. Furthermore, the average secrecy capacity (ASC) and probability of SPSC for a multiple input multiple output (MIMO) system are investigated. Compared to the traditional OAM multiplexing system based on Laguerre-Gaussian (LG) beams, the LOAMM system with a probe beam assisted DMA-AO technique has potential advantages for improving the security performance in UWOC.
Development of a Framework for the Implementation of Synchronous Digital Mental Health: Realist Synthesis of Systematic Reviews
Villarreal-Zegarra D, Alarcon-Ruiz CA, Melendez-Torres GJ, Torres-Puente R, Navarro-Flores A, Cavero V, Ambrosio-Melgarejo J, Rojas-Vargas J, Almeida G, Albitres-Flores L, Romero-Cabrera AB and Huarcaya-Victoria J
The use of technologies has served to reduce gaps in access to treatment, and digital health interventions show promise in the care of mental health problems. However, to understand what and how these interventions work, it is imperative to document the aspects related to their challenging implementation.
High resolution optical mapping of cardiac electrophysiology in pre-clinical models
O'Shea C, Winter J, Kabir SN, O'Reilly M, Wells SP, Baines O, Sommerfeld LC, Correia J, Lei M, Kirchhof P, Holmes AP, Fabritz L, Rajpoot K and Pavlovic D
Optical mapping of animal models is a widely used technique in pre-clinical cardiac research. It has several advantages over other methods, including higher spatial resolution, contactless recording and direct visualisation of action potentials and calcium transients. Optical mapping enables simultaneous study of action potential and calcium transient morphology, conduction dynamics, regional heterogeneity, restitution and arrhythmogenesis. In this dataset, we have optically mapped Langendorff perfused isolated whole hearts (mouse and guinea pig) and superfused isolated atria (mouse). Raw datasets (consisting of over 400 files) can be combined with open-source software for processing and analysis. We have generated a comprehensive post-processed dataset characterising the baseline cardiac electrophysiology in these widely used pre-clinical models. This dataset also provides reference information detailing the effect of heart rate, clinically used anti-arrhythmic drugs, ischaemia-reperfusion and sympathetic nervous stimulation on cardiac electrophysiology. The effects of these interventions can be studied in a global or regional manner, enabling new insights into the prevention and initiation of arrhythmia.
CACONET: a novel classification framework for microbial correlation networks
Xu Y, Nash K, Acharjee A and Gkoutos GV
Existing microbiome-based disease prediction relies on the ability of machine learning methods to differentiate disease from healthy subjects based on the observed taxa abundance across samples. Despite numerous microbes have been implicated as potential biomarkers, challenges remain due to not only the statistical nature of microbiome data but also the lack of understanding of microbial interactions which can be indicative of the disease.
Interactions Between Atrial Fibrillation and Natriuretic Peptide in Predicting Heart Failure Hospitalization or Cardiovascular Death
Brady PF, Chua W, Nehaj F, Connolly DL, Khashaba A, Purmah YJV, Ul-Qamar MJ, Thomas MR, Varma C, Schnabel RB, Zeller T, Fabritz L and Kirchhof PF
Background Natriuretic peptides are routinely quantified to diagnose heart failure (HF). Their concentrations are also elevated in atrial fibrillation (AF). To clarify their value in predicting future cardiovascular events, we measured natriuretic peptides in unselected patients with cardiovascular conditions and related their concentrations to AF and HF status and outcomes. Methods and Results Consecutive patients with cardiovascular conditions presenting to a large teaching hospital underwent clinical assessment, 7-day ECG monitoring, and echocardiography to diagnose AF and HF. NT-proBNP (N-terminal pro-B-type natriuretic peptide) was centrally quantified. Based on a literature review, four NT-proBNP groups were defined (<300, 300-999, 1000-1999, and ≥2000 pg/mL). Clinical characteristics and NT-proBNP concentrations were related to HF hospitalization or cardiovascular death. Follow-up data were available in 1616 of 1621 patients (99.7%) and analysis performed at 2.5 years (median age, 70 [interquartile range, 60-78] years; 40% women). HF hospitalization or cardiovascular death increased from 36 of 488 (3.2/100 person-years) in patients with neither AF nor HF, to 55 of 354 (7.1/100 person-years) in patients with AF only, 92 of 369 (12.1/100 person-years) in patients with HF only, and 128 of 405 (17.7/100 person-years) in patients with AF plus HF (<0.001). Higher NT-proBNP concentrations predicted the outcome in patients with AF only (C-statistic, 0.82; 95% CI, 0.77-0.86; <0.001) and in other phenotype groups (C-statistic in AF plus HF, 0.66; [95% CI, 0.61-0.70]; <0.001). Conclusions Elevated NT-proBNP concentrations predict future HF events in patients with AF irrespective of the presence of HF, encouraging routine quantification of NT-proBNP in the assessment of patients with AF.
Minding the gap - Heterogeneity of antithrombotic treatment preferences in complex scenarios in absence of evidence-based guidelines
Fender AC, Bruns F and Dobrev D
Mutation in a Family with a Strong History of Sudden Cardiac Death
Keil L, Berisha F, Knappe D, Kubisch C, Shoukier M, Kirchhof P, Fabritz L, Hellenbroich Y, Woitschach R and Magnussen C
We report a family with heterozygous deletion of exons 3-6 of the gene. The main presentation of affected family members was characterized by ventricular and supraventricular arrhythmias, atrioventricular (AV) block and sudden cardiac death (SCD) but also by severe dilative cardiomyopathy (DCM). We report on two siblings, a 36-year-old female and her 40-year-old brother, who suffer from heart failure with mildly reduced ejection fraction, AV conduction delays and premature ventricular complexes. Their 65-year-old mother underwent heart transplantation at the age of 55 due to advanced heart failure. Originally, the mutation was detected in one of the uncles. This index patient and three of his brothers died of SCD as well as their father and aunt. The two siblings were treated with implanted defibrillators in our specialized tertiary heart failure center. This case report places this specific genetic variant in the context of LMNA-associated familial DCM.
Atrial fibrillation and stroke: are we looking in the right direction?
Hatem SN and Cohen A
Clinical and electrophysiological predictors of device-detected new-onset atrial fibrillation during 3 years after cardiac surgery
Bidar E, Zeemering S, Gilbers M, Isaacs A, Verheule S, Zink MD, Maesen B, Bramer S, Kawczynski M, Van Gelder IC, Crijns HJGM, Maessen JG and Schotten U
Postoperative atrial fibrillation (POAF) after cardiac surgery is an independent predictor of stroke and mortality late after discharge. We aimed to determine the burden and predictors of early (up to 5th postoperative day) and late (after 5th postoperative day) new-onset atrial fibrillation (AF) using implantable loop recorders (ILRs) in patients undergoing open chest cardiac surgery.
Pathophysiological differences between atrial fibrillation subgoups: Is there a fibrillatory-induced atherosclerotic disease progression?
Goette A
Clearing the cognitive cloud: direct oral anticoagulants or vitamin K antagonists for reducing dementia risk in patients with atrial fibrillation?
Chua W
Proteomics: A promising approach to discover new biomarkers for atrial fibrillation
Song J, Dobrev D and Li N
Electrophysiological Consequences of Cardiac Fibrosis
Verheule S and Schotten U
For both the atria and ventricles, fibrosis is generally recognized as one of the key determinants of conduction disturbances. By definition, fibrosis refers to an increased amount of fibrous tissue. However, fibrosis is not a singular entity. Various forms can be distinguished, that differ in distribution: replacement fibrosis, endomysial and perimysial fibrosis, and perivascular, endocardial, and epicardial fibrosis. These different forms typically result from diverging pathophysiological mechanisms and can have different consequences for conduction. The impact of fibrosis on propagation depends on exactly how the patterns of electrical connections between myocytes are altered. We will therefore first consider the normal patterns of electrical connections and their regional diversity as determinants of propagation. Subsequently, we will summarize current knowledge on how different forms of fibrosis lead to a loss of electrical connectivity in order to explain their effects on propagation and mechanisms of arrhythmogenesis, including ectopy, reentry, and alternans. Finally, we will discuss a histological quantification of fibrosis. Because of the different forms of fibrosis and their diverging effects on electrical propagation, the total amount of fibrosis is a poor indicator for the effect on conduction. Ideally, an assessment of cardiac fibrosis should exclude fibrous tissue that does not affect conduction and differentiate between the various types that do; in this article, we highlight practical solutions for histological analysis that meet these requirements.
Effective termination of atrial fibrillation by SK channel inhibition is associated with a sudden organization of fibrillatory conduction
Gatta G, Sobota V, Citerni C, Diness JG, Sørensen US, Jespersen T, Bentzen BH, Zeemering S, Kuiper M, Verheule S, Schotten U and van Hunnik A
Pharmacological termination of atrial fibrillation (AF) remains a challenge due to limited efficacy and potential ventricular proarrhythmic effects of antiarrhythmic drugs. SK channels are proposed as atrial-specific targets in the treatment of AF. Here, we investigated the effects of the new SK channel inhibitor AP14145.
Nitric oxide as a fragile switch between cardioprotection and cardiac injury
Fender AC and Dobrev D
Evolutionarily conserved transcriptional landscape of the heart defining the chamber specific physiology
Gandhi S, Witten A, De Majo F, Gilbers M, Maessen J, Schotten U, de Windt LJ and Stoll M
Cardiovascular disease (CVD) remains the leading cause of death worldwide. A deeper characterization of regional transcription patterns within different heart chambers may aid to improve our understanding of the molecular mechanisms involved in myocardial function and further, our ability to develop novel therapeutic strategies. Here, we used RNA sequencing to determine differentially expressed protein coding (PC) and long non-coding (lncRNA) transcripts within the heart chambers across seven vertebrate species and identified evolutionarily conserved chamber specific genes, lncRNAs and pathways. We investigated lncRNA homologs based on sequence, secondary structure, synteny and expressional conservation and found most lncRNAs to be conserved by synteny. Regional co-expression patterns of transcripts are modulated by multiple factors, including genomic overlap, strandedness and transcript biotype. Finally, we provide a community resource designated EvoACTG, which informs researchers on the conserved yet intertwined nature of the coding and non-coding cardiac transcriptome across popular model organisms in CVD research.
Diminished PLK2 Induces Cardiac Fibrosis and Promotes Atrial Fibrillation
Künzel SR, Hoffmann M, Weber S, Künzel K, Kämmerer S, Günscht M, Klapproth E, Rausch JSE, Sadek MS, Kolanowski T, Meyer-Roxlau S, Piorkowski C, Tugtekin SM, Rose-John S, Yin X, Mayr M, Kuhlmann JD, Wimberger P, Grützmann K, Herzog N, Küpper JH, O'Reilly M, Kabir SN, Sommerfeld LC, Guan K, Wielockx B, Fabritz L, Nattel S, Ravens U, Dobrev D, Wagner M and El-Armouche A
[Figure: see text].
Considerations for the Assessment of Substrates, Genetics and Risk Factors in Patients with Atrial Fibrillation
Linz D, Verheule S, Isaacs A and Schotten U
Successful translation of research focussing on atrial arrhythmogenic mechanisms has potential to provide a mechanism-tailored classification and to support personalised treatment approaches in patients with AF. The clinical uptake and clinical implementation of new diagnostic techniques and treatment strategies require translational research approaches on various levels. Diagnostic translation involves the development of clinical diagnostic tools. Additionally, multidisciplinary teams are required for collaborative translation to describe genetic mechanisms, molecular pathways, electrophysiological characteristics and concomitant risk factors. In this article, current approaches for AF substrate characterisation, analysis of genes potentially involved in AF and strategies for AF risk factor assessment are summarised. The authors discuss challenges and obstacles to clinical translation and implementation into clinical practice.
The virtual patient - Estimating the health utility of aspirin in simulated populations
Fender AC and Dobrev D
Polarimetric visualization of healthy brain fiber tracts under adverse conditions: studies
Rodríguez-Núñez O, Schucht P, Hewer E, Novikova T and Pierangelo A
We suggest using the wide-field imaging Mueller polarimetry to contrast optically anisotropic fiber tracts of healthy brain white matter for the detection of brain tumor borders during neurosurgery. Our prior studies demonstrate that this polarimetric imaging modality detects correctly the in-plane orientation of brain white matter fiber tracts of a flat formalin-fixed thick brain specimen in reflection geometry [IEEE Trans. Med. Imaging39, 4376 (2020)10.1109/TMI.2020.3018439]. Here we present the results of polarimetric studies of large cross-sections of fresh calf brain in reflection geometry with a special focus on the impact of the adverse measurement conditions (e.g. complex surface topography, presence of blood, etc.) on the quality of polarimetric images and the detection performance of white matter fiber tracts and their in-plane orientation.
Oxidative stress: a bystander or a causal contributor to atrial remodelling and fibrillation?
Dobrev D and Dudley SC
Remodeling of Ion Channel Trafficking and Cardiac Arrhythmias
Blandin CE, Gravez BJ, Hatem SN and Balse E
Both inherited and acquired cardiac arrhythmias are often associated with the abnormal functional expression of ion channels at the cellular level. The complex machinery that continuously traffics, anchors, organizes, and recycles ion channels at the plasma membrane of a cardiomyocyte appears to be a major source of channel dysfunction during cardiac arrhythmias. This has been well established with the discovery of mutations in the genes encoding several ion channels and ion channel partners during inherited cardiac arrhythmias. Fibrosis, altered myocyte contacts, and post-transcriptional protein changes are common factors that disorganize normal channel trafficking during acquired cardiac arrhythmias. Channel availability, described notably for hERG and K1.5 channels, could be another potent arrhythmogenic mechanism. From this molecular knowledge on cardiac arrhythmias will emerge novel antiarrhythmic strategies.
Atrial Cardiomyopathy: Pathophysiology and Clinical Consequences
Goette A and Lendeckel U
Around the world there are 33.5 million patients suffering from atrial fibrillation (AF) with an annual increase of 5 million cases. Most AF patients have an established form of an atrial cardiomyopathy. The concept of atrial cardiomyopathy was introduced in 2016. Thus, therapy of underlying diseases and atrial tissue changes appear as a cornerstone of AF therapy. Furthermore, therapy or prevention of atrial endocardial changes has the potential to reduce atrial thrombogenesis and thereby cerebral stroke. The present manuscript will summarize the underlying pathophysiology and remodeling processes observed in the development of an atrial cardiomyopathy, thrombogenesis, and atrial fibrillation. In particular, the impact of oxidative stress, inflammation, diabetes, and obesity will be addressed.
Childhood infection and modern malnutrition: Do childhood infections create an inflammatory foundation for atherosclerosis in adult life?
Fender AC and Dobrev D
Heart failure in patients with atrial fibrillation: why it matters now more than ever
Chua W and Fabritz L
Taking the heavy load off arrhythmogenic right ventricular cardiomyopathy
Fabritz L, Patten M and Kirchhof P
Revealing the molecular history of the transition from paroxysmal to permanent atrial fibrillation
Hatem SN
Oral anticoagulation and therapy of atrial flutter: discontinuation of anticoagulation revisited
Gawałko M and Dobrev D
Challenges and opportunities in improving the management of atrial fibrillation: recent research advances and their clinical translation
Nattel S, Lip GYH, Filgueiras-Rama D and Dobrev D
From translation to integration: how to approach the complexity of atrial fibrillation mechanisms
Schotten U
Gut-microbiota derived TMAO: A risk factor, a mediator or a bystander in the pathogenesis of atrial fibrillation?
Gawałko M, Linz D and Dobrev D
Mobile Apps to Improve Medication Adherence in Cardiovascular Disease: Systematic Review and Meta-analysis
Al-Arkee S, Mason J, Lane DA, Fabritz L, Chua W, Haque MS and Jalal Z
Adherence rates of preventative medication for cardiovascular disease (CVD) have been reported as 57%, and approximately 9% of all CVD events in Europe are attributable to poor medication adherence. Mobile health technologies, particularly mobile apps, have the potential to improve medication adherence and clinical outcomes.
Dynamics of Atrial Fibrillation Mechanisms and Comorbidities
Heijman J, Linz D and Schotten U
Atrial fibrillation (AF) contributes to morbidity and mortality of millions of individuals. Its molecular, cellular, neurohumoral, and hemodynamic pathophysiological mechanisms are complex, and there is increasing awareness that a wide range of comorbidities can contribute to AF-promoting atrial remodeling. Moreover, recent research has highlighted that AF risk is not constant and that the temporal variation in concomitant conditions contributes to the complexity of AF dynamics. In this review, we provide an overview of fundamental AF mechanisms related to established and emerging comorbidities or risk factors and their role in the AF-promoting effects. We focus on the accumulating evidence for the relevance of temporally dynamic changes in these risk factors and the consequence for AF initiation and maintenance. Finally, we highlight the important implications for future research and clinical practice resulting from the dynamic interaction between AF risk factors and mechanisms.
A comparison of alendronate to varying magnitude PEMF in mitigating bone loss and altering bone remodeling in skeletally mature osteoporotic rats
Androjna C, Yee CS, White CR, Waldorff EI, Ryaby JT, Zborowski M, Alliston T and Midura RJ
Pulsed electromagnetic field (PEMF) treatments stimulate bone formation activities though further work is needed to optimize its therapeutic benefit. PEMF can generate local potential gradients and electric currents that have been suggested to mimic bone electrochemical responses to load. In line with this reasoning, a recent publication reported that PEMF application on isolated bone tissue induced detectable micro-vibrations (doi:https://doi.org/10.1109/TMAG.2016.2515069). To determine the ability of PEMF to intervene in a rat model of osteoporosis, we tested its effect on trabecular and cortical bone following ovariectomy. Four PEMF treatments, with increasing sinusoidal amplitude rise with time (3850 Hz pulse frequency and 15 Hz repetition rate at 10 tesla/sec (T/s), 30 T/s, 100 T/s, or 300 T/s), were compared to the efficacy of an osteoporosis drug, alendronate, in reducing levels of trabecular bone loss in the proximal tibia. Herein, the novel findings from our study are: (1) 30 T/s PEMF treatment approached the efficacy of alendronate in reducing trabecular bone loss, but differed from it by not reducing bone formation rates; and (2) 30 T/s and 100 T/s PEMF treatments imparted measurable alterations in lacunocanalicular features in cortical bone, consistent with osteocyte sensitivity to PEMF in vivo. The efficacy of specific PEMF doses may relate to their ability to modulate osteocyte function such that the 30 T/s, and to a lesser extent 100 T/s, doses preferentially antagonize trabecular bone resorption while stimulating bone formation. Thus, PEMF treatments of specific magnetic field magnitudes exert a range of measurable biological effects in trabecular and cortical bone tissue in osteoporotic rats.
Learning functionals via LSTM neural networks for predicting vessel dynamics in extreme sea states
Del Águila Ferrandis J, Triantafyllou MS, Chryssostomidis C and Karniadakis GE
Predicting motions of vessels in extreme sea states represents one of the most challenging problems in naval hydrodynamics. It involves computing complex nonlinear wave-body interactions, hence taxing heavily computational resources. Here, we put forward a new simulation paradigm by training recurrent type neural networks (RNNs) that take as input the stochastic wave elevation at a certain sea state and output the main vessel motions, e.g. pitch, heave and roll. We first compare the performance of standard RNNs versus GRU and LSTM neural networks (NNs) and show that LSTM NNs lead to the best performance. We then examine the testing error of two representative vessels, a catamaran in sea state 1 and a battleship in sea state 8. We demonstrate that good accuracy is achieved for both cases in predicting the vessel motions for unseen wave elevations. We train the NNs with expensive CFD simulations , but upon training, the prediction of the vessel dynamics can be obtained at a fraction of a second. This work is motivated by the universal approximation theorem for functionals (Chen & Chen, 1993. , 910-918 (doi:10.1109/72.286886)), and it is the first implementation of such theory to realistic engineering problems.
Corrections to "Visual Analytics for Decision-Making During Pandemics"
Reinert A, Snyder LS, Zhao J, Fox AS, Hougen DF, Nicholson C and Ebert DS
[This corrects the article DOI: 10.1109/MCSE.2020.3023288.].
Short P-Wave Duration is a Marker of Higher Rate of Atrial Fibrillation Recurrences after Pulmonary Vein Isolation: New Insights into the Pathophysiological Mechanisms Through Computer Simulations
Auricchio A, Özkartal T, Salghetti F, Neumann L, Pezzuto S, Gharaviri A, Demarchi A, Caputo ML, Regoli F, De Asmundis C, Chierchia GB, Brugada P, Klersy C, Moccetti T, Schotten U and Conte G
Background Short ECG P-wave duration has recently been demonstrated to be associated with higher risk of atrial fibrillation (AF). The aim of this study was to assess the rate of AF recurrence after pulmonary vein isolation in patients with a short P wave, and to mechanistically elucidate the observation by computer modeling. Methods and Results A total of 282 consecutive patients undergoing a first single-pulmonary vein isolation procedure for paroxysmal or persistent AF were included. Computational models studied the effect of adenosine and sodium conductance on action potential duration and P-wave duration (PWD). About 16% of the patients had a PWD of 110 ms or shorter (median PWD 126 ms, interquartile range, 115 ms-138 ms; range, 71 ms-180 ms). At Cox regression, PWD was significantly associated with AF recurrence (=0.012). Patients with a PWD <110 ms (hazard ratio [HR], 2.20; 95% CI, 1.24-3.88; =0.007) and patients with a PWD ≥140 (HR, 1.87, 95% CI, 1.06-3.30; =0.031) had a nearly 2-fold increase in risk with respect to the other group. In the computational model, adenosine yielded a significant reduction of action potential duration 90 (52%) and PWD (7%). An increased sodium conductance (up to 200%) was robustly accompanied by an increase in conduction velocity (26%), a reduction in action potential duration 90 (28%), and PWD (22%). Conclusions One out of 5 patients referred for pulmonary vein isolation has a short PWD which was associated with a higher rate of AF after the index procedure. Computer simulations suggest that shortening of atrial action potential duration leading to a faster atrial conduction may be the cause of this clinical observation.
Inertial Sensor-Based Centripetal Acceleration as a Correlate for Lateral Margin of Stability During Walking and Turning
Fino PC, Horak FB and Curtze C
There is growing interest in using inertial sensors to continuously monitor gait during free-living mobility. Inertial sensors can provide many gait measures, but they struggle to capture the spatial stability of the center-of-mass due to limitations estimating sensor-to-sensor distance. While the margin of stability (MoS) is an established outcome describing the instantaneous mechanical stability of gait relating to fall-risk, methods to estimate the MoS from inertial sensors have been lacking. Here, we developed and tested a framework, based on centripetal acceleration, to determine a correlate for the lateral MoS using inertial sensors during walking with or without turning. Using three synchronized sensors located bilaterally on the feet and lumbar spine, the average centripetal acceleration over the subsequent step can be used as a correlate for lateral MoS. Relying only on a single sensor on the lumbar spine yielded similar results if the stance foot can be determined from other means. Additionally, the centripetal acceleration correlate of lateral MoS demonstrates clear differences between walking and turning, inside and outside turning limbs, and speed. While limitations and assumptions need to be considered when implemented in practice, this method presents a novel correlate for the lateral MoS during walking and turning using inertial sensors, although further validation is required for other activities and populations.
Corrections to "Academic Review and Perspectives on Robotic Exoskeletons"
Bao G, Pan L, Fang H, Wu X, Yu H, Cai S, Yu B and Wan Y
We have noticed some errors in the above-titled paper (DOI: 10.1109/TNSRE.2019.2944655) [1].
Psychosocial and Pharmacological Interventions for the Treatment of Cannabis Use Disorder
Sabioni P and Le Foll B
(Reprinted with permission from Sabioni P and Le Foll B. Psychosocial and pharmacological interventions for the treatment of cannabis use disorder [version 1; referees: 3 approved]. F1000Research 2018, 7(F1000 Faculty Rev):173 (https://doi.org/10.12688/f1000research.11191.1)).
Generation of a human iPSC-derived cardiomyocyte/fibroblast engineered heart tissue model
Cumberland MJ, Euchner J, Azad AJ, T N Vo N, Kirchhof P, Holmes AP, Denning C and Gehmlich K
Animal models have proven integral to broadening our understanding of complex cardiac diseases but have been hampered by significant species-dependent differences in cellular physiology. Human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) have shown great promise in the modelling of cardiac diseases despite limitations in functional and structural maturity. 3D stem cell-derived cardiac models represent a step towards mimicking the intricate microenvironment present in the heart as an model. Incorporation of non-myocyte cell types, such as cardiac fibroblasts, into engineered heart tissue models (EHTs) can help better recapitulate the cell-to-cell and cell-to-matrix interactions present in the human myocardium. Integration of human-induced pluripotent stem cell-derived cardiac fibroblasts (hiPSC-CFs) and hiPSC-CM into EHT models enables the generation of a genetically homogeneous modelling system capable of exploring the abstruse structural and electrophysiological interplay present in cardiac pathophysiology. Furthermore, the construction of more physiologically relevant 3D cardiac models offers great potential in the replacement of animals in heart disease research. Here we describe efficient and reproducible protocols for the differentiation of hiPSC-CMs and hiPSC-CFs and their subsequent assimilation into EHTs. The resultant EHT consists of longitudinally arranged iPSC-CMs, incorporated alongside hiPSC-CFs. EHTs with both hiPSC-CMs and hiPSC-CFs exhibit slower beating frequencies and enhanced contractile force compared to those composed of hiPSC-CMs alone. The modified protocol may help better characterise the interplay between different cell types in the myocardium and their contribution to structural remodelling and cardiac fibrosis.
Stage 2 Registered Report: Anomalous perception in a Ganzfeld condition - A meta-analysis of more than 40 years investigation
Tressoldi PE and Storm L
This meta-analysis is an investigation into anomalous perception (i.e., conscious identification of information without any conventional sensorial means). The technique used for eliciting an effect is the Ganzfeld condition (a form of sensory homogenization that eliminates distracting peripheral noise). The database consists of studies published between January 1974 and December 2020 inclusive. The overall effect size estimated both with a frequentist and a Bayesian random-effect model, were in close agreement yielding an effect size of approximately .08 (.04 -.12). This result passed four publication bias tests and seems not contaminated by questionable research practices. Trend analysis carried out with a cumulative meta-analysis and a meta-regression model with year of publication as a covariate, did not indicate sign of decline of this effect size. The moderators' analyses show that the selected participants' effect size was almost three-times that obtained by non-selected participants and that tasks that simulate telepathic communication show a two-fold effect size for tasks requiring the participants to guess a target. The Stage 1 Registered Report can be accessed here: https://doi.org/10.12688/f1000research.24868.3.
JUPPI: A Multi-Level Feature Based Method for PPI Prediction and a Refined Strategy for Performance Assessment
Halder AK, Bandyopadhyay SS, Chatterjee P, Nasipuri M, Plewczynski D and Basu S
Over the years, several methods have been proposed for the computational PPI prediction with different performance evaluation strategies. While attempting to benchmark performance scores, most of these methods often suffer with ill-treated cross-validation strategies, adhoc selection of positive/negative samples etc. To address these issues, in our proposed multi-level feature based PPI prediction approach (JUPPI), using sequence, domain and GO information as features, a refined evaluation strategy has been introduced. During the evaluation process, we first extract high quality negative data using three-stage filtering, and then introduce a pair-input based cross validation strategy with three difficulty levels for test-set predictions. Our proposed evaluation strategy reduces the component-level overlapping issue in test sets. Performance of JUPPI is compared with those of the state-of-the-art approaches in this domain and tested on six independent PPI datasets. In almost all the datasets, JUPPI outperforms the state-of-the-art not only at human proteome level for PPI prediction, but also for prediction of interactors for intrinsic disordered human proteins. https://figshare.com/projects/JUPPI_A_Multi-level_Feature_Based_Method_for_PPI_Prediction_and_a_Refined_Strategy_for_Performance_Assessment/81656 JUPPI tool and the developed datasets (JUPPId) are available in public domain for academic use along with supplementary materials, which can be found on the Computer Society Digital Library at http://doi.ieeecomputersociety.org/10.1109/TCBB.2020.3004970.
On the evaluation of outlier detection and one-class classification: a comparative study of algorithms, model selection, and ensembles
Marques HO, Swersky L, Sander J, Campello RJGB and Zimek A
It has been shown that unsupervised outlier detection methods can be adapted to the one-class classification problem (Janssens and Postma, in: Proceedings of the 18th annual Belgian-Dutch on machine learning, pp 56-64, 2009; Janssens et al. in: Proceedings of the 2009 ICMLA international conference on machine learning and applications, IEEE Computer Society, pp 147-153, 2009. 10.1109/ICMLA.2009.16). In this paper, we focus on the comparison of one-class classification algorithms with such adapted unsupervised outlier detection methods, improving on previous comparison studies in several important aspects. We study a number of one-class classification and unsupervised outlier detection methods in a rigorous experimental setup, comparing them on a large number of datasets with different characteristics, using different performance measures. In contrast to previous comparison studies, where the models (algorithms, parameters) are selected by using examples from both classes (outlier and inlier), here we also study and compare different approaches for model selection in the absence of examples from the outlier class, which is more realistic for practical applications since labeled outliers are rarely available. Our results showed that, overall, SVDD and GMM are top-performers, regardless of whether the ground truth is used for parameter selection or not. However, in specific application scenarios, other methods exhibited better performance. Combining one-class classifiers into ensembles showed better performance than individual methods in terms of accuracy, as long as the ensemble members are properly selected.
Efficacy and safety of chimeric antigen receptor T-cell (CAR-T) therapy in hematologic malignancies: a living systematic review on comparative studies
Saiz LC, Leache L, Gutiérrez-Valencia M, Erviti J and Rojas Reyes MX
Chimeric antigen receptor T-cell (CAR-T) cell therapies have been claimed to be curative in responsive patients. Nonetheless, response rates can vary according to different characteristics, and these therapies are associated with important adverse events such as cytokine release syndrome, neurologic adverse events, and B-cell aplasia.
Protein Fold Recognition From Sequences Using Convolutional and Recurrent Neural Networks
Villegas-Morcillo A, Gomez AM, Morales-Cordovilla JA and Sanchez V
The identification of a protein fold type from its amino acid sequence provides important insights about the protein 3D structure. In this paper, we propose a deep learning architecture that can process protein residue-level features to address the protein fold recognition task. Our neural network model combines 1D-convolutional layers with gated recurrent unit (GRU) layers. The GRU cells, as recurrent layers, cope with the processing issues associated to the highly variable protein sequence lengths and so extract a fold-related embedding of fixed size for each protein domain. These embeddings are then used to perform the pairwise fold recognition task, which is based on transferring the fold type of the most similar template structure. We compare our model with several template-based and deep learning-based methods from the state-of-the-art. The evaluation results over the well-known LINDAHL and SCOP_TEST sets, along with a proposed LINDAHL test set updated to SCOP 1.75, show that our embeddings perform significantly better than these methods, specially at the fold level. Supplementary material, which can be found on the Computer Society Digital Library at http://doi.ieeecomputersociety.org/10.1109/TCBB.2020.3012732, source code and trained models are available at http://sigmat.ugr.es/~amelia/CNN-GRU-RF+/.
SARS-CoV-2 Vaccination-Induced Immunogenicity in Heart Transplant Recipients
Memenga F, Kueppers ST, Borof K, Kirchhof P, Duengelhoef PM, Barten MJ, Lütgehetmann M, Berisha F, Fluschnik N, Becher PM, Kondziella C, Bernhardt AM, Reichenspurner H, Blankenberg S, Magnussen C and Rybczynski M
Among heart transplant (HT) recipients, a reduced immunological response to SARS-CoV-2 vaccination has been reported. We aimed to assess the humoral and T-cell response to SARS-CoV-2 vaccination in HT recipients to understand determinants of immunogenicity. HT recipients were prospectively enrolled from January 2021 until March 2022. Anti-SARS-CoV-2-Spike IgG levels were quantified after two and three doses of a SARS-CoV-2 vaccine (BNT162b2, mRNA1273, or AZD1222). Spike-specific T-cell responses were assessed using flow cytometry. Ninety-one patients were included in the study (69% male, median age 55 years, median time from HT to first vaccination 6.1 years). Seroconversion rates were 34% after two and 63% after three doses. Older patient age ( = 0.003) and shorter time since HT ( = 0.001) were associated with lower antibody concentrations after three vaccinations. There were no associations between vaccine types or immunosuppressive regimens and humoral response, except for prednisolone, which was predictive of a reduced response after two ( = 0.001), but not after three doses ( = 0.434). A T-cell response was observed in 50% after two and in 74% after three doses. Despite three vaccine doses, a large proportion of HT recipients exhibits a reduced immune response. Additional strategies are desirable to improve vaccine immunogenicity in this vulnerable group of patients.
Stage 2 Registered Report: How subtle linguistic cues prevent unethical behaviors
Guo W, Liu H, Yang J, Mo Y, Zhong C and Yamada Y
Differences in descriptions can influence people's evaluations and behaviors. A previous study by Bryan and colleagues suggested that subtle linguistic differences in ethical reminders can differentially prevent readers' unethical behavior. The present study tried to replicate the previous finding in the Japanese context (Experiment 1); additionally, we explored the influence of unfamiliar Japanese instruction words that captured participants' attention (Experiment 2). In two online experiments, participants were asked to make 10 coin-tosses and report the number of "heads" results, which would indicate the amount of money that they could earn. In Experiment 1, we analyzed the difference in the number of "heads" results as reported by 768 participants under three conditions with different instructions ("Don't cheat" vs. "Don't be a cheater" vs. baseline as a control). In Experiment 2, we conducted an extended experiment with an additional task in which more attention was directed toward the text. In Experiment 1, we successfully replicated the results of the original experiment. The results of Experiment 2 showed no evidence that the results in Experiment 1 were influenced by attentional factors. In conclusion, the results of the present study supported the hypothesis that self-identity-related words of moral reminder curb unethical behaviors more effectively. Stage 1 report: https://doi.org/10.12688/f1000research.20183.4.
Mental health following an initial period of COVID-19 restrictions: findings from a cross-sectional survey in the Republic of Ireland
Troya MI, Joyce M, Khashan A, Buckley C, Chakraborti K, Hoevel P, Humphries R, Kearney PM, Kiely E, Murphy M, Perry I and Arensman E
: We assessed the mental health of individuals in the general population, during an initial period of easing of COVID-19 restrictions in the Republic of Ireland (RoI). Data were collected through a nationally representative cross-sectional telephone survey, during the first period of easing of restrictions during the COVID-19 pandemic between May and July 2020. Mental health was examined using the Patient Health Questionnaire Anxiety Depression Scale. Poisson regression analyses were conducted to estimate risk ratios with robust variance estimation of the association between selected demographic factors and the risk of having depression and anxiety symptoms. : Of the 1,983 participants, 27.7% (n = 549; 95% CI: 0.26 - 0.30) reported depression and anxiety symptoms, while 74 (3.8%; 95% CI: 0.03 - 0.05) disclosed self-harm and/or suicidal thoughts. Females (RR: 1.60, 95% CI: 1.37 - 1.87, p < 0.0005), employed individuals who experienced a change in work status (RR: 1.50, 95% CI: 1.24 - 1.82, p < 0.0005), participants cocooning due to a health condition (RR: 1.34, 95% CI: 1.08 - 1.66, p< 0.01), participants who were self-isolating (RR: 1.25, 95% CI: 1.03 - 1.51, p=0.025) and moderate-heavy drinkers (RR: 1.27, 95% CI: 1.09 - 1.47, p<0.01) were at increased risk of depression and anxiety. Young people aged 18-29 years and those in the two lowest income categories were most likely to report self-harm and/or suicidal thoughts. : As the COVID-19 pandemic continues, with further waves and associated restrictions, the impact on mental health in the population as a whole and in specific subgroups must be considered. : doi.org/10.12688/hrbopenres.13103.2.
Errata to "Quantifying Tremor in Essential Tremor Using Inertial Sensors Validation of an Algorithm"
Mcgurrin P, Mcnames J, Wu T, Hallett M and Haubenberger D
[This corrects the article DOI: 10.1109/JTEHM.2020.3032924.].
Evaluation of System Modelling Techniques for Waste Identification in Lean Healthcare Applications
Alkaabi M, Simsekler MCE, Jayaraman R, Al Kaf A, Ghalib H, Quraini D, Ellahham S, Tuzcu EM and Demirli K
Waste identification plays a vital role in lean healthcare applications. While the value stream map (VSM) is among the most commonly used tools for waste identification, it may be limited to visualize the behaviour of dynamic and complex healthcare systems. To address this limitation, system modelling techniques (SMTs) can be used to provide a comprehensive picture of various system-wide wastes. However, there is a lack of evidence in the current literature about the potential contribution of SMTs for waste identification in healthcare processes.
Stage 2 Registered Report: How responsibility attributions to self and others relate to outcome ownership in group decisions
Jaquiery M and El Zein M
Responsibility judgements have important consequences in human society. Previous research focused on how someone's responsibility determines the outcome they deserve, for example, whether they are rewarded or punished. Here, in a pre-registered study (Stage 1 Registered Report: https://doi.org/10.12688/wellcomeopenres.16480.2), we investigate the opposite link: How outcome ownership influences responsibility attributions in a social context.  In an online study, participants in a group of three perform a majority vote decision-making task between gambles that can lead to a reward or no reward. Only one group member receives the outcome and participants evaluate their and the other players' responsibility for the obtained outcome. We found that outcome ownership increases responsibility attributions even when the control over an outcome is similar. Moreover, ownership had an effect on the valence bias: participants' higher responsibility attributions for positive vs negative outcomes was stronger for players who received the outcome. Finally, this effect was more pronounced when people rated their own responsibility as compared to when they were rating another's player responsibility. The findings of this study reveal how credit attributions can be biased toward particular individuals who receive outcomes as a result of collective work, both when people judge their own and someone else's responsibility.
Remote Design of a Smartphone and Wearable Detected Atrial Arrhythmia in Older Adults Case Finding Study: Smart in OAC - AFNET 9
Fabritz L, Connolly D, Czarnecki E, Dudek D, Zlahoda-Huzior A, Guasch E, Haase D, Huebner T, Jolly K, Kirchhof P, Schotten U, Zapf A and Schnabel RB
Screening for atrial fibrillation and timely initiation of oral anticoagulation, rhythm management, and treatment of concomitant cardiovascular conditions can improve outcomes in high-risk populations. Whether wearables can facilitate screening in older adults is not known.
Extended ECG Improves Classification of Paroxysmal and Persistent Atrial Fibrillation Based on P- and f-Waves
Zink MD, Laureanti R, Hermans BJM, Pison L, Verheule S, Philippens S, Pluymaekers N, Vroomen M, Hermans A, van Hunnik A, Crijns HJGM, Vernooy K, Linz D, Mainardi L, Auricchio A, Zeemering S and Schotten U
The standard 12-lead ECG has been shown to be of value in characterizing atrial conduction properties. The added value of extended ECG recordings (longer recordings from more sites) has not been systematically explored yet.
Stage 2 Registered Report: Variation in neurodevelopmental outcomes in children with sex chromosome trisomies: testing the double hit hypothesis
Newbury DF, Simpson NH, Thompson PA and Bishop DVM
: The presence of an extra sex chromosome is associated with an increased rate of neurodevelopmental difficulties involving language. The 'double hit' hypothesis proposes that the adverse impact of the extra sex chromosome is amplified when genes that are expressed from the sex chromosomes interact with autosomal variants that usually have only mild effects. We predicted that the impact of an additional sex chromosome on neurodevelopment would depend on common autosomal variants involved in synaptic functions.   We analysed data from 130 children with sex chromosome trisomies (SCTs: 42 girls with trisomy X, 43 boys with Klinefelter syndrome, and 45 boys with XYY). Two comparison groups were formed from 370 children from a twin study. Three indicators of phenotype were: (i) Standard score on a test of nonword repetition; (ii). A language factor score derived from a test battery; (iii) A general scale of neurodevelopmental challenges based on all available information. Preselected regions of two genes, and , were tested for association with neurodevelopmental outcomes using Generalised Structural Component Analysis. There was wide phenotypic variation in the SCT group, as well as overall impairment on all three phenotypic measures. There was no association of phenotype with or variants in either the SCT group or the comparison groups. Supplementary analyses found no indication of any impact of trisomy type on the results, and exploratory analyses of individual SNPs confirmed the lack of association. We cannot rule out that a double hit may be implicated in the phenotypic variability in children with SCTs, but our analysis does not find any support for the idea that common variants in or are associated with the severity of language and neurodevelopmental impairments that often accompany an extra X or Y chromosome. http://dx.doi.org/10.12688/wellcomeopenres.13828.2.