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Device-detected subclinical atrial fibrillation (AF) refers to infrequent, short-lasting, asymptomatic AF that is detected only with long-term continuous monitoring. Subclinical AF is common and associated with an increased risk of stroke; however, the risk of stroke with subclinical AF is lower than for clinical AF, and very few patients with subclinical AF alone have been included in large AF anticoagulation trials. The net benefit of anticoagulation in patients with subclinical AF is unknown. ARTESiA is a prospective, multicenter, double-blind, randomized controlled trial, recruiting patients with subclinical AF detected by an implanted pacemaker, defibrillator, or cardiac monitor, and who have additional risk factors for stroke. Patients with clinical AF documented by surface electrocardiogram will be excluded from the study. Participants will be randomized to receive either apixaban (according to standard AF dosing) or aspirin 81mg daily. The primary outcome is the composite of stroke, transient ischemic attack with diffusion-weighted magnetic resonance imaging evidence of cerebral infarction, and systemic embolism. Approximately 4,000 patients will be enrolled from around 230 clinical sites, with an anticipated mean follow-up of 36months until 248 adjudicated primary outcome events have occurred. ARTESiA will determine whether oral anticoagulation therapy with apixaban compared with aspirin reduces the risk of stroke or systemic embolism in patients with subclinical AF and additional risk factors.

SCN5A Mutations and the Role of Genetic Background in the Pathophysiology of Brugada Syndrome Vincent Probst, MD, PhD ; Arthur A.M. Wilde, MD, PhD ; Julien Barc, MS ; Frederic Sacher, MD ; Dominique Babuty, MD ; Philippe Mabo, MD ; Jacques Mansourati, MD ; Solena Le Scouarnec, PhD ; Florence Kyndt, PharmD, PhD ; Cedric Le Caignec, MD, PhD ; Pascale Guicheney, PhD ; Laetitia Gouas, PhD ; Juliette Albuisson, MD ; Paola G. Meregalli, MD ; Hervé Le Marec, MD, PhD ; Hanno L. Tan, MD, PhD and Jean-Jacques Schott, PhD From the INSERM (V.P., J.B., S.L.S., F.K., H.L.M., J.J.S.), UMR915; CNRS (V.P., J.B., S.L.S., F.K., H.L.M., J.J.S.), ERL3147; Université de Nantes (V.P., J.B., S.L.S., F.K., H.L.M., J.J.S.), l’institut du thorax; CHU Nantes (V.P., H.L.M., J.J.S.), l’institut du thorax, Service de cardiologie, Nantes, France; Department of Cardiology (A.A.M.W., P.G.M., H.L.T.), Academic Medical Center, University of Amsterdam, The Netherlands; Service de rythmologie (F.S.), Hôpital cardiologique du Haut Leveque, Bordeaux, France; Service de cardiologie B (D.B.), Hôpital Trousseau, Tours, France; Departement de cardiologie (P.M.), Hôpital Pontchaillou, Rennes, France; Service de cardiologie (J.M.), centre hospitalo-universitaire de Brest, Brest, France; Service de Génétique Médicale (F.K., C.L.C., J.A.), Institut de Biologie, CHU de Nantes, France; INSERM (P.G., L.G.), U582, Institut de Myologie, Paris, France; and AP-HP (P.G., L.G.), Groupe Hospitalier Pitié-Salpêtrière, Paris, France. Correspondence to Vincent Probst, MD, PhD, Service de cardiologie du CHU de Nantes, CHU de Nantes, Hôpital Nord, Bd Jacques Monod, 44093 Nantes Cedex, France. E-mail vincent.probst{at}chu-nantes.fr Received January 22, 2009; accepted July 14, 2009. Background— Mutations in SCN5A are identified in 20% to 30% of probands affected by Brugada syndrome (BrS). However, in familial studies, the relationship between SCN5A mutations and BrS remains poorly understood. The aim of this study was to investigate the association of SCN5A mutations and BrS in a group of large genotyped families. Methods and Results— Families were included if at least 5 family members were carriers of the SCN5A mutation, which was identified in the proband. Thirteen large families composed of 115 mutation carriers were studied. The signature type I ECG was present in 54 mutation carriers (BrS-ECG+; 47%). In 5 families, we found 8 individuals affected by BrS but with a negative genotype (mutation-negative BrS-ECG+). Among these 8 mutation-negative BrS-ECG+ individuals, 3, belonging to 3 different families, had a spontaneous type I ECG, whereas 5 had a type I ECG only after the administration of sodium channel blockers. One of these 8 individuals had also experienced syncope. Mutation carriers had, on average, longer PR and QRS intervals than noncarriers, demonstrating that these mutations exerted functional effects. Conclusions— Our results suggest that SCN5A mutations are not directly causal to the occurrence of a BrS-ECG+ and that genetic background may play a powerful role in the pathophysiology of BrS. These findings add further complexity to concepts regarding the causes of BrS, and are consistent with the emerging notion that the pathophysiology of BrS includes various elements beyond mutant sodium channels. Key Words: death, sudden (if surviving, use heart arrest) • Brugada syndrome • SCN5A • genetics • tachyarrhythmias • arrhythmia   CLINICAL PERSPECTIVE Drs Probst and Wilde contributed equally to this work. Related Article Nature’s Genetic Gradients and the Clinical Phenotype Ali J. Marian Circ Cardiovasc Genet 2009 2: 537-539. [Extract] [Full Text] [PDF]

BackgroundEstimated plasma volume status (ePVS) has diagnostic and prognostic value in patients with heart failure (HF). However, it remains unclear which congestion markers (i.e., biological, imaging, and hemodynamic markers) are preferentially associated with ePVS. In addition, there is evidence of sex differences in both the hematopoietic process and myocardial structure/function.Method and resultsPatients with significant dyspnea (NYHA ≥ 2) underwent echocardiography and lung ultrasound within 4 h prior to cardiac catheterization. Patients were divided according to tertiles based on sex-specific ePVS thresholds calculated from hemoglobin and hematocrit measurements using Duarte’s formula. Among the 78 included patients (median age 74.5 years; males 69.2%; HF 48.7%), median ePVS was 4.1 (percentile25–75 = 3.7–4.9) mL/g in males (N = 54) and 4.8 (4.4–5.3) mL/g in females (N = 24). Patients with the highest ePVS had more frequently HF, higher NT-proBNP, larger left atrial volume, and higher E/e’ (all p values < 0.05), but no difference in inferior vena cava diameter or pulmonary congestion assessed by lung ultrasound (all p values > 0.10). In multivariable analysis, higher E/e’ and lower diastolic blood pressure were significantly associated with increased ePVS. The association between ePVS and congestion variables was not sex-dependent except for left-ventricular end-diastolic pressure, which was only correlated with ePVS in females (Spearman Rho = 0.53, p < 0.01 in females and Spearman Rho = − 0.04, p = 0.76 in males; pinteraction = 0.08).ConclusionePVS is associated with E/e’ regardless of sex, while only associated with invasively measured left-ventricular end-diastolic pressure in females. These results suggest that ePVS is preferably associated with left-sided hemodynamic markers of congestion.

BackgroundIncreasing use of cardiovascular implantable electronic devices (CIED), as permanent pacemakers (PPM), implantable cardioverter defibrillators (ICD), or cardiac resynchronization therapy (CRT), is associated with the emergence of CIED-related infective endocarditis (CIED-IE). We aimed to characterize CIED-IE profile, temporal trends, and prognostic factors.MethodsCIED-IE diagnosed at Rennes University Hospital during years 1992–2017 were identified through computerized database, and included if they presented all of the following: (1) clinical signs of infection; (2) microbiological documentation through blood and/or CIED lead cultures; (3) lead or valve vegetation, or definite IE according to Duke criteria. Data were retrospectively extracted from medical charts. The cohort was categorized in three periods: 1992–1999, 2000–2008, and 2009–2017.ResultsWe included 199 patients (51 women, 148 men, median age 73 years [interquartile range, 64–79]), with CIED-IE: 158 PPMs (79%), 24 ICD (12%), and 17 CRT (9%). Main pathogens were coagulase-negative staphylococci (CoNS: n = 86, 43%), Staphylococcus aureus (n = 60, 30%), and other Gram-positive cocci (n = 28, 14%). Temporal trends were remarkable for the decline in CoNS (P = 0.002), and the emergence of S. aureus as the primary cause of CIED-IE (24/63 in 2009–2017, 38%). Factors independently associated with one-year mortality were chronic obstructive pulmonary disease (COPD: hazard ratio 3.84 [1.03–6.02], P = 0.03), left-sided endocarditis (HR 2.25 [1.09–4.65], P = 0.03), pathogens other than CoNS (HR 3.16 [1.19–8.39], P = 0.02), and CIED removal/reimplantation (HR 0.41 [0.20–0.83], P = 0.01).ConclusionsS. aureus has emerged as the primary cause of CIED-IE. Left-sided endocarditis, COPD, pathogens other than CoNS, and no CIED removal/reimplantation are independent risk factors for one-year mortality.

Brugada syndrome (BS) is a genetic pathological condition associated with a high risk for sudden cardiac death (SCD). Ventricular depolarization disorders have been suggested as a potential electrophysiological mechanism associated with high SCD risk on patients with BS. This paper aims to characterize the dynamic changes of ventricular depolarization observed during physical exercise in symptomatic and asymptomatic BS patients. To this end, cardiac ventricular depolarization features were automatically extracted from 12-lead ECG recordings acquired during standardized exercise stress test in 110 BS patients, of whom 25 were symptomatic. Conventional parameters were evaluated, including QRS duration, R and S wave amplitudes ([Formula: see text], [Formula: see text]), as well as QRS morphological features, such as up-stroke and down-stroke slopes of the R and S waves ([Formula: see text], [Formula: see text] and [Formula: see text]). The effects of physical exercise and recovery on the dynamics of these markers were assessed in both BS populations. Features showing significantly different dynamics between the studied groups were used alone and in combination with the clinical characteristics of the patients in a logistic regression analysis. Results show larger changes in the second half of the QRS complex through [Formula: see text] and [Formula: see text] measured in the right precordial leads for asymptomatic patients, especially during recovery, when the vagal tone is more pronounced. Multivariate analysis involving both types of features resulted in a reduced model of three relevant features ([Formula: see text] in lead V2, Sex and heart rate recovery, HRR), which achieved a suitable discrimination performance between groups; sensitivity = 80% and specificity = 75% (AUC = 83%). However, after controlling the model for possible confounding factors, only one feature ([Formula: see text]) remained meaningful. This adjusted model significantly improved the overall discrimination performance by up to: sensitivity = 84% and specificity = 100% (AUC = 94%). The study highlights the importance of physical exercise test to unmask differentiated behaviors between symptomatic and asymptomatic BS patients through depolarization dynamic analysis. This analysis together with the obtained model may help to identify asymptomatic patients at low or high risk of future cardiac events, but it should be confirmed by further prospective studies.

Ventricular arrhythmias in Brugada syndrome (BS) typically occur at rest and especially during sleep, suggesting that changes in the autonomic modulation may play an important role in arrhythmogenesis. The autonomic response to exercise and subsequent recovery was evaluated on 105 patients diagnosed with BS (twenty-four were symptomatic), by means of a time-frequency heart rate variability (HRV) analysis, so as to propose a novel predictive model capable of distinguishing symptomatic and asymptomatic BS populations. During incremental exercise, symptomatic patients showed higher HFnu values, probably related to an increased parasympathetic modulation, with respect to asymptomatic subjects. In addition, those extracted HRV features best distinguishing between populations were selected using a two-step feature selection approach, so as to build a linear discriminant analysis (LDA) classifier. The final features subset included one third of the total amount of extracted autonomic markers, mostly acquired during incremental exercise and active recovery, thus evidencing the relevance of these test segments in BS patients classification. The derived predictive model showed an improved performance with respect to previous works in the field (AUC = 0.92 ± 0.01; Se = 0.91 ± 0.06; Sp = 0.90 ± 0.05). Therefore, based on these findings, some of the analyzed HRV markers and the proposed model could be useful for risk stratification in Brugada syndrome.

Although the therapeutic effects of Vagus Nerve Stimulation (VNS) have been recognized in pre-clinical and pilot clinical studies, the effect of different stimulation configurations on the cardiovascular response is still an open question, especially in the case of VNS delivered synchronously with cardiac activity. In this paper, we propose a formal mathematical methodology to analyze the acute cardiac response to different VNS configurations, jointly considering the chronotropic, dromotropic and inotropic cardiac effects. A latin hypercube sampling method was chosen to design a uniform experimental plan, composed of 75 different VNS configurations, with different values for the main parameters (current amplitude, number of delivered pulses, pulse width, interpulse period and the delay between the detected cardiac event and VNS onset). These VNS configurations were applied to 6 healthy, anesthetized sheep, while acquiring the associated cardiovascular response. Unobserved VNS configurations were estimated using a Gaussian process regression (GPR) model. In order to quantitatively analyze the effect of each parameter and their combinations on the cardiac response, the Sobol sensitivity method was applied to the obtained GPR model and inter-individual sensitivity markers were estimated using a bootstrap approach. Results highlight the dominant effect of pulse current, pulse width and number of pulses, which explain respectively 49.4%, 19.7% and 6.0% of the mean global cardiovascular variability provoked by VNS. More interestingly, results also quantify the effect of the interactions between VNS parameters. In particular, the interactions between current and pulse width provoke higher cardiac effects than the changes on the number of pulses alone (between 6 and 25% of the variability). Although the sensitivity of individual VNS parameters seems similar for chronotropic, dromotropic and inotropic responses, the interacting effects of VNS parameters provoke significantly different cardiac responses, showing the feasibility of a parameter-based functional selectivity. These results are of primary importance for the optimal, subject-specific definition of VNS parameters for a given therapy and may lead to new closed-loop methods allowing for the optimal adaptation of VNS therapy through time.

Vagus nerve stimulation (VNS) is an established adjunctive therapy for pharmacologically refractory epilepsy and depression and is currently in active clinical research for other applications. In current clinical studies, VNS is delivered in an open-loop approach, where VNS parameters are defined during a manual titration phase. However, the physiological response to a given VNS configuration shows significant inter and intra-patient variability and may significantly evolve through time. VNS closed-loop approaches, allowing for the optimization of the therapy in an adaptive manner, may be necessary to improve efficacy while reducing side effects. This paper proposes a generic, closed-loop control VNS system that is able to optimize a number of VNS parameters in an adaptive fashion, in order to keep a control variable within a specified range. Although the proposed control method is completely generic, an example application using the cardiac beat to beat interval (RR) as control variable will be developed in this paper. The proposed controller is based on a state transition model (STM) that can be configured using a partially or a fully-connected architecture, different model orders and different state-transition algorithms. The controller is applied to the adaptive regulation of heart rate and evaluated on 6 sheep, for 13 different targets, using partially-connected STM with 10 states. Also, partially and fully-connected STM defined by 30 states were applied to 7 other sheep for the same 10 targets. Results illustrate the interest of the proposed fully-connected STM and the feasibility of integrating this control system into an implantable neuromodulator.

Non–vitamin K oral anticoagulants (NOACs) are currently recommended for patients with nonvalvular atrial fibrillation since the publication of the 4 major pivotal trials evaluating the efficacy and safety of factor IIa and factor Xa inhibitors. The definition of nonvalvular atrial fibrillation is unclear, varying from one trial to another and even between North American and European guidelines, which is a source of uncertainties in clinical practice. However, many patients with atrial fibrillation present signs of valvular involvement, and clarification of this term is needed to not deny NOACs to patients based on the wrong perception that they may have valvular atrial fibrillation. The currently unique contraindications to NOACs are patients with mechanical heart valves and those with moderate-to-severe mitral stenosis, as stated by the recent 2015 position paper of the European Heart Rhythm Association. Patients with native heart valve involvement, regardless of their severity, are suitable for NOAC therapy. Patients with bioprosthetic heart valves and mitral valve repair may be suitable for NOACs except for the first 3 and the first 3-6 months postoperatively, respectively. Patients with transaortic valve implantation or percutaneous transluminal aortic valvuloplasty are also considered as being eligible for NOACs, although the bleeding risk has to be carefully considered in this population often requiring a combination with antiplatelet therapy. Future studies are warranted to increase the level of evidence of use of NOACs, particularly in patients with transaortic valve implantation and valvular surgery, and to determine whether they could be used in the future in the only 2 remaining contraindications.