2023 ACC/AHA/ACCP/HRS Guideline for the Diagnosis and Management of Atrial Fibrillation: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines.

AIM: The "2023 ACC/AHA/ACCP/HRS Guideline for the Diagnosis and Management of Atrial Fibrillation" provides recommendations to guide clinicians in the treatment of patients with atrial fibrillation. METHODS: A comprehensive literature search was conducted from May 12, 2022, to November 3, 2022, encompassing studies, reviews, and other evidence conducted on human subjects that were published in English from PubMed, EMBASE, the Cochrane Library, the Agency for Healthcare Research and Quality, and other selected databases relevant to this guideline. Additional relevant studies, published through November 2022, during the guideline writing process, were also considered by the writing committee and added to the evidence tables, where appropriate. STRUCTURE: Atrial fibrillation is the most sustained common arrhythmia, and its incidence and prevalence are increasing in the United States and globally. Recommendations from the "2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation" and the "2019 AHA/ACC/HRS Focused Update of the 2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation" have been updated with new evidence to guide clinicians. In addition, new recommendations addressing atrial fibrillation and thromboembolic risk assessment, anticoagulation, left atrial appendage occlusion, atrial fibrillation catheter or surgical ablation, and risk factor modification and atrial fibrillation prevention have been developed.

Quantum approximate optimization of the long-range Ising model with a trapped-ion quantum simulator.

Quantum computers and simulators may offer significant advantages over their classical counterparts, providing insights into quantum many-body systems and possibly improving performance for solving exponentially hard problems, such as optimization and satisfiability. Here, we report the implementation of a low-depth Quantum Approximate Optimization Algorithm (QAOA) using an analog quantum simulator. We estimate the ground-state energy of the Transverse Field Ising Model with long-range interactions with tunable range, and we optimize the corresponding combinatorial classical problem by sampling the QAOA output with high-fidelity, single-shot, individual qubit measurements. We execute the algorithm with both an exhaustive search and closed-loop optimization of the variational parameters, approximating the ground-state energy with up to 40 trapped-ion qubits. We benchmark the experiment with bootstrapping heuristic methods scaling polynomially with the system size. We observe, in agreement with numerics, that the QAOA performance does not degrade significantly as we scale up the system size and that the runtime is approximately independent from the number of qubits. We finally give a comprehensive analysis of the errors occurring in our system, a crucial step in the path forward toward the application of the QAOA to more general problem instances.

High-resolution characterization of the structural features and genetic variation of six feline leukocyte antigen class I loci via single molecule, real-time (SMRT) sequencing.

Of the 12 full-length feline leukocyte antigen class I (FLAI) loci, 3 are presumed to be classical: FLAI-E, FLAI-H, and FLAI-K. As diversity is a class Ia hallmark, multi-allelism is an important surrogate supporting a classical designation, in the absence of direct demonstration of T-cell restriction. Conversely, limited polymorphism at an expressed locus suggests regulation of immune effectors with invariant receptors, and non-classical status. FLAI-A, FLAI-J, FLAI-L, and FLAI-O are putative class Ib genes in cats. For both classes, identifying prevalent variants across outbred populations can illuminate specific genotypes to be prioritized for immune studies, as shared alleles direct shared responses. Since variation is concentrated in exons 2 and 3, which encode the antigen-binding domains, partial-length cloning/sequencing can be used for allele discovery, but is laborious and occasionally ambiguous. Here we develop a targeted approach to FLAI genotyping, using the single-molecule real-time (SMRT) platform, which allows full-length (3.4-kb) reads without assembly. Consensus sequences matched full-length Sanger references. Thirty-one new class Ia genes were found in 17 cats. Alleles segregated strongly by loci, and the origins of formerly difficult-to-assign sequences were resolved. Although not targeted, FLAI-L and FLAI-J, and the pseudogene FLAI-F, were also returned. Eighteen class Ib alleles were identified. Diversity was restricted and outside hypervariable regions. Both class Ib genes were transcriptionally active. Novel alternative splicing of FLAI-L was observed. SMRT sequencing of FLAI amplicons is useful for full-length genotyping at feline class Ia loci. High-throughput sequencing could allow highly accurate allele surveys in large cat cohorts.

Use of oral anticoagulants in patients with valvular atrial fibrillation: findings from the NCDR PINNACLE Registry.

Recent data suggest direct oral anticoagulants are as safe and efficacious as warfarin among select patients with valvular heart disease and atrial fibrillation (AF). However, real-world treatment patterns of AF stroke prophylaxis in the setting of valvular AF are currently unknown. Accordingly, using the prospective, ambulatory National Cardiovascular Data Registry Practice Innovation and Clinical Excellence (PINNACLE) Registry, we sought to characterize overall use, temporal trends in use, and the extent of practice-level variation in the use of any direct oral anticoagulant and warfarin among patients with valvular AF from January 1, 2013, to March 31, 2019.

Podoplanin-rich stromal networks induce dendritic cell motility via activation of the C-type lectin receptor CLEC-2.

To initiate adaptive immunity, dendritic cells (DCs) move from parenchymal tissues to lymphoid organs by migrating along stromal scaffolds that display the glycoprotein podoplanin (PDPN). PDPN is expressed by lymphatic endothelial and fibroblastic reticular cells and promotes blood-lymph separation during development by activating the C-type lectin receptor, CLEC-2, on platelets. Here, we describe a role for CLEC-2 in the morphodynamic behavior and motility of DCs. CLEC-2 deficiency in DCs impaired their entry into lymphatics and trafficking to and within lymph nodes, thereby reducing T cell priming. CLEC-2 engagement of PDPN was necessary for DCs to spread and migrate along stromal surfaces and sufficient to induce membrane protrusions. CLEC-2 activation triggered cell spreading via downregulation of RhoA activity and myosin light-chain phosphorylation and triggered F-actin-rich protrusions via Vav signaling and Rac1 activation. Thus, activation of CLEC-2 by PDPN rearranges the actin cytoskeleton in DCs to promote efficient motility along stromal surfaces.

Potential unrealized mortality benefit of glucagon-like peptide-1 receptor agonists and sodium-glucose co-transport-2 inhibitors: A report from the Veterans Health Administration Clinical Assessment, Reporting and Tracking program.

AIM: To assess the unrealized potential of glucagon-like peptide-1 receptor agonist (GLP-1RA) or sodium-glucose co-transport-2 inhibitor (SGLT2i) use to reduce mortality in veterans with type 2 diabetes (T2D), coronary artery disease (CAD), and other characteristics congruent with clinical trial cohorts that established the efficacy of these agents. METHODS: Veterans with T2D and CAD on angiography in 2014 who were untreated with either a GLP-1RA or a SGLT2i were assessed for key eligibility criteria of the LEADER (GLP-1RA) and EMPA-REG OUTCOME (SGLT2i) trials. Trial hazard ratios and 95% confidence intervals for all-cause death were applied to deaths observed in veterans through 2018 to estimate the potential benefit of GLP-1RA or SGLT2i use. RESULTS: Median observation was 4.3 years. Of 15 987 veterans with T2D and CAD, 1186 (7.4%) were excluded for GLP-1RA or SGLT2i treatment, and 1386 lacked glycated haemoglobin measurement. Of the remaining 13 415 patients, 4103 (30.1%) and 5313 (39.6%) fulfilled the key criteria for the LEADER and EMPA-REG OUTCOME trials, respectively. Death occurred in 1009 (24.6%) of LEADER-eligible patients and 1335 (25.1%) of EMPA-REG OUTCOME-eligible patients. Under treatment with liraglutide in LEADER-eligible veterans, a 3.5% (0.7%-6.2%) potential absolute mortality reduction, corresponding to 144 (28-253) fewer deaths (0.88 [0.17-1.56] per 100 person-years), might have been expected. Similarly, under treatment with empagliflozin in EMPA-REG OUTCOME-eligible veterans, a 7.9% (4.5%-10.8%) potential absolute mortality reduction, corresponding to 418 (230-573) fewer deaths (1.98 [1.14-2.72] per 100 person-years), might have been expected. CONCLUSIONS: This analysis indicates unrealized opportunities to reduce mortality in selected veterans with T2D and CAD via increased GLP-1RA and SGLT2i use.

The prognostic value of diastolic and systolic mechanical left ventricular dyssynchrony among patients with coronary artery disease and heart failure.

BACKGROUND: Prevalence and prognostic value of diastolic and systolic dyssynchrony in patients with coronary artery disease (CAD) + heart failure (HF) or CAD alone are not well understood. METHODS: We included patients with gated single-photon emission computed tomography (GSPECT) myocardial perfusion imaging (MPI) between 2003 and 2009. Patients had at least one major epicardial obstruction ≥ 50%. We assessed the association between dyssynchrony and outcomes, including all-cause and cardiovascular death. RESULTS: Of the 1294 patients, HF was present in 25%. Median follow-up was 6.7 years (IQR 4.9-9.3) years with 537 recorded deaths. Patients with CAD + HF had a higher incidence of dyssynchrony than patients with CAD alone (diastolic BW 28.8% for the HF + CAD vs 14.7% for the CAD alone). Patients with CAD + HF had a lower survival than CAD alone at 10 years (33%; 95% CI 27-40 vs 59; 95% CI 55-62, P < 0.0001). With one exception, HF was found to have no statistically significant interaction with dyssynchrony measures in unadjusted and adjusted survival models. CONCLUSIONS: Patients with CAD + HF have a high prevalence of mechanical dyssynchrony as measured by GSPECT MPI, and a higher mortality than CAD alone. However, clinical outcomes associated with mechanical dyssynchrony did not differ in patients with and without HF.

Same-day discharge among patients undergoing elective PCI: Insights from the VA CART Program.

BACKGROUND: Available data suggest that same-day discharge (SDD) after elective percutaneous coronary intervention (PCI) is safe in select patients. Yet, little is known about contemporary adoption rates, safety, and costs in a universal health care system like the Veterans Affairs Health System. METHODS: Using data from the Veterans Affairs Clinical Assessment Reporting and Tracking Program linked with Health Economics Resource Center data, patients undergoing elective PCI for stable angina between October 1, 2007 and Sepetember 30, 2016, were stratified by SDD versus overnight stay. We examined trends of SDD, and using 2:1 propensity matching, we assessed 30-day rates of readmission, mortality, and total costs at 30 days. RESULTS: Of 21,261 PCIs from 67 sites, 728 were SDDs (3.9% of overall cohort). The rate of SDD increased from 1.6% in 2008 to 9.7% in 2016 (P < .001). SDD patients had lower rates of atrial fibrillation, peripheral arterial disease, and prior coronary artery bypass grafting and were treated at higher-volume centers. Thirty-day readmission and mortality did not differ significantly between the groups (readmission: 6.7% SDD vs 5.6% for overnight stay, P = .24; mortality: 0% vs. 0.07%, P = .99). The mean (SD) 30-day cost accrued by patients undergoing SDD was $23,656 ($15,480) versus $25,878 ($17,480) for an overnight stay. The accumulated median cost savings for SDD was $1503 (95% CI $738-$2,250). CONCLUSIONS: Veterans Affairs Health System has increasingly adopted SDD for elective PCI procedures, and this is associated with cost savings without an increase in readmission or mortality. Greater adoption has the potential to reduce costs without increasing adverse outcomes.

Overdrive pacing mapping: An alternative approach used in scar associated localized atrial tachycardia.

BACKGROUND: Mapping and ablation of localized reentry atrial tachycardia (AT) can be challenging, especially in those with varying cycle length (CL). OBJECTIVE: We attempted to use the traditional maneuver of overdrive pacing to facilitate AT mapping. METHODS: Data were collected from 12 patients with localized ATs. All patients had prior cardiac surgery or prior atrial fibrillation ablation. Overdrive pacing mapping (ODPM) was performed to find independent local activity (ILA) and compared with conventional activation mapping (CAM) during ongoing AT to determine its accuracy and efficacy. Patients with macro-reentry AT around the tricuspid or mitral annulus were excluded. RESULTS: Twelve patients with 14 localized ATs were included. All 14 ATs including 4 (29%) with varying CL successfully completed ODPM and had the ILA, although two ATs terminated during ODP and required repeated mapping. Radiofrequency ablation focused on critical sites with ILA was successful in all 12 patients. Using CAM, however, 6 of 14 ATs (43%) mapping attempts were aborted due to AT termination (2 ATs) or varying CL (4 ATs), and only 5 of 8 (63%) located "critical sites" were ultimately confirmed by entrainment and ablation results. After 25 ± 9 months of follow-up, no patient had AT recurrence. CONCLUSION: Our preliminary results demonstrated that ODPM is superior to CAM in ATs that were poorly sustained or with varying CL and is a useful supplement to CAM.

Podoplanin maintains high endothelial venule integrity by interacting with platelet CLEC-2.

Circulating lymphocytes continuously enter lymph nodes for immune surveillance through specialized blood vessels named high endothelial venules, a process that increases markedly during immune responses. How high endothelial venules (HEVs) permit lymphocyte transmigration while maintaining vascular integrity is unknown. Here we report a role for the transmembrane O-glycoprotein podoplanin (PDPN, also known as gp38 and T1α) in maintaining HEV barrier function. Mice with postnatal deletion of Pdpn lost HEV integrity and exhibited spontaneous bleeding in mucosal lymph nodes, and bleeding in the draining peripheral lymph nodes after immunization. Blocking lymphocyte homing rescued bleeding, indicating that PDPN is required to protect the barrier function of HEVs during lymphocyte trafficking. Further analyses demonstrated that PDPN expressed on fibroblastic reticular cells, which surround HEVs, functions as an activating ligand for platelet C-type lectin-like receptor 2 (CLEC-2, also known as CLEC1B). Mice lacking fibroblastic reticular cell PDPN or platelet CLEC-2 exhibited significantly reduced levels of VE-cadherin (also known as CDH5), which is essential for overall vascular integrity, on HEVs. Infusion of wild-type platelets restored HEV integrity in Clec-2-deficient mice. Activation of CLEC-2 induced release of sphingosine-1-phosphate from platelets, which promoted expression of VE-cadherin on HEVs ex vivo. Furthermore, draining peripheral lymph nodes of immunized mice lacking sphingosine-1-phosphate had impaired HEV integrity similar to Pdpn- and Clec-2-deficient mice. These data demonstrate that local sphingosine-1-phosphate release after PDPN-CLEC-2-mediated platelet activation is critical for HEV integrity during immune responses.

JAK2 V617F-positive acute myeloid leukaemia (AML): a comparison between de novo AML and secondary AML transformed from an underlying myeloproliferative neoplasm. A study from the Bone Marrow Pathology Group.

The JAK2 V617F mutation is characteristic of most Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs) and occurs rarely in de novo acute myeloid leukaemia (AML). We sought to characterize AMLs that harbour this mutation and distinguish those that arise de novo (AML-DN) from those that reflect transformation of an underlying MPN (AML-MPN). Forty-five patients with JAK2 V617F-mutated AML were identified; 15 were AML-DN and 30 were AML-MPN. AML-MPN cases were more likely to have splenomegaly (P = 0·02), MPN-like megakaryocytes and higher mean JAK2 V617F VAF at diagnosis (P = 0·04). Mutations involving TET2 were exclusively identified in AML-DN patients. Mutations of genes affecting DNA methylation were more common in AML-DN (P < 0·01). A complex karyotype was more frequent in AML-MPN cases than in AML-DN (P < 0·01), with AML-DN more likely to display a normal karyotype (P = 0·02). Bone marrow histology after recovery from induction chemotherapy in AML-DN cases revealed no morphological evidence of any previously occult MPNs, while this was evident in most of the AML-MPN specimens (P < 0·01). These findings in this largest study of JAK2 V617F-mutated AMLs indicate that AML-DN is distinct from AML-MPN.

Sex and Race/Ethnicity Differences in Implantable Cardioverter-Defibrillator Counseling and Use Among Patients Hospitalized With Heart Failure: Findings from the Get With The Guidelines-Heart Failure Program.

BACKGROUND: Previous studies have found that women and black patients eligible for a primary prevention implantable cardioverter-defibrillator (ICD) are less likely than men or white patients to receive one. METHODS: We performed an observational analysis of the Get With The Guidelines-Heart Failure Program from January 1, 2011, to March 21, 2014. Patients admitted with heart failure and an ejection fraction ≤35% without an ICD were included. Rates of ICD counseling among eligible patients and ICD receipt among counseled patients were examined by sex and race/ethnicity. RESULTS: Among 21 059 patients from 236 sites, 4755 (22.6%) received predischarge ICD counseling. Women were counseled less frequently than men (19.3% versus 24.6%, P<0.001, adjusted odds ratio [OR], 0.84; 95% confidence interval [CI], 0.78-0.91). Racial and ethnic minorities were less likely to receive counseling than white patients (black 22.6%, Hispanic 18.6%, other race/ethnic group 14.4% versus white 24.3%, P<0.001 for each): adjusted OR versus white, 0.69; 95% CI, 0.63 to 0.76 for black patients; adjusted OR, 0.62; 95% CI, 0.55 to 0.70 for Hispanic patients; adjusted OR, 0.53; 95% CI, 0.43 to 0.65 for other patients. Among the 4755 counseled patients, 2977 (62.6%) received an ICD or had one planned for placement after hospital stay. Among those counseled, women and men were similarly likely to receive an ICD (adjusted OR, 1.13; 95% CI, 0.99-1.29). However, black (adjusted OR, 0.70; 95% CI, 0.56-0.88) and Hispanic patients (adjusted OR, 0.68; 95% CI, 0.46-1.01) were less likely to receive an ICD. CONCLUSIONS: Up to 4 of 5 hospitalized patients with heart failure eligible for ICD counseling did not receive it, particularly women and minority patients. Among counseled patients, ICD use differences by race and ethnicity persisted.

The prognostic value of mechanical left ventricular dyssynchrony defined by phase analysis from gated single-photon emission computed tomography myocardial perfusion imaging among patients with coronary heart disease.

BACKGROUND: The prognostic value of left ventricular dyssynchrony measured by gated single-photon emission computed tomography (GSPECT) myocardial perfusion imaging (MPI) and its relationship to electrical dyssynchrony measured by QRS duration are incompletely understood. The aim of this study was therefore to examine the independent and incremental prognostic value of dyssynchrony in yet the largest group of patients with coronary artery disease (CAD). METHODS AND RESULTS: Patients presenting for GSPECT- MPI between July 1993 and May 1999 in normal sinus rhythm were identified from the Duke Nuclear Cardiology Databank and the Duke Databank for Cardiovascular Disease (N = 1244). After a median of 4.2 years, 336 deaths occurred. At 8 years, the Kaplan-Meier estimates of the probability of death were 34.0% among patients with a phase bandwidth <100° and 56.8% among those with a bandwidth ≥100°. After adjustment for standard clinical variables, QRS dyssynchrony was independently associated with death (Hazard Ratio (HR), per 10°: 1.092, 95% Confidence Interval (CI) 1.048,1.139, P < .0001). Phase bandwidth was similarly associated with death after clinical adjustment (HR per 10°: 1.056, 95% CI 1.041,1.072, P < .0001). In clinically adjusted models examining QRS duration in addition to phase bandwidth, phase bandwidth had a stronger association with mortality. After accounting for left ventricular ejection fraction (LVEF), neither QRS duration nor phase bandwidth were statistically significant. Among patients with EF >35%, QRS duration and phase bandwidth together provided value above that provided by LVEF alone (P = 0.0181). When examining cardiovascular death, results were consistent with all-cause death. CONCLUSIONS: Among patients with CAD, mechanical left ventricular dyssynchrony measured by GSPECT MPI has a stronger relationship with outcomes than electrical dyssynchrony measured by QRS duration. After adjustment for baseline characteristics and LVEF, neither mechanical nor electrical dyssynchrony is independently associated with all-cause death or cardiac death. Among patients with EF >35%, mechanical and electrical dyssynchrony together provided prognostic value above that afforded by LVEF.

Adherence and outcomes to direct oral anticoagulants among patients with atrial fibrillation: findings from the veterans health administration.

BACKGROUND: The direct oral anticoagulants (DOACs) reduce the risk of stroke in moderate to high-risk patients with non-valvular atrial fibrillation (AF). Yet, concerns remain regarding its routine use in real world practice. We sought to describe adherence patterns and the association between adherence and outcomes to the DOACs among outpatients with AF. METHODS: We performed a retrospective cohort study of patients in the VA Healthcare System who initiated pharmacotherapy with dabigatran, rivaroxaban, or apixaban between November 2010 and January 2015 for non-valvular AF with CHA2DS2-VASc score ≥ 2. Adherence was determined using pharmacy refill data and estimated by the proportion of days covered (PDC) over the first year of therapy. Clinical outcomes, including all-cause mortality and stroke, were measured at 6 months and used to assess measures of adherence for each DOAC. RESULTS: A total of 2882 patients were included. Most were prescribed dabigatran (72.7%), compared with rivaroxaban (19.8%) or apixaban (7.5%). The mean PDC was 0.84 ± 0.20 for dabigatran, 0.86 ± 0.18 for rivaroxaban, and 0.89 ± 0.14 for apixaban (p < 0.01). The proportion of non-adherent patients, PDC <0.80, was 27.6% for all and varied according DOAC. Lower adherence to dabigatran was associated with higher risk of mortality and stroke (HR 1.07; 1.03-1.12 per 0.10 decline in PDC). CONCLUSIONS: In a real-world VA population being prescribed anticoagulation for AF, more than one quarter had sub-optimal adherence. Lower adherence was associated with a higher risk of mortality and stroke. Efforts identifying non-adherent patients, and targeted adherence interventions are needed to improve outcomes.

Platelet immunoreceptor tyrosine-based activation motif (ITAM) signaling and vascular integrity.

Platelets are well-known for their critical role in hemostasis, that is, the prevention of blood loss at sites of mechanical vessel injury. Inappropriate platelet activation and adhesion, however, can lead to thrombotic complications, such as myocardial infarction and stroke. To fulfill its role in hemostasis, the platelet is equipped with various G protein-coupled receptors that mediate the response to soluble agonists such as thrombin, ADP, and thromboxane A2. In addition to G protein-coupled receptors, platelets express 3 glycoproteins that belong to the family of immunoreceptor tyrosine-based activation motif receptors: Fc receptor γ chain, which is noncovalently associated with the glycoprotein VI collagen receptor, C-type lectin 2, the receptor for podoplanin, and Fc receptor γII A, a low-affinity receptor for immune complexes. Although both genetic and chemical approaches have documented a critical role for platelet G protein-coupled receptors in hemostasis, the contribution of immunoreceptor tyrosine-based activation motif receptors to this process is less defined. Studies performed during the past decade, however, have identified new roles for platelet immunoreceptor tyrosine-based activation motif signaling in vascular integrity in utero and at sites of inflammation. The purpose of this review is to summarize recent findings on how platelet immunoreceptor tyrosine-based activation motif signaling controls vascular integrity, both in the presence and absence of mechanical injury.

Catheter ablation for ventricular tachycardia in patients with an implantable cardioverter defibrillator (CALYPSO) pilot trial.

INTRODUCTION: We conducted this pilot randomized clinical trial to determine the feasibility of a large clinical trial aimed at testing whether early use of catheter ablation of ventricular tachycardia (VT) is superior to antiarrhythmic medications at reducing mortality. METHODS AND RESULTS: Patients were enrolled at 4 sites if they had ischemic heart disease, an implantable cardioverter defibrillator (ICD), and received ≥1 ICD shock or ≥3 antitachycardia pacing therapies for VT. Patients were randomized to 2 arms: (1) antiarrhythmic medication (n = 14) and (2) catheter ablation (n = 13); patients were followed at 3 and 6 months. Endpoints included recurrent VT, time to first ICD therapy for VT, and death. Of 243 screened patients, 27 were enrolled. Main reasons for screen failures were: (1) patient was already on an antiarrhythmic medication (88 [41%]), (2) VT due to a reversible cause (23 [11%]), and (3) incessant VT (20 [9%]). Fourteen patients had recurrent VT, 8 (62%) in the ablation arm and 6 (43%) in the antiarrhythmic medication arm. Median time to recurrent VT was 75 days (25th, 75th: 51, 89) in the ablation arm and 57 days (30, 145) in the antiarrhythmic arm. Four patients died, 2 in each arm. CONCLUSION: This clinical trial shows that most patients in clinical practice have already failed antiarrhythmic drug therapy before catheter ablation is considered, and the VT recurrence rates and death in these patients are high. For a large clinical trial to be feasible, factors limiting early consideration of catheter ablation need to be identified and addressed.

Early management of atrial fibrillation to prevent cardiovascular complications.

Atrial fibrillation (AF) is generally considered a progressive disease, typically evolving from paroxysmal through persistent to 'permanent' forms, a process attributed to electrical and structural remodelling related to both the underlying disease and AF itself. Medical treatment has yet to demonstrate clinical efficacy in preventing progression. Large clinical trials performed to date have failed to show benefit of rhythm control compared with rate control, but these trials primarily included patients at late stages in the disease process. One possible explanation is that intervention at only an early stage of progression may improve prognosis. Evolving observations about the progressive nature of AF, along with the occurrences of major complications such as strokes upon AF presentation, led to the notion that earlier and more active approaches to AF detection, rhythm-reversion, and maintenance of sinus rhythm may be a useful strategy in AF management. Approaches to early and sustained rhythm control include measures that prevent development of the AF substrate, earlier catheter ablation, and novel antiarrhythmic drugs. Improved classifications of AF mechanism, pathogenesis, and remodelling may be helpful to enable patient-specific pathophysiological diagnosis and therapy. Potential novel therapeutic options under development include microRNA-modulation, heatshock protein inducers, agents that influence Ca(2+) handling, vagal stimulators, and more aggressive mechanism-based ablation strategies. In this review, of research into the basis and management of AF in acute and early settings, it is proposed that progression from paroxysmal to persistent AF can be interrupted, with potentially favourable prognostic impact.

Addressing barriers to optimal oral anticoagulation use and persistence among patients with atrial fibrillation: Proceedings, Washington, DC, December 3-4, 2012.

Approximately half of patients with atrial fibrillation and with risk factors for stroke are not treated with oral anticoagulation (OAC), whether it be with vitamin K antagonists (VKAs) or novel OACs (NOACs); and of those treated, many discontinue treatment. Leaders from academia, government, industry, and professional societies convened in Washington, DC, on December 3-4, 2012, to identify barriers to optimal OAC use and adherence and to generate potential solutions. Participants identified a broad range of barriers, including knowledge gaps about stroke risk and the relative risks and benefits of anticoagulant therapies; lack of awareness regarding the potential use of NOAC agents for VKA-unsuitable patients; lack of recognition of expanded eligibility for OAC; lack of availability of reversal agents and the difficulty of anticoagulant effect monitoring for the NOACs; concerns with the bleeding risk of anticoagulant therapy, especially with the NOACs and particularly in the setting of dual antiplatelet therapy; suboptimal time in therapeutic range for VKA; and costs and insurance coverage. Proposed solutions were to define reasons for oral anticoagulant underuse classified in ways that can guide intervention and improve use, to increase awareness of stroke risk as well as the benefits and risks of OAC use via educational initiatives and feedback mechanisms, to better define the role of VKA in the current therapeutic era including eligibility and ineligibility for different anticoagulant therapies, to identify NOAC reversal agents and monitoring strategies and make knowledge regarding their use publicly available, to minimize the duration of dual antiplatelet therapy and concomitant OAC where possible, to improve time in therapeutic range for VKA, to leverage observational data sets to refine understanding of OAC use and outcomes in general practice, and to better align health system incentives.

Implantable cardioverter-defibrillators for primary prevention of sudden cardiac death in CKD: a meta-analysis of patient-level data from 3 randomized trials.

BACKGROUND: The benefit of a primary prevention implantable cardioverter-defibrillator (ICD) among patients with chronic kidney disease is uncertain. STUDY DESIGN: Meta-analysis of patient-level data from randomized controlled trials. SETTING & POPULATION: Patients with symptomatic heart failure and left ventricular ejection fraction<35%. SELECTION CRITERIA FOR STUDIES: From 7 available randomized controlled studies with patient-level data, we selected studies with available data for important covariates. Studies without patient-level data for baseline estimated glomerular filtration rate (eGFR) were excluded. INTERVENTION: Primary prevention ICD versus usual care effect modification by eGFR. OUTCOMES: Mortality, rehospitalizations, and effect modification by eGFR. RESULTS: We included data from the Multicenter Automatic Defibrillator Implantation Trial I (MADIT-I), MADIT-II, and the Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT). 2,867 patients were included; 36.3% had eGFR<60 mL/min/1.73m2. Kaplan-Meier estimate of the probability of death during follow-up was 43.3% for 1,334 patients receiving usual care and 35.8% for 1,533 ICD recipients. After adjustment for baseline differences, there was evidence that the survival benefit of ICDs in comparison to usual care depends on eGFR (posterior probability for null interaction P<0.001). The ICD was associated with survival benefit for patients with eGFR≥60 mL/min/1.73 m2 (adjusted HR, 0.49; 95% posterior credible interval, 0.24-0.95), but not for patients with eGFR<60 mL/min/1.73 m2 (adjusted HR, 0.80; 95% posterior credible interval, 0.40-1.53). eGFR did not modify the association between the ICD and rehospitalizations. LIMITATIONS: Few patients with eGFR<30 mL/min/1.73 m2 were available. Differences in trial-to-trial measurement techniques may lead to residual confounding. CONCLUSIONS: Reductions in baseline eGFR decrease the survival benefit associated with the ICD. These findings should be confirmed by additional studies specifically targeting patients with varying eGFRs.

Niche-DE: niche-differential gene expression analysis in spatial transcriptomics data identifies context-dependent cell-cell interactions.

Existing methods for analysis of spatial transcriptomic data focus on delineating the global gene expression variations of cell types across the tissue, rather than local gene expression changes driven by cell-cell interactions. We propose a new statistical procedure called niche-differential expression (niche-DE) analysis that identifies cell-type-specific niche-associated genes, which are differentially expressed within a specific cell type in the context of specific spatial niches. We further develop niche-LR, a method to reveal ligand-receptor signaling mechanisms that underlie niche-differential gene expression patterns. Niche-DE and niche-LR are applicable to low-resolution spot-based spatial transcriptomics data and data that is single-cell or subcellular in resolution.