Inhibition of RNA polymerase II transcription in human cells by synthetic DNA-binding ligands

Sequence-specific DNA-binding small molecules that can permeate human cells potentially could regulate transcription of specific genes. Multiple cellular DNA-binding transcription factors are required by HIV type 1 for RNA synthesis. Two pyrrole-imidazole polyamides were designed to bind DNA sequences immediately adjacent to binding sites for the transcription factors Ets-l, lymphoid-enhancer binding factor 1, and TATA-box binding protein. These synthetic ligands specifically inhibit DNA-binding of each transcription factor and HIV type 1 transcription in cell-free assays. When used in combination, the polyamides inhibit virus replication by >99% in isolated human peripheral blood lymphocytes, with no detectable cell toxicity, The ability of small molecules to target predetermined DNA sequences located within RNA polymerase II promoters suggests a general approach for regulation of gene expression, as well as a mechanism for the inhibition of viral replication

The Changing Landscape for Stroke\ua0Prevention in AF: Findings From the GLORIA-AF Registry Phase 2

Background GLORIA-AF (Global Registry on Long-Term Oral Antithrombotic Treatment in Patients with Atrial Fibrillation) is a prospective, global registry program describing antithrombotic treatment patterns in patients with newly diagnosed nonvalvular atrial fibrillation at risk of stroke. Phase 2 began when dabigatran, the first non\u2013vitamin K antagonist oral anticoagulant (NOAC), became available. Objectives This study sought to describe phase 2 baseline data and compare these with the pre-NOAC era collected during phase 1. Methods During phase 2, 15,641 consenting patients were enrolled (November 2011 to December 2014); 15,092 were eligible. This pre-specified cross-sectional analysis describes eligible patients\u2019 baseline characteristics. Atrial fibrillation disease characteristics, medical outcomes, and concomitant diseases and medications were collected. Data were analyzed using descriptive statistics. Results Of the total patients, 45.5% were female; median age was 71 (interquartile range: 64, 78) years. Patients were from Europe (47.1%), North America (22.5%), Asia (20.3%), Latin America (6.0%), and the Middle East/Africa (4.0%). Most had high stroke risk (CHA2DS2-VASc [Congestive heart failure, Hypertension, Age  6575 years, Diabetes mellitus, previous Stroke, Vascular disease, Age 65 to 74 years, Sex category] score  652; 86.1%); 13.9% had moderate risk (CHA2DS2-VASc = 1). Overall, 79.9% received oral anticoagulants, of whom 47.6% received NOAC and 32.3% vitamin K antagonists (VKA); 12.1% received antiplatelet agents; 7.8% received no antithrombotic treatment. For comparison, the proportion of phase 1 patients (of N = 1,063 all eligible) prescribed VKA was 32.8%, acetylsalicylic acid 41.7%, and no therapy 20.2%. In Europe in phase 2, treatment with NOAC was more common than VKA (52.3% and 37.8%, respectively); 6.0% of patients received antiplatelet treatment; and 3.8% received no antithrombotic treatment. In North America, 52.1%, 26.2%, and 14.0% of patients received NOAC, VKA, and antiplatelet drugs, respectively; 7.5% received no antithrombotic treatment. NOAC use was less common in Asia (27.7%), where 27.5% of patients received VKA, 25.0% antiplatelet drugs, and 19.8% no antithrombotic treatment. Conclusions The baseline data from GLORIA-AF phase 2 demonstrate that in newly diagnosed nonvalvular atrial fibrillation patients, NOAC have been highly adopted into practice, becoming more frequently prescribed than VKA in Europe and North America. Worldwide, however, a large proportion of patients remain undertreated, particularly in Asia and North America. (Global Registry on Long-Term Oral Antithrombotic Treatment in Patients With Atrial Fibrillation [GLORIA-AF]; NCT01468701

Personalized management of atrial fibrillation:Proceedings from the fourth Atrial Fibrillation competence NETwork/European Heart Rhythm Association consensus conference

<p>The management of atrial fibrillation (AF) has seen marked changes in past years, with the introduction of new oral anticoagulants, new antiarrhythmic drugs, and the emergence of catheter ablation as a common intervention for rhythm control. Furthermore, new technologies enhance our ability to detect AF. Most clinical management decisions in AF patients can be based on validated parameters that encompass type of presentation, clinical factors, electrocardiogram analysis, and cardiac imaging. Despite these advances, patients with AF are still at increased risk for death, stroke, heart failure, and hospitalizations. During the fourth Atrial Fibrillation competence NETwork/European Heart Rhythm Association (AFNET/EHRA) consensus conference, we identified the following opportunities to personalize management of AF in a better manner with a view to improve outcomes by integrating atrial morphology and damage, brain imaging, information on genetic predisposition, systemic or local inflammation, and markers for cardiac strain. Each of these promising avenues requires validation in the context of existing risk factors in patients. More importantly, a new taxonomy of AF may be needed based on the pathophysiological type of AF to allow personalized management of AF to come to full fruition. Continued translational research efforts are needed to personalize management of this prevalent disease in a better manner. All the efforts are expected to improve the management of patients with AF based on personalized therapy.</p>

Early rhythm-control therapy in patients with atrial fibrillation

BACKGROUND Despite improvements in the management of atrial fibrillation, patients with this condition remain at increased risk for cardiovascular complications. It is unclear whether early rhythm-control therapy can reduce this risk. METHODS In this international, investigator-initiated, parallel-group, open, blinded-outcome-assessment trial, we randomly assigned patients who had early atrial fibrillation (diagnosed ≤1 year before enrollment) and cardiovascular conditions to receive either early rhythm control or usual care. Early rhythm control included treatment with antiarrhythmic drugs or atrial fibrillation ablation after randomization. Usual care limited rhythm control to the management of atrial fibrillation–related symptoms. The first primary outcome was a composite of death from cardiovascular causes, stroke, or hospitalization with worsening of heart failure or acute coronary syndrome; the second primary outcome was the number of nights spent in the hospital per year. The primary safety outcome was a composite of death, stroke, or serious adverse events related to rhythm-control therapy. Secondary outcomes, including symptoms and left ventricular function, were also evaluated. RESULTS In 135 centers, 2789 patients with early atrial fibrillation (median time since diagnosis, 36 days) underwent randomization. The trial was stopped for efficacy at the third interim analysis after a median of 5.1 years of follow-up per patient. A first-primary-outcome event occurred in 249 of the patients assigned to early rhythm control (3.9 per 100 person-years) and in 316 patients assigned to usual care (5.0 per 100 person-years) (hazard ratio, 0.79; 96% confidence interval, 0.66 to 0.94; P=0.005). The mean (±SD) number of nights spent in the hospital did not differ significantly between the groups (5.8±21.9 and 5.1±15.5 days per year, respectively; P=0.23). The percentage of patients with a primary safety outcome event did not differ significantly between the groups; serious adverse events related to rhythm-control therapy occurred in 4.9% of the patients assigned to early rhythm control and 1.4% of the patients assigned to usual care. Symptoms and left ventricular function at 2 years did not differ significantly between the groups. CONCLUSIONS Early rhythm-control therapy was associated with a lower risk of adverse cardiovascular outcomes than usual care among patients with early atrial fibrillation and cardiovascular conditions

Patterns of oral anticoagulant use and outcomes in Asian patients with atrial fibrillation: a post-hoc analysis from the GLORIA-AF Registry

Background: Previous studies suggested potential ethnic differences in the management and outcomes of atrial fibrillation (AF). We aim to analyse oral anticoagulant (OAC) prescription, discontinuation, and risk of adverse outcomes in Asian patients with AF, using data from a global prospective cohort study. Methods: From the GLORIA-AF Registry Phase II-III (November 2011-December 2014 for Phase II, and January 2014-December 2016 for Phase III), we analysed patients according to their self-reported ethnicity (Asian vs. non-Asian), as well as according to Asian subgroups (Chinese, Japanese, Korean and other Asian). Logistic regression was used to analyse OAC prescription, while the risk of OAC discontinuation and adverse outcomes were analysed through Cox-regression model. Our primary outcome was the composite of all-cause death and major adverse cardiovascular events (MACE). The original studies were registered with ClinicalTrials.gov, NCT01468701, NCT01671007, and NCT01937377. Findings: 34,421 patients were included (70.0&nbsp;±&nbsp;10.5 years, 45.1% females, 6900 (20.0%) Asian: 3829 (55.5%) Chinese, 814 (11.8%) Japanese, 1964 (28.5%) Korean and 293 (4.2%) other Asian). Most of the Asian patients were recruited in Asia (n&nbsp;=&nbsp;6701, 97.1%), while non-Asian patients were mainly recruited in Europe (n&nbsp;=&nbsp;15,449, 56.1%) and North America (n&nbsp;=&nbsp;8378, 30.4%). Compared to non-Asian individuals, prescription of OAC and non-vitamin K antagonist oral anticoagulant (NOAC) was lower in Asian patients (Odds Ratio [OR] and 95% Confidence Intervals (CI): 0.23 [0.22-0.25] and 0.66 [0.61-0.71], respectively), but higher in the Japanese subgroup. Asian ethnicity was also associated with higher risk of OAC discontinuation (Hazard Ratio [HR] and [95% CI]: 1.79 [1.67-1.92]), and lower risk of the primary composite outcome (HR [95% CI]: 0.86 [0.76-0.96]). Among the exploratory secondary outcomes, Asian ethnicity was associated with higher risks of thromboembolism and intracranial haemorrhage, and lower risk of major bleeding. Interpretation: Our results showed that Asian patients with AF showed suboptimal thromboembolic risk management and a specific risk profile of adverse outcomes; these differences may also reflect differences in country-specific factors. Ensuring integrated and appropriate treatment of these patients is crucial to improve their prognosis. Funding: The GLORIA-AF Registry was funded by Boehringer Ingelheim GmbH

Correction to: Comparative effectiveness and safety of non-vitamin K antagonists for atrial fibrillation in clinical practice: GLORIA-AF Registry

International audienceIn this article, the name of the GLORIA-AF investigator Anastasios Kollias was given incorrectly as Athanasios Kollias in the Acknowledgements. The original article has been corrected