Varespladib and cardiovascular events in patients with an acute coronary syndrome: the VISTA-16 randomized clinical trial

IMPORTANCE: Secretory phospholipase A2(sPLA2) generates bioactive phospholipid products implicated in atherosclerosis. The sPLA2inhibitor varespladib has favorable effects on lipid and inflammatory markers; however, its effect on cardiovascular outcomes is unknown. OBJECTIVE: To determine the effects of sPLA2inhibition with varespladib on cardiovascular outcomes. DESIGN, SETTING, AND PARTICIPANTS: A double-blind, randomized, multicenter trial at 362 academic and community hospitals in Europe, Australia, New Zealand, India, and North America of 5145 patients randomized within 96 hours of presentation of an acute coronary syndrome (ACS) to either varespladib (n = 2572) or placebo (n = 2573) with enrollment between June 1, 2010, and March 7, 2012 (study termination on March 9, 2012). INTERVENTIONS: Participants were randomized to receive varespladib (500 mg) or placebo daily for 16 weeks, in addition to atorvastatin and other established therapies. MAIN OUTCOMES AND MEASURES: The primary efficacy measurewas a composite of cardiovascular mortality, nonfatal myocardial infarction (MI), nonfatal stroke, or unstable angina with evidence of ischemia requiring hospitalization at 16 weeks. Six-month survival status was also evaluated. RESULTS: At a prespecified interim analysis, including 212 primary end point events, the independent data and safety monitoring board recommended termination of the trial for futility and possible harm. The primary end point occurred in 136 patients (6.1%) treated with varespladib compared with 109 patients (5.1%) treated with placebo (hazard ratio [HR], 1.25; 95%CI, 0.97-1.61; log-rank P = .08). Varespladib was associated with a greater risk of MI (78 [3.4%] vs 47 [2.2%]; HR, 1.66; 95%CI, 1.16-2.39; log-rank P = .005). The composite secondary end point of cardiovascular mortality, MI, and stroke was observed in 107 patients (4.6%) in the varespladib group and 79 patients (3.8%) in the placebo group (HR, 1.36; 95% CI, 1.02-1.82; P = .04). CONCLUSIONS AND RELEVANCE: In patients with recent ACS, varespladib did not reduce the risk of recurrent cardiovascular events and significantly increased the risk of MI. The sPLA2inhibition with varespladib may be harmful and is not a useful strategy to reduce adverse cardiovascular outcomes after ACS. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01130246. Copyright 2014 American Medical Association. All rights reserved

Improved functionalization of oleic acid-coated iron oxide nanoparticles for biomedical applications

Superparamagnetic iron oxide nanoparticles can providemultiple benefits for biomedical applications in aqueous environments such asmagnetic separation or magnetic resonance imaging. To increase the colloidal stability and allow subsequent reactions, the introduction of hydrophilic functional groups onto the particles’ surface is essential. During this process, the original coating is exchanged by preferably covalently bonded ligands such as trialkoxysilanes. The duration of the silane exchange reaction, which commonly takes more than 24 h, is an important drawback for this approach. In this paper, we present a novel method, which introduces ultrasonication as an energy source to dramatically accelerate this process, resulting in high-quality waterdispersible nanoparticles around 10 nmin size. To prove the generic character, different functional groups were introduced on the surface including polyethylene glycol chains, carboxylic acid, amine, and thiol groups. Their colloidal stability in various aqueous buffer solutions as well as human plasma and serum was investigated to allow implementation in biomedical and sensing applications.status: publishe

Cause of Death and Predictors of All-Cause Mortality in Anticoagulated Patients With Nonvalvular Atrial Fibrillation : Data From ROCKET AF

M. Kaste on työryhmän ROCKET AF Steering Comm jäsen.Background-Atrial fibrillation is associated with higher mortality. Identification of causes of death and contemporary risk factors for all-cause mortality may guide interventions. Methods and Results-In the Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF) study, patients with nonvalvular atrial fibrillation were randomized to rivaroxaban or dose-adjusted warfarin. Cox proportional hazards regression with backward elimination identified factors at randomization that were independently associated with all-cause mortality in the 14 171 participants in the intention-to-treat population. The median age was 73 years, and the mean CHADS(2) score was 3.5. Over 1.9 years of median follow-up, 1214 (8.6%) patients died. Kaplan-Meier mortality rates were 4.2% at 1 year and 8.9% at 2 years. The majority of classified deaths (1081) were cardiovascular (72%), whereas only 6% were nonhemorrhagic stroke or systemic embolism. No significant difference in all-cause mortality was observed between the rivaroxaban and warfarin arms (P=0.15). Heart failure (hazard ratio 1.51, 95% CI 1.33-1.70, P= 75 years (hazard ratio 1.69, 95% CI 1.51-1.90, P Conclusions-In a large population of patients anticoagulated for nonvalvular atrial fibrillation, approximate to 7 in 10 deaths were cardiovascular, whereasPeer reviewe

The role of substrate holding in achieving critical swimming speeds: a case study using the invasive round goby (Neogobius melanostomus)

The swimming performance of fishes has generally been assessed using a stepped velocity test where the speed at fatigue is considered the critical swimming performance (Ucrit). Although this test was designed for fishes that swim in the water column, it has been applied to fishes that adhere to the substrate. Here we examined the extent to which substrate holding, slipping and swimming contributed to reaching Ucrit in an example substrate holding fish, the invasive round goby. A linear model indicated that each behavior contributed significantly to Ucrit, but that substrate holding was by far the biggest contributor (65.8 ± 3.9 % vs. 5.8 ± 0.9 and 28.4 ± 3.4 % slipping and swimming). We also used our behavioural analysis to determine the critical substrate holding speed (Uhold: 28.6 ± 1.1 cm s−1). We conclude that the Ucrit test can be applied to substrate holding fish but that it is not just an indication of critical swimming speed as is often considered and must be interpreted with caution

THE “PROTOCOL” STUDY: PRELIMINARY RESULTS

Aim. To reveal the association of gene polymorphism CYP2С19*2 and recurrent early stent thrombosis in coronary vessels, and paradoxal response to clopidogrel intake in patients — the inhabitants of Siberian Region — after acute coronary syndrome.Material and methods. Totally 105 patients studied, hospitalized for stenting of coronary arteries in acute coronary syndrome, never received clopidogrel previously. The polymorphism of studied СУР2С19: *2, *3, *17 alleles, as assessment of platelet aggregation with ADP before and after clopidogrel intake, as of endpoints on safety and efficacy during 30 days (thrombotic complications, bleeding).Results. Within the selected patients there was no any significant association of any CYP2С19*2 and/or CYP2С19*3 alleles and paradoxic laboratory reaction. There was significant association of the CYP2C19*17 gene carriage and bleedings. When comparing the groups of patients having or not having complications related to clopidogrel (thrombotic or bleedings), there was significant difference in residual platelet aggregation.Conclusion. The results of the study might be strongly significant for the decisions making on double antiplatelet therapy and on the tactics of drugs preference

Genetic markers of risk for ST-elevated myocardial infarction

Aim. To identify genetic markers of risk for ST-elevated myocardial infarction (STEMI).Material and methods. The study included 210 patients (119 men, 91 women) with STEMI, hospitalized from December 21, 2016 to June 16, 2017 The average age of men was 55,5±9,5 years, women — 57,5±9,1 years. The diagnosis of STEMI was verified according to the criteria of the European Society of Cardiology (2015, 2017). During hospitalization, patients underwent clinical and instrumental examination, stipulated by medical care standards and clinical guidelines We also conducted a genetic study of single nucleotide polymorphisms (SNPs), which showed their association with the risk of coronary artery disease (CAD) and acute myocardial infarction (AMI) according to the GWAS: rs2820315 of the LMOD1 gene (Leiomodin 1, mapped on chromosome 1), rs9349379 of the PHACTR1 gene (regulator 1 of actin and phosphotase, localized on chromosome 6p241), rs867186 of the PROCR gene (Protein C receptor, located on chromosome 20q11.22), rsi1799883 of the FABP2 gene (Fatty acid-binding protein 2, located on chromosome 4q26). Statistical data analysis was performed using the SPSS 170.5 software package and authorial odds ratio (OR) calculator.Results. Carriage of the CC genotype of rs2820315 polymorphism of the LMOD gene is associated with an increased risk of STEMI by 1,87 times (95% CI 1,2862,722, p=0,016). Carriers of the CT genotype of rs2820315 polymorphism have a reduced risk of STEMI (OR 0,633; 95% CI 0,436-0,918, p=0,016).Conclusion. In order to identify risk groups for STEMI development, the study of the rs2820315 polymorphism of the LMOD gene is recommended. This will define the high-risk group for STEMI for developing of personalized programs for primary and secondary prevention of cardiovascular events in practical health care, which will contribute to reducing of STEMI mortality

The influence of factors on five-year outcomes after acute coronary syndrome

Aim. To identify the factors of long-term adverse prognosis of patients with acute coronary syndrome as a result of five-year follow-up.Material and methods. The study included 280 patients with ACS hospitalized in the 1st cardiology Department of the Novosibirsk municipal CLINICAL hospital № 1 in 2010-2011. The study cohort included 145 patients with ACS (107 men and 38 women), 135 patients with ACS (93 men and 43 women). The average age of men was 56,3±5,2, women 52,1±5,3 years. The criteria of the European society of cardiology (2015, 2017) were used for the diagnosis of ACS. For five years, all patients included in the study were contacted through communication and annual medical examinations, to which patients were invited to the clinic. The examinations included the following clinical and instrumental examinations: clinical examination, electrocardiography, Holter monitoring of electrocardiogram, echocardiography, lipid profile, inflammatory cytokines and molecular genetic parameters. In the study, a mathematical model for predicting five-year outcomes Oxpt and Oxbt. Results. Five-year observation allowed using the constructed mathematical model to determine not only the place of each factor in the cardiovascular prognosis, but also to assess how the role of these prognostic markers changes over time. Conclusion. The use of a mathematical model for predicting long-term adverse outcomes of ACS allows to assess the value of specific risk factors and predictors, respectively, makes a significant contribution to the optimization of secondary prevention and personalized approach to treatment. At the same time, the influence of the identified predictors weakens in proportion to the increase in the number of years from a vascular accident. Thus, the identified risk factors have the maximum impact in the first year after ACS, in subsequent years, the role of these factors is reduced, which is probably due not only to the importance of the factors themselves, but also to the addition of other risk factors to the overall picture of the disease of patients. Nevertheless, the use of this model is necessary to solve the problem of reducing cardiovascular risk

Genetic predictors of five-year outcomes of acute coronary syndrome

Aim. To determine the genetic predictors of five-year outcomes in patients with acute coronary syndrome (ACS).Material and methods. The study included patients admitted to the City clinical hospital № 1 (CCH №1) in Novosibirsk with a diagnosis of ACS in the period 2010-3 2011 (n=280). All patients were examined in accordance with clinical guidelines and standards of care, genetic markers were assessed. Genotyping included determination of single nucleotide polymorphisms (SNPs), confirming its association with the development of the ACS according to the results of an international genomeassociated studies: rs1376251, rs4804611, rs 1333049, rs619203, rs10757278, rs2549513, rs499818, rs17465637. All patients are kept in touch from the moment of initial contact to the present time, with the help of available means of communication and annual examinations in order to assess the end points. “End points” included: repeated nonfatal myocardial infarction (MI), hospitalization for myocardial ischemia, re-revascularization or chronic heart failure (CHF), nonfatal acute cerebrovascular accident (NACA), cardiovascular death.Results. We revealed SNPs, which play a role in predicting long-term outcomes of ACS: rs10757278, rs 4804611, rs 1333049, rs 2549513. The genotype of rs2549513 as 2,9-fold (95% CI 1,06-8,03; p=0,041) increases the risk of unfavorable long-term prognosis in the subgroup of men older than 55 years. The AA genotype rs10757278 and GG genotype rs1333049 are associated with a favorable long-term prognosis (OR=0,47, 95% CI 0,23-0,96; p=0,042 and OR=0,41, 95% CI 0,22-0,78; p=0,049, respectively) in the group of patients older than 55 years. For the GG genotype rs1333049 association was characteristic only for women. The AA genotype rs4804611 is associated with a favorable outcome of ACS at the age of 55 years (OR=0,036, 95% CI 0,14-0,96; p=0,053), significant differences were obtained in the group of men (p=0,36).Conclusion. The use of identified genetic predictors to assess the risk of five-year outcomes will strengthen a personalized approach to patients and, together with conventional prevention measures, will reduce cardiovascular mortality