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"Thomas Binder"
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Class II HLA interactions modulate genetic risk for multiple sclerosis
Gil McVean and colleagues report a meta-analysis of Immunochip studies including over 17,000 multiple sclerosis cases and 30,000 controls, with imputation of classical HLA alleles. They find two interactions involving class II HLA alleles but no evidence for significant epistatic interactions or interactions between HLA and non-HLA risk variants.
Association studies have greatly refined the understanding of how variation within the human leukocyte antigen (HLA) genes influences risk of multiple sclerosis. However, the extent to which major effects are modulated by interactions is poorly characterized. We analyzed high-density SNP data on 17,465 cases and 30,385 controls from 11 cohorts of European ancestry, in combination with imputation of classical HLA alleles, to build a high-resolution map of HLA genetic risk and assess the evidence for interactions involving classical HLA alleles. Among new and previously identified class II risk alleles (HLA-DRB1*15:01, HLA-DRB1*13:03, HLA-DRB1*03:01, HLA-DRB1*08:01 and HLA-DQB1*03:02) and class I protective alleles (HLA-A*02:01, HLA-B*44:02, HLA-B*38:01 and HLA-B*55:01), we find evidence for two interactions involving pairs of class II alleles: HLA-DQA1*01:01–HLA-DRB1*15:01 and HLA-DQB1*03:01–HLA-DQB1*03:02. We find no evidence for interactions between classical HLA alleles and non-HLA risk-associated variants and estimate a minimal effect of polygenic epistasis in modulating major risk alleles.
Journal Article
Neutrophil extracellular traps and fibrocytes in ST-segment elevation myocardial infarction
Leukocyte-mediated inflammation is central in atherothrombosis and ST-segment elevation myocardial infarction (STEMI). Neutrophil extracellular traps (NETs) have been shown to enhance atherothrombosis and stimulate fibroblast function. We analyzed the effects of NETs on cardiac remodeling after STEMI. We measured double-stranded (ds)DNA and citrullinated histone H3 (citH3) as NET surrogate markers in human culprit site and femoral blood collected during primary percutaneous coronary intervention (n = 50). Fibrocytes were characterized in whole blood by flow cytometry, and in culprit site thrombi and myocardium by immunofluorescence. To investigate mechanisms of fibrocyte activation, isolated NETs were used to induce fibrocyte responses in vitro. Enzymatic infarct size was assessed using creatine-phosphokinase isoform MB area under the curve. Left ventricular function was measured by transthoracic echocardiography. NET surrogate markers were increased at the culprit site compared to the femoral site and were positively correlated with infarct size and left ventricular dysfunction at follow-up. In vitro, NETs promoted fibrocyte differentiation from monocytes and induced fibrocyte activation. Highly activated fibrocytes accumulated at the culprit site and in the infarct transition zone. Our data suggest that NETs might be important mediators of fibrotic remodeling after STEMI, possibly by stimulating fibrocytes.
Journal Article
Pulmonary Hypertension in Heart Failure. Epidemiology, Right Ventricular Function, and Survival
Abstract
Rationale
Patients with pulmonary hypertension due to left heart disease (PH-LHD) and a diastolic pulmonary vascular pressure gradient ≥7 mm Hg, representing PH out of proportion to pulmonary arterial wedge pressure, have pulmonary vascular disease and increased mortality. Little information exists on this condition, recently labeled as “combined pre- and post-capillary PH” (Cpc-PH).
Objectives
To investigate epidemiology, risk factors, right ventricular function, and outcomes in patients with chronic heart failure and Cpc-PH.
Methods
The study population was identified from a retrospective chart review of a clinical database of 3,107 stable patients who underwent first diagnostic right heart catheterization and from a prospective cohort of 800 consecutive patients at a national university-affiliated tertiary center.
Measurements and Main Results
The retrospective cohort had 664 patients with systolic heart failure (SHF) and 399 patients with diastolic heart failure (DHF), 12% of whom were classified as Cpc-PH. The prospective cohort had 172 patients with SHF (14% Cpc-PH) and 219 patients with DHF (12% Cpc-PH). Chronic obstructive pulmonary disease (P = 0.034) and the tricuspid annular plane systolic excursion to systolic pulmonary artery pressure ratio (P = 0.015) predicted Cpc-PH in SHF. Younger age (P = 0.004), valvular heart disease (P = 0.046), and the tricuspid annular plane systolic excursion to systolic pulmonary artery pressure ratio predicted Cpc-PH in DHF (P = 0.016). Right ventricular–pulmonary vascular coupling was worse in Cpc-PH patients (end-systolic elastance to effective arterial elastance [Ees/Ea]: SHF: 1.05 ± 0.25; P = 0.002; DHF: 1.17 ± 0.27; P = 0.027) than in those with isolated post-capillary PH (Ees/Ea: SHF: 1.52 ± 0.51; DHF: 1.45 ± 0.29).
Conclusions
Cpc-PH is rare in chronic heart failure. Right ventricular–pulmonary vascular coupling is poor in Cpc-PH and could be one explanation for dismal outcomes.
Journal Article
Analysis of immune-related loci identifies 48 new susceptibility variants for multiple sclerosis
The International Multiple Sclerosis Genetics Consortium reports the discovery of 48 new susceptibility variants for multiple sclerosis through targeted follow-up of immune-related loci. They also report fine mapping of association signals at established susceptibility loci and provide insights into the immune system processes underlying this disease.
Using the ImmunoChip custom genotyping array, we analyzed 14,498 subjects with multiple sclerosis and 24,091 healthy controls for 161,311 autosomal variants and identified 135 potentially associated regions (
P
< 1.0 × 10
−4
). In a replication phase, we combined these data with previous genome-wide association study (GWAS) data from an independent 14,802 subjects with multiple sclerosis and 26,703 healthy controls. In these 80,094 individuals of European ancestry, we identified 48 new susceptibility variants (
P
< 5.0 × 10
−8
), 3 of which we found after conditioning on previously identified variants. Thus, there are now 110 established multiple sclerosis risk variants at 103 discrete loci outside of the major histocompatibility complex. With high-resolution Bayesian fine mapping, we identified five regions where one variant accounted for more than 50% of the posterior probability of association. This study enhances the catalog of multiple sclerosis risk variants and illustrates the value of fine mapping in the resolution of GWAS signals.
Journal Article
Echocardiographic assessment of right ventricular function: current clinical practice
Echocardiographic evaluation of right ventricular (RV) function is a challenge due to the complex anatomy of the RV. Several transthoracic echocardiographic methods have been suggested for the quantification of RV function. However, many of the parameters are time consuming and need dedicated hardware and software. We suspected that the majority of the established markers are not used on a wide basis. In a multinational online survey, we evaluated the use of current clinical standards for the quantification of RV function in clinical practice. Through the network of an Ultrasound Online Teaching Platform, echocardiographers were invited to participate in an open online survey. The participants were asked about the parameters (eyeballing, TAPSE, S′, fractional area change, RIMP, 3D-EF, dp/dt, longitudinal strain) they used in clinical practice. A total of 1150 participants from 109 countries completed the survey. Only eyeballing (72%), TAPSE (69%), and S′ (31%) were commonly used in clinical routine. These methods were applied significantly less common in low-income economies when compared to high-income economies. Twenty-three percent of all participants stated to rely on eyeballing only, when evaluating RV function in clinical routine. New technologies, such as global longitudinal strain (3%) and 3D echocardiography (1%) were rarely applied independent of region and economic strength. Eyeballing and TAPSE are the most widely used methods in echocardiography for the assessment of RV function. Although advanced parameters such as longitudinal strain and 3D echocardiography were shown to be highly accurate, they are rarely used in clinical routine.
Journal Article
5-Azacytidine Promotes an Inhibitory T-Cell Phenotype and Impairs Immune Mediated Antileukemic Activity
Demethylating agent, 5-Azacytidine (5-Aza), has been shown to be active in treatment of myeloid malignancies. 5-Aza enhances anticancer immunity, by increasing expression of tumor-associated antigens. However, the impact of 5-Aza immune responses remains poorly understood. Here, T-cell mediated tumor immunity effects of 5-Aza, are investigated in vitro and in vivo. T-cells from healthy donors were treated with 5-Aza and analyzed by qRT-PCR and flow cytometry for changes in gene expression and phenotype. Functionality was assessed by a tumor lysis assay. Peripheral blood from patients treated with 5-Aza after alloSCT was monitored for changes in T-cell subpopulations. 5-Aza treatment resulted in a decrease in CD8+ T-cells, whereas CD4+ T-cells increased. Furthermore, numbers of IFN-γ+ T-helper 1 cells (Th1) were reduced, while Treg-cells showed substantial increase. Additionally, CD8+ T-cells exhibited limited killing capacity against leukemic target cells. In vivo data confirm the increase of Treg compartment, while CD8+ T-effector cell numbers were reduced. 5-Aza treatment results in a shift from cytotoxic to regulatory T-cells with a functional phenotype and a major reduction in proinflammatory Th1-cells, indicating a strong inhibition of tumor-specific T-cell immunity by 5-Aza.
Journal Article
Left atrial size predicts outcome in severe but asymptomatic mitral regurgitation
Patients with severe asymptomatic primary mitral regurgitation (MR) can be safely managed with an active surveillance strategy. Left atrial (LA) size is affected by MR severity, left ventricular function and is also associated with the risk of atrial fibrillation and may be an integrative parameter for risk stratification. The present study sought to determine the predictive value of LA size in a large series of asymptomatic patients with severe MR. 280 consecutive patients (88 female, median age 58 years) with severe primary MR and no guideline-based indications for surgery were included in a follow-up program until criteria for mitral surgery were reached. Event-free survival was determined and potential predictors of outcome were assessed. Survival free of any indication for surgery was 78% at 2 years, 52% at 6 years, 35% at 10 years and 19% at 15 years, respectively. Left atrial (LA) diameter was the strongest independent echocardiographic predictor of event-free survival with incremental predictive value for the thresholds of 50, 60 and 70 mm, respectively. In a multivariable analysis that encompassed age at baseline, previous history of atrial fibrillation, left ventricular end systolic diameter), LA diameter, sPAP > 50 mmHg and year of inclusion, LA diameter was the strongest independent echocardiographic predictor of event-free survival (adjusted HR = 1.039, p < 0.001). LA size is a simple and reproducible predictor of outcome in asymptomatic severe primary MR. In particular, it may help to identify patients who may benefit from early elective valve surgery in heart valve centers of excellence.
Journal Article
On the relevance of animal behavior to the management and conservation of fishes and fisheries
There are many syntheses on the role of animal behavior in understanding and mitigating conservation threats for wildlife. That body of work has inspired the development of a new discipline called conservation behavior. Yet, the majority of those synthetic papers focus on non-fish taxa such as birds and mammals. Many fish populations are subject to intensive exploitation and management and for decades researchers have used concepts and knowledge from animal behavior to support management and conservation actions. Dr. David L. G. Noakes is an influential ethologist who did much foundational work related to illustrating how behavior was relevant to the management and conservation of wild fish. We pay tribute to the late Dr. Noakes by summarizing the relevance of animal behavior to fisheries management and conservation. To do so, we first consider what behavior has revealed about how fish respond to key threats such as habitat alteration and loss, invasive species, climate change, pollution, and exploitation. We then consider how behavior has informed the application of common management interventions such as protected areas and spatial planning, stock enhancement, and restoration of habitat and connectivity. Our synthesis focuses on the totality of the field but includes reflections on the specific contributions of Dr. Noakes. Themes emerging from his approach include the value of fundamental research, management-scale experiments, and bridging behavior, physiology, and ecology. Animal behavior plays a key role in understanding and mitigating threats to wild fish populations and will become more important with the increasing pressures facing aquatic ecosystems. Fortunately, the toolbox for studying behavior is expanding, with technological and analytical advances revolutionizing our understanding of wild fish and generating new knowledge for fisheries managers and conservation practitioners.
Journal Article
Cardiac remodeling in ambitious endurance-trained amateur athletes older than 50 years–an observational study
Data on cardiac remodeling in veteran athletes are conflicting but of clinical importance.
Sixty-nine clinically stable and healthy individuals >50 years were identified (median 55 (IQR 52-64), 26% female). Echocardiographic features were identified in individuals, who have performed endurance sports at 70% of their maximum heart rate for at least 1 hour 3 times/ week over the previous 5 years.
Median training time in all participants was 6 hours per week. Therefore, based on these 6 hours of weekly training, participants were grouped into 45 ambitious endurance-trained amateur athletes (EAA) and 24 recreationally active endurance-trained athletes (RAP) training ≥6 hours (6-10) and <6 hours (3.5-5), respectively. Left ventricular (LV) diameters were slightly larger in EAA than in RAP (27 mm/m2 (25-28) vs. 25 mm/m2 (24-27), p = 0.023) and EAA showed preserved diastolic function (p = 0.028) with lower E/E' ratio (7 (6-9) vs. 9 (7-10), p = 0.039). Interventricular septal thickness and relative wall thickness ratio were similar. Global right ventricular and LV strain were similar, but left atrial (LA) reservoir strain was higher in EAA than in RAP (27% (22-34) vs. 20% (15-29), p = 0.002).
Endurance training in healthy athletes >50 years is not associated with chamber dilatation or LV hypertrophy. A weekly training duration of ≥6 hours seems beneficial to preserve diastolic function associated with an increased LA reservoir function.
Journal Article