The innate immune response to coxsackievirus B3 predicts progression to cardiovascular disease and heart failure in male mice

<p>Abstract</p> <p>Background</p> <p>Men are at an increased risk of dying from heart failure caused by inflammatory heart diseases such as atherosclerosis, myocarditis and dilated cardiomyopathy (DCM). We previously showed that macrophages in the spleen are phenotypically distinct in male compared to female mice at 12 h after infection. This innate immune profile mirrors and predicts the cardiac immune response during acute myocarditis.</p> <p>Methods</p> <p>In order to study sex differences in the innate immune response, five male and female BALB/c mice were infected intraperitoneally with coxsackievirus B3 (CVB3) or phosphate buffered saline and their spleens were harvested 12 h later for microarray analysis. Gene expression was determined using an Affymetrix Mouse Gene 1.0 ST Array. Significant gene changes were verified by quantitative real-time polymerase chain reaction or ELISA.</p> <p>Results</p> <p>During the innate immune response to CVB3 infection, infected males had higher splenic expression of genes which are important in regulating the influx of cholesterol into macrophages, such as phospholipase A₂(PLA₂) and the macrophage scavenger receptor compared to the infected females. We also observed a higher expression in infected males compared to infected females of squalene synthase, an enzyme used to generate cholesterol within cells, and Cyp2e1, an enzyme important in metabolizing cholesterol and steroids. Infected males also had decreased levels of the translocator protein 18 kDa (TSPO), which binds PLA₂and is the rate-limiting step for steroidogenesis, as well as decreased expression of the androgen receptor (AR), which indicates receptor activation. Gene differences were not due to increased viral replication, which was unaltered between sexes.</p> <p>Conclusions</p> <p>We found that, compared to females, male mice had a greater splenic expression of genes which are important for cholesterol metabolism and activation of the AR at 12 h after infection. Activation of the AR has been linked to increased cardiac hypertrophy, atherosclerosis, myocarditis/DCM and heart failure in male mice and humans.</p

Beyond the looking glass: recent advances in understanding the impact of environmental exposures on neuropsychiatric disease

The etiologic pathways leading to neuropsychiatric diseases remain poorly defined. As genomic technologies have advanced over the past several decades, considerable progress has been made linking neuropsychiatric disorders to genetic underpinnings. Interest and consideration of nongenetic risk factors (e.g., lead exposure and schizophrenia) have, in contrast, lagged behind heritable frameworks of explanation. Thus, the association of neuropsychiatric illness to environmental chemical exposure, and their potential interactions with genetic susceptibility, are largely unexplored. In this review, we describe emerging approaches for considering the impact of chemical risk factors acting alone and in concert with genetic risk, and point to the potential role of epigenetics in mediating exposure effects on transcription of genes implicated in mental disorders. We highlight recent examples of research in nongenetic risk factors in psychiatric disorders that point to potential shared biological mechanisms—synaptic dysfunction, immune alterations, and gut–brain interactions. We outline new tools and resources that can be harnessed for the study of environmental factors in psychiatric disorders. These tools, combined with emerging experimental evidence, suggest that there is a need to broadly incorporate environmental exposures in psychiatric research, with the ultimate goal of identifying modifiable risk factors and informing new treatment strategies for neuropsychiatric disease

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Becoming aWARE: The Development of a Web-Based Tool for Autism Research and the Environment

A sharp rise in autism spectrum disorder (ASD) prevalence estimates, beginning in the 1990s, suggested factors additional to genetics were at play. This stimulated increased research investment in nongenetic factors, including the study of environmental chemical exposures, diet, nutrition, lifestyle, social factors, and maternal medical conditions. Consequently, both peer- and non-peer-reviewed bodies of evidence investigating environmental contributors to ASD etiology have grown significantly. The heterogeneity in the design and conduct of this research results in an inconclusive and unwieldy ‘virtual stack’ of publications. We propose to develop a Web-based tool for Autism Research and the Environment (aWARE) to comprehensively aggregate and assess these highly variable and often conflicting data. The interactive aWARE tool will use an approach for the development of systematic evidence maps (SEMs) to identify and display all available relevant published evidence, enabling users to explore multiple research questions within the scope of the SEM. Throughout tool development, listening sessions and workshops will be used to seek perspectives from the broader autism community. New evidence will be indexed in the tool annually, which will serve as a living resource to investigate the association between environmental factors and ASD

Sex Differences in Translocator Protein 18 kDa (TSPO) in the Heart: Implications for Imaging Myocardial Inflammation

Myocarditis is more severe in men than women and difficult to diagnose due to a lack of imaging modalities that directly detect myocardial inflammation. Translocator protein 18 kDa (TSPO) is used extensively to image brain inflammation due to its presence in CD11b(+) brain microglia. In this study we examined expression of TSPO and CD11b in mice with coxsackievirus B3 (CVB3) myocarditis and biopsy sections from myocarditis patients in order to determine if it could be used to image myocarditis. We found that male mice with CVB3 myocarditis upregulated more genes associated with TSPO activation than females. TSPO expression was increased in the heart of male mice and men with myocarditis compared to females due to testosterone, where it was expressed predominantly in CD11b(+) immune cells. We show that TSPO ligands detect myocardial inflammation using microSPECT, with increased uptake of [(125)I]-IodoDPA-713 in male mice with CVB3 myocarditis compared to undiseased controls

Sex Differences in Translocator Protein 18 kDa (TSPO) in the Heart: Implications for Imaging Myocardial Inflammation

Myocarditis is more severe in men than women and difficult to diagnose due to a lack of imaging modalities that directly detect myocardial inflammation. Translocator protein 18 kDa (TSPO) is used extensively to image brain inflammation due to its presence in CD11b(+) brain microglia. In this study we examined expression of TSPO and CD11b in mice with coxsackievirus B3 (CVB3) myocarditis and biopsy sections from myocarditis patients in order to determine if it could be used to image myocarditis. We found that male mice with CVB3 myocarditis upregulated more genes associated with TSPO activation than females. TSPO expression was increased in the heart of male mice and men with myocarditis compared to females due to testosterone, where it was expressed predominantly in CD11b(+) immune cells. We show that TSPO ligands detect myocardial inflammation using microSPECT, with increased uptake of [(125)I]-IodoDPA-713 in male mice with CVB3 myocarditis compared to undiseased controls

Synopsis of an integrated guidance for enhancing the care of familial hypercholesterolaemia: an Australian perspective

Summary: Introduction: Familial hypercholesterolaemia (FH) is a common, heritable and preventable cause of premature coronary artery disease, with significant potential for positive impact on public health and healthcare savings. New clinical practice recommendations are presented in an abridged guidance to assist practitioners in enhancing the care of all patients with FH. Main recommendations: Core recommendations are made on the detection, diagnosis, assessment and management of adults, children and adolescents with FH. There is a key role for general practitioners (GPs) working in collaboration with specialists with expertise in lipidology. Advice is given on genetic and cholesterol testing and risk notification of biological relatives undergoing cascade testing for FH; all healthcare professionals should develop skills in genomic medicine. Management is under-pinned by the precepts of risk stratification, adherence to healthy lifestyles, treatment of non-cholesterol risk factors, and appropriate use of low-density lipoprotein (LDL)-cholesterol lowering therapies, including statins, ezetimibe and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors. Recommendations on service design are provided in the full guidance. Potential impact on care of FH: These recommendations need to be utilised using judicious clinical judgement and shared decision making with patients and families. Models of care need to be adapted to both local and regional needs and resources. In Australia new government funded schemes for genetic testing and use of PCSK9 inhibitors, as well as the National Health Genomics Policy Framework, will enable adoption of these recommendations. A broad implementation science strategy is, however, required to ensure that the guidance translates into benefit for all families with FH