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Metabolic alterations precede cardiometabolic disease onset. Here we present ceramide- and dihydroceramide-profiling data from a nested case-cohort (type 2 diabetes [T2D, n  = 775]; cardiovascular disease [CVD, n  = 551]; random subcohort [ n  = 1137]) in the prospective EPIC-Potsdam study. We apply the novel NetCoupler-algorithm to link a data-driven (dihydro)ceramide network to T2D and CVD risk. Controlling for confounding by other (dihydro)ceramides, ceramides C18:0 and C22:0 and dihydroceramides C20:0 and C22:2 are associated with higher and ceramide C20:0 and dihydroceramide C26:1 with lower T2D risk. Ceramide C16:0 and dihydroceramide C22:2 are associated with higher CVD risk. Genome-wide association studies and Mendelian randomization analyses support a role of ceramide C22:0 in T2D etiology. Our results also suggest that (dh)ceramides partly mediate the putative adverse effect of high red meat consumption and benefits of coffee consumption on T2D risk. Thus, (dihydro)ceramides may play a critical role in linking genetic predisposition and dietary habits to cardiometabolic disease risk. Among lipid classes, ceramides are linked to impaired cardiometabolic health. Here the authors report the association of specific ceramides and dihydroceramides on the risk of developing type 2 diabetes and or cardiovascular disease in a prospective population cohort.

Abstract Context Observational studies suggest that variations in normal range thyroid function are associated with cardiovascular diseases. However, it remains to be determined whether these associations are causal or not. Objective To test whether genetically determined variation in normal range thyroid function is causally associated with the risk of stroke and coronary artery disease (CAD) and investigate via which pathways these relations may be mediated. Design, Setting, and Participants Mendelian randomization analyses for stroke and CAD using genetic instruments associated with normal range thyrotropin (TSH) and free thyroxine levels or Hashimoto’s thyroiditis and Graves’ disease. The potential mediating role of known stroke and CAD risk factors was examined. Publicly available summary statistics data were used. Main Outcome Measures Stroke or CAD risk per genetically predicted increase in TSH or FT4 levels. Results A 1 standard deviation increase in TSH was associated with a 5% decrease in the risk of stroke (odds ratio [OR], 0.95; 95% confidence interval [CI], 0.91-0.99; P = 0.008). Multivariable MR analyses indicated that this effect is mainly mediated via atrial fibrillation. MR analyses did not show a causal association between normal range thyroid function and CAD. Secondary analyses showed a causal relationship between Hashimoto’s thyroiditis and a 7% increased risk of CAD (OR, 1.07; 95% CI, 1.01-1.13; P = 0.026), which was mainly mediated via body mass index. Conclusion These results provide important new insights into the causal relationships and mediating pathways between thyroid function, stroke, and CAD. We identify variation in normal range thyroid function and Hashimoto’s thyroiditis as risk factors for stroke and CAD, respectively.

In the past decades, Chimeric Antigen Receptor (CAR)-T cell therapy has achieved remarkable success, leading to the approval of six therapeutic products for haematological malignancies. Recently, the therapeutic potential of this therapy has also been demonstrated in non-tumoral diseases. Currently, the manufacturing process to produce clinical-grade CAR-T cells is complex, time-consuming, and highly expensive. It involves multiple steps, including the collection of T cells from patients or healthy donors, in vitro engineering and expansion, and finally reinfusion into patients. Therefore, despite the impressive clinical outcomes, ex vivo manufacturing process makes CAR-T cells out of reach for many cancer patients. Direct in vivo engineering of T cells could be a more rapid solution able to circumvent both the complexity and the costs associated with ex vivo manufactured CAR-T cells. This novel approach allows to completely eliminate ex vivo cell manipulation and expansion while producing therapeutic cell populations directly in vivo. To date, several studies have demonstrated the feasibility of in vivo T cell reprogramming, by employing injectable viral- or nanocarrier-based delivery platforms in tumour animal models. Additionally, in vivo production of CAR-T cells might reduce the incidence, or at least the severity, of systemic toxicities frequently occurring with ex vivo produced CAR-T cells, such as cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome. In this review, we highlight the challenges associated with the current ex vivo manufacturing protocols and review the latest progresses in the emerging field of in vivo CAR-T therapy, by comparing the various platforms so far investigated. Moreover, we offer an overview of the advantages deriving from in vivo reprogramming of other immune cell types, such as Natural Killer and macrophages, with CAR constructs.

Key Points The myocardium adapts to continued stress—either physiological or pathological—by modulating gene expression in its constituent cells Methylation of cytosine and post-translational chemical alteration of histones—known as epigenetic modification—render regulatory elements of genes more or less permissive to interaction with the transcriptional machinery These alterations create an epigenetic landscape, or 'epigenome', that is probably specific to a particular physiological or pathological state A plethora of noncoding RNAs, such as microRNAs and long noncoding RNAs, is centrally involved in the regulation of probably all biological processes, including gene expression Epigenetic modifications and noncoding RNAs form an integrated and highly complex regulatory network to control gene expression; heart failure is associated with disruption of this network The reversibility of epigenetic modifications and the relative ease with which noncoding RNAs can be manipulated augur well for the development of much-needed novel pharmaceuticals for treatment of heart failure Cardiomyocyte function is regulated by epigenetic modifications (to cytosine residues on DNA, and post-translational acetylation or methylation of histones), as well as by noncoding RNAs (such as microRNAs and long noncoding RNAs). In this Review, Greco and Condorelli describe the complex roles of these two layers of gene-expression regulation in the pathogenesis of cardiac hypertrophy and failure. The regulatory networks governing gene expression in cardiomyocytes are under intense investigation, not least because dysregulation of the gene programme has a fundamental role in the development of a failing myocardium. Epigenetic modifications and functional non-protein-coding RNAs (ncRNAs) are important contributors to this process. The epigenetic modifications that regulate transcription comprise post-translational changes to histones—the proteins around which DNA is wound—as well as modifications to cytosine residues on DNA. The most studied of the histone changes are acetylation and methylation. Histone acetylation is known to be important in cardiac physiology and pathophysiology, but the roles of other histone modifications and of cytosine methylation are only starting to be investigated. Understanding of the role of microRNAs has also seen major advancements, but the function of long ncRNAs is less well defined. Moreover, the connection between ncRNAs and epigenetic modifications is poorly understood in the heart. In this Review, we summarize new insights into how these two layers of gene-expression regulation might be involved in the pathogenesis of cardiac hypertrophy and failure, and how we are only beginning to appreciate the complexity of the interactive network of which they are part.

Mindfulness interventions have garnered significant attention as a complementary health treatment for many physical and psychological conditions. While some research has shown that mindfulness training can decrease psychological and physiological stress responses, it remains unclear whether mindfulness training impacts inflammation-a predictor of poor health outcomes. In addition, little research has examined the active components of mindfulness that may drive health-related improvements. Here, we provide data from two 3-arm randomized controlled trials that examined the effect of mindfulness training on inflammation in stressed community adults. Specifically, we examined whether training individuals to have an accepting attitude towards present moment experiences is a key emotion regulation skill that can lead to decreases in inflammation. Both studies randomly assigned participants to one of three conditions: mindfulness training that taught both attention monitoring and acceptance skills (Monitor+Accept); mindfulness training teaching monitoring without the acceptance component (Monitor Only); or a control condition. Study 1 employed a novel 2-week smartphone-based intervention and Study 2 employed a standard 8-week Mindfulness-Based Stress Reduction (MBSR) intervention. We hypothesized that Monitor+Accept training would lead to reductions in the inflammatory biomarker C-Reactive Protein (CRP) compared to Monitor Only training and control groups. Contrary to this hypothesis, we found that Monitor+Accept mindfulness training did not lead to reductions in CRP. Exploratory analyses combining study subsamples, however, suggest that both mindfulness interventions may reduce CRP in populations at risk for systemic inflammation-midlife-to-older adults and individuals with high BMI. Overall, the present studies contribute significantly to the question of whether mindfulness interventions can reduce systemic markers of low-grade inflammation.

BackgroundPubertal timing has psychological and physical sequelae. While observational studies have demonstrated an association between age at menarche and adult body mass index (BMI), confounding makes it difficult to infer causality.MethodsThe Mendelian randomization (MR) technique is not limited by traditional confounding and was used to investigate the presence of a causal effect of age at menarche on adult BMI. MR uses genetic variants as instruments under the assumption that they act on BMI only through age at menarche (no pleiotropy). Using a two-sample MR approach, heterogeneity between the MR estimates from individual instruments was used as a proxy for pleiotropy, with sensitivity analyses performed if detected. Genetic instruments and estimates of their association with age at menarche were obtained from a genome-wide association meta-analysis on 182,416 women. The genetic effects on adult BMI were estimated using data on 80,465 women from the UK Biobank. The presence of a causal effect of age at menarche on adult BMI was further investigated using data on 70,692 women from the GIANT Consortium.ResultsThere was evidence of pleiotropy among instruments. Using the UK Biobank data, after removing instruments associated with childhood BMI that were likely exerting pleiotropy, fixed-effect meta-analysis across instruments demonstrated that a 1 year increase in age at menarche reduces adult BMI by 0.38 kg/m2 (95% CI 0.25–0.51 kg/m2). However, evidence of pleiotropy remained. MR-Egger regression did not suggest directional bias, and similar estimates to the fixed-effect meta-analysis were obtained in sensitivity analyses when using a random-effect model, multivariable MR, MR-Egger regression, a weighted median estimator and a weighted mode-based estimator. The direction and significance of the causal effect were replicated using GIANT Consortium data.ConclusionMR provides evidence to support the hypothesis that earlier age at menarche causes higher adult BMI. Complex hormonal and psychological factors may be responsible.

Heart failure (HF) is a leading cause of mortality. Inflammation is implicated in HF, yet clinical trials targeting pro-inflammatory cytokines in HF were unsuccessful, possibly due to redundant functions of individual cytokines. Searching for better cardiac inflammation targets, here we link T cells with HF development in a mouse model of pathological cardiac hypertrophy and in human HF patients. T cell costimulation blockade, through FDA-approved rheumatoid arthritis drug abatacept, leads to highly significant delay in progression and decreased severity of cardiac dysfunction in the mouse HF model. The therapeutic effect occurs via inhibition of activation and cardiac infiltration of T cells and macrophages, leading to reduced cardiomyocyte death. Abatacept treatment also induces production of anti-inflammatory cytokine interleukin-10 (IL-10). IL-10-deficient mice are refractive to treatment, while protection could be rescued by transfer of IL-10-sufficient B cells. These results suggest that T cell costimulation blockade might be therapeutically exploited to treat HF. Abatacept is an FDA-approved drug used for treatment of rheumatoid arthritis. Here the authors show that abatacept reduces cardiomyocyte death in a mouse model of heart failure by inhibiting activation and heart infiltration of T cells and macrophages, an effect mediated by IL-10, suggesting a potential therapy for heart failure.

High-throughput techniques allow us to measure a wide-range of phospholipids which can provide insight into the mechanisms of hypertension. We aimed to conduct an in-depth multi-omics study of various phospholipids with systolic blood pressure (SBP) and diastolic blood pressure (DBP). The associations of blood pressure and 151 plasma phospholipids measured by electrospray ionization tandem mass spectrometry were performed by linear regression in five European cohorts (n = 2786 in discovery and n = 1185 in replication). We further explored the blood pressure-related phospholipids in Erasmus Rucphen Family (ERF) study by associating them with multiple cardiometabolic traits (linear regression) and predicting incident hypertension (Cox regression). Mendelian Randomization (MR) and phenome-wide association study (Phewas) were also explored to further investigate these association results. We identified six phosphatidylethanolamines (PE 38:3, PE 38:4, PE 38:6, PE 40:4, PE 40:5 and PE 40:6) and two phosphatidylcholines (PC 32:1 and PC 40:5) which together predicted incident hypertension with an area under the ROC curve (AUC) of 0.61. The identified eight phospholipids are strongly associated with triglycerides, obesity related traits (e.g. waist, waist-hip ratio, total fat percentage, body mass index, lipid-lowering medication, and leptin), diabetes related traits (e.g. glucose, insulin resistance and insulin) and prevalent type 2 diabetes. The genetic determinants of these phospholipids also associated with many lipoproteins, heart rate, pulse rate and blood cell counts. No significant association was identified by bi-directional MR approach. We identified eight blood pressure-related circulating phospholipids that have a predictive value for incident hypertension. Our cross-omics analyses show that phospholipid metabolites in the circulation may yield insight into blood pressure regulation and raise a number of testable hypothesis for future research.

Aggressive arterial aneurysms, such as thoracic aortic aneurysms and aortic dissection, were found to be caused by mutations in the genes encoding the transforming growth factor β (TGF-β) receptor I or II, which are characteristic of the Loeys–Dietz syndrome. Screening for these mutations in persons at risk may allow preventive measures to be taken. Aggressive arterial aneurysms were found to be caused by mutations in the genes encoding the transforming growth factor β receptor I or II. Screening for these mutations in persons at risk may allow preventive measures to be taken. Mutations in the genes encoding transforming growth factor β (TGF-β) receptors 1 and 2 ( TGFBR1 and TGFBR2, respectively) have recently been found in association with a continuum of clinical features. On the mild end, the mutations have been found in association with a presentation similar to that of Marfan's syndrome or with familial thoracic aortic aneurysm and dissection, 1 , 2 and on the severe end, they are associated with a complex phenotype in which aortic dissection or rupture commonly occurs in childhood. 3 This complex phenotype is characterized by the triad of widely spaced eyes (hypertelorism); a bifid uvula, cleft palate, . . .