Long-term activation of the innate immune system in atherosclerosis

Efforts to reverse the pathologic consequences of vulnerable plaques are often stymied by the complex treatment resistant pro-inflammatory environment within the plaque. This suggests that pro-atherogenic stimuli, such as LDL cholesterol and high fat diets may impart longer lived signals on (innate) immune cells that persist even after reversing the pro-atherogenic stimuli. Recently, a series of studies challenged the traditional immunological paradigm that innate immune cells cannot display memory characteristics. Epigenetic reprogramming in these myeloid cell subsets, after exposure to certain stimuli, has been shown to alter the expression of genes upon re-exposure. This phenomenon has been termed trained innate immunity or innate immune memory. The changed responses of \u27trained\u27 innate immune cells can confer nonspecific protection against secondary infections, suggesting that innate immune memory has likely evolved as an ancient mechanism to protect against pathogens. However, dysregulated processes of immunological imprinting mediated by trained innate immunity may also be detrimental under certain conditions as the resulting exaggerated immune responses could contribute to autoimmune and inflammatory diseases, such as atherosclerosis. Pro-atherogenic stimuli most likely cause epigenetic modifications that persist for prolonged time periods even after the initial stimulus has been removed. In this review we discuss the concept of trained innate immunity in the context of a hyperlipidemic environment and atherosclerosis. According to this idea the epigenome of myeloid (progenitor) cells is presumably modified for prolonged periods of time, which, in turn, could evoke a condition of continuous immune cell over-activation. reserved

Oral Microbiome in Relation to Periodontitis Severity and Systemic Inflammation

Systemic inflammation induced by periodontitis is suggested to be the link between periodontitis and cardiovascular disease. The aim of this work was to explore the oral microbiome in periodontitis in relation to disease severity and systemic inflammation. The saliva and subgingival microbiome from periodontal pocket samples of patients with severe (n = 12) and mild periodontitis (n = 13) were analyzed using metagenomic shotgun sequencing. The taxa and pathways abundances were quantified. The diversity was assessed and the abundances to phenotype associations were performed using ANCOM and linear regression. A panel of inflammatory markers was measured in blood and was associated with taxa abundance. The microbial diversity and species richness did not differ between severe and mild periodontitis in either saliva or periodontal pockets. However, there were significant differences in the microbial composition between severe and mild periodontitis in the subgingival microbiome (i.e., pocket samples) and, in a lower grade, in saliva, and this is positively associated with systemic inflammatory markers. The “red complex” and “cluster B” abundances in periodontal pockets were strongly associated with inflammatory markers interleukin-6 and the white blood cell count. Our data suggest that systemic inflammation in severe periodontitis may be driven by the oral microbiome and may support the indirect (inflammatory) mechanism for the association between periodontitis and cardiovascular disease

Impact of lifelong exercise training on endothelial ischemia-reperfusion and ischemic preconditioning in humans.

Reperfusion is essential for ischemic tissue survival, but causes additional damage to the endothelium (i.e. ischemia-reperfusion [IR] injury). Ischemic preconditioning (IPC) refers to short repetitive episodes of ischemia that can protect against IR. However, IPC efficacy attenuates with older age. Whether physical inactivity contributes to the attenuated efficacy of IPC to protect against IR injury in older humans is unclear. We tested the hypotheses that lifelong exercise training relates to 1) attenuated endothelial IR and 2) maintained IPC efficacy that protects veteran athletes against endothelial IR. In 18 sedentary male individuals (SED, 20 years, 63±7 years) and 20 veteran male athletes (ATH, >5 exercise hours/week for >20 years, 63±6 years), we measured brachial artery endothelial function with flow-mediated dilation (FMD) before and after IR. We induced IR by 20-minutes of ischemia followed by 20-minutes of reperfusion. Randomized over 2 days, participants underwent either 35-minute rest or IPC (3 cycles of 5-minutes cuff inflation to 220 mmHg with 5-minutes of rest) before IR. In SED, FMD decreased after IR (median [interquartile range]): (3.0% [2.0-4.7] to 2.1% [1.5-3.9], P=0.046) and IPC did not prevent this decline (4.1% [2.6-5.2] to 2.8% [2.2-3.6],P=0.012). In ATH, FMD was preserved after IR (3.0% [1.7-5.4] to 3.0% [1.9-4.1], P=0.82) and when IPC preceded IR (3.2% [1.9-4.2] to 2.8% [1.4-4.6],P=0.18). These findings indicate that lifelong exercise training is associated with increased tolerance against endothelial IR. These protective, preconditioning effects of lifelong exercise against endothelial ischemia-reperfusion may contribute to the cardio-protective effects of exercise training

Wake Up and Smell the Coffee: Yet Another No Go for Cardiac Patients?: Editorial to “Caffeinated Coffee Blunts the Myocardial Protective Effects of Statins Against Ischemia–reperfusion Injury in the Rat” by Ye et al.

Contains fulltext : 69414.pdf (publisher's version ) (Closed access

Circulating adenosine increases during human experimental endotoxemia but blockade of its receptor does not influence the immune response and subsequent organ injury

Contains fulltext : 95720.pdf (publisher's version ) (Open Access)INTRODUCTION: Preclinical studies have shown that the endogenous nucleoside adenosine prevents excessive tissue injury during systemic inflammation. We aimed to study whether endogenous adenosine also limits tissue injury in a human in vivo model of systemic inflammation. In addition, we studied whether subjects with the common 34C > T nonsense variant (rs17602729) of adenosine monophosphate deaminase (AMPD1), which predicts increased adenosine formation, have less inflammation-induced injury. METHODS: In a randomized double-blinded design, healthy male volunteers received 2 ng/kg E. Coli LPS intravenously with (n = 10) or without (n = 10) pretreatment with the adenosine receptor antagonist caffeine (4 mg/kg body weight). In addition, lipopolysaccharide (LPS) was administered to 10 subjects heterozygous for the AMPD1 34C > T variant. RESULTS: The increase in adenosine levels tended to be more pronounced in the subjects heterozygous for the AMPD1 34C > T variant (71 +/- 22%, P=0.04), compared to placebo- (59 +/- 29%, P=0.012) and caffeine-treated (53 +/- 47%, P=0.29) subjects, but this difference between groups did not reach statistical significance. Also the LPS-induced increase in circulating cytokines was similar in the LPS-placebo, LPS-caffeine and LPS-AMPD1-groups. Endotoxemia resulted in an increase in circulating plasma markers of endothelial activation [intercellular adhesion molecule (ICAM) and vascular cell adhesion molecule (VCAM)], and in subclinical renal injury, measured by increased urinary excretion of tubular injury markers. The LPS-induced increase of these markers did not differ between the three groups. CONCLUSIONS: Human experimental endotoxemia induces an increase in circulating cytokine levels and subclinical endothelial and renal injury. Although the plasma adenosine concentration is elevated during systemic inflammation, co-administration of caffeine or the presence of the 34C > T variant of AMPD1 does not affect the observed subclinical organ damage, suggesting that adenosine does not affect the inflammatory response and subclinical endothelial and renal injury during human experimental endotoxemia. TRIAL REGISTRATION: ClinicalTrials (NCT): NCT00513110

Diversity and Ecology of Caudoviricetes Phages with Genome Terminal Repeats in Fecal Metagenomes from Four Dutch Cohorts

The human gut harbors numerous viruses infecting the human host, microbes, and other inhabitants of the gastrointestinal tract. Most of these viruses remain undiscovered, and their influence on human health is unknown. Here, we characterize viral genomes in gut metagenomic data from 1950 individuals from four population and patient cohorts. We focus on a subset of viruses that is highly abundant in the gut, remains largely uncharacterized, and allows confident complete genome identification—phages that belong to the class Caudoviricetes and possess genome terminal repeats. We detect 1899 species-level units belonging to this subset, 19% of which do not have complete representative genomes in major public gut virome databases. These units display diverse genomic features, are predicted to infect a wide range of microbial hosts, and on average account for 5% of individuals in a cohort). Finally, we find 34 associations between highly prevalent phages and human phenotypes, 24 of which can be explained by the relative abundance of potential hosts

A role for artificial intelligence in molecular imaging of infection and inflammation

The detection of occult infections and low-grade inflammation in clinical practice remains challenging and much depending on readers' expertise. Although molecular imaging, like [F-18]FDG PET or radiolabeled leukocyte scintigraphy, offers quantitative and reproducible whole body data on inflammatory responses its interpretation is limited to visual analysis. This often leads to delayed diagnosis and treatment, as well as untapped areas of potential application. Artificial intelligence (AI) offers innovative approaches to mine the wealth of imaging data and has led to disruptive breakthroughs in other medical domains already. Here, we discuss how AI-based tools can improve the detection sensitivity of molecular imaging in infection and inflammation but also how AI might push the data analysis beyond current application toward predicting outcome and long-term risk assessment

Traditional Cardiovascular Risk Factors Are Stronger Related to Carotid Intima-Media Thickness Than to Presence of Carotid Plaques in People Living With HIV

BACKGROUND: Cardiovascular disease is a major cause of morbidity and mortality in people living with HIV, who are at higher risk than the general population. We assessed, in a large cohort of people living with HIV, which cardiovascular, HIV-specific, and lipoproteomic markers were associated with carotid intima-media thickness (cIMT) and carotid plaque presence. We also studied guideline adherence on lipid-lowering medication in individuals with high and very high risk for cardiovascular disease. METHODS AND RESULTS: In 1814 individuals with a median (interquartile range) age of 53 (44–60) years, we found a carotid plaque in 909 (50.1%) and a median (interquartile range) intima-media thickness of 0.66 (0.57–0.76) mm. Ultrasonography was used for the assessment of cIMT and plaque presence. Univariable and multivariable regression models were used for associations with cIMT and presence of plaques. Age, Black race, body mass index, type 2 diabetes, and smoking (pack years) were all positively associated with higher cIMT. Levels of high-density lipoprotein cholesterol, specifically medium and large high-density lipoprotein subclasses, were negatively associated with higher cIMT. Only age and prior myocardial infarction were positively related to the presence of a carotid plaque. Lipid-lowering treatment was prescribed in one-third of people living with HIV, who are at high and very high risk for cardiovascular disease. CONCLUSIONS: Traditional cardiovascular risk factors were significantly associated with higher cIMT but not with carotid plaques, except for age. HIV-specific factors were not associated with both ultrasound measurements. Future studies are needed to elucidate which factors contribute to plaque formation. Improvement of guideline adherence on prescription of lipid-lowering treatment in high-and very high-risk patients for cardiovascular disease is recommended.</p