Marker Of Low-grade Inflammation Research Articles

Low-grade inflammation and serotonin 4 receptor binding in the healthy and the depressed brain

Inflammatory status affects healthy brain function and also low-grade inflammation putatively contributes to the pathophysiology of Major Depressive Disorder (MDD). This psychoneuro-immunological interplay is complex, bidirectional, and not fully understood. Also, it is not clear to what extent depressive states induce inflammation and/or if increased inflammation leads to depressive symptoms by affecting brain biology including serotonin signaling. The serotonin 4 receptor (5-HT4R) is an interesting new antidepressant target; direct stimulation has antidepressant-like, and pro-cognitive effects, and may also index serotonin tone at least in the adult healthy brain.Here, we investigate whether a peripheral marker of low-grade inflammation (hsCRP) is associated with 5-HT4R brain binding in both a healthy and in an unmedicated MDD group. 5-HT4R PET imaging data and hsCRP measures from 112 healthy and 79 unmedicated MDD individuals were available from the Cimbi database. We evaluated the associations between hsCRP level and 5-HT4R binding in three regions of interest (neocortex, hippocampus, and neostriatum) using multiple linear regression models adjusted for relevant covariates.We did not observe a statistically significant association between hsCRP and 5-HT4R binding. This applied to both the healthy and the MDD group.Our findings do not support a coupling between low-grade inflammation and brain 5-HT4R availability, which suggests that the serotonergic system is not sensitive to low-grade inflammation captured by hsCRP, neither in healthy nor in depressed states. Future studies are needed to test if the brain serotonin system is coupled to other inflammatory markers, for instance in conditions with high-grade and/or prolonged immunoactivation.

Association of inflammatory markers and ultrasonographic indicators of endothelial (dys)function in humans

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): The Austrian Science Fund (FWF) Introduction It has been widely known that chronic inflammation is a crucial factor in the process of atherogenesis and atherosclerosis. Also, endothelial dysfunction presents the first and still reversible step of that process.(1) It is a challenge to find a laboratory marker whose levels would be informative about the extent of endothelial dysfunction and atherogenesis in humans. Purpose The aim of the present study was to determine associations between markers of chronic, low-grade inflammation and ultrasonographic indicators of endothelial (dys)function in healthy volunteers (H) and in patients with metabolic syndrome (MS). Methods Any kind of clinically manifest acute inflammatory or infectious disease, as well as chronic inflammatory, autoimmune or malignant disease was an exclusion criterion for participation. Serum levels of C-reactive protein (CRP) were measured using standard clinical chemistry analyser, and serum levels of interleukin-6 (IL-6) using electro-chemiluminescence immunoassay. Blood vessel wall function was quantified as flow-mediated dilation (FMD) and nitroglycerin-mediated dilation (NMD), which were measured automatically and continuously using the ultrasound device with linear probe (10 MHz) and the software for ultrasound blood vessel diameter analysis,(2) following currently valid guidelines.(3,4,5) Results A total of 130 individuals were enrolled in the study (65 H and 65 MS), with a median age of 56 (IQR 50.0, 60.0) years and 47.7% women in each group. CRP and IL-6 levels, although being very low and within the intervals that are considered normal in everyday clinical practice for both groups [CRP - H: 1.2 (0.6, 2.3), MS: 2.4 (1.2, 5.5) μg/mL; IL-6 - H: 2.3 (1.7, 3.0), MS: 4.1 (2.7, 6.8) pg/mL], were significantly higher in the MS compared to H (both p<0.001). The MS group also had significantly lower FMD (p=0.013) and NMD (p=0.033) compared to H. In H, IL-6 levels were significantly negatively correlated with FMD (r=-0.46, p<0.001), but not with NMD; whereas no significant associations of IL-6 levels with FMD or NMD were observed in the MS group. CRP levels were not significantly associated with FMD or NMD in neither the H nor MS group. Conclusion Higher IL-6 serum levels in the absence of acute inflammatory or infectious disease are significantly associated with lower FMD values among individuals with low risk for cardiovascular diseases, who are still considered healthy. Direct correlation is attenuated and lost among individuals with developed clinical signs of metabolic syndrome, probably due to its complex pathophysiology, as well as redundant and interdependent mechanisms contributing to the occurrence of endothelial dysfunction in such an environment. Further investigation on larger cohorts is needed to determine whether IL-6 serum levels could serve as a marker of endothelial dysfunction in individuals without clinically developed traditional risk factors and symptoms of cardiovascular disease.

#1815 The neutrophil/lymphocyte, neutrophil/HDL-cholesterol, and monocyte/HDL-cholesterol ratios as simple markers of low-grade inflammation in CKD patients

Abstract Background and Aims Chronic kidney disease (CKD) has been associated with inflammation and oxidative stress, as well as with high cardiovascular (CV) morbidity and mortality. The neutrophil/lymphocyte (NLR), neutrophil/HDL-cholesterol (NHR), and monocyte/HDL-cholesterol (MHR) ratios have been linked both to inflammation and increased CV risk in a variety of diseases. The aim of this study was to investigate changes in these ratios in CKD patients of stage 2-5 without any clinical and laboratory signs of inflammation, and to compare these indicators with those in healthy volunteers. Method A retrospective cross-sectional study was conducted in 88 healthy volunteers and 187 CKD patients (50 of stage 2, 44 of stage 3a, 45 of stage 3b and 48 of stage 4-5). Patients with acute renal impairment, nephrotic proteinuria, infections, systemic inflammation, malignancies and hematologic diseases were excluded, as were those receiving hypolipidemic, corticosteroid, immunosuppressive or immunostimulant drugs. The whole blood samples were collected and the absolute numbers of neutrophils, lymphocytes, and monocytes were used for calculation of NLR, NHR and MHR, respectively. Serum creatinine, HDL-cholesterol, C-reactive protein (CRP) and albumin were measured and eGFR calculated according to the CKD EPI equation. Statistical analysis was performed with the Mann-Whitney, Shapiro–Wilk, Kruskal-Wallis, and Spearman's correlation tests using the SPSS software. Results The NLR, NHR and MHR were higher in CKD patients when compared to healthy volunteers (P < 0,001), but only NLR and NHR increased significantly across CKD stages (P < 0,01). The ratio differences between CKD stages were more evident for NHR which was also in best correlation with eGFR (ρ = −0,406, P < 0,001). The CRP values increased across CKD stages as well (P < 0,01) although remaining within the reference range. The NLR, NHR and MHR were significantly related to CRP with NHR providing the best correlation (ρ = 0,289, P < 0,001). Conclusion This study showed that NLR and NHR increased across CKD stages 2-5 and could be used to identify low-grade inflammation in this population even within normal CRP values.

Feasibility and Preliminary Efficacy of American Elderberry Juice for Improving Cognition and Inflammation in Patients with Mild Cognitive Impairment.

Despite data showing that nutritional interventions high in antioxidant/anti-inflammatory properties (anthocyanin-rich foods, such as blueberries/elderberries) may decrease risk of memory loss and cognitive decline, evidence for such effects in mild cognitive impairment (MCI) is limited. This study examined preliminary effects of American elderberry (Sambucus nigra subsp. canadensis) juice on cognition and inflammatory markers in patients with MCI. In a randomized, double-blind, placebo-controlled trial, patients with MCI (n = 24, Mage = 76.33 ± 6.95) received American elderberry (n = 11) or placebo (n = 13) juice (5 mL orally 3 times a day) for 6 months. At baseline, 3 months, and 6 months, patients completed tasks measuring global cognition, verbal memory, language, visuospatial cognitive flexibility/problem solving, and memory. A subsample (n = 12, 7 elderberry/5 placebo) provided blood samples to measure serum inflammatory markers. Multilevel models examined effects of the condition (elderberry/placebo), time (baseline/3 months/6 months), and condition by time interactions on cognition/inflammation outcomes. Attrition rates for elderberry (18%) and placebo (15%) conditions were fairly low. The dosage compliance (elderberry-97%; placebo-97%) and completion of cognitive (elderberry-88%; placebo-87%) and blood-based (elderberry-100%; placebo-100%) assessments was high. Elderberry (not placebo) trended (p = 0.09) towards faster visuospatial problem solving performance from baseline to 6 months. For the elderberry condition, there were significant or significantly trending decreases over time across several markers of low-grade peripheral inflammation, including vasorin, prenylcysteine oxidase 1, and complement Factor D. Only one inflammatory marker showed an increase over time (alpha-2-macroglobin). In contrast, for the placebo, several inflammatory marker levels increased across time (L-lactate dehydrogenase B chain, complement Factor D), with one showing deceased levels over time (L-lactate dehydrogenase A chain). Daily elderberry juice consumption in patients with MCI is feasible and well tolerated and may provide some benefit to visuospatial cognitive flexibility. Preliminary findings suggest elderberry juice may reduce low-grade inflammation compared to a placebo-control. These promising findings support the need for larger, more definitive prospective studies with longer follow-ups to better understand mechanisms of action and the clinical utility of elderberries for potentially mitigating cognitive decline.

Role of inflammatory signaling pathways involving the CD40-CD40L-TRAF cascade in diabetes and hypertension-insights from animal and human studies.

CD40L-CD40-TRAF signaling plays a role in atherosclerosis progression and affects the pathogenesis of coronary heart disease (CHD). We tested the hypothesis that CD40L-CD40-TRAF signaling is a potential therapeutic target in hyperlipidemia, diabetes, and hypertension. In mouse models of hyperlipidemia plus diabetes (db/db mice) or hypertension (1mg/kg/d angiotensin-II for 7days), TRAF6 inhibitor treatment (2.5mg/kg/d for 7 or 14days) normalized markers of oxidative stress and inflammation. As diabetes and hypertension are important comorbidities aggravating CHD, we explored whether the CD40L-CD40-TRAF signaling cascade and their associated inflammatory pathways are expressed in CHD patients suffering from comorbidities. Therefore, we analyzed vascular bypass material (aorta or internal mammary artery) and plasma from patients with CHD with diabetes and/or hypertension. Our Olink targeted plasma proteomic analysis using the IMMUNO-ONCOLOGY panel revealed a pattern of step-wise increase for 13/92 markers of low-grade inflammation with significant changes. CD40L or CD40 significantly correlated with 38 or 56 other inflammatory targets. In addition, specific gene clusters that correlate with the comorbidities were identified in isolated aortic mRNA of CHD patients through RNA-sequencing. These signaling clusters comprised CD40L-CD40-TRAF, immune system, hemostasis, muscle contraction, metabolism of lipids, developmental biology, and apoptosis. Finally, immunological analysis revealed key markers correlated with comorbidities in CHD patients, such as CD40L, NOX2, CD68, and 3-nitrotyrosine. These data indicate that comorbidities increase inflammatory pathways in CHD, and targeting these pathways will be beneficial in reducing cardiovascular events in CHD patients with comorbidities.

The value of neck adipose tissue as a predictor for metabolic risk in health and type 2 diabetes

Upper-body adiposity is adversely associated with metabolic health whereas the opposite is observed for the lower-body. The neck is a unique upper-body fat depot in adult humans, housing thermogenic brown adipose tissue (BAT), which is increasingly recognised to influence whole-body metabolic health. Loss of BAT, concurrent with replacement by white adipose tissue (WAT), may contribute to metabolic disease, and specific accumulation of neck fat is seen in certain conditions accompanied by adverse metabolic consequences. Yet, few studies have investigated the relationships between neck fat mass (NFM) and cardiometabolic risk, and the influence of sex and metabolic status. Typically, neck circumference (NC) is used as a proxy for neck fat, without considering other determinants of NC, including variability in neck lean mass. In this study we develop and validate novel methods to quantify NFM using dual x-ray absorptiometry (DEXA) imaging, and subsequently investigate the associations of NFM with metabolic biomarkers across approximately 7000 subjects from the Oxford BioBank. NFM correlated with systemic insulin resistance (Homeostatic Model Assessment for Insulin Resistance; HOMA-IR), low-grade inflammation (plasma high-sensitivity C-Reactive Protein; hsCRP), and metabolic markers of adipose tissue function (plasma triglycerides and non-esterified fatty acids; NEFA). NFM was higher in men than women, higher in type 2 diabetes mellitus compared with non-diabetes, after adjustment for total body fat, and also associated with overall cardiovascular disease risk (calculated QRISK3 score). This study describes the development of methods for accurate determination of NFM at scale and suggests a specific relationship between NFM and adverse metabolic health.

Salivary α-amylase activity is associated with cardiometabolic and inflammatory biomarkers in overweight/obese, non-diabetic Qatari women.

Obesity, prevalent in approximately 80% of Qatar's adult population, increases the risk of complications like type 2 diabetes and cardiovascular diseases. Predictive biomarkers are crucial for preventive strategies. Salivary α-amylase activity (sAAa) inversely correlates with obesity and insulin resistance in adults and children. However, the connection between sAAa and cardiometabolic risk factors or chronic low-grade inflammation markers remains unclear. This study explores the association between serum sAAa and adiposity markers related to cardiovascular diseases, as well as markers indicative of chronic low-grade inflammation. Serum samples and clinical data of 1500 adult, non-diabetic, Overweight/Obese participants were obtained from Qatar Biobank (QBB). We quantified sAAa and C reactive protein (CRP) levels with an autoanalyzer. Cytokines, adipokines, and adiponectin of a subset of 228 samples were quantified using a bead-based multiplex assay. The associations between the sAAa and the adiposity indices and low-grade inflammatory protein CRP and multiple cytokines were assessed using Pearson's correlation and adjusted linear regression. The mean age of the participants was 36 ± 10 years for both sexes of which 76.6% are women. Our analysis revealed a significant linear association between sAAa and adiposity-associated biomarkers, including body mass index β -0.032 [95% CI -0.049 to -0.05], waist circumference β -0.05 [95% CI -0.09 to -0.02], hip circumference β -0.052 [95% CI -0.087 to -0.017], and HDL β 0.002 [95% CI 0.001 to 0.004], albeit only in women. Additionally, sAAa demonstrated a significant positive association with adiponectin β 0.007 [95% CI 0.001 to 0.01]while concurrently displaying significant negative associations with CRP β -0.02 [95% CI -0.044 to -0.0001], TNF-α β -0.105 [95% CI -0.207 to -0.004], IL-6 β [95% CI -0.39 -0.75 to -0.04], and ghrelin β -5.95 [95% CI -11.71 to -0.20], specifically within the female population. Our findings delineate significant associations between sAAa and markers indicative of cardiovascular disease risk and inflammation among overweight/obese adult Qatari females. Subsequent investigations are warranted to elucidate the nuances of these gender-specific associations comprehensively.

EXPRESS: Effectiveness of HMG-CoA reductase inhibitors on inflammation and metabolic markers in the US-Mexico border Hispanic population.

HMG-CoA reductase inhibitors (statins) are commonly used for dyslipidemia management to reduce the risk of cardiovascular disease (CVD). High-sensitivity C-reactive protein (hs-CRP) is an emerging systematic low-grade inflammatory marker associated with atherosclerotic CVD development. Despite racial/ethnic disparities in the use and response of statins and the anti-inflammatory effects of statins, the effectiveness of statins on inflammation and metabolic markers is unknown among Hispanics. We performed a retrospective cohort study using 150 adult patients scheduled for an annual physical exam at a family medicine clinic between January 1, 2021, and December 31, 2021. Effect size with a 95% confidence interval (CI) was estimated using adjusted regression analyses. Among 150 patients, 52 (34.67%) received statins. Patients who received statins had significantly reduced median hs-CRP (1.9 vs. 3.2, p=0.007), mean low-density lipoprotein (LDL-C) (101.18 vs. 124.6, p<0.001), and total cholesterol (172.6 vs. 194.5, p<0.001) concentrations compared to those who did not receive statins. In the propensity-scores matched analysis, lower concentrations of log-transformed hs-CRP (regression coefficient [RC], -0.48; 95%CI: -0.89, -0.07), LDL-C (RC, -19.57; 95%CI: -33.04, -6.1), and total cholesterol (RC, -23.47; 95%CI: -38.96, -7.98) were associated with statin use. In addition, hepatic steatosis (adjusted relative risk [aRR]=0.25; 95%CI: 0.08, 0.78, p= 0.017) was significantly lower among patients with the use of statins. Our study suggests that HMG-CoA reductase inhibitors may help reduce inflammation among Hispanic patients with dyslipidemia and hypertension. These findings have useful implications for preventing risk and disparities associated with cardiovascular and other inflammatory-induced diseases among the fastest-growing US Hispanic minorities.

Multifunctional dietary interventions, low-grade inflammation and cardiometabolic profile: a scoping review.

Growing evidence highlights the significant impact of diet to modify low-grade inflammation closely linked to cardiometabolic profile. Multifunctionnal diets, combining several compounds have been shown to beneficially impact metabolic parameters. This study synthesizes the knowledge on the impact of RCTs combining dietary multifunctional compounds on low-grade inflammation in humans. We investigate whether the effects of dietary multifunctional interventions on inflammatory markers were parallel to alterations of cardiometabolic parameters. We considered both the integrated dietary interventions (ID, i.e. global diets such as Mediterranean, Nordic…) and the dietary interventions based on selected bioactive mix (BM) compounds, in healthy individuals and those at cardiometabolic risk. Out of 221 screened publications, we selected 27 studies: 11 for BM (polyphenols and/or omega-3 fatty acids and/or antioxidants and/or dietary fiber) and 16 for ID (Mediterranean, paleo, Nordic, Dietary Approaches to Stop Hypertension (DASH) diet…). ID studies reflected significant improvements in inflammatory markers (CRP, IL-6, IL-10, IL-1b), concomitantly with beneficial changes in metabolic parameters. In BM studies, pronounced effects on low-grade inflammatory markers were observed, while improvements in metabolic parameters were not consistent. Both types of studies suggested a favorable impact on oxidative stress, a factor closely linked to the inflammatory profile. Our findings showed that multifunctional RCT diets have differential role in managing low-grade inflammation and cardiometabolic health, with a large heterogeneity in explored inflammatory markers. Further research is imperative to elucidate the link between low-grade inflammation and other cardiometabolic risk factors, such as intestinal inflammation or postprandial inflammatory dynamics, aiming to attain a comprehensive understanding of the mechanisms involved in these processes. These future investigations not only have the potential to deepen our insights into the connections among these elements but also pave the way for significant advancements in the prevention and management of conditions related to the cardiovascular and metabolic systems.

Difference of thrombocyte profile between obesity and central obesity in women

Background: Obesity considered as a low-grade inflammation. Increased body fat has known to trigger inflammation. Platelet profile is a number of platelet-related parameters that can predict inflammation consisting of: platelet count (PLT), Platelet Larger Cell Ratio (P-LCR), Mean Platelet Volume (MPV). Differences in platelet profiles (PLT, P-LCR, MPV) in women with and without central obesity have only been investigated in a few studies.Objective: To prove differences in platelet profiles in women with and without central obesity.Materials and Methods: A cross-sectional observational study was conducted on 88 women with and without central obesity in RSND during July-September 2021. Data included age, abdominal circumference, hip circumference, PLT, P-LCR, and MPV. PLT, P-LCR, and MPV were measured using Sysmex XS-500i instrument. Statistical analysis was using Mann-Whitney test.Results: Mean of women PLT with and without central obesity were 338.72±71.09x103/uL and 309.09±44.36x103/uL. Difference platelet levels in women with and without central obesity was p=0.022. Median MPV of women with and without central obesity were 10.5 (8.5-11.8)fL and 9.7 (8.5-11.6)fL. Difference MPV values in women with and without central obesity was p=0.000. Median P-LCR of women with and without central obesity were 28.2 (12.3-44.3)% and 21.5 (15.2-37.1)%, respectively. Difference P-LCR value in women with and without central obesity was p=0.002.Conclusion: Platelet profiles (PLT, MPV, P-LCR) can be used as a marker of chronic low-grade inflammation in women with central obesity.Keywords : central obesity; MPV; PLT; P-LCR

Low-grade systemic inflammation and left ventricular dysfunction in hypertensive compared to non-hypertensive hypertrophic cardiomyopathy

BackgroundArterial hypertension (HTN) is associated with excess mortality in hypertrophic cardiomyopathy (HCM), but underlying mechanisms are largely elusive. The objective of this study was to investigate the association between HTN and markers of left ventricular (LV) dysfunction and low-grade systemic inflammation in a HCM cohort. MethodsThis was a single-center cross-sectional case-control study comparing echocardiographic and plasma-derived indices of LV dysfunction and low-grade systemic inflammation between 30 adult patients with HCM and HTN (HTN+) and 30 sex- and age-matched HCM patients without HTN (HTN-). Echocardiographic measures were assessed using post-processing analyses by blinded investigators. ResultsMean age of the study population was 55.1 ± 10.4 years, 30% were women. Echocardiographic measures of systolic and diastolic dysfunction, including speckle-tracking derived parameters, did not differ between HTN+ and HTN-. Moreover, levels of N-terminal pro B-type natriuretic peptide were balanced between cases and controls. Compared with HTN-, HTN+ patients exhibited a higher white blood cell count [8.1 ± 1.8 109/l vs. 6.4 ± 1.6 109/l; p < 0.001] as well as higher plasma levels of interleukin-6 [2.8 pg/ml (2.0, 5.4) vs. 2.1 pg/ml (1.5, 3.4); p = 0.008] and high-sensitivity C-reactive protein [2.6 mg/l (1.4, 6.5) vs. 1.1 mg/l (0.9, 2.4); p = 0.004]. ConclusionThis study demonstrates that HTN is associated with indices of low-grade systemic inflammation among HCM patients. Moreover, this analysis indicates that the adverse impact of HTN in HCM patients is a consequence of systemic effects rather than alterations of cardiac function, as measures of LV systolic and diastolic dysfunction did not differ between HTN+ and HTN-.

Impact of type 2 diabetes mellitus on low-grade inflammation in patients with ST-elevated myocardial infarction

Chronic low-grade inflammation has emerged as a hallmark of type 2 diabetes mellitus (T2DM), contributing significantly to the pathogenesis of various cardiovascular diseases, notably ST-elevated myocardial infarction (STEMI). The intricate interplay between inflammation and cardiovascular health in the context of T2DM has been a subject of intensive research in recent years. In particular, the development of various markers of inflammation has provided valuable tools for better understanding the complex relationship between low-grade inflammation and cardiovascular disease in T2DM. Elevated levels of these markers have been consistently associated with increased cardiovascular risk in patients with T2DM, indicating their potential as prognostic indicators. The aim of the study was to investigate the potential association between type 2 diabetes mellitus and low-grade inflammation markers in patients with ST-elevated myocardial infarction through a comparative analysis of systemic immune-inflammation indices, fibronectin, and soluble suppression of tumorogenesis-2 (sST2) levels in ST-elevated myocardial infarction patients with and without type 2 diabetes mellitus. We enrolled 158 patients diagnosed with STEMI who were admitted to the Ivano-Frankivsk Regional Clinical Cardiological Center. The study population was divided into three groups: 1 – consisting of 45 patients with both STEMI and T2DM, and the 2 – consisting of 34 patients with STEMI only, T2DM only group – 69 patients, Control group – 10 healthy patients. In summary, the findings from the study provide compelling evidence to support the notion that patients who suffer from both STEM and T2DM exhibit a more robust inflammatory response and higher platelet count, compared to those with STEMI alone. These results suggest that the presence of T2DM may exacerbate the pro-inflammatory and pro-thrombotic state that is typically associated with STEMI, thereby emphasizing the critical need for early intervention to prevent or mitigate inflammation and platelet activation in this particular patient population. Type 2 diabetes mellitus patients with ST-segment elevation myocardial infarction show higher levels of inflammation markers and fibronectin, indicating greater low-grade inflammation. Elevated levels of soluble suppression of tumorigenicity 2 suggest myocardial remodeling. Targeting low-grade inflammation could be a potential therapy for STEMI in T2DM patients.

C-Reactive Protein Levels Correlate with Measures of Dysglycemia and Gut Microbiome Profiles.

C-reactive protein (CRP) is a commonly used marker of low-grade inflammation as well as a marker of acute infection. CRP levels are elevated in those with diabetes and increased CRP concentrations are a risk factor for developing type 2 diabetes. Gut microbiome effects on metabolism and immune responses can impact chronic inflammation, including affecting CRP levels, that in turn can lead to the development and maintenance of dysglycemia. Using a high-sensitivity C-reactive protein (hsCRP) assay capable of detecting subtle changes in C-reactive protein, we show that higher hsCRP levels specifically correlate with worsening glycemia, reduced microbial richness and evenness, and with a reduction in the Firmicutes/Bacteroidota ratio. These data demonstrate a pivotal role for CRP not only in the context of worsening glycemia and changes to the gut microbiota, but also highlight CRP as a potential target for mitigating type 2 diabetes progression or as a therapeutic target that could be manipulated through the microbiome. Understanding these processes will provide insights into the etiology of type 2 diabetes in addition to opening doors leading to possible novel diagnostic strategies and therapeutics.

Soluble P2X7 Receptor Plasma Levels in Obese Subjects before and after Weight Loss via Bariatric Surgery

Obesity is a systemic disease frequently associated with important complications such as type 2 diabetes and cardiovascular diseases. It has also been proven that obesity is a disease associated with chronic low-grade systemic inflammation and that weight loss improves this low-grade chronic inflammatory condition. The P2X7 purinergic receptor (P2X7R), belonging to the family of the receptors for extracellular ATP, is a main player in inflammation, activating inflammasome and pro-inflammatory cytokine production. In this study, we evaluated the plasma levels of soluble P2X7R (sP2X7R) measured in a group of obese patients before and one year after bariatric surgery. Furthermore, we evaluated the relation of sP2X7R to inflammatory marker plasma levels. We enrolled 15 obese patients who underwent laparoscopic sleeve gastrectomy, evaluating anthropometric parameters (weight, height, BMI and waist circumference) before and after surgery. Moreover, we measured the plasma levels of inflammatory markers (CRP, TNFα and IL-6) before and after weight loss via bariatric surgery. The results of our study show that one year after bariatric surgery, obese patients significantly decrease body weight with a significant decrease in CRP, TNF-alfa and IL-6 plasma levels. Similarly, after weight loss, obese subjects showed a significant reduction in sP2X7R plasma levels. Moreover, before surgery, plasma levels of sP2X7R were inversely related with those of CRP, TNF-alfa and IL-6. Given the role of P2X7R in inflammation, we hypothesized that, in obese subjects, sP2X7R could represent a possible marker of chronic low-grade inflammation, hypothesizing a possible role as a mediator of obesity complications.

Metabolomics and frailty: a "from bench to bedside" approach to atrial fibrillation in older patients

Abstract Background Atrial fibrillation (AF) is the most common sustained arrhythmia diagnosed at an advanced age. The most important complications of AF are stroke, heart failure and dementia. The pathophysiology of the arrhythmia is complex and multifaceted and several aspects are still not completely understood. Purpose Our project aimed at exploring the molecular characteristics of AF in older patients using an untargeted metabolomics approach, an analytical technique that provides an insight of the global metabolic profile at an individual level. As secondary endpoints, we evaluated the association between metabolomics and acylcarnitines, which are mediators of myocyte electrical instability, and difference in metabolomics profile between healthy controls (C) and AF patients (AF-P). Method We evaluated 50 consecutive older AF-P with persistent AF, waiting to be treated with elective electrical cardioversion of the arrhythmia, and 22 healthy controls (C). In all patients, the cardiological evaluation was integrated with tools of the Geriatric Multidimensional Assessment (GMA) to describe neurocognitive function (Mini-Mental State Examination, MMSE), depressive symptoms (15-item Geriatric Depression Scale, GDS), and physical performance (Short Physical Performance Battery, SPPB). Interleukin-6 (IL-6), a marker of low-grade inflammation, was measured with ELISA assays. Metabolomics analysis and acylcarnitine measurements were carried out using gas chromatography coupled with mass spectrometry (GC-MS). Results AF-P and C did not differ by age (76 ± 6 vs. 70 ± 14 years, p = 0.055); patients had a lower proportion of women (AF-P: 32% vs. C: 64%, p = 0.012). Cluster analysis applied to metabolomic data in all population identified two subset of subjects, characterized by a different body mass index (BMI; 23.57 vs. 32.53 Kg/m², p = 0.046). When studying only the AF-P group, the simultaneous presence of a higher CHA2DS2-VASc score (4.17 ± 1.32 vs. 2.88 ± 1.83, p = 0.007), a lower physical function (SPPB; 8.97± 2.22 vs. 10.75 ± 1.13, p = 0.009), and higher IL-6 levels (4.42 vs. 2.39 pg/mL, p = 0.002) described the cluster with a worse clinical phenotype and a specific metabolomics pattern. Furthermore, an association between IL-6 and medium- long-chain acylcarnitines emerged (acylcarnitine 12:1, β = 31.7 ± 9.4, R = 0.446, p = 0.001). Conclusions Present analysis demonstrated that a specific metabolomics profile was characteristic of older AF patients with a frail phenotype, identified by higher CHA2DS2-VASc score and IL-6 concentration, and lower physical performance. Future studies are needed to reveal the single molecular pathways responsible of these behaviour, potentially useful to guide a targeted therapy. Last, inflammation per se could contribute to electrical instability in AF, while body mass index, a surrogate measure of undernutrition, could identify different metabolic pathways in controls and in patients with the arrhythmia.Metabolomics by clinical phenotypes

A-206 Association of Lipids and Glucose with High-sensitivity CRP (hs-CRP) in a Community-based Adult Population

Abstract Background Research and clinical studies have established a pivotal role of inflammation in the development and progression of both cardiac and vascular diseases, responsive to injurious factors such as smoking, hypertension, dyslipidemia, and hyperglycemia. This study analyzed the association of various lipids, HbA1c and glucose with high-sensitivity CRP (hs-CRP), a marker of low-grade chronic inflammation, in a community-based adult population. Methods Data analysis was carried out on within-collection results obtained from adults (&amp;gt; = 20 yrs) from 2019 to 2022. Tests included hs-CRP, with cholesterol (n = 74 560), triglycerides (n = 74 551), LDL-C (n = 73 426), HDL-C (n = 74 458), non-HDL-C (n = 69 808), ApoB (n = 3122), Lp(a) (n = 4444), fasting glucose (n = 42 954) or HbA1c (n = 62 486). All tests were performed on Roche Cobas instrumentation. Chi square tests were performed to evaluate the association between each lipid and glycemic indicator with hs-CRP. Relative risk (RR) and odds ratio (OR) were calculated to assess the strength of the association. Results Chi-square test demonstrated association of hs-CRP with HDL-C, triglycerides, HbA1c, non-HDL-C, LDL-C, fasting glucose, cholesterol and ApoB, but not Lp(a). Increased risk and odds to have elevated hs-CRP (3.0 -10.0 mg/L) were observed with abnormal glucose and lipid levels. Higher RR and OR were seen with decreased HDL-C and elevated HbA1c, fasting glucose, triglycerides, and non-HDL-C. Slightly increased RR and OR were also observed with elevated LDL-C, ApoB, but not Lp(a). Conclusion Glucose and most lipid parameters were associated with hs-CRP. Stronger association was observed with HDL-C and carbohydrates (glucose and triglycerides), followed by triglycerides-rich non-HDL-C. LDL-C, ApoB and cholesterol had weaker association, and Lp(a) had no association with hs-CRP. This observation from a large data set from a community population may provide helpful insight to prevention and clinical management of low-grade chronic inflammation.

Effects of long-term consumption of two plant-based dietary supplements on cardiovascular health and low-grade inflammation in middle-aged and elderly people: study protocol for a randomised, controlled trial

BackgroundAgeing is a process characterised by chronic low-grade inflammation and oxidative stress which could lead to increased prevalence of both physical and mental age-related chronic conditions. A healthy balanced diet, rich in fruit and vegetables as well as omega-3 polyunsaturated fatty acids (n3 PUFA), could reduce oxidative stress and improve markers of low-grade inflammation. Nonetheless, considering that a large part of the population struggles to meet current guidelines on fruit and vegetable and n3 PUFA recommendations, fruit and vegetable concentrate supplements and mixed omega fatty acid supplements could be an effective strategy to bridge the gap between actual and recommended intakes.MethodsIn this randomised, controlled, open-labelled, parallel-grouped clinical trial, 112 participants will be allocated to one of four arms (n = 28 on each arm): an encapsulated juice powder concentrate, a plant-based omega fatty acid supplement, both or a control group. We aim to investigate whether long-term separate or combined ingestion of the two can affect biomarkers of cardiovascular health, low-grade inflammation and indicators of ageing, including cognitive function, in middle-aged and elderly people. We will additionally explore the effect of the different supplementations on plasma levels of vitamins, carotenoids and fatty acids. Intervention will last 2 years and participants will be assessed at baseline and at follow-up visits at 6, 12, 18 and 24 months.DiscussionThis study will provide evidence whether long-term, plant-based dietary supplementation can support cardiovascular health, anti-inflammatory processes, immunity and nutritional status in ageing.Trial registration This trial was registered at ClinicalTrials.gov (NCT04763291) on February 21, 2021.

The Association of suPAR with Cardiovascular Risk Factors in Young and Healthy Adults.

The soluble urokinase plasminogen activator receptor (suPAR), as a correlate of chronic low-grade inflammation, may be used to predict individual cardiovascular risk. Since chronic low-grade inflammation is thought to be associated with the development of cardiovascular disease, this study aimed to evaluate if suPAR plasma levels are correlated with cardiovascular risk factors in young and healthy adults (aged 25-41 years). Consequently, data from the GAPP (genetic and phenotypic determinants of blood pressure and other cardiovascular risk factors) study were used to investigate suPAR plasma levels in relation to the following cardiovascular risk factors and laboratory parameters: BMI, physical activity, alcohol consumption, smoking status, blood pressure parameters, glucose status, and lipid levels. Additionally, suPAR was compared to the healthy lifestyle score and the Framingham score representing the overall cardiovascular risk profile. These associations were assessed using two different statistical approaches. Firstly, all cardiovascular risk factors and scores were compared amongst sex-specific suPAR plasma levels with ANOVA analysis. Secondly, sex-specific multivariable linear regressions were performed. Female participants had higher plasma suPAR levels than male participants (1.73 ng/mL versus 1.50 ng/mL; p < 0.001). A significant inverse correlation between suPAR plasma levels and HDL cholesterol was found in men (p = 0.001) and women (p < 0.001). Furthermore, male (p < 0.001) and female participants (p < 0.001) who smoked showed significantly higher plasma levels of suPAR (p < 0.001). For male participants, an inverse correlation of the healthy lifestyle score with suPAR plasma levels (p = 0.001) and a positive correlation of the Framingham score with suPAR plasma levels (p < 0.001) were detected. In women, no such correlation was found. The cholesterol levels (p = 0.001) and HbA1c (p = 0.008) correlated significantly with plasma suPAR levels in female participants. suPAR plasma levels were found to be strongly associated with certain cardiovascular risk factors; however, sex-specific differences were found. These sex-specific differences might be explained by the higher prevalence of cardiovascular risk factors in men resulting in a stronger correlation of suPAR as a marker of low-grade inflammation, since the existence of the risk factors already led to subclinical damage in men. Further research on suPAR levels in an older study population is needed.

Uncovering Novel Biomarkers of Inflammation as Potential Screening Targets of Disease Risk in Healthcare Shift Workers: A Pilot Study.

Shift work, experienced by nearly 30% of the U.S. workforce, is hazardous to health and has become a pervasive labor practice in the healthcare sector worldwide. It increases the risk of stroke, diabetes, cancer, and cardiovascular disease. Nonetheless, specific screening targets for shift workers still need to be defined. In this study, we have begun uncovering these targets as specific low-grade systemic inflammation markers and functional endotoxin-elicited responses that may foreshadow disease risk in shift workers. One hundred four participants (normothermic and normotensive) were healthy, non-smoking, and drug- and medication-free volunteers recruited from Atlanta area hospitals and medical schools. We assessed the concentration of three proteins in plasma samples from day workers and shift workers (lipopolysaccharide-binding protein, IL-10, and TNF-α), and the relationship between these baseline biomarkers and their response to an ex-vivo endotoxin challenge. We show that shift work increases low-grade systemic inflammation and disrupts discrete endotoxin responses. As shift work exposure increases, the correlation between low-grade systemic inflammation markers and their endotoxin responses was disrupted; this effect was more robust for TNF-α than for IL-10. With increased shift work exposure, these events, alone or combined, represent potential systemic and functional signals that may be harnessed to develop screening tools to identify at-risk individuals.

Renal hemodynamics in patients with resistant hypertension and type 2 diabetes mellitus.

Aim To study renal hemodynamics in patients with resistant arterial hypertension (RAH) in combination with type 2 diabetes mellitus (DM2) and to identify factors involved in the increase in intrarenal vascular resistance.Material and methods This study included 59 patients (25 men) with RAH in combination with DM2. Mean age of patients was 60.3±7.9 years; 24-h blood pressure (24-BP) (systolic, diastolic, SBP/DBP) was 158.0±16.3 / 82.5±12.7 mm Hg during the treatment with 4.3 [4.0;5.0] antihypertensive drugs; glycated hemoglobin (HbA1c) was 7.5±1.5 %; estimated glomerular filtration rate (eGFR) was 73.1±21.8 ml/min / 1.73 m2 (CKD-EPI equation). Measurement of office BP, 24-h BP monitoring, renal artery (RA) Doppler, routine lab tests including determination of GFR (CKD-EPI), 24-h urine albumin excretion, and ELISA measurement of blood lipocalin-2, cystatin C, high-sensitive C-reactive protein (hsCRP), and asymmetric dimethylarginine (ADMA) were performed for all patients.Results Incidence of increased RA resistive index (RI) was 39% despite the high rate of vasodilator treatment (93% for renin-angiotensin-aldosterone system inhibitors, 78% for calcium antagonists). According to a correlation and regression analysis, RA RI values were correlated with the kidney function (r=-0.46, p&lt;0.001 for eGFR, r=0.56; p=0.006 for lipocalin-2), age (r=0.54, p&lt;0.001), increases in concentrations of hsCRP (r=0.35, p&lt;0.001) and ADMA (r=0.39, p=0.028), the increase in vascular stiffness (r=0.59, p&lt;0.001 for pulse BP (PBP) as well as DM2 duration, and HbA1c (r=0.33, p&lt;0.001 for both). The independent association of RA RI with the age, PBP, and duration of DM2 was confirmed by the results of multivariate regression analysis. According to the ROC analysis, the threshold level of RA RI corresponding to a decrease in GFR &lt;60 ml / min / 1.73 m2 was ≥0.693 conv. units.Conclusion In more than one third of patients with RAH in combination with DM2, increased renal vascular resistance was documented, which was closely associated with impaired kidney function, age, DM2 duration and severity, and markers of low-grade inflammation, endothelial dysfunction, and vascular stiffness. The value of RA RI ≥0.693 conv. units was a threshold for the development of chronic kidney disease (CKD).