Biomarkers Of Cardiovascular Risk Research Articles

#1591 Analysis of microvesicles and their relationship with oxidative stress as biomarkers of cardiovascular damage in chronic kidney disease

Abstract Background and Aims Chronic kidney disease (CKD) is associated with a higher incidence of cardiovascular diseases. These diseases are preceded by endothelial dysfunction and alterations in coagulation systems. One of the challenges of research in this field is the search for diagnostic and predictive biomarkers of cardiovascular pathology. Our hypothesis is that endothelial dysfunction and cardiovascular risk could be evidenced by the increased release of endothelial microvesicles (EMVs) and platelet microvesicles (PMVs), as well as a greater expression of tissue factor (TF). We also propose a relationship between the release of microvesicles and the oxidative stress observed in these patients. The aim of the study was to analyze the levels of MVEs and MVPs, the expression of FT and its relationship with pro-oxidant and antioxidant parameters as possible early biomarkers of cardiovascular and thrombotic risk in different stages and treatments of CKD. Method It is a cross-sectional study consisted of 116 patients (40 with advanced chronic disease (CKD), 40 undergoing hemodialysis (HD) and 36 undergoing peritoneal dialysis (PD)), as well as 17 healthy subjects (CT). Microvesicle phenotyping was performed by direct immunofluorescence and flow cytometry in plasma isolated by centrifugation from peripheral blood. The analysis of oxidative stress parameters was carried out by spectrophotometry, after isolation of plasma and mononuclear and polymorphonuclear leukocytes by means of a ficoll gradient. Results Patients on PD have higher plasma PMVs levels (p = 0.0005 vs ACKD and p = 0,0002 vs HD), while those on HD and PD have higher levels of EMVs compared to ACKD (p = 0,0001 and p = 0,0125, respectively). FT expression in PMVs is lower in HD (p < 0.0001 vs ACKD) and FT expression in EMVs is lower in HD and PD compared to ACKD (p = 0,0004 and p= 0.0033, respectively) (Fig. 1). Patients with CKD have a higher activity of pro-oxidant enzymes (XO, GPx), as well as high levels of lipid peroxidation by-products (TBARS-MDA) and lower activity of antioxidant enzymes (GSH, CAT, SOD) at the plasma and cellular level. A positive relationship has been observed between pro-oxidant parameters and the release of MVP and MVE, as well as the expression of FT (Table 1). Patients with cardiovascular events during the years of follow-up have higher levels of FT expressed in microvesicles, and long-term survival decreases in patients with elevated FT levels. Conclusion Patients with CKD have higher plasma levels of PMVs and EMVs and higher FT expression, related to a state of oxidative stress. These parameters could be considered as biomarkers for predicting, diagnosing, and prognostic cardiovascular events in CKD.

Inflammation, Immunonutritive, and Cardiovascular Risk Biomarkers in Men With Alcohol Use Disorder.

Alcohol Use Disorder (AUD) is a significant public health issue associated with serious health risks. This study aims to reveal the relationship between AUD and inflammatory, immunonutritive, and cardiovascular risk markers by evaluating hemogram and biochemistry parameters together in AUD. The data of 54 male patients with AUD and 45 male controls were included in the study. Sociodemographic-clinical data of the participants and Alcohol Use Disorders Identification Test (AUDIT) results were obtained from medical records. Systemic immune inflammation index (SII) was obtained with the platelet x neutrophil/lymphocyte formula; systemic immune response index (SIRI) was obtained with the monocyte x neutrophil/lymphocyte formula, plasma atherogenicity index (AIP) was obtained with the ratio of triglyceride to High-density Lipoprotein (HDL) cholesterol. C-Reactive Protein (CRP) albumin-lymphocyte (CALLY) index was obtained with the albumin x lymphocyte/CRP x 104 formula. Aspartate aminotransferase (AST), Gamma Glutamyl Transferase (GGT) activities, neutrophil, CRP, ferritin, SII, and SIRI levels were significantly higher in those with AUD compared to controls. Laboratory results of those with AUD were consistent with atherogenic dyslipidemia; higher triglyceride and total cholesterol levels and AIP values were found compared to controls. The amount of alcohol consumed was a predictor for high SII, SIRI, and AIP levels. The CALLY index, which evaluates immune function, inflammation, and nutritional status together, was significantly lower in patients compared to controls. The amount of alcohol use and the total AUDIT score were predictors for a low CALLY index. The results of this study support that AUD is a chronic inflammatory psychiatric disorder. We suggest that new inflammatory, immunonutritive, and cardiovascular biomarkersSII, SIRI, AIP, and CALLY index could be promising clinical tools to evaluate the severity, potential complications, and treatment response of AUD.

Screening for Coronary Artery Disease in Asymptomatic Pilots with Diabetes Mellitus.

INTRODUCTION: Coronary artery disease (CAD) is a cause of death in 75% of patients with diabetes. Its often asymptomatic nature delays diagnosis. In aeronautics, it can cause in-flight incapacitation, beyond which it represents a major fear for the medical expert. Screening for CAD is still a topical subject with the advent of new cardiovascular (CV) risk biomarkers and more effective screening tests. We report the experience of the Aeromedical Expertise Center of Rabat in this screening of diabetic pilots, with a recommendations review.METHODS: A prospective study over 1 yr included diabetic pilots who benefited from systematic screening for CAD after a CV risk stratification. Coronary angiography is performed if a screening test is positive. Subsequent follow-up is carried out in consultation with the attending physician with regular evaluation in our center.RESULTS: There were 38 pilots included in our study. The average age was 55 ± 4.19 yr and about 73% had a high CV risk. CAD was detected in 4 cases (10.52%) who had abnormal resting electrocardiograms and required revascularization with the placement of active stents. Approximately 75% of pilots with CAD returned to fly through a waiver with restrictions.DISCUSSION: Screening for coronary disease in diabetics is controversial, and current recommendations are not unanimous. In our study, the screening did not identify coronary diabetic pilots who could benefit from bypass surgery. Nevertheless, coronary disease was diagnosed, justifying grounding to preserve flight safety, which is an absolute priority in aviation medicine.Zerrik M, Moumen A, El Ghazi M, Smiress FB, Iloughmane Z, El M'hadi C, Chemsi M. Screening for coronary artery disease in asymptomatic pilot with diabetes mellitus. Aerosp Med Hum Perform. 2024; 95(4):200-205.

High Growth Differentiation Factor-15 (GDF-15) in Rheumatoid Arthritis Patients Potential Risk for Cardiovascular Disease

Rheumatoid arthritis (RA) is a chronic autoimmune disorder primarily affecting joints, leading to pain, stiffness, and functional disability. The inflammatory mechanisms underlying RA also impact various organ systems, with significant implications for morbidity and mortality. In this study, we analyzed the growth differentiation factor-15 (GDF-15), a cytokine implicated in inflammation and associated with RA and cardiovascular diseases. We conducted a case-control study involving 150 RA patients and 150 healthy individuals, assessing various biomarkers (ACPA, CRP, ESR, and RF) including GDF-15, lipid profile, and inflammatory markers. Our results demonstrated significantly elevated levels of GDF-15 in RA patients (309.44 pg/ml) compared to controls (64.40 pg/ml), indicating its potential role as a biomarker for RA and cardiovascular risk (p<0.001). Furthermore, RA patients exhibited dyslipidemia characterized by elevated total cholesterol, triglycerides, LDL cholesterol, and atherogenic indices, along with decreased HDL cholesterol levels, predisposing them to a higher risk of atherosclerosis and cardiovascular complications (p<0.001). Correlation analyses revealed associations between GDF-15 levels, lipid profile parameters, and disease severity markers, highlighting the intricate interplay between inflammation, lipid metabolism, and RA progression. These findings demonstrated the importance of early detection and management of dyslipidemia in RA patients to mitigate cardiovascular risk. Overall, our study contributes to understanding the pathophysiology of RA and identifies potential biomarkers for disease monitoring and risk stratification.

Abstract P298: Cross-Sectional and Longitudinal Associations Between Fast Food Outlet Access and Inflammatory Markers in the US-Based Nurses’ Health Study II

Background: Access to fast food outlets (FFO) has increased in recent years and may decrease diet quality and increase cardiovascular disease risk. Inflammation is a well-established cardiovascular disease risk factor, but it remains unclear whether inflammation is one of the pathways explaining associations between the food environment and inflammatory markers. Methods: We included 6,609 participants from the US-based Nurses’ Health Study II (NHS-II), a prospective cohort of registered female nurses. Counts of FFO were obtained from the Infogroup US Historical Business Data within 1500-meter circular buffers and assigned to participants’ residential addresses from 1998 to 2011. Biomarkers included C-reactive protein (CRP), Interleukin-6 (IL-6), Tumor necrosis factor α receptor 2 (TNFαR2, in a subset), and adiponectin. We evaluated cross-sectional associations between counts of FFO (1998) and inflammatory markers (1999) in linear regression models and evaluated longitudinal associations by the change in counts of FFO between 1998 and 2010 and the change in inflammatory markers between 1999 and 2011 using linear mixed models. Models were adjusted for age, race/ethnicity, partners’ education level, smoking, neighborhood socioeconomic status, and population density. Interaction terms were included to explore effect modification by baseline neighborhood socioeconomic status and population density. Results: Our study comprised women with a mean age of 45.3 (+/- 4.4) years at 1998. A one-unit higher count of FFO within a 1500m buffer was not cross-sectionally associated with CRP (β: 0.004, 95%CI: -0.004, 0.010), IL-6 (β: 0.001, 95%CI: -0.001, 0.004), TNFR2 (β: 0.051, 95%CI: -1.495, 1.597), or adiponectin (β: -6.054, 95%CI: -14.576, 2.468). No associations were found in longitudinal models (CRP (β: 0.000, 95%CI: -0.007, 0.008), IL-6 (β: 0.001, 95%CI: -0.002, 0.003), or adiponectin (β: -1.127, 95%CI: -11.889, 14.3152)). No significant effect modification was found between count of FFO and neighborhood socioeconomic status, or population density (P-for-interaction >0.1). Conclusions: While several previous studies have found an association between frequency of consumption of food at fast food restaurants and biomarkers of cardiovascular risk, at the community level, we did not find associations between the count of FFO and several inflammatory markers in a population of US female nurses.

Atherogenic Index as a Cardiovascular Biomarker in Mexican Workers from Marginalized Urban Areas Occupationally Exposed to Metals

Cardiovascular disease (CVD) is one of the main causes of death and disability worldwide. The etiology of CVD is often associated with multiple risk factors, with environmental factors receiving considerable attention. Individuals with precarious jobs are among the groups most affected by chronic exposure to environmental pollutants. This study aimed to evaluate occupational exposure to heavy metals among individuals in precarious job settings and investigate atherogenic indices as biomarkers of cardiovascular risk. A total of 137 workers participated in this cross-sectional study conducted in three work environments in San Luis Potosi, Mexico. Urine and blood samples were collected to assess metal exposure and biochemical profiles, including atherogenic indices. The results showed that workers in the brick sector exhibited the highest levels of metal exposure, particularly arsenic (44.06 µg/L), followed by stonecutters and garbage collectors (24.7 and 16.9 µg/L, respectively). Similarly, Castelli risk index (CRI) and the atherogenic index of plasma (AIP) were higher in brickmakers (3.883 and 0.499) compared to stonecutters (3.285 and 0.386) and garbage collectors (3.329 and 0.367). Evidence of exposure to heavy metals was observed in the three populations, in addition to the fact that individuals with greater exposure to arsenic also exhibited higher CRI and AIP.

Epicardial Adipose Tissue: A Precise Biomarker for Cardiovascular Risk, Metabolic Diseases, and Target for Therapeutic Interventions.

Epicardial adipose tissue (EAT) is located between the heart muscle and visceral pericardium, where it has direct contact with coronary blood vessels. Elevated thickness of this tissue can induce local inflammation affecting the myocardium and the underlying coronary arteries, contributing to various cardiovascular diseases such as coronary artery disease, atrial fibrillation, or heart failure with preserved ejection fraction. Recent studies have identified EAT thickness as a simple and reliable biomarker for certain cardiovascular outcomes. Examples include the presence of atherosclerosis, incident cardiovascular disease (CVD) in individuals with type 2 diabetes mellitus (T2DM), and the prevalence of atrial fibrillation. Furthermore, EAT measurements can help to identify patients with a higher risk of developing metabolic syndrome. Since the EAT thickness can be easily measured using echocardiography, such examinations could serve as a useful and cost-effective preventive tool for assessing cardiovascular health. This review also summarizes therapeutical interventions aimed at reducing EAT. Reducing EAT thickness has been shown to be possible through pharmacological, surgical, or lifestyle-change interventions. Pharmaceutical therapies, including thiazolidinediones, glucagon-like peptide 1-receptor agonists, sodium-glucose cotransporter 2 inhibitors, dipeptidyl peptidase-4 inhibitors, and statins, have been shown to influence EAT thickness. Additionally, EAT thickness can also be managed more invasively through bariatric surgery, or noninvasively through lifestyle changes to diet and exercise routines.

Influence of arsenic exposure and TGF-β gene single nucleotide polymorphisms (gene-environment interaction) on cardiovascular risk biomarkers levels in Mexican people from San Luis Potosi, Mexico

Influence of arsenic exposure and TGF-β gene single nucleotide polymorphisms (gene-environment interaction) on cardiovascular risk biomarkers levels in Mexican people from San Luis Potosi, Mexico

Low Density Lipoprotein Cholesterol Decreases the Expression of Adenosine A2A Receptor and Lipid Rafts-Protein Flotillin-1: Insights on Cardiovascular Risk of Hypercholesterolemia.

High blood levels of low-density lipoprotein (LDL)-cholesterol (LDL-C) are associated with atherosclerosis, mainly by promoting foam cell accumulation in vessels. As cholesterol is an essential component of cell plasma membranes and a regulator of several signaling pathways, LDL-C excess may have wider cardiovascular toxicity. We examined, in untreated hypercholesterolemia (HC) patients, selected regardless of the cause of LDL-C accumulation, and in healthy participants (HP), the expression of the adenosine A2A receptor (A2AR), an anti-inflammatory and vasodilatory protein with cholesterol-dependent modulation, and Flotillin-1, protein marker of cholesterol-enriched plasma membrane domains. Blood cardiovascular risk and inflammatory biomarkers were measured. A2AR and Flotillin-1 expression in peripheral blood mononuclear cells (PBMC) was lower in patients compared to HP and negatively correlated to LDL-C blood levels. No other differences were observed between the two groups apart from transferrin and ferritin concentrations. A2AR and Flotillin-1 proteins levels were positively correlated in the whole study population. Incubation of HP PBMCs with LDL-C caused a similar reduction in A2AR and Flotillin-1 expression. We suggest that LDL-C affects A2AR expression by impacting cholesterol-enriched membrane microdomains. Our results provide new insights into the molecular mechanisms underlying cholesterol toxicity, and may have important clinical implication for assessment and treatment of cardiovascular risk in HC.

Soluble urokinase plasminogen activator receptor (suPAR) in children with obesity or type 1 diabetes as a marker of endothelial dysfunction: a cross-sectional study.

Pediatric obesity and type 1 diabetes mellitus (T1DM) represent two common chronic diseases associated with chronic inflammation, endothelial dysfunction and long-term complications. The aim of the present study was to assess the possible diagnostic and prognostic value of soluble urokinase plasminogen activator receptor (suPAR), a marker of inflammation and impaired endothelial function, in children with the diseases.In this cross-sectional study, children and adolescents with T1DM (N = 41) or obesity (N = 37), aged < 18 years old, and without proteinuria were included, together with children of similar age and without evident morbidity that served as controls (N = 42). Serum samples were obtained during standard outpatient follow up and the urokinase-type plasminogen activator receptor (suPAR) concentrations were measured using a commercially available sandwich ELISA kit (DUP00, R&D systems). Clinical and biochemical indices that were also assessed include body mass index (BMI) z-score, Tanner stages, glycosylated haemoglobin (HbA1c), fasting lipid profile and serum creatinine. Mean serum suPAR levels were significantly higher in patients with obesity compared to patients with T1DM and controls, while children with T1DM had similar suPAR levels to controls. Also, serum suPAR levels showed a negative correlation with age (Spearman rho -0.359, p < 0.001) and serum creatinine levels (Spearman rho -0.334, p = 0.005), and a positive correlation with BMI z-score (Spearman rho 0.354, p = 0.009) in the whole cohort. Conclusion: Serum suPAR may be a useful predictive marker of inflammation or endothelial dysfunction for children with obesity and T1DM, as well as a promising therapeutic target. Further studies are needed in order to clarify whether the reported differences in suPAR levels could reflect a greater impairment of the inflammation status and endothelial function in children with obesity compared to children with T1DM. What is Known: • Paediatric obesity and type 1 diabetes are characterised by chronic inflammation and metabolic dysregulation. • Urokinase plasminogen activator receptor (uPAR) has been proposed as a useful biomarker for chronic inflammation and cardiovascular risk in adults. What is New: • Serum suPAR levels were increased in children and adolescents with obesity compared to those with T1DM and healthy controls; thus, obesity may affect the inflammatory status and endothelial function to a higher degree than T1DM during childhood. • Serum suPAR may serve as a diagnostic and predictive marker of inflammation and endothelial dysfunction for children and adolescents with obesity and T1DM.

Exposure to green spaces, cardiovascular risk biomarkers and incident cardiovascular disease in older adults: The Seniors-Enrica II cohort

IntroductionThe impact of residential green spaces on cardiovascular health in older adults remains uncertain. MethodsCohort study involving 2114 adults aged ≥ 65 years without cardiovascular disease (CVD), residing in five dense municipalities (Prince et al., 2015) of the Madrid region and with detailed characterization of their socioeconomic background, health behaviors, CVD biological risk factors, and mental, physical, and cognitive health. Greenness exposure was measured using the Normalized Difference Vegetation Index (NDVI) at varying distances from participants' homes. Traffic exposure, neighborhood environment, neighborhood walkability, and socioeconomic deprivation at the census level were also assessed. Serum N-terminal pro-B-type natriuretic peptide (NT-ProBNP), high-sensitivity troponin T (hs-TnT), interleukin 6 (IL-6), and Growth Differentiation Factor 15 (GDF‐15) were measured at baseline, and incident CVD events identified through electronic medical records (International Classification of Primary Care-2 codes K74, K75, K77, K90, and K92). ResultsAfter adjusting for sex, age, educational attainment, financial hardship and socioeconomic deprivation at the census level, an interquartile range (IQR) increase in NDVI at 250, 500, 750, and 1000 m around participants' homes was associated with mean differences in ProBNP of −5.56 % (95 %CI: −9.77; −1.35), −5.05 % (-9.58; −0.53), −4.24 % (-8.19, −0.19), and −4.16 % (-7.59; −0.74), respectively; and mean differences in hs-TnT among diabetic participants of −8.03 % (95 %CI: −13.30; −2.77), −9.52 % (-16.08; −2.96), −8.05 % (-13.94, −2.16) and −5.56 % (-10.75; −0.54), respectively. Of similar magnitude, although only statistically significant at 250 and 500 m, were the observed lower IL-6 levels with increasing greenness. GDF-15 levels were independent of NDVI. In prospective analyses (median follow-up 6.29 years), an IQR increase in residential greenness at 500, 750, and 1000 m was associated with a lower risk of incident CVD. The variables that contributed most to the apparent beneficial effects of greenness on CVD were lower exposure to traffic, improved cardiovascular risk factors, and enhanced physical performance. Additionally, neighborhood walkability and increased physical activity were notable contributors among individuals with diabetes. ConclusionIncreased exposure to residential green space was associated with a moderate reduction in CVD risk in older adults residing in densely populated areas.

Clonal chromosomal mosaicism and loss of chromosome Y in elderly men increase vulnerability for SARS-CoV-2.

The pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, COVID-19) had an estimated overall case fatality ratio of 1.38% (pre-vaccination), being 53% higher in males and increasing exponentially with age. Among 9578 individuals diagnosed with COVID-19 in the SCOURGE study, we found 133 cases (1.42%) with detectable clonal mosaicism for chromosome alterations (mCA) and 226 males (5.08%) with acquired loss of chromosome Y (LOY). Individuals with clonal mosaic events (mCA and/or LOY) showed a 54% increase in the risk of COVID-19 lethality. LOY is associated with transcriptomic biomarkers of immune dysfunction, pro-coagulation activity and cardiovascular risk. Interferon-induced genes involved in the initial immune response to SARS-CoV-2 are also down-regulated in LOY. Thus, mCA and LOY underlie at least part of the sex-biased severity and mortality of COVID-19 in aging patients. Given its potential therapeutic and prognostic relevance, evaluation of clonal mosaicism should be implemented as biomarker of COVID-19 severity in elderly people.

C-reactive protein, cardiovascular issues of an acute-phase protein: an update for theclinician

Inflammation is an important pathogenic factor for the development of atherosclerotic cardiovascular disease. Currently, the most frequently used biomarker reflecting systemic inflammation is C-reactive protein (CRP), an acute-phase protein produced primarily by hepatocytes under the influence of interleukin-6, interleukin-1 beta, and tumor necrosis factor. Growing evidence from epidemiological studies has shown a robust association between elevated serum or plasma CRP concentrations and the incidence of a first cardiovascular adverse event (including acute myocardial infarction, ischemic stroke, and sudden cardiac death) in the general population, as well as recurrence of major adverse cardiovascular events among patients with established disease. The additive value that CRP measurement gives to traditional risk factors is reflected in novel cardiovascular risk calculators and in current intervention regimens, which already consider CRP as a target therapeutic. However, the variations in CRP levels, that depend on sex, ethnicity, hormonal status, and some peculiarities of the measurement assays, must be taken into consideration when deciding to implement CRP as a useful biomarker in the study and treatment of atherosclerotic cardiovascular disease. This review aims to offer an updated vision of the importance of measuring CRP levels as a biomarker of cardiovascular risk beyond the traditional factors that estimate the risk of atherosclerotic disease.

ApoB100 and Atherosclerosis: What's New in the 21st Century?

ApoB is the main protein of triglyceride-rich lipoproteins and is further divided into ApoB48 in the intestine and ApoB100 in the liver. Very low-density lipoprotein (VLDL) is produced by the liver, contains ApoB100, and is metabolized into its remnants, intermediate-density lipoprotein (IDL) and low-density lipoprotein (LDL). ApoB100 has been suggested to play a crucial role in the formation of the atherogenic plaque. Apart from being a biomarker of atherosclerosis, ApoB100 seems to be implicated in the inflammatory process of atherosclerosis per se. In this review, we will focus on the structure, the metabolism, and the function of ApoB100, as well as its role as a predictor biomarker of cardiovascular risk. Moreover, we will elaborate upon the molecular mechanisms regarding the pathophysiology of atherosclerosis, and we will discuss the disorders associated with the APOB gene mutations, and the potential role of various drugs as therapeutic targets.

Reversal of High Fat Diet-Induced Obesity, Systemic Inflammation, and Astrogliosis by the NLRP3 Inflammasome Inhibitors NT-0249 and NT-0796.

Systemic and cerebral inflammatory responses are implicated in the pathogenesis of obesity and associated metabolic impairment. While the NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome has been linked to obesity-associated inflammation, whether it contributes to the development or maintenance of obesity is unknown. We provide support for a direct role of saturated fatty acids, such as palmitic acid, as NLRP3 activating stimuli in obese states. To investigate whether NLRP3 activation contributes to the pathogenesis of diet-induced obesity (DIO) in mice, we tested two different clinical-stage NLRP3 inflammasome inhibitors. We demonstrate a contributory role of this key inflammasome to established obesity and associated systemic and cerebral inflammation. By comparing their effects to calorie restriction, we aimed to identify specific NLRP3-sensitive mechanisms contributing to obesity-induced inflammation (as opposed to be those regulated by weight loss per se). In addition, a direct comparison of an NLRP3 inhibitor to a glucagon like peptide-1 receptor agonist, semaglutide (Wegovy), in the DIO model allowed an appreciation of the relative efficacy of these two therapeutic strategies on obesity, its associated systemic inflammatory response, and cerebral gliosis. We show that two structurally distinct, NLRP3 inhibitors, NT-0249 and NT-0796, reverse obesity in the DIO mouse model and that brain exposure appears necessary for efficacy. In support of this, we show that DIO-driven hypothalamic glial fibrillary acidic protein expression is blocked by dosing with NT-0249/NT-0796. While matching weight loss driven by semaglutide or calorie restriction, remarkably, NLRP3 inhibition provided enhanced improvements in disease-relevant biomarkers of acute phase response, cardiovascular inflammation, and lipid metabolism. SIGNIFICANCE STATEMENT: Obesity is a global health concern that predisposes individuals to chronic disease such as diabetes and cardiovascular disease at least in part by promoting systemic inflammation. We report that in mice fed a high-fat, obesogenic diet, obesity is reversed by either of two inhibitors of the intracellular inflammatory mediator NLRP3. Furthermore, NLRP3 inhibition reduces both hypothalamic gliosis and circulating biomarkers of cardiovascular disease risk beyond what can be achieved by either the glucagon like peptide-1 agonist semaglutide or calorie restriction alone.

Circulating Monocytes Are Predictive and Responsive in Moderate-to-Severe Plaque Psoriasis Subjects Treated with Apremilast

Monocytes play a critical role in the inflammation associated with psoriasis, and their abnormalities have been reported as biomarkers of cardiovascular event risk, a psoriasis comorbidity. Monocytic cells in chronic inflammatory disorders express elevated levels of cAMP phosphodiesterase. Restoring cAMP levels using the oral cAMP phosphodiesterase-4 inhibitor, apremilast, improves clinical outcomes for a subset of patients with psoriasis. We asked whether aberrant monocyte subsets or transcriptomic pathways can function as biomarkers of psoriasis endotypes that can predict enhanced clinical responses to cAMP phosphodiesterase inhibition. A 16-week open-label study of 22 patients with monocyte flow cytometric and transcriptomic analysis was performed. Subjects with elevated hyperadhesive monocyte doublets at baseline were more likely to be responders to apremilast (P < .0001); 82% of subjects with elevated hyperadhesive monocyte doublets achieved 50% reduction in PASI compared with 46% in those without elevated doublets. We observed a significant reduction in hyperadhesive monocyte-containing doublets and monocyte-platelet aggregates, suggesting an effect of apremilast on the adhesiveness of blood monocytes during chronic inflammation. Monocyte differentially expressed gene transcripts predictive of clinical response uncovered pharmacoendotypes with distinct patterns of nucleotide metabolism, energetics, and differentiation. Further study to understand the basis of drug responsiveness and to develop an apremilast psoriasis treatment algorithm using monocyte-refined gene expression is required to validate and become practical in clinical use, offering patients a test that personalizes their likelihood of clinical response.

Negative work-to-family spillover stress and heightened cardiovascular risk biomarkers in midlife and older adults

ObjectivesThe current study aimed to investigate the health implications of negative work-to-family spillover on cardiovascular risk biomarkers. MethodsIn a large-scale cross-sectional dataset of working or self-employed midlife and older adults in the United States (N = 1179), we examined five biomarkers linked to cardiovascular risk, including high-density lipoprotein (HDL) cholesterol, low-density lipoprotein cholesterol, triglyceride, interleukin-6, and C-reactive protein. Negative work-to-family spillover, measured using a four-item self-reported questionnaire, was included into our model to study its association with these cardiovascular risk biomarkers. ResultsOur findings indicate a significant association between negative work-to-family spillover and cardiovascular risk biomarkers – higher triglycerides (β = 0.108, p < .001), interleukin-6 (β = 0.065, p = .026), and C-reactive protein (β = 0.067, p = .022), and lower HDL cholesterol (β = −0.104, p < .001). The associations on triglycerides (β = 0.094, p = .001) and HDL cholesterol (β = −0.098, p < .001) remained significant even after controlling numerous control variables of demographics, medication, health-status, and health-related behaviors. The findings were also consistent against slight variations in the analytic method and adjustment for multiple comparisons. ConclusionsThe current study supports the premise that spillover of work-related tensions into family life is associated with objective physiological changes that contribute to cardiovascular risk.

Plasma and Urinary Platelet Factor 4 as Biomarkers for Cardiovascular Risk in Children with Chronic Kidney Disease.

Children suffering from chronic kidney disease (CKD) have a high risk of cardiovascular disease (CVD). The early detection and diagnosis of subclinical CVD in pediatric CKD can reduce mortality later in life. Plasma factor 4 (PF4) is a chemokine released by activated platelets. We examined whether or not PF4 in the plasma and urine, its kidney function normalized ratio, and fractional excretion have differential associations with CVD risk markers in 139 youths aged 3 to 18 years old with CKD stages G1-G4. Significant negative correlations were observed between plasma PF4 and cardiovascular surrogate markers, such as the left ventricular mass index (LVMI), carotid intima-media thickness (cIMT), and pulse wave velocity (PWV). The plasma PF4/creatinine (Cr) ratio was lower in CKD children with a high daytime BP and 24 h BP, high BP load, and nocturnal non-dipping status. After adjusting for confounders, the plasma PF4 and plasma PF4/Cr ratio still independently predicted an abnormal ABPM profile. In addition, both the plasma PF4 and plasma PF4/Cr ratio presented a negative correlation with the L-arginine and asymmetric dimethylarginine ratio. These findings provide convincing evidence supporting the link between PF4 and CVD markers in pediatric CKD. Our study highlights the importance of further research to assess the performance of PF4-related biomarkers in predicting CVD events and CKD progression in children with CKD.

Platelet RNA Biomarker of Ticagrelor-Responsive Genes Is Associated With Platelet Function and Cardiovascular Events.

Identifying patients with the optimal risk:benefit for ticagrelor is challenging. The aim was to identify ticagrelor-responsive platelet transcripts as biomarkers of platelet function and cardiovascular risk. Healthy volunteers (n=58, discovery; n=49, validation) were exposed to 4 weeks of ticagrelor with platelet RNA data, platelet function, and self-reported bleeding measured pre-/post-ticagrelor. RNA sequencing was used to discover platelet genes affected by ticagrelor, and a subset of the most informative was summarized into a composite score and tested for validation. This score was further analyzed (1) in CD34+ megakaryocytes exposed to an P2Y12 inhibitor in vitro, (2) with baseline platelet function in healthy controls, (3) in peripheral artery disease patients (n=139) versus patient controls (n=30) without atherosclerosis, and (4) in patients with peripheral artery disease for correlation with atherosclerosis severity and risk of incident major adverse cardiovascular and limb events. Ticagrelor exposure differentially expressed 3409 platelet transcripts. Of these, 111 were prioritized to calculate a Ticagrelor Exposure Signature score, which ticagrelor reproducibly increased in discovery and validation cohorts. Ticagrelor's effects on platelets transcripts positively correlated with effects of P2Y12 inhibition in primary megakaryocytes. In healthy controls, higher baseline scores correlated with lower baseline platelet function and with minor bleeding while receiving ticagrelor. In patients, lower scores independently associated with both the presence and extent of atherosclerosis and incident ischemic events. Ticagrelor-responsive platelet transcripts are a biomarker for platelet function and cardiovascular risk and may have clinical utility for selecting patients with optimal risk:benefit for ticagrelor use.

P116: Cessation of caregiving due to institutionalization: Dementia family caregivers’ profile. A 3 year longitudinal study

Objective:Caregiving of a relative with dementia is considered a chronic stressful situation that generates physical and psychological strain and that may have negative effects on caregivers’ health. Many caregivers make the decision to enter their relatives in a nursing-home, however, there are few studies that analyze psychosocial (e.g., guilt) and biomarkers of cardiovascular risk (C-reactive protein, CRP) variables that are related to this decision during the caregiving process stress. The aim of this study was to analyze caregivers’ differences between caregivers who finish the role of caring of their relatives with dementia and those who continue their caregiving role throughout the process of caring in a 3-year period.Methods:The sample consisted of 294 family caregivers of people with dementia and was divided in two groups; a) caregivers who institutionalized their relatives during a 3-year period (12.7%); and caregivers who maintained their role as caregivers (87.3%).Results:Preliminary results show that caregivers who institutionalized their relatives with dementia in some time point of the caregiving process presented at baseline more frequency of behavioral problems (t = -2.95; p &lt; .01), more feelings of guilt (t = -3.52; p &lt; .01) and compassion (t = -3.79; p &lt; .01), reported less frequency of dysfunctional thoughts about caregiving (t = 1.99; p &lt; .05) and presented higher levels of CRP (t = 2.72; p &lt; .01), compared to caregivers who maintained their role as caregivers. In addition, caregivers who institutionalized their relative were younger (t= 2.13; p &lt; .05) and reported more weekly hours (t= -3.46; p &lt; .01) and more days (t= -3.01; p &lt; .01) of home help compared to those caregivers who maintained their role. No significant effects were found for caregivers’ gender (p = .38), daily hours caring (t= 1.54; p = .13) nor time caring (t=-1.1; p = .27).Discussion:The results of this study present several clinical implications. Knowing variables that are related to the decision of institutionalization could prevent it as well as it can be useful to accompany caregivers by providing support throughout the entire process.