Plasma hs-CRP Research Articles

Serum Magnesium Levels in Patients with Chronic Kidney Disease: Is There a Relationship with Inflammation Status?

Magnesium (Mg2+) is a fundamental mineral that maintains cellular function, and low levels may be linked to inflammation in patients with chronic kidney disease (CKD). This cross-sectional study evaluated the correlation between serum Mg2+ levels and the inflammatory status in patients undergoing dialysis. Two hundred patients with CKD [150 undergoing hemodialysis (HD), 50 (18) years; BMI 24 (4.8) kg/m²; and 50 patients on peritoneal dialysis (PD), 54 (17.7) years; BMI, 27.5 (7.3) kg/m²] were included. Serum Mg2+ levels were evaluated using a colourimetric test and commercial kit. Inflammatory markers were assessed by ELISA and multiplex bead-based assay. Lipid peroxidation was evaluated using thiobarbituric acid-reactive substances. The median serum Mg2+ levels were 2.3 (0.5) mg/dL, and 21% of patients presented Mg2+ deficiency (< 2.07mg/dL or 0.85 mmol/L). We found no difference in Mg2+ serum levels between the two groups. A significant negative correlation was observed between serum Mg2+ levels and plasma hs-CRP (r =-0.17, p = 0.01), IL-8 (r =-0.35, p = 0.01), and MCP-1 (r =-0.31, p = 0.03) levels. Mg2+ serum levels were negatively correlated with inflammatory status in patients with CKD on dialysis.

1491-P: ER Stress Drives the VEGF Expression in Monocytic Cells by Mechanisms Involving CHOP/ROS/HIF-1alpha/NRF2 and NF-kappaB/p38 MAPK Pathways

Obesity is marked by metabolic inflammation and by metabolic impairment caused by increased endotoxin, free fatty acids, and vascular endothelial growth factor (VEGF) levels; and involves the endoplasmic reticulum (ER) stress as well. However, it remains unclear whether the ER stress can induce/amplify VEGF expression in metabolically-stressed monocytic cells; and if so, by which mechanism(s). To test this, metabolic stress was induced in THP-1 monocytic cells by treating cells separately with lipopolysaccharide (LPS), palmitic acid (PA), and oleic acid (OA), in presence/absence of ER stressor thapsigargin (TG). Gene expression of VEGF/ER stress markers was assessed by qRT-PCR, protein expression by ELISA, ROS by DCFH-DA assay, phosphorylation of HIF-1α, NF-κB, ERK1/2, and p38 MAPK by immunoblotting, and the insulin response in stressed cells by glucose-uptake assay. Regarding clinical analyses, adipose VEGF gene and protein expression was detected using qRT-PCR and IHC, respectively, while plasma hs-CRP, TNF-α, MDA, and OX-LDL levels were measured by ELISA. The experimental data show that a cooperative interaction between the metabolic and ER stresses led to the expression of VEGF, ROS, CHOP, ATF6, SOD2, and NRF2 (P˂0.05), as well as stimulated the CHOP and NRF2 promoter activities in reporter cells (P˂0.05). However, the glucose uptake was not impaired. The VEGF expression was dependent on phosphorylation of HIF-1α, NF-κB, and p38 MAPK; and the inhibitors of NF-κB/MAPK pathways as well as antioxidants or ROS scavengers suppressed the VEGF production. Further, individuals with obesity showed increased VEGF expression which associated positively with plasma levels of hs-CRP, TNF-α, MDA, and OX-LDL (P≤0.05). Overall, our findings support a cooperativity model in which the ER and metabolic stresses interact to augment VEGF expression in monocytic cells via the mechanisms involving CHOP/ROS/HIF-1α/NRF2 and NF-κB/p38 MAPK pathways. Disclosure S.A.K.Sindhu: None. F.Alzaid: None. F.Almulla: None. R.Ahmad: None. N.Akhter: None. A.Wilson: None. H.Arefanian: None. A.Al madhoun: None. R.S.Thomas: None. S.P.Kochumon: None. F.Alrashed: None. F.Bahman: None. Funding Kuwait Foundation for the Advancement of Sciences (RA2015-027, RA2010-003, RAHM-2019-022)

Sympathoinhibitory electroacupuncture (EA) interacts positively with anti-inflammatory EA alleviating blood pressure in hypertensive rats.

Elevated sympathetic activity and chronic inflammation are known contributory factors observed in hypertension. We have observed that sympathoinhibitory electroacupuncture (SI-EA) at acupoints ST36-37 alleviates sympathetic activity and hypertension. Additionally, EA at acupoints SP6-7 exerts anti-inflammatory (AI-EA) effects. However, it is not known whether simultaneous stimulation of this combination of acupoints attenuates or enhances individual effects. A 2 × 2 factorial design was used to test the hypothesis that combining SI-EA and AI-EA (cEA) leads to greater reduction of hypertension by decreasing sympathetic activity and inflammation in hypertensive rats than either set of acupoints alone. Dahl salt-sensitive hypertensive (DSSH) rats were treated with four EA regimens including cEA, SI-EA, AI-EA, and sham-EA twice weekly for five weeks. A group of normotensive (NTN) rats served as control. Systolic and diastolic BP (SBP and DBP) and heart rate (HR) were measured non-invasively by tail-cuff. Plasma norepinephrine (NE), high-sensitivity C-reactive protein (hs-CRP) and interleukin 6 (IL-6) concentrations were determined with ELISA at the completion of treatments. DSSH rats on high salt diet progressively developed moderate hypertension within five weeks. DSSH rats treated with sham-EA showed continuous increase in SBP and DBP and elevations in plasma NE, hs-CRP, and IL-6 levels relative to NTN control. Both SI-EA and cEA decreased SBP and DBP, and had corresponding changes in biomarkers (NE, hs-CRP, and IL-6) compared with sham-EA. AI-EA prevented SBP and DBP elevation and decreased IL-6 and hs-CRP relative to sham-EA. Importantly in DSSH rats that received repetitive cEA treatment, SI-EA interacted positively with AI-EA leading to greater reduction of SBP, DBP, NE, hs-CRP, and IL-6 than SI-EA or AI-EA alone. These data suggest that by targeting both elevated sympathetic activity and chronic inflammation, cEA regimen results in a greater reduction of BP effects in treating hypertension compared to using individual SI-EA or AI-EA alone.

Metabolic and vascular effect of a new standardized bergamot phytocomplex: a three-arm, placebocontrolled, double-blind clinical trial.

In addition to healthy lifestyle and balanced diet, nutraceutical supplementation may be useful to maintain overall metabolic wellness. The aim of the present study was to assess the metabolic and vascular effects of a new, highly standardized bergamot phytocomplex supplement in healthy volunteers with the features of metabolic syndrome. We carried out a double-blind, randomized, placebo-controlled, three-arm, parallel-group clinical trial in 90 adult subjects (30 per group) treated for 12 weeks with two different dosages of a highly standardized bergamot phytocomplex (Endoberg by AKHYNEX and Kalita by Giellepi) or placebo. Lipid plasma levels, glycemia, plasma hs-CRP, HOMA-IR, body fat, endothelial reactivity and fatty liver index were assessed at baseline, after 6 weeks and at the end of treatment in all subjects. At the end of treatment, both tested bergamot extract doses were able to significantly improve atherogenic dyslipidemia and insulin sensitivity (p < 0.05) compared to placebo. In the high-dose treated group, total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), non high-density lipoprotein cholesterol (HDL-C), and triglycerides (TG) improved versus placebo (p < 0.05) just after 6 weeks of treatment. After 12 weeks of treatment, TC decreased by 13.2 ±2.1%, LDL-C by 17.7 ±3.2%, non-HDL-C by 17.5 ±3.1%, TG by 16.6 ±3.3%, TG/HDL-C by 22.5 ±4.4%, homeostasis insulin resistance index (HOMA-IR) by 12.2 ±2.1%, γ-glutamyl transferase (GGT) by 22.2 ±4.6%, and high-sensitivity C-reactive protein (hs-CRP) by 17.9 ±3.4% versus baseline (p < 0.05) and vs. placebo (p < 0.05). Percentage body fat and endothelial reactivity improved versus baseline, but not versus placebo, in the high-dose treatment only (p < 0.05). The tested bergamot phytocomplex was able to significantly improve glucose and lipid metabolism, as well as inflammation, and might represent a novel multi-target approach to control metabolic syndrome.

Self-compassion, but not compassion toward others, is associated with better physical health: A cross-sectional study.

Compassion is a modifiable construct that is associated with better physical health outcomes but, to our knowledge, has seldom been studied in people with schizophrenia (PwS) despite its applicability to counteract widespread depression in this community that might prevent positive health behaviors. We hypothesized that, compared to non-psychiatric comparison subjects (NCs), PwS would have lower compassion toward self (CTS), lower compassion toward others (CTO), and a positive association between compassion and health outcomes, such as physical wellbeing, comorbidities, and plasma hs-CRP. This cross-sectional study examined differences in physical health, CTS, and CTO in 189 PwS and 166 NCs. We used general linear models to analyze the relationship between compassion and health. As hypothesized, PwS had lower levels of CTS and CTO, worse physical well-being, more comorbidities, and higher levels of plasma hs-CRP than NCs. In the combined sample, higher CTS was significantly associated with better physical well-being and fewer comorbidities, while higher CTO was significantly associated with more comorbidities. In PwS alone, higher CTS was significantly associated with better physical well-being and lower levels of hs-CRP. CTS seemed to have a larger positive association with physical health than CTO, with depression acting as a potential mediator for CTS. Exploring effects of CTS interventions on physical health and health behaviors could be a promising next step.

Clinical response to EPA supplementation in patients with major depressive disorder is associated with higher plasma concentrations of pro-resolving lipid mediators

Chronic inflammation has been implicated in the pathophysiology of major depressive disorder (MDD). Activating the resolution of inflammation through ω-3 fatty acid supplementation may prove to be a successful therapeutic strategy for the treatment of MDD. Patients with MDD, body mass index >25 kg/m2, and plasma high-sensitivity C-reactive protein ≥3 μg/mL (n = 61) were enrolled in a 12-week randomized trial consisting of 4 parallel arms: EPA 1, 2, and 4 g/d, and placebo. The supplement contained EPA and DHA in a 3.9:1 ratio. Depression symptoms were assessed using the IDS-C30 scale. Plasma fatty acids and pro-resolving lipid mediators (SPMs) were measured in 42 study completers at baseline and at the end of treatment by liquid chromatography/mass spectrometry. The response rate (≥50% reduction in IDS-30 score) was higher in the 4 g/d EPA arm than placebo (Cohen d = 0.53). In the 4 g/d EPA arm, responders had significantly greater increases in 18-hydroxyeicosapentaenoic acid (18-HEPE) and 13-hydroxydocosahexaenoic acid (13-HDHA) than non-responders (p < 0.05). Within the 4 g/d EPA arm, the increase in 18-HEPE was significantly associated with reductions in plasma hs-CRP concentrations (p < 0.05) and IDS-C30 scores (p < 0.01). In summary, response rates were greater among patients with MDD randomized to EPA 4 g/d supplementation and in those who showed a greater ability to activate the synthesis of 18-HEPE. The inverse association of 18-HEPE with both systemic inflammation and symptoms of depression highlights the activation of the resolution of inflammation as a likely mechanism in the treatment of MDD with ω-3 fatty acid supplementation.

PS-BPC12-7: ANTI-INFLAMMATORY AND PRO-INFLAMMATORY BIOMARKERS IN PATIENTS WITH NON-ALCOHOLIC FATTY LIVER DISEASE AND HYPERTENSION

Introduction: Non-alcoholic fatty liver disease (NAFLD) affects up to 50% of patients with hypertension (HT). Research data indicate a decrease in the activity of anti-inflammatory biomarkers with a simultaneous increase in the levels of pro-inflammatory agents. Objective: To assess the changes in anti-inflammatory systems (using kallistatin, IL-10) and pro-inflammatory activity (using IL-1β; and high-sensitivity CRP (hsCRP)) in patients with NAFLD under the influence of concomitant HT. Design and method: 63 patients with NASH and HT and 52 patients with isolated NASH were examined. Plasma kallistatin, IL-10, IL-1β; and hsCRP levels were evaluate using ELISA. The results were statistically processed using standard methods. Results: Kallistatin levels in patients with NAFLD and HT were on average 65.03 ng/ml (95% CI 61.38; 68.68), which was significantly lower than in the group with isolated NAFLD (83.42 ng/ml (95% CI 81.89; 84.94), p &lt; 0.001) and control results (111.70 ng/ml (95% CI 106.14; 113.22), p &lt; 0.001). The level of anti-inflammatory IL-10 in the group of NAFLD and HT also reached minimal values (12.69 pg/ml (95% CI 11.93; 12.95) against 14.34 pg/ml (95% CI 13.27; 14,34) in the group with isolated NAFLD (p &lt; 0.001) and 16.19 pg/ml (95% CI 15.15; 17.74) in the control group (p &lt; 0.001)). The opposite results were observed in the study of IL-1β; content, which was increased in the group with NAFLD and HT (17.55 pg/ml (95% CI 17.06; 19.73) versus 15.72 pg/ml (95% CI 15,25; 17.44) in the group with isolated NAFLD (p &lt; 0.001) and 8.26 (95% CI 7.79; 8.46) in the control group (p &lt; 0.001)). In addition, patients with NAFLD and HT had an increase in CRP (7.90 mg/l (95% CI 7.96; 8.75) versus 6.55 mg/l (95% CI 6.47; 7.57) in the group with isolated NAFLD (p &lt; 0.001) and 2.07 mg/l (95% CI 1.83; 2.85 mg/l) in the control group (p &lt; 0.001)). It has been shown that with the progression of HT in patients with NAFLD, the level of kallistatin significantly decreases (p &lt; 0.001, p = 0.011 for the HT stage and BP grade) and IL-10 (p &lt; 0.001) with a simultaneous increase in IL-1β; (p &lt; 0.001) and CRP levels (p &lt; 0.001). Conclusions: Thus, patients with NAFLD and HT are likely to experience changes in biomarker status toward a pro-inflammatory profile and deepening of these deviations with the progression of concomitant hypertension.

Biomarkers in Determining the Risk of Liver Fibrosis in Patients with Non-Alcoholic Fatty Liver Disease and Hypertension

IntroductionNon-alcoholic steatohepatitis (NASH) affects up to 50% of patients with arterial hypertension (HT). Laboratory biomarkers are believed to help in liver fibrosis (LF) risk determination in patients with NASH and HT. PurposeTo assess the kallistatin, IL-10, IL-1β and high-sensitivity CRP (hsCRP) significance in LF risk evaluation in patients with NASH and HT. Methods. 63 patients with NASH and HT and 52 patients with isolated NASH were examined. Plasma kallistatin, IL-10, IL-1β and hsCRP levels were evaluate using ELISA. The results were statistically processed with the ROC analysis, the area under ROC curve (AUC), sensitivity (SE) and specificity (SP) were determined. ResultsKallistatin showed excellent diagnostic characteristics for LF development and progression risk determination in patients with NASH and HT (AUC=0.975, p=0.003, SE=95%, SP=100%; AUC=0.881, p<0.001; SE=95%, SP=76.9%) and isolated NASH (AUC=0.867, p<0.001); SE=76.5%, SP=81.0%; AUC=0.889, p<0.001, SE=92.3%, SP=81.3%). Interleukins showed good diagnostic characteristics for LF development risk in both groups (IL-10: AUC=0.769, p=0.012, SE=70%, SP=64.1%; AUC=0.710, p=0.009, SE=94.4%, SP=69.2%, IL 1β: AUC=0.752, p=0.02, SE=71.8%, SP=75.0%, AUC=0.788, p=0.007, SE= 84.6%, SP=66.7%), hsCRP showed diagnostical potential only in NASH and HT patients (AUC=0.849, p<0.001, SE=71.8%; SP=75.0%). Simultaneous evaluation of all biomarkers showed excellent and very good diagnostic characteristics for LF development and progression risk determination in NASH and HT patients (AUC=1.000, SE=100%, SP=100%, p=0.002; AUC=0.874, SE=82.1%, SP=85.0%, p<0.001) and isolated NASH group (AUC=0.874, SE=94.1%, SP=71.4%, p<0.001; AUC=0.889, SE=84.6%, SP=94.4%, p<0.001). ConclusionsThis allows us to offer kallistatin, IL-10, IL-1β, and hsCRP combination for LF identification in patients with NASH and HT.

The Relationship between Obesity-Related Factors and Graves' Orbitopathy: A Pilot Study.

Background and Objectives: The aim of this study was to investigate the relationships between obesity-related factors including body mass index (BMI), diabetes or prediabetes, hyperlipidemia, fasting plasma glucose, fasting plasma insulin, homeostasis model assessment-estimated insulin resistance (HOMA-IR), highly sensitive C-reactive protein (hs-CRP) and Graves' orbitopathy (GO). Materials and Methods: Eighty-four patients with Graves' disease (GD) (42 without GO and 42 with GO) were enrolled in this cross-sectional cohort study. Gender, age, GD treatment history, height, body weight, waist circumference, smoking status, co-morbidities, levels of free thyroxin, thyroid-stimulating hormone, thyroid-stimulating hormone receptor (TSHR) antibodies, fasting plasma glucose and insulin, and hs-CRP were recorded. The eye condition was evaluated using the consensus statement of the European Group of Graves' Orbitopathy (EUGOGO) and the NOSPECS classification. Results: In this study, multivariate regression analysis showed that BMI, fasting plasma insulin, and HOMA-IR were associated with the presence of GO after adjusting the age, gender, smoking, TSHR antibodies, and steroid usage (adjusted odd's ratio (aOR) 1.182, 95% confidence interval (95% CI), 1.003-1.393, p = 0.046; aOR 1.165, 95% CI, 1.001-1.355, p = 0.048; and aOR 1.985, 95% CI, 1.046-3.764, p = 0.036, respectively). In addition, BMI, fasting plasma glucose, fasting plasma insulin, HOMA-IR, and hs-CRP levels were positively correlated with the severity of GO. Conclusions: The findings of this study suggest that obesity-related factors, especially fasting plasma insulin and HOMA-IR, are related to GO. Our study highlighted the importance of obesity-related factors in GO. Obesity-related factors may cause the development of GO or occur simultaneously with GO.

Predictive Value of the HEART Score Combined with Hypersensitive C-Reactive Protein for 30 d Adverse Cardiovascular Events in Patients with Acute Chest Pain.

This study aimed to explore the predictive value of the HEART score combined with hypersensitive C-reactive protein (hs-CRP) for 30 d major adverse cardiovascular events (MACEs) in patients with acute chest pain. 103 patients with acute chest pain admitted to the emergency department of our hospital from May 2020 to May 2022 were selected as the study subjects. The patients' HEART score and plasma hs-CRP level were recorded. The patients were followed up for 30 d to observe whether MACE occurred. Among 103 patients with acute chest pain, MACE occurred in 8 cases within 30 d of follow-up, and the probability of MACE was 7.76%. There was a statistically significant difference in 30 d MACE risk among patients with different HEART score stratification (P < 0.05). The age, HEART score, and hs-CRP levels of patients in the MACE group were higher than those in the non-MACE group (P < 0.05). The HEART score and the hs-CRP level were independent risk factors for 30 d MACE in patients with acute chest pain (P < 0.05). The AUC of the HEART score combined with hs-CRP in the occurrence of 30 d MACE in patients with acute chest pain was 0.901, which was significantly higher than 0.720 and 0.758 of single detection. The HEART score combined with hs-CRP can better predict the occurrence of 30 d MACE in patients with acute chest pain.

RF16 | PSUN159 Poor Diet Habits, Depression and Low Physical Activity Correlate with Cardiometabolic Risk Markers in Persons with Severe Mental Illness on Second-Generation Antipsychotic Medications.

Abstract Cardiovascular morbidity and mortality are high in persons with severe mental illness. Psychotropic medications, particularly second-generation antipsychotics (SGA), and also adverse health behaviors are mediators of adverse cardiometabolic health outcomes in persons with severe mental illness. Identifying and addressing specific risk factors early and aggressively is key to improving health outcomes in these patients; yet studies addressing the above problems are limited. We therefore evaluated 39 patients with schizophrenia, schizoaffective, or bipolar disorder on SGA in a comprehensive cardiometabolic, lifestyle, and mental health screening program. Data were analyzed using SPSS version 24. As previously reported, the majority of screened patients had prediabetes (PD) or diabetes mellitus (DM), 74% per oral Glucose Tolerance Testing (oGTT), 56% per HbA1c criteria. Pulse rates, insulin resistance indices (Homeostatic Model Assessment of Insulin Resistance, HOMA IR, and Matsuda) were significantly different between patients classified as normal or with PD/DM, using either oGTT or HbA1c criteria. However, patients with PD/DM per HbA1c, but not oGTT criterium, also had higher waist/hip ratios (p=0.01), triglyceride (p=0.01) and hsCRP levels (p=0.04) as well as lower HDL levels (p=0.04). We then determined whether dietary habits (by UK Diabetes and Diet Questionnaire, UKDDQ), mood (by Patient Health Questionnaire, PHQ-9) and/or physical activity (average daily step count) were associated with unfavorable, and potentially modifiable cardiometabolic biomarkers (fasting, 2h-oGTT plasma glucose, serum insulin, triglycerides, HDL, LDL, HbA1c, hsCRP and adiponectin). We find that fasting plasma glucose and triglyceride levels significantly correlated with UKDDQ scores (fasting plasma glucose: r=0.34, p=0.03, fasting triglyceride levels: r=0.37, p=0.02); a trend was observed for higher insulin resistance indices (HOMA IR) being associated with higher UKDDQ scores (r=0.31, p=0.06). We also confirm a strong negative correlation of the average daily step count with hsCRP levels (r=-0.62, p&amp;lt;0.0001). PHQ-9 scores negatively correlated with adiponectin levels (r=-0.475, p&amp;lt;0.005). Altogether, in our patient population with severe mental illness on SGA, unhealthy diet habits, low physical activity, and symptoms of depression were associated with higher fasting glucose and triglycerides, higher hsCRP and lower adiponectin levels, all of which may potentially contribute to adverse cardiometabolic outcomes. Future studies should assess the impact of specifically tailored individual lifestyle counseling and medical management interventions in this high-risk patient population. Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m., Sunday, June 12, 2022 1:06 p.m. - 1:11 p.m.

Does arterial stiffness progression temporally precede higher low-grade inflammation in adolescents? Causal longitudinal evidence using auto-regressive cross-lagged structural equation models

Abstract Background Arterial stiffness, a precursor of arteriosclerosis, measured using carotid-femoral pulse wave velocity (cfPWV) is a strong predictor of cardiovascular morbidity and mortality in adults. Emerging evidence among adolescents, young adults, and middle-aged adults suggest that arterial stiffness may predict the risk of hypertension, obesity, insulin resistance, and the onset of type 2 diabetes and could be a causal risk factor for these diseases. However, it is unknown whether higher arterial stiffness temporally precedes elevated inflammation in the young population or if there is a bi-directional relationship. This evidence is crucial to developing interventions for attenuating arterial stiffness in early life. Purpose To examine the temporal causal longitudinal associations between repeated measures of cfPWV and high sensitivity C-reactive protein (hsCRP). Methods We studied 3862 adolescents, aged 17.7 years, followed-up for 7 years, from Avon Longitudinal Study of Parents and Children, birth cohort, UK. Fasting plasma hsCRP was assessed at 17.7 and 24.5-year clinic visits. In the same clinic visits, cfPWV was computed from pressure waveforms obtained using the Vicorder device (Skidmore Medical, Bristol, UK), 5 minutes after participants rested in a semi-prone position, with 2 blood pressure measurement channels and 2 Velcro pressure sensor cuffs applied over each of the carotid and femoral arteries. The assessment was repeated until three readings that were within 0.5 m/s of each other were recorded. We conducted autoregressive cross-lagged structural equation model path analyses to untangle temporal associations. We adjusted for sex, time in years between ages 17.7 and 24.5 years, age, low-density lipoprotein cholesterol, insulin, triglyceride, high-density lipoprotein cholesterol, fasting blood glucose, systolic blood pressure, heart rate, dual-energy Xray absorptiometry measured total fat mass and lean mass, ActiGraph measured moderate to vigorous physical activity at 15.5 years, smoking status, and family history of cardiovascular and metabolic diseases. Results Among 3862 adolescents (55.5% female), median (IQR) hsCRP at 17.7 and 24.5 years were 0.56 (0.98) mg/L and 0.84 (1.62) mg/L, respectively. The median (IQR) cfPWV at 17.7 and 24.5 years were 5.79 (0.66) m/s and 6.12 (1.12) m/s, respectively. Higher hsCRP at age 17.7 years was associated with higher cfPWV [Standardized β = 0.058, standard error = 0.004, p=0.037] at age 24.5 years. However, higher cfPWV at age 17.7 years was not associated with higher hsCRP [β = 0.023, standard error = 0.243, p=0.341] at 24.5 years. Conclusion We observed that elevated low-grade inflammation in adolescence may temporally cause higher arterial stiffness 7 years later, but not vice versa. Clinical and public health interventions targeted at reducing low-grade inflammation to regress the development of arteriosclerotic cardiovascular disease before mid-adulthood are needed. Funding Acknowledgement Type of funding sources: Private grant(s) and/or Sponsorship. Main funding source(s): Finnish Cultural Foundation

Temporal causal longitudinal associations of high-sensitivity C-reactive protein with carotid intima-media thickness progression in adolescents: the ALSPAC birth cohort study

Abstract Background The causal role of high-sensitivity C-reactive protein (hsCRP) in the evolution of preclinical cardiovascular disease remains unclear. A previous longitudinal study concluded that hsCRP measured in childhood was not associated with a single measure of carotid intima-media thickness (cIMT) assessed at mid-adulthood. The use of hsCRP samples stored for 25 years prior to analysis might have confounded this previous findings. In the young population of adolescents and young adults no study has investigated whether elevated hsCRP temporally precedes higher cIMT or if bi-directional associations exist, due to the lack of repeated measures of cIMT. Purpose To examine the temporal causal longitudinal associations between repeated measures of cIMT and hsCRP in a young population. Methods We studied 3862 adolescents, aged 17.7 years, followed-up for 7 years, from Avon Longitudinal Study of Parents and Children, birth cohort, UK. Fasting plasma hsCRP was assessed at age 17.7 and 24.5-year clinic visits. cIMT from the right and left common carotid arteries at 17 years was assessed by ultrasound using a linear 12-MHz transducer (Vivid7, GE Medical, Chicago, Illinois) and cIMT from the right and left common carotid arteries at 24 years was measured using an ultrasound machine (CardioHealth Panasonic and a 13.5 MHz linear array broadband transducer (probe; centre frequency 9.0 MHz). We conducted autoregressive cross-lagged structural equation model path analyses to untangle temporal and bi-directional associations. We adjusted for sex, time in years between ages 17.7 and 24.5 years, age, low-density lipoprotein cholesterol, insulin, triglyceride, high-density lipoprotein cholesterol, fasting plasma glucose, systolic blood pressure, heart rate, dual-energy Xray absorptiometry measured total fat mass and lean mass, ActiGraph measured moderate to vigorous physical activity at 15.5 years, smoking status, and family history of cardiovascular and metabolic diseases. Results Among 3862 adolescents (55.5% female), median (IQR) hsCRP values at 17.7 and 24.5 years were 0.56 (0.98) mg/L and 0.84 (1.62) mg/L, respectively. The median (IQR) cIMT values at 17.7 and 24.5 years were 0.48 (0.05) mm and 0.54 (0.09) mm, respectively. Higher hsCRP at age 17.7 years was associated with cIMT [Standardized β = 0.062, standard error = 0.004, p=0.035] at age 24.5 years. However, higher cIMT at age 17.7 years was not associated with higher hsCRP [β = −0.014, standard error = 0.284, p=0.523] at 24.5 years. Conclusion These findings in the largest adolescent population to date suggest that higher inflammation in adolescence temporally precede higher carotid thickness 7 years later and there was no bi-directional relationship. Clinical and public health interventions targeted at reducing low-grade inflammation to potentially attenuate the development of atherosclerotic cardiovascular disease in the young population are warranted. Funding Acknowledgement Type of funding sources: Private grant(s) and/or Sponsorship. Main funding source(s): Finnish Cultural Foundation

Association of higher plasma leptin levels with HOMA-IR index, high sensitivity C-reactive protein and glycolipid metabolism in patients with chronic schizophrenia: A multi-center cross-sectional study.

BackgroundPrevious research has revealed that plasma leptin levels were closely related to glycolipid metabolism in schizophrenic patients. Insulin resistance (IR) and high sensitivity C-reactive protein (hs-CRP) were involved in glucolipid metabolism disorders. This study explored the correlation between plasma higher leptin levels, homeostasis model assessment of insulin resistance (HOMA-IR) index, hs-CRP and glycolipid metabolism in patients with chronic schizophrenia (CS).Methods322 subjects were enrolled, and the psychopathological symptoms of each patient were assessed by a 30-item Positive and Negative Syndrome Scale (PANSS−30). Patients' plasma leptin levels were measured by enzyme-linked immunosorbent assay (ELISA). Fasting blood glucose (FBG) levels were determined by oxidase method. Insulin levels were tested by electrochemiluminescence, and hs-CRP levels were tested by immunoturbidimetry. IBM SPSS 22.0 was used for data analysis.ResultsCompared to the lower leptin group, patients in the higher leptin group had significantly higher body mass index (BMI), total cholesterol (TC), triglycerides (TG), low-density lipoprotein (LDL-C), insulin, HOMA-IR and hs-CRP levels; and lower negative factor scores, cognitive factor scores, and PANSS total scores (P < 0.05). Plasma leptin levels in CS patients were positively correlated with BMI, TC, TG, LDL-C, insulin, HOMA-IR and hs-CRP levels, and were negatively correlated with gender (male = 1, Female = 2), positive factor scores, negative factor scores, cognitive factor scores and PANSS total scores. Multiple linear regression analysis revealed that gender, BMI, positive factor scores, PANSS total scores, FBG, LDL-C, insulin, HOMA-IR and hs-CRP levels were independent influencing factors of leptin levels in CS patients (P < 0.05).ConclusionGender, BMI, positive factor scores, PANSS total scores, FBG, LDL-C, insulin, HOMA-IR and hs-CRP levels were independent influencing factors of plasma leptin levels in CS patients. Plasma leptin, HOMA-IR and hs-CRP levels should be measured regularly in CS patients to prevent or treat the disorders of glucose and lipid metabolism comorbidity with schizophrenia patients in clinical diagnosis and treatment.

Omega-3 Fatty Acids for Major Depressive Disorder With High Inflammation: A Randomized Dose-Finding Clinical Trial.

Objective: This study compared the impact of 3 eicosapentaenoic acid (EPA) doses versus placebo on inflammatory biomarkers and depressive symptoms.Methods: Sixty-one unmedicated adults (75% female; 45.5 ± 13.8 years) with DSM-5 major depressive disorder (MDD), body mass index > 25 kg/m2, and plasma high-sensitivity C-reactive protein (hs-CRP) ≥ 3.0 mg/L were randomly assigned to receive EPA 1 g/d, 2 g/d, or 4 g/d or placebo for 12 weeks. Prespecified endpoints were a ≥ 0.40 effect size decrease in plasma interleukin (IL)-6, peripheral blood mononuclear cell (PBMC) cytokines, and lipopolysaccharide-stimulated tumor necrosis factor (TNF) production. Response was defined as a ≥ 50% decrease of Inventory of Depressive Symptomatology, Clinician-Rated version (IDS-C30) scores. We compared outcomes for the 3 EPA doses versus placebo.Results: In 45 completers, only median PBMC TNF decreased at 2 g/d EPA. No EPA dose produced a ≥ 0.35 effect size reduction in plasma IL-6 or mitogen-stimulated TNF. Response rates for EPA 4 g/d were 64%, versus 40% for placebo (odds ratio [OR] = 2.63; Cohen d = 0.53), 38% for EPA 1 g/d, and 36% for EPA 2 g/d (all P > .05). EPA 4 g/d showed a significant correlation between percent decrease in plasma hs-CRP and IDS-C30 symptom reduction at 12 weeks (Spearman ρ = 0.691, P = .019).Conclusions: EPA 4 g/d demonstrated a medium effect size for response rates versus placebo. This dose may alleviate MDD in overweight individuals with elevated inflammatory markers, and change in hs-CRP may be correlated with clinical response.Trial Registration: ClinicalTrials.gov identifier: NCT02553915.

Inflammation drives residual risk in chronic kidney disease: a CANTOS substudy.

Hyperlipidaemia and inflammation jointly contribute to atherosclerotic disease. Yet, after the initiation of statin therapy, the relative contributions of these processes may differ in patient groups, such as those with and without impaired kidney function. Among 9151 stable statin-treated post-myocardial infarction patients participating in the CANTOS trial, the contributions of residual cholesterol risk and residual inflammatory risk were evaluated as determinants of recurrent major adverse cardiovascular events (MACE) and total mortality, stratified by baseline estimated glomerular filtration rate (eGFR) above or below 60 mL/min/1.73 m2 using the race agnostic CKD-EPI 2021 formula (all participants had eGFR > 30 mL/min/1.73 m2). Analyses of residual inflammatory risk focused on high-sensitivity C-reactive protein (hsCRP) and interleukin-6 (IL-6) while analyses of residual cholesterol risk focused on LDL-cholesterol (LDL-C) and non-HDL-cholesterol (non-HDL-C). Participants were followed for a period of up to 5 years (median 3.7 years). Median baseline levels of LDL-C and hsCRP were 81 mg/dL and 4.2 mg/L. Among participants with eGFR ≥ 60 mL/min/1.73 m2, increasing quartiles of plasma hsCRP, IL-6, LDL-C, and non-HDL-C all positively associated with risks of recurrent MACE [hazard ratios (HR) comparing the top to bottom quartile for hsCRP 1.45; for IL-6 2.48; for LDL-C 1.64; and for non-HDL-C 1.68] (all P < 0.0001). By contrast, among those with eGFR < 60 mL/min/1.73 m2, increasing quartiles of hsCRP and IL-6 significantly predicted recurrent MACE [HR comparing the top to bottom quartile for hsCRP 1.50 (P = 0.021); for IL-6 1.84 (P = 0.048)], whereas increasing quartiles of LDL-C and non-HDL-C did not [HR comparing the top to bottom quartile for LDL-C 1.04 (P = 0.80); for non-HDL-C 0.98 (P = 0.88)]. The predictive utility of hsCRP and IL-6 in the setting of eGFR < 60 mL/min/1.73 m2 remained significant after adjustment for a wide range of potential confounding factors including age, sex, smoking status, blood pressure, body mass index, and diabetes. For the endpoint of total mortality, both hsCRP (HR 1.77, P = 0.0021) and IL-6 (HR 2.15, P = 0.015) were significant predictors among those with eGFR < 60 mL/min/1.73 m2, whereas LDL-C (HR 0.91, P = 0.56) and non-HDL-C (HR 0.85, P = 0.31) were not. Similar effects were observed in analyses stratified by the albumin to creatinine ratio rather than eGFR. Among atherosclerosis patients with impaired kidney function already aggressively treated with statin therapy, residual inflammatory risk plays a substantial role in determining the risk of recurrent cardiovascular events. These data have implications for risk stratification of individuals with chronic kidney disease and for the development of novel agents that target inflammatory processes in this high-risk group of patients. ClinicalTrials.gov: NCT01327846.

C-reactive protein as a moderator and insulin resistance as a mediator for the association between Endothelin-1 and dysglycemia among African Americans: Jackson Heart Study

To explore high sensitivity C-reactive protein (hsCRP) as a moderator and homeostatic model assessment of insulin resistance (HOMAIR) as a mediator for endothelin-1 (ET-1)-glycemic progression association in African Americans. 1692 participants free of dysglycemia (prediabetes and diabetes) at baseline were assessed for: 1) risk ratios (RR) and 95% confidence intervals (CI) for dysglycemia by Zou's modified Poisson multivariable models; 2) moderation effect of hsCRP in a multivariable adjusted model; and 3) mediation effect of HOMAIR on dysglycemia through ET-1 by Valeri and VanderWeele's mediation approach. Compared to quartile 1 (<0.9 pg/mL) of ET-1, quartile 2 (0.9–1.2 pg/mL) was associated with higher risk of diabetes (RR = 1.19 [95% CI 1.02, 1.40]). Plasma ET-1 level and hsCRP level had a synergistic effect on risk of diabetes (RR = 1.06 [95% CI 1.02, 1.09]). The association between plasma ET-1 and dysglycemia was mediated by HOMAIR with a proportion of 47%. African Americans with higher ET-1 levels have an increased risk of glycemic progression. When hsCRP elevates, increased ET-1 facilitates diabetes. HOMAIR involved in glucose imbalance leads to dysglycemia.

Thyroid Antibody Titers and Hypothalamic-Pituitary-Thyroid Axis Activity in Levothyroxine-Treated Women With Autoimmune Subclinical Hypothyroidism Receiving Atorvastatin or Metformin.

Both metformin and statins reduce thyroid antibody titers in individuals with Hashimoto thyroiditis. The present study compared the impact of low-grade systemic inflammation and insulin resistance on levothyroxine action in subjects with this disorder. The study included 3 groups of women with autoimmune subclinical hypothyroidism matched for thyroid antibody titers and hormone levels: patients receiving atorvastatin (group A) or metformin (group B) and statin- and metformin-naïve women (group C). Over the entire study period (6 months), all individuals received levothyroxine. Titers of thyroid antibodies, as well as concentrations of thyrotropin, free thyroid hormones, prolactin, lipids, glucose, insulin, high-sensitivity C-reactive protein (hsCRP), and 25-hydroxyvitamin D were assessed at baseline and 6 months later. At baseline, the study groups differed in plasma lipids, insulin sensitivity, and hsCRP. In all groups of patients, levothyroxine decreased thyroid antibody titers, reduced thyrotropin levels and increased free thyroid hormone levels. Treatment-induced changes in antibody titers and free thyroid hormone levels were strongest in group A, while the changes in thyrotropin were most pronounced in group B. The decrease in antibody titers correlated to a greater degree with hsCRP levels than with insulin sensitivity. The obtained results suggest that low-grade systemic inflammation is a more important factor determining the impact of levothyroxine on thyroid autoimmunity and thyroid hormone levels than insulin resistance.

Association Between Baseline C-Reactive Protein and the Risk of Lung Cancer: A Prospective Population-Based Cohort Study.

In this prospective population-based cohort study, we found an association between higher plasma hsCRP and an increased risk of developing lung cancer, with stronger associations observed among nonobese participants.

Reduced leukocyte mitochondrial copy number in metabolic syndrome and metabolically healthy obesity.

ObjectiveThis study aimed to investigate the associations between peripheral blood leukocyte mitochondrial copy number, metabolic syndrome, and adiposity-related body composition phenotypes in a high prevalence population.MethodsA single center cross-sectional study was conducted, consisting of 521 middle-aged subjects of Maltese-Caucasian ethnicity. Participants were stratified according to the presence of metabolic syndrome and different metabolic health definitions based on NCEP-ATP III criteria. Relative leukocyte mitochondrial DNA copy number was determined by quantitative polymerase chain reaction and corrected for leukocyte and platelet count. The associations between mitochondrial copy number and metabolic syndrome components was evaluated and adjusted for age and gender.ResultsSignificant negative correlations between mtDNA copy number and BMI, waist circumference, triglyceride levels, fasting plasma glucose, HbA1c, HOMA-IR and hsCRP were observed, along with a positive correlation with HDL-C levels. Mitochondrial copy number was lower in individuals with metabolic syndrome. When compared to metabolically healthy normal weight subjects, a reduction in mtDNA copy number was observed in both the metabolically healthy and unhealthy obese categories.ConclusionOur data supports the association between reduced leukocyte mtDNA copy number, obesity, and metabolic syndrome. This investigation expands on the spectrum of associations between mtDNA copy number and metabolic phenotypes in different populations and underpins the role of mitochondrial dysfunction in the development and progression of metabolic syndrome and its components.