Janus kinase (JAK) inhibitors are an effective treatment option in rheumatoid arthritis and other autoimmune diseases. However, the use of JAK inhibitors is associated with increased total cholesterol, LDL cholesterol, triglycerides, and creatinine kinase, reducing the net clinical benefit of using them. Adding Rho-associated protein kinase (ROCK) inhibition to JAK inhibition might provide cardioprotection as ROCK inhibitors have been shown to reduce vascular inflammation, improve endothelial function, and prevent cardiac remodelling in preclinical models. In this study we investigated CPL409116 (hereafter referred to as CPL'116), a novel dual JAK and ROCK inhibitor, in patients with rheumatoid arthritis with inadequate response to methotrexate, to assess dose-dependent effects on disease control, pharmacokinetics, and laboratory abnormalities among other safety events.

This phase 2, randomised, double-blind, dose-ranging, placebo-controlled, parallel group trial enrolled patients aged 18-75 years at nine hospitals or clinics in Poland and Ukraine. Main inclusion criteria were a documented diagnosis of adult-onset, moderate-to-severe rheumatoid arthritis for at least 6 months before screening, and inadequate response to current methotrexate treatment (oral or injected 15-25 mg once weekly, or ≥10 mg once weekly if reduced due to side-effects or intolerance). Participants were randomly assigned via an interactive web response system (1:1:1:1, block size of four, stratified by age) to oral CPL'116 (60 mg, 120 mg, or 240 mg) or placebo twice daily for 12 weeks, with continuation of background methotrexate. The primary endpoint of the study was the change from baseline in Disease Activity Score based on 28 joints and C-reactive protein (DAS28-CRP) at week 12, analysed with a mixed-effects repeated measures model by a modified intention-to-treat approach. p values were nominal. Safety parameters including adverse events, vital functions, and laboratory results were closely monitored and reported for the safety analysis population, comprising all participants who received at least one dose of CPL'116 or placebo. People with lived experience were not involved in the study. The trial was registered with ClinicalTrials.gov, NCT05374785, and is completed.

Between May 30, 2022, and Feb 7, 2024, 106 patients were randomly assigned (27 in the CPL'116 60 mg group, 25 in the 120 mg group, 26 in the 240 mg group, and 28 in the placebo group). Overall mean age was 54·4 years (SD 10·5); 79 (75%) of 106 participants were women and 27 (25%) were men, and all individuals self-reported as White. The least squares mean difference in the change from baseline in DAS28-CRP at 12 weeks with CPL'116 versus placebo was -0·15 (95% CI -0·81 to 0·52; p=0·67) for the 60 mg dose; -0·56 (-1·25 to 0·12; p=0·10) for the 120 mg dose; and -0·89 (-1·56 to -0·22; p=0·010) for the 240 mg dose. Thus the primary endpoint was met for the 240 mg dose only. Overall CPL'116 was well tolerated. Two participants had serious treatment-emergent adverse events (one in the 60 mg dose group [non-fatal non-ST-elevation myocardial infarction, deemed possibly related to CPL'116] and one in the 240 mg dose group [non-muscle invasive bladder cancer, deemed unrelated to CPL'116]); both events led to discontinuation of CPL'116. CPL'116 was also discontinued due to leukopenia which was deemed to be possibly related to CPL'116 in one participant who received the 240 mg dose. No severe adverse events or deaths were reported. No laboratory or haematology abnormalities were recorded at any CPL'116 dose.

The findings of this study suggest a dose-dependent response with CPL'116, with significant efficacy at the high dose of 240 mg twice daily. The drug was generally well tolerated and was not associated with lipid abnormalities or creatinine kinase increase. These findings warrant further investigation in larger studies and different clinical settings.

Celon Pharma and the National Centre for Research and Development (Poland).

Individuals suffering from acute COVID-19 (AC) often develop long COVID-19 (LC) syndrome that is associated with aberrant levels of lipoproteins and inflammatory mediators. Yet, these dysregulations are heterogenous due to the uncertain prevalence and require a more extensive characterization.

This study aimed to investigate LC-associated dysregulations in inflammatory mediators and lipids by longitudinal Nuclear Magnetic Resonance (NMR) lipoprotein analysis and cytokine profiling in human blood.

We quantitatively profiled lipoproteins and inflammatory parameters in LC patients at 5 (n = 95), 9 (n = 73), 12 (n = 95), 16 (n = 78), and 20 (n = 85) months post AC by in vitro diagnostics research (IVDr)-based NMR spectroscopy. Simultaneously, we assessed inflammatory meditators with a 13-plex cytokine panel by flow cytometry. We then compared the lipoprotein profiles with historical data from AC (N = 307) and healthy cohorts collected before the COVID-19 pandemic (N = 305), whereas the cytokine profiles were correlated with that of the AC cohort.

We identified 31 main and 80 significantly altered subclass lipoproteins, respectively. LC was associated with higher serum levels of very low-density, intermediate-density, low-density, high-density lipoproteins, along with triglycerides, cholesterols, and apolipoprotein a-I & a-II lipoproteins compared to the healthy cohort. We also observed significantly lower concentrations of NMR-based inflammatory parameters in LC than in AC cohort, whilst proinflammatory mediators IFN-α2, IFN-γ, TNF-α, CXCL8/IL-8, IL-12p70, IL-17 A, and IL-23 displayed significantly higher concentrations in LC compared with the AC cohort. Conversely, CCL2/MCP-1, IL-6, and IL-18 were significantly higher in the AC cohort than in LC.

Our findings demonstrate a persistent hyperlipidemic phenotype in LC alongside signs of chronic inflammation and lipoprotein metabolism that vary in states of acute and chronic inflammation.

Significant associations exist between major depressive disorder (MDD), metabolic syndrome (MetS), and cardiovascular disease, potentially attributable to heightened atherogenicity. This study aimed to ascertain if MDD, depression severity, suicidal behaviors, and neuroticism associate with elevated pro-atherogenic indices and reduced anti-atherogenic indices, including a reverse cholesterol transport (RCT) index.

This study comprised 34 healthy controls and 33 MDD patients without MetS, and 35 controls and 31 MDD patients with MetS. It assessed total cholesterol (TC) and free cholesterol (FC), high-density lipoprotein cholesterol (HDLc), low-density lipoprotein cholesterol (LDLc), triglycerides (TG), apolipoprotein (ApoA), ApoB, cholesterol esterification rate, and a RCT composite.

No significant associations between MDD and lipids were seen in the total study group that combined individuals with and without MetS. In individuals devoid of MetS, MDD is significantly correlated with (a) elevated FC, TG, ApoB, Castelli risk index 1, and ApoB/ApoA, and (b) diminished HDLc, ApoA, and RCT index. In individuals without MetS, there are notable correlations between the severity of depression, suicidal tendencies, neuroticism, and ApoB/ApoA, Castelli risk, and RCT indices.

The link between lipids and MDD features cannot be adequately estimated by combining participants with and without MetS. It should be examined in a study sample that excludes subjects with MetS. The depression phenome, suicidal behaviors, and neuroticism correlate with diminished RCT and heightened atherogenicity, which are likely implicated in the pathophysiology of MDD. Increased atherogenicity and lowered RCT may represent novel drug targets for the treatment and prevention of MDD, neuroticism, and suicidal behaviors.

Participants with CAD (n = 723) had 12% higher mean relative levels of nHDLox compared with those with invasively excluded CAD (n = 502, P < 0.001). Patients presenting with symptoms of an ACS had the highest nHDLox values when compared with the elective cohort (median 1.35, IQR 0.97 to 1.85, P < 0.001). In multivariate analysis adjusted for age, sex, body mass index, and hypertension, nHDLox was a strong independent predictor of ACS (P < 0.001) but not of CAD (P > 0.05).

HDL antioxidant function is reduced in patients with CAD. nHDLox is strongly associated with ACS.

German Clinical Trials Register DRKS00014037.

Brandenburg Medical School Theodor Fontane, the BIOX Stiftung, and NIH grants R01AG059501 and R03AG059462.

High-density lipoprotein (HDL) function rather than its concentration plays an important role in the pathogenesis of coronary artery disease (CAD). The aim of the present study was to determine whether reduced antioxidant function of HDL is associated with the presence of a stable CAD or acute coronary syndrome (ACS).

HDL function was measured in 2 cohorts: 1225 patients admitted electively for coronary angiography and 196 patients with ACS. A validated cell-free biochemical assay was used to determine reduced HDL antioxidant function, as assessed by increased HDL-lipid peroxide content (HDLox), which was normalized by HDL-C levels and the mean value of a pooled serum control from healthy participants (nHDLox; unitless). Results are expressed as median with interquartile range (IQR).

Rheumatoid arthritis (RA) and atherosclerosis share many common inflammatory pathways. We studied whether a multi-biomarker panel for RA disease activity (MBDA) would associate with changes in arterial inflammation in an interventional trial.

In the TARGET Trial, RA patients with active disease despite methotrexate were randomly assigned to the addition of either a TNF inhibitor or sulfasalazine+hydroxychloroquine (triple therapy). Baseline and 24-week follow-up [18F]fluorodeoxyglucose-PET/CT scans were assessed for change in arterial inflammation measured as the maximal arterial target-to-blood background ratio of FDG uptake in the most diseased segment of the carotid arteries or aorta (MDS-TBRmax). The MBDA test, measured at baseline and weeks 6, 18 and 24, was assessed for its association with the change in MDS-TBRmax.

Interpretable scans were available at baseline and week 24 for 112 patients. The MBDA score at week 24 was significantly correlated with the change in MDS-TBRmax (Spearman's rho = 0.239; P = 0.011) and remained significantly associated after adjustment for relevant confounders. Those with low MBDA at week 24 had a statistically significant adjusted reduction in arterial inflammation of 0.35 units vs no significant reduction in those who did not achieve low MBDA. Neither DAS28-CRP nor CRP predicted change in arterial inflammation. The MBDA component with the strongest association with change in arterial inflammation was serum amyloid A.

Among treated RA patients, achieved MBDA predicts changes in arterial inflammation. Achieving low MBDA at 24 weeks was associated with clinically meaningful reductions in arterial inflammation, regardless of treatment.

Hypertension is a prevalent chronic non-communicable disease associated with cardiovascular issues, strokes, kidney disorders, and depression. Most hypertensive patients have dyslipidemia and metabolic abnormalities. The non-high-density lipoprotein to high-density lipoprotein cholesterol ratio (NHHR) is a novel index that more accurately assesses the risk of atherosclerotic cardiovascular diseases and metabolic issues like insulin resistance. The association between NHHR and hypertension prevalence is still unclear. The study aims to examine the link between NHHR and hypertension prevalence in American adults. N10,410 adults from the National Health and Nutrition Examination Survey (NHANES) (2005-2016) were included in this cross-sectional analysis. Multivariable logistic regression constructed to analyze the relationship between NHHR and hypertension, with additional analyses including restricted cubic spline regression (RCS), threshold and saturation effect analyses, effect point calculations, subgroup analyses, and sensitivity analyses. Machine learning methods combined with the Boruta algorithm were employed to identify key predictors of hypertension risk. Of the 10,410 participants, 48% were male, with a hypertension prevalence of 37.03%. NHHR was higher in hypertensive patients compared to non-hypertensive individuals (2.74 vs 2.90, P < .001). In models that were completely confounded with factors including general demographic data, BMI, smoking status, alcohol consumption, diabetes, total cholesterol, history of coronary heart disease, LDL, and dietary cholesterol, NHHR showed a significant positive correlation with hypertension prevalence. RCS regression indicated a non-linear relationship, with a saturation effect point at 3.058. Subgroup analyses showed significant interactions by race and education level (P < .05). Machine learning models demonstrated AUCs > 0.8, affirming the importance of NHHR in predicting hypertension. NHHR levels are significantly elevated in hypertensive individuals compared to non-hypertensive adults in the U.S. Furthermore, a non-linear positive correlation exists between NHHR and hypertension risk, suggesting its potential as a predictive biomarker for early hypertension prevention.

Background/Objectives: In hemodialysis (HD), inflammatory biomarkers are discussed as prognostic markers for survival and cardiovascular events (CVEs). The results of the studies are not uniform and there are particularities related to population groups and comorbidities. In addition, it is known that inflammation determines protein malnutrition and less about the effect of adipose tissue on inflammation in HD. This study investigates the relationship between inflammatory molecules and nutritional biomarkers, and CVE and survival in HD patients. Methods: We included, in an observational, longitudinal study, 65 patients with chronic HD (53 without diabetes and 22 smokers), with a mean age of 60.1 ± 12.4 years. High-sensitivity C-reactive protein (hs-CRP), interleukin 1 beta, tumor necrosis factor alpha (TNF-alpha), interleukin 6, soluble tumor necrosis factor-like weak inducer of apoptosis (sTWEAK), soluble CD163 (sCD163), and fibroblast growth factor 21 were determined. We recorded survival and cardiovascular events for 60 months. Univariate and multivariate analyses were performed. Results: Hs-CRP was significantly associated with survival (p = 0.014) in the total group. In smokers and former smokers, TNF-α lower than 368.34 pg/mL was associated with better survival. In multivariate analysis, hs-CRP was correlated with adipose tissue biomarkers (p = 0.006), and sCD163 was correlated with total and LDL cholesterol (p = 0.002). In addition, in univariate analysis, sTWEAK was correlated with serum albumin (p = 0.026, r = -0.30). In conclusion, in HD patients, hs-CRP was significantly associated with survival, and low TNF-alpha values in smokers and former smokers were linked to better survival. Hs-CRP was also correlated with adipose tissue biomarkers, CD163 was correlated with total and LDL cholesterol, and albumin was inversely associated with sTWEAK. The relation between inflammatory molecules and adipose tissue biomarkers was less identified in HD patients until now.

Epidemiological studies have revealed that patients with higher levels of high-density lipoprotein cholesterol (HDL-C) were more resistant to cardiovascular diseases (CVD), and yet targeting HDL for CVD prevention, risk assessment, and pharmacological management has not proven to be very effective. The mechanistic investigations have demonstrated that HDL exerts anti-atherogenic functions via mediating reverse cholesterol transport, antioxidant action, anti-inflammatory activity, and anti-thrombotic activity. Contrary to expectations, however, adverse cardiovascular events were reported in clinical trials of drugs that raised HDL levels. This has sparked a debate between HDL quantity and quality. Patients with atherosclerotic CVD are associated with dysfunctional HDL, and the degree of HDL dysfunction is correlated with the severity of the disease, independent of HDL-C levels. This growing body of evidence has underscored the need for integrating HDL functional assays in clinical practice for CVD risk management. Because HDL exerts diverse athero-protective functions, there is no single method for capturing HDL functionality. This review critically evaluates the various techniques currently being used for monitoring HDL functionality and discusses key structural changes in HDL indicative of dysfunctional HDL and the technical challenges that need to be addressed to enable the integration of HDL function-based metrics in clinical practice for CVD risk estimation and the development of newer therapies targeting HDL function.

Heart failure (HF) is a heterogeneous clinical syndrome affecting a growing global population. Due to the high incidence of cardiovascular risk factors, a large proportion of the Western population is at risk for heart failure. Oxidative stress and inflammation play a crucial role in the pathophysiology of heart failure with preserved ejection fraction (HFpEF). While previous studies have demonstrated an association between dysfunctional HDL and heart failure, the specific link between oxidized HDL and HF remains unexplored.

In this cross-sectional observational study, the antioxidant function of HDL was assessed in 366 patients with suspected heart failure. HFpEF assessment was conducted according to current guidelines. A validated cell-free biochemical assay was used to determine reduced HDL antioxidant function as assessed by increased HDL-lipid peroxide content (HDLox), normalized by HDL-C levels and the mean value of a pooled serum control from healthy participants (nHDLox; no units). Results were expressed as median with interquartile range (IQR).

Participants with HFpEF (n = 88) had 15% higher mean relative levels of nHDLox than those without heart failure (n = 180). Using a basic multivariate model adjusted for age, sex, eGFR and a full multivariate model (adjusted for diabetes, hypertension, atrial fibrillation, LDL cholesterol, hsCRP, and coronary artery disease), nHDLox was an independent predictor for HFpEF (p < 0.05). An increase in 1-SD in nHDLox was associated with a 67% increased risk for HFpEF if compared with participants without heart failure (p = 0.02).

HDL antioxidant function is reduced in patients with HFpEF. Improving HDL function is a promising target for early heart failure treatment.

Insulin resistance (IR) and metabolic syndrome (MetS) are significant global health challenges that increase the risk of various chronic diseases. The lymphocyte-to-high-density lipoprotein cholesterol ratio (LHR) has emerged as a novel inflammatory metabolic marker. The present study focused on evaluating the association between the LHR and both IR and MetS.

We analyzed data from 14,779 adults aged ≥ 20 years from the National Health and Nutrition Examination Survey (2007-2018). To investigate the relationship between LHR and both IR and MetS, we conducted multivariable logistic regression analyses. The reliability of the results was validated through both stratified and sensitivity analyses. Furthermore, we thoroughly examined possible nonlinear associations by implementing a restricted cubic spline in conjunction with a threshold effect analysis.

Compared to the lowest LHR quartile, individuals in the highest quartile indicated significantly increased prevalence of IR (odds ratio = 3.72, 95% confidence intervals: 3.01-4.59) and MetS (odds ratio = 11.38, 95% confidence intervals: 8.85-14.63) in fully adjusted models. Subgroup analyses demonstrated that the association between the LHR and IR remained consistent across all subgroups, with no significant interaction effect observed. However, the association between LHR and MetS was more pronounced in female participants. Restricted cubic spline analyses revealed nonlinear associations between LHR and both IR and MetS. The threshold effect analyses identified inflection points at 0.055 for these non-linear relationships.

An elevated LHR was positively associated with the prevalence of IR and MetS, indicating its promising role in early screening and disease prevention through biological monitoring.

To investigate serum lipid profile in early, treatment-naïve psoriatic arthritis (PsA) and to determine whether changes in classical lipids or apolipoproteins are specific to PsA.

Total cholesterol, non-high-density lipoprotein cholesterol (non-HDL-c), low-density lipoprotein cholesterol (LDL-c), HDL-c, triglycerides, apolipoprotein B (ApoB) and apolipoprotein A1 (ApoA1) were compared in newly diagnosed untreated PsA patients (n=75) to sex- and age-matched controls (healthy control (HC)) (n=61) and early untreated rheumatoid arthritis (RA) patients (n=50).

Among classical lipid measurements, HDL-c levels were lower in PsA than in HC and RA (df 2, χ210, p=0.006, PsA vs HC p=0.013). Significant differences in ApoA1 and ApoB levels were observed between PsA, RA and controls. ApoB was higher in PsA than in RA patients but lower than in controls (df2, χ243.8; p<0.001). ApoA1 was markedly lower in PsA patients compared with both RA and controls (df2, χ2118.9; p<0.001). In regression models, the levels of ApoA1, adjusted for additional factors, were predictive of PsA diagnosis with 90.6% accuracy. In receiver operating characteristic analysis, ApoA1 was predictive of the diagnosis of PsA with a specificity of 82.4% and a sensitivity of 83.8% at an optimal cut-off value of 1403 µg/mL (area under the curve (95% CI), 0.886 (0.83 to 0.941)).

Early, treatment-naïve PsA patients exhibit a distinct pro-atherogenic lipid profile, characterised by decreased ApoA1 and increased ApoB levels, distinguishing them from early RA patients and healthy controls. These findings highlight the potential of apolipoprotein measurements to serve as more accurate indicators of lipid disturbances in PsA than traditional serum lipids and as aid to diagnosis of patients presenting with early arthritis.

The anti-atherosclerotic effects of high-density lipoprotein (HDL) prevent the onset of cerebral infarction and provide cerebroprotective effects against ischemia-reperfusion injury. These inhibitory effects have been attributed to its antioxidant, anti-inflammatory, and antithrombotic properties. However, pharmacotherapeutic strategies to clinically realize these effects have not been demonstrated. Therefore, we aimed to develop paraoxonase 1 (PON1), a hydrolytic enzyme associated with HDL that exhibits antioxidant and anti-inflammatory effects, as a novel therapeutic agent against ischemia-reperfusion injury in cerebral infarction. We established a method to extract PON1 from human plasma with high purity and recovery while maintaining its activity. The purified PON1 exhibited antioxidant activity against human-derived LDL and HDL. Furthermore, PON1 actively suppressed the oxidation chain reaction by hydrolyzing lipid peroxides. The HDL-binding ability of PON1 was evaluated based on its activity in fractionated HDL from mice administered PON1 intravenously, which showed that most intravenously administered PON1 specifically bound to HDL. The cerebroprotective effect of intravenously administered PON1 was assessed using a mouse middle cerebral artery ischemia-reperfusion model by measuring infarct volume, long-term neurological scores, and walking time on a rotarod. Administration of PON1 after reperfusion reduced infarct volume 24 h after ischemia-reperfusion. Additionally, daily administration of PON1 for three days significantly improved neurological scores and walking time by approximately one month. Analysis of gene arrays in brain tissue indicated that PON1 suppresses biological functions and pathways associated with oxidative stress, inflammation, vascular dysfunction, thrombosis, and fibrosis. PON1 enhances the cerebroprotective effects of HDL and is a potential candidate for acute stroke therapy.

Japanese adults typically have healthier lipid profiles than American and European adults and a lower prevalence and later onset of atherosclerotic cardiovascular disease (ASCVD). Many Japanese also have uniquely elevated levels of high-density lipoprotein cholesterol (HDL-C). The following analysis examined the relationship between HDL-C level and HDL-C peroxide content, a bioindicator of unhealthy lipid metabolism in Japanese adults. Blood samples were collected from 463 participants, 31-84 years of age, who lived in Tokyo. A second blood sample was collected 5 years later from 241 of the participants, allowing us to evaluate the temporal stability of the inverse correlation between HDL-C level and HDL-C peroxide content. Glucoregulation and inflammatory activity were assessed because both can be associated with dyslipidemia and HDL-C dysfunction. Obesity and central adiposity were also considered. Overall, women had healthier HDL-C profiles than men. Elevated HDL-C (>90 mg/dL) was common (16.6%) and found more often in women. Higher HDL-C peroxide content was associated with older age and central adiposity and incremented further when HA1c and CRP were higher. When assessed 5 years later, lower HDL-C peroxide content continued to be evident in adults with higher HDL-C. While similar associations have been described for other populations, most Japanese adults typically had healthier levels of HDL-C with lower HDL-C peroxide content than previously reported for American adults.

Autoimmune rheumatic diseases (ARDs) exhibit an elevated incidence of cardiovascular disease (CVD). The elevation of inflammatory and immune stress accompanying ARDs contributes to atherosclerosis development and alterations in lipid metabolism and lipoprotein profile add to cardiovascular (CV) risk. The plasma concentration of high-density lipoprotein cholesterol (HDLc) is inversely related to CVD and serves as a discriminator of CV risk. However, this association is not unequivocal, and changes in HDL functionality appear to emerge as a better indicator of CV risk, albeit difficult to measure and monitor clinically. The modulation of HDLc itself can bring benefits in controlling autoimmunity and reducing ARD activity. Understanding HDL function and each peculiarity involved in ARDs enables to seek means to prevent ischemic outcomes associated with CVD, in the face of the residual CV risk persisting even with controlled disease activity and classic risk factors. By comprehending HDL's structural and functional nuances, it will be possible to develop more effective strategies to manage the evolution and outcomes of ARDs. It is also necessary to standardize diagnostic methods and establish different markers for each specific disease allowing the design of intervention strategies to restore HDL functionality, reduce residual CV, and prevent, alleviate, or even suppress ARD activity.

In rheumatoid arthritis (RA), the risk of cardiovascular death is 50% higher compared to the general population. This increased risk is partly due to the systemic inflammation characteristic of RA and changes in the lipoprotein profiles. This study investigated plasma lipid levels, lipid ratios, and the composition and functionality of high-density lipoprotein (HDL) in control individuals and RA subjects based on the disease's inflammatory score (DAS28). This study included 50 control (CTR) individuals and 56 subjects with RA, divided into remission/low-activity disease (DAS28 < 3.2; n = 13) and active disease (DAS28 ≥ 3.2; n = 43). Plasma lipids (total cholesterol, TC; triglycerides, TG) and the HDL composition (TC; TG; phospholipids, PL) were determined using enzymatic methods; apolipoprotein B (apoB) and apoA-1 were measured by immunoturbidimetry. HDL-mediated cholesterol efflux and anti-inflammatory activity were assessed in bone marrow-derived macrophages. Comparisons were made using the Mann-Whitney test, and binary logistic regression was used to identify the predictors of active RA. A p-value < 0.05 was considered significant. TC, HDLc, and the TC/apoB ratio were higher in RA subjects compared to the CTR group. Subjects with active disease exhibited higher levels of TG and the TG/HDLc ratio and lower levels of HDLc, the TG/apoB ratio, TC, and apoA-1 in HDL particles compared to those with remission/low-activity RA. Increased levels of HDLc [odds ratio (OR) 0.931, 95% CI = 0.882-0.984], TC/apoB (OR 0.314, 95% CI = 0.126-0.78), HDL content in TC (OR 0.912, 95% CI = 0.853-0.976), PL (OR 0.973, 95% CI = 0.947-1.000), and apoA-1 (OR 0.932, 95% CI = 0.882-0.985) were associated with a decreased risk of active disease, but BMI (OR 1.169, 95% CI = 1.004-1.360) and TG (OR 1.031, 95% CI = 1.005-1.057) were positively associated with active disease. A reduction in HDL-mediated cholesterol efflux increased the OR for active RA by 26.2%. The plasma levels of HDLc, along with the composition and functionality of HDL, influence the inflammatory score in RA and may affect the development of cardiovascular disease.

Cardiovascular disease through accelerated atherosclerosis is a leading cause of mortality for patients with systemic lupus erythematosus (SLE), likely due to increased chronic inflammation and cardiometabolic defects over age. We investigated age-associated changes in metabolomic profiles of SLE patients and healthy controls (HCs).

Serum NMR metabolomic profiles from female SLE patients (n = 164, age = 14-76) and HCs (n = 123, age = 13-72) were assessed across age by linear regression and by age group between patients/HCs (Group 1, age ≤ 25, n = 62/46; Group 2, age = 26-49, n = 50/46; Group 3, age ≥ 50, n = 52/31) using multiple t tests. The impact of inflammation, disease activity and treatments were assessed, and UK Biobank disease-wide association analysis of metabolites was performed.

Age-specific metabolomic profiles were identified in SLE patients vs HCs, including reduced amino acids (Group 1), increased very-low-density lipoproteins (Group 2), and increased low-density lipoproteins (Group 3). Twenty-five metabolites were significantly altered in all SLE age groups, dominated by decreased atheroprotective high-density lipoprotein (HDL) subsets, HDL-bound apolipoprotein (Apo)A1 and increased glycoprotein acetyls (GlycA). Furthermore, ApoA1 and GlycA were differentially associated with disease activity and serological measures, as well as atherosclerosis incidence and myocardial infarction mortality risk through disease-wide association. Separately, glycolysis pathway metabolites (acetone/citrate/creatinine/glycerol/lactate/pyruvate) uniquely increased with age in SLE, significantly influenced by prednisolone (increased pyruvate/lactate) and hydroxychloroquine (decreased citrate/creatinine) treatment and associated with type 1 and type 2 diabetes by disease-wide association.

Increasing HDL (ApoA1) levels through therapeutic/nutritional intervention, whilst maintaining low disease activity, in SLE patients from a young age could improve cardiometabolic disease outcomes. Biomarkers from the glycolytic pathway could indicate adverse metabolic effects of current therapies.

Rheumatoid arthritis (RA) is a chronic inflammatory disease mainly affecting the peripheral diarthrodial joints symmetrically and also presenting many extra-articular manifestations. Morbidity and mortality in RA patients are higher compared to the general population. Cardiovascular (CV) disease is one of the most common causes of death in these patients. Classical or traditional risk factors for atherosclerosis development occur more frequently in RA patients compared to those without this condition. Studies have showed that RA patients often present comorbidities such as hypertension, dyslipidemia, diabetes mellitus and obesity. However, the high incidence of CV events occurring in RA patients is not explained by the presence of traditional risk factors. Systemic inflammation, as it is expressed with the presence of proinflammatory cytokines and increased acute phase reactants, may contribute to the development of premature atherosclerosis in these patients. In this review, we explore the risk factors for CV disease, the generation of dyslipidemia, the lipid paradox and the role of systemic inflammation in the atherosclerotic process in RA. We discuss also the role of early therapeutic intervention that suppresses inflammation which may have beneficial effects on CV disease in RA patients.

This study aimed to analyze the associations between rheumatoid arthritis (RA) and all-cause mortality and cardiovascular disease (CVD)-related mortality using data from the National Health and Nutrition Examination Survey (NHANES) and examine the potential mediating role of depression in these correlations.

19,165 participants across five NHANES cycles from 2007 to 2016 participated in this study. Multifactorial Cox regression models between RA, depression and two mortality outcomes and multifactorial regression models between RA and depression were constructed to examine their associations. The mediating role of depression has also been investigated.

The prevalence of RA in this study was 6.57 %, the all-cause mortality of RA patients was 20.57 %, and the CVD-related mortality was 6.12 %. In the fully adjusted model, RA was associated with all-cause mortality [hazard ratio (HR) = 1.28, 95 % confidence interval (CI) = 1.12 to 1.48] and CVD-related mortality (HR = 1.33, 95 % CI = 1.03 to 1.72), without detectable interaction among subgroups (P for interaction >0.05). RA also had a positive correlation with depression. Depression score demonstrated pronounced mediating effects in the connections between RA and two types of mortality, with mediation ratios of 18.2 % and 18.9 %.

The diagnosis of RA is self-reported and may be subject to recall bias.

RA was positively correlated with the risk of all-cause mortality and CVD-related mortality. Depression partially mediates these associations. Close attention to and active improvement of mental health in RA patients will be critical to decrease all-cause mortality and CVD-related mortality.

Dementia is a multifactorial disease with Alzheimer's disease (AD) and vascular dementia (VaD) pathologies making the largest contributions. Yet, most genome-wide association studies (GWAS) focus on AD.

We conducted a GWAS of all-cause dementia (ACD) and examined the genetic overlap with VaD. Our dataset includes 800,597 individuals, with 46,902 and 8702 cases of ACD and VaD, respectively. Known AD loci for ACD and VaD were replicated. Bioinformatic analyses prioritized genes that are likely functionally relevant and shared with closely related traits and risk factors.

For ACD, novel loci identified were associated with energy transport (SEMA4D), neuronal excitability (ANO3), amyloid deposition in the brain (RBFOX1), and magnetic resonance imaging markers of small vessel disease (SVD; HBEGF). Novel VaD loci were associated with hypertension, diabetes, and neuron maintenance (SPRY2, FOXA2, AJAP1, and PSMA3).

Our study identified genetic risks underlying ACD, demonstrating overlap with neurodegenerative processes, vascular risk factors, and cerebral SVD.

We conducted the largest genome-wide association study of all-cause dementia (ACD) and vascular dementia (VaD). Known genetic variants associated with AD were replicated for ACD and VaD. Functional analyses identified novel loci for ACD and VaD. Genetic risks of ACD overlapped with neurodegeneration, vascular risk factors, and cerebral small vessel disease.

This prospective observational study compared the 1H NMR blood lipidomes and metabolomes of 71 patients with community-acquired pneumonia (CAP), 75 patients with COVID-19 pneumonia, and 75 healthy controls (matched by age and sex) to identify potential biomarkers and pathways associated with respiratory infections. Both pneumonia groups had comparable severity indices, including mortality, invasive mechanical ventilation, and intensive care unit admission rates. Patients with COVID-19 pneumonia exhibited more pronounced hypolipidemia, with significantly lower levels of total cholesterol and LDL-c compared to patients with CAP. Atherogenic lipoprotein subclasses (VLDL-cholesterol, IDL-cholesterol, IDL-triglyceride, and LDL-triglyceride/LDL-cholesterol) were significantly increased in severe cases of both pneumonia types, while lower HDL-c and small, dense HDL particles were associated with more severe illness. Both infected groups showed decreased esterified cholesterol and increased triglycerides, along with reduced phosphatidylcholine, lysophosphatidylcholine, PUFA, omega-3 fatty acids, and DHA. Additionally, infected patients had elevated levels of glucose, lactate, 3-hydroxybutyrate, and acetone, which are linked to inflammation, hypoxemia, and sepsis. Increased levels of branched-chain amino acids, alanine, glycine, and creatine, which are involved in energy metabolism and protein catabolism, were also observed. Neurotransmitter synthesis metabolites like histidine and glutamate were higher in infected patients, especially those with COVID-19. Notably, severe infections showed a significant decrease in glutamine, essential for lymphocyte and macrophage energy. The severity of COVID-19 pneumonia was also associated with elevated glycoprotein levels (glycoprotein A, glycoprotein B, and glycoprotein F), indicating an inflammatory state. These findings suggest that metabolomic and lipidomic changes in pneumonia are connected to bioenergetic pathways regulating the immune response.

Low levels of high-density lipoprotein-cholesterol (HDL-C) is considered a major cardiovascular risk factor. However, recent studies have suggested a more U-shaped association between HDL-C and cardiovascular disease. It has been shown that the cardioprotective effect of HDL is related to the functions of HDL particles rather than their cholesterol content. HDL particles are highly heterogeneous and have multiple functions relevant to cardiometabolic conditions including cholesterol efflux capacity, anti-oxidative, anti-inflammatory, and vasoactive properties. There are quantitative and qualitative changes in HDL as well as functional abnormalities in both type 1 and type 2 diabetes. Non-enzymatic glycation, carbamylation, oxidative stress, and systemic inflammation can modify the HDL composition and therefore the functions, especially in situations of poor glycemic control. Studies of HDL proteomics and lipidomics have provided further insights into the structure-function relationship of HDL in diabetes. Interestingly, HDL also has a pleiotropic anti-diabetic effect, improving glycemic control through improvement in insulin sensitivity and β-cell function. Given the important role of HDL in cardiometabolic health, HDL-based therapeutics are being developed to enhance HDL functions rather than to increase HDL-C levels. Among these, recombinant HDL and small synthetic apolipoprotein A-I mimetic peptides may hold promise for preventing and treating diabetes and cardiovascular disease.

Introduction Age-related macular degeneration, a chronic and progressive disease, is one of the leading causes of vision loss globally among the elderly population. Multiple hypotheses have been proposed regarding its pathogenesis, including the presence of lipid metabolism alteration. Dysfunctional lipid handling within retinal pigment epithelial cells has been implicated in the accumulation of lipofuscin and subsequent induction of oxidative stress and inflammation, all contributing to retinal degeneration. The present study aims to comparatively analyze the serum lipid fraction distributions in patients with neovascular age-related macular degeneration (AMD) and controls. Materials and methods A retrospective study was carried out between January 2021 and December 2023 on 91 naïve patients with neovascular AMD and 90 controls admitted for routine cataract surgery. All subjects underwent a comprehensive ophthalmological exam, including ophthalmoscopy and optical coherence tomography (OCT) with central macular thickness (CMT) measurement. A complete blood count with differential and lipid fractions values was analyzed. The neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and triglycerides (TG) were comparatively analyzed between the control group and the test group. Results The groups were comparable in terms of age (73.84 ±7.52 years for the neovascular AMD group vs 72.1±10.92 years in controls; p=0.8) and gender distribution (p=0.243). The mean NLR and PLR values were slightly higher in the AMD group but not statistically significant (p=0.51, p>0.99, respectively). Comparative analysis of lipid profile fractions showed significantly higher HDL-C values in the exudative AMD group compared to normal subjects (61.27±19.4 mg/dL vs 50.99±7.86 mg/dL, p=0.006). Also, the proportion of subjects with HDL-C>60 mg/dL was higher in the exudative AMD group (p=0.014). There were no significant differences in total cholesterol (189.77±53.39 mg/dL vs 190.43±37.84 mg/dL, p=0.681), LDL-C, and TG. Logistic regression analysis showed that serum HDL-C and HDL-C values >60 mg/dL are significantly associated factors with neovascular AMD. However, there is no statistical correlation between the values of these biochemical parameters and visual acuity or CMT in the neovascular AMD patient group. Conclusions There were no correlations between NLR and PLR with neovascular AMD in the study group. Higher HDL-C values exceeding 60 mg/dL were associated with neovascular age-related macular degeneration and could represent a possible therapeutic target in neovascular AMD.

High density lipoprotein (HDL) functions are mostly mediated through a complex proteome, particularly its enzymes. HDL can provide a scaffold for the assembly of several proteins that affect each other's function. HDL particles, particularly small, dense HDL3, are rich in paraoxonase 1 (PON1), which is an important enzyme in the functionality of HDL, so the antioxidant and antiatherogenic properties of HDL are largely attributed to this enzyme. There is an increasing need to represent a valid, reproducible, and reliable method to assay HDL function in routine clinical laboratories. In this context, HDL-associated proteins may be key players; notably PON1 activity (its arylesterase activity) may be a proper candidate because its decreased activity can be considered an important risk factor for HDL dysfunctionality. Of note, automated methods have been developed for the measurement of serum PON1 activity that facilitates its assay in large sample numbers. Arylesterase activity is proposed as a preferred activity among the different activities of PON1 for its assay in epidemiological studies. The binding of PON1 to HDL is critical for the maintenance of its activity and it appears apolipoprotein A-I plays an important role in HDL-PON1 interaction as well as in the biochemical and enzymatic properties of PON1. The interrelationships between HDL, PON1, and HDL's other components are complex and incompletely understood. The purpose of this review is to discuss biochemical and clinical evidence considering the interactions of PON1 with HDL and the role of this enzyme as an appropriate biomarker for HDL function as well as a potential therapeutic target.

The aim of the current study was to explore the changes in lipid and NT-proBNP levels in rheumatoid arthritis (RA) patients through different phases of the disease: from the pre-clinical stage and RA onset up to the treatment phase with biological disease-modifying anti-rheumatic drugs (bDMARDS).

Thirty-eight consecutive patients, initially with arthralgia and rheumatoid factor and/or anti-citrullinated protein antibodies without arthritis, who later developed RA and eventually started treatment with bDMARDs, were included. Lipid spectrum and N-terminal pro-brain natriuretic peptide (NT-proBNP) levels were measured longitudinally from several months before diagnosis through treatment with bDMARDs.

From baseline, C-reactive protein (CPR) initially increased sharply, decreasing with the start of biological treatment. Low-density lipoprotein-cholesterol (LDL-c) remained stable, high-density lipoprotein-cholesterol (HDL-c) increased, apolipoprotein A1 (ApoA1 and lipoprotein (a) (Lp(a)), and total cholesterol (TC)/HDL-c ratio and apolipoprotein B (ApoB) decreased during follow-up. NT-proBNP closely followed progression of CRP. TC, LDL-c, TC/HDL-c ratio, ApoA and ApoB inverse correlated with CRP, while Lp(a) positively correlated. HDL-c and triglycerides showed no correlation.

Changes in the lipid profile and NT-proBNP in RA patients seem to be related to inflammation, with changes reflecting an increase in CVD risk occurring along with rises in CRP levels. These changes seem to already be present at diagnosis, indicating the need for timely control of inflammation.

Serum amyloid A (SAA) is bound to high-density lipoproteins (HDL) in blood. Although SAA is increased in the blood of patients with asthma, it is not known whether this modifies asthma severity.

We sought to define the clinical characteristics of patients with asthma who have high SAA levels and assess whether HDL from SAA-high patients with asthma is proinflammatory.

SAA levels in serum from subjects with and without asthma were quantified by ELISA. HDLs isolated from subjects with asthma and high SAA levels were used to stimulate human monocytes and were intravenously administered to BALB/c mice.

An SAA level greater than or equal to 108.8 μg/mL was defined as the threshold to identify 11% of an asthmatic cohort (n = 146) as being SAA-high. SAA-high patients with asthma were characterized by increased serum C-reactive protein, IL-6, and TNF-α; older age; and an increased prevalence of obesity and severe asthma. HDL isolated from SAA-high patients with asthma (SAA-high HDL) had an increased content of SAA as compared with HDL from SAA-low patients with asthma and induced the secretion of IL-6, IL-1β, and TNF-α from human monocytes via a formyl peptide receptor 2/ATP/P2X purinoceptor 7 axis. Intravenous administration to mice of SAA-high HDL, but not normal HDL, induced systemic inflammation and amplified allergen-induced neutrophilic airway inflammation and goblet cell metaplasia.

SAA-high patients with asthma are characterized by systemic inflammation, older age, and an increased prevalence of obesity and severe asthma. HDL from SAA-high patients with asthma is proinflammatory and, when intravenously administered to mice, induces systemic inflammation, and amplifies allergen-induced neutrophilic airway inflammation. This suggests that systemic inflammation induced by SAA-high HDL may augment disease severity in asthma.

Cardiopulmonary bypass (CPB) is linked to systemic inflammatory responses and oxidative stress. Paraoxonase 1 (PON1) is an antioxidant enzyme with a cardioprotective role whose activity is decreased in systemic inflammation and in patients with acute myocardial and global ischemia. Glucocorticoids counteract the effect of oxidative stress by upregulating PON1 gene expression. The authors aimed to determine the effect of methylprednisolone on PON1 activity during cardiac surgery on CPB.

Prospective, randomized, controlled clinical trial.

The University Medical Center Ljubljana, Slovenia.

Forty adult patients who underwent complex cardiac surgery on CPB between February 2016 and December 2017 were randomized into methylprednisolone and control groups (n = 20 each).

Patients in the methylprednisolone group received 1 g of methylprednisolone in the CPB priming solution, whereas patients in the control group were not given methylprednisolone during CPB.

The effect of methylprednisolone from the CPB priming solution was compared with standard care during CPB on PON1 activity until postoperative day 5. Correlations of PON1 activity with lipid status, mediators of inflammation, and hemodynamics were analyzed also. No significant differences were found between study groups for PON1 activity, high-density lipoprotein, and low-density lipoprotein in any of the measurement intervals (p > 0.016). The methylprednisolone group had significantly lower tumor necrosis factor alpha (p < 0.001) and interleukin-6 (p < 0.001), as well as C-reactive protein and procalcitonin (p < 0.016) after surgery. No significant difference was found between groups for hemodynamic parameters. A positive correlation existed between PON1 and lipid status, whereas a negative correlation was found between PON1 activity and tumor necrosis factor alpha, interleukin-6, and CPB duration.

Methylprednisolone does not influence PON1 activity during cardiac surgery on CPB.

Spinal cord injury (SCI) results in a large amount of tissue cell debris in the lesion site, which interacts with various cytokines, including inflammatory factors, and the intrinsic glial environment of the central nervous system (CNS) to form an inhibitory microenvironment that impedes nerve regeneration. The efficient clearance of tissue debris is crucial for the resolution of the inhibitory microenvironment after SCI. Macrophages are the main cells responsible for tissue debris removal after SCI. However, the high lipid content in tissue debris and the dysregulation of lipid metabolism within macrophages lead to their transformation into foamy macrophages during the phagocytic process. This phenotypic shift is associated with a further pro-inflammatory polarization that may aggravate neurological deterioration and hamper nerve repair. In this review, we summarize the phenotype and metabolism of macrophages under inflammatory conditions, as well as the mechanisms and consequences of foam cell formation after SCI. Moreover, we discuss two strategies for foam cell modulation and several potential therapeutic targets that may enhance the treatment of SCI.

Cardiovascular disease remains an important comorbidity in patients with rheumatoid arthritis (RA), but traditional models do not accurately predict cardiovascular risk in patients with RA. The addition of biomarkers could improve prediction.

The TARGET (Treatments Against RA and Effect on FDG PET/CT) trial assessed whether different treatment strategies in RA differentially impact cardiovascular risk as measured by the change in arterial inflammation on arterial target to background ratio on fluorodeoxyglucose positron emission tomography/computed tomography scans conducted 24 weeks apart. A group of 24 candidate biomarkers supported by prior literature was assessed at baseline and 24 weeks later. Longitudinal analyses examined the association between baseline biomarker values, measured in plasma EDTA, and the change in arterial inflammation target to background ratio. Model fit was assessed for the candidate biomarkers only, clinical variables only, and models combining both. One hundred nine patients with median (interquartile range) age 58 years (53-65 years), RA duration 1.4 years (0.5-6.6 years), and 82% women had biomarkers assessed at baseline and follow-up. Because the main trial analyses demonstrated significant target to background ratio decreases with both treatment strategies but no difference across treatment groups, we analyzed all patients together. Baseline values of serum amyloid A, C-reactive protein, soluble tumor necrosis factor receptor 1, adiponectin, YKL-40, and osteoprotegerin were associated with significant change in target to background ratio. When selected candidate biomarkers were added to the clinical variables, the adjusted R2 improved from 0.20 to 0.33 (likelihood ratio P=0.0005).

A candidate biomarker approach identified several promising biomarkers that associate with baseline and treatment-associated changes in arterial inflammation in patients with RA. These will now be tested in an external validation cohort.

HDL (high-density lipoprotein), owing to its high protein content and small size, is the densest circulating lipoprotein. In contrast to lipid-laden VLDL (very-low-density lipoprotein) and LDL (low-density lipoprotein) that promote atherosclerosis, HDL is hypothesized to mitigate atherosclerosis via reverse cholesterol transport, a process that entails the uptake and clearance of excess cholesterol from peripheral tissues. This process is mediated by APOA1 (apolipoprotein A-I), the primary structural protein of HDL, as well as by the activities of additional HDL proteins. Tracer-dependent kinetic studies are an invaluable tool to study HDL-mediated reverse cholesterol transport and overall HDL metabolism in humans when a cardiovascular disease therapy is investigated. Unfortunately, HDL cholesterol-raising therapies have not been successful at reducing cardiovascular events suggesting an incomplete picture of HDL biology. However, as HDL tracer studies have evolved from radioactive isotope- to stable isotope-based strategies that in turn are reliant on mass spectrometry technologies, the complexity of the HDL proteome and its metabolism can be more readily addressed. In this review, we outline the motivations, timelines, advantages, and disadvantages of the various tracer kinetics strategies. We also feature the metabolic properties of select HDL proteins known to regulate reverse cholesterol transport, which in turn underscore that HDL lipoproteins comprise a heterogeneous particle population whose distinct protein constituents and kinetics likely determine its function and potential contribution to cholesterol clearance.

Copper-induced cell death, also known as cuproptosis, is distinct from other types of cell death such as apoptosis, necrosis, and ferroptosis. It can trigger the accumulation of lethal reactive oxygen species, leading to the onset and progression of aging. The significant increases in copper ion levels in the aging populations confirm a close relationship between copper homeostasis and vascular aging. On the other hand, vascular aging is also closely related to the occurrence of various cardiovascular diseases throughout the aging process. However, the specific causes of vascular aging are not clear, and different living environments and stress patterns can lead to individualized vascular aging. By exploring the correlations between copper-induced cell death and vascular aging, we can gain a novel perspective on the pathogenesis of vascular aging and enhance the prognosis of atherosclerosis. This article aims to provide a comprehensive review of the impacts of copper homeostasis on vascular aging, including their effects on endothelial cells, smooth muscle cells, oxidative stress, ferroptosis, intestinal flora, and other related factors. Furthermore, we intend to discuss potential strategies involving cuproptosis and provide new insights for copper-related vascular aging.

COVID-19, caused by the SARS-CoV-2 coronavirus, emerged as a global pandemic in late 2019, resulting in significant global public health challenges. The emerging evidence suggests that diminished high-density lipoprotein (HDL) cholesterol levels are associated with the severity of COVID-19, beyond inflammation and oxidative stress. Here, we used nuclear magnetic resonance spectroscopy to compare the lipoprotein and metabolic profiles of COVID-19-infected patients with non-COVID-19 pneumonia. We compared the control group and the COVID-19 group using inflammatory markers to ensure that the differences in lipoprotein levels were due to COVID-19 infection. Our analyses revealed supramolecular phospholipid composite (SPC), phenylalanine, and HDL-related parameters as key discriminators between COVID-19-positive and non-COVID-19 pneumonia patients. More specifically, the levels of HDL parameters, including apolipoprotein A-I (ApoA-I), ApoA-II, HDL cholesterol, and HDL phospholipids, were significantly different. These findings underscore the potential impact of HDL-related factors in patients with COVID-19. Significantly, among the HDL-related metrics, the cholesterol efflux capacity (CEC) displayed the strongest negative association with COVID-19 mortality. CEC is a measure of how well HDL removes cholesterol from cells, which may affect the way SARS-CoV-2 enters cells. In summary, this study validates previously established markers of COVID-19 infection and further highlights the potential significance of HDL functionality in the context of COVID-19 mortality.

Rheumatoid arthritis (RA) is an autoimmune inflammatory disease, of which the leading cause of death is cardiovascular disease (CVD). The levels of total cholesterol (TC), low-density lipoprotein cholesterol (LDL-c), and high-density lipoprotein cholesterol (HDL-c) in RA decrease especially under hyperinflammatory conditions. It is conflictive with the increased risk of CVD in RA, which is called "lipid paradox". The systemic inflammation may explain this apparent contradiction. The increased systemic proinflammatory cytokines in RA mainly include interleukin-6(IL-6)、interleukin-1(IL-1)and tumor necrosis factor alpha(TNF-α). The inflammation of RA cause changes in the subcomponents and structure of HDL particles, leading to a weakened anti-atherosclerosis function and promoting LDL oxidation and plaque formation. Dysfunctional HDL can further worsen the abnormalities of LDL metabolism, increasing the risk of cardiovascular disease. However, the specific mechanisms underlying lipid changes in RA and increased CVD risk remain unclear. Therefore, this article comprehensively integrates the latest existing literature to describe the unique lipid profile of RA, explore the mechanisms of lipid changes, and investigate the impact of lipid changes on cardiovascular disease.

One of the most complicated eye disorders is age-related macular degeneration (AMD) which is the leading cause of irremediable blindness all over the world in the elderly. AMD is classified as early stage to late stage (advanced AMD), in which this stage is divided into the exudative or neovascular form (wet AMD) and the nonexudative or atrophic form (dry AMD). Clinically, AMD primarily influences the central area of retina known as the macula. Importantly, the wet form is generally associated with more severe vision loss. AMD has a systemic component, where many factors, like aging, genetic, environment, autoimmune and non-autoimmune disorders are associated with this disease. Additionally, healthy lifestyles, regular exercise, maintaining a normal lipid profile and weight are crucial to decreasing the risk of AMD. Furthermore, therapeutic strategies for limiting AMD should encompass a variety of factors to avoid and improve drug interventions, and also need to take into account personalized genetic information. In conclusion, with the development of technology and research progress, visual impairment and legal blindness from AMD have been substantially reduced in incidence. This review article is focused on identifying and developing the knowledge about the association between genetics, and etiology with AMD. We hope that this review will encourage researchers and lecturers, open new discussions, and contribute to a better understanding of AMD that improves patients' visual acuity, and upgrades the quality of life of AMD patients.

Age-related macular degeneration (AMD) is one of the major causes of vision loss. Early AMD needs to be taken seriously, but the causal effects of lipid biomarkers on early AMD remain unclear.

In this study, two-sample Mendelian randomization (MR) analysis was performed to systematically assess the causal relationships between seven serum lipid biomarkers (apolipoprotein A (ApoA), apolipoprotein B (ApoB), total cholesterol (CHOL), high-density lipoprotein cholesterol (HDL-C), direct low-density lipoprotein cholesterol (LDL-C), lipoprotein A [Lp(a)], and triglycerides (TG)) and risk of early AMD. In total, 14,034 cases and 91,214 controls of European ancestry were included in the analysis (number of SNPs = 11,304,110).

MR estimates revealed that a higher HDL-C level is strongly associated with increased risk of early AMD (OR = 1.25, 95% CI: 1.15-1.35, P = 2.61 × 10^-8). In addition, level of ApoA is also positively associated with risk of early AMD (OR = 2.04, 95% CI: 1.50-2.77, P = 6.27 × 10^-6). Conversely, higher levels of TG significantly decrease the risk of early AMD (OR = 0.77, 95% CI: 0.71-0.84, P = 5.02 × 10^-10). Sensitivity analyses further supported these associations. Moreover, multivariable MR analyses, adjusted for the effects of correlated lipid biomarkers, yielded similar results.

This study identifies causal relationships between elevated circulating HDL-C/ApoA levels and increased risk of early AMD, in addition to finding that TG specifically reduces the risk of early AMD. These findings contribute to a better understanding of the role of lipid metabolism in drusen formation, particularly in early AMD development.

High density lipoproteins (HDL) promote homeostasis and counteract stressful tissue damage that underlie cardiovascular and other diseases by mediating reverse cholesterol transport, reducing inflammation, and abrogating oxidative damage. However, metabolically stressful conditions associated with atherosclerosis can impair these effects. Hepatocytes play a major role in the genesis and maturation of circulating HDL, and liver stress elicits marked regulatory changes to circulating HDL abundance and composition, which affect its functionality. The mechanisms linking liver stress to HDL function are incompletely understood. In this study, we sought to determine whether stress defending transcription factors nuclear factor erythroid 2 related factor-1 (Nrf1) and -2 (Nrf2) promote hepatocyte production of functional HDL. Using genetically engineered mice briefly fed a mild metabolically stressful diet, we investigated the effect of hepatocyte-specific deletion of Nrf1, Nrf2, or both on circulating HDL cholesterol, protein composition, and function. Combined deletion, but not single gene deletion, reduced HDL cholesterol and apolipoprotein A1 levels as well as the capacity of HDL to accept cholesterol undergoing efflux from cultured macrophages and to counteract tumor necrosis factor α-induced inflammatory effect on cultured endothelial cells. This coincided with substantial alteration to the HDL proteome, which correlated with liver gene expression profiles of corresponding proteins. Thus, our findings show complementary actions by hepatocyte Nrf1 and Nrf2 play a role in shaping HDL abundance and composition to promote production of functionally viable HDL. Consequently, our study illuminates the possibility that enhancing stress defense programming in the liver may improve atheroprotective and perhaps other health promoting actions of HDL.

HDL particles may act to buffer host cells from excessive inflammatory mediators. The aim of this study is to investigate if the lipid profile provides a prognostic biomarker for COVID-19 outcomes.

This was a prospective study of the characteristics of 125 adult COVID-19 patients with a lipid profile performed on the day of admission analyzed with regard to clinical outcomes.

Seventy-seven patients (61.2%) were men, with a mean age of 66.3 (15.6) years. 54.1% had bilateral pneumonia. The all-cause mortality rate during hospitalization was 20.8%. We found a direct association between more severe disease assessed by the WHO classification, admission to the ICU and death with more pronounced lymphopenia, higher levels of CRP, ferritin (p < 0.001), D-dímer and lactate dehydrogenase (LDH) all statistically significant. Lower leves of HDL-c and LDL-c were also associated with a worse WHO classification, ICU admission, and death,. HDL-c levels were inversely correlated with inflammatory markers CRP (r = -0.333; p < 0.001), ferritin (r = -0.354; p < 0.001), D-dímer (r = -0.214; p < 0.001), LDH (r = -0.209; p < 0.001. LDL-c levels were significantly associated with CRP (r = -0.320; p < 0.001) and LDH (r = -0.269; p < 0.001). ROC curves showed that HDL [AUC = 0.737(0.586-0.887), p = 0.005] and lymphocytes [AUC = 0.672(0.497-0.847], p < 0.043] had the best prognostic accuracy to predict death. In a multivariate analysis, HDL-c (β = -0.146(0.770-0.971), p = 0.014) and urea (β = 0.029(1.003-1.057), p = 0.027) predicted mortality.

Hypolipidemia including HDL levels at admission identifies patients with a higher risk of death and worse clinical manifestations who may require more intensive care.