oxLDL Levels Research Articles

Pro-Inflammatory and Pro-Oxidative Changes during Nilotinib Treatment in CML Patients: Results of a Prospective Multicenter Front-Line TKIs Study (KIARO Study)

Background: Tyrosine kinase inhibitors (TKI) may offer a normal life expectancy to Chronic Myeloid Leukemia (CML) patients. However, during treatment with nilotinib, a higher than expected incidence of arterial occlusive events (AOEs) was observed. We retrospectively showed an “inflammatory status” during nilotinib treatment that may explain this increased incidence of AOEs. Here, we report results of a prospective multicenter (KIARO) study including 186 CML patients (89 imatinib, 59 nilotinib, 38 dasatinib) in which pro/anti-inflammatory cytokines were measured at diagnosis and during treatment, with the aim to investigate potential changes in each patient's inflammatory status possibly favoring AOEs.Aims: The aims of this study are: 1) to analyze prospectively inflammation status during TKI treatment; 2) to record AOEs; 3) to calculate the SCORE and evaluate its predictive role for AOEs; 4) to analyze possible associations of AOEs with altered inflammation status.Methods: Inflammatory status was evaluated by measuring IL6, IL10, TNFα, oxLDL and hs-CRP plasma levels at diagnosis and during treatment (+1, +3, +6, +12 months); additionally, clinical and biochemical pro-atherothrombotic profiles and the 10-year SCORE chart were also evaluated.Results: 186 newly-diagnosed CML patients starting either imatinib, nilotinib or dasatinib treatment, entered this study. Regarding the inflammation status, we observed that TNFα and IL6 levels were high at diagnosis and decreased during the first 12 months of treatment regardless the type of TKI; instead, IL10 levels were comparable among the 3 TKI cohorts at baseline, but showed a remarkably different evolution during treatment. In fact, IL10 levels were significantly higher after 6 and 12 months of imatinib (p=0.012 and p=0.009, respectively) and dasatinib (p=0.032 and p=0.014, respectively) compared to nilotinib. Consequently, TNFα/IL10 ratio was significantly higher in nilotinib cohort at 6 and 12 months respect to imatinib (p=0.044 at 6 months and p=0.041 at 12 months) and dasatinib (p=0.040 at 6 months and p=0.044 at 12 months). As well, IL6/IL10 ratio was significantly higher in nilotinib cohort compared to imatinib and dasatinib both at 6 (p=0.042 and p=0.049, respectively) and 12 months (p=0.040 and p=0.041, respectively) (Figure 1). OxLDL levels were similar in the 3 groups for the first 6 months. At 12 months we detected a significant increase of oxLDL levels in the nilotinib cohort (p=0.041), respect to imatinib and dasatinib. We did not find significant differences in hs-CRP levels across the 3 TKIs, although a trend for higher levels was observed in nilotinib cohort. Overall, these results suggest a TKI-driven pro-inflammatory status in nilotinib treated patients.After a median follow-up of 23.3 months of TKI treatment, 10 patients (5.4%) suffered an AOE, specifically: 6 ACS, 2 PAOD, 1 TIA and 1 stroke. 5 events (50%) occurred in patients treated with nilotinib, either in first line (4 patients) or in third line (1 patient, after failure following brief treatment with imatinib and dasatinib). In this subgroup of 10 patients experiencing an AOE, we observed a trend of increased IL6 and TNFα median values both at diagnosis and at each time point, compared with the remaining no-AOE patients. IL10 and oxLDL had similar median concentrations in both AOE and no-AOE cohorts, except for oxLDL at 12 months which resulted higher in patients who experienced AOEs. Moreover, regarding AOEs, nilotinib treatment showed a 3.1 times increased risk compared to other TKIs (HR 3.1, 95% CI 2.6-4.4 p< 0.001), whereas 10-year SCORE was not predictive in the whole cohort (HR 0.6, 95% CI 0.33-0.94 p= 0.094) or in any subgroup (imatinib HR 0.8, 95% CI 0.49-1.03 p= 0.067; nilotinib HR 0.4, 95% CI 0.29-0.76 p= 0.112, dasatinib HR 0.6, 95% CI 0.37-0.92 p= 0.082).Conclusions: Our results showed a pro-inflammatory/oxidative milieu increasing along treatment with nilotinib compared with imatinib or dasatinib, as demonstrated by higher IL6/IL10 and TNFα/IL10 ratios, higher levels of oxLDL and a trend for higher hs-CRP only in nilotinib cohort. However, due to the low number of observed events, a formal statistical analysis for any association between AOEs and pro/anti-inflammatory cytokines levels was not possible. Therefore, a longer follow-up is needed to further confirm the active role of nilotinib in AOEs pathogenesis. [Display omitted] DisclosuresAbruzzese: Incyte: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria. Galimberti: Incyte: Speakers Bureau; AbbVie, Janssen: Honoraria, Other: Travel grants. Stagno: Pfizer: Consultancy, Honoraria, Other: Support for attending meetings and/or travel; InCyte: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Other: Support for attending meetings and/or travel, Research Funding.

Plasma Apolipoproteins A1/B and OxLDL Levels in Patients with Covid-19 As Possible Markers of the Disease.

The COVID-19 infection is associated with dyslipidemia and cardiovascular complications. The aim of the study was to determine the content of ApoA1, ApoB, and oxidized low-density lipoproteins (oxLDL) in the plasma of patients (n = 81) with COVID-19, diabetes, and cardiovascular disease (CVD). ApoA1, ApoB, and oxLDL were determined using enzyme-linked immunosorbent assay kits (Elabscience, United States). The measurements were performed at an optical wavelength of 450 nm. It was shown that the level of ApoA1 in the blood of patients with type 2 diabetes and especially with COVID-19 was significantly lower than in the blood of healthy people. Blood ApoA1 levels did not show a further decrease in patients with both COVID-19 and diabetes or CVD compared to patients with COVID-19 without concomitant diseases. It was found that the level of ApoB in the blood of patients with diabetes and, especially, with COVID-19 is significantly higher than in the blood of healthy people. Blood levels of ApoB and oxLDL are higher in patients with both COVID-19 and diabetes or CVD compared to patients with COVID-19 without comorbidities. Thus, levels of ApoA1, ApoB, and oxLDL may be promising markers of COVID-19.

OXIDATIVE MODIFICATIONS OF LIPOPROTEINS IN PATIENTS WITH VIBRATION DISEASE AND METABOLIC DISORDERS

Introduction: Diabetes mellitus (DM) and metabolic syndrome (MS) are characterized by development of atherosclerosis and cardiovascular pathology. Vibration disease (VD) affects oxidative metabolism leading to the development of microangiopathies. However, the evidence on the combined effect of VD and DM or MS on oxidative modification of lipids remains limited. Aim: To study oxidative modification of lipoproteins in individuals with vibrationa disease and metabolic disorders. Metods: In total, 59 patients with VD (group I), 73 people with VD combined with MS (group II) and 35 people with VD and type 2 diabetes (group III) took part in the study. We assessed concentrations of total cholesterol, low density lipoproteins (LDL), oxidized low density lipoproteins (oxLDL), antibodies to oxLDL and thiol status. Results: Serum levels of total cholesterol, oxLDL and antibodies to oxLDL in all groups exceeded the reference values. The proportion of people with a high content of oxLDL varied between 61 % to 72 %. Increased levels of antibodies to oxLDL were observed in 63 % - 85 % of patients in all groups. The concentration of LDL cholesterol was the highest in group II: 3,6 (3,2-4,2) mM/l. Concentrations of oxLDL correlated with the levels of total cholesterol and LDL cholesterol. Lower thiol concentrations were found in 57 % of cases in group II). Conclusion: Our results suggest that individuals with VD have hypercholesterinemia, increased oxidative lipid metabolism and increased production of antibodies to oxLDL independently of metabolic disorders Patients with VD and type 2 diabetes may have decrease antioxidant defense.

Relation of biomarkers of inflammation, oxidative stress and fibrosis in patient with atrial fibrillation

Abstract Background Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia in clinical practice. The patogenesis of AF is linked to an inflammatory reaction and oxidative stress that leads to fibrosis of the atria and progression of the disease. However, the role of different biomarkers in patients with AF is poorly defined. The purpose of this study is to define the role of several biomarkers of inflammation, oxidative stress and fibrosis (myeloperoxidase (MPO), high-sensitivity C-reactive protein (hsCRP), galectin-3 (Gal-3), oxidized low-density lipoprotein (oxLDL)) in patients with AF. Methods We included 75 patients with paroxysmal/persistent AF, who were admitted for electrical cardioversion or pulmonary vein isolation. MPO, hsCRP, Gal-3 and oxLDL were measured before the procedures. We compared the results with 75 healthy age-, sex- and blood pressure-matched individuals. Results Patients with AF had higher MPO (77.1 vs 41.7 ng/ml, p&amp;lt;0.001) compared the healthy subjects. There was also significantly higher hsCRP (3.7 vs 1.6 mg/L, p&amp;lt;0.001) and Gal-3 (12.3 vs 10.4 mg/L, p=0.003). No difference in oxLDL levels (78.8 vs 75.3 U/L, p=0.414) were seen (Table 1). MPO (β=0.012, p=0.014), hsCRP (β=0.213, p=0.046), and weight (β=0.037, p=0.006), were independently associated with AF in a logistic regression analysis (Table 2). Conclusions Patients with AF have increased markers of inflammation and fibrosis, whereas no increase in oxidative stress markers was detected. MPO, hsCRP and age weight were independently predictive of AF. These findings support the role of inflammatory and fibrotic mechanisms as important factors in the electrical and structural remodelling progress in the atria of patients with AF. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Estonian Research Council

Complement Inhibition Targeted to Injury Specific Neoepitopes Attenuates Atherogenesis in Mice.

Rationale: Previous studies have indicated an important role for complement in atherosclerosis, a lipid-driven chronic inflammatory disease associated to oxidative stress in the vessel wall. However, it remains unclear how complement is activated in the process of atherogenesis. An accepted general model for complement activation in the context of ischemia reperfusion injury is that ischemia induces the exposure of neoepitopes that are recognized by natural self-reactive IgM antibodies, and that in turn activate complement.Objective: We investigated whether a similar phenomenon may be involved in the pathogenesis of atherosclerosis, and whether interfering with this activation event, together with inhibition of subsequent amplification of the cascade at the C3 activation step, can provide protection against atherogenesis.Methods and Results: We utilized C2scFv-Crry, a novel construct consisting of a single chain antibody (scFv) linked to Crry, a complement inhibitor that functions at C3 activation. The scFv moiety was derived from C2 IgM mAb that specifically recognizes phospholipid neoepitopes known to be expressed after ischemia. C2scFv-Crry targeted to the atherosclerotic plaque of Apoe−/− mice, demonstrating expression of the C2 neoepitope. C2scFv-Crry administered twice per week significantly attenuated atherosclerotic plaque in the aorta and aortic root of Apoe−/− mice fed with a high-fat diet (HFD) for either 2 or 4 months, and treatment reduced C3 deposition and membrane attack complex formation as compared to vehicle treated mice. C2scFv-Crry also inhibited the uptake of oxidized low-density-lipoprotein (oxLDL) by peritoneal macrophages, which has been shown to play a role in pathogenesis, and C2scFv-Crry-treated mice had decreased lipid content in the lesion with reduced oxLDL levels in serum compared to vehicle-treated mice. Furthermore, C2scFv-Crry reduced the deposition of endogenous total IgM in the plaque, although it did not alter serum IgM levels, further indicating a role for natural IgM in initiating complement activation.Conclusion: Neoepitope targeted complement inhibitors represent a novel therapeutic approach for atherosclerosis.

Oxidized Low-Density Lipoprotein Links Hypercholesterolemia and Bladder Cancer Aggressiveness by Promoting Cancer Stemness.

Hypercholesterolemia is a prevalent metabolic disorder that has been implicated in the development of steroid-targeted cancers. However, the link between hypercholesterolemia and urinary bladder cancer (UBC), a non-steroid-targeted cancer, remains unresolved. Here we show that diet-induced and Ldlr deficiency-induced hypercholesterolemia enhances both UBC stemness and progression. Inhibition of intestinal cholesterol absorption by ezetimibe reversed diet-induced hypercholesterolemia and cancer stemness. As a key component in hypercholesterolemic sera, oxidized low-density lipoprotein (ox-LDL), but not native low-density lipoprotein-cholesterol or metabolite 27-hydroxycholesterol, increased cancer stemness through its receptor CD36. Depletion of CD36, ectopic expression of an ox-LDL binding-disabled mutant form of CD36(K164A), and the neutralization of ox-LDL and CD36 via neutralizing antibodies all reversed ox-LDL-induced cancer stemness. Mechanistically, ox-LDL enhanced the interaction of CD36 and JAK2, inducing phosphorylation of JAK2 and subsequently activating STAT3 signaling, which was not mediated by JAK1 or Src in UBC cells. Finally, ox-LDL levels in serum predicted poor prognosis, and the ox-LDLhigh signature predicted worse survival in patients with UBC. These findings indicate that ox-LDL links hypercholesterolemia with UBC progression by enhancing cancer stemness. Lowering serum ox-LDL or targeting the CD36/JAK2/STAT3 axis might serve as a potential therapeutic strategy for UBCs with hypercholesterolemia. Moreover, elevated ox-LDL may serve as a biomarker for UBC. SIGNIFICANCE: This study demonstrates how hypercholesterolemia-induced oxidized LDL promotes urinary bladder cancer stemness via a CD36/STAT3 signaling axis, highlighting these factors as biomarkers and potential therapeutic targets of aggressive disease.

The effect of vitamin D deficiency state on oxidized low-density lipoprotein alteration in patients with type 2 diabetes

Introduction: The aim of this study was to compare oxidized low-density lipoprotein (oxLDL) and blood glucose in very low and low levels of vitamin D.Methods: A total of 25 type-2 diabetic patients with very low serum levels of 25-hydroxy vitamin D (severe deficiency – &lt;10 ng/ml); and 25 type-2 diabetic patients with low serum levels of 25-hydroxy vitamin D (deficient – 10 to 30 ng/ml) were recruited in this cross-sectional study. Fasting plasma glucose (FBS), postprandial glucose (PPG), HbA1C, oxLDL, and high-sensitivity C-reactive protein (hs-CRP) were measured. Diagnostic accuracies were determined by receiver-operating characteristic (ROC) curve analysis and measuring the area under the curve (AUC).Results: Patients with severe vitamin D deficiency had higher FBS, PPG, HbA1C, and oxLDL than the vitamin D deficient group (P&lt;0.05). We showed that the AUC of FBS, PPG, HbA1C, and oxLDL were in the range of 0.7-0.9, which indicates moderate accuracies in differentiating severe vitamin D deficiency from deficiency condition.Conclusion: In conclusion, diabetic patients with severe vitamin D deficiency had higher FBS, PPG, and oxLDL levels compared with deficient ones. ROC curve analysis of FBS, PPG, HbA1C, and oxLDL showed these markers are independent predictors of severe vitamin D deficiency and significantly discriminate between very low and low levels of vitamin D deficiency in patients with diabetes. Keywords: Type 2 diabetes mellitus. Vitamin D deficiency. OxLDL. Fasting blood glucose.

Interaction of Smoking and Lead Exposure among Carriers of Genetic Variants Associated with a Higher Level of Oxidative Stress Indicators.

Smoking and lead (Pb) exposure increased oxidative stress in human body, and people with some gene variants may be susceptible to Pb and smoking via oxidative stress. The aim of this study is to evaluate oxidative stress by measuring thiobarbituric acid reactive substances (TBARS) and the relationship of lipid peroxidation markers in Pb workers with different gene polymorphisms (rs4673 and rs1050450) in both smokers and nonsmokers. Blood samples were collected from 267 Pb workers who received their annual health examination in the Kaohsiung Medical University Hospital. Glutathione peroxidase 1 (GPx-1) rs1050450 and cytochrome B-245 Alpha Chain (CYBA) rs4673 single-nucleotide polymorphisms (SNP) were analyzed by specific primer-probes using Real-Time PCR methods. The interaction between blood Pb and smoking increased serum levels of TBARS and the ratio of oxidative low-density lipoprotein and low-density lipoprotein (oxLDL/LDL). Analysis of workers with rs1050450 SNPs showed higher blood Pb levels in the workers with CC genotype than those with CT genotype. Smokers had significantly higher blood Pb, alanine transaminase (ALT), TBARS, and OxLDL levels than nonsmokers. TBARS increased 0.009 nmol/mL when blood Pb increased one µg/dL in smokers compared to nonsmokers. The ratio of OxLDL/LDL increased 0.223 when blood Pb increased one µg/dL in smokers compared to nonsmokers. TBARS levels and the ratio of OxLDL/LDL were positively correlated and interacted between blood Pb and smoking after the adjustment of confounders, suggesting that smoking cessation is an important issue in the Pb-exposed working environment.

Oxidized low-density lipoproteins and its connection with dyslipidemia, inflammatory markers, and oxidative stress in patients with occupational chronic obstructive pulmonary disease

The role of low-density oxidized lipoproteins (OxLDL) in the pathogenesis of occupational chronic obstructive pulmonary disease (COPD) is not understood well enough.The study aims to determine the serum levels of oxidized low-density lipoproteins and their relationship with lipid profile, the level of oxidative stress and level C-reactive protein in patients with occupational chronic obstructive pulmonary disease.Methods. 116 patients diagnosed with occupational COPD and 25 patients with no respiratory diseases (comparison group) were examined. Serum levels of OxLDL was determined by solid phase enzyme-linked immunosorbent assay (ELISA) using the commercial reagent kit MDA-oxLDL from Biomedica Gruppe, Austria.Results. Circulating OxLDL was detected in serum in a significant proportion of patients with stable occupational COPD. In most of the patients, the concentration of OxLDL was within the values observed in the comparison group or exceeded them by no more than two times. In the minority of patients with occupational COPD (16.5%), the concentration of OxLDL was high and 4 – 10 times higher than its average value in the comparison group. It can be assumed that the revealed differences in the concentration of OxLDL are due to the different degree and intensity of oxidation of low-density lipoproteins. The relationships between OxLDL and lipid metabolism, oxidative stress (OS), the antioxidant capacity of serum (AOS), and serum levels of C-reactive protein were described.Conclusion. Serum OxLDL levels in patients with occupational COPD, the relationship between OxLDL and lipid metabolism, oxidative stress, and inflammation will provide an expanded view of the pathogenetic aspects of occupational COPD.

Oxidative stress-responsive apoptosis-inducing protein in patients with heterozygous familial hypercholesterolemia.

Oxidative stress, an inducer of apoptosis, plays a critical role in ischemia/reperfusion injury and atherosclerosis. We previously identified an apoptosis-inducing ligand, the post-translationally modified secreted form of eukaryotic translation initiation factor 5A (eIF5A), 'oxidative stress-responsive apoptosis-inducing protein' (ORAIP). In this study, we investigated the role of ORAIP in patients with heterozygous familial hypercholesterolemia (HeFH), a leading cause of premature cardiovascular disease. We analyzed plasma ORAIP and oxidized low-density lipoprotein (oxLDL) levels in 60 patients with HeFH (60% male, 57.0 ± 13.6years of age) and 20 patients with LDL-C hypercholesterolemia (DL, 85% male, 64.1±13.3years of age). The coronary artery atherosclerosis from the patients with HeFH who had a coronary artery bypass graft was investigated by double immunostaining. The plasma ORAIP levels in the patients with HeFH were significantly elevated compared to those in the patients with DL (73.5 ± 46.0 vs. 48.3 ± 21.4ng/mL, p = 0.0277). The plasma oxLDL levels in HeFH patients were also elevated (156.8 ± 65.2 vs. 123.7 ± 46.6mg/dL, p = 0.0461) compared to those in DL patients and correlated with maxLDL-C levels (R = 0.4454, p = 0.00648). Double-immunostaining of ORAIP and oxLDL in the coronary artery from patients with HeFH who had a coronary artery bypass graft showed that ORAIP and oxLDL were colocalized with apoptotic vascular smooth muscle cells in the atherosclerotic plaque. ORAIP plays a role in the development of oxidative stress-induced atherosclerosis and may be an important therapeutic target for plaque rupture in patients with HeFH.

Oxidized LDLs as Signaling Molecules.

Levels of oxidized low-density lipoproteins (oxLDLs) are usually low in vivo but can increase whenever the balance between formation and scavenging of free radicals is impaired. Under normal conditions, uptake and degradation represent the physiological cellular response to oxLDL exposure. The uptake of oxLDLs is mediated by cell surface scavenger receptors that may also act as signaling molecules. Under conditions of atherosclerosis, monocytes/macrophages and vascular smooth muscle cells highly exposed to oxLDLs tend to convert to foam cells due to the intracellular accumulation of lipids. Moreover, the atherogenic process is accelerated by the increased expression of the scavenger receptors CD36, SR-BI, LOX-1, and SRA in response to high levels of oxLDL and oxidized lipids. In some respects, the effects of oxLDLs, involving cell proliferation, inflammation, apoptosis, adhesion, migration, senescence, and gene expression, can be seen as an adaptive response to the rise of free radicals in the vascular system. Unlike highly reactive radicals, circulating oxLDLs may signal to cells at more distant sites and possibly trigger a systemic antioxidant defense, thus elevating the role of oxLDLs to that of signaling molecules with physiological relevance.

Proprotein Convertase Subtilisin Kexin Type 9 Inhibitors Reduce Platelet Activation Modulating ox-LDL Pathways.

Background: Proprotein convertase subtilisin kexin type 9 inhibitors (PCSK9i) lower LDL-cholesterol and slow atherosclerosis preventing cardiovascular events. While it is known that circulating PCSK9 enhances platelet activation (PA) and that PCSK9i reduce it, the underlying mechanism is not still clarified. Methods: In a multicenter before–after study in 80 heterozygous familial hypercholesterolemia (HeFH) patients on treatment with maximum tolerated statin dose ± ezetimibe, PA, soluble-NOX2-derived peptide (sNOX2-dp), and oxidized-LDL (ox-LDL) were measured before and after six months of PCSK9i treatment. In vitro study investigates the effects of plasma from HeFH patients before and after PCK9i on PA in washed platelets (wPLTs) from healthy subjects. Results: Compared to baseline, PCSK9i reduced the serum levels of LDL-c, ox-LDL, Thromboxane (Tx) B2, sNOX2-dp, and PCSK9 (p < 0.001). The decrease of TxB2 correlates with that of ox-LDL, while ox-LDL reduction correlated with PCSK9 and sNOX2-dp delta. In vitro study demonstrated that wPLTs resuspended in plasma from HeFH after PCSK9i treatment induced lower PA and sNOX2-dp release than those obtained using plasma before PCSK9i treatment. This reduction was vanished by adding ox-LDL. ox-LDL-induced PA was blunted by CD36, LOX1, and NOX2 inhibition. Conclusions: PCSK9i treatment reduces PA modulating NOX2 activity and in turn ox-LDL formation in HeFH patients.

The effect of vitamin D supplementation on flow-mediated dilatation, oxidized LDL and intracellular adhesion molecule 1 on type 2 diabetic patients with hypertension: A randomized, placebo-controlled, double-blind trial

AimsCurrent study aimed to evaluate the effect of vitamin D supplementation on flow-mediated dilatation (FMD), oxidized LDL (oxLDL) and intracellular adhesion molecule 1 (ICAM1) in type 2 diabetic patients with hypertension. MethodsIn a double-blinded, placebo-controlled trial, 44 patients were randomly divided into vitamin D group (2000 IU/d, n = 23) and placebo group (control, n = 21) for 12 weeks. Vascular function with FMD, Serum 25-OH vitamin D, oxLDL and ICAM1 were assessed at the baseline and after the intervention. This clinical trial was registered at Iranian Registry of Clinical Trials (IRCT20191223045861N1). ResultsIn intervention group serum level of vitamin D increased from 32.42 ± 10.56 to 40.45 ± 12.94 (p < 0.001). In the vitamin D group, oxLDL and ICAM1 significantly decreased and FMD increased significantly in both groups (p < 0.001). The level of oxLDL (p = 0.017) and ICAM1 (p < 0.001) were significantly lower in the vitamin D group than the placebo group and FMD (p < 0.001) was significantly higher in the vitamin D group. ConclusionsVitamin D supplementation of 2000 IU/d for 12 weeks can improve endothelial function and decrease ICAM1 and oxLDL in type 2 diabetic patients with hypertension.

Assessment of Coronary Artery Disease With Computed Tomography Angiography and Inflammatory and Immune Activation Biomarkers Among Adults With HIV Eligible for Primary Cardiovascular Prevention

Cardiovascular disease (CVD) is increased among people with HIV (PWH), but little is known regarding the prevalence and extent of coronary artery disease (CAD) and associated biological factors in PWH with low to moderate traditional CVD risk. To determine unique factors associated with CVD in PWH and to assess CAD by coronary computed tomography angiography (CTA) and critical pathways of arterial inflammation and immune activation. This cohort study among male and female PWH, aged 40 to 75 years, without known CVD, receiving stable antiretroviral therapy, and with low to moderate atherosclerotic cardiovascular disease (ASCVD) risk according to the 2013 American College of Cardiology/American Heart Association pooled cohort equation, was part of the Randomized Trial to Prevent Vascular Events in HIV (REPRIEVE), a large, ongoing primary prevention trial of statin therapy among PWH conducted at 31 US sites. Participants were enrolled from May 2015 to February 2018. Data analysis was conducted from May to December 2020. HIV disease. The primary outcome was the prevalence and composition of CAD assessed by coronary CTA and, secondarily, the association of CAD with traditional risk indices and circulating biomarkers, including insulin, monocyte chemoattractant protein 1 (MCP-1), interleukin (IL) 6, soluble CD14 (sCD14), sCD163, lipoprotein-associated phospholipase A2 (LpPLA2), oxidized low-density lipoprotein (oxLDL), and high-sensitivity C-reactive protein (hsCRP). The sample included 755 participants, with a mean (SD) age of 51 (6) years, 124 (16%) female participants, 267 (35%) Black or African American participants, 182 (24%) Latinx participants, a low median (interquartile range) ASCVD risk (4.5% [2.6%-6.8%]), and well-controlled viremia. Overall, plaque was seen in 368 participants (49%), including among 52 of 175 participants (30%) with atherosclerotic CVD (ASCVD) risk of less than 2.5%. Luminal obstruction of at least 50% was rare (25 [3%]), but vulnerable plaque and high Leaman score (ie, >5) were more frequently observed (172 of 755 [23%] and 118 of 743 [16%], respectively). Overall, 251 of 718 participants (35%) demonstrated coronary artery calcium score scores greater than 0. IL-6, LpPLA2, oxLDL, and MCP-1 levels were higher in those with plaque compared with those without (eg, median [IQR] IL-6 level, 1.71 [1.05-3.04] pg/mL vs 1.45 [0.96-2.60] pg/mL; P = .008). LpPLA2 and IL-6 levels were associated with plaque in adjusted modeling, independent of traditional risk indices and HIV parameters (eg, IL-6: adjusted odds ratio, 1.07; 95% CI, 1.02-1.12; P = .01). In this study of a large primary prevention cohort of individuals with well-controlled HIV and low to moderate ASCVD risk, CAD, including noncalcified, nonobstructive, and vulnerable plaque, was highly prevalent. Participants with plaque demonstrated higher levels of immune activation and arterial inflammation, independent of traditional ASCVD risk and HIV parameters.

Estimation of 6Ckine and Chemokine Receptor Type 7 With Some Biomarkers in Type 2 Diabetes Mellitus Patients

Type 2 Diabetes Mellitus (T2DM) It is a complex disease associated with metabolic disorders. The main aim of the study was to accurately measure the concentration of 6Ckine and chemokine receptor type 7 with some biomarkers in T2DM patients and compare it with healthy controls. Identical in gender and age, 60 diabetics and 30 healthy controls participated in this study of 6Ckine and chemokine receptor type 7 serum concentration was estimated by ELISA technique. An 6Ckine and chemokine receptor type 7 have high concentration in T2DM patients compared to healthy controls, Ox-LDL show significant between studied groups. also Insulin Hormone show significant in T2DM patients compared to healthy controls and each for age and BMI Also significant between T2DM patients and healthy controls. This study showed an increase in the level of Ox-LDL in patients compare with healthy control, no different between patients and healthy control in levels of both 6Ckine and chemokine receptor type 7, decrease in insulin level in patients compare with healthy control.

Role of circulating oxidized LDL: a useful diagnostic risk marker in cardiovascular disease

The aim: to assess levels of circulating plasma ox-LDL in various subgroups with different CVD and their relationship with oxidative stress markers, MDA, catalase, and traditional coronary disease risk factors.&#x0D; Material and methods: a total of 215 subjects divided into four groups comprising 54 healthy controls, patients with the SAP were 52 persons, with the UAP 53 ones, and with the AMI there were 56 persons, respectively. Lipid profile parameters (TC, TG, HDL-C, LDL-C, and VLDL-C), plasma MDA, catalase were estimated by kit methods, TBARS method, and colorimetric assay respectively. Plasma Ox-LDL was estimation by competitive ELISA kit method (Mercodia) with the help of specific monoclonal antibody mAb4Eb. Results were present as mean ± SD, significance level at p-values&lt;0.05 with Student’s unpaired t-test. Data analysis was performed by software package SPSS version 17.0.&#x0D; Results: it showed a highly significant (p&lt;0.001) correlation in SAP, UAP, and AMI except for age in the SAP subgroup, moderately significant (p&lt;0.01). Lipid profile except HDL-C was found highly elevated (p&lt;0.001) in subgroups than in healthy controls. HDL-C was higher (p&lt;0.001) in controls with respect to patient subgroups. Comparison of oxidative stress markers (MDA and catalase) and ox-LDH in control with patient’s subgroup indicates highly significant (p&lt;0.001) correlation. The correlation between SAP &amp; UAP was insignificant (p&lt;0.05), SAP with AMI was significant (p&lt;0.05), and UAP &amp; AMI were highly significant (p&lt;0.001). Large interquartile range in SAP subgroup suggesting scattered deviation in the mean value as compared to UAP and AMI showed in the box and whiskers plot and concluded that significantly elevated level of ox-LDL in SAP, UAP, and AMI subgroups indicate its diagnostic importance of CVD.&#x0D; Conclusions: study concluded that significantly elevated level of ox-LDL in SAP, UAP, and AMI subgroups indicate its diagnostic importance of CVD.

MO627ASSOCIATION OF OXIDIZED LDL CHOLESTEROL WITH MORTALITY AND PROGRESSION OF PROTEINURIC DIABETIC KIDNEY DISEASE

Abstract Background and Aims Oxidative modification of low-density lipoprotein (oxLDL) contributes to the pathogenesis and progression of oxidative stress (OS) and atherosclerosis in both Type 2 Diabetes Mellitus (T2DM) and Chronic Kidney Disease (CKD). Compared to normo-and micro-albuminuric, T2DM patients with macroalbuminuria have significantly higher plasma oxLDL levels. In this study we aimed to assess the possible predictive role of oxLDL for mortality and deterioration of renal function in a cohort of patients with proteinuric diabetic CKD. Method 91 patients with diabetic retinopathy, persistent proteinuria and eGFR below 90ml/min were recruited. At baseline, oxLDL, proteinuria and eGFR were assessed and patients were categorized according to median oxLDL (above or below 66.22 U/L). All patients were prospectively followed for a period of 10 years or the occurrence of a combined outcome of mortality or at least 30% decline in eGFR and/or progression to end stage renal disease (ESRD), requiring renal replacement therapy. At the end of the follow-up period, renal function was re-assessed with a new estimation of eGFR, using the CKD-EPI formula. We performed a statistical analysis with receiver operation curves (ROC) to further examine the possible effect of oxLDL on the percentage change in eGFR and proteinuria over time (calculated as ΔeGFR/baseline eGFR and Δproteinuria/baseline proteinuria respectively) and divided by the follow-up time. Results The mean age of the patients was 67.02±8.2 years, and the mean duration of T2DM was 14.5±8.0 years. At baseline, compared to the low, patients with high circulating oxLDL levels had significantly higher levels of triglycerides, higher diastolic blood pressure and lower eGFR (P=0.001, P=0.04 and P-0.013, respectively, Mann-Whitney test). After a 10-year follow up, 10/46 patients in the low and 20/45 patients in the high ox-LDL group presented the composite outcome. Kaplan-Meier curves (Figure 1) showed that patients with oxLDL levels above median (&amp;gt;66.22 U/L) presented a significantly higher risk for the outcome compared to the low oxLDL group (P=0.001, log-rank test). Univariate Cox proportional hazard analysis revealed that high circulating oxLDL levels were independent predictors of the composite endpoint (HR=3.42, 95%CI: 1.55-7.56, P=0.002). After adjustment for all factors that were associated with the outcome in univariate models (baseline proteinuria, serum albumin, duration of T2DM and triglycerides), multivariate Cox analysis showed that the association between high oxLDL levels and the study endpoint remained significant (HR=3.76, 95%CI: 1.52-9.27, P=0.004). At ROC analysis the area under the curve (AUC) for oxLDL to identifying progressor patients was 0.68 (95% CI: 0.56-0.80, P=0.005). Of note, this AUC was virtually identical to that of baseline proteinuria. OxLDL failed to show any association with the change of proteinuria over time. Conclusion Circulating ox-LDL might play an important role in the progression of proteinuric DKD.

Oxidized LDL Modifies the Association between Proteinuria and Deterioration of Kidney Function in Proteinuric Diabetic Kidney Disease.

Proteinuria is characterized by low accuracy for predicting onset and development of diabetic kidney disease (DKD) because it is not directly associated with molecular changes that promote DKD, but is a result of kidney damage. Oxidized low-density lipoprotein (ox-LDL) reflects oxidative stress and endothelial dysfunction, both underlying the development of proteinuria and loss of kidney function in DKD. We aimed to investigate whether ox-LDL modifies the association between proteinuria and progression of DKD in a cohort of 91 patients with proteinuric DKD and diabetic retinopathy, followed for 10 years. The primary endpoint was a combined kidney outcome of eGFR decline ≥30% or progression to end-stage kidney disease. After the end of the study, we considered the percentage change of eGFR over time as our secondary outcome. Proteinuria was associated with both outcomes, and ox-LDL amplified the magnitude of this link (p < 0.0001 for primary and p < 0.0001 for secondary outcome, respectively). After adjustment for duration of diabetes, history of cardiovascular disease and serum albumin, ox-LDL remained a significant effect modifier of the association between proteinuria and eGFR decline over time (p = 0.04). Our study shows that in proteinuric DKD, circulating ox-LDL levels amplified the magnitude of the association between proteinuria and progression of DKD.

Hengshun Aromatic Vinegar Ameliorates Vascular Endothelial Injury via Regulating PKCζ-Mediated Oxidative Stress and Apoptosis.

Vascular endothelial injury (VEI) is an early event of atherosclerosis, and reversing endothelial dysfunction has become a new trend in the prevention and treatment of cardiovascular diseases. Hengshun aromatic vinegar (HSAV), a traditional vinegar, has been reported to have many pharmacological activities, but its effect against VEI and the molecular mechanism are still unknown. In this study, effects of HSAV on VEI were evaluated in H2O2-induced human umbilical vein endothelial cells (HUVECs) and methionine-induced VEI in rats. Results showed that HSAV significantly increased cell viability, inhibited apoptosis, and reduced the generation of reactive oxygen species (ROS) in H2O2-induced HUVECs. Meanwhile, HSAV decreased serum homocysteine (Hcy), endothelin 1 (ET-1), and oxidized low-density lipoprotein (ox-LDL) levels, increased nitric oxide (NO) and endothelin nitric oxide synthase (eNOS) levels, ameliorated pathological changes in rats with VEI induced by methionine. In parallel, HSAV relieved oxidative stress by decreasing malondialdehyde (MDA) level and increasing superoxide dismutase (SOD), glutathione (GSH), and glutathione peroxidase (GSH-Px) levels in rats with VEI. Mechanism studies indicated that HSAV markedly downregulated the expression of protein kinase C zeta (PKCζ), and consequently regulated sirtuin 1 (Sirt1)-mediated oxidative stress signal pathway, and protein inhibitor of activated STATy (PIASy)-mediated apoptosis pathway, leading to the alleviation of oxidative stress and inhibition of apoptosis. These regulative effects of HSAV were further validated by knockdown and overexpression of PKCζ in vitro. In conclusion, HSAV showed protective effect against VEI by inhibiting PKCζ and, thereby, ameliorating oxidative stress and inhibiting apoptosis. This study not only provides guidance for the consumption of vinegar in daily life but also promotes the development of diet supplement for disease prevention.

LIPG endothelial lipase and breast cancer risk by subtypes

Experimental data showed that endothelial lipase (LIPG) is a crucial player in breast cancer. However, very limited data exists on the role of LIPG on the risk of breast cancer in humans. We examined the LIPG-breast cancer association within our population-based case–control study from Galicia, Spain, BREOGAN (BREast Oncology GAlicia Network). Plasma LIPG and/or OxLDL were measured on 114 breast cancer cases and 82 controls from our case–control study, and were included in the present study. The risk of breast cancer increased with increasing levels of LIPG (multivariable OR for the highest category (95% CI) 2.52 (1.11–5.81), P-trend = 0.037). The LIPG-breast cancer association was restricted to Pre-menopausal breast cancer (Multivariable OR for the highest LIPG category (95% CI) 4.76 (0.94–28.77), P-trend = 0.06, and 1.79 (0.61–5.29), P-trend = 0.372, for Pre-menopausal and Post-menopausal breast cancer, respectively). The LIPG-breast cancer association was restricted to Luminal A breast cancers (Multivariable OR for the highest LIPG category (95% CI) 3.70 (1.42–10.16), P-trend = 0.015, and 2.05 (0.63–7.22), P-trend = 0.311, for Luminal A and non-Luminal A breast cancers, respectively). Subset analysis only based on HER2 receptor indicated that the LIPG-breast cancer relationship was restricted to HER2-negative breast cancers (Multivariable OR for the highest LIPG category (95% CI) 4.39 (1.70–12.03), P-trend = 0.012, and 1.10 (0.28–4.32), P-trend = 0.745, for HER2-negative and HER2-positive tumors, respectively). The LIPG-breast cancer association was restricted to women with high total cholesterol levels (Multivariable OR for the highest LIPG category (95% CI) 6.30 (2.13–20.05), P-trend = 0.018, and 0.65 (0.11–3.28), P-trend = 0.786, among women with high and low cholesterol levels, respectively). The LIPG-breast cancer association was also restricted to non-postpartum breast cancer (Multivariable OR for the highest LIPG category (95% CI) 3.83 (1.37–11.39), P-trend = 0.003, and 2.35 (0.16–63.65), P-trend = 0.396, for non-postpartum and postpartum breast cancer, respectively), although we lacked precision. The LIPG-breast cancer association was more pronounced among grades II and III than grade I breast cancers (Multivariable ORs for the highest category of LIPG (95% CI) 2.73 (1.02–7.69), P-trend = 0.057, and 1.90 (0.61–6.21), P-trend = 0.170, for grades II and III, and grade I breast cancers, respectively). No association was detected for OxLDL levels and breast cancer (Multivariable OR for the highest versus the lowest category (95% CI) 1.56 (0.56–4.32), P-trend = 0.457).