Malondialdehyde-modified Low-density Lipoprotein Research Articles

Serum Malondialdehyde-Modified Low-Density Lipoprotein Level May Be a Biomarker Associated with Aortic Stiffness Among Patients Undergoing Peritoneal Dialysis.

Serum malondialdehyde-oxidized low-density lipoprotein (MDA-oxLDL) is associated with atherosclerosis and increased risk of cardiovascular disease (CVD). Vascular calcification frequently occurs with arterial stiffness in patients on peritoneal dialysis (PD). This cross-sectional study aimed to elucidate the correlation between aortic stiffness and MDA-oxLDL levels in patients on PD. Overall, 92 patients on PD were included. The carotid-femoral pulse wave velocity (cfPWV) was evaluated using cuff-based volumetric displacement, and blood samples were obtained from all patients. Aortic stiffness was classified based on cfPWV values (>10 m/s indicating aortic stiffness). Serum MDA-ox-LDL levels were quantified using commercial enzyme-linked immunosorbent assay kits. In total, 33 (35.9%) patients were classified into the aortic stiffness group. Factors, including systolic blood pressure (SBP), serum triglyceride levels, C-reactive protein levels, age, weight, body mass index (BMI), waist circumference, MDA-oxLDL levels, and diabetes mellitus (DM) prevalence, were significantly higher in the aortic stiffness group. Multivariable logistic regression analysis revealed significant associations between aortic stiffness and MDA-oxLDL levels, BMI, and SBP. Furthermore, multivariable forward stepwise linear regression analysis revealed serum MDA-oxLDL levels as a significant independent predictor of cfPWV values. Serum MDA-oxLDL levels correlate positively with cfPWV values and may predict aortic stiffness among PD patients, highlighting its potential role in assessing CVD risk in this population.

Pro-Inflammatory Signaling Cascade Markers, Oxidative Stress-Inflammatory Signaling Axis, and Chronic Total Occlusion of Tibial Artery in Elderly Patients Suffering from Occlusion of Coronary Arteries.

Oxidative response is a risk factor in the progression of arterial atherosclerosis. This research study aimed to examine the effects of oxidative response on atherosclerotic susceptibility as well as the development of arteriosclerosis occlusions of the tibial artery through pro-inflammatory mediator genes in elderly patients with occlusion of coronary arteries. We determined that oxidative stress biomarkers (Malondialdehyde-modified Low-density Lipoprotein (MDA-LDL), Oxidized Low-density Lipoprotein (Ox-LDL) as well as Heme Oxygenase- 1 (HO-1)] and the expressions of pro-inflammatory mediator genes [Toll-like Receptor 4 (TLR4), Nuclear Factor kappa-B (NF-κB), Myeloid Differentiating factor 88 (MyD88) and Growth Arrest-specific gene 6 (GAS6)] have an impact on the severity of arteriosclerosis occlusions of tibial artery in elderly patients suffering from occlusion of coronary arteries. Levels of MDA-LDL, Ox-LDL, HO-1, TLR4, NF-κB, MyD88, and GAS6 were increased in the occlusion of tibial arteries + two-vessel coronary occlusion group compared to the CON group and occlusion of tibial arteries + one-vessel coronary occlusion group, respectively (p < 0.001); they were also elevated in occlusion of tibial arteries + multiple-vessel coronary occlusion group compared to occlusion of tibial arteries + one-vessel coronary occlusion group and occlusion of tibial arteries + two-vessel coronary occlusion group, respectively (P < 0.001). This has indicated the key roles of oxidative stress and pro-inflammatory mediator genes in arteriosclerosis occlusions of tibial artery in elderly patients with occlusion of coronary arteries. Oxidative response may promote the expressions of inflammatory genes and enhance susceptibility to arteriosclerosis occlusions of the tibial artery in elderly patients with chronic total coronary occlusions.

Age-Related Effects of Olive Oil Polyphenol Ingestion on Oxidation of Low-Density Lipoprotein in Healthy Japanese Men: A Randomized Controlled Double-Blind Crossover Trial.

The function of olive oil polyphenols in suppressing the oxidation of low-density lipoprotein (LDL) is well-known in Europeans. However, it remains unclear whether olive oil polyphenols exert antioxidant effects in Japanese people. The objective of this study was to determine whether the ingestion of olive oil polyphenols suppresses LDL oxidation in the Japanese population and whether this effect depends on age. This randomized controlled double-blind crossover trial with a 2-week washout enrolled 80 healthy Japanese men aged 35-64 years. Participants ingested either 14 g of extra virgin olive oil containing 5.0 mg of olive oil polyphenols (test food) or 14 g of refined olive oil containing 0.3 mg of olive oil polyphenols (control food) for 3 weeks. The primary outcome was oxidized LDL (malondialdehyde-modified LDL; MDA-LDL). Subgroup analyses based on age (35-50 and 51-64 years) were also performed. In all of the participants (35-64 years), there were no significant differences in MDA-LDL between the control and test groups. However, in the 35-50 years subgroup, ingestion of olive oil polyphenols led to a significantly larger reduction in MDA-LDL as compared with the control group (p < 0.025). The significantly lower dietary total polyphenol intake of the 35-50 years subgroup compared to the 51-64 years subgroup suggests that the suppressive function of olive oil polyphenol intake on LDL oxidation in Japanese men is influenced by dietary habits and is more clearly demonstrated in the younger age population with a relatively low total polyphenol intake.

Very short-term effects of a single dose of a proprotein convertase subtilisin/kexin 9 inhibitor before percutaneous coronary intervention: A single-arm study

Background and aimsThe short-term (within 6 weeks) effects of proprotein convertase subtilisin/kexin 9 (PCSK9) inhibitors on lipid plaques have not been adequately evaluated. We aimed to investigate whether a single dose of a PCSK9 inhibitor before percutaneous coronary intervention (PCI) could reduce the abundance of lipid-core plaques identified via near-infrared spectroscopy intravascular ultrasound (NIRS-IVUS) at target lesions within a very short period. MethodsThis prospective, single-arm, single-center interventional study enrolled 27 consecutive patients with coronary artery disease. These patients underwent NIRS-IVUS during coronary angiography and repeat NIRS-IVUS during PCI performed between 2 and 6 weeks after the single-dose administration of 420 mg evolocumab. Changes in lesion lipid-core burden index (LCBI) and maximal LCBI over any 4-mm segment (max-LCBI4mm) were assessed using NIRS at the target lesions, along with lipid profile. ResultsThe max-LCBI4mm significantly decreased from 387 before PCSK9 inhibitor administration to 315 after its administration (interquartile range [IQR]: 268–572 and 221–488, respectively; p = 0.02) within a very short period. The lesion LCBI also decreased from 161 to 117 (IQR: 105–263 and 65–226, respectively; p = 0.02). No significant changes were observed in the minimum lumen area and diameter. After PCSK9 inhibitor administration, low-density lipoprotein (LDL) cholesterol (p < 0.001), lipoprotein(a) (p = 0.001), and malondialdehyde-modified LDL (p < 0.001) levels decreased compared with those before its administration. ConclusionsA single dose of the PCSK9 inhibitor administered before PCI reduced the abundance of lipid-core plaques identified via NIRS-IVUS at target lesions within a very short period of 2–6 weeks.

Increased circulating levels of malondialdehyde-modified low-density lipoprotein in patients with coronary microvascular dysfunction

Coronary microvascular dysfunction (CMD) is associated with angina symptoms and adverse clinical outcomes in patients without obstructive coronary artery disease (CAD). Malondialdehyde-modified low-density lipoprotein (MDA-LDL) is reportedly a marker of the initiation and acceleration of epicardial coronary atherosclerosis. However, its impact on CMD remains unclear. We aimed to investigate the relationship between CMD and MDA-LDL levels. This study included 95 patients who did not receive lipid-lowering medications and had no obstructive CAD. Obstructive CAD was defined as >50 % diameter reduction on coronary angiography or fractional flow reserve of ≤0.80. We retrospectively analyzed coronary flow reserve (CFR), index of microcirculatory resistance (IMR), and MDA-LDL levels. CMD was defined as either CFR <2.0 or IMR ≥25. CMD was observed in 29 (31 %) patients. MDA-LDL levels were significantly higher in patients with CMD than in those without CMD (124.8 ± 37.6 vs. 95.3 ± 29.5 U/L; p < 0.01). Univariable logistic regression analysis indicated a significant relationship between CMD and MDA-LDL levels (odds ratio (OR): 1.03; p < 0.01). In the multivariable model, MDA-LDL levels were significantly associated with CMD (OR: 1.02; p < 0.01). Regression analysis showed a significant correlation between MDA-LDL levels and CFR (r = -0.42, p < 0.01) and IMR (r = 0.35, p < 0.01). In the multiple regression analysis, MDA-LDL levels were independently associated with CFR (β = -0.30, p < 0.01) and IMR (β = 0.26, p = 0.02). MDA-LDL levels were associated with CMD in patients without obstructive CAD.

Roles of MDA-LDL/OX-LDL/LOX-1 and TNF-α/TLR4/NF-κB Signaling Pathways in Myocardial Damage by Implantations of Cardiac Pacemakers in Elderly Patients.

Permanent pacemakers are an established treatment for sick sinus syndrome and high-grade atrioventricular block. Permanent cardiac pacemaker implantations may damage the myocardium. This study evaluated markers of myocardial injury, oxidative stress and inflammation in elderly patients with permanent pacemaker implantations. Various markers were measured at 1, 2, 3 and 4 months after permanent pacemaker implantations in elderly patients. The levels of high-sensitivity troponin T (hsTnT), lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1), malondialdehyde-modified low-density lipoprotein (MDA-LDL), oxidized low-density lipoprotein (OX-LDL), tumour necrosis factor-α (TNF-α), toll-like receptor 4 (TLR4) and nuclear factor-kappa B (NF-κB) were increased in 2-month group compared with control and 1- month groups (P<0.001), and were further increased at 4-month group compared with 2- and 3- month groups after pacemaker implantations (P<0.001). Patients with dual-chamber pacemakers had higher levels of hsTnT, LOX-1, MDA-LDL, OX-LDL, TNF-α, TLR4 and NF-κB than patients with single chamber pacemakers (P<0.001). Patients who underwent the pacemakers with the active fixation leads had raised levels of hsTnT, LOX-1, MDA-LDL, OX-LDL, TNF-α, TLR4 and NF-κB compared patients with pacemakers using the passive fixation leads (P<0.001). Myocardial blood flows in 3-month and 4-month groups were lower than 1-month and 2-month groups (P<0.001). Levels of hsTnT, LOX-1, MDA-LDL, OX-LDL, TNF-α, TLR4 and NF-κB were elevated in elderly patients with permanent pacemaker implantations and the activations of oxidative stress and pro-inflammatory signalling pathways may be associated with myocardial damages and ischemia after pacemaker implantations in elderly patients.

Serum Malondialdehyde-Modified Low-Density Lipoprotein as a Risk Marker for Peripheral Arterial Stiffness in Maintenance Hemodialysis Patients.

Background and Objectives: Peripheral arterial stiffness (PAS), assessed by brachial-ankle pulse wave velocity (baPWV), is an independent biomarker of cardiovascular diseases (CVD) in patients on maintenance hemodialysis (HD). Malondialdehyde-modified low-density lipoprotein (MDA-LDL), an oxidative stress marker, has been linked to atherosclerosis and CVD. However, the association between serum MDA-LDL and PAS among HD patients has not been fully elucidated. This study aimed to examine the association of serum MDA-LDL with PAS in HD patients and to identify the optimal cutoff value of serum MDA-LDL for predicting PAS. Materials and Methods: A cross-sectional study was conducted in 100 HD patients. Serum MDA-LDL was quantified using an enzyme-linked immunosorbent assay (ELISA), and baPWV was measured using a volume plethysmographic device. Patients were divided into the PAS group (baPWV > 18.0 m/s) and the non-PAS group (baPWV ≤ 18.0 m/s). The associations of baPWV and other clinical and biochemical parameters with serum MDA-LDL were assessed by multivariable logistic regression analyses. A receiver operating characteristic (ROC) curve analysis was performed to determine the optimal cutoff value of serum MDA-LDL for predicting PAS. Results: In multivariable logistic regression analysis, higher serum MDA-LDL, older age, and higher serum C-reactive protein [odds ratios (ORs) and 95% confidence intervals: 1.014 (1.004-1.025), 1.044 (1.004-1.085) and 3.697 (1.149-11.893)] were significantly associated with PAS. In the ROC curve analysis, the optimal cutoff value of MDA-LDL for predicting PAS was 80.91 mg/dL, with a sensitivity of 79.25% and a specificity of 59.57%. Conclusions: Greater serum MDA-LDL levels, particularly ≥80.91 mg/dL, were independently associated with PAS in HD patients. The findings suggest that oxidative stress plays a crucial role in the pathogenesis of PAS, and targeting MDA-LDL may be a potential therapeutic strategy for reducing cardiovascular risk in HD patients.

Cardiac Radiofrequency Ablation Exacerbates Myocardial Injury through Pro-Inflammatory Response and Pro-Oxidative Stress in Elderly Patients with Persistent Atrial Fibrillation.

There is a need to assess myocardial damage after radiofrequency ablation of the pulmonary veins (PV) for persistent atrial fibrillation (PAF) in elderly patients. To evaluate oxidative stress, inflammatory response and myocardial damage in elderly patients with PAF after radiofrequency ablation of the PV. High-sensitivity troponin T (hsTnT), malondialdehyde-modified low-density lipoprotein (MDA-LDL), acrolein (ACR), lipid hydroperoxide (LHP), toll-like receptor 4 (TLR4), soluble growth stimulation expressed gene 2 (sST2), angiotensin II (Ang II) and myocardial blood flow (MBF) were determined before ablation and at 1, 3 and 5 months after radiofrequency ablation. The levels of hsTnT, MDA-LDL, ACR, LHP, TLR4, sST2 and Ang II were increased 3 months after ablations compared with before ablation and 1 month after ablation, respectively (P<0.001); they were further increased at 5 months after ablation compared with the 1- and 3-month groups, respectively (P<0.001). MBF was decreased in the 3 months group after ablations compared with before ablation and 1-month after ablation, respectively (P<0.001), and was further decreased in 5-months after ablations compared with 1-month and 3-month groups, respectively (P<0.001). Patients with epicardial monopolar radiofrequency ablation had higher levels of hsTnT, MDA-LDL, ACR, LHP, TLR4, sST2, Ang II and lower MBF than patients with endocardial monopolar and bipolar radiofrequency ablations, respectively (P<0.001). Monopolar radiofrequency ablation method could result in more myocardial injury than bipolar radiofrequency ablation. Oxidative stress and inflammatory response may be involved in cardiac radiofrequency ablation-induced myocardial injury, resulting in myocardial ischemia in elderly patients with PAF.

Dicarbonyl-modified low-density lipoproteins are key inducers of LOX-1 and NOX1 gene expression in cultured human umbilical vein endotheliocytes

The expression of LOX-1 and NOX1 genes in human umbilical vein endotheliocytes (HUVECs) when cultured in the presence of low-density lipoproteins (LDL) modified with various natural dicarbonyls was investigated for the first time. It was found that of the investigated dicarbonyl-modified LDLs (malondialdehyde (MDA)-modified LDLs, glyoxal-modified LDLs, and methylglyoxal-modified LDLs), namely MDA-modified LDLs caused the greatest induction of LOX-1 and NOX1 genes, as well as genes of antioxidant enzymes and genes of signaling molecules in HUVECs. MDA-modified LDLs also induce the highest peroxiredoxins expression of the studied antioxidant enzyme genes. The key role of dicarbonyl-modified LDLs in the molecular mechanisms of vascular wall damage and endothelial dysfunction is discussed.

Dicarbonyl-Modified Low-Density Lipoproteins Are Key Inducers of LOX-1 and NOX1 Gene Expression in the Cultured Human Umbilical Vein Endotheliocytes.

Expression of LOX-1 and NOX1 genes in the human umbilical vein endotheliocytes (HUVECs) cultured in the presence of low-density lipoproteins (LDL) modified with various natural dicarbonyls was investigated for the first time. It was found that among the investigated dicarbonyl-modified LDLs (malondialdehyde (MDA)-modified LDLs, glyoxal-modified LDLs, and methylglyoxal-modified LDLs), the MDA-modified LDLs caused the greatest induction of the LOX-1 and NOX1 genes, as well as of the genes of antioxidant enzymes and genes of proapoptotic factors in HUVECs. Key role of the dicarbonyl-modified LDLs in the molecular mechanisms of vascular wall damage and endothelial dysfunction is discussed.

Lipid Peroxidation via Regulating the Metabolism of Docosahexaenoic Acid and Arachidonic Acid in Autistic Behavioral Symptoms.

The association between the lipid peroxidation product malondialdehyde (MDA)-modified low-density lipoprotein (MDA-LDL) and the pathophysiology of autism spectrum disorder (ASD) is unclear. This association was studied in 17 children with ASD and seven age-matched controls regarding autistic behaviors. Behavioral symptoms were assessed using the Aberrant Behavior Checklist (ABC). To compensate for the small sample size, adaptive Lasso was used to increase the likelihood of accurate prediction, and a coefficient of variation was calculated for suitable variable selection. Plasma MDA-LDL levels were significantly increased, and plasma SOD levels were significantly decreased in addition to significantly increased plasma docosahexaenoic acid (DHA) levels and significantly decreased plasma arachidonic acid (ARA) levels in the 17 subjects with ASD as compared with those of the seven healthy controls. The total ABC scores were significantly higher in the ASD group than in the control group. The results of multiple linear regression and adaptive Lasso analyses revealed an association between increased plasma DHA levels and decreased plasma ARA levels, which were significantly associated with total ABC score and increased plasma MDA-LDL levels. Therefore, an imbalance between plasma DHA and ARA levels induces ferroptosis via lipid peroxidation. Decreased levels of α-linolenic acid and γ-linolenic acid may be connected to the total ABC scores with regard to lipid peroxidation.

Anti-MDA-LDL antibody levels indicate protection from coronary CT-derived valve calcification in the SCOT-HEART Trial

Abstract Introduction Coronary CT-derived valve calcification is becoming increasingly important in the multi-modality assessment of valvular disease, especially in aortic and mitral stenosis, where trans-catheter structural heart interventions may be indicated. Separately, natural antibodies targeted against malondialdehyde-modified LDL (MDA-LDL), an important subset of all oxidised low-density lipoproteins, are related to less coronary atherosclerosis and freedom from cardiovascular events. Purpose To investigate possible relationships between coronary CT-derived valve calcification and anti-MDA-LDL antibodies. Methods In a substudy of the multicentre randomised controlled SCOT-HEART trial (Scottish COmputed Tomography of the HEART), we investigated the association between manually assessed presence or absence of mitral and aortic valve calcification and IgM/ IgG anti-MDA-LDL antibodies. Serological biomarkers were measured using laboratory-developed enzyme-linked immunosorbent assays and assessed in tertiles versus imaging parameters, with adjustment for the ASSIGN cardiovascular risk score. Results In 830 patients (53% male, 57.6±9.8 years) with a heavy burden of cardiovascular risk factors (36% hypertension, 12% diabetes mellitus and 55% history of current or ex-smoking), the highest tertile of IgM anti-MDA-LDL related to a lower incidence of aortic valve calcification (odds ratio [95% confidence interval], 0.59 [0.36 – 0.96], p=0.04, p=0.07 for trend across tertiles) and mitral valve calcification (0.26 [0.07–0.72], p=0.02, p=0.05 for trend). There was also a trend for the highest tertile of IgG anti-MDA-LDL antibodies relating to a lower incidence of aortic valve calcification (0.36 [0.10–0.99], p=0.05, p=0.25 for trend), but not for mitral valve calcification. Conclusions Anti-MDA-LDL antibody levels were associated with a lower incidence of aortic and mitral valve calcification. Assessment of these novel biomarkers, which are known to relate to freedom from cardiovascular events, may be useful in screening patients prior to coronary CT for planning suitability for trans-catheter structural heart interventions.

Malondialdehyde-Modified Low-Density Lipoprotein as a Predictor of Major Adverse Limb Events after Endovascular Therapy in Patients with Lower Extremity Arterial Disease.

Adverse limb events after endovascular therapy (EVT) are a major concern. This study aimed to investigate the relationship between serum malondialdehyde-modified low-density lipoprotein (MDA-LDL) level, a potentially potent indicator of atherosclerosis, and clinical outcomes after EVT in patients with lower extremity arterial disease (LEAD). A total of 208 LEAD patients who underwent EVT and MDA-LDL measurements were retrospectively analyzed. Those with chronic limb-threatening ischemia (CLTI) were included in the CLTI subgroup (n=106). Patients were further categorized into the High or Low MDA-LDL groups according to the cut-off value calculated by receiver operating characteristic analysis. Major adverse limb events (MALE), a composite of cardiovascular death, limb-related death, major amputation, and target-limb revascularization, were evaluated. MALE occurred in 73 (35%) patients. The median follow-up interval was 17.4 months. The MDA-LDL cut-off values were 100.5 U/L (area under the curve [AUC] 0.651) in the overall population and 98.0 U/L (AUC 0.724) in the CLTI subgroup. Overall, the High MDA-LDL group showed significantly higher total cholesterol (189.7±37.5 mg/dL vs. 159.3±32.0 mg/dL, p＜0.01), low-density lipoprotein cholesterol (114.3± 29.7 mg/dL vs. 87.3±25.3 mg/dL, p＜0.01), and triglyceride (166.9±91.1 mg/dL vs. 115.8±52.3 mg/dL, p＜ 0.01) than the Low MDA-LDL group. Multivariate Cox regression analyses revealed that MDA-LDL and C-reactive protein were independent predictors of MALE. In the CLTI subgroup, MDA-LDL was an independent predictor of MALE. The High MDA-LDL group showed worse MALE-free survival rates than the Low MDA-LDL group in overall (p＜0.01) and in the CLTI subgroup (p=0.01). Serum MDA-LDL level was associated with MALE after EVT.

Lipid Peroxidation of the Docosahexaenoic Acid/Arachidonic Acid Ratio Relating to the Social Behaviors of Individuals with Autism Spectrum Disorder: The Relationship with Ferroptosis.

Polyunsaturated fatty acids (PUFAs) undergo lipid peroxidation and conversion into malondialdehyde (MDA). MDA reacts with acetaldehyde to form malondialdehyde-modified low-density lipoprotein (MDA-LDL). We studied unsettled issues in the association between MDA-LDL and the pathophysiology of ASD in 18 individuals with autism spectrum disorders (ASD) and eight age-matched controls. Social behaviors were assessed using the social responsiveness scale (SRS). To overcome the problem of using small samples, adaptive Lasso was used to enhance the interpretability accuracy, and a coefficient of variation was used for variable selections. Plasma levels of the MDA-LDL levels (91.00 ± 16.70 vs. 74.50 ± 18.88) and the DHA/arachidonic acid (ARA) ratio (0.57 ± 0.16 vs. 0.37 ± 0.07) were significantly higher and the superoxide dismutase levels were significantly lower in the ASD group than those in the control group. Total SRS scores in the ASD group were significantly higher than those in the control group. The unbeneficial DHA/ARA ratio induced ferroptosis via lipid peroxidation. Multiple linear regression analysis and adaptive Lasso revealed an association of the DHA/ARA ratio with total SRS scores and increased MDA-LDL levels in plasma, resulting in neuronal deficiencies. This unbeneficial DHA/ARA-ratio-induced ferroptosis contributes to autistic social behaviors and is available for therapy.

Clearance and Utilization of Dicarbonyl-Modified LDL in Monkeys and Humans.

The kinetics of elimination of various dicarbonyl-modified low-density lipoproteins from the bloodstream of Macaca mulatta monkeys were investigated. The low-density lipoproteins (LDL) in the monkey blood plasma were isolated by density gradient ultracentrifugation and labeled in vitro with the fluorescent dye FITC; thereupon, they were modified with different natural low molecular-weight dicarbonyls: malondialdehyde (MDA), glyoxal, or methylglyoxal. The control native FITC-labeled LDL and dicarbonyl-modified FITC-labeled LDL were injected into the monkey's ulnar vein; thereafter, blood samples were taken at fixed time intervals during 24 h. The plasma level of FITC-labeled LDL was determined with spectrofluorimetry. The study established that glyoxal- and monkeysglyoxal-labeled LDL circulated in monkey virtually at the same time as native (non-modified) LDL. In contrast, MDA-modified LDL disappeared from the blood extremely rapidly. Administration of the PCSK9 inhibitor involocumab (which increases LDL utilization) to patients with coronary heart disease (CHD) was found to significantly reduce levels of MDA-modified LDL.

Effect of febuxostat on the level of malondialdehyde-modified low-density lipoprotein, an oxidative stress marker: A subanalysis of the PRIZE study.

Febuxostat is a selective xanthine oxidase inhibitor that reportedly exhibits antioxidant properties. We previously performed a multicentre, randomized controlled (PRIZE) study for vascular evaluation under uric acid (UA) control by febuxostat to investigate the progression of carotid lesions in asymptomatic hyperuricemic patients with carotid atherosclerosis for 2 years. The current subanalysis of the PRIZE study aimed to assess the effect of febuxostat on the level of malondialdehyde-modified low-density lipoprotein (MDA-LDL), an oxidative stress marker. We recruited 383 patients (febuxostat group, n = 200; control group, n = 183) from the PRIZE trial for whom MDA-LDL measurements were available. The UA, MDA-LDL, low-density lipoprotein cholesterol (LDL-C) levels, and MDA-LDL/LDL-C ratio were identified, represented as the estimated difference from baseline to 24months. We also evaluated the relationship between febuxostat dose (10, ≤20 to <40, and ≤40 to ≤60 mg) and changes in the MDA-LDL level, LDL-C level, or MDA-LDL/LDL-C ratios. The estimated change in MDA-LDL/LDL-C ratio from baseline to 24monthswas significantly lower in the febuxostat group than in the control group (p = .025), whereas the estimated changes in MDA-LDL (p = .235) and LDL-C (p = .323) levels did not differ between the two groups. No significant correlation existed between the febuxostat doses and the estimated change in the MDA-LDL level (p = .626), LDL-C level (p = .896), or MDA-LDL/LDL-C ratio (p = .747). Our findings may indicate a possibility that febuxostat can lower the MDA-LDL/LDL-C ratio, a potential marker of atherosclerosis and oxidative stress, in asymptomatic hyperuricemic patients with carotid atherosclerosis. Further studies are required to validate our findings and elucidate the clinical antioxidant effect of febuxostat.

Simultaneous Electrochemical Detection of LDL and MDA-LDL Using Antibody-Ferrocene or Anthraquinone Conjugates Coated Magnetic Beads.

The simultaneous detection of atherosclerotic cardiovascular disease (ACSVD) biomarkers was recently of great scientific interest. In this work, magnetic beads-based immunosensors for the simultaneous detection of low density lipoprotein (LDL) and malondialdehyde-modified low density lipoprotein (MDA-LDL) were presented. The approach proposed was based on the formation of two types of specific immunoconjugates consisting of monoclonal antibodies: anti-LDL or anti-MDA-LDL, together with redox active molecules: ferrocene and anthraquinone, respectively, coated on magnetic beads (MBs). The decrease in redox agent current in the concentration range: 0.001-1.0 ng/mL for LDL and 0.01-10.0 ng/mL for MDA-LDL, registered by square wave voltammetry (SWV), was observed upon the creation of complex between LDL or MDA-LDL and appropriate immunoconjugates. The detection limits of 0.2 ng/mL for LDL and 0.1 ng/mL for MDA-LDL were estimated. Moreover, the results of selectivity against the possible interferents were good, as human serum albumin (HSA) and high density lipoprotein (HDL), stability and recovery studies demonstrated the potential of platform proposed for early prognosis and diagnosis of ASCVD.

Impact of triglyceride-rich lipoproteins on early in-stent neoatherosclerosis formation in patients undergoing statin treatment

Neoatherosclerosis (NA), which refers to neointimal atherosclerosis within a stent, is considered one of the underlying causes of late-phase stent failure following a newer generation drug-eluting stent (DES) placement procedure. Even contemporary guideline-directed medical therapy may be insufficient to prevent NA. This study aimed to investigate how intricately lipid markers are associated with NA formation in the early phase of treatment with well-maintained low-density lipoprotein cholesterol (LDL-C) levels. We enrolled 114 consecutive patients undergoing statin treatment and percutaneous coronary intervention (PCI) with current-generation DES for coronary artery disease. At a median 12 months after PCI, optical coherence tomography (OCT) was performed. Various lipid markers, including LDL-C, triglyceride (TG), triglyceride-rich lipoprotein cholesterol (TRL-C), non-high-density lipoprotein cholesterol (non-HDL-C), malondialdehyde-modified LDL (MDA-LDL), and several apolipoproteins, were also evaluated. NA was observed in 17 (14.9%) patients. The LDL-C level was equivalent in patients with or without NA (77.2 vs. 69.8 mg/dL; p=0.15). However, the levels of TG, apolipoprotein C3 (apoC3), TRL-C, non-HDL-C, and apolipoprotein B (apoB), and MDA-LDL were significantly higher in the patients with NA. Furthermore, multivariate logistic regression adjusting for HbA1c and stent duration revealed apoC3, TRL-C, non-HDL-C, apoB, and MDA-LDL levels as risk factors for NA. However, when apoB was included as a covariate, other factors became nonsignificant. Abnormal triglyceride-rich lipoprotein metabolism and high atherogenic apoB-containing lipoprotein particle numbers are associated with the formation of NA in patients undergoing statin treatment at a median 12 months post-PCI.

PS-C34-7: EFFECT OF FEBUXOSTAT ON THE LEVEL OF MALONDIALDEHYDE-MODIFIED LOW-DENSITY LIPOPROTEIN, AS AN OXIDANT MARKER, FROM THE SUB-ANALYSES OF PRIZE STUDY

Background: Febuxostat is a selective xanthine oxidase inhibitor that has been reported to possess antioxidant properties in experimental and animal studies. We previously conducted the program of vascular evaluation under uric acid control by xanthine oxidase inhibitor, febuxostat: multicenter, randomized controlled (PRIZE) study to evaluate the progression of carotid lesions in asymptomatic hyperuricemic patients with carotid atherosclerosis treated with febuxostat for 2 years compared with a control group. In the present sub-analysis study of the PRIZE study, the effect of febuxostat on the level of malondialdehyde modified low density lipoprotein (MDA-LDL), one of the oxidative stress markers, was examined. Methods: The subjects were 381 patients enrolled in the PRIZE trial for whom MDA-LDL measurements were available at baseline and at 24 months (182 in the febuxostat group and 199 in the control group). Uric acid (UA) levels, MDA-LDL levels, and MDA-LDL/LDL-C were determined, expressed as the estimated difference from baseline to 24 months, and compared between the two groups. We also examined the relationship between febuxostat dose (10 mg, 20–40 mg, 40–60 mg) and changes in MDA-LDL or MDA-LDL/LDL-C. Results: Febuxostat significantly reduced the level of UA, compared with that in the control group, in a dose-dependent manner (p &lt; 0.001). The estimated difference in MDA-LDL/LDL-C from baseline to 24 months was significantly lower in the Febuxostat group than that in the control group (p = 0.025), while the estimated difference in MDA-LDL from baseline to 24 months was not different in the two groups (p = 0.235). There was no significant correlation between the dose of febuxostat and the estimated difference in MDA-L/LDL-C (p = 0.626). Conclusions: In asymptomatic hypereuricemia patients with carotid atherosclerosis, febuxostat may have some antioxidant effect, but the effect may not be dose-dependent.

Atherogenic Lipoproteins for the Statin Residual Cardiovascular Disease Risk

Randomized controlled trials (RCTs) show that decreases in low-density lipoprotein cholesterol (LDL-C) by the use of statins cause a significant reduction in the development of cardiovascular disease (CVD). However, one of our previous studies showed that, among eight RCTs that investigated the effect of statins vs. a placebo on CVD development, 56-79% of patients had residual CVD risk after the trials. In three RCTs that investigated the effect of a high dose vs. a usual dose of statins on CVD development, 78-87% of patients in the high-dose statin arms still had residual CVD risk. The risk of CVD development remains even when statins are used to strongly reduce LDL-C, and this type of risk is now regarded as statin residual CVD risk. Our study shows that elevated triglyceride (TG) levels, reduced high-density lipoprotein cholesterol (HDL-C), and the existence of obesity/insulin resistance and diabetes may be important metabolic factors that determine statin residual CVD risk. Here, we discuss atherogenic lipoproteins that were not investigated in such RCTs, such as lipoprotein (a) (Lp(a)), remnant lipoproteins, malondialdehyde-modified LDL (MDA-LDL), and small-dense LDL (Sd-LDL). Lp(a) is under strong genetic control by apolipoprotein (a), which is an LPA gene locus. Variations in the LPA gene account for 91% of the variability in the plasma concentration of Lp(a). A meta-analysis showed that genetic variations at the LPA locus are associated with CVD events during statin therapy, independent of the extent of LDL lowering, providing support for exploring strategies targeting circulating concentrations of Lp(a) to reduce CVD events in patients receiving statins. Remnant lipoproteins and small-dense LDL are highly associated with high TG levels, low HDL-C, and obesity/insulin resistance. MDA-LDL is a representative form of oxidized LDL and plays important roles in the formation and development of the primary lesions of atherosclerosis. MDA-LDL levels were higher in CVD patients and diabetic patients than in the control subjects. Furthermore, we demonstrated the atherogenic properties of such lipoproteins and their association with CVD as well as therapeutic approaches.