Malondialdehyde-modified Low-density Lipoprotein Levels Research Articles

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 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 methods 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.

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.

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.

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.

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.

The Placebo-Controlled Effect of Percutaneous Coronary Intervention on Exercise Induced Changes in Anti-Malondialdehyde-LDL Antibody Levels in Stable Coronary Artery Disease: A Substudy of the ORBITA Trial.

Aim: Malondialdehyde-modified low-density lipoprotein (MDA-LDL) forms a significant component of oxidised LDL. The effects of exercise on levels of MDA-LDL and anti-MDA-LDL antibodies are not well-understood. Furthermore, it is not known whether these can be modified in patients with coronary artery disease by percutaneous coronary intervention (PCI).Methods: The Objective Randomised Blinded Investigation with optimal medical Therapy of Angioplasty in stable angina (ORBITA) trial was the first blinded, multi-centre randomised trial of PCI vs. placebo procedure for angina relief. Serum samples were available at four time-points: pre-randomisation pre- (P1) and post- (P2) exercise and post-randomisation (6-weeks following the PCI or placebo procedure), pre- (P3) and post- (P4) exercise. ELISAs were performed using laboratory-developed assays for MDA-LDL (adjusted for Apolipoprotein B) and anti-MDA-LDL antibodies.Results: One hundred ninety-six of the 200 patients (age 66.1 [SD 8.99] years, 28% female) with severe single vessel coronary artery disease suitable for PCI enrolled in the ORBITA trial had blood available for analysis. With exercise at pre-randomisation (P2–P1) there was no significant change in adjusted MDA-LDL (−0.001, 95% CI −0.004 to 0.001; p = 0.287); however, IgG and IgM anti-MDA-LDL significantly declined (−0.022, 95% CI −0.029 to −0.014, p < 0.0001; −0.016, 95% CI −0.024 to −0.008, p = 0.0002, respectively). PCI did not have a significant impact on either the pre-exercise values (P3 controlling for P1) of MDA-LDL (p = 0.102), IgG (p = 0.444) or IgM anti-MDA-LDL (p = 0.909). Nor did PCI impact the exercise induced changes in these markers (P4 controlling for P1, P2, and P3) for MDA-LDL (p = 0.605), IgG (p = 0.725) or IgM anti-MDA-LDL (p = 0.171). Pre-randomisation ischaemia on stress echo did not impact these interactions.Conclusions: Exercise results in an acute reduction in anti-oxLDL antibodies in patients with severe single vessel coronary disease, possibly indicating an induction in homoeostatic clearance via the innate immune system. However, PCI did not ameliorate this effect.

Pro-Oxidative Stress, TLR4/NF-κB/MyD88 and GAS6 Pathways, and Atherosclerotic Susceptibility: Development of Tibial Artery Occlusions in Elderly Patients With Chronic Total Coronary Occlusions

Background: Oxidative stress is an important factor in the progression of arterial atherosclerosis. The present study investigated the effects of oxidative stress on atherosclerotic susceptibility and development of arteriosclerosis occlusions of tibial artery through pro-inflammatory mediator genes in elderly patients with chronic total coronary occlusions. Methods: We measured the oxidative stress biomarkers [malondialdehyde-modified low-density lipoprotein (MDA-LDL), oxidized low density lipoprotein (OX-LDL) and 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)] for their impacts on the severity of arteriosclerosis occlusions of tibial artery in elderly patients with chronic total coronary occlusions. Findings: Levels of MDA-LDL, OX-LDL, HO-1, TLR4, NF-κB, MyD88 and GAS6 were significantly increased (P< 0.001) in the patients. This indicated the key roles for oxidative stress and pro-inflammatory mediator genes in arteriosclerosis occlusions of tibial artery in elderly patients with chronic total coronary occlusions. Interpretation: Oxidative stress may promote the over-expressions of pro-inflammatory genes and enhanced susceptibility to arteriosclerosis occlusions of tibial artery in elderly patients with chronic total coronary occlusions. Funding Information: Not applicable. Declaration of Interests: The authors declare that they have no competing financial interests. Ethics Approval Statement: The research was approved by the Human Research Ethics Committee of the Xuzhou Medical University and the Affiliated Huaian Hospital of Xuzhou Medical University according to the relevant laws and regulations of China, and the written informed consent was obtained from all the participants according to the Declaration of Helsinki.

Increased Circulating Malondialdehyde-Modified Low-Density Lipoprotein Level Is Associated with High-Risk Plaque in Coronary Computed Tomography Angiography in Patients Receiving Statin Therapy

Objective: To evaluate the association of serum malondialdehyde low-density lipoprotein (MDA-LDL), an oxidatively modified LDL, with the prevalence of high-risk plaques (HRP) determined with coronary computed tomography angiography (CTA) in statin-treated patients. Methods: This study was a single-center retrospective cohort comprising 268 patients (mean age 67 years, 58% men) with statin therapy and who underwent coronary CTA for suspected stable coronary artery disease. Patients were classified into two groups according to median MDA-LDL level or median LDL-C level. Coronary CTA-verified HRP was defined when two or more characteristics, including positive remodeling, low-density plaques, and spotty calcification, were present. Results: Patients with HRP had higher MDA-LDL (p = 0.011), but not LDL-C (p = 0.867) than those without HRP. High MDA-LDL was independently associated with HRP (odds ratio 1.883, 95% confidential interval 1.082–3.279) after adjustment for traditional risk factors. Regarding incremental value of MDA-LDL for predicting CTA-verified HRP, addition of serum MDA-LDL levels to the baseline model significantly increased global chi-square score from 26.1 to 32.8 (p = 0.010). Conclusions: A high serum MDA-LDL level is an independent predictor of CTA-verified HRP, which can lead to cardiovascular events in statin-treated patients.

Impact of malondialdehyde-modified low-density lipoprotein on clinical outcomes after fractional flow reserve-guided deferral of revascularization.

Cardiovascular events can occur after deferred revascularization, and malondialdehyde-modified low-density lipoprotein (MDA-LDL) has been suggested to be an atherogenic marker. We investigated the relationship between serum MDA-LDL levels and clinical outcomes in patients with fractional flow reserve (FFR)-guided deferral of revascularization. Among 3084 patients undergoing coronary angiography, we retrospectively analyzed 127 patients with intermediate stenosis and deferred revascularization based on FFR > 0.80. Median follow-up interval was 30.4months, and serum MDA-LDL was measured prior to the measurement of FFR. We evaluated the composite of major adverse cardiac events (MACEs), including cardiac death, myocardial infarction, ischemia-driven deferred lesion revascularization, and any revascularization. MACEs occurred in 18 (14.2%) patients. The MACE group presented with significantly higher MDA-LDL levels than the non-MACE group (134.9 ± 33.3 U/L vs. 95.6 ± 32.2 U/L, P < 0.001). In analysis of the receiver operating characteristics curve for the prediction of MACEs, MDA-LDL presented a significantly larger area under the curve than low-density lipoprotein-cholesterol (LDL-C; 0.810 vs. 0.687, P = 0.042). Univariate Cox regression analysis indicated a significant relationship between MACEs and MDA-LDL (per 10 U/L, HR 1.20; P = 0.004), as did the multivariate model (per 10 U/L, HR 1.17; P = 0.019). When compared according to the median LDL-C (98mg/dL), the MACE group had significantly higher MDA-LDL in both the high (147.2 ± 27.3 U/L vs. 113.9 ± 31.2 U/L, P = 0.001) and low (103.2 ± 27.3 U/L vs. 80.2 ± 24.0 U/L, P = 0.045) LDL-C groups. Serum MDA-LDL levels were associated with cardiac events in patients with deferral of revascularization based on FFR.

Association of coronary high-intensity plaque on T1-weighted magnetic resonance imaging and circulating malondialdehyde-modified low-density lipoprotein levels with cardiac events

Abstract Background Although elevated oxidized low-density lipoprotein could play critical roles in vulnerable plaque, there are no studies that compared coronary high-intensity plaque (HIP) on non-contrast T1-weighted magnetic resonance imaging (T1WI_MRI) and circulating malondialdehyde-modified low-density lipoprotein (MDA-LDL) levels for the prediction of cardiac events. Methods and results A total of 139 patients with coronary artery stenosis (&amp;gt;70%) were examined with non-contrast T1WI using a 1.5-T MRI (HIP: n=63, non-HIP: n=76). Scheduled percutaneous coronary intervention (PCI) for culprit lesions was performed within 48 h after MRI. HIP was defined as a signal intensity of coronary plaque to cardiac muscle ratio (PMR) of ≥1.4. At admission, circulating levels of MDA-LDL and other lipid-related markers were measured. We evaluated the subsequent cardiac events, which were defined as major adverse cardiac events (MACE; cardiac death, myocardial infarction, and/or ischemia-driven PCI) during follow-up periods (5.6±1.3 years). Circulating MDA-LDL levels were significantly higher in patients with HIP than in those without HIP (p&amp;lt;0.0001). MDA-LDL levels were significantly correlated with PMR (r=0.490, p&amp;lt;0.0001). In multivariable logistic regression analysis, MDA-LDL levels were independently associated with the presence of HIP (OR 1.05; 95% CI, 1.02–1.08, p&amp;lt;0.0001). The incidence of MACE was significantly higher in patients with HIP (27%) than in those without HIP (5%; p=0.011 by the log-rank test). In the multivariable Cox proportional hazard analysis, the MDA-LDL levels (HR 1.03; 95% CI:1.01–1.05, p=0.007) and PMR (HR 2.39; 95% CI:1.19–4.65, p=0.016) were significantly associated with MACE. For MACE prediction, the C-statistic values for MDA-LDL, PMR, and PMR+MDA-LDL were 0.724, 0.791, and 0.800, respectively. Compared with MDA-LDL alone, the addition of PMR to MDA-LDL increased the net reclassification improvement by 0.78 (p=0.012). Conclusions MDA-LDL levels might be associated with the presence of HIP in patients with coronary artery disease. Furthermore, adding PMR to MDA-LDL levels markedly improved MACE prediction. Funding Acknowledgement Type of funding source: None

Evaluation of Enhanced Lipid Oxidation and Compensatory Suppression using Natriuretic Peptide in Patients with Cardiovascular Diseases

Malondialdehyde-modified low-density lipoprotein (MDA-LDL) is recognized as a surrogate marker of lipid oxidation and is associated with arteriosclerosis. However, there are limited reports on the relationship between heart failure and MDA-LDL. Therefore, we aimed to determine whether MDA-LDL is activated in patients with left ventricular (LV) dysfunction and examine our hypothesis that the B-type natriuretic peptide (BNP) masks the enhancement of MDA-LDL in patients with LV dysfunction by its strong antioxidative action. The study population comprised 2,976 patients with various cardiovascular diseases. Patients were divided into four groups depending on the LV ejection fraction (LVEF) or plasma BNP level. A nonparametric analysis with the Kruskal–Wallis test was used to perform an interquartile comparison. In addition, structural equation modeling and Bayesian estimation were used to compare the effects of LVEF and BNP on MDA-LDL. MDA-LDL levels did not significantly change (P > 0.05) with respect to the degree of LVEF among the four groups. In contrast, MDA-LDL levels were significantly decreased (P < 0.001) with respect to the degree of BNP among the four groups. A path model based on structural equation modeling clearly showed a significant effect of LVEF (standardized regression coefficient; β: -0.107, P < 0.001) and BNP (β: -0.114, P < 0.001) on MDA-LDL, with a significant inverse association between LVEF and BNP (correlation coefficient -0.436, P < 0.001). MDA-LDL should be activated in patients with LV dysfunction; however, BNP is thought to exert a strong compensatory suppression on lipid oxidation, masking the relationship between heart failure and lipid oxidation.

Increased Serum Malondialdehyde-Modified Low-Density Lipoprotein and Coronary Angiographic Progression After Drug-Eluting Stent Implantation in Patients With Stable Angina.

Cardiac events can occur after drug-eluting stent (DES) implantation due to coronary plaque progression at non-stented sites. Malondialdehyde-modified low-density lipoprotein (MDA-LDL) is suggested to be an atherogenic marker. This study investigated the relationship between serum MDA-LDL and angiographic progression after DES implantation.Methods and Results:In total, 207 patients who underwent percutaneous coronary intervention (PCI) using DES and follow-up coronary angiography were retrospectively analyzed. MDA-LDL was serially measured before PCI and at follow up. Persistent high MDA-LDL was defined as a MDA-LDL level more than the median value both before PCI and at follow up. Angiographic progression was assessed by serial analysis of quantitative coronary angiography. Angiographic progression occurred in 35 patients (16.9%). MDA-LDL before PCI was significantly higher in the progression group than the non-progression group in all patients (143.4±35.8 U/L vs. 103.0±33.5U/L, P<0.001) and in patients with controlled LDL-cholesterol (LDL-C <100 mg/dL both before PCI and at follow up; 121.8±32.7 U/L vs. 84.9±24.9 U/L, P<0.001). There were positive correlations between % diameter stenosis changes and serum MDA-LDL before PCI in all patients (r=0.33, P<0.01) and those with controlled LDL-C (r=0.23, P=0.04). In multivariate logistic regression analysis, persistent high MDA-LDL was an independent predictor of plaque progression. Increased serum MDA-LDL was associated with angiographic progression after DES implantation.

Serum Malondialdehyde-Modified Low-Density Lipoprotein Is a Risk Factor for Central Arterial Stiffness in Maintenance Hemodialysis Patients.

Circulating malondialdehyde-modified low-density lipoprotein (MDA-LDL) acts as a marker of oxidative stress and is associated with atherosclerotic cardiovascular disease. The relationship between serum MDA-LDL levels and aortic stiffness (AS) in patients with hemodialysis (HD) was evaluated. There were 155 HD patients enrolled in this study. Carotid-femoral pulse wave velocity (cfPWV) was measured by a validated tonometry system. Patients with cfPWV >10 m/s were used to define the AS group, while those with values of ≤10 m/s were regarded as the control group. Serum MDA-LDL levels were measured using a commercial enzyme-linked immunosorbent assay. Sixty-eight patients (43.9%) who were defined as AS sufferers, and were older, had a higher percentage of diabetes and hypertension and higher systolic blood pressure and serum MDA-LDL level compared to subjects in the control group. After adjusting for factors significantly associated with AS by multivariable logistic regression analysis, it was revealed that serum MDA-LDL levels, diabetes, and hypertension were independent predictors of AS in HD patients. Multivariable forward stepwise linear regression analysis also showed that a logarithmically transformed MDA-LDL level was significantly correlated with cfPWV values in HD patients. In HD patients, a high serum MDA-LDL level was positively associated with cfPWV values and was a significant predictor of the development of high AS.

The Association between the Triglyceride to High-density Lipoprotein Cholesterol Ratio and Low-density Lipoprotein Subclasses.

Objective The triglyceride (TG)/high-density lipoprotein cholesterol (HDL-C) ratio is related to insulin resistance (IR). However, information about whether or not the TG/HDL-C ratio is associated with low-density lipoprotein (LDL) subclasses in the Japanese population is limited. Methods In total, 1,068 Japanese subjects who underwent an annual health examination and who were not taking medications were recruited. The association between the TG/HDL-C ratio and LDL subclasses was investigated using correlation, multiple regression, and receiver operating characteristic analyses. Results A correlation analysis revealed that both malondialdehyde-modified low-density lipoprotein (MDA-LDL) and small dense low-density lipoprotein cholesterol (sdLDL-C) were positively associated with the TG/HDL-C ratio. Furthermore, a multiple linear regression analysis revealed that the TG/HDL-C ratio was positively associated with MDA-LDL and sdLDL-C in both men and women. The multiple logistic regression analysis also revealed that the TG/HDL-C ratio was positively associated with the upper tertile of MDA-LDL and sdLDL-C in men and women. The LDL-C levels increased with the increasing TG/HDL-C ratio. The MDA-LDL and sdLDL-C are known to be positively associated with LDL-C. However, within the same LDL-C range, both MDA-LDL and sdLDL-C levels increased with the TG/HDL-C ratio, except for MDA-LDL levels in the LDL-C <112 mg/dL group in women. These results further supported the notion that the TG/HDL-C ratio was positively associated with the MDA-LDL and sdLDL-C levels, especially in the higher LDL-C range, in both men and women. The optimal cut-off points of the TG/HDL-C ratio for the upper tertile of MDA-LDL and sdLDL-C were 1.85 and 2.03 in men and 0.88 and 1.30 in women, respectively. Conclusion The TG/HDL-C ratio is positively associated with MDA-LDL and sdLDL-C in Japanese subjects. The relationship was particularly notable in subjects with high LDL-C levels.

The role of lipid peroxidation in individuals with autism spectrum disorders.

The role of malondialdehyde-modified low-density lipoprotein (MDA-LDL), an oxidized LDL, in the pathophysiology of autism spectrum disorder (ASD) is unclear. We studied association between MDA-LDL and behavioral symptoms in 11 individuals with ASD and 7 age -matched normal controls. Behavioral symptoms were assessed using the Aberrant Behavior Checklists (ABC). Because small sample size in this study, three measures were conducted: first, employment of adaptive Lasso for enhancing the accuracy of prediction and interpretability; second, calculation of coefficient of variation for an appropriate selection of plasma variables; and third, selection of good candidates of plasma variables. Plasma levels of MDA-LDL, eicosapentaenoic acid, docosahexaenoic acid (DHA) and DHA/arachidonic acid ratios were significantly higher, while plasma superoxide dismutase (SOD) levels were significantly lower in the ASD group than in the control group. The total ABC scores were significantly higher in the ASD group than in the control group. Multiple linear regression analysis and the adaptive Lasso revealed association of increased plasma DHA levels with the ABC total scores and increased plasma MDA-LDL levels. Such association between DHA and plasma MDA-LDL levels may contribute to behavior in individuals with ASD.

P3098Association with coronary high-intensity plaque on T1-weighted magnetic resonance imaging and circulating levels of malondialdehyde-modified low-density lipoprotein

Abstract Objectives This study aimed to evaluate the association with coronary high-intensity plaque (HIP) on non-contrast T1-weighted magnetic resonance imaging (T1WI) and circulating levels of malondialdehyde-modified low-density lipoprotein (MDA-LDL). Methods A total of 139 patients with coronary artery stenosis (&gt;70%) were imaged with non-contrast T1WI by using a 1.5-T magnetic resonance system (HIP: n=60, non-HIP: n=79). HIP was defined as a signal intensity of coronary plaque to cardiac muscle ratio (PMR) of ≥1.4. At admission, circulating levels of MDA-LDL and other lipid-related markers (triglyceride, HDL, LDL, Lp(a), RLP-C, and EPA/AA) were measured. Results Circulating levels of MDA-LDL (p=0.001) and LDL (p=0.041) were significantly higher in patients with HIP than those without, whereas the other lipid-related markers were not significantly different between both groups. In multivariable logistic regression analysis, MDA-LDL levels were independently associated with the presence of HIP (OR 1.03; 95% CI, 1.00–1.06, p=0.015) after adjusting for cofounding factors (age, sex, triglyceride, LDL, Lp(a), RLP-C, and EPA/AA). The optimal MDA-LDL threshold for predicting coronary HIP was 90.4 U/L, identified by the receiver operating characteristic curve. Conclusion MDA-LDL levels might be associated with the presence of HIP in patients with coronary artery disease.