Lipoprotein-associated Phospholipase A2 Activity Levels Research Articles

Lipoprotein-associated phospholipase A2 activity levels is associated with artery to artery embolism in symptomatic intracranial atherosclerotic disease

BackgroundLipoprotein-associated phospholipase A2 activity (Lp-PLA2-A) is a pivotal enzyme involved in the inflammatory process and atherosclerotic plaque vulnerability. This study aimed to investigate the potential of Lp-PLA2-A as a biomarker for reflecting artery-to-artery embolism (AAE), a critical mechanism with high risk of stroke recurrence in symptomatic intracranial atherosclerotic disease (sICAD). MethodsThe current analysis included a cohort of 1,908 patients with sICAD and baseline levels of Lp-PLA2-A from the Third China National Stroke Registry (CNSR-III). The baseline Lp-PLA2-A levels were quantified centrally using an automatic enzyme assay system. Diagnosis of sICAD was made by experienced stroke neurologists based on the presence of a cerebral infarction within the territory of a stenotic (>50 %) or occluded artery, or when clinical symptoms were consistent with the diagnosis. Infarct lesions affecting the cortex serve as imaging biomarkers for stroke mechanism involving AAE.The relationship between baseline Lp-PLA2-A quartile levels and the presence of cortical infarction was analyzed using multivariate logistic regression. ResultsCompared to patients in the first Lp-PLA2-A quartile, those in the second, third and fourth quartiles demonstrated a significantly higher proportion of AAE. The proportion of patients with cortical infarction increased with rising Lp-PLA2-A quartiles, observed at 39.3 %, 47.1 %, 47.4 %, and 50.7 % for the first, second, third and fourth quartiles respectively (P for trend=0.004). Compared with the first quartile, the odds ratios (ORs) were 1.38 (95 % CI = 1.06-1.79) for the second, 1.33 (95 % CI = 1.02-1.72) for the third quartile and 1.48 (95 % CI = 1.14-1.92) for the fourth quartile. The association between higher Lp-PLA2-A and increased proportion of cortical infarction was also present in the subgroups defined by age <65 years, male, and high-sensitivity C-reactive protein ≥2 mg/L. In sensitivity analyses, the positive correlation between Lp-PLA2-A levels and proportion of cortical infarction remained consistent. ConclusionsThis research highlights the significance of Lp-PLA2-A as a biomarker for reflecting stroke mechanism in sICAD. Additional studies are warranted to explore the potential of targeting Lp-PLA2-associated inflammatory pathways as a pivotal approach in arresting the advancement of intracranial atherosclerotic stenosis and reducing the incidence of embolic strokes.

Higher serum Lp-PLA2 is associated with cognitive impairment in Parkinson's disease patients.

To explore the association between lipoprotein-associated phospholipase A2 (Lp-PLA2) and the risk of cognitive impairment in Parkinson's disease (PD-CI). A case-control study involving 100 hospitalized PD patients and 60 healthy controls was carried out. Serum Lp-PLA2 level was detected by automatic biochemical analyzer. Based on whether Parkinson's patients have cognitive impairment, PD patients were subdivided to analyze the clinical value of Lp-PLA2. Relationship between Lp-PLA2 and PD-CI risk was analyzed by logistic regression. Diagnostic value of Lp-PLA2 in PD-CI patients was investigated using receiver's operator characteristic curves. The levels of serum Lp-PLA2 activity in Parkinson's disease with normal cognition (PD-NC) and PD-CI patients were significantly higher than those in healthy controls (HCs), respectively. Furthermore, compared to the PD-NC group, the serum Lp-PLA2 activity level was significantly higher in PD-CI patients. Multivariable logistic regression analysis indicated that higher Lp-PLA2 level was an independent risk factor for PD patients with cognitive impairment. Moreover, the area under the efficacy curve of Lp-PLA2 for predicting PD-CI is 0.659. Our study shows that higher levels of Lp-PLA2 activity in PD patients are associated with the risk of developing cognitive impairment. Therefore, given the wide availability, safety, and convenience of monitoring serum Lp-PLA2 activity, it may serve as an early biomarker for cognitive impairment in PD patients.

Lipoprotein-Associated Phospholipase A2 Activity as Potential Biomarker of Vascular Dementia.

A wealth of evidence suggests that Lipoprotein-associated phospholipase A2 (Lp-PLA2) plays a relevant role in atherogenesis and inflammation, which in turn are associated with the risk of developing dementia. The aim of this study was to evaluate whether serum Lp-PLA2 activity might be an early and/or late biomarker for different forms of dementia. Serum Lp-PLA2 activity was assessed in older patients with mild cognitive impairment (MCI, n = 166; median clinical follow-up = 29 months), Late-Onset Alzheimer's disease (LOAD, n = 176), vascular dementia (VAD, n = 43), dementia characterized by an overlap between LOAD and VAD (AD-VAD MIXED dementia) (n = 136), other dementia subtypes (n = 45), and cognitively normal controls (n = 151). We found a significant trend towards higher levels of Lp-PLA2 activity in VAD compared with the other groups (ANOVA, p = 0.028). Similarly, Lp-PLA2 activity was greater in MCI converting to VAD compared with those that did not or did convert to the other types of dementia (ANOVA, p = 0.011). After adjusting for potential confounders, high levels of Lp-PLA2 activity were associated with the diagnosis of VAD (O.R. = 2.38, 95% C.I. = 1.06-5.10), but not with other types of dementia. Our data suggest that increased serum Lp-PLA2 activity may represent a potential biomarker for the diagnosis of VAD.

Comparison of Lp-PLA2 Activity, Lp-PLA2 Mass and Lp-PLA2 mRNA in Acute Coronary Syndrome Patients

Background: Lipoprotein-associated phospholipase A2 (Lp-PLA2) is a risk predictor for cardiovascular diseases (CVD). Generally, plasma Lp-PLA2 was thought to be secreted by circulatory inflammatory cells. Lp-PLA2 mRNA expression of PBMC may also be a risk predictor. Methods: A total of 104 subjects angiographically verified ACS patients were enrolled, including 73 unstable angina pectoris (UAP) patients and 31 acute myocardial infarction (AMI) patients. Plasma lipids, Lp-PLA2 activity and Lp-PLA2 mass were measured. Lp-PLA2 mRNA expression of PBMC was relatively quantified by real-time fluorescence PCR. Results: Plasma Lp-PLA2 activity was increased in AMI patients compared to UAP patients (395.21±145.91 vs. 328.53±127.03 U/L, p=0.024). Lp-PLA2 mass of AMI patients was also higher than UAP patients (136.43±45.46 vs. 119.16±44.19 ng/mL, p=0.093), while PBMC mRNA expression was not statistically different [1.07 (0.74, 1.57) vs. 0.88(0.49, 1.99), p=0.453]. Comparing Lp-PLA2 mRNA by groups, Lp-PLA2 mRNA level was higher in male ACS patients and smoking ACS patients (p=0.008, p=0.048, respectively). Multivariate logistic regression analysis showed that Lp-PLA2 activity was an AMI risk predictor (OR=5.224, 95% CI 1.687-16.181, p=0.004), after smoking, systolic blood pressure, diabetes and hyperlipidemia were adjusted. Recurrent ACS patients were older (p=0.035), but they showed lower levels of Lp-PLA2 mass and Lp-PLA2 activity (p=0.014, p=0.045, respectively), compared to primary ACS patients. Conclusion: Smoking may be an important regulatory factor for Lp-PLA2 mRNA expression in PBMC. Among three Lp-PLA2 indexes, Lp-PLA2 activity was the best marker indicating AMI risk, while Lp-PLA2 mass maybe play better role as a predictor in avoiding ACS recurrence.

Prediction of Lipoprotein-Associated Phospholipase A2 and Inflammatory Markers in Subclinical Atherosclerosis in Premature Ovarian Failure Patients.

Lipoprotein-associated phospholipase A2 (Lp-PLA2) activity has been associated with the risk of clinical cardiovascular events. In this study, we aimed to investigate whether the activity of Lp-PLA2 presents a risk for subclinical atherosclerosis in young patients with premature ovarian failure (POF). Consecutive patients with clinical and biochemical evidence of naïve POF (n = 66) in January and February 2018 and age-matched healthy controls (n = 73) were enrolled. Lp-PLA2 activity, fibrinogen concentrations, high- sensitivity C-reactive protein (Hs-CRP) levels, and carotid intima-media thickness (CIMT) were measured in all participants. Plasma Lp-PLA2 activity (24.6 ± 3.2 nmol/mL vs. 18.6 ± 1.6 nmol/mL; p < 0.001), mean Hs-CRP (0.620 ± 0.26 mg/dL vs. 0.450 ± 0.28 mg/dL; p < 0.001) and fibrinogen (0.310 ± 0.12 g/dL vs. 0.24 ± 0.11 g/dL; p < 0.001) levels were significantly higher in the patients with POF than control subjects. Mean CIMT was significantly higher in the POF patients than in controls (0.499 ± 0.122 mm vs. 0.323 ± 0.079 mm; p < 0.001). There was a possitive and strong correlation between CIMT and Lp-PLA2 activity (r = 0.548; 95% CI 0.445-0.644; p < 0.001) and a weak correlation Hs-CRP (r = 0.228, 95% CI 0.060-0.398; p = 0.007). In multivariate analysis, Lp-PLA2 activity (B = 1.456, 95% CI 0.908-2.003; p < 0.001) and 17β-E2 (B = -0.077, 95% CI -0.131 - -0.023; p = 0.006) were found to be independently associated with CIMT (R2 = 0.46). The present study showed that mean CIMT and Lp-PLA2 activity were significantly higher in POF subjects than control subjects. Moreover, Lp-PLA2 activity and 17β-E2 levels were independently associated with CIMT in young POF patients.

Lipoprotein-Associated Phospholipase A2 in Cardiac Disease: a Potential Early Biomarker of Unstable Coronary Artery Disease.

Lipoprotein-associated phospholipase A2 (Lp-PLA2) is a serine lipase that deteriorates the stability of atherosclerotic plaques. This study aims to investigate Lp-PLA2 activity and its diagnostic potential in the early period of acute coronary syndromes (ACS). Two hundred sixty-two patients referred for acute chest pain within 6 hours of symptom onset were included. Among the candidates, 67 were diagnosed with ST-elevation myocardial infarction (STEMI) and 167 unstable angina (UA). The STEMI patients were divided into cardiac troponin I (cTnI) negative and cTnI positive groups according to the cTnI values at admission. As control, 184 stable coronary artery disease (CAD) patients were also enrolled. Blood samples were collected immediately after admission. The levels of Lp-PLA2 activity and lipids were measured. The diagnostic value of Lp-PLA2 was determined based on receiver operating characteristic curves. Lp-PLA2 activity levels of STEMI and UA groups were dramatically higher than that in CAD group. However, Lp-PLA2 values showed no marked difference between STEMI and UA groups. Similar results were obtained between cTnI negative and positive groups among STEMI patients. In the three groups combined, there was a significant correlation between LDL-C concentration and Lp-PLA2 activity. In the ACS group, the area under the curve was 0.719 (95% CI: 0.671 - 0.768), and the optimal Lp-PLA2 cutoff value was 306.4 U/L, with a sensitivity of 67% and specificity of 69%. Lp-PLA2 activity was significantly elevated in the early stage of ACS. The obtained statistical data suggest that Lp-PLA2 activity may represent a novel early marker of unstable coronary disease.

Lp-PLA2 and dual antiplatelet agents in intracranial arterial stenosis.

To evaluate the interaction effect of lipoprotein-associated phospholipase A2 (Lp-PLA2) activity on the efficacy and safety of dual/single antiplatelet therapy in patients with and without intracranial arterial stenosis (ICAS) by the Clopidogrel in High-Risk Patients with Acute Non-disabling Cerebrovascular Events trial. Patients with both MRI analysis and Lp-PLA2 testing results were included in the current subanalysis. The interaction of Lp-PLA2 activity with the effects of dual and single antiplatelet therapy were analyzed through Cox proportional hazards regressions model. Among the 797 patients, the mean age was 63.1 ± 10.8 years, 518 (65%) were men, 356 (44.7%) had ICAS, and 441 (55.3%) did not. There were significantly more patients with elevated Lp-PLA2 activity in the ICAS group than in the non-ICAS group (43.8% vs 35.4%, p = 0.02). There was significant interaction between Lp-PLA2 activity levels and the 2 antiplatelet therapies for prevention of stroke recurrences and combined vascular events even after adjustment for confounding factors exclusively for patients with ICAS (p = 0.017, 0.017, respectively), but not for those without (p = 0.332, 0.674, respectively). Compared with aspirin alone, dual antiplatelet therapy significantly reduced the risk of stroke recurrences and combined vascular events (adjusted hazard ratio 0.33 [0.12-0.89], p = 0.028; 0.33 [0.12-0.89], p = 0.028, respectively) for patients with ICAS and nonelevated Lp-PLA2 activity. Presence of both ICAS and nonelevated Lp-PLA2 activity may predict better response to dual antiplatelet therapy in prevention of recurrent strokes and combined vascular events for patients with minor stroke or high-risk TIA. NCT00979589.

Lipoprotein-Associated Phospholipase A2 Activity and Mass as Independent Risk Factor of Stroke: A Meta-Analysis.

Background The association between lipoprotein-associated phospholipase A2 (Lp-PLA2) and stroke risk is inconsistent. We conducted a meta-analysis to determine whether elevated Lp-PLA2 is a risk factor for stroke. Methods Studies were included if they reported Lp-PLA2 mass and/or activity levels and adjusted risk estimates of stroke. The primary outcome was overall stroke incidence. The combined results were shown as relative risks (RRs) with 95% confidence intervals (CI) for per 1 standard deviation (SD) higher value of Lp-PLA2 and the highest versus lowest Lp-PLA2 category. Results Twenty-two studies involving 157,693 participants were included for analysis. After adjusting for conventional risk factors, the RRs for overall stroke with 1 SD higher Lp-PLA2 activity and mass were 1.07 (95% CI 1.02–1.13) and 1.11 (95% CI 1.04–1.19), respectively. The RRs of ischemic stroke with 1 SD higher Lp-PLA2 activity and mass were 1.08 (95% CI 1.01–1.15) and 1.11 (95% CI 1.02–1.22), respectively. When comparing the highest and lowest levels of Lp-PLA2, the RRs of stroke for Lp-PLA2 activity and mass were 1.26 (95% CI 1.03–1.54) and 1.56 (95% CI 1.21–2.00), respectively. Finally, when comparing the highest and lowest levels of Lp-PLA2, the pooled RRs of ischemic stroke for Lp-PLA2 activity and mass were 1.29 (95% CI 1.07–1.56) and 1.68 (95% CI 1.12–2.53), respectively. Conclusions Elevated baseline Lp-PLA2 levels, detected either by activity or mass, are associated with increased stroke risk.

Interleukin-6 and lipoprotein-associated phospholipase A2 are associated with functional trajectories.

Background/ObjectivesInflammatory biomarkers have been associated with stroke and mortality, but inflammation may also have detrimental effects beyond acute events. We hypothesized that serum concentrations of interleukin-6 (IL6) and lipoprotein-associated phospholipase A2 (LpPLA2) were inversely associated with long-term functional decline independently of vascular risk factors, stroke and myocardial infarction (MI) occurring during follow-up.DesignProspective population based cohort studySettingThe Northern Manhattan StudyParticipants (including the sample size)Race/ethnically diverse stroke-free individuals in northern Manhattan aged ≥40 years (n = 3298).InterventionNoneMeasurementsAnnual functional assessments with the Barthel index (BI), for a median of 13 years. BI was analyzed as a continuous variable (range 0–100). Baseline demographics, risk factors, and laboratory studies were collected, including IL6 (n = 1679), LpPLA2 mass (n = 1912) and activity (n = 1937). Separate mixed models estimated standardized associations between each biomarker and baseline functional status and change over time, adjusting for demographics, vascular risk factors, social variables, cognition, and depression measured at baseline, and stroke and MI occurring during follow-up.ResultsMean age was 69 (SD 10) years, 35% were male, 53% Hispanic, 74% hypertensive, and 16–24% diabetic. LogIL6 was associated with decline in BI over time (-0.13 points per year, 95% CI -0.24, -0.02) and marginally with baseline BI (-0.20, 95% CI -0.40, 0.01). LpPLA2 activity levels were associated with baseline BI (-0.36, 95% CI -0.68, -0.04) but not change over time, and LpPLA2 mass levels were not associated with either.ConclusionIn this large population-based study, higher serum inflammatory biomarker levels were associated with disability, even when adjusting for baseline covariates and stroke and MI occurring during follow-up.

Lp-PLA2 activity is associated with increased risk of diabetic retinopathy: a longitudinal disease progression study

Aims/hypothesisThe aim of the study was to examine the association between lipoprotein-associated phospholipase A2 (Lp-PLA2) activity levels and incident diabetic retinopathy and change in retinopathy grade.MethodsThis was a cohort study of diabetic participants with serum collected at baseline and routinely collected diabetic retinal screening data. Participants with type 2 diabetes from the GoDARTS (Genetics of Diabetes Audit and Research in Tayside Scotland) cohort were used. This cohort is composed of individuals of white Scottish ancestry from the Tayside region of Scotland. Survival analysis accounting for informative censoring by modelling death as a competing risk was performed for the development of incident diabetic retinopathy from a disease-free state in a 3 year follow-up period (n = 1364) by stratified Lp-PLA2 activity levels (in quartiles). The same analysis was performed for transitions to more severe grades.ResultsThe hazard of developing incident diabetic retinopathy was 2.08 times higher (95% CI 1.64, 2.63) for the highest quartile of Lp-PLA2 activity compared with the lowest. Higher Lp-PLA2 activity levels were associated with a significantly increased risk for transitions to all grades. The hazards of developing observable (or more severe) and referable (or more severe) retinopathy were 2.82 (95% CI 1.71, 4.65) and 1.87 (95% CI 1.26, 2.77) times higher for the highest quartile of Lp-PLA2 activity compared with the lowest, respectively.Conclusions/interpretationHigher Lp-PLA2 levels are associated with increased risk of death and the development of incident diabetic retinopathy, as well as transitions to more severe grades of diabetic retinopathy. These associations are independent of calculated LDL-cholesterol and other traditional risk factors. Further, this biomarker study shows that the association is temporally sensitive to the proximity of the event to measurement of Lp-PLA2.

The associations of stroke, transient ischemic attack, and/or stroke-related recurrent vascular events with Lipoprotein-associated phospholipase A2: A systematic review and meta-analysis.

Background:Studies on stroke and lipoprotein-associated phospholipase A2 (Lp-PLA2) have produced conflicting results.Objective:The aim of the study was to assess the associations of Lp-PLA2 levels (mass and activity) with recurrent vascular events in patients with transient ischemic attack (TIA) and/or first ischemic stroke and with stroke in the general population.Methods:The MEDLINE, Embase, the Cochrane Library, Web of Science, Science Direct, China National Knowledge Infrastructure, China Biology Medical Disc (CBMdisc), and WanFang were searched for prospective observational studies reported until January 2017. Eligible studies reported Lp-PLA2 levels and adjusted risk estimates of recurrent vascular events and/or stroke. Risk ratio (RR) with corresponding 95% confidence intervals (CIs) were used to express the pooled data in a random-effects model.Results:A total of 11 studies that comprised 20,284 participants (4,045 were TIA and/or first ischemic stroke patients and 16,239 were residents in general population) were identified, which reported either Lp-PLA2 mass levels (4 studies) or Lp-PLA2 activity levels (10 studies). The pooled RR of recurrent vascular events (467 cases) in TIA and/or first ischemic group was 2.24 (95% CI, 1.33–3.78), whereas the pooled RR of stroke (1604 cases) in the general population was 1.47 (95% CI, 1.10–1.97). The pooled RRs of Lp-PLA2 mass and activity levels with the risk of stroke in the general population were 1.69 (95% CI, 1.03–2.79) and 1.28 (95% CI, 0.88–1.85), respectively.Conclusions:In patients with TIA and first ischemic stroke, elevated Lp-PLA2 activity levels were associated with recurrent vascular events. And in the general population elevated Lp-PLA2 levels were associated with the risk of stroke, although the association between Lp-PLA2 activity levels and the risk of stroke was less profound compared with the corresponding association of stroke risk with the Lp-PLA2 mass levels.

Lipoprotein‐associated phospholipase A2 activity in obese adolescents with and without type 2 diabetes

Lipoprotein-associated phospholipase A2 (Lp-PLA2) was identified as a strong predictor for cardiovascular events. Furthermore, it is highly associated with obesity. The role of Lp-PLA2 in diabetes mellitus is controversial and analyses, especially in adolescents with type 2 diabetes (T2D), are missing. Therefore, we compared Lp-PLA2 activity between two obese age-, sex-, and BMI-matched cohorts of adolescents with and without T2D. Relationships between Lp-PLA2 activity and age, BMI, hemoglobin A1c, lipids, and adipokines were evaluated. Lp-PLA2 activity was analyzed in serum of 72 obese adolescents without T2D (mean age 15.2±1.6years) and in 65 obese adolescents with T2D (mean age 15.5±1.8years). Clinical data were obtained from the Diabetes-Patienten-Verlaufsdokumentation (DPV) registry. Surprisingly, obese adolescents with T2D had lower levels of Lp-PLA2 activity than obese children without T2D (160.2±45.0 versus 180.9±35.6nmol/min/ml, p=0.003), but this decrease could only be detected in male (158.8±45.3 versus 190.8±31.3nmol/min/ml, p<0.001) and not in female adolescents (162.1±45.5 versus 167.7±37.1nmol/min/ml, p=0.60). In multiple linear regression analysis, differences in Lp-PLA2 activity between cohorts remained large and significant (ß-coefficient: -31.60, 95% confidence interval [-49.27;-13.93], p<0.001). Furthermore, Lp-PLA2 activity was positively associated with BMI (ß-coefficient: 2.04 [0.68;3.40], p=0.004) and negatively associated with the adipokines leptin (ß-coefficient: -0.53 [-0.89;-0.17], p=0.004) and adiponectin (ß-coefficient: -3.06, [-5.63;-0.48], p=0.02). Elevated mean glucose concentrations in adolescents with T2D were not associated with an increase but with a decrease of Lp-PLA2 activity. Hence, in young patients with T2D the Lp-PLA2 activity as a risk predictor for cardiovascular events needs further investigation.

Associations among oxidative stress, Lp-PLA2 activity and arterial stiffness according to blood pressure status at a 3.5-year follow-up in subjects with prehypertension

Background and aimsWe aimed to determine changes in oxidative stress, lipoprotein-associated phospholipase A2 (Lp-PLA2) activity and arterial stiffness in subjects with persistent prehypertensive symptoms during a 3.5-year follow-up period. MethodsWe divided 254 subjects with prehypertension according to their blood pressure (BP) status at 3.5 years of follow-up into three groups: reversed normotensive, persistent prehypertensive and developed hypertensive group. BP, serum lipid profile, oxidized LDL (ox-LDL), Lp-PLA2 activity and brachial-ankle pulse wave velocity (ba-PWV) were measured at baseline and the 3.5-year follow-up. ResultsThe reversed normotensive group showed a significant reduction in average BP (14.7/10.1 mmHg), whereas the developed hypertensive group showed a significant increase in average BP (15.2/11.5 mmHg). The persistent prehypertensive group showed increases in serum lipid profiles, circulating levels of Lp-PLA2 activity, ox-LDL and arterial stiffness as measured by ba-PWV at 3.5 years. The persistent prehypertensive and developed hypertensive groups showed greater increases in ox-LDL than the reversed normotensive group. The developed hypertensive group showed greater increases in Lp-PLA2, 8-epi-PGF2α, and ba-PWV than those observed in the reversed normotensive and persistent prehypertensive groups. In all subjects, changes (Δ) in systolic blood pressure (SBP) positively correlated with Δ Lp-PLA2, Δ ox-LDL, Δ urinary 8-epi-PGF2α and Δ ba-PWV. ConclusionsThis study indicates that in persistent prehypertension, increased ox-LDL hydrolysis by Lp-PLA2 enhances arterial stiffness without an age-related increase in BP.

Darapladib, a Lipoprotein-Associated Phospholipase A2 Inhibitor, Reduces Rho Kinase Activity in Atherosclerosis.

PurposeIncreased lipoprotein-associated phospholipase A2 (Lp-PLA2) activity and Rho kinase activity may be associated with atherosclerosis. The principal aim of this study was to examine whether darapladib (a selective Lp-PLA2 inhibitor) could reduce the elevated Lp-PLA2 and Rho kinase activity in atherosclerosis.Materials and MethodsStudies were performed in male Sprague-Dawley rats. The atherosclerosis rats were prepared by feeding them with a high-cholesterol diet for 10 weeks. Low-dose darapladib (25 mg·kg-1·d-1) and high-dose darapladib (50 mg·kg-1·d-1) interventions were then administered over the course of 2 weeks.ResultsThe serum levels of triglycerides, total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), high-sensitivity C-reactive protein (hs-CRP), and Lp-PLA2, significantly increased in atherosclerosis model groups, as did Rho kinase activity and cardiomyocyte apoptosis (p<0.05 vs. sham group), whereas nitric oxide (NO) production was reduced. Levels of TC, LDL-C, CRP, Lp-PLA2, and Rho kinase activity were respectively reduced in darapladib groups, whereas NO production was enhanced. When compared to the low-dose darapladib group, the reduction of the levels of TC, LDL-C, CRP, and Lp-PLA2 was more prominent in the high-dose darapladib group (p<0.05), and the increase of NO production was more prominent (p<0.05). Cardiomyocyte apoptosis of the high-dose darapladib group was also significantly reduced compared to the low-dose darapladib group (p<0.05). However, there was no significant difference in Rho kinase activity between the low-dose darapladib group and the high-dose darapladib group (p>0.05).ConclusionDarapladib, a Lp-PLA2 inhibitor, leads to cardiovascular protection that might be mediated by its inhibition of both Rho kinase and Lp-PLA2 in atherosclerosis.

Lipoprotein associated phospholipase A2 activity, apolipoprotein C3 loss-of-function variants and cardiovascular disease: The Atherosclerosis Risk In Communities Study.

Lipoprotein-associated phospholipase A2 (LpPLA2) activity was associated with higher CHD risk in a meta-analysis, which was partly dependent on circulating lipid levels. Apolipoprotein C3 loss-of-function (ApoC3 LOF) mutations were related with reduced postprandial lipemia and CHD risk. However, the association of LpPLA2 activity with ApoC3 LOF is not known. We examined the association of LpPLA2 activity and ApoC3 LOF mutations and incident cardiovascular disease (CVD) (defined as coronary heart disease [CHD] plus ischemic stroke) and all-cause mortality in the biracial longitudinal Atherosclerosis Risk In Communities (ARIC) study. The mean LpPLA2 activity was 229.3nmol/min/mL and was higher in men and whites. LpPLA2 activity correlated positively with atherogenic dyslipidemia. ApoC3 LOF carriers had lower LpPLA2 activity levels compared to non-carriers, and there was inverse association between LpPLA2 activity and ApoC3 LOF mutations in whites. In a fully adjusted model, greater LpPLA2 activity was independently associated with incident CVD (HR 1.35, 1.09-1.68 for highest vs. lowest quintile), which was mainly explained by its association with CHD, and was also associated with all-cause mortality (HR 1.65, 1.38-1.98). Greater LpPLA2 activity was associated with increased CHD and all-cause mortality in both whites and African-Americans in the ARIC study. The inverse relation between LpPLA2 activity and ApoC3 LOF mutations suggests that delayed lipoprotein clearance may at least in part explain the observed association of LpPLA2 activity with increased CVD risk.

Comparison of Lipoprotein-Associated Phospholipase A2 and High Sensitive C-Reactive Protein as Determinants of Metabolic Syndrome in Subjects without Coronary Heart Disease: In Search of the Best Predictor.

High sensitivity C-reactive protein (hsCRP) is a marker of metabolic syndrome (MS) and cardiovascular (CV) disease. Lipoprotein-associated phospholipase A2 (Lp-PLA2) also predicts CV disease. There are no reports comparing these markers as predictors of MS. Methods. Cross-sectional study comparing Lp-PLA2 and hsCRP as predictors of MS in asymptomatic subjects was carried out; 152 subjects without known atherosclerosis participated. Data were collected on demographics, cardiovascular risk factors, anthropometric and biochemical measurements, and hsCRP and Lp-PLA2 activity levels. A logistic regression analysis was performed with each biomarker and receiver operating characteristic (ROC) curves were constructed for MS. Results. Mean age was 46 ± 11 years, and 38% of the subjects had MS. Mean Lp-PLA2 activity was 185 ± 48 nmol/mL/min, and mean hsCRP was 2.1 ± 2.2 mg/L. Subjects with MS had significantly higher levels of Lp-PLA2 (P = 0.03) and hsCRP (P < 0.0001) than those without MS. ROC curves showed that both markers predicted MS. Conclusion. Lp-PLA2 and hsCRP are elevated in subjects with MS. Both biomarkers were independent and significant predictors for MS, emphasizing the role of inflammation in MS. Further research is necessary to determine if inflammation predicts a higher risk for CV events in MS subjects.

Lipoprotein Phospholipase A2 Mass and Activity Are Not Associated with the Diagnosis of Acute Brain Ischemia

Background: Elevated lipoprotein-associated phospholipase A2 (Lp-PLA2) levels are associated with both coronary artery and cerebrovascular diseases. The clinical diagnosis of neurovascular events, specifically transient ischemic attack can be challenging, although there is disagreement among vascular trained neurologists regarding this. Currently, there is no single accurate biomarker for the diagnosis of acute brain ischemia. Aim: We studied the relationship between Lp-PLA2 mass and activity levels and the diagnosis of acute brain ischemia in the acute phase among patients evaluated in the emergency department following transient focal neurological symptoms. Methods: Patients evaluated in our academic center for transient neurological symptoms of possible ischemic mechanism were enrolled with informed consent. Lp-PLA2 mass and activity levels were performed by DiaDexus, Inc. Results: 100 patients were enrolled: 58 were ischemic (30 stroke, 28 TIA), 10 were unknown, and 28 were non-ischemic. Blood samples were collected after a median delay of 23 h (IQR: 17, 36) after symptom onset. The median levels of Lp-PLA2 activity level for ischemic (stroke and TIA) versus non-ischemic events were 186.5 nmol/ml/min (IQR = 153, 216.3) and 169 nmol/ml/min (IQR = 137, 212.5), respectively. The median levels of Lp-PLA2 mass level for ischemic versus non-ischemic events were 202 ng/ml (IQR = 171.6, 226.1) and 192 ng/ml (167.8, 230). The differences in median Lp-PLA2 mass and activity levels were not statistically significant in the ischemic versus non-ischemic patients. Vessel imaging revealed a symptomatic stenosis in 14 patients (10 intracranial and 4 cervical). The median Lp-PLA2 mass and activity levels among patients with a symptomatic stenosis were not significantly higher than the levels measured in TIA/stroke patients without stenosis. Conclusion: The results of our study do not support the early measurement of Lp-PLA2 mass or activity levels for confirming an ischemic etiology in patients experiencing minor or transient focal neurological events.

Lipoprotein-Associated Phospholipase A2 Is Associated with Atherosclerotic Stroke Risk: The Northern Manhattan Study

BackgroundLipoprotein-associated phospholipase A2 (LpPLA2) levels are associated with stroke, though whether this extends to all populations and stroke subtypes is unknown.MethodsSerum samples from stroke-free community participants in the Northern Manhattan Study were assayed for LpPLA2 mass and activity. Participants were followed annually for stroke. Cox-proportional-hazard models were fitted to estimate hazard-ratios and 95% confidence intervals (HR, 95% CI) for the association of LpPLA2 levels with ischemic stroke (IS), after adjusting for demographic and medical risk factors.ResultsSerum samples were available in 1946 participants, of whom 151 (7.8%) experienced a first IS during median follow-up 11 years. Mean age was 69 (SD 10), 35.6% were men, 20% non-Hispanic Whites, 22% non-Hispanic Blacks, and 55% Hispanics. LpPLA2 mass and activity levels were not associated with overall IS risk.LpPLA2 mass but not activity levels were associated with strokes due to large artery atherosclerosis (LAA; adjusted HR per SD 1.55, 95% CI 1.17–2.04). There was a dose-response relationship with LAA (compared to first quartile, 2nd quartile HR = 1.43, 95% CI 0.23–8.64; 3rd quartile HR = 4.47, 95% CI 0.93–21.54; 4th quartile HR = 5.07, 95% CI 1.07–24.06). The associations between LpPLA2-mass and LAA-stroke risk differed by race-ethnicity (p = 0.01); LpPLA2-mass was associated with increased risk of LAA among non-Hispanic Whites (adjusted HR per SD 1.44, 95% CI 0.98–2.11), but not other race-ethnic groups.ConclusionLpPLA2-mass levels were associated with risk of atherosclerotic stroke among non-Hispanic White participants, but not in other race-ethnic groups in the cohort. Further study is needed to confirm these race-ethnic differences and the reasons for them.

Elevated Lipoprotein-Associated Phospholipase A2 Is Associated with Progression of Nonculprit Lesions after Percutaneous Coronary Intervention

Lipoprotein-associated phospholipase A2 (Lp-PLA2) is an enzyme that hydrolyzes oxidized phospholipids to generate bioactive proatherogenic products. Nonculprit lesions have been assumed to contribute to the pathogenesis of recurrent acute coronary syndrome (ACS). The role of LP-PLA2 in the progression of nonculprit coronary lesions after successful percutaneous coronary intervention (PCI) remains unclear. Our study included 123 patients with ACS who underwent initial PCI and a long-term follow-up (mean interval, one year) with coronary angiography. Among them, 19 patients were diagnosed as the progression of nonculprit lesions, based on the presence of at least one of the following factors: (1) ≥ 10% reduction in the diameter of a preexisting ≥ 50% stenosis; (2) ≥ 30% reduction in the diameter of a < 50% stenosis; and (3) early-onset stenosis with ≥ 30% reduction in the diameter of a segment that was normal on the primary angiogram. Blood sampling was drawn from all patients at 12-14 hours after PCI. The ACS patients with progression had higher total cholesterol (4.47 ± 1.02 mmol/L vs. 3.59 ± 0.57 mmol/L, P < 0.05), higher levels of Lp-PLA2 activity (14.39 ± 6.13 nmol/min/ml vs. 8.86 ± 3.14 nmol/min/ml, P < 0.001) and a higher proportion of multi-vessel disease than those without progression. Multivariate logistic regression analysis showed that Lp-PLA2 activity (β = 0.024, P = 0.005) was an independent predictor for rapid progression of nonculprit coronary lesions. In conclusion, elevated Lp-PLA2 activity is associated with rapid progression of nonculprit coronary lesions in ACS patients who underwent PCI.

Relationship of Lipoprotein-Associated Phospholipase A2 Mass and Activity with Incident Vascular Events among Primary Prevention Patients Allocated to Placebo or to Statin Therapy: An Analysis from the JUPITER Trial

Although lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) levels are associated with cardiovascular events, Lp-PLA(2) is physically linked to LDL cholesterol (LDL-C). Whether measures of Lp-PLA(2) mass or activity continue to predict risk after LDL-C reduction by statin therapy is uncertain. Lp-PLA(2) mass concentration and activity were evaluated at baseline and after treatment in the Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) trial comparing rosuvastatin 20 mg to placebo among 17 802 men and women without cardiovascular disease or diabetes at study entry. The relationships of Lp-PLA(2) mass and activity with risk of future vascular events were evaluated in the placebo and rosuvastatin groups. Before randomization, levels of Lp-PLA(2) mass and activity correlated moderately with each other and with LDL-C. The magnitude of these correlations increased after statin therapy. Rosuvastatin reduced Lp-PLA(2) mass by 33.8%, Lp-PLA(2) activity by 33.2%, and LDL-C by 48.7% (all P < 0.0001). Among those study participants allocated to placebo, increasing quartiles of Lp-PLA(2) activity (P(trend) = 0.04) but not Lp-PLA(2) mass (P(trend) = 0.92) were associated with incident cardiovascular events after adjustment for LDL-C and conventional risk factors. Comparable analyses conducted among those allocated to rosuvastatin revealed no significant relationship between Lp-PLA(2) levels and subsequent vascular events. The ability of rosuvastatin to reduce vascular events was not significantly modified by baseline Lp-PLA(2) level. Among JUPITER trial participants allocated to placebo, levels of Lp-PLA(2) activity, but not mass, were associated with cardiovascular risk. However, Lp-PLA(2) no longer predicted risk or modified clinical outcomes when participants were treated with rosuvastatin.