Lipoprotein-associated Phospholipase A2 Mass Research Articles

Lipoprotein-associated phospholipase A2 testing usefulness among patients with symptomatic intracranial atherosclerotic disease

Background and purposeCirculating lipoprotein-associated phospholipase A2 (Lp-PLA2) has emerged as a novel biomarker for cardiovascular diseases. Our aim was to determine Lp-PLA2 mass and activity in a selected cohort of first-ever transient ischemic attack (TIA) or ischemic stroke patients with intracranial atherosclerotic disease (ICAD) and to investigate its relationship with the presence of classical vascular risk factors, response to secondary prevention treatments and risk of recurrent vascular events. MethodsLp-PLA2 mass and activity were measured 3 months after TIA or stroke by means of the PLAC test and CAM-assay (diaDexus, Inc.) respectively in 75 patients. Classic vascular risk factors, preventive treatments and clinical characteristics at the time of the index event were recorded. Follow-up transcranial Doppler ultrasonography (TCD) was performed and the presence of a new vascular event was assessed every 6 months. ResultsSeveral preventive treatments (statins and clopidogrel) were significantly associated with lower Lp-PLA2 mass and activity. During follow-up (median time 23 months), eighteen patients (24%) suffered a new vascular event. Baseline factors associated with new vascular events were: history of coronary artery disease, number of intracranial stenoses detected by TCD and also Lp-PLA2 activity, which was the only independent predictor for new vascular events (hazard ratio 2.89; 95% CI 1.029 to 8.096; p=0.044) after multivariate analysis (Cox regression). ConclusionsLp-PLA2 activity might be a useful tool to identify intracranial large-artery occlusive disease patients at higher risk of suffering new vascular events.

Plasma Cholesteryl Ester Transfer, But Not Cholesterol Esterification, Is Related to Lipoprotein-Associated Phospholipase A2: Possible Contribution to an Atherogenic Lipoprotein Profile

Plasma lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) predicts incident cardiovascular disease and is associated preferentially with negatively charged apolipoprotein B-containing lipoproteins. The plasma cholesteryl ester transfer (CET) process, which contributes to low high-density lipoprotein cholesterol and small, dense low-density lipoproteins, is affected by the composition and concentration of apolipoprotein B-containing cholesteryl ester acceptor lipoproteins. We tested relationships of CET with Lp-PLA(2) in subjects with and without metabolic syndrome (MetS). In 68 subjects with MetS and 74 subjects without MetS, plasma Lp-PLA(2) mass, cholesterol esterification (EST), lecithin:cholesterol acyltransferase (LCAT) activity level, CET, CET protein (CETP) mass, and lipoproteins were measured. EST, LCAT activity, CET (P < 0.001 for all), and CETP (P = 0.030) were increased, and Lp-PLA(2) was decreased (P = 0.043) in MetS. CET was correlated positively with Lp-PLA(2) in subjects with and without MetS (P < 0.05 for both). EST and LCAT activity were unrelated to Lp-PLA(2), despite a positive correlation between EST and CET (P < 0.001). After controlling for age, sex, and diabetes status, CET was determined by Lp-PLA(2) in the whole group (β = 0.245; P < 0.001), and in subjects with (β = 0.304; P = 0.001) and without MetS (β = 0.244; P = 0.006) separately, independently of triglycerides and CETP. Plasma CET is related to Lp-PLA(2) in subjects with and without MetS. The process of CET, but not EST, may be influenced by Lp-PLA(2). These findings provide a rationale to evaluate whether maneuvers that inhibit Lp-PLA(2) will reduce CET, and vice versa to document effects of CETP inhibition on Lp-PLA(2).

Ambient Air Pollution and Lipoprotein-Associated Phospholipase A 2 in Survivors of Myocardial Infarction

Background: Increasing evidence suggests a proatherogenic role for lipoprotein-associated phospholipase A2 (Lp-PLA2). A meta-analysis of published cohorts has shown that Lp-PLA2 is an independent predictor of coronary heart disease events and stroke.Objective: In this study, we investigated whether the association between air pollution and cardiovascular disease might be partly explained by increased Lp-PLA2 mass in response to exposure.Methods: A prospective longitudinal study of 200 patients who had had a myocardial infarction was performed in Augsburg, Germany. Up to six repeated clinical examinations were scheduled every 4–6 weeks between May 2003 and March 2004. Supplementary to the multicenter AIRGENE protocol, we assessed repeated plasma Lp-PLA2 concentrations. Air pollution data from a fixed monitoring site representing urban background concentrations were collected. We measured hourly means of particle mass [particulate matter (PM) < 10 µm (PM10) and PM < 2.5 µm (PM2.5) in aerodynamic diameter] and particle number concentrations (PNCs), as well as the gaseous air pollutants carbon monoxide (CO), sulfur dioxide (SO2), ozone (O3), nitric oxide (NO), and nitrogen dioxide (NO2). Data were analyzed using mixed models with random patient effects.Results: Lp-PLA2 showed a positive association with PM10, PM2.5, and PNCs, as well as with CO, NO2, NO, and SO2 4–5 days before blood withdrawal (lag 4–5). A positive association with O3 was much more immediate (lag 0). However, inverse associations with some pollutants were evident at shorter time lags.Conclusion: These preliminary findings should be replicated in other study populations because they suggest that the accumulation of acute and subacute effects or the chronic exposure to ambient particulate and gaseous air pollution may result in the promotion of atherosclerosis, mediated, at least in part, by increased levels of Lp-PLA2.

Combining Rosuvastatin with Sartans of Different Peroxisome Proliferator-Activated Receptor-γ Activating Capacity Is Not Associated with Different Changes in Low-Density Lipoprotein Subfractions and Plasma Lipoprotein-Associated Phospholipase A2

Rosuvastatin reduces low-density lipoprotein cholesterol (LDL-C) and plasma lipoprotein-associated phospholipase A₂ (Lp-PLA₂) Some sartans partially activate peroxisome proliferator-activated receptor-γ (PPARγ), possibly having a favorable effect on metabolic parameters. Telmisartan is the most potent partial PPARγ activator, followed by irbesartan, whereas olmesartan does not hold such capacity. In an open-label randomized study, we assessed the effects of combining sartans of different PPARγ- activating capacity with rosuvastatin on LDL subfractions and plasma Lp-PLA₂ in patients with mixed dyslipidemia, hypertension, and prediabetes. Following dietary intervention, patients were allocated randomly to rosuvastatin (10 mg/day) plus telmisartan 80 mg/day (RT group, n = 52) or irbesartan 300 mg/day (RI group, n = 48) or olmesartan 20 mg/day (RO group, n = 51). After 6 months of treatment, changes in LDL subfraction cholesterol and plasma Lp-PLA(2) activity and mass were evaluated blindly. A total of 151 patients (73 male; mean age 60 years) were included. Large LDL-C decreased in the RT (-36%), RI (-39%), and RO (-41%) groups (P < 0.001 for all vs. baseline). Small dense LDL-C decreased in the RT (-67%), RI (-58%), and RO (-61%) groups (P < 0.001 for all vs. baseline). All regimens increased LDL particle size versus baseline (RT + 1.4%, P = 0.002; RI + 1.0%, P = 0.04; and RO + 1.4%, P = 0.001). No difference for the change of LDL subfractions and LDL size was noticed among groups. Plasma Lp-PLA₂ activity decreased equally in all groups (RT -38%, RI -38%, RO -43%) (P < 0.001 for all vs. baseline). Plasma Lp-PLA₂ mass decreased similarly in all groups versus baseline (RT -28%, P = 0.001; RI -32%, P = 0.01; and RO -27%, P = 0.001). No difference for the change of Lp-PLA₂ mass or activity was noticed among groups. The combination of rosuvastatin with sartans of different PPARγ-activating capacity did not differentiate alterations of LDL subfraction cholesterol and plasma Lp-PLA(2) activity and mass.

Lipoprotein-Associated Phospholipase A2Activity Predicts Progression of Subclinical Coronary Atherosclerosis

Lipoprotein-associated phospholipase A₂ (Lp-PLA₂) is a lipoprotein-associated enzyme that cleaves oxidized phosphatidylcholines, generating pro-atherosclerotic lysophosphatidylcholine and oxidized free fatty acids. Lp-PLA₂ is independently associated with cardiovascular disease (CVD) in a variety of populations. Coronary calcium is a measure of subclinical CVD, and progression of coronary calcification predicts future CVD events. In type 1 diabetes there is an increase in coronary calcium and CVD despite a favorable lipid profile. Levels of Lp-PLA₂ in type 1 diabetes are not known, nor is the relationship between Lp-PLA₂ and progression of coronary calcification. The Coronary Artery Calcification in Type 1 Diabetes study measured coronary calcium by electron-beam computed tomography twice over a 2.6 ± 0.3-year interval. Lp-PLA₂ mass and activity were measured at baseline (n = 1,097 subjects, 506 with and 591 without type 1 diabetes). In type 1 diabetes Lp-PLA₂ mass was marginally higher (285 ± 79 vs. 278 ± 78 ng/mL, P = 0.1), and Lp-PLA₂ activity was significantly lower (137 ± 30 vs. 146 ± 36 nmol/min/mL, P < 0.0001) than in those without diabetes. There was a greater proportion of those with progression of coronary calcification in type 1 diabetes compared with those without diabetes (24% vs. 10%, P < 0.0001). Lp-PLA₂ activity was independently associated with progression of coronary calcification in multivariate analysis (4th quartile verses bottom three quartiles, odds ratio = 1.77 [1.08-2.91], P = 0.02). LpPLA₂ mass was not significantly associated with progression of coronary calcification in this cohort (P = 0.09). Lp-PLA₂ activity predicts progression of subclinical atherosclerosis in individuals with and without type 1 diabetes.

Carotid intima media thickness is associated with plasma lipoprotein-associated phospholipase A2 mass in nondiabetic subjects but not in patients with type 2 diabetes

A recent meta-analysis showed that both plasma lipoprotein-associated phospholipase A(2) (Lp-PLA(2) ) mass and activity independently predict cardiovascular events. Notably, Lp-PLA(2) activity but not mass was found to be a determinant of cardiovascular outcome in type 2 diabetes mellitus. We questioned whether relationships of carotid intima media thickness (IMT), a measure of subclinical atherosclerosis, with Lp-PLA(2) mass differ between diabetic and nondiabetic subjects. Relationships of IMT with plasma Lp-PLA(2) mass (turbidimetric immunoassay) were compared in 74 patients with type 2 diabetes and in 64 nondiabetic subjects. IMT was increased (P=0·016), but plasma Lp-PLA(2) mass was decreased in patients with diabetes compared to nondiabetic subjects (277±66 vs. 327±62μgL(-1) , P<0·001). In nondiabetic subjects, IMT was correlated positively with Lp-PLA(2) (r=0·325, P<0·009); multiple linear regression analysis confirmed an independent association of IMT with Lp-PLA(2) (ß=0·192, P=0·048). In contrast, IMT was unrelated to Lp-PLA(2) in patients with diabetes (r=0·021, P=0·86), and the relationship of IMT with Lp-PLA(2) was different in diabetic and control subjects (P<0·001). The relationship of Lp-PLA(2) with the total cholesterol/high-density lipoprotein (HDL) cholesterol ratio also differed between diabetic and nondiabetic subjects (P<0·001). Plasma Lp-PLA(2) may relate to early stages of atherosclerosis development. In diabetes mellitus, in contrast, the association of IMT with plasma Lp-PLA(2) mass is abolished, which could be partly ascribed to redistribution of Lp-PLA(2) mass from apolipoprotein B-containing lipoproteins towards HDL. These findings raise questions about the usefulness of plasma Lp-PLA(2) mass measurement as a marker of subclinical atherosclerosis in type 2 diabetes mellitus.

Lipoprotein phospholipase A2 in patients with isolated coronary artery ectasia

Lipoprotein-associated phospholipase A2 (Lp-PLA2) is among the multiple cardiovascular biomarkers that have been associated with increased cardiovascular disease. Lp-PLA2 appears, however, to be relatively unique in its high specificity for vascular inflammation as opposed to systemic inflammation, its low biologic variability, and its direct role in the causal pathway of plaque inflammation. Nevertheless, the relation between LP-PLA2 and isolated coronary artery ectasia (CAE) has not been investigated yet. The aim of our study was to assess this relation. Twenty-five patients with isolated CAE without stenosis and 25 control subjects with angiographically normal coronary arteries were included in this study. Lp-PLA2 mass was determined in serum by a dual monoclonal antibody immunoassay. Patients with isolated CAE had significantly higher level of Lp-PLA2 compared to the control subjects with angiographically normal coronary arteries (284 ± 102 ng/ml in ectasia and 199 ± 62 ng/ml in control group, respectively, p 0.001). Also we detected a significant positive correlation between the presence of CAE and Lp-PLA2 (r = 0.452, p 0.001). We have demonstrated for the first time increased Lp-PLA2 level in patients with isolated CAE, suggesting that Lp-PLA2 may be involved in the pathogenesis of CAE.

Lipoprotein-associated phospholipase A2 mass and activity in children with heterozygous familial hypercholesterolemia and unaffected siblings: Effect of pravastatin

Lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) is an independent risk factor of cardiovascular disease and a target of treatment. Lp-PLA(2) levels in children have not been previously reported. The effect of statin therapy on Lp-PLA(2) mass and activity in children with familial hypercholesterolemia (FH) is also not known. Lp-PLA(2) mass and activity levels were measured at baseline and after 2 years in 178 children with FH randomized to pravastatin or placebo and in 78 unaffected and untreated siblings. At the end of the randomized period, all FH children were then placed on pravastatin for an additional 2 years, and Lp-PLA(2) mass and activity levels were correlated with changes in carotid intima-media thickness during 4 years of follow-up. Baseline levels of Lp-PLA(2) mass and activity were significantly greater in children with FH compared with unaffected siblings (mass: 240.3 ± 41.6 vs 222.1 ± 36.5 ng/mL, P = .002; activity: 205.7 ± 41.6 vs 124.3±23.0 nmol/min/mL, P < .0001). In the randomized FH cohort, after 2 years treatment, Lp-PLA(2) mass (217.8 ± 35.0 vs 231.5 ± 34.8 ng/mL, P = .001) and activity (178.8 ± 37.3 vs 206.2 ± 33.5 nmol/min/mL, P < .0001) were significantly reduced by pravastatin compared with placebo. Change in Lp-PLA(2) activity was related to change in low-density lipoprotein cholesterol (pravastatin: r = 0.53, P < .0001, placebo: r = 0.23, P < .001) but change in Lp-PLA(2) mass was not related to change in low-density lipoprotein cholesterol. Baseline levels of Lp-PLA(2) mass and activity were not significantly associated with carotid intima-media thickness at baseline or at 4 years. Lp-PLA(2) mass and activity are significantly elevated in children with heterozygous FH compared with unaffected siblings and are significantly reduced by pravastatin therapy.

Lipoprotein‐associated phospholipase A2 activity and mass in relation to vascular disease and nonvascular mortality

To assess whether associations of circulating lipoprotein-associated phospholipase A₂ (Lp-PLA₂) with vascular disease are independent of other risk factors. Lp-PLA₂ activity and mass, lipids and other characteristics were measured at baseline in 19,037 individuals at high risk of vascular disease in a randomized trial of simvastatin with 5-year average follow-up. Lp-PLA₂ activity and mass were correlated with each other (r = 0.56), lipids and other vascular risk factors. The moderate association of Lp-PLA₂ activity with occlusive coronary events (n = 2531) in analyses adjusted for nonlipid factors (hazard ratio per 1 SD [HR] 1.11, 95% CI 1.06-1.15) became nonsignificant after further adjustment for apolipoproteins (HR 1.02, 0.97-1.06). Such adjustment also attenuated HRs with Lp-PLA₂ mass from 1.08 (1.03-1.12) to 1.05 (1.01-1.09). By contrast, the HR with apolipoprotein-B100 of 1.15 (1.10-1.19) was only slightly attenuated to 1.14 (1.09-1.19) after further adjustment for apolipoprotein A₁ and Lp-PLA₂. Age- and sex-adjusted HRs for other cardiac events (n = 1007) with either Lp-PLA₂ activity or mass were about 1.20, but HRs reduced after adjustment for nonlipid factors (activity: 1.11, 1.04-1.18; mass: 1.08, 1.02-1.15). Adjusted HRs for ischaemic stroke (n = 900) were weak and nonsignificant and for nonvascular mortality (n = 1040) were 1.01 (0.94-1.09) with activity and 1.12 (1.05-1.19) with mass. Simvastatin reduced Lp-PLA₂ levels by about one-quarter, but simvastatin's vascular protection did not vary with baseline Lp-PLA₂ concentration. Associations of Lp-PLA₂ with occlusive coronary events depend considerably on lipid levels, whereas those with other cardiac events appear to reflect confounding from cardiovascular medication and prior vascular disease.

Eight genetic loci associated with variation in lipoprotein-associated phospholipase A2 (Lp-PLA2) mass and activity: Meta-analysis of genome-wide association studies from five community-based studies

Eight genetic loci associated with variation in lipoprotein-associated phospholipase A2 (Lp-PLA2) mass and activity: Meta-analysis of genome-wide association studies from five community-based studies

Effect of increasing doses of Rosuvastatin and Atorvastatin on apolipoproteins, enzymes and lipid transfer proteins involved in lipoprotein metabolism and inflammatory parameters

This paper contains detailed results of a sub-population of the prospective randomized RADAR (Rosuvastatin and Atorvastatin in different Dosages And Reverse cholesterol transport) study.Objective:Statin treatment results in substantially decreased incidence of cardiovascular events but the exact pathophysiological mechanism of their beneficial effect is yet unclear. We aimed to examine the effects of up-titrated doses of two widely used statins (atorvastatin (ATOR) and rosuvastatin (ROSU)) on parameters involved in lipoprotein metabolism, in patients with low high density lipoprotein cholesterol values (HDL-C).Research design and methods:In this RADAR substudy, 80 patients, aged 40–80 years, with known cardiovascular disease and low HDL-C (<1.0 mmol/l), were randomized to receive, after an initial 6 week dietary run-in phase, either ATOR 20 mg (n = 41) or ROSU 10 mg (n = 39). The doses were up-titrated (in 6 week intervals) to 80 mg of ATOR or 40 mg of ROSU at 12 weeks. Serum lipoproteins and lipoprotein metabolism parameters were measured at baseline and at 6 and 18 weeks of follow up.Results:Both statins significantly reduced total cholesterol (TChol) and non-HDL-C values with ROSU being more effective for the doses studied (p < 0.05). No statistically significant effect on HDL-C was observed for either statin. Apolipoproteins (apo) B, CI, CIII, AV and E were significantly reduced in both groups (p < 0.05), while the ratio of HDL particles containing both apoAI and apoAII (LpAI-AII) over HDL containing apoAI alone (LpAI) was changed for both statins with the decrease of LpAI being more prominent in the ATOR group (p = 0.028). Cholesterol ester transfer protein (CETP) mass and activity, phospholipid transfer protein (PLTP) activity and lipoprotein-associated phospholipase A2 (Lp-PLA2) mass and activity were all significantly reduced in both treatment groups over the follow-up period (p < 0.001). ATOR displayed a more prominent decrease of PLTP activity compared to ROSU (p = 0.043), while ROSU displayed a more prominent decrease of Lp-PLA2 activity compared to ATOR (p = 0.04). Both statins effectively reduced, in a dose-dependent way, high sensitivity C-reactive protein values over time, while no effect on the levels of circulating inter cellular adhesion molecule 1 (cICAM-1) was observed.Conclusions:The effects of statin treatment extend further and beyond a mere TChol and LDL cholesterol reduction, as demonstrated by the aforementioned alterations of lipoproteins, enzymes and lipid transfer proteins involved in lipoprotein metabolism and pro-atherogenic and inflammatory molecules. ROSU and ATOR displayed a similar pattern of effect on lipid metabolism with discrete differences in the magnitude of this effect in certain variables. Despite the limitations of small population size and lack of clinical end points, reported data provide an insight for the possible pathophysiological mechanisms implicated in the effect of increasing dosages of different statin treatments.

Pericardial Fat Volume Correlates With Inflammatory Markers: The Framingham Heart Study

The objective of this study was to determine whether systemic inflammatory and oxidative stress marker concentrations correlate with pericardial and intrathoracic fat volumes. Participants of the Framingham Offspring Study (n = 1,175, 53% women, mean age 59 +/- 9 years) had pericardial and intrathoracic fat volumes assessed by multidetector computed tomography (MDCT) scans, and provided fasting blood and urine samples to measure concentrations of 14 inflammatory markers: C-reactive protein (CRP), interleukin-6, monocyte chemoattractant protein-1 (MCP-1), CD40 ligand, fibrinogen, intracellular adhesion molecule-1, lipoprotein-associated phospholipase A(2) activity and mass, myeloperoxidase, osteoprotegerin, P-selectin, tumor necrosis factor-alpha, tumor necrosis factor receptor-2, and urinary isoprostanes. Multivariable linear regression models were used to determine the association of log-transformed inflammatory marker concentrations with fat volumes, using fat volume as the dependent variable. Due to smaller sample sizes, models were rerun after adding urinary isoprostanes (n = 961) and tumor necrosis factor-alpha (n = 813) to the marker panel. Upon backward elimination, four of the biomarkers correlated positively with each fat depot: CRP (P < 0.0001 for each fat depot), interleukin-6 (P < 0.05 for each fat depot), MCP-1 (P < 0.01 for each fat depot), and urinary isoprostanes (P < 0.01 for pericardial fat; P < 0.001 for intrathoracic fat). Even after adjusting for BMI, waist circumference (WC), and abdominal visceral fat, CRP (P = 0.0001) and urinary isoprostanes (P = 0.02) demonstrated significant positive associations with intrathoracic fat, but not with pericardial fat. Multiple markers of inflammation and oxidative stress correlated with pericardial and intrathoracic fat volumes, extending the known association between regional adiposity and inflammation and oxidative stress.

Genome-Wide Association Study of Lp-PLA2 Activity and Mass in the Framingham Heart Study

Lipoprotein-associated phospholipase A2 (Lp-PLA2) is an emerging risk factor and therapeutic target for cardiovascular disease. The activity and mass of this enzyme are heritable traits, but major genetic determinants have not been explored in a systematic, genome-wide fashion. We carried out a genome-wide association study of Lp-PLA2 activity and mass in 6,668 Caucasian subjects from the population-based Framingham Heart Study. Clinical data and genotypes from the Affymetrix 550K SNP array were obtained from the open-access Framingham SHARe project. Each polymorphism that passed quality control was tested for associations with Lp-PLA2 activity and mass using linear mixed models implemented in the R statistical package, accounting for familial correlations, and controlling for age, sex, smoking, lipid-lowering-medication use, and cohort. For Lp-PLA2 activity, polymorphisms at four independent loci reached genome-wide significance, including the APOE/APOC1 region on chromosome 19 (p = 6×10−24); CELSR2/PSRC1 on chromosome 1 (p = 3×10−15); SCARB1 on chromosome 12 (p = 1×10−8) and ZNF259/BUD13 in the APOA5/APOA1 gene region on chromosome 11 (p = 4×10−8). All of these remained significant after accounting for associations with LDL cholesterol, HDL cholesterol, or triglycerides. For Lp-PLA2 mass, 12 SNPs achieved genome-wide significance, all clustering in a region on chromosome 6p12.3 near the PLA2G7 gene. Our analyses demonstrate that genetic polymorphisms may contribute to inter-individual variation in Lp-PLA2 activity and mass.

Lipoprotein-Associated Phospholipase A2 Mass Is Significantly Reduced in Dyslipidemic Patients Treated With Lifestyle Modification and Combination Lipid-Modifying Drug Therapy

Lipoprotein-associated phospholipase A2 (Lp-PLA(2)) mass is a novel inflammatory biomarker. In human blood, Lp-PLA(2) is predominately associated with low-density lipoprotein (LDL). This study examines the ability of lifestyle modification (diet and exercise) and combination lipid therapy to reduce Lp-PLA(2) levels while also determining the relationship between changes in LDL cholesterol and Lp-PLA(2). Thirty dyslipidemic patients who received lifestyle intervention and combination lipid therapy for an average of 6 months were included in these analyses (mean age, 60.9 years); 40% had stable angiographically established coronary artery disease, 40% had the metabolic syndrome, and 70% were men. Drug therapy included omega-3 fish oil, extended-release niacin, colesevelam hydrochloride, and a fixed combination of 10-mg ezetimibe and 40-mg simvastatin. The study revealed a 33% reduction in mean Lp-PLA(2) values (baseline 224.9+/-47.5 vs posttreatment 149.5+/-35.5 ng/mL; P<.001). Significant changes in mean LDL cholesterol from baseline (127.9+/-49.3 vs posttreatment 65.2+/-32.1 mg/dL; P<.001) were also observed. However, regression analysis revealed only a weak positive relationship between changes in LDL cholesterol and Lp-PLA(2) mass (R(2)=0.29; P<.01). Thus, Lp-PLA(2) mass is significantly reduced with lifestyle and combination lipid therapy. Changes in Lp-PLA(2) were only partially explained by the changes observed for LDL cholesterol.

Lipoprotein-associated phospholipase A2 and atherosclerosis

There is substantial data from over 50 000 patients that increased lipoprotein-associated phospholipase A2 (Lp-PLA2) mass or activity is associated with an increased risk of cardiac death, myocardial infarction, acute coronary syndromes and ischemic stroke. However, only recently have data emerged demonstrating a role of Lp-PLA2 in development of advanced coronary artery disease. Indeed, Lp-PLA2 may be an important link between lipid homeostasis and the vascular inflammatory response. Lp-PLA2, also known as platelet-activating factor acetylhydrolase, rapidly cleaves oxidized phosphatidylcholine molecules produced during the oxidation of LDL and atherogenic lipoprotein Lp(a), generating the soluble proinflammatory and proapoptotic lipid mediators, lyso-phosphatidylcholine and oxidized nonesterified fatty acids. These proinflammatory lipids play an important role in the development of atherosclerotic necrotic cores, the substrate for acute unstable coronary disease by recruiting and activating leukocytes/macrophages, inducing apoptosis and impairing the subsequent removal of dead cells. Selective inhibition of Lp-PLA2 reduces development of necrotic cores and may result in stabilization of atherosclerotic plaques. Recent data have shown that immune pathways play a major role in the development and progression of high-risk atherosclerosis, which leads to ischemic sudden death, myocardial infarction, acute coronary syndromes and ischemic strokes. Persistent and sustained macrophage apoptosis appears to play a major role in the resulting local inflammatory response in part by effects elicited by Lp-PLA2. Selective inhibition of Lp-PLA2 has been postulated to reduce necrotic core progression and the clinical sequelae of advanced, unstable atherosclerosis.

Effects of prescription omega-3-acid ethyl esters on lipoprotein particle concentrations, apolipoproteins AI and CIII, and lipoprotein-associated phospholipase A2 mass in statin-treated subjects with hypertriglyceridemia

Prescription omega-3-acid ethyl esters (P-OM3) often are used for hypertriglyceridemic patients receiving statin therapy who have residual increases in atherogenic lipoprotein lipid levels. To date, limited information has been published regarding the effects of omega-3 fatty acid consumption on lipoprotein particle concentrations. We evaluated the effects of adding P-OM3 4g/d to an ongoing regimen of simvastatin 40mg/d on lipoprotein particles (P) in subjects with hypertriglyceridemia. Data were analyzed from the multicenter, randomized, double-blind, placebo-controlled Combination of Prescription Omega-3s with Simvastatin (COMBOS) study. After an 8-week simvastatin lead-in, 254 subjects received P-OM3 (n=122) or placebo (n=132) for an additional 8 weeks. Nuclear magnetic resonance spectroscopy was used to assess lipoprotein concentrations and sizes. Remnant-like particle cholesterol, apolipoprotein (Apo) CIII, Apo AI, and lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) levels also were measured. Compared with placebo, P-OM3 reduced mean very-low-density lipoprotein (VLDL-P) size and increased low-density lipoprotein particle (LDL-P) size (P < .006 for both) without altering high-density lipoprotein particle (HDL-P) size. P-OM3 did not significantly change total VLDL-P or LDL-P concentrations relative to placebo, but large VLDL-P and intermediate-density lipoprotein particle (IDL-P) concentrations were lowered (P < .01 for both), and the large LDL-P concentration was increased (P < .0001). HDL-P concentration was reduced (P < .0001) as the result of a decrease in medium HDL-P. Remnant-like particle cholesterol, Apo CIII, and Lp-PLA(2) concentrations were reduced compared with placebo (all P < .003). P-OM3 induces changes in sizes, concentrations, and compositions of lipoproteins that may have relevance for the atherothrombotic process.

Relationship of lipoprotein-associated phospholipase A2 and oxidized low density lipoprotein in carotid atherosclerosis

Plasma levels of lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) and oxidized low density lipoprotein (oxLDL) have been identified as risk factors for cardiovascular disease. Lp-PLA(2) is the sole enzyme responsible for the hydrolysis of oxidized phospholipids on LDL particles in atherosclerotic plaques. We have studied the relationship between Lp-PLA(2) and oxLDL in carotid endarterectomy (CEA) tissues and in matched plasmas. In extracts from CEA anatomical segments, the levels of oxLDL were significantly associated with the levels of Lp-PLA(2) protein (r = 0.497) and activity (r = 0.615). OxLDL and Lp-PLA(2) mass/activity were most abundant in the carotid bifurcation and internal segments where plaque was most abundant. In extracts from CEA atheroma, the levels of oxLDL and Lp-PLA(2) were significantly correlated (r = 0.634). In matched plasma and atheroma extracts, the levels of Lp-PLA(2) were negatively correlated (r = - 0.578). The ratio of Lp-PLA(2) to oxLDL was higher in atheromatous tissue (277:1) than in normal tissue (135:1) and plasma (13:1). Immunohistochemical experiments indicated that in plaques, oxLDL and Lp-PLA(2) existed in overlapping but distinctly different distribution. Fluorescence microscopy showed both oxLDL and Lp-PLA(2) epitopes on the same LDL particle in plasma but not in plaque. These results suggest that the relationship between Lp-PLA(2) and oxLDL in the atherosclerotic plaque is different from that in the plasma compartment.

Effects of lifestyle counseling and combination lipid-modifying therapy on lipoprotein-associated phospholipase A2 mass concentration

Lipoprotein-associated phospholipase A2 (Lp-PLA(2)) is a novel inflammatory biomarker that is associated with increased cardiovascular disease risk independent of and additive to traditional risk factors. Lp-PLA(2) activity is correlated with the degree of inflammation in the atherosclerotic plaque. In human blood, approximately 80% of Lp-PLA(2) is associated with low-density lipoproteins (LDL). Thus, it is hypothesized that changes in Lp-PLA(2) should imitate the changes in the LDL cholesterol. In this present study, we examined the efficacy of lifestyle intervention and combination lipid-lowering therapy on reducing the Lp-PLA(2) levels and determined the relationship between changes in LDL-C and Lp-PLA(2). This retrospective chart review study includes two hundred forty eight patients (58% men and 42% women) who completed the life style intervention in combination with pharmacologic therapy for an average period of 10.5 months. Life style modification included diet and exercise counseling. Combination therapy included omega 3 fish oil (2000mg/d), extended-release niacin (500-1000mg/d), ezetimibe (10mg/d), fenofibrate 160mg/d and colesevelam HCI (1850mg/d), as well as statins. The statins used were either simvastatin (20-40mg/d) or rosuvastatin (5-20mg/d). Sixty five percent (n=161) received low to medium doses of simvastatin, whereas 35% (n=87) received low to medium doses of rosuvastatin. The study revealed a 32.5% reduction in mean Lp-PLA(2) values (baseline 181.1±41.5 vs 122.1±28.1 ng/mL after treatment; P<.001). The change observed in LDL-C was 41%, (baseline 126.2±43 vs 73.9±37.7mg/dL after treatment), which also was significant (P < .001). However, a Pearson correlation test analysis revealed only a weak positive association between changes in Lp-PLA(2) and LDL-C (r(2)=0.052, P < .001). Lp-PLA(2) is reduced with the use of life style counseling and combination lipid lowering therapy. Results also revealed that changes in Lp-PLA(2) may be partially explained by the changes in LDL-C.

Smoking induces lipoprotein-associated phospholipase A2 in cardiovascular disease free adults: The ATTICA Study

ObjectivesWe studied the association of lipoprotein-associated phospholipase A2 (Lp-PLA2) mass and activity with various lifestyle, clinical and biochemical characteristics in cardiovascular disease (CVD) free adults. BackgroundLipoprotein-associated phospholipase A2 (Lp-PLA2) is a novel biomarker of inflammation and risk for CVD. The Lp-PLA2 mass and activity are primarily influenced by the plasma levels of low-density lipoprotein (LDL), however the influence of various lifestyle characteristics on Lp-PLA2 have not been adequately studied. Methods and resultsIn a random sub-sample of 186 subjects, 64 men (52±13 years) and 122 women (48±13 years) from the ATTICA Study (Greece), Lp-PLA2 activity and mass in total plasma as well as the enzyme activity and mass associated with high-density lipoprotein (HDL-Lp-PLA2) were determined using established methods. Several socio-demographic, lifestyle, clinical and biochemical parameters were assessed in all participants. Multiple linear regression analysis revealed that among the lifestyle characteristics, total plasma Lp-PLA2 activity and mass were positively and independently associated with current smoking (p=0.02 and p=0.05, respectively), as well as with exposure to second-hand smoke (p=0.02 and p=0.01, respectively). Furthermore, HDL-Lp-PLA2 activity and mass were inversely and independently associated with current smoking (p=0.04 and p=0.09, respectively). ConclusionsSmoking is associated with and might even induce an increase in proatherogenic total plasma Lp-PLA2, but attenuates antiatherogenic HDL-Lp-PLA2. These results further support the role of smoking as an important avoidable cause of CVD.

Association of Lipoprotein-Associated Phospholipase A2 Mass and Activity with Coronary and Aortic Atherosclerosis: Findings from the Dallas Heart Study

Our aim was to characterize the association of lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) with coronary and aortic atherosclerosis in a large population-based study. Lp-PLA(2) mass and activity were measured in 2171 subjects 30-65 years old participating in the Dallas Heart Study. We examined the association of Lp-PLA(2) levels with 3 atherosclerosis phenotypes: coronary artery calcium (CAC) measured by electron-beam computed tomography and abdominal aortic plaque (AAP) and aortic wall thickness (AWT) measured by magnetic resonance imaging. CAC and AAP were detected in 21% and 40% of subjects, respectively, and mean AWT (SD) was 1.70 (0.32) mm. In univariable analyses, Lp-PLA(2) mass (but not activity) was higher in both men (P = 0.04) and women (P = 0.02) with detectable CAC. Lp-PLA(2) mass and activity were higher (P = 0.004 and P = 0.01, respectively) and AWT was greater (P < 0.001 and P = 0.02, respectively) in women with aortic atheroma, but not in men. After adjustment for traditional atherosclerosis risk factors and C-reactive protein concentrations, Lp-PLA(2) mass and activity were not associated with AAP or AWT in either sex, but Lp-PLA(2) mass remained modestly associated with detectable CAC only in men (odds ratio 1.20 per 1 standard deviation increase, 95% CI 1.01-1.42, P = 0.04). Although Lp-PLA(2) mass was independently associated with CAC in men, it was not associated with AAP or AWT in men or with any of the atherosclerosis phenotypes in women. These findings suggest that if Lp-PLA(2) independently influences clinical events, it does so by promoting atherosclerotic plaque instability rather than by stimulating atherogenesis.