Lipoprotein-associated Phospholipase A2 Concentration Research Articles

Concentration of lipoprotein - associated phospholipase A2 in chronic dental diseases and stable coronary artery disease

Lipoprotein-associated phospholipase A2 (Lp-PLA2) is an enzyme that has been shown to be a risk factor of cardiovascular disease (CVD) and that is involved in the degradation of the phospholipid mediator platelet-activating factor (PAF), a potent mediator of inflammation. The aim of the present study was to investigate concentration of Lp-PLA2 in control group and patients with chronic dental diseases and stable coronary artery disease (CAD). We studied 10 patients with chronic dental diseases, 10 patients with stable coronary artery disease and 10 healthy individuals as controls. Our patients with stable coronary artery disease were using anti-hypertension medicaments, acetylsalicylic acid and statins although patients with chronic dental diseases were not. A plasma Lp-PLA2 assay kit (ELISA, Human, Life Inc., Wuhan, China) was used. Our results showed that both groups of patients with chronic dental diseases and stable coronary artery disease had significantly increased Lp-PLA2 mass as compared to controls. However, Lp-PLA2 mass in patients with chronic dental diseases and stable coronary artery disease was non-significant statistically. We concluded that patients with chronic dental diseases have increased the serum lipoprotein-associated phospholipase A2, which is believed to be an independent cardiovascular risk factor, although future studies are required.

Regression of atherosclerosis in apolipoprotein E-deficient mice by lentivirus-mediated gene silencing of lipoprotein-associated phospholipase A2

Overexpression of lipoprotein-associated phospholipase A2 (Lp-PLA2) is implicated in atherosclerosis. We tested the hypothesis that lentivirus-mediated Lp-PLA2 silencing could inhibit atherosclerosis in apolipoprotein E-deficient mice. Sixty eight apolipoprotein E-deficient mice were fed a high-fat diet and a constrictive collar was placed around the left carotid artery to induce plaque formation. The mice were randomly divided into control, negative control (NC) and RNA interference (RNAi) groups. Lp-PLA2 RNAi or scrambled NC lentivirus viral suspensions were constructed and transfected into the carotid plaques 8weeks after surgery; the control group was administered saline. The carotid plaques were assessed 7weeks later using hematoxylin and eosin, Masson’s trichrome and oil red O staining; plasma and lesion inflammatory gene expression were examined using ELISAs and real-time PCR. Seven weeks after transfection, the serum concentration and plaque mRNA expression of Lp-PLA2 was significantly lower in the RNAi group, and lead to reduced local and systemic inflammatory gene expression. Lp-PLA2 RNAi also ameliorated plaque progression, reduced the plaque lipid content and increased the plaque collagen content. The effects of Lp-PLA2 RNAi were independent of serum lipoprotein levels, as the triglyceride and total cholesterol levels of the control, NC and RNAi groups were not significantly different. These findings support the hypothesis that lentivirus-mediated Lp-PLA2 gene silencing has therapeutic potential to inhibit atherosclerosis and increase plaque stability, without altering the plasma lipoprotein profile.

Abstract 2552: Lipoprotein-associated phospholipase A2 predicts atherosclerotic stroke risk: The Northern Manhattan Study

Background: Lipoprotein-associated phospholipase A2 (Lp-PLA2) has pro-inflammatory properties and may contribute to atherosclerosis, plaque rupture, and stroke. Lp-PLA2 levels may improve risk stratification, though whether this ability extends to all populations and stroke subtypes remains uncertain. We hypothesized that Lp-PLA2 levels would predict first ischemic stroke in a multiethnic, urban, population. Methods: Serum samples from stroke-free community participants in the Northern Manhattan Study were assayed using a microplate based ELISA to measure the mass concentration of Lp-PLA2 (PLAC Test, diaDexus, Inc). Participants were followed annually for stroke, and stroke subtype was determined according to the TOAST criteria. Cox proportional hazard models were fitted to estimate hazard ratios and 95% confidence intervals (HR, 95% CI) for the association of Lp-PLA2 mass levels with ischemic stroke, unadjusted and after adjusting for demographic, behavioral and medical risk factors. Results: Serum samples were available in 1946 participants with median follow up of 11 years; 151 subjects (7.8%) experienced a first ischemic stroke, of which 26 were large artery atherosclerotic strokes. Mean age was 69 (SD 10), 35.6% were men, 20% non-Hispanic Whites, 22% Blacks, and 55% Hispanics. The mean Lp-PLA2 level was 308.7 (SD 88.5) ng/mL. In non-Hispanic Whites, there was a trend toward increased risk of ischemic stroke with Lp-PLA2 levels (adjusted HR per SD 1.44, 95% CI 0.98-2.11), but not in Blacks (p for interaction with white=0.045); or in Hispanics (p for interaction with white=0.13). Lp-PLA2 levels were predictive of large artery atherosclerotic strokes (LAA) in the entire cohort (adjusted HR per SD 1.55, 95% CI 1.17-2.04). When analyzed by quartile, there were dose-response relationship with LAA (compared to the lowest 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). When the analysis was stratified by race, Lp-PLA2 was associated with increased risk of LAA among whites, but not blacks or Hispanics (chi-squared 2 degrees of freedom, p for interaction=0.01). Conclusion: Lp-PLA2 was 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.

Association of Serum Lipoprotein-Associated Phospholipase A2 Level with Nonalcoholic Fatty Liver Disease

Nonalcoholic fatty liver disease (NAFLD) is the hepatic manifestation of metabolic syndrome and is one of the most common causes of chronic liver disease, worldwide. Lipoprotein-associated phospholipase A2 (Lp-PLA2) was recently characterized as a novel inflammatory biomarker that is correlated with several components constituting the metabolic syndrome. In this study, we determined the serum levels of Lp-PLA2 in patients with definite nonalcoholic steatohepatitis (NASH, n=25), borderline NASH (n=22), simple fatty liver (n=10), and healthy controls without evidence of liver disease (n=38). The levels of Lp-PLA2 were measured by enzyme-linked immunosorbent assay and compared in the four study groups. Moreover, concentrations of Lp-PLA2 were assessed in relation to the general characteristics of the study participants and the results of liver biopsy. Concentrations of Lp-PLA2 were significantly higher in patients with definite NASH (161.8±0.9 μg/L, P<0.001), borderline NASH (135.4±47.7 μg/L, P=0.001), and simple fatty liver (132.4±46.2 μg/L, P=0.042) compared with healthy controls (86.2±40.7 μg/L). Furthermore, the serum Lp-PLA2 level was strongly associated to histological steatosis scores in patients with NAFLD (β=0.32, t=2.50, P=0.016). Although subject to future confirmation, our data suggest that Lp-PLA2 levels are elevated in NAFLD.

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.

Increased plasma lipoprotein-associated phospholipase A2 (Lp-PLA2) levels are related to good collateral development in patients with isolated left coronary artery disease

Development of coronary collaterals (CCs) is a time-dependent adaptive response to an ischemic process arising from the gradient between obstructed arteries and myocardial ischemia. It is a complex inter-relationship among various factors [1]. A complex interaction exists between new blood vessel formation and inflammation. However, little data are available on the relation between inflammation and the development of CCs [2,3]. Inflammation has emerged as central to the initiation and progression of atherosclerosis. The mechanism(s) underlining collateral artery growth closely resemble those of atherosclerosis. Lipoprotein-associated phospholipase A2(Lp-PLA2) is actively secreted by monocyte-derived macrophages in atherosclerotic plaque. Lp-PLA2 is a unique inflammatory biomarker, as it is highly vascular specific, has low biologic variability, and is directly related to the propensity of plaque rupture and the degree of inflammation present in the walls of coronary arteries [4]. The inflammatory process is also associatedwith an increased oxidant environment. In a recent study, it was indicated that oxidative stress may also play an important role in the development of CCs [5]. Ischemia modified albumin (IMA), the earliest ischemic marker, in atherosclerosis has been extensively studied, but, there is no data on the possible involvement of Lp-PLA2 and IMA in the development of coronary collaterals. In this prospective preliminary study, it was aimed to investigate the possible role and involvement of plasma Lp-PLA2, IMA and oxidant stress status in patients with isolated left coronary artery disease (CAD). This prospective study was conducted between January 2007 and September 2009 in our university hospital setting. Clinical indications were considered in all patients undergoing coronary angiography by using the standard femoral approach by the Judkins technique. Because the multi-vessel coronary disease has a significant influence on the development of collaterals, we mainly evaluated the single-vessel disease group, with ≥90% narrowing or total occlusion of the left anterior descending (LAD) and nonsignificant (b30%) narrowing of the non-LAD (5). The study was approved by the local Ethics Committee. Coronary collateral development was graded according to the Cohen– Rentrop method [6]. Classification of the patients according to the Rentrop's score yielded 24 of patients with poor developed CCs, (Rentrop's score of 0 to 1), and 21 had good developed CCs (Rentrop's score of 2 to 3). The Gensini score was computed for each patient from the coronary arteriogram by assigning a severity score to each coronary stenosis [7]. The levels of serum total cholesterol (TC), triglyceride (TG), LDL cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDLC) were determined by enzymaticmethods using a ROCHE autoanalyzer (Modular System,GmbH,Mannheim,Germany). hs-CRPwas assessed by the latex enhanced immunonephelometric method (DADE BEHRING, GmbH, Marburg, Germany). Lp-PLA2 concentration (mass) was measured by a turbidimetric immunoassay method (PLAC® test, diaDexus). Lp-PLA2 activity was measured in an autoanalyzer (Roche, Cobas-6000). The inter-assay coefficient of variation (CV) was 6.2%. Serum total antioxidative capacity (TAC), total oxidant status (TOS) and Oxidative Stress Index (OSI) were assayed as described previously [8]. Inter-assay CVswere 2.5% and 3.1% respectively. The IMA level was assayed by using Bar-Or et al.'s method [9]. The results were reported as absorbance units (AbsUs). Inter-assay CV was 4.2%. Of the inflammation markers, Lp-PLA2 was found to be significantly higher in patients with good CCs thanwith poor CCs (pb0.020) while hs-CRP was lower in patients with good CCs thanwith poor CCs. The results of the present prospective study demonstrated that Lp-PLA2 has an independent association with good coronary collateral development andwithGensini score in patientswith isolated left coroner artery involvement. This is the first report investigating the plasma Lp-PLA2 level in coronary collateral development. Lp-PLA2 plays a pivotal role for inflammatory progress of the atherosclerotic process [10]. Lp-PLA2 is a unique inflammatory biomarker, as it is highly vascular specific, and has low biologic variability compared to the hs-CRP (4). Little data are available on the relation between inflammation and the development of CCs [11]. In those studies, authors showed an inverse relationship between CRP and coronary collateral development. Similar distribution of the CRP level between poor and good CC groups was observed in the

The relation between Lp-PLA2 levels with periodic limb movements

Lipoprotein-associated phospholipase A2 (Lp-PLA2), a novel marker of vulnerable plaque to prone rupture, is a predictor of both cardiovascular event and cerebrovascular event, and highly sensitive-C-reactive protein (hs-CRP) is an acute-phase response protein implicated in a broad range of cardiovascular diseases. We aimed to examine the association between periodic limb movements in sleep (PLMs) with circulating Lp-PLA2 and hs-CRP levels in patients with PLMs. Seventy patients with newly diagnosed PLM with polysomnography were enrolled this study. Patients were divided into two groups according to PLM index (normal PLM index, <15; elevated PLM index, ≥15). Lp-PLA2 and hs-CRP concentrations were measured in serum samples by turbidimetric and nephelometric methods, respectively. The concentrations of these parameters were compared between two groups and correlation analysis was performed between PLMs and Lp-PLA2 and hs-CRP levels. Lp-PLA2 levels and hs-CRP were significantly increased in elevated PLM index group compared with the control group (206.8 ± 78.1 vs 157.8 ± 56.7, p = 0.003, and 4.2 ± 3.5 vs 2.4 ± 2.1, p = 0.02, respectively). PLM index was positively correlated with Lp-PLA2 levels (r = 0.40, p = 0.001) and hs-CRP (r = 0.24, p = 0.05). In the linear regression model, Lp-PLA2 was an independent predictor of PLM index (R(2) = 0.36, p = 0.005). This study demonstrated an independent linear relation between PLM index and Lp-PLA2. In addition, it was seen increased Lp-PLA2 and hs-CRP levels in patients with elevated PLM index. Based on these results, we can suggest that risk of vascular events may be increased in patients with PLMs and with increased PLM index.

108 Long term pronostic role of lipoprotein-associated phospholipase A2 levels in patients with acute heart failure without acute coronary syndrome

Vascular inflammation increased in HFand produced pro-inflammatory cytokines, activation of complement and adhesion molecules that sustain inflammatory state. Lipoprotein-associated phospholipase A2 (Lp-PLA2) hydrolyze phospholipids and is a marker of inflammation that plays a critical role in atherogenesis and endothelial dysfunction. In this study, we evaluated (1) predictive value of Lp-PLA2 in patients with de novo cardiogenic shock (CS) without acute coronary syndrome (ACS), (2) evolution of this biomarker when cardiac function improved upon cardiac treatment during a 30 ± 3 month follow-up. Inclusion criteria for patients: CS defined by systolic BP<90 mmHg with peripheral hypoperfusion. Exclusion criteria: pace makers or other shock etiologies. All patients had cardiac (echocardiography, coronarography) and biological evaluations (troponin; NT-proBNP; Lp-PLA2 with turbidimetric immunoassay). 22 consecutive patients with CS (95% men, 57.5 ± 10.7y, LVEF 25.1 ± 7.5%, proBNP 8540 ng/L) were included: 7 ischemic CM, 15 dilated CM [12 idiopathic, 2 toxic and 1 myocarditis]. Cardiovascular risks: diabetes (n = 11), HBP (n = 7), tabacco (n = 9), dyslipidemia (n = 8). At 30 months, HF symptoms decreased in 6 patients and 3 normalized their LVEF. Mortality was 23% (due to cardiac complications) and morbidity 48% (iterative hospitalizations for HF and/or arrhythmia). Lp-PLA2 were elevated in CS (226 ± 77 μg/L), when referred to our controls (156.4 ± 45.0 μg/L, p = 0.005). Upon admission, Lp-PLA2 was more elevated in ICM than DCM group (266 ± 74 and 203 ± 72 μg/L, p = 0.08). In ICM, Lp-PLA2 levels significantly decreased when inotrope treatment was withdrawn (208 ± 63 vs 266 ± 74; p < 0.03) without significant difference with DCM group. Using multivariate regression Lp-PLA2 appears to be an independent prognostic factor for the major cardiac events (death, HF, rehospitalization, arrhythmias) (total r = 0.76; p = 0.005) with a a predictive rule-out of 254 μg/L 1) Lp-PLA2 concentrations were elevated in population with CS and more elevated in ICM group than DCM group; 2) Lp-PLA2 might be a good predictive factor for major cardiac events. Lp-PLA2 levels decreased significantly upon inotrope.

Association of Lipoprotein-Associated Phospholipase A2with Characteristics of Vulnerable Coronary Atherosclerotic Plaques

PurposeLipoprotein-associated phospholipase A2 (Lp-PLA2) is an inflammatory enzyme expressed in atherosclerotic plaques. We investigated the association of circulating Lp-PLA2 with characteristics of vulnerable coronary atherosclerotic plaques.Materials and MethodsWe recruited 113 patients with either unstable angina (UA, n=59) and stable angina (SA, n=54) by coronary angiography. Thirty-six healthy subjects served as controls. Intravascular ultrasound (IVUS) was used to evaluate the characteristics of coronary atherosclerotic plaque, and serum Lp-PLA2 concentration was measured as well.ResultsLp-PLA2 concentration was significantly higher in both UA and SA patients [(396±36) µg/L and (321±39) µg/L, respectively] compared with the controls [(127±49) µg/L, p<0.01], and higher in UA than SA group. IVUS findings showed that remodeling index (RI) (0.91±0.15 vs. 0.85±0.11, p=0.005) and eccentricity index (EI) (0.73±0.16 vs. 0.65±0.22, p=0.039) were larger in UA than in SA group, and fibrous caps were thicker in SA than UA group [(0.91±0.23) mm vs. (0.63±0.21) mm, p=0.032]. Moreover, Lp-PLA2 correlated positively with EI (r=0.439, p<0.01) and RI (r=0.592, p<0.05) in UA group. There was an inverse relationship between Lp-PLA2 and fibrous cap thickness in both UA (r=-0.587, p<0.001) and SA (r=-0.318, p<0.05) groups. The independent risk factors in UA group were Lp-PLA2 (OR=1.055, 95% CI: 1.03-1.08, p=0.013), LDL-cholesterol (OR=0.032, 95% CI: 0.00-0.05, p=0.041) and fibrous cap thickness (OR=0.008, 95% CI: 0.00-0.45, p=0.019). Lp-PLA2 was strongly associated with both EI and fibrous cap thickness in both groups.ConclusionSerum level of Lp-PLA2 is associated with both eccentricity index and fibrous cap thickness in both UA and SA groups. Elevated levels of circulating Lp-PLA2 might to be a strong risk factor and more serious for unstable angina than stable angina.

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.

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.

The Spin Stops Here: Inhibition of Lipoprotein-Associated Phospholipase A2— A Promising Target but a Negative Initial Trial?

Current treatment strategies have resulted in significant reductions in morbidity and mortality associated with cardiovascular disease; however, significant residual risk remains. As an example, in the PROVE IT–TIMI 22 trial (Pravastatin or Atorvastatin Evaluation and Infection Therapy–Thrombolysis in Myocardial Infarction 22), 22.4% of patients experienced an adverse event despite achieving a median LDL cholesterol concentration of 62 mg/dL (1.6 mmol/L) (1). These and similar findings have led to the search for novel therapeutic modalities. A logical place to start is control of inflammation. Darapladib (GlaxoSmithKline) is a novel oral therapeutic agent with potential antiinflammatory properties that inhibits lipoprotein-associated phospholipase A2 (Lp-PLA2).1 Lp-PLA2 is produced by macrophages and circulates bound to LDL. In experimental models, it appears to be central in the atherosclerotic process. Lp-PLA2 acts on oxidized phospholipids to produce free oxidized fatty acids and lysophosphatidylcholine, a proatherogenic inflammatory mediator that increases expression of adhesion molecules and cytokines, is a chemoattractant for macrophages, and induces vascular smooth muscle migration (2)(3). Immunohistochemical studies have shown that Lp-PLA2 is present in atherosclerotic lesions, and is particularly intense in “rupture-prone lipid laden” lesions with thin-cap fibroatheromas, (4). Unlike many other inflammatory mediators, Lp-PLA2 is not an acute-phase reactant (5); thus issues associated with acute-phase reactants are averted. For these reasons, Lp-PLA2 has emerged recently as an independent marker of cardiovascular risk and events. Although not all prospective studies have demonstrated an association between high plasma Lp-PLA2 concentrations and poor cardiovascular outcomes, the majority of studies reported are strongly positive. In a recent metaanalysis (6) including more than 20 000 patients from 14 epidemiologic studies, high Lp-PLA2 concentration was an independent risk factor for cardiovascular events. This is especially true in regard to the associations with stroke, which seem particularly strong (7)(8). These findings have persisted despite multiple iterations …

Prevalence and Cluster of Cardiometabolic Biomarkers in Overweight and Obese Schoolchildren: Results from a Large Survey in Southwest Germany

Obesity is associated with substantial metabolic changes and subclinical inflammation. We explored associations between body mass index (BMI) and cardiometabolic biomarkers and their clustering in overweight and obese schoolchildren. In this population-based, cross-sectional study among 450 children 10 years old, we measured adiponectin, leptin, inflammatory markers, apolipoprotein (apo) AI and B, and lipoprotein-associated phospholipase A(2) (Lp-PLA(2)). Except for adiponectin and apoAI (10th percentile) the 90th percentile was used as cutoff point. Body weight was categorized in age- and sex-specific BMI percentiles and overweight and obesity according to International Obesity Task Force definitions. In linear regression models, all cardiometabolic markers except apoB were statistically significantly associated with overweight. In logistic regression models, compared with the reference category (25th-75th percentile of BMI), overweight was associated with increased concentrations of leptin [odds ratio (OR) 59.80; 95% CI 16.68-214.39], C-reactive protein (6.30; 2.95-13.45), fibrinogen (2.82; 1.33-6.01), and low apoAI (2.62; 1.19-5.75). Overweight was positively associated with interleukin-6, Lp-PLA(2), and apoB concentrations and inversely with adiponectin concentrations. Most importantly, in obese children 35% showed one, 20% two, 10% three, and 15% four or more abnormal cardiometabolic biomarkers. The number of abnormal cardiometabolic markers increased in overweight (p(trend) <0.001) and obese (p(trend) <0.001) children. Overweight and obesity in children are associated with complex metabolic changes and a low-grade inflammatory response, and thus might not only accelerate cardiovascular disease later on, but may also be associated with the initiation of atherosclerosis in early life.

Variability of Serial Lipoprotein-Associated Phospholipase A2 Measurements in Post–Myocardial Infarction Patients: Results from the AIRGENE Study Center Augsburg

Of the numerous emerging biomarkers for coronary heart disease (CHD), lipoprotein-associated phospholipase A(2) (Lp-PLA(2)), an enzyme involved in lipid metabolism and inflammatory pathways, seems to be a promising candidate. Implementation of Lp-PLA(2) measurement into clinical practice, however, requires data on the reliability of such measurements. We measured Lp-PLA(2) concentrations by ELISA in blood samples drawn from 200 post-myocardial infarction patients (39-76 years) at 6 monthly intervals between May 2003 and February 2004, for a total of 1143 samples. We estimated analytical, within-individual, and between-individual variation, the critical difference, and the intraclass correlation coefficient of reliability (ICC) to assess the reliability of serial Lp-PLA(2) measurements. The mean (SD) plasma Lp-PLA(2) concentration for the study participants was 188.7 (41.8) microg/L, with no significant difference between men and women. The analytical CV for Lp-PLA(2) was 4.4%, the within-individual biological CV was 15%, and the between-individual CV was 22%. The ICC was 0.66. An important part of the total variation in plasma Lp-PLA(2) concentration was explained by the between-individual variation (as a percentage of the total variance, 66.1%), whereas the within-individual variance was 31.3%. The analytical variance was as low as 2.6%. Between-individual variation in Lp-PLA(2) concentration was substantially greater than within-individual variation. In general, our data demonstrate considerable stability and good reproducibility of serial Lp-PLA(2) measurements, results that compared favorably with those for the more commonly measured lipid markers.

Lack of an Effect of Pioglitazone or Glipizide on Lipoprotein-Associated Phospholipase A2 in Type 2 Diabetes

To study the effects of pioglitazone, a peroxisome proliferator-activated receptor-y agonist with vascular beneficial effects, and glipizide, an insulin secretagogue, on novel inflammatory vascular risk markers in subjects with and without type 2 diabetes. We studied 11 subjects without diabetes and 19 matched subjects with diabetes. The subjects with diabetes were randomly assigned to receive either 45 mg daily of pioglitazone (N = 8) or 10 mg daily of glipizide (N = 11) (median dose) for 12 weeks. Lipoprotein-associated phospholipase A2 (LpPLA2), vascular cell adhesion molecule (VCAM-1), intracellular adhesion molecule (ICAM-1), and e-selectin were measured by established techniques before and after therapy with either agent. The subjects without diabetes were studied only once. The study subjects with diabetes had higher (P<0.05) LpPLA2, e-selectin, and VCAM-1 levels than did those without diabetes. ICAM-1 levels tended to be higher (P = 0.07) in the study subjects with than in those without diabetes. Neither pioglitazone nor glipizide therapy significantly altered LpPLA2 or VCAM-1 concentrations. While pioglitazone therapy reduced (P<0.05) eselectin concentrations, glipizide therapy reduced (P<0.03) ICAM-1 concentrations. Type 2 diabetes is associated with elevated concentrations of the novel vascular risk marker LpPLA2 and inflammatory risk markers e-selectin and VCAM-1. Neither pioglitazone nor glipizide significantly altered LpPLA2, VCAM-1, or highly sensitive C-reactive protein levels after 12 weeks of therapy. In study subjects with type 2 diabetes, e-selectin concentrations declined significantly with pioglitazone therapy, whereas ICAM-1 concentrations decreased significantly with glipizide therapy.

Lipoprotein-associated phospholipase A2 concentrations in plasma are associated with the extent of coronary artery disease and correlate to adipose tissue levels of marine n-3 fatty acids

Lipoprotein-associated phospholipase A2 (Lp-PLA2) is an emerging risk factor for cardiovascular disease. In the present study, plasma levels of Lp-PLA2 were measured in patients (n=301) admitted to elective coronary angiography because of suspected coronary artery disease (CAD). In a multiple linear regression analysis, the degree of CAD (0-, 1-, 2- or 3-vessel disease) and plasma LDL cholesterol significantly correlated to Lp-PLA2 levels. Also the content of the marine n-3 fatty acid, eicosapentaenoic acid (EPA) in adipose tissue, a measure of long-term intake of seafood independently and inversely (r=−0.18, p<0.01) correlated with plasma levels of Lp-PLA2. The results support the view that Lp-PLA2 may relate to CAD and that intake of marine n-3 fatty acids might reduce plasma Lp-PLA2 suggesting another mechanism by which n-3 fatty acids could reduce the risk of cardiovascular disease.

O4-03-05 Dietary omega-3 docosahexaenoic acid DHA regulates CNS insulin signaling and related kinase pathways involved in actin assembly, synaptic plasticity and memory in an Alzheimer (AD) model

Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), the primary omega-3 fatty acids in fish oil, have been shown to reduce cardiovascular disease (CVD) risk.This study aimed to examine the independent effects of EPA and DHA on lipid and apolipoprotein levels, as well as on inflammatory biomarkers of CVD risk, using doses often used in the general population.A blinded, randomized 6-week trial was performed in 121 healthy, normolipidemic subjects who received olive oil placebo 6 g/d, EPA 600 mg/d, EPA 1800 mg/d, or DHA 600 mg/d. The EPA was derived from genetically modified yeast.The subjects tolerated the supplements well with no safety issues; and the expected treatment-specific increases in plasma EPA and DHA levels were observed. Compared to placebo, the DHA group had significant decreases in postprandial triglyceride (TG) concentrations (− 20%, − 52.2 mg/dL, P = 0.03), significant increases in fasting and postprandial low-density lipoprotein cholesterol (LDL-C) (+ 18.4%, 17.1 mg/dL, P = 0.001), with no significant changes in inflammatory biomarkers. No significant effects were observed in the EPA 600 mg/d group. The high-dose EPA group had significant decreases in lipoprotein-associated phospholipase A2 concentrations (Lp-PLA2) (− 14.1%, − 21.4 ng/mL, P = 0.003).The beneficial effects of EPA 1800 mg/d on CVD risk reduction may relate in part to the lowering of Lp-PLA2 without adversely affecting LDL-C. In contrast, DHA decreased postprandial TG, but raised LDL-C. Our observations indicate that these dietary fatty acids have divergent effects on cardiovascular risk markers.