Lp-PLA2 Mass Research Articles

Effect of Statin Treatment on Lipoprotein-Associated Phospholipase A2 Mass and Activity: A Systematic Review and Meta-analysis of Randomized Placebo-Controlled Trials.

The goal of this meta-analysis was to establish whether statin treatment reduces Lp-PLA2 mass concentration and/or activity. PubMed, Scopus, Web of Science, ClinicalTrials.gov, and Google Scholar databases were searched using MESH terms and keywords. Randomized controlled trials (RCT) with either parallel or cross-over design examining the effect of statins on Lp-PLA2 mass and/or activity were included in meta-analysis. Out of 256 articles, 10 RCT were selected for meta-analysis. Statin therapy significantly reduced both Lp-PLA2 mass (WMD -44.46 ng/mL; 95%CI -59.01, -29.90; p < 0.001; I2 = 93%) and activity (WMD -39.37 nmol/min/mL; 95%CI -69.99, -8.75; p = 0.01; I2 = 100%). The sensitivity analysis was robust for Lp-PLA2 mass and was also positive for two studies concerning Lp-PLA2 activity. Statin therapy significantly reduced both Lp-PLA2 mass and activity.

Increased sedentary time and decreased physical activity increases lipoprotein associated phospholipase A2 in obese individuals

Background and aimsLipoprotein-associated Phospholipase A2 (Lp-PLA2) is a protein produced by inflammatory cells in circulation and is associated with cardiovascular disease (CVD) risk. Physical activity (PA) is known to reduce inflammation and risk for CVD. However, Lp-PLA2 has yet to be examined in relation to PA and sedentary time. The purpose of this study was to determine if PA and sedentary time impacts Lp-PLA2 mass. A total of 25 subjects with an average BMI of 30.6 ± 5.7 were included in the data analysis. Methods and resultsData collected included anthropometric data, Lp-PLA2 mass, peak oxygen uptake (VO2peak), resting heart rate and blood pressure, obstructive sleep apnea (OSA) risk, and assessment of PA using an accelerometer. Sedentary minutes per day was positively associated with Lp-PLA2 (r = 0.41, P < 0.05). Light intensity PA was negatively associated (r = −0.51. P = 0.01) with Lp-PLA2. When subjects were divided into 2-quantiles by Lp-PLA2, the group with the higher Lp-PLA2 mass accumulated more sedentary time per day (P < 0.001) and less light intensity PA per day (P = 0.001). OSA risk and Lp-PLA2 showed no relationship. Sedentary behavior was higher, and light intensity PA was lower in subjects with hiLp-PLA2 mass. No difference was seen in moderate-to-vigorous intensity PA or steps per day. ConclusionsThis suggests that, total PA habits, including time spent sedentary and lower intensity PA, impacts the levels of Lp-PLA2, an important inflammatory marker and marker of CVD risk.

Circulating biomarkers of immunity and inflammation, risk of Alzheimer\u2019s disease, and hippocampal volume: a Mendelian randomization study

The aim of this study was to explore the association between genetically predicted circulating levels of immunity and inflammation, and the risk of Alzheimer’s disease (AD) and hippocampal volume, by conducting a two-sample Mendelian Randomization Study. We identified 12 markers of immune cells and derived ratios (platelet count, eosinophil count, neutrophil count, basophil count, monocyte count, lymphocyte count, platelet-to-lymphocyte ratio, monocyte-to-lymphocyte ratio, CD4 count, CD8 count, CD4-to-CD8 ratio, and CD56) and 5 signaling molecules (IL-6, fibrinogen, CRP, and Lp-PLA2 activity and mass) as primary exposures of interest. Other genetically available immune biomarkers with a weaker a priori link to AD were considered secondary exposures. Associations with AD were evaluated in The International Genomics of Alzheimer’s Project (IGAP) GWAS dataset (21,982 cases; 41,944 controls of European ancestry). For hippocampal volume, we extracted data from a GWAS meta-analysis on 33,536 participants of European ancestry. None of the primary or secondary exposures showed statistically significant associations with AD or with hippocampal volume following P-value correction for multiple comparisons using false discovery rate < 5% (Q-value < 0.05). CD4 count showed the strongest suggestive association with AD (odds ratio 1.32, P < 0.01, Q > 0.05). There was evidence for heterogeneity in the MR inverse variance-weighted meta-analyses as measured by Cochran Q, and weighted median and weighted mode for multiple exposures. Further cluster analyses did not reveal clusters of variants that could influence the risk factor in distinct ways. This study suggests that genetically predicted circulating biomarkers of immunity and inflammation are not associated with AD risk or hippocampal volume. Future studies should assess competing risk, explore in more depth the role of adaptive immunity in AD, in particular T cells and the CD4 subtype, and confirm these findings in other ethnicities.

Lipoprotein-associated phospholipase A2 activity, genetics and calcific aortic valve stenosis in humans

BackgroundLipoprotein-associated phospholipase A2 (Lp-PLA2) activity has been shown to predict calcific aortic valve stenosis (CAVS) outcomes. Our objective was to test the association between plasma Lp-PLA2 activity and genetically elevated...

Role of vitamin D in risk factors of patients with type 2 diabetes mellitus

Introduction and objectivesPrevious observational studies have suggested that low vitamin D status is associated with high circulating C-reactive protein levels, as well as other plasma inflammatory cytokines. However, there is no study to explore the relationship between vitamin D status and Lp-PLA2, a new biomarker of vascular-specific inflammation. The aim of this study was to examine the association between vitamin D status and circulating Lp-PLA2 levels in subjects with type 2 diabetes mellitus. Material and methodsThis descriptive cross-sectional study enrolled diabetic subjects who underwent physical examination at Taizhou People's Hospital between August 2016 and January 2017. Blood pressure, anthropometry, metabolic profiles, serum 25(OH)D levels and Lp-PLA2 mass levels were measured in all participants. ResultsA total of 196 participants were recruited into this study. The vitamin D insufficiency group had higher serum LP-PLA2 levels than the vitamin D sufficiency group (t=−2.765, p=.005). A significant negative correlation was noted between Lp-PLA2 and 25(OH)D in the vitamin D insufficiency group (r=−0.364, p=0.009). However, no significant relationship between serum Lp-PLA2 concentration and 25(OH)D levels was observed in subjects with vitamin D sufficiency. ConclusionsFrom this cohort of patients with type 2 diabetes, regardless of traditional cardiovascular risk factors, we observed a statistically significant inverse relation between Lp-PLA2 and 25(OH)D at levels <30ng/mL.

Role of vitamin D in risk factors of patients with type 2 diabetes mellitus

Introduction and objectivesPrevious observational studies have suggested that low vitamin D status is associated with high circulating C-reactive protein levels, as well as other plasma inflammatory cytokines. However, there is no study to explore the relationship between vitamin D status and Lp-PLA2, a new biomarker of vascular-specific inflammation. The aim of this study was to examine the association between vitamin D status and circulating Lp-PLA2 levels in subjects with type 2 diabetes mellitus. Material and methodsThis descriptive cross-sectional study enrolled diabetic subjects who underwent physical examination at Taizhou People's Hospital between August 2016 and January 2017. Blood pressure, anthropometry, metabolic profiles, serum 25(OH)D levels and Lp-PLA2 mass levels were measured in all participants. ResultsA total of 196 participants were recruited into this study. The vitamin D insufficiency group had higher serum LP-PLA2 levels than the vitamin D sufficiency group (t=−2.765, p=.005). A significant negative correlation was noted between Lp-PLA2 and 25(OH)D in the vitamin D insufficiency group (r=−0.364, p=0.009). However, no significant relationship between serum Lp-PLA2 concentration and 25(OH)D levels was observed in subjects with vitamin D sufficiency. ConclusionsFrom this cohort of patients with type 2 diabetes, regardless of traditional cardiovascular risk factors, we observed a statistically significant inverse relation between Lp-PLA2 and 25(OH)D at levels <30ng/mL.

Lp-PLA2, scavenger receptor class B type I gene (SCARB1) rs10846744 variant, and cardiovascular disease.

BackgroundWe previously reported association of SCARB1 SNP rs10846744 with common carotid IMT (cIMT) and cardiovascular disease (CVD) events. Since rs10846744 has been reported in association with Lp-PLA2 mass and activity, we hypothesized that inflammatory pathways might mediate the association of rs10846744 with atherosclerosis.MethodsWe first examined association of rs10846744 in CVD in multiple large-scale consortium-based genome-wide association studies. We further examined 27 parameters of interest, including Lp-PLA2 mass and activity, inflammatory markers, and plasma phospholipid fatty acids, and fatty acid ratios in participants from the Multi-Ethnic Study of Atherosclerosis (MESA), as potential mediators in the pathway linking rs10846744 with cIMT and incident CVD. Finally, we examined the association of rs10846744 with Lp-PLA2 activity, cardiovascular outcomes, and interaction with the Lp-PLA2 inhibitor, darapladib, in the Stabilization of Atherosclerotic Plaque by Initiation of Darapladib Therapy (STABILITY) and Stabilization of Plaque using Darapladib-Thrombolysis in Myocardial Infarction 52 (SOLID-TIMI 52) studies.ResultsSCARB1 rs10846744 was associated with coronary artery disease events in CARDIoGRAMplusC4D (odds ratio 1.05; 95% CI [1.02, 1.07]; P = 1.4x10-4). In combined analysis across race/ethnic groups in MESA, rs10846744 was associated with Lp-PLA2 mass (P = 0.04) and activity (P = 0.001), homocysteine (P = 0.03), LDL particle number (P = 0.01), docosahexaenoic acid [DHA] (P = 0.01), docosapentaenoic acid [DPA] (P = 0.04), DPA/ eicosapentaenoic acid [EPA] ratio (P = 0.002), and DHA/EPA ratio (P = 0.008). Lp-PLA2 activity was identified as a mediator of rs10846744 with cIMT in a basic model (P = 8x10-5), but not after adjustment for CVD risk factors. There was no interaction or modifier effect of the Lp-PLA2 inhibitor darapladib assignment on the relationship between rs10846744 and major CVD events in either STABILITY or SOLID-TIMI 52.SummarySCARB1 rs10846744 is significantly associated with Lp-PLA2 activity, atherosclerosis, and CVD events, but Lp-PLA2 activity is not a mediator in the association of rs10846744 with cIMT in MESA.

Characterization of PLAC® tests in the quantization of lipoprotein associated phospholipase A2 for assessment of cardiovascular diseases

BackgroundPLAC® mass test (diaDexus, Inc.) does not detect all Lp-PLA2 proteins in the circulation. The total circulating Lp-PLA2 mass can be quantized by using the CHAPS modified PLAC® mass test. To compare the difference of the PLAC® mass, CHAPS modified PLAC® mass and PLAC® activity tests in risk assessment of CVD, the 3 Lp-PLA2 quantization methods were characterized using a collection of serum and plasma from CVD patents and matched non-symptomatic controls. Improvement on risk assessment for ischemic stroke by Lp-PLA2 and lipids were also investigated. MethodsNinety one human sera and plasma from elderly patients with first CVD incidents and 78 matched controls were collected at clinics. Lp-PLA2 was assessed by PLAC® mass, CHAPS modified PLAC® mass and PLAC® activity tests and data were subjected to statistical analyses. Correlation with lipid cholesterols or Apo proteins was compared for all formats of PLAC® tests. Ratios of Lp-PLA2 by different PLAC® tests to different lipids were assessed for synergistic enhancement in the indication of ischemic stroke. ResultsThe PLAC® mass test was superior to other formats of PLAC® tests in the assessment of CVD and is independent of lipids. The Lp-PLA2 by the CHAPS modified PLAC® mass test has no separation between the CVD and control groups. ConclusionsBoth PLAC® mass and PLAC® activity tests are effective but the CHAPS modified PLAC® mass test has no or less utility in the risk assessment of CVD. The ratio of Lp-PLA2 by either PLAC® mass or PLAC® activity over ApoA1 or (Apo A1 + Apo B) synergistically enhance the risk assessment power for ischemic stroke.

Lipoprotein-associated Phospholipase A2 and Coronary Heart Disease.

In the last decades, the role of inflammation in the pathogenesis of atherosclerosis has been the topic of intense research. Several markers of inflammation have shown predictive value for first and recurrent coronary events in patients without and with established Coronary Heart Disease (CHD). Among these markers, lipoprotein- associated phospholipase A2 (Lp-PLA2) has recently received considerable attention. In the present review, the potential role of Lp-PLA2 as a marker of CHD risk and as a therapeutic target is discussed. Elevated Lp- PLA2 mass and activity appears to be associated with increased risk for CHD, both in the general population and in patients with established CHD. However, it is unclear whether the measurement of Lp-PLA2 improves risk discrimination when incorporated in models that include traditional cardiovascular risk factors. Moreover, the lack of effect on CHD events of darapladib, a potent, selective Lp-PLA2 inhibitor, in two large, randomized, placebo-controlled trials and the mostly negative findings of genetic association studies suggest that Lp-PLA2 is unlikely to represent a causal factor in atherogenesis. Therefore, it is doubtful whether Lp-PLA2 will constitute a therapeutic target for the prevention of CHD.

Circulating Interleukin-6 is a biomarker for coronary atherosclerosis in nonalcoholic fatty liver disease: Results from the Multi-Ethnic Study of Atherosclerosis

BackgroundBiomarkers to predict the presence and severity of subclinical cardiovascular disease (CVD) in nonalcoholic fatty liver disease (NAFLD) are lacking. Methods3876 participants from the Multi-Ethnic Study of Atherosclerosis (MESA), without known chronic liver disease underwent baseline non-contrast cardiac CT, with NAFLD defined by validated liver:spleen ratio (L:S) < 1.0, and subclinical CVD defined by coronary artery calcium (CAC) score > 0. Randomly-selected subgroups underwent detailed inflammatory marker testing, including LpPLA2 mass (N = 2951), activity (N = 3020), high-sensitivity C-reactive protein (hsCRP; N = 3849), and interleukin-6 (IL-6; N = 3764). Among those with NAFLD, we estimated the prevalence of CAC > 0 and CAC > 100 for each SD biomarker increase, using multivariable log-binomial regression models adjusted for cardiometabolic risk factors. ResultsSeventeen percent (N = 668) of participants met the criteria for NAFLD. NAFLD participants were younger (mean age 61 ± 10 vs. 63 ± 10 years, p < .0001) but more likely to have an elevated BMI (mean 31.1 ± 5.5 vs. 28.0 ± 5.2 kg/m2, p < .0001), diabetes (22% vs. 11%, p < .0001), and increased inflammatory biomarkers, including LpPLA2 activity, hsCRP and IL-6 (all p < .0001). Among NAFLD participants, IL-6 was the only biomarker independently associated with prevalent CAC > 0 (PR = 1.06 [1.00–1.11]), or CAC > 100 (PR = 1.09 [1.02–1.17]). In contrast, circulating LpPLA2 mass/activity and hsCRP were not associated with either the prevalence or severity of subclinical CVD (all p > .05). ConclusionIn a large, multi-ethnic population with NAFLD, IL-6 is independently associated with the prevalence and severity of subclinical atherosclerosis. Further research into the longitudinal effects of NAFLD on progressive CVD will determine whether IL-6 is a marker or mediator of NAFLD-related atherosclerosis.

Possible effects of lipoprotein-associated phospholipase A2 single-nucleotide polymorphisms on cardiovascular risk in patients with preeclampsia

Purpose: Lipoprotein lipase-associated phospholipase A2 (Lp-PLA2) is a vascular inflammatory marker associated with cardiovascular diseases (CVD). Women with preeclampsia (PE) have elevated vascular inflammation and at higher CVD risk in the later life. We hypothesize that vascular inflammation related genetic variations increase the risk for developing future cardiovascular disease in women with PE. To test this hypothesis, we studied PLA2G7 gene polymorphisms, Lp-PLA2 mass, activity, index, and other cardiovascular risk factors in women with preeclampsia.Methods: A total of 200 pregnant women were included into the study. We stratified the PE group: early (28.7 ± 3.0 weeks) and late onset (36.0 ± 1.4 weeks). Serum Lp-PLA2 mass in the early PE and the late PE group were significantly higher than the control group (p = .000). Lp-PLA2 index, Hs-C-reactive protein (CRP), serum amyloid A (SAA), calprotectin, and PTX3 levels were higher in early and late PE (p = .000). Single-nucleotide mutations of PLA2G7 rs1805017 (r = −0.228, p < .05) and rs9381475 (r = 0.216, p < .05) were correlated with LpPLA2 mass for the early PE group. Logistic regression analysis showed that LP-PA2 mass an independent risk factor for early PE with rs1805017 and rs9381475 carriers.Conclusions: Lp-PLA2 genetic variability with vascular inflammatory markers might contribute the incidence of future cardiovascular events.

Lp-PLA2 activity and mass for prediction of incident abdominal aortic aneurysms: A prospective longitudinal cohort study

Background and aimsThe pathogenesis of abdominal aortic aneurysm (AAA) shares several common pathways with atherosclerosis. Prospective clinical plasma biomarker studies in AAA have been hampered by the need for very large cohorts and long follow-up time. MethodsWe analyzed a prospective longitudinal cohort of middle-aged individuals from the cardiovascular cohort of the Malmö Diet and Cancer study (n = 5551; 1991-94). The plasma biomarkers lipoprotein-associated phospholipase A2 (Lp-PLA2 activity and mass), proneurotensin and C-reactive protein, and conventional risk factors at baseline were measured in patients with incident AAA during follow-up, and compared to individuals without a diagnosis of AAA. Subjects were followed until December 31st, 2013. Multivariable analyses were expressed in terms of hazard ratios (HR) per 1 standard deviation increment of each respective log-transformed plasma biomarker in the Cox proportional hazard models. ResultsCumulative incidence of AAA was 1.5% (men 2.9%, women 0.5%) during a median follow-up period of 20.7 years. Overall, 84 individuals had an incident AAA, of whom 22 (26.2%) were operated on and 16 (19.0%) had ruptured. Mean age of individuals with incident AAA was 59.7 years at study entry and AAA was diagnosed on average 14 years later. When adjusting for age, gender, smoking, body mass index, hypertension, and diabetes mellitus, Lp-PLA2 activity (HR 1.40; 95% CI 1.15–1.72) and Lp-PLA2 mass (HR 1.23; 95% CI 1.00–1.51) were independently associated with incident AAA. ConclusionsThe plasma biomarkers Lp-PLA2 activity and mass were markers of AAA risk and this implies that AAA is an athero-thrombotic related disease.

Higher Levels of Lipoprotein Associated Phospholipase A2 is associated with Increased Prevalence of Cognitive Impairment: the APAC Study

Lipoprotein-associated phospholipase A2 (Lp-PLA2) is a unique circulating phospholipase with inflammatory and oxidative activities and the limited data regarding the relationship between Lp-PLA2 and cognitive impairment are conflicted. We conducted a cross-sectional study including 1,374 Chinese adults recruited from 2010 to 2011, aiming to evaluate the relationship between Lp-PLA2 levels and the prevalence of cognitive impairment in a Chinese community-based population. Participants underwent standardized evaluation. Serum Lp-PLA2 mass was measured by ELISA. Cognition status was evaluated via the Mini-Mental Status Exam (MMSE) and cognitive impairment was identified as MMSE <24. Multivariable logistic regression models were used to assess the associations of Lp-PLA2 mass with cognitive impairment. Lp-PLA2 mass was significantly associated with the prevalence of cognitive impairment after adjusting for other potential confounding factors (compared with the first quartile, adjusted ORs of the second, third, and fourth quartile were 2.058 (95% CI, 0.876–4.835), 2.834 (95% CI, 1.255–6.398), and 4.882 (95% CI, 2.212–10.777), p < 0.0001). In conclusion, elevated level of Lp-PLA2 mass was independently associated with the prevalence of cognitive impairment in Chinese adults.

Lipoprotein-associated phospholipase A2 distribution among lipoproteins differs in type 1 diabetes

LpPLA2 mass and activity have been variably related to cardiovascular disease risk, and the distribution of LpPLA2 in patients with type 1 diabetes (T1D), wherein cardiovascular disease risk is high despite normal or higher levels of high-density lipoprotein (HDL) cholesterol, is unknown. To determine whether there are differences in the distribution of LpPLA2 mass and activity across lipoproteins and their association with coronary artery calcium (CAC) in patients with T1D. Men with T1D (n=19) not on statins, with and without CAC progression, and men without diabetes matched for HDL cholesterol (n=25) had lipoproteins separated by fast protein liquid chromatography. Both LpPLA2 mass and activity were found within low-density lipoprotein (LDL) and HDL pools with more LpPLA2 mass being associated with HDL (54% vs 44%; P-value <.001) and more LpPLA2 activity being associated with LDL (56% vs 40%; P value=.02). In T1D, more LpPLA2 activity was associated with large- or less-dense LDL compared to those without diabetes. However, no difference in LpPLA2 activity or mass between lipoprotein subfractions was observed between all groups, and there was no relationship between LpPLA2 activity or mass and its distribution and CAC score progression in healthy or T1D men. LpPLA2 is found in both LDL and HDL and is distributed differently in men with T1D without any relationship to CAC score progression.

Lipids and lipoproteins and inflammatory markers in patients with chronic apical periodontitis.

BackgroundSince chronic apical periodontitis (CAP) appears to be a risk factor for coronary heart disease, the aim of the study was to determine the relationship between the size of CAP lesion and inflammatory markers (hsCRP, IL-6, TNF-α), as well as lipids and lipoproteins (LpPLA2, apoAI, apoB level) in blood serum of patients with CAP.MethodsThe patients studied (n = 43) were divided into groups: patients under 50 and over 50 years of age, and a separate subgroup of the oldest age with the largest size of CAP lesions. Apolipoprotein AI (apoAI) above 150 mg/dL and below 150 mg/dL was used as an important criterion for the division of patients into groups. The CAP lesion size was measured using the Kodak digital imaging system software. The control group consisted of clinically healthy volunteers (n = 20) without CAP. Lipids were measured on a Siemens analyzer (Germany), apoAI, apoB, hsCRP levels were determined by immunonephelometric method, using the Health Care Diagnostic Product (Siemens GmbH, Germany), and IL-6, TNF-α and LpPLAG7 assay kits (ELISA, R&D Systems) were used.ResultsThe findings suggested that in patients with CAP and their age increase, the CAP lesion size, the concentration of inflammatory markers and LpPLA2 mass increased. Correlations between the CAP lesion size and LpPLA2 mass and between the CAP lesion size and TG level in patients with apoAI 150 ≤ mg/dL showed increase TG in atherogenic apoB-containing triglyceride-rich lipoprotein and TC in cholesterol-rich lipoprotein. The patients with a low apoAI and high LpPLA2 level can have a higher risk of odontogenic disease and progression of atherosclerosis and coronary heart disease.ConclusionWe have found a positive correlation between apoAI level and the CAP lesion size and a negative correlation between LpPLA2 level and the CAP lesion size. The results suggest that apoAI and LpPLA2 in HDL particles have antiinflammatory action and together can limit the CAP lesion size in patient with a higher apoAI level. The literature data on the distribution of lipoprotein particles in subjects are still insufficient, so this problem requires further studies.

The possibility of reducing the Lp-PLA2 mass level using simvastatin monotherapy and combination therapy with ezetimibe

AimTo assess the impact of combined treatment with simvastatin and ezetimibe or treatment with simvastatin only on lipoprotein-associated phospholipase A2 mass level in patients with coronary heart disease. MethodsOne hundred patients with angiographically documented coronary atherosclerosis took part in the investigation. Lp-PLA2 mass level and cholesterol fractions were determined at baseline and after 6 months of treatment. Lp-PLA2 mass was determined by PLAC Test; DiaDexus, Inc. ResultsCombined treatment with ezetimibe and simvastatin led to significantly greater declines in Lp-PLA2 and lipid profile compared with treatment only with simvastatin (P<0.05). Combination therapy with ezetimibe and simvastatin 20mg/day proved to be as effective as monotherapy with simvastatin 80mg/day on the effect on Lp-PLA2 mass level and lipids (P<0.05). Lp-PLA2 mass level was initially higher in patients with three-vessel coronary artery disease, compared with patients with one-vessel coronary artery disease while baseline levels of lipids and hs-CRP did not differ significantly. ConclusionsCombined treatment, using half the dose of simvastatin, led to greater reduction of Lp-PLA2 mass level total cholesterol and LDL-C, compared to monotherapy with simvastatin. Due to the steady decline of target levels of LDL-C, which leads to prescribing high doses of statins (and it is not always possible because of the presence of co-morbidities), combination therapy with statin and ezetimibe is a reliable alternative, which allows not only to largely reduce LDL-C but also to significantly reduce such important participants of atherosclerosis process and markers of inflammation, as Lp-PLA2 and CRP.

Intensive Lifestyle Modification Reduces Lp-PLA2 in Dyslipidemic HIV/HAART Patients

Patients with dyslipidemia associated with HIV-1 infection and highly active antiretroviral therapy (HAART) have elevated levels of Lp-PLA2 and CCL5/regulated on activation, normal T-cell expressed and secreted (RANTES), which may increase the risk of cardiovascular disease. This study aimed to determine whether an intensive diet and exercise (D/E) program, independently or combined with fenofibrate or niacin, could reduce Lp-PLA2 or RANTES. Patients with hypertriglyceridemic HIV on stable HAART (n = 107) were randomized to one of five interventions: 1) usual care, 2) D/E with placebos, 3) D/E with fenofibrate and placebo, 4) D/E with niacin and placebo, or 5) D/E with fenofibrate and niacin for 24 wk. Lp-PLA2 and RANTES concentrations were measured in fasting plasma samples at baseline and postintervention. General linear models were used to compare Lp-PLA2 and RANTES levels between the five groups postintervention, controlling for baseline levels, age, body mass index, CD4 T-cell count, viral load, duration of infection, and HAART. At baseline, fasting plasma Lp-PLA2 (388.5 ± 127.5 ng·mL) and RANTES (43.8 ± 25.5 ng·mL) levels were elevated when compared with healthy controls. Posttreatment Lp-PLA2 mass was lower in patients who received D/E only (323.0 ± 27.2 ng·mL), D/E plus fenofibrate (327.2 ± 25.9 ng·mL), and D/E plus niacin (311.1 ± 27.8 ng·mL) when compared with patients receiving usual care (402.2 ± 25.3 ng·mL). RANTES concentrations were not significantly affected by any intervention. Elevated plasma Lp-PLA2 mass can be reduced by an intensive D/E program in patients with HIV/HAART-associated dyslipidemia. RANTES is elevated but is not reduced by lifestyle modification, fenofibrate, or niacin.

Interpretation of lipoprotein-associated phospholipase A2 levels is influenced by cardiac disease, comorbidities, extension of atherosclerosis and treatments

PurposeLipoprotein-associated phospholipase A2 (Lp-PLA2) is an inflammatory biomarker secreted in the atherosclerotic plaque. Blood levels of Lp-PLA2 predict future cardiovascular events in patients with ischemic disease and heart failure. This association seems to be independent of traditional cardiovascular risk factors.The aims of our study were (1) to assess relationships between Lp-PLA2 levels, cardiac disease and treatments; (2) to evaluate the association of Lp-PLA2 level with the severity of angiographic coronary artery disease (CAD) and the extracoronary atherosclerosis. MethodsBetween December 2009 and June 2010, 494 subjects were recruited from a population scheduled for diagnostic coronary angiography. Routine clinical (age, gender, BMI and treatment), cardiac (echocardiography, coronarography, carotid ultrasonography) and biochemical parameters were recorded for all patients. Lp-PLA2 mass concentration was assessed in serum with a Plac®-test turbidimetric immunoassay. Control Lp-PLA2 values were specifically obtained in 61 healthy subjects aged 44.5±17.6years (range: 25 to 59years) without known cardiovascular risk factors (diabetes, smoking, hypertension, dyslipidemia) or cardiac treatment. ResultsIn healthy controls, mean Lp-PLA2 level was 163±43μg/L (166±45μg/L in men and 159±39μg/L in women, non significant difference).In our cohort of 494 patients (69.8% men) aged 64.2±16.7years, the main etiologies of cardiomyopathies were ischemic (40%), valvular (22%), cardiac failure with left ventricular (LV) dysfunction (14%), infection (5%) and aortic aneurysm (7%). Mean Lp-PLA2 levels were 216±17μg/L. Lp-PLA2 correlated with age, BMI, current smoking, history of hypertension but not with diabetes and gender. The bivariate analysis showed a significant correlation between Lp-PLA2, and BMI (p=0.001) but no correlation with serum creatinine or NYHA status. A multivariate correlation showed that Lp-PLA2 was associated with total cholesterol, LDL-cholesterol and apoB (r=0.95, p<0.0001) but not with Lp(a). We observed that Lp-PLA2 was significantly associated with treatments such as statins and ACEi/ARA2 but not with β-blockers, antiaggregant drugs or diuretics.Lp-PLA2 levels were significantly higher in patients with CAD than in patients without CAD (223±54 vs. 208±52μg/L, respectively; p<0.007). Moreover, Lp-PLA2 levels were significantly higher in patients with the most extensive angiographic CAD [single (n=24)=215.2±52μg/L; two (n=55)=222±53μg/L and three vessels (n=140)=251.9±53.7μg/L, respectively; p<0.0001]. Patients with heart failure, sepsis or aortic aneurysm had increased Lp-PLA2 levels: 256.2±46.8; 226.7±47.3; 218.1±38.9μg/L, respectively, as compared to controls (p<0.0001).In patients with carotid artery disease, Lp-PLA2 significantly increased with the severity of atherosclerosis. Mean Lp-PLA2 levels were 218.8±51μg/L in the group without any stenosis (n=108), 224±51μg/L in the group with mild stenosis (n=101), and 231±46μg/L in the group with severe stenosis (n=22); p=0.004. ConclusionThis study clearly shows that interpretation of Lp-PLA2 levels needs a good assessment of cardiac parameters and treatments, especially statins and ACEi/ARA2. Lp-PLA2 levels are significantly associated with coronary heart disease and with the extension of extra coronary disease after adjustment for age and gender.

Apo E4 and lipoprotein-associated phospholipase A2 synergistically increase cardiovascular risk

ObjectiveApolipoprotein E (apoE) has been implicated as conveying increased risk for coronary artery disease (CAD). Previous studies suggest a role of apoE as a modulator of immune response and inflammatory properties. We hypothesized that the presence of apo E4 is associated with an increased inflammatory burden in subjects with CAD as compared to subjects without CAD. MethodsApoE genotypes, systemic (C-reactive protein [CRP], fibrinogen, serum amyloid-A [SAA]) and vascular inflammatory markers (Lipoprotein-associated phospholipase A2 [Lp-PLA2] and pentraxin-3 [PTX-3]) were assessed in 324 Caucasians and 208 African Americans, undergoing coronary angiography. ResultsFor both ethnic groups, Lp-PLA2 index, an integrated measure of Lp-PLA2 mass and activity, increased significantly and stepwise across apoE isoforms (P = 0.009 and P = 0.026 for African Americans and Caucasians respectively). No differences were found for other inflammatory markers tested (CRP, fibrinogen, SAA and PTX-3). For the top cardiovascular score tertile, apo E4 carriers had a significantly higher level of Lp-PLA2 index in both ethnic groups (P = 0.027 and P = 0.010, respectively). ConclusionThe presence of the apo E4 isoform was associated with a higher level of Lp-PLA2 index, a marker of vascular inflammation. Our results suggest that genetic variation at the apoE locus may impact cardiovascular disease risk through enhanced vascular inflammation.

Translational Studies of Lipoprotein-Associated Phospholipase A2 in Inflammation and Atherosclerosis

This study sought to examine the role of lipoprotein-associated phospholipase A₂ (Lp-PLA₂/PLA2G7) in human inflammation and coronary atherosclerosis. Lp-PLA₂ has emerged as a potential therapeutic target in coronary heart disease. Data supporting Lp-PLA₂ are indirect and confounded by species differences; whether Lp-PLA₂ is causal in coronary heart disease remains in question. We examined inflammatory regulation of Lp-PLA₂ during experimental endotoxemia in humans, probed the source of Lp-PLA₂ in human leukocytes under inflammatory conditions, and assessed the relationship of variation in PLA2G7, the gene encoding Lp-PLA₂, with coronary artery calcification. In contrast to circulating tumor necrosis factor-alpha and C-reactive protein, blood and monocyte Lp-PLA₂ messenger ribonucleic acid decreased transiently, and plasma Lp-PLA₂ mass declined modestly during endotoxemia. In vitro, Lp-PLA₂ expression increased dramatically during human monocyte to macrophage differentiation and further in inflammatory macrophages and foamlike cells. Despite only a marginal association of single nucleotide polymorphisms in PLA2G7 with Lp-PLA₂ activity or mass, numerous PLA2G7 single nucleotide polymorphisms were associated with coronary artery calcification. In contrast, several single nucleotide polymorphisms in CRP were significantly associated with plasma C-reactive protein levels but had no relation with coronary artery calcification. Circulating Lp-PLA₂ did not increase during acute phase response in humans, whereas inflammatory macrophages and foam cells, but not circulating monocytes, are major leukocyte sources of Lp-PLA₂. Common genetic variation in PLA2G7 is associated with subclinical coronary atherosclerosis. These data link Lp-PLA₂ to atherosclerosis in humans while highlighting the challenge in using circulating Lp-PLA₂ as a biomarker of Lp-PLA₂ actions in the vasculature.