Jeanenne J. Nelson

Elevated Lp-PLA2 Levels Add Prognostic Information to the Metabolic Syndrome on Incidence of Cardiovascular Events Among Middle-Aged Nondiabetic Subjects

Background—To explore potential interrelationships between lipoprotein-associated phosholipase A2 (Lp-PLA2), the metabolic syndrome (MetS), and incident cardiovascular disease (CVD). Methods and Results—MetS was defined by the National Cholesterol Education Program Adult treatment Panel III criteria in 4480 nondiabetic Malmö Diet and Cancer Study subjects without history of CVD. Incidence of first CVD event (stroke [130 cases] or myocardial infarction [131]) was monitored over 10 years of follow-up. Lp-PLA2 activity and mass were significantly higher in subjects with MetS. Lp-PLA2 activity compared with Lp-PLA2 mass was more strongly correlated to individual components and increased more linearly with number of MetS components. Elevated Lp-PLA2 activity (top compared with bottom tertile), but not elevated Lp-PLA2 mass, increased risk for incident CVD (relative risk, RR: 1.54, 95% CI 1.07 to 2.24), as did MetS (1.42, 1.06 to 1.90) after taking possible confounders into account. Relative to those without either elevated Lp-PLA2 activity or MetS, combination of MetS and elevated Lp-PLA2 activity increased risk for CVD (1.97, 1.34 to 2.90). Elevated Lp-PLA2 activity without MetS increased risk for CVD (1.40, 1.03 to 1.92) but not MetS without elevated Lp-PLA2 activity (1.46, 0.94 to 2.27). Conclusion—Lp-PLA2 is associated to the MetS. Higher plasma levels of Lp-PLA2 increased risk for incident CVD regardless of MetS. The simultaneous presence of elevated Lp-PLA2 activity and MetS may identify an especially high risk individual.

Lipoprotein-associated phospholipase A2 as a target of therapy.

Purpose of review Considerable discussion continues regarding the precise role that secreted lipoprotein-associated phospholipase A2 (Lp-PLA2), also called platelet-activating factor acetylhydrolase, plays in atherosclerosis. Since interest in this enzyme as a putative drug target has been based primarily upon its association with low-density lipoprotein (LDL) in human plasma, this review will focus on Lp-PLA2 and human coronary heart disease. Recent findings Recent reports have linked Lp-PLA2 enrichment not only to the most atherogenic of LDL particles but also to the most advanced, rupture-prone, plaques. Electronegative LDL has been shown to be highly enriched in Lp-PLA2; and in advanced atheroma, Lp-PLA2 levels are highly upregulated, colocalizing with macrophages in both the necrotic core and fibrous cap. Lp-PLA2 is well placed, whether on an oxidation susceptible LDL particle or in the highly oxidative environment of an advanced rupture-prone plaque, to hydrolyse oxidized phospholipid and generate significant quantities of the two pro-inflammatory mediators, lysophosphatidylcholine and oxidized nonesterified fatty acid. Several studies have confirmed that Lp-PLA2 is an independent risk factor for cardiovascular events (i.e. myocardial infarction and stroke). Although epidemiology studies consistently support a relationship between plasma Lp-PLA2 levels and susceptibility to coronary heart disease this is not the case for Lp-PLA2 polymorphisms. Two clinical studies have linked the Ala-379→Val polymorphism with a reduced risk of myocardial infarction, but functional differences between the AA and VV polymorphs have yet to be demonstrated. Summary Lp-PLA2 is intimately associated with several aspects of human atherogenesis. Although various lipid-lowering therapies, such as statins, have been shown to reduce plasma levels of Lp-PLA2, none has been studied in terms of its ability to lower the large macrophage-mediated upregulation of Lp-PLA2 within advanced plaques.

Eight genetic loci associated with variation in lipoprotein-associated phospholipase A2 mass and activity and coronary heart disease: meta-analysis of genome-wide association studies from five community-based studies

AIMS Lipoprotein-associated phospholipase A2 (Lp-PLA2) generates proinflammatory and proatherogenic compounds in the arterial vascular wall and is a potential therapeutic target in coronary heart disease (CHD). We searched for genetic loci related to Lp-PLA2 mass or activity by a genome-wide association study as part of the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. METHODS AND RESULTS In meta-analyses of findings from five population-based studies, comprising 13 664 subjects, variants at two loci (PLA2G7, CETP) were associated with Lp-PLA2 mass. The strongest signal was at rs1805017 in PLA2G7 [P = 2.4 × 10(-23), log Lp-PLA2 difference per allele (beta): 0.043]. Variants at six loci were associated with Lp-PLA2 activity (PLA2G7, APOC1, CELSR2, LDL, ZNF259, SCARB1), among which the strongest signals were at rs4420638, near the APOE-APOC1-APOC4-APOC2 cluster [P = 4.9 × 10(-30); log Lp-PLA2 difference per allele (beta): -0.054]. There were no significant gene-environment interactions between these eight polymorphisms associated with Lp-PLA2 mass or activity and age, sex, body mass index, or smoking status. Four of the polymorphisms (in APOC1, CELSR2, SCARB1, ZNF259), but not PLA2G7, were significantly associated with CHD in a second study. CONCLUSION Levels of Lp-PLA2 mass and activity were associated with PLA2G7, the gene coding for this protein. Lipoprotein-associated phospholipase A2 activity was also strongly associated with genetic variants related to low-density lipoprotein cholesterol levels.

Cardiovascular events with increased lipoprotein-associated phospholipase A 2 and low high-density lipoprotein-cholesterol the veterans affairs HDL intervention trial

Objective—Lipoprotein-associated phospholipase A2 (Lp-PLA2), a proinflammatory enzyme that predominantly circulates with low-density lipoprotein (LDL), has been shown in general populations to predict cardiovascular (CV) events. We sought to determine whether increased Lp-PLA2 would also predict CV events in the absence of high LDL-cholesterol (LDL-C), in a population with low high-density lipoprotein-cholesterol (HDL-C). Methods and Results—Plasma Lp-PLA2 activity was measured at baseline and after 6 months on-trial in 1451 men with low HDL-C (mean, 32 mg/dL) and low LDL-C (mean 110 mg/dL), randomized to either placebo or gemfibrozil therapy in the Veterans Affairs HDL Intervention Trial (VA-HIT). Over a quartile range of increasing Lp-PLA2 there was a significant increase in LDL-C and decrease in HDL-C (P<0.0001), and an increased percentage of myocardial infarction (MI), stroke, or CHD death (P=0.03 for trend). In Cox models, adjusted for major CV risk factors, a 1-SD increase in Lp-PLA2 was associated with a significant increase in CV events (hazard ratio [HR] 1.17 95% CI 1.04 to 1.32). Although gemfibrozil reduced Lp-PLA2 only modestly (6.6%), at higher levels of Lp-PLA2 gemfibrozil produced a significant reduction in CV events. Conclusions—In VA-HIT, a population with low HDL-C and LDL-C, high Lp-PLA2 independently predicted CV events that were reduced by gemfibrozil.

Lp-PLA 2 activity and mass are associated with increased incidence of ischemic stroke: A population-based cohort study from Malmö, Sweden

BACKGROUND Data regarding the association between lipoprotein-associated phospholipase A2 (Lp-PLA(2)) level and incidence of cardiovascular (CV) events are conflicting. This prospective urban population-based study explored the relationship between baseline Lp-PLA(2) activity and mass, respectively, levels and incidence of first coronary heart disease (CHD) and ischemic stroke, respectively. METHODS Lp-PLA(2) activity and mass were assessed in 5393 (60% women) subjects who participated in the Malmö Diet and Cancer Study cardiovascular program during 1991-1994. RESULTS In all 347 subjects had an event (195 CHD and 152 ischemic strokes) during the follow-up period (mean 10.6+/-1.7 years). In an age-, sex- and CV risk factors-adjusted Cox regression analysis, comparing top to bottom tertile of Lp-PLA(2) activity, the relative risk [RR; 95% confidence interval (CI)] for incident CHD and ischemic stroke events were 1.48; 0.92-2.37 and RR: 1.94; 1.15-3.26, respectively. The corresponding figures for Lp-PLA(2) mass were 0.95; 0.65-1.40 and RR: 1.92; 1.20-3.10. CONCLUSION Elevated levels of Lp-PLA(2) activity and mass, respectively, were in this study, independently of established risk factors related to the incidence of ischemic stroke but after adjustment for lipids not significant related to incident CHD.

Lipoprotein-associated phospholipase A2 (Lp-PLA2) and risk of cardiovascular disease in older adults: Results from the Cardiovascular Health Study

OBJECTIVE To examine associations between lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) antigen level (mass) and enzymatic activity (activity) and cardiovascular disease (CVD) in older adults. METHODS We examined associations of Lp-PLA(2) mass and activity with incident myocardial infarction (MI; n=508), stroke (n=565) and CVD death (n=665) using Cox regressions adjusted for age, sex, ethnicity and CVD risk factors in 3949 older adults, aged > or =65 years at baseline, from the Cardiovascular Health Study (CHS). RESULTS Lp-PLA(2) was associated with incident CVD events in these older adults. Hazard ratios (95% confidence intervals) for highest versus lowest tertiles of Lp-PLA(2) mass were 1.49 (1.19-1.85) for MI, 1.21 (0.98-1.49) for stroke and 1.11 (0.92-1.33) for CVD death. The highest tertile of Lp-PLA(2) activity was associated with MI (1.36; 1.09-1.70) and CVD death (1.23; 1.02-1.50). Combined Lp-PLA(2) tertile 3 and CRP>3mg/l, compared to Lp-PLA(2) tertile 1 and CRP<1mg/l, was associated with MI (2.29; 1.49-3.52) for Lp-PLA(2) mass and MI (1.66; 1.10-2.51) and CVD death (1.57; 1.08-2.26) for activity. For MI, both mass and activity added excess risk to elevated CRP alone ( approximately 20% excess risk) and activity added excess risk for CVD death ( approximately 12%). CONCLUSION Lp-PLA(2) mass and activity were associated with incident CVD events in older adults in CHS. Lp-PLA(2) and CRP were independent and additive in prediction of events. While associations were modest, these results support further exploration of Lp-PLA(2) to identify older individuals at risk for CVD.

Distribution and correlates of lipoprotein-associated phospholipase A2 in an elderly cohort: the Cardiovascular Health Study.

OBJECTIVES: To determine whether high levels of lipoprotein‐associated phospholipase A2 (Lp‐PLA2) are associated with prevalent cardiovascular disease (CVD) and to evaluate factors most influencing Lp‐PLA2 levels in a community‐based cohort of older adults.

Lipoprotein-associated phospholipase A2 activity and mass are associated with increased incidence of ischemic stroke. A population-based study from Malmö, Sweden

BACKGROUND Data regarding the association between lipoprotein-associated phospholipase A2 (Lp-PLA(2)) level and incidence of cardiovascular (CV) events are conflicting. This prospective urban population-based study explored the relationship between baseline Lp-PLA(2) activity and mass, respectively, levels and incidence of first coronary heart disease (CHD) and ischemic stroke, respectively. METHODS Lp-PLA(2) activity and mass were assessed in 5393 (60% women) subjects who participated in the Malmö Diet and Cancer Study cardiovascular program during 1991-1994. RESULTS In all 347 subjects had an event (195 CHD and 152 ischemic strokes) during the follow-up period (mean 10.6+/-1.7 years). In an age-, sex- and CV risk factors-adjusted Cox regression analysis, comparing top to bottom tertile of Lp-PLA(2) activity, the relative risk [RR; 95% confidence interval (CI)] for incident CHD and ischemic stroke events were 1.48; 0.92-2.37 and RR: 1.94; 1.15-3.26, respectively. The corresponding figures for Lp-PLA(2) mass were 0.95; 0.65-1.40 and RR: 1.92; 1.20-3.10. CONCLUSION Elevated levels of Lp-PLA(2) activity and mass, respectively, were in this study, independently of established risk factors related to the incidence of ischemic stroke but after adjustment for lipids not significant related to incident CHD.

Lipoprotein-associated phospholipase A2, inflammatory biomarkers, and risk of cardiovascular disease in the Prospective Study of Pravastatin in the Elderly at Risk (PROSPER)

OBJECTIVE Lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) is an inflammatory biomarker that circulates mainly bound to LDL. We evaluated the association of Lp-PLA(2) with vascular events in the elderly where the importance of LDL is diminished as a risk factor for coronary disease. METHODS Mass and activity of Lp-PLA(2) were related to risk over 3.2 years for vascular events (definite or suspected death from CHD, non-fatal MI, fatal or non-fatal stroke) in the 2804 men and 3000 women age 70-82 years in the Prospective Study of Pravastatin in the Elderly (PROSPER). RESULTS Lp-PLA(2) showed a moderate, positive association with risk of a vascular event with hazard ratios of 1.25 (confidence interval (CI) 1.02-1.54) for mass and 1.39 (CI 1.14-1.70) for activity for top versus bottom quartile. Risk associations were attenuated when classical risk factors, lipids and inflammatory markers - C-reactive protein and white cell count - were included in the models. Lp-PLA(2) was unrelated to stroke risk. Inclusion of all three inflammatory markers in multivariate models negated the association of HDL cholesterol with risk (hazard ratio 0.98; CI 0.88-1.10) and increased prediction of coronary events; the C statistic rose from 63.2% to 64.4% (P<0.001). CONCLUSION In elderly people Lp-PLA(2), alongside other inflammatory indices, is a potential biomarker for vascular events, particularly CHD.

Lipoprotein-associated phospholipase A(2) and risk of congestive heart failure in older adults: the Cardiovascular Health Study.

Background—Inflammation may be a causative factor in congestive heart failure (CHF). Lipoprotein-associated phospholipase A2 (Lp-PLA2) is an inflammation marker associated with vascular risk. One previous study showed an association of Lp-PLA2 activity with CHF risk, but there were only 94 CHF cases and Lp-PLA2 antigen, which is available clinically in the United States, was not measured. Methods and Results—We measured baseline Lp-PLA2 antigen and activity in 3991 men and women without baseline CHF or cardiovascular disease who were participating in the Cardiovascular Health Study, a prospective observational study of adults 65 years or older. Cox proportional hazards models adjusted for age, sex, clinic site, race, low-density and high-density lipoprotein cholesterol, body mass index, systolic and diastolic blood pressure, hypertension, smoking status, pack-years, and diabetes were used to calculate hazard ratios and 95% CIs for incident CHF. Further models adjusted for coronary disease events during follow-up and C-reactive protein. Eight hundred twenty-nine participants developed CHF during 12.1 years. Adjusted hazard ratios for CHF with Lp-PLA2 in the fourth compared with the first quartile were 1.44 (95% CI, 1.16 to 1.79) for Lp-PLA2 antigen and 1.06 (95% CI, 0.84 to 1.32) for activity. Adjustment for incident coronary disease attenuated the hazard ratio for Lp-PLA2 antigen to 1.26 (95% CI, 1.02 to 1.57), adjustment for C-reactive protein had minimal impact. Conclusions—Lp-PLA2 antigen was associated with risk of future CHF in older people, independent of CHF and coronary risk factors, and partly mediated by coronary disease events. Further clinical and basic research is needed to better understand the role of Lp-PLA2 in CHF.