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Colin H. Macphee - One of the best experts on this subject based on the ideXlab platform.
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Lipoprotein-Associated Phospholipase A2: a target directed at the atherosclerotic plaque
Expert Opinion on Therapeutic Targets, 2020Co-Authors: Colin H. Macphee, Keith E SucklingAbstract:Lipoprotein-Associated Phospholipase A2 (Lp-PLA2)is so named because it is found in human plasma largely associated with low-density lipoprotein (LDL). It is secreted by macrophages and able to hydrolyse oxidised fatty acids from oxidised phospholipids in LDL thereby releasing pro-atherogenic lysophosphatidylcholine and fatty acids. Inhibition of this enzyme activity was proposed to be antiatherogenic and this hypothesis has been confirmed both in vitro and in animal studies using specific inhibitors. In addition, the enzyme has been shown to be present in human atherosclerotic plaques and to be a potential risk factor for coronary heart disease in epidemiological studies. However, Lp-PLA2 is identical to platelet-activating factor acetylhydrolase (PAF-AH), whose activity is regarded as antiatherogenic. The role of this enzyme in humans, represented as Lp-PLA2 or PAF-AH, remains to be clarified. Specific and potent inhibitors of Lp-PLA2 have been described and help address this question. This is a novel a...
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Effect of darapladib treatment on endarterectomy carotid plaque Lipoprotein-Associated Phospholipase A2 activity: a randomized, controlled trial.
PLOS ONE, 2014Co-Authors: Joel L. Johnson, Rose Snipes, Salim Janmohamed, Timothy E. Rolfe, Bill Davis, Anthony D. Postle, Colin H. MacpheeAbstract:Background The aim of this study was to assess the effects of darapladib, a selective oral investigational Lipoprotein-Associated Phospholipase A2 inhibitor, on both plasma and plaque Lipoprotein-Associated Phospholipase A2 activity. Methods Patients undergoing elective carotid endarterectomy were randomized to darapladib 40 mg (n = 34), 80 mg (n = 34), or placebo (n = 34) for 14 days, followed by carotid endarterectomy 24 hours after the last dose of study medication. Results Darapladib 40 mg and 80 mg reduced plasma Lipoprotein-Associated Phospholipase A2 activity by 52% and 81%, respectively, versus placebo (both P
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Platelet Aggregation Unchanged by Lipoprotein-Associated Phospholipase A2 Inhibition: Results from an In Vitro Study and Two Randomized Phase I Trials
PLOS ONE, 2014Co-Authors: Bonnie C. Shaddinger, Colin H. Macphee, Yanmei Xu, James H. Roger, Malcolm Handel, Charlotte A. Baidoo, Mindy Magee, John J. Lepore, Dennis L. SprecherAbstract:Background We explored the theorized upregulation of platelet-activating factor (PAF)– mediated biologic responses following Lipoprotein-Associated Phospholipase A2 (Lp-PLA2) inhibition using human platelet aggregation studies in an in vitro experiment and in 2 clinical trials.
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The effect of Lipoprotein-Associated Phospholipase A2 deficiency on pulmonary allergic responses in aspergillus fumigatus sensitized mice
Respiratory Research, 2012Co-Authors: Zhilong Jiang, Colin H. Macphee, Melane Fehrenbach, Giulia Ravaioli, Blerina Kokalari, Imre G. Redai, Steven A. Sheardown, Stephen S. Wilson, Angela Franciska HaczkuAbstract:Background Lipoprotein-Associated Phospholipase A2 (Lp-PLA2)/platelet-activating factor acetylhydrolase (PAF-AH) has been implicated in the pathogenesis of cardiovascular disease. A therapeutic targeting of this enzyme was challenged by the concern that increased circulating platelet activating factor (PAF) may predispose to or increase the severity of the allergic airway response. The aim of this study was to investigate whether Lp-PLA2 gene deficiency increases the risk of PAF and IgE-mediated inflammatory responses in vitro and in vivo using mouse models.
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Lipoprotein-Associated Phospholipase A2 and atherosclerosis
Current Opinion in Lipidology, 2009Co-Authors: Robert L. Wilensky, Colin H. MacpheeAbstract:Purpose of reviewThere 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 ha
Muriel J. Caslake - One of the best experts on this subject based on the ideXlab platform.
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lipoprotein associated Phospholipase A2 as an independent predictor of coronary heart disease
The New England Journal of Medicine, 2009Co-Authors: C J Packard, Colin H. Macphee, Muriel J. Caslake, Denis St J Oreilly, Alex D Mcmahon, Ian Ford, Josephine Cooney, Keith E Suckling, M Krishna, Francis E WilkinsonAbstract:Background Chronic inflammation is believed to increase the risk of coronary events by making atherosclerotic plaques in coronary vessels prone to rupture. We examined blood constituents potentially affected by inflammation as predictors of risk in men with hypercholesterolemia who were enrolled in the West of Scotland Coronary Prevention Study, a trial that evaluated the value of pravastatin in the prevention of coronary events. Methods A total of 580 men who had had a coronary event (nonfatal myocardial infarction, death from coronary heart disease, or a revascularization procedure) were each matched for age and smoking status with 2 control subjects (total, 1160) from the same cohort who had not had a coronary event. Lipoprotein-Associated Phospholipase A2, C-reactive protein, and fibrinogen levels and the white-cell count were measured at base line, along with other traditional risk factors. The association of these variables with the risk of coronary events was tested in regression models and by divi...
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Lipoprotein-Associated Phospholipase A2 as a biomarker for coronary disease and stroke.
Nature Reviews Cardiology, 2005Co-Authors: Muriel J. Caslake, Chris J. PackardAbstract:Risk factors identified by the Framingham Heart Study are useful for assessing a person's risk of cardiovascular disease; however, additional risk factors are needed. In this review, the potential role of Lipoprotein-Associated Phospholipase A2as a novel inflammatory marker for cardiovascular risk assessment is discussed. Lipoprotein-Associated Phospholipase A2 (Lp-PLA2), also known as platelet-activating factor acetylhydrolase, is a plasma enzyme that circulates bound to lipoproteins. The association between Lp-PLA2 and atherosclerosis is ambiguous, as it can both degrade and generate potentially damaging vasoactive molecules. In this article, we speculate that Lp-PLA2 associated with HDL might have cardioprotective properties, whereas the same enzyme bound to LDL might contribute directly to atherosclerosis at all stages, from lipoprotein oxidation to endothelial dysfunction, and plaque initiation and growth. Genetic and animal model studies give varying indications as to the contribution of Lp-PLA2 to atherogenesis and tend to support the view that higher Lp-PLA2 levels are cardioprotective. By contrast, a series of population studies point clearly to a positive association between plasma Lp-PLA2 levels or activity levels and risk of coronary heart disease or stroke. Typically, people with Lp-PLA2 levels in the highest quintile of the population have about a twofold greater risk than those in the lowest quintile. It is, perhaps, too early to introduce Lp-PLA2 as a population-wide biomarker for coronary heart disease risk; however, with accumulating evidence, it might find a place in a stepwise risk assessment of individuals who require more aggressive intervention to prevent vascular disease.
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Lipoprotein-Associated Phospholipase A2 (platelet-activating factor acetylhydrolase) and cardiovascular disease.
Current Opinion in Lipidology, 2003Co-Authors: Muriel J. Caslake, Chris J. PackardAbstract:Purpose of reviewPlasma lipoproteins carry a number of highly active enzymes in the circulation. One of these is Lipoprotein-Associated Phospholipase A2 (Lp-PLA2), also known as platelet-activating factor acetylhydrolase. This review addresses the molecular properties of Lp-PLA2, the controversy sur
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lipoprotein associated Phospholipase A2 as an independent predictor of coronary heart disease west of scotland coronary prevention study group
The New England Journal of Medicine, 2000Co-Authors: C J Packard, Colin H. Macphee, Muriel J. Caslake, Denis St J Oreilly, Alex D Mcmahon, Ian Ford, Josephine Cooney, Keith E Suckling, M Krishna, Francis E WilkinsonAbstract:Chronic inflammation is believed to increase the risk of coronary events by making atherosclerotic plaques in coronary vessels prone to rupture. We examined blood constituents potentially affected by inflammation as predictors of risk in men with hypercholesterolemia who were enrolled in the West of Scotland Coronary Prevention Study, a trial that evaluated the value of pravastatin in the prevention of coronary events.A total of 580 men who had had a coronary event (nonfatal myocardial infarction, death from coronary heart disease, or a revascularization procedure) were each matched for age and smoking status with 2 control subjects (total, 1160) from the same cohort who had not had a coronary event. Lipoprotein-Associated Phospholipase A2, C-reactive protein, and fibrinogen levels, and the white-cell count were measured at base line, along with other traditional risk factors. The association of these variables with the risk of coronary events was tested in regression models and by dividing the range of values according to quintiles.Levels of C-reactive protein, the white-cell count, and fibrinogen levels were strong predictors of the risk of coronary events; the risk in the highest quintile of the study cohort for each variable was approximately twice that in the lowest quintile. However, the association of these variables with risk was markedly attenuated when age, systolic blood pressure, and lipoprotein levels were included in multivariate models. Levels of Lipoprotein-Associated Phospholipase A2 (platelet-activating factor acetylhydrolase), the expression of which is regulated by mediators of inflammation, had a strong, positive association with risk that was not confounded by other factors. It was associated with almost a doubling of the risk in the highest quintile as compared with the lowest quintile.Inflammatory markers are predictors of the risk of coronary events, but their predictive ability is attenuated by associations with other coronary risk factors. Elevated levels of Lipoprotein-Associated Phospholipase A2 appear to be a strong risk factor for coronary heart disease, a finding that has implications for atherogenesis and the assessment of risk.
Peter A. Mccullough - One of the best experts on this subject based on the ideXlab platform.
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Darapladib and atherosclerotic plaque: Should Lipoprotein-Associated Phospholipase A2 be a therapeutic target?
Current Atherosclerosis Reports, 2009Co-Authors: Peter A. McculloughAbstract:There is great interest in developing a reliable measure of atherosclerotic disease activity that can serve as an index of response to antiatherosclerotic therapies. The epidemiologic relationship between lipid measures, most notably low-density lipoprotein cholesterol (LDL-C), and binary cardiovascular events has been confirmed in treatment trials reliably demonstrating a reduction in LDL-C translating into improved cardiovascular outcomes. Lipoprotein-Associated Phospholipase A2 (LpPLA2) is part of a family of lipases involved in the modification of lipids within the atheroma and may be a complimentary therapeutic target to the reduction of LDL-C in patients with advanced atherosclerosis. Darapladib is an orally available, specific inhibitor of LpPLA2 activity and has been shown to reduce lysophosphatidylcholine content and expression of multiple genes associated with macrophage and T-lymphocyte functioning, with considerable decrease in plaque and necrotic core area. Thus, this agent holds the hope of being a bona fide antiatherosclerotic therapy that can be gauged through blood measurement of LpPLA2 activity.
Keith E Suckling - One of the best experts on this subject based on the ideXlab platform.
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Lipoprotein-Associated Phospholipase A2: a target directed at the atherosclerotic plaque
Expert Opinion on Therapeutic Targets, 2020Co-Authors: Colin H. Macphee, Keith E SucklingAbstract:Lipoprotein-Associated Phospholipase A2 (Lp-PLA2)is so named because it is found in human plasma largely associated with low-density lipoprotein (LDL). It is secreted by macrophages and able to hydrolyse oxidised fatty acids from oxidised phospholipids in LDL thereby releasing pro-atherogenic lysophosphatidylcholine and fatty acids. Inhibition of this enzyme activity was proposed to be antiatherogenic and this hypothesis has been confirmed both in vitro and in animal studies using specific inhibitors. In addition, the enzyme has been shown to be present in human atherosclerotic plaques and to be a potential risk factor for coronary heart disease in epidemiological studies. However, Lp-PLA2 is identical to platelet-activating factor acetylhydrolase (PAF-AH), whose activity is regarded as antiatherogenic. The role of this enzyme in humans, represented as Lp-PLA2 or PAF-AH, remains to be clarified. Specific and potent inhibitors of Lp-PLA2 have been described and help address this question. This is a novel a...
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lipoprotein associated Phospholipase A2 as an independent predictor of coronary heart disease
The New England Journal of Medicine, 2009Co-Authors: C J Packard, Colin H. Macphee, Muriel J. Caslake, Denis St J Oreilly, Alex D Mcmahon, Ian Ford, Josephine Cooney, Keith E Suckling, M Krishna, Francis E WilkinsonAbstract:Background Chronic inflammation is believed to increase the risk of coronary events by making atherosclerotic plaques in coronary vessels prone to rupture. We examined blood constituents potentially affected by inflammation as predictors of risk in men with hypercholesterolemia who were enrolled in the West of Scotland Coronary Prevention Study, a trial that evaluated the value of pravastatin in the prevention of coronary events. Methods A total of 580 men who had had a coronary event (nonfatal myocardial infarction, death from coronary heart disease, or a revascularization procedure) were each matched for age and smoking status with 2 control subjects (total, 1160) from the same cohort who had not had a coronary event. Lipoprotein-Associated Phospholipase A2, C-reactive protein, and fibrinogen levels and the white-cell count were measured at base line, along with other traditional risk factors. The association of these variables with the risk of coronary events was tested in regression models and by divi...
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lipoprotein associated Phospholipase A2 as an independent predictor of coronary heart disease west of scotland coronary prevention study group
The New England Journal of Medicine, 2000Co-Authors: C J Packard, Colin H. Macphee, Muriel J. Caslake, Denis St J Oreilly, Alex D Mcmahon, Ian Ford, Josephine Cooney, Keith E Suckling, M Krishna, Francis E WilkinsonAbstract:Chronic inflammation is believed to increase the risk of coronary events by making atherosclerotic plaques in coronary vessels prone to rupture. We examined blood constituents potentially affected by inflammation as predictors of risk in men with hypercholesterolemia who were enrolled in the West of Scotland Coronary Prevention Study, a trial that evaluated the value of pravastatin in the prevention of coronary events.A total of 580 men who had had a coronary event (nonfatal myocardial infarction, death from coronary heart disease, or a revascularization procedure) were each matched for age and smoking status with 2 control subjects (total, 1160) from the same cohort who had not had a coronary event. Lipoprotein-Associated Phospholipase A2, C-reactive protein, and fibrinogen levels, and the white-cell count were measured at base line, along with other traditional risk factors. The association of these variables with the risk of coronary events was tested in regression models and by dividing the range of values according to quintiles.Levels of C-reactive protein, the white-cell count, and fibrinogen levels were strong predictors of the risk of coronary events; the risk in the highest quintile of the study cohort for each variable was approximately twice that in the lowest quintile. However, the association of these variables with risk was markedly attenuated when age, systolic blood pressure, and lipoprotein levels were included in multivariate models. Levels of Lipoprotein-Associated Phospholipase A2 (platelet-activating factor acetylhydrolase), the expression of which is regulated by mediators of inflammation, had a strong, positive association with risk that was not confounded by other factors. It was associated with almost a doubling of the risk in the highest quintile as compared with the lowest quintile.Inflammatory markers are predictors of the risk of coronary events, but their predictive ability is attenuated by associations with other coronary risk factors. Elevated levels of Lipoprotein-Associated Phospholipase A2 appear to be a strong risk factor for coronary heart disease, a finding that has implications for atherogenesis and the assessment of risk.
Francis E Wilkinson - One of the best experts on this subject based on the ideXlab platform.
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lipoprotein associated Phospholipase A2 as an independent predictor of coronary heart disease
The New England Journal of Medicine, 2009Co-Authors: C J Packard, Colin H. Macphee, Muriel J. Caslake, Denis St J Oreilly, Alex D Mcmahon, Ian Ford, Josephine Cooney, Keith E Suckling, M Krishna, Francis E WilkinsonAbstract:Background Chronic inflammation is believed to increase the risk of coronary events by making atherosclerotic plaques in coronary vessels prone to rupture. We examined blood constituents potentially affected by inflammation as predictors of risk in men with hypercholesterolemia who were enrolled in the West of Scotland Coronary Prevention Study, a trial that evaluated the value of pravastatin in the prevention of coronary events. Methods A total of 580 men who had had a coronary event (nonfatal myocardial infarction, death from coronary heart disease, or a revascularization procedure) were each matched for age and smoking status with 2 control subjects (total, 1160) from the same cohort who had not had a coronary event. Lipoprotein-Associated Phospholipase A2, C-reactive protein, and fibrinogen levels and the white-cell count were measured at base line, along with other traditional risk factors. The association of these variables with the risk of coronary events was tested in regression models and by divi...
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lipoprotein associated Phospholipase A2 as an independent predictor of coronary heart disease west of scotland coronary prevention study group
The New England Journal of Medicine, 2000Co-Authors: C J Packard, Colin H. Macphee, Muriel J. Caslake, Denis St J Oreilly, Alex D Mcmahon, Ian Ford, Josephine Cooney, Keith E Suckling, M Krishna, Francis E WilkinsonAbstract:Chronic inflammation is believed to increase the risk of coronary events by making atherosclerotic plaques in coronary vessels prone to rupture. We examined blood constituents potentially affected by inflammation as predictors of risk in men with hypercholesterolemia who were enrolled in the West of Scotland Coronary Prevention Study, a trial that evaluated the value of pravastatin in the prevention of coronary events.A total of 580 men who had had a coronary event (nonfatal myocardial infarction, death from coronary heart disease, or a revascularization procedure) were each matched for age and smoking status with 2 control subjects (total, 1160) from the same cohort who had not had a coronary event. Lipoprotein-Associated Phospholipase A2, C-reactive protein, and fibrinogen levels, and the white-cell count were measured at base line, along with other traditional risk factors. The association of these variables with the risk of coronary events was tested in regression models and by dividing the range of values according to quintiles.Levels of C-reactive protein, the white-cell count, and fibrinogen levels were strong predictors of the risk of coronary events; the risk in the highest quintile of the study cohort for each variable was approximately twice that in the lowest quintile. However, the association of these variables with risk was markedly attenuated when age, systolic blood pressure, and lipoprotein levels were included in multivariate models. Levels of Lipoprotein-Associated Phospholipase A2 (platelet-activating factor acetylhydrolase), the expression of which is regulated by mediators of inflammation, had a strong, positive association with risk that was not confounded by other factors. It was associated with almost a doubling of the risk in the highest quintile as compared with the lowest quintile.Inflammatory markers are predictors of the risk of coronary events, but their predictive ability is attenuated by associations with other coronary risk factors. Elevated levels of Lipoprotein-Associated Phospholipase A2 appear to be a strong risk factor for coronary heart disease, a finding that has implications for atherogenesis and the assessment of risk.