Koenig W

References (6)

Title : Lipoprotein-Associated Phospholipase A2 Activity Is a Marker of Risk But Not a Useful Target for Treatment in Patients With Stable Coronary Heart Disease - Wallentin_2016_J.Am.Heart.Assoc_5_
Author(s) : Wallentin L , Held C , Armstrong PW , Cannon CP , Davies RY , Granger CB , Hagstrom E , Harrington RA , Hochman JS , Koenig W , Krug-Gourley S , Mohler ER, 3rd , Siegbahn A , Tarka E , Steg PG , Stewart RA , Weiss R , Ostlund O , White HD
Ref : J Am Heart Assoc , 5 : , 2016
Abstract : BACKGROUND: We evaluated lipoprotein-associated phospholipase A2 (Lp-PLA2) activity in patients with stable coronary heart disease before and during treatment with darapladib, a selective Lp-PLA2 inhibitor, in relation to outcomes and the effects of darapladib in the STABILITY trial. METHODS AND RESULTS: Plasma Lp-PLA2 activity was determined at baseline (n=14 500); at 1 month (n=13 709); serially (n=100) at 3, 6, and 18 months; and at the end of treatment. Adjusted Cox regression models evaluated associations between Lp-PLA2 activity levels and outcomes. At baseline, the median Lp-PLA2 level was 172.4 micromol/min per liter (interquartile range 143.1-204.2 micromol/min per liter). Comparing the highest and lowest Lp-PLA2 quartile groups, the hazard ratios were 1.50 (95% CI 1.23-1.82) for the primary composite end point (cardiovascular death, myocardial infarction, or stroke), 1.95 (95% CI 1.29-2.93) for hospitalization for heart failure, 1.42 (1.07-1.89) for cardiovascular death, and 1.37 (1.03-1.81) for myocardial infarction after adjustment for baseline characteristics, standard laboratory variables, and other prognostic biomarkers. Treatment with darapladib led to a =65% persistent reduction in median Lp-PLA2 activity. There were no associations between on-treatment Lp-PLA2 activity or changes of Lp-PLA2 activity and outcomes, and there were no significant interactions between baseline and on-treatment Lp-PLA2 activity or changes in Lp-PLA2 activity levels and the effects of darapladib on outcomes. CONCLUSIONS: Although high Lp-PLA2 activity was associated with increased risk of cardiovascular events, pharmacological lowering of Lp-PLA2 activity by =65% did not significantly reduce cardiovascular events in patients with stable coronary heart disease, regardless of the baseline level or the magnitude of change of Lp-PLA2 activity. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT00799903.
ESTHER : Wallentin_2016_J.Am.Heart.Assoc_5_
PubMedSearch : Wallentin_2016_J.Am.Heart.Assoc_5_
PubMedID: 27329448

Title : Darapladib for the treatment of cardiovascular disease - Campos_2015_Expert.Rev.Cardiovasc.Ther_13_33
Author(s) : Campos CM , Suwannasom P , Koenig W , Serruys PW , Garcia-Garcia HM
Ref : Expert Rev Cardiovasc Ther , 13 :33 , 2015
Abstract : Elevated levels of phospholipase A2 have been linked to atherosclerotic plaque progression, instability via promoting inflammation and subsequent acute coronary events. Epidemiological studies have demonstrated the correlation between elevated levels associated phospholipase A2 and cardiovascular events. Therefore, specific inhibition of lipoprotein-associated phospholipase A2 with darapladib has been tested as a therapeutic option for atherosclerosis. The aim of this profile is to review the physiologic aspects of lipoprotein-associated phospholipase A2 and to revisit the clinical evidence of darapladib as therapeutic option for atherosclerosis.
ESTHER : Campos_2015_Expert.Rev.Cardiovasc.Ther_13_33
PubMedSearch : Campos_2015_Expert.Rev.Cardiovasc.Ther_13_33
PubMedID: 25521799

Title : 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 - Grallert_2012_Eur.Heart.J_33_238
Author(s) : Grallert H , Dupuis J , Bis JC , Dehghan A , Barbalic M , Baumert J , Lu C , Smith NL , Uitterlinden AG , Roberts R , Khuseyinova N , Schnabel RB , Rice KM , Rivadeneira F , Hoogeveen RC , Fontes JD , Meisinger C , Keaney JF, Jr. , Lemaitre R , Aulchenko YS , Vasan RS , Ellis S , Hazen SL , van Duijn CM , Nelson JJ , Marz W , Schunkert H , McPherson RM , Stirnadel-Farrant HA , Psaty BM , Gieger C , Siscovick D , Hofman A , Illig T , Cushman M , Yamamoto JF , Rotter JI , Larson MG , Stewart AF , Boerwinkle E , Witteman JC , Tracy RP , Koenig W , Benjamin EJ , Ballantyne CM
Ref : Eur Heart J , 33 :238 , 2012
Abstract : 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 x 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 x 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.
ESTHER : Grallert_2012_Eur.Heart.J_33_238
PubMedSearch : Grallert_2012_Eur.Heart.J_33_238
PubMedID: 22003152
Gene_locus related to this paper: human-PLA2G7

Title : Dense genotyping of candidate gene loci identifies variants associated with high-density lipoprotein cholesterol - Edmondson_2011_Circ.Cardiovasc.Genet_4_145
Author(s) : Edmondson AC , Braund PS , Stylianou IM , Khera AV , Nelson CP , Wolfe ML , Derohannessian SL , Keating BJ , Qu L , He J , Tobin MD , Tomaszewski M , Baumert J , Klopp N , Doring A , Thorand B , Li M , Reilly MP , Koenig W , Samani NJ , Rader DJ
Ref : Circ Cardiovasc Genet , 4 :145 , 2011
Abstract : BACKGROUND: Plasma levels of high-density lipoprotein cholesterol (HDL-C) are known to be heritable, but only a fraction of the heritability is explained. We used a high-density genotyping array containing single-nucleotide polymorphisms (SNPs) from HDL-C candidate genes selected on known biology of HDL-C metabolism, mouse genetic studies, and human genetic association studies. SNP selection was based on tagging SNPs and included low-frequency nonsynonymous SNPs. METHODS AND
RESULTS: Association analysis in a cohort containing extremes of HDL-C (case-control, n=1733) provided a discovery phase, with replication in 3 additional populations for a total meta-analysis in 7857 individuals. We replicated the majority of loci identified through genome-wide association studies and present on the array (including ABCA1, APOA1/C3/A4/A5, APOB, APOE/C1/C2, CETP, CTCF-PRMT8, FADS1/2/3, GALNT2, LCAT, LILRA3, LIPC, LIPG, LPL, LRP4, SCARB1, TRIB1, ZNF664) and provide evidence that suggests an association in several previously unreported candidate gene loci (including ABCG1, GPR109A/B/81, NFKB1, PON1/2/3/4). There was evidence for multiple, independent association signals in 5 loci, including association with low-frequency nonsynonymous variants.
CONCLUSIONS: Genetic loci associated with HDL-C are likely to harbor multiple, independent causative variants, frequently with opposite effects on the HDL-C phenotype. Cohorts comprising subjects at the extremes of the HDL-C distribution may be efficiently used in a case-control discovery of quantitative traits.
ESTHER : Edmondson_2011_Circ.Cardiovasc.Genet_4_145
PubMedSearch : Edmondson_2011_Circ.Cardiovasc.Genet_4_145
PubMedID: 21303902
Gene_locus related to this paper: human-LIPG

Title : Lp-PLA2 Inhibition-The Atherosclerosis Panacea? - Karakas_2010_Pharmaceuticals.(Basel)_3_1360
Author(s) : Karakas M , Koenig W
Ref : Pharmaceuticals (Basel) , 3 :1360 , 2010
Abstract : Based on the complex pathophysiology of atherosclerosis, a large number of biomarkers that relate to lipids, inflammation, immunity, thrombosis and hemostasis, have been investigated experimentally, in epidemiologic studies and in clinical trials. Interest focuses on their potential role to aid in risk stratification, as possible surrogate markers of atherosclerosis, and potential targets for therapy. More recently, one lipid associated biomarker, lipoprotein-associated phospholipase A2 (Lp-PLA), has gained considerable interest. In addition to a plausible pathophysiological role by generating pro-inflammatory and pro-atherogenic compounds from oxidized LDL in the vessel wall, there is a large, fairly consistent epidemiological database indicating that increased levels of Lp-PLA(2) mass or activity are associated with increased risk for cardiovascular outcomes; such data further suggest that it might improve risk stratification. In addition, clinical studies indicate that increased Lp-PLA levels are associated with endothelial dysfunction. Moreover, it may also serve as an interesting therapeutic target, since a specific inhibitor of the enzyme is available with promising animal data and initial positive data in humans. Recent experimental data from a hyperlipidemic diabetic pig model strongly suggest that increased Lp-PLA(2) in the vessel wall is associated with a more vulnerable plaque phenotype which can be modulated by inhibiting Lp-PLA activity. A biomarker study in more than 1,000 patients with CHD over three months has demonstrated a positive effect on various inflammatory molecules. In addition, an imaging study using IVUS based modalities (greyscale, virtual histology, and palpography) together with a panel of biomarkers (IBIS-2) has been done in more than 300 patients with CHD treated over 12 months and results indicate that the progression of the necrotic core of the plaque can be retarded. Inhibition of the pro-atherogenic and pro-inflammatory effects of Lp-PLA may therefore contribute to decrease the residual risk in high risk patients already on polypharmacotherapy. This hypothesis is now being tested in two large phase 3 clinical trials. Thus, Lp-PLA indeed may represent a biomarker and a promising target for intervention.
ESTHER : Karakas_2010_Pharmaceuticals.(Basel)_3_1360
PubMedSearch : Karakas_2010_Pharmaceuticals.(Basel)_3_1360
PubMedID: 27713307

Title : Collaborative meta-analysis of individual participant data from observational studies of Lp-PLA2 and cardiovascular diseases - Ballantyne_2007_Eur.J.Cardiovasc.Prev.Rehabil_14_3
Author(s) : Ballantyne C , Cushman M , Psaty B , Furberg C , Khaw KT , Sandhu M , Oldgren J , Rossi GP , Maiolino G , Cesari M , Lenzini L , James SK , Rimm E , Collins R , Anderson J , Koenig W , Brenner H , Rothenbacher D , Berglund G , Persson M , Berger P , Brilakis E , McConnell JP , Sacco R , Elkind M , Talmud P , Cannon CP , Packard C , Barrett-Connor E , Hofman A , Kardys I , Witteman JC , Criqui M , Corsetti JP , Rainwater DL , Moss AJ , Robins S , Bloomfield H , Collins D , Wassertheil-Smoller S , Ridker P , Danesh J , Gu D , Nelson JJ , Thompson S , Zalewski A , Zariffa N , Di Angelantonio E , Kaptoge S , Thompson A , Walker M , Watson S , Wood A
Ref : Eur J Cardiovasc Prev Rehabil , 14 :3 , 2007
Abstract : BACKGROUND: A large number of observational epidemiological studies have reported generally positive associations between circulating mass and activity levels of lipoprotein-associated phospholipase A2 (Lp-PLA2) and the risk of cardiovascular diseases. Few studies have been large enough to provide reliable estimates in different circumstances, such as in different subgroups (e.g., by age group, sex, or smoking status) or at different Lp-PLA2 levels. Moreover, most published studies have related disease risk only to baseline values of Lp-PLA2 markers (which can lead to substantial underestimation of any risk relationships because of within-person variability over time) and have used different approaches to adjustment for possible confounding factors. OBJECTIVES: By combination of data from individual participants from all relevant observational studies in a systematic 'meta-analysis', with correction for regression dilution (using available data on serial measurements of Lp-PLA2), the Lp-PLA2 Studies Collaboration will aim to characterize more precisely than has previously been possible the strength and shape of the age and sex-specific associations of plasma Lp-PLA2 with coronary heart disease (and, where data are sufficient, with other vascular diseases, such as ischaemic stroke). It will also help to determine to what extent such associations are independent of possible confounding factors and to explore potential sources of heterogeneity among studies, such as those related to assay methods and study design. It is anticipated that the present collaboration will serve as a framework to investigate related questions on Lp-PLA2 and cardiovascular outcomes. METHODS: A central database is being established containing data on circulating Lp-PLA2 values, sex and other potential confounding factors, age at baseline Lp-PLA2 measurement, age at event or at last follow-up, major vascular morbidity and cause-specific mortality. Information about any repeat measurements of Lp-PLA2 and potential confounding factors has been sought to allow adjustment for possible confounding and correction for regression dilution. The analyses will involve age-specific regression models. Synthesis of the available observational studies of Lp-PLA2 will yield information on a total of about 15 000 cardiovascular disease endpoints.
ESTHER : Ballantyne_2007_Eur.J.Cardiovasc.Prev.Rehabil_14_3
PubMedSearch : Ballantyne_2007_Eur.J.Cardiovasc.Prev.Rehabil_14_3
PubMedID: 17301621
Gene_locus related to this paper: human-PLA2G7