Skip Navigation


European Heart Journal Advance Access originally published online on February 21, 2007
European Heart Journal 2007 28(6):699-704; doi:10.1093/eurheartj/ehl565
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
28/6/699    most recent
ehl565v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrow Search for citing articles in:
ISI Web of Science (6)
Right arrowRequest Permissions
Google Scholar
Right arrow Articles by Oldgren, J.
Right arrow Articles by Wallentin, L.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Oldgren, J.
Right arrow Articles by Wallentin, L.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

© The European Society of Cardiology 2007. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

Lipoprotein-associated phospholipase A2 does not predict mortality or new ischaemic events in acute coronary syndrome patients

Jonas Oldgren1,*, Stefan K. James1, Agneta Siegbahn2 and Lars Wallentin1

1 Uppsala Clinical Research Center, Uppsala University Hospital, S-751 85 Uppsala, Sweden
2 Department of Medical Sciences, Clinical Chemistry, Uppsala University Hospital, S-751 85 Uppsala, Sweden

Received 21 June 2006; revised 22 January 2007; accepted 1 February 2007; online publish-ahead-of-print 21 February 2007.

* Corresponding author. Tel: +46 18 611 9502; fax: +46 18 506638. E-mail address: jonas.oldgren{at}ucr.uu.se


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 Acknowledgements
 References
 
Aim Lipoprotein-associated phospholipase A2 (Lp-PLA2) has been suggested as an independent predictor of cardiovascular events in epidemiological studies. We sought to evaluate Lp-PLA2 as a risk factor for future cardiovascular events in patients with acute coronary syndromes (ACS) and to elucidate the relationship between Lp-PLA2 and other known risk markers in ACS patients and healthy control subjects.

Methods and results Blood samples were obtained at randomization in a random subset of ACS patients in the FRISC II (n = 1362) and GUSTO IV (n = 904) studies and in 435 apparently healthy controls of similar age and gender. Median Lp-PLA2 (mass) levels were 305 ng/mL (FRISC II), 373 ng/mL (GUSTO IV), and 254 ng/mL (healthy controls). Time delay from symptom onset did not influence Lp-PLA2 levels. In the FRISC II patients and healthy controls, Lp-PLA2 was significantly correlated with cholesterol (r = 0.3), low-density lipoprotein (r = 0.4 and r = 0.3, respectively), and C-reactive protein (r = 0.08 and r = 0.1, respectively), all P < 0.01. Lp-PLA2 was not correlated with age, interleukin-6, troponin T, or NT-proBNP in any of the three cohorts. There was no difference in the composite of death and myocardial infarction at 30 days (GUSTO IV) or 180 days (FRISC II) in relation to low, middle, and top tertiles of Lp-PLA2 at randomization. In FRISC II, the 1 year mortality was 4.2, 4.2, and 4.8% in the low, middle, and top Lp-PLA2 tertiles, respectively, P = 0.8. In GUSTO IV, 1 year mortality was 7.0, 8.3, and 9.6% in the low, middle, and top Lp-PLA2 tertiles, respectively, P = 0.5.

Conclusion ACS patients had higher Lp-PLA2 levels than healthy controls. Lp-PLA2 was significantly correlated to lipid levels but only weakly correlated or unrelated to other well-established risk markers in ACS. The risk of future cardiovascular events or mortality was not related to Lp-PLA2 levels in ACS patients. The biological role of Lp-PLA2 and its role as a risk marker in ACS patients still remain unclear.

Key Words: Acute coronary syndromes • Inflammation


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 Acknowledgements
 References
 
Inflammation plays a major role in the development and progression of atherosclerosis.1 The atherosclerotic plaque contains large amounts of inflammatory cells, such as macrophages2 and T lymphocytes,3 which may destabilize the plaque, and inflammation may thus be involved in the initiation of acute coronary syndromes (ACS).4 Inflammation in ACS is evident by elevated levels of cytokines5 and acute phase proteins,6,7 which have been related to future increased mortality.8,9 The elevation of inflammatory markers in ACS may originate from the ruptured atherosclerotic plaque, reflect a widespread inflammation in the coronary tree,10 and represent an acute-phase reaction owing to myocardial cell necrosis.11

Lipoprotein-associated phospholipase A2 (Lp-PLA2) is a potential novel inflammatory risk factor for coronary artery disease and has been suggested to provide information related to and additional to that obtained from traditional lipid analyses12 and complementary to C-reactive protein.13 This enzyme is secreted by monocytes, macrophages, T-lymphocytes, and mast cells.13 In plasma, ~80% of Lp-PLA2 circulates bound to low-density lipoproteins (LDL) and 15–20% is bound to high-density lipoproteins. Increased Lp-PLA2 mRNA has been found in macrophages from human and rabbit arteriosclerotic lesions.14 A growing number of epidemiological studies have suggested Lp-PLA2 as an independent predictor of cardiovascular events13,15,16 and higher levels of Lp-PLA2 have also been associated with stable coronary artery disease in case–control studies.12,17,18 These observations have provided the rationale to suggest causal links between Lp-PLA2 and plaque vulnerability in ACS patients, although sparse data are available in this population.19

We sought to evaluate Lp-PLA2 as a risk factor for future cardiovascular events in ACS patients and to elucidate the relationship between Lp-PLA2 and other known risk markers in ACS patients and healthy control subjects.


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 Acknowledgements
 References
 
The FRISC II substudy
The FRISC II trial was a Scandinavian prospective, randomized, multicentre study in which ACS patients were randomized in a factorial design to an early non-invasive or invasive strategy and to long-term treatment with dalteparin or placebo.20,21 Patients were eligible for inclusion if they had experienced symptoms of ischaemia within 48 h before the start of dalteparin or unfractionated heparin treatment. Myocardial ischaemia had to be verified by electrocardiogram or by elevated biochemical markers of myocardial necrosis. Randomization was scheduled within 72 h of the start of open-label dalteparin/heparin treatment. Thereafter, all patients were treated with subcutaneous injections of aspirin and dalteparin for 5–7 days, followed by aspirin and twice-daily subcutaneous injections of either dalteparin or placebo for a period of 3 months. Blood samples for analyses of Lp-PLA2 were obtained at randomization and analysed in 1362 (out of 2457) randomly selected patients.

The GUSTO IV substudy
The GUSTO-IV trial included 7800 patients with non-ST-elevation ACS from 458 centres in 24 countries during 1999 and 2000.22 In summary, eligible patients were at least 21 years of age, with chest pain lasting more than 5 min, within 24 h of admission and either a positive cardiac Troponin test or ST-segment depression. The patients were randomly assigned to abciximab bolus and subsequent infusion for 24 or 48 h or corresponding placebo infusion. All patients received aspirin for long-term treatment as well as either unfractionated heparin infusion or subcutaneous dalteparin. Coronary angiography was discouraged during or within 12 h after the completion of study agent infusion. During 30 days of follow-up, mortality and rate of all adjudicated myocardial infarctions were recorded. At 12 months, only all-cause mortality was collected. Levels of Lp-PLA2 were analysed from serum obtained at randomization in 904 randomly selected patients.

Healthy controls
The study population consisted of 435 men and women included in the SWISCH study23 during 2000–2003. The SWISCH study was a case–control study on risk factors for coronary artery diseases in elderly men and women. In this study, subjects were matched for age and sex with ACS patients included at six hospitals in the FRISC II study during 1996–1998. Controls were screened by history and clinical examination. Exclusion criteria were established cardiovascular disease, other chronic disease or acute illness, or cardiovascular medication. All controls had normal levels of haemoglobin, white blood cell count, platelet count, creatinine, and blood glucose. They provided written informed consent, and the Ethics Committees of all participating hospitals approved the study.

Blood sampling and analyses
In the FRISC II and in the GUSTO IV study, blood was obtained at randomization by a direct vein puncture. In the FRISC II, blood was anticoagulated with EDTA, and plasma was prepared within 30 min of collection by centrifugation at 2000 g at room temperature for 20 min. In GUSTO IV, samples were centrifuged and serum was stored in aliquots. In the healthy controls, venous blood samples were obtained at an outpatient visit, anticoagulated with EDTA, and plasma was prepared within 30 min of collection by centrifugation at 2000 g at room temperature for 20 min. All samples were frozen and stored in aliquots at –70°C and sent to the Department of Clinical Chemistry, Uppsala, Sweden for analyses. Lp-PLA2 was analysed with the commercially available PLAC test (diaDexus Inc.), an ELISA test with two specific monoclonal antibodies.24

Statistics
Baseline characteristics for the three study populations are presented as means with standard deviations or proportions, as appropriate. Lp-PLA2 levels are presented as medians with first and third quartiles. All statistical tests were two-sided and P-values of less than 0.05 were considered significant. The levels of Lp-PLA2 in relation to baseline characteristics were compared with Mann–Whitney U-tests, and correlation of Lp-PLA2 with other biomarkers were evaluated with Spearman correlations. In the statistical analyses, the three different study populations were analysed separately and presented in tables and figures accordingly, except for the analysis of Lp-PLA2 levels in relation to time from symptom onset. The two ACS populations were pooled for the analysis of Lp-PLA2 (natural logarithm) in relation to time from symptom onset to blood sampling (individually calculated for each ACS patient). This was evaluated by linear regression analyses and the interaction of the two ACS populations was evaluated with covariance analysis.

Clinical endpoints, i.e. death and myocardial infarction at 30 days (GUSTO IV) and 180 days (FRISC II) and mortality up to 2 years, were evaluated with log-rank test in relation to tertiles of Lp-PLA2 at randomization. A Cox regression analysis was also performed with pooled data from the two ACS cohorts evaluating 1 year mortality in relation to the natural logarithm of Lp-PLA2 at randomization and the interaction between study cohort and Lp-PLA2.


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 Acknowledgements
 References
 
The baseline characteristics were similar in the subjects studied in the FRISC II and GUSTO IV trials despite minor differences in inclusion criteria, Table 1. The median time from symptom onset to randomization was 38 h (interquartile range 28–53) in FRISC II and 15 h (interquartile range 9.4–20) in the GUSTO IV study cohort.


View this table:
[in this window]
[in a new window]

  		Table 1 Baseline characteristics

 
Lp-PLA2 levels were slightly higher in the ACS patients, with median levels of 305 (interquartile range 244–371) ng/mL in the FRISC II study, 373 (297–454) ng/mL in the GUSTO IV study, compared with 254 (217–324) ng/mL in the healthy controls (SWISCH study). No significant differences in Lp-PLA2 levels were found in relation to gender, smoking, previous myocardial infarction, hypertension, or diabetes mellitus, Table 2, except for significantly lower Lp-PLA2 levels in females and higher levels in smokers in the GUSTO IV population. Lp-PLA2 levels were unrelated to the severity of coronary artery disease as judged by coronary angiography in 883 FRISC II patients, Table 2.


View this table:
[in this window]
[in a new window]

  		Table 2 Lp-PLA2 in relation to baseline characteristics and coronary angiography

 
There were weak but statistically significant correlations between Lp-PLA2 and C-reactive protein in the FRISC II and SWISCH cohorts, Table 3. The correlations for Lp-PLA2 with cholesterol and LDL were stronger. Oxidized LDL was correlated with Lp-PLA2 in the FRISC II but not in SWISCH cohort. Lp-PLA2 was also weakly, but significantly, correlated with fibrinogen in the FRISC II patients and with creatinine in GUSTO IV patients. There were no significant correlations between Lp-PLA2 and interleukin-6, troponin T, NT-proBNP, or triglycerides in any of the study cohorts.


View this table:
[in this window]
[in a new window]

  		Table 3 Correlation of Lp-PLA2 with age and other biomarkers

 
The time delay from symptom onset to blood sampling (up to 84 h) seemed not to influence the levels of Lp-PLA2 in the total cohort of ACS patients, Figure 1, with a slope coefficient of only –0.003, although significant (P < 0.001) because of the large number of observations. There was no significant interaction between the two study populations.


Figure 1
View larger version (16K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Figure 1 Lp-PLA2 (natural logarithm) in relation to time from symptom onset in ACS patients (FRISC II and GUSTO IV trials), n = 2159, slope coefficient –0.003, P < 0.001.

 
In the GUSTO IV study, 8.3, 6.0, and 8.3% had experienced a clinical event, i.e. composite of death or myocardial (re-)infarction, at 30 days in the low (<324 ng/L), middle (324–430 ng/mL), and top tertiles (>430 ng/mL), respectively, P = 0.5. Similarly, in the FRISC II study, 12.1, 12.8, and 13.4% had experienced a clinical event at 6 months in the low (<265 ng/L), middle (265–344 ng/mL), and top tertiles (>344 ng/mL), respectively, P = 0.8. One year mortality in relation to tertiles of Lp-PLA2 is presented in Figures 2 and 3, with no significant differences in any of the two study cohorts. Two year follow-up data were available in 1087 of the 1362 patients in the FRISC II cohort, with 5.2, 2.7, and 4.9% mortality in the low, middle, and top tertiles, respectively, P = 0.2. There were no differences in clinical outcome in relation to Lp-PLA2 in different subgroups based on treatment assignment, i.e. invasive vs. non-invasive, dalteparin vs. placebo, or abciximab vs. placebo.


Figure 2
View larger version (8K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Figure 2 Cumulative probability of death during 1 year according to tertiles of Lp-PLA2 levels on admission in 1362 patients enrolled in the FRISC II trial, P = 0.8 by log-rank test.

 

Figure 3
View larger version (9K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Figure 3 Cumulative probability of death during 1 year according to tertiles of Lp-PLA2 levels on admission in 904 patients enrolled in the GUSTO IV trial, P = 0.5 by log-rank test.

 
In a Cox regression analysis using the natural logarithm of Lp-PLA2 in pooled data from the 2266 patients in both ACS cohorts, the hazard ratio for 1 year mortality was 1.4 (95% C.I. 0.77–2.5), P = 0.3. There was no significant interaction observed between study cohort and Lp-PLA2, P = 0.9.


   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
Acknowledgements
 References
 
In our two large ACS cohorts, we found slightly higher levels of Lp-PLA2 than in healthy control subjects, similar to findings in previous case–control studies in stable coronary artery disease.12,17,18 There seems to be no acute-phase elevation of Lp-PLA2, as the levels of Lp-PLA2 were unaffected by time from symptom onset up to 84 h, in contrast to other inflammatory markers such as interleukin-6 and C-reactive protein, which have a dynamic time-course with a peak at 36–42 h and 48–54 h after symptom onset, respectively.11 In the FRISC II study, Lp-PLA2 was weakly correlated to C-reactive protein and also to fibrinogen, which is regarded as a marker of a more chronic low-grade inflammation in ACS.7,11 As expected by previously published data, we found significant correlations between Lp-PLA2 and total cholesterol and LDL25–27 but no correlation with age or other established risk markers in ACS, such as interleukin-6, troponin T, NT-proBNP, or triglycerides (in any of the three study cohorts). Neither was Lp-PLA2 related to the severity of coronary artery disease, as judged by early angiograms obtained in a large subset of FRISC II patients.

We found no signs of an association with Lp-PLA2 in the acute phase and risk of mortality or future cardiovascular events in these two large cohorts of ACS patients. Similarly, Lp-PLA2 (neither mass nor activity) in the acute phase was unrelated to the risk of a composite of future cardiovascular events in recently published results from the PROVE IT-TIMI22 trial.19 The authors found Lp-PLA2 activity in the highest quintile significantly associated with lower mortality. In contrast, top quintile of Lp-PLA2 activity measured after 30 days was independently associated with higher rate of a composite of future cardiovascular events.19

Large-scale epidemiological studies have previously demonstrated that Lp-PLA2 levels (mass or activity) are higher in those in whom future cardiovascular events develop.13,15,16 The results have not been entirely consistent and risk estimates of death, coronary events, or stroke have in some studies been attenuated and not statistically significant after full adjustment for several cardiovascular risk factors including LDL.25,28

The biological role of this enzyme in humans has not been clarified.29 Lp-PLA2 is expressed in greater concentrations on atherosclerotic lesions.30 The enzyme is able to hydrolyse oxidized fatty acids from oxidized phospholipids in LDL, thereby releasing lysophosphatidylcholine and oxidized non-esterified fatty acids, both of which are potent pro-inflammatory products that may contribute to the formation of atherosclerotic plaques.29 Lp-PLA2, at least in vitro, is suppressed by pro-inflammatory cytokines and endotoxin31 but has not, or only weakly, been correlated with C-reactive protein levels in humans13,15,26,28 as in the present study. Initially, Lp-PLA2 was identified as platelet-activating factor (PAF) acetylhydrolase. PAF is a molecule with pro-inflammatory and pro-thrombotic properties.32 Hence, Lp-PLA2 was viewed to have a protective role in atherosclerosis by deactivating PAF. Deficiency of Lp-PLA2 has mainly been described in the Japanese population and is associated with increased risk of developing atherosclerosis and its clinical manifestations, e.g. myocardial infarction and stroke,30 thereby supporting the concept of a protective effect by Lp-PLA2.

Limitations to the present study include that it contains retrospective analyses on patients recruited in two different clinical trials. Nevertheless, despite minor differences in inclusion and exclusion criteria, baseline characteristics were strikingly similar in the two cohorts from FRISC II and GUSTO IV, except for the time from symptom onset to randomization. Lp-PLA2 was analysed in a randomly selected subset of FRISC II and GUSTO IV patients. The numbers of patients were based on previous experiences with risk predictors. It thus seems unlikely that analyses of Lp-PLA2 in a larger subset or all of the FRISC II or GUSTO IV patients would have identified Lp-PLA2 as an independent risk predictor in multivariable analyses including other relevant and already established strong risk predictors, such as C-reactive protein, NT-proBNP, or troponins. Another limitation is the use of an ELISA test evaluating only Lp-PLA2 mass, although Lp-PLA2 activity can also be assessed. Only a modest correlation have previously been shown between Lp-PLA2 activity and Lp-PLA2 mass, the latter assessed by the commercially available ELISA method used in the present study.19,26

In summary, the levels of Lp-PLA2 were higher than in healthy controls in these two large cohorts of ACS patients, but there were no signs of an acute-phase response. Lp-PLA2 was related to lipid levels but only weakly related or unrelated to age or other well-established risk markers in ACS, including interleukin-6, C-reactive protein, troponin T, NT-proBNP, and creatinine. In ACS patients, the risk of future cardiovascular events or mortality was not related to Lp-PLA2 levels in the acute phase, similar to previously presented data.19 We conclude that the biological role of Lp-PLA2 and its potential as an independent, clinically useful risk marker in ACS patients still remains to be proved.


   Acknowledgements
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Acknowledgements
References
 
We gratefully acknowledge Robert Wolfert, diaDexus Inc., who provided the PLAC tests, Helena Vretman for skilful Lp-PLA2 analyses, and Sylvia Olofsson at UCR for statistical analyses.

Conflict of interest: none declared.


   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Acknowledgements
 References
 

  1. Ross R. (1999) Atherosclerosis—an inflammatory disease. N Engl J Med 340:115–126.[Free Full Text]
  2. Jude B, Agraou B, McFadden EP, Susen S, Bauters C, Lepelley P, Devos P, Cosson A, Asseman P. (1994) Evidence for time-dependent activation of monocytes in the systemic circulation in unstable angina but not in acute myocardial infarction or in stable angina. Circulation 90:1662–1668.
  3. Neri Serneri GG, Prisco D, Martini F, Gori AM, Brunelli T, Poggesi L, Rostagno C, Gensini GF, Abbate R. (1997) Acute T-cell activation is detectable in unstable angina. Circulation 95:1806–1812.
  4. Libby P. (2001) Current concepts of the pathogenesis of the acute coronary syndromes. Circulation 104:365–372.
  5. Biasucci LM, Vitelli A, Liuzzo G, Altamura S, Cligiuri G, Monaco C, Rebuzzi AG, Ciliberto G, Maseri A. (1996) Elevated levels of interleukin-6 in unstable angina. Circulation 94:874–877.
  6. Berk BC, Weintraub WS, Alexander RW. (1990) Elevation of C-reactive protein in ‘active’ coronary artery disease. Am J Cardiol 65:168–172.[CrossRef][ISI][Medline]
  7. Oldgren J, Wallentin L, Grip L, Linder R, Norgaard BL, Siegbahn A. (2003) Myocardial damage, inflammation and thrombin inhibition in unstable coronary artery disease. Eur Heart J 24:86–93.[Abstract/Free Full Text]
  8. Lindmark E, Diderhom E, Wallentin L, Siegbahn A. (2001) Relationship between interleukin-6 and mortality in patients with unstable coronary artery disease. Effects of an early invasive or non-invasive strategy. JAMA 286:2107–2113.[Abstract/Free Full Text]
  9. Lindahl B, Toss H, Siegbahn A, Venge P, Wallentin L. (2000) Markers of myocardial damage and inflammation in relation to long-term mortality in unstable coronary artery disease. FRISC Study Group. Fragmin during Instability in Coronary Artery Disease. N Engl J Med 343:1139–1147.[Abstract/Free Full Text]
  10. Buffon A, Biasucci LM, Liuzzo G, D'Onofrio G, Crea F, Maseri A. (2002) Widespread coronary inflammation in unstable angina. N Engl J Med 347:5–12.[Abstract/Free Full Text]
  11. James SK, Oldgren J, Lindback J, Johnston N, Siegbahn A, Wallentin L. (2005) An acute inflammatory reaction induced by myocardial damage is superimposed on a chronic inflammation in unstable coronary artery disease. Am Heart J 149:619–626.[CrossRef][ISI][Medline]
  12. Caslake MJ, Packard CJ, Suckling KE, Holmes SD, Chamberlain P, Macphee CH. (2000) Lipoprotein-associated phospholipase A(2), platelet-activating factor acetylhydrolase: a potential new risk factor for coronary artery disease. Atherosclerosis 150:413–419.[CrossRef][ISI][Medline]
  13. Koenig W, Khuseyinova N, Lowel H, Trischler G, Meisinger C. (2004) Lipoprotein-associated phospholipase A2 adds to risk prediction of incident coronary events by C-reactive protein in apparently healthy middle-aged men from the general population: results from the 14-year follow-up of a large cohort from southern Germany. Circulation 110:1903–1908.
  14. Hakkinen T, Luoma JS, Hiltunen MO, Macphee CH, Milliner KJ, Patel L, Rice SQ, Tew DG, Karkola K, Yla-Herttuala S. (1999) Lipoprotein-associated phospholipase A(2), platelet-activating factor acetylhydrolase, is expressed by macrophages in human and rabbit atherosclerotic lesions. Arterioscler Thromb Vasc Biol 19:2909–2917.[Abstract/Free Full Text]
  15. Packard CJ, O'Reilly DS, Caslake MJ, McMahon AD, Ford I, Cooney J, Macphee CH, Suckling KE, Krishna M, Wilkinson FE, Rumley A, Lowe GD. (2000) Lipoprotein-associated phospholipase A2 as an independent predictor of coronary heart disease. West of Scotland Coronary Prevention Study Group. N Engl J Med 343:1148–1155.[Abstract/Free Full Text]
  16. Oei HH, van der Meer IM, Hofman A, Koudstaal PJ, Stijnen T, Breteler MM, Witteman JC. (2005) Lipoprotein-associated phospholipase A2 activity is associated with risk of coronary heart disease and ischaemic stroke: the Rotterdam Study. Circulation 111:570–575.
  17. Khuseyinova N, Imhof A, Rothenbacher D, Trischler G, Kuelb S, Scharnagl H, Maerz W, Brenner H, Koenig W. (2005) Association between Lp-PLA2 and coronary artery disease: focus on its relationship with lipoproteins and markers of inflammation and hemostasis. Atherosclerosis 182:181–188.[CrossRef][ISI][Medline]
  18. Blankenberg S, Stengel D, Rupprecht HJ, Bickel C, Meyer J, Cambien F, Tiret L, Ninio E. (2003) Plasma PAF-acetylhydrolase in patients with coronary artery disease: results of a cross-sectional analysis. J Lipid Res 44:1381–1386.[Abstract/Free Full Text]
  19. O'Donoghue M, Morrow DA, Sabatine MS, Murphy SA, McCabe CH, Cannon CP, Braunwald E. (2006) Lipoprotein-associated phospholipase A2 and its association with cardiovascular outcomes in patients with acute coronary syndromes in the PROVE IT-TIMI 22 (PRavastatin Or atorVastatin Evaluation and Infection Therapy-Thrombolysis In Myocardial Infarction) trial. Circulation 113:1745–1752.
  20. FRISC-II. (1999) Invasive compared with non-invasive treatment in unstable coronary-artery disease: FRISC II prospective randomised multicentre study. FRagmin and Fast Revascularisation during InStability in Coronary artery disease Investigators. Lancet 354:708–715.[CrossRef][ISI][Medline]
  21. FRISC-II. (1999) Long-term low-molecular-mass heparin in unstable coronary-artery disease: FRISC II prospective randomised multicentre study. Lancet 354:701–707.[CrossRef][ISI][Medline]
  22. GUSTO-IV-ACS I. (2001) Effect of glycoprotein IIb/IIIa receptor blocker abciximab on outcome in patients with acute coronary syndromes without early coronary revascularisation: the GUSTO IV-ACS randomised trial. Lancet 357:1915–1924.[CrossRef][ISI][Medline]
  23. Johnston N, Jernberg T, Lindahl B, Lindback J, Stridsberg M, Larsson A, Venge P, Wallentin L. (2004) Biochemical indicators of cardiac and renal function in a healthy elderly population. Clin Biochem 37:210–216.[CrossRef][ISI][Medline]
  24. Dada N, Kim NW, Wolfert RL. (2002) Lp-PLA2: an emerging biomarker of coronary heart disease. Expert Rev Mol Diagn 2:17–22.[CrossRef][Medline]
  25. Blake GJ, Dada N, Fox JC, Manson JE, Ridker PM. (2001) A prospective evaluation of lipoprotein-associated phospholipase A(2) levels and the risk of future cardiovascular events in women. J Am Coll Cardiol 38:1302–1306.[Abstract/Free Full Text]
  26. Persson M, Nilsson JA, Nelson JJ, Hedblad B, Berglund G. (2006) The epidemiology of Lp-PLA(2): distribution and correlation with cardiovascular risk factors in a population-based cohort. Atherosclerosis 190:388–396.
  27. Brilakis ES, McConnell JP, Lennon RJ, Elesber AA, Meyer JG, Berger PG. (2005) Association of lipoprotein-associated phospholipase A2 levels with coronary artery disease risk factors, angiographic coronary artery disease, and major adverse events at follow-up. Eur Heart J 26:137–144.[Abstract/Free Full Text]
  28. Ballantyne CM, Hoogeveen RC, Bang H, Coresh J, Folsom AR, Heiss G, Sharrett AR. (2004) Lipoprotein-associated phospholipase A2, high-sensitivity C-reactive protein, and risk for incident coronary heart disease in middle-aged men and women in the Atherosclerosis Risk in Communities (ARIC) study. Circulation 109:837–842.
  29. Zalewski A and Macphee C. (2005) Role of lipoprotein-associated phospholipase A2 in atherosclerosis: biology, epidemiology, and possible therapeutic target. Arterioscler Thromb Vasc Biol 25:923–931.[Abstract/Free Full Text]
  30. Caslake MJ and Packard CJ. (2003) Lipoprotein-associated phospholipase A2 (platelet-activating factor acetylhydrolase) and cardiovascular disease. Curr Opin Lipidol 14:347–352.[CrossRef][ISI][Medline]
  31. Cao Y, Stafforini DM, Zimmerman GA, McIntyre TM, Prescott SM. (1998) Expression of plasma platelet-activating factor acetylhydrolase is transcriptionally regulated by mediators of inflammation. J Biol Chem 273:4012–4020.[Abstract/Free Full Text]
  32. Stafforini DM, McIntyre TM, Zimmerman GA, Prescott SM. (1997) Platelet-activating factor acetylhydrolases. J Biol Chem 272:17895–17898.[Free Full Text]

Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?


This article has been cited by other articles:


Home page
 Arterioscler. Thromb. Vasc. Bio.Home page
M. S. Sabatine, D. A. Morrow, M. O'Donoghue, K. A. Jablonksi, M. M. Rice, S. Solomon, Y. Rosenberg, M. J. Domanski, J. Hsia, and for the PEACE Investigators
Prognostic Utility of Lipoprotein-Associated Phospholipase A2 for Cardiovascular Outcomes in Patients With Stable Coronary Artery Disease
Arterioscler. Thromb. Vasc. Biol., November 1, 2007; 27(11): 2463 - 2469.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
28/6/699    most recent
ehl565v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrow Search for citing articles in:
ISI Web of Science (6)
Right arrowRequest Permissions
Google Scholar
Right arrow Articles by Oldgren, J.
Right arrow Articles by Wallentin, L.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Oldgren, J.
Right arrow Articles by Wallentin, L.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?