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Clinical Chemistry 53: 1440-1447, 2007. First published June 15, 2007; 10.1373/clinchem.2007.086298
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Right arrow Lipids, Lipoproteins, and Cardiovascular Risk Factors
(Clinical Chemistry. 2007;53:1440-1447.)
© 2007 American Association for Clinical Chemistry, Inc.

Lipids, Lipoproteins, and Cardiovascular Risk Factors

Lipoprotein-Associated Phospholipase A2 Predicts 5-Year Cardiac Mortality Independently of Established Risk Factors and Adds Prognostic Information in Patients with Low and Medium High-Sensitivity C-Reactive Protein (The Ludwigshafen Risk and Cardiovascular Health Study)

Karl Winkler1,a, Michael M. Hoffmann1, Bernhard R. Winkelmann2, Isolde Friedrich1, Günther Schäfer1, Ursula Seelhorst3, Britta Wellnitz3, Heinrich Wieland1, Bernhard O. Boehm4 and Winfried März5

1 Department of Clinical Chemistry, University Medical Center Freiburg, Germany.
2 Cardiology Group, Frankfurt-Sachsenhausen, Germany.
3 LURIC Study Nonprofit LLC, Freiburg, Germany.
4 Division of Endocrinology, Department of Medicine, University Hospital, Ulm, Germany.
5 Synlab Center of Laboratory Diagnostics, Heidelberg, Germany.

aAddress correspondence to this author at: Department of Medicine, Hugstetter Straße 55, D-79106 Freiburg, Germany. Fax 49-761-270-3444; e-mail kwinkler{at}ukl.uni-freiburg.de.


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Background: Lipoprotein-associated phospholipase A2 (LpPLA2), also denoted as platelet-activating factor acetylhydrolase, is a lipoprotein-bound enzyme involved in inflammation and atherosclerosis. In this cohort study we investigated LpPLA2 activity to predict cardiac mortality in patients scheduled for coronary angiography.

Methods: LpPLA2 activity was determined in 2513 patients with and in 719 patients without angiographically confirmed coronary artery disease (CAD).

Results: During the median observation period of 5.5 years, 501 patients died. In patients with tertiles of LpPLA2 activity of 420–509 U/L or ≥510 U/L, unadjusted hazard ratios (HRs) for cardiac death were 1.7 (95% CI 1.3–2.4; P = 0.001), and 1.9 (95% CI 1.4–2.5; P <0.001), respectively, compared with patients with LpPLA2 activity ≤419 U/L. After we accounted for established risk factors and included angiographic CAD status, high-sensitivity C-reactive protein (hsCRP), and N-terminal pro-B-type natriuretic peptide, the 3rd tertile of LpPLA2 activity predicted cardiac 5-year mortality with an HR of 2.0 (95% CI 1.4–3.1; P = 0.001). LpPLA2 activity increased the adjusted risk for cardiac death by 2-fold in patients with hsCRP <3 mg/L in the 2nd (HR 2.4, 95% CI 1.4–4.2; P = 0.002) and 3rd (HR 2.1, 95% CI 1.1–4.0; P = 0.02) tertiles of LpPLA2 activity and in patients with hsCRP of 3–10 mg/L in the 3rd tertile (HR 1.9, 95% CI 1.0–3.6; P = 0.03) of LpPLA2 activity.

Conclusions: LpPLA2 activity predicts risk for 5-year cardiac mortality independently from established risk factors and indicates risk for cardiac death in patients with low and medium-high hsCRP concentrations. Therefore, LpPLA2 activity may provide information for the identification and management of patients at risk beyond established risk stratification strategies.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Inflammation plays a major role in the pathophysiology of atherosclerosis and, consequently, for cardiovascular events. Markers of inflammation such as high-sensitivity C-reactive protein (hsCRP)1 have attracted much interest as predictors of cardiovascular risk. Measurement of hsCRP has been recommended to refine risk assessment (1) because hsCRP may add to the prognostic information provided by widely accepted risk stratification algorithms (2)(3).

Platelet-activating factor (PAF) is a potent lipid mediator that may be involved in inflammation (4) as well as in atherogenesis (5). In plasma, PAF is hydrolyzed and inactivated by PAF-acetylhydrolase (AH; EC 3.1.1.47), a Ca2+-independent phospholipase A2 (6). Plasma PAF-AH is complexed to lipoproteins in vivo; hence it is also denoted lipoprotein-associated phospholipase A2 (LpPLA2) (7).

LpPLA2, which is secreted by macrophages, degrades PAF and proinflammatory oxidized phospholipids, actions that suggest it may be a potent antiinflammatory and antiatherogenic enzyme (8). On the other hand, LpPLA2 may also generate bioactive oxidized free fatty acids (7) and lysophosphatidylcholine (9). Because LpPLA2 may play dual pro- and antiinflammatory roles depending on the concentration and the availability of potential substrates (10), the question of whether LpPLA2 is pro- or antiatherogenic poses a challenge to investigators.

Numerous clinical studies link LpPLA2 to coronary artery disease (CAD) in healthy people and CAD patients (11)(12)(13)(14)(15)(16)(17), as well as in patients with type 2 diabetes mellitus (18). In one study, however, LpPLA2 was not independently associated with other risk factors in healthy middle-aged women (19), and in another study with healthy middle-aged individuals LpPLA2 was independently associated with CAD only at LDL cholesterol (LDL-C) concentrations >3.4 mmol/L (130 mg/dL) (20).

LpPLA2 and hsCRP may play complementary roles in enabling identification of individuals at increased risk for cardiovascular events (17)(20), and LpPLA2 has recently been shown to predict future cardiovascular events in patients with CAD independently of traditional risk marker and markers of inflammation, renal function, and hemodynamic stress (21). To date, however, prospective data on LpPLA2-associated cardiac mortality are lacking. In this study we examined the prognostic value of LpPLA2 activity in relation to other established and novel risk factors, especially hsCRP, for long-term cardiac mortality in 3232 individuals scheduled for angiography.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
study design and participants
To examine the relationships between LpPLA2 activity and cardiovascular mortality we studied participants in the Ludwigshafen Risk and Cardiovascular Health (LURIC) study. LURIC is an ongoing prospective hospital-based cohort study investigating environmental, biochemical, and genetic risk factors for CAD (22). This study adds to previous cross-sectional angiographic data of 3148 individuals of the LURIC cohort who had undergone coronary angiography at Ludwigshafen General Hospital (17). In the meantime complete clinical and biochemical data were available for 3248 individuals, but 16 patients were lost to follow-up. Thus, information on life status was available for 3232 (99.5%) of patients. Of these, 501 deaths were recorded, and causes of death were obtained from official death certificates of local person registries, where information was filed by the physician who was in charge for the respective patient. Death was assigned to the following causes: cardiac death, n = 313; fatal stroke, n = 25; fatal cancer, n = 56; fatal infections, n = 30; and other causes of death, n = 77. Because of the low incidence of other causes of death, we investigated cardiac and total mortality. The median time of follow-up was 5.5 years (range, 0.1–7.2 years). The study was approved by the institutional review board at the "Ärztekammer Rheinland-Pfalz". Informed written consent was obtained from each of the participants.

In the LURIC study, clinically relevant CAD [proven CAD (CAD+)] was defined as the occurrence of at least 1 stenosis ≥20% in at least 1 of 15 coronary segments (23). Angiograms were analyzed by visual analysis. To minimize the interobserver variability of visual analysis, we assessed all angiograms in a standardized fashion using enlarged projection. Furthermore, visual analysis was limited to 5 experienced angiographers. The final catheterization report was released only after approval by the senior cardiologist (22). Individuals with stenoses <20% were considered CAD negative (CAD–). Individuals classified as having diabetes mellitus were those with plasma glucose >1.25 g/L in the fasting state or >2.00 g/L 2 h after the oral glucose load (performed in individuals without a previous type 2 diabetes mellitus diagnosis) (24) or those receiving oral diabetes medication or insulin. Hypertension was diagnosed if the systolic and/or diastolic blood pressure exceeded 140 and/or 90 mmHg or if the patient was on antihypertensive medication (22).

laboratory procedures
The standard laboratory methods used have previously been described in detail (22). LpPLA2 activity was measured by use of the Azwell Auto PAF-AH reagent set (Azwell) (25) on a Hitachi 912 autoanalyzer, N-terminal pro-B-type natriuretic peptide (NT-pro-BNP) by electrochemiluminescence on an Elecsys 2010 (Roche Diagnostics), and hsCRP by immunonephelometry on a Behring Nephelometer II (N High Sensitivity CRP; Dade Behring). Interassay CVs for PAF-AH activity, NT-pro-BNP, and hsCRP were <5%.

statistical analysis
Study participants were divided into tertile ranges of LpPLA2 activity according to values in individuals without CAD (reference population) with LpPLA2 activities values of ≤419 U/L, 420–509 U/L, or ≥510 U/L. Clinical and anthropometric characteristics of individuals grouped according to tertiles of LpPLA2 activity and CAD status are presented as percentages for categorical variables and as mean (SD) or medians and interquartile ranges for continuous variables, as appropriate. Associations of continuous and categorical variables with tertiles of LpPLA2 activity and CAD status (CAD– or CAD+) were analyzed by use of a general linear model (GLM) or logistic regression. To examine the effect of LpPLA2 activity on cardiac and total mortality, we calculated hazard ratios (HRs) using the Cox proportional hazards regression model. Since triglycerides (TG), hsCRP, and NT-pro-BNP do not show gaussian distribution, these variables were transformed logarithmically to logTG, logCRP, and logNT-pro-BNP for adjustments. Multivariable adjustments were carried out with information at baseline for age, sex, body mass index, type 2 diabetes mellitus, hypertension, smoking (former and present), use of lipid-lowering drugs, use of aspirin and/or other antiplatelet agents, LDL-C, HDL cholesterol (HDL-C), logTG, logCRP, logNT-pro-BNP, or presence of angiographic CAD, as indicated. In patients with angiographically CAD+ the proportion of patients without fatal cardiac events and the total survival rates over time were calculated by grouping individuals according to tertiles of LpPLA2 activity. To further assess whether LpPLA2 activity adds information to hsCRP with regard to cardiac mortality, individuals were categorized into 3 clinically relevant groups according to hsCRP concentration (<3, 3–10, and >10 mg/L) (1) and further stratified into tertiles of LpPLA2 activity. Either the unadjusted or adjusted HR of tertiles of LpPLA2 activity was calculated separately in each stratum of hsCRP by use of the respective lowest tertile of LpPLA2 activity as reference. In addition, we constructed ROC curves after adjustment for covariates and calculated the area under the curve (AUC) with its 95% CI. Significance of differences between ROC curves were tested by the likelihood of the corresponding logistic regression models. All statistical tests were 2-sided. P <0.05 was considered statistically significant. The SPSS 14.0 statistical package (SPSS) was used for all analyses.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
patient characteristics according to LPPLA2 activity and cad status
Patients with CAD (CAD+) were older and male; type 2 diabetes mellitus, hypertension, and smoking were more prevalent in this group than in individuals without CAD (CAD–). In the CAD+ patient group compared with the CAD– and total mortality groups, TG and LDL-C were increased, whereas HDL-C was decreased. hsCRP as well as NT-pro-BNP were increased in CAD+ patients, and death attributable to cardiac-related causes (P = 0.004) and any cause (P = 0.002) was more frequent in CAD+ patients (Table 1 ). In CAD– patients, tertiles of LpPLA2 activity were associated with male sex, TG, LDL-C, and HDL-C and with cardiac mortality (P = 0.020; Table 1 ). Similarly, in CAD+ patients, tertiles of LpPLA2 activity were associated with male sex, TG, LDL-C, and HDL-C. In addition, cardiac (P <0.001) and total mortality (P <0.001) were more frequent with increasing tertiles of LpPLA2 activity (Table 1 ).


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  		Table 1. Fatal incidences and clinical and biochemical characteristics according to tertiles of LpPLA2 activity and angiographic CAD.

mortality risk according to LPPLA2 activity
Unadjusted HRs for cardiac mortality were 1.87 (95% CI 1.39–2.51; P <0.001) for the 3rd tertile of LpPLA2 activity compared with the reference tertile (model 1); 2.30 (95% CI 1.55–3.41; P <0.001) in the model adjusted for age, sex, body mass index, smoking, type 2 diabetes mellitus, hypertension, use of lipid-lowering drugs or aspirin and/or other antiplatelet agents, LDL-C, HDL-C, and logTG (model 2); and 2.26 (95% CI 1.52–3.35; P <0.001) after additional adjustment for angiographic CAD status (CAD+/CAD–; model 3). Tertiles of LpPLA2 activity remained predictive even if further adjusted for logCRP and logNT-pro-BNP: The adjusted HR of the 3rd tertile of LpPLA2 activity compared with the reference tertile was 2.03 (95% CI 1.35–3.05; P = 0.001) for cardiac mortality (model 4), and 1.59 (95% CI 1.14–2.22; P = 0.006) for total mortality (model 5), respectively (Table 2 ). The adjusted prognostic value for total mortality was robust, even if LpPLA2 activity was used as quartiles or as a continuous variable (data not shown).


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  		Table 2. HRs according to tertiles of LpPLA2 activity.

roc analysis for risk prediction of cardiac and total mortality
The incremental contribution of LpPLA2 activity to predict risk for cardiac and total mortality in the presence of classical risk factors was quantified. The ROC curve analysis indicated that the addition of logNT-pro-BNP to a basic model including age, sex, smoking, diabetes, hypertension, use of lipid-lowering drugs, LDL-C, and angiographic CAD status increased the AUC to 0.760 (95% CI 0.733–0.787; P <0.001) and 0.773 (95% CI 0.751–0.795; P <0.001) for cardiac and total mortality, respectively, and further addition of logCRP increased the AUC to 0.761 (95% CI 0.734–0.788; P = 0.219) and 0.775 (95% CI 0.753–0.796; P = 0.011), respectively. However, inclusion of LpPLA2 activity along with all the previous adjustors increased the AUC even further, to 0.773 (95% CI 0.747–0.799; P = 0.011) for cardiac and to 0.784 (95% CI 0.763–0.806; P <0.001) for total mortality (Table 3 ).


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  		Table 3. Accuracy of various multivariate models to predict cardiac or total mortality as measured by an increase in the area under the ROC curve after inclusion of several biomarkers.1

cardiac death and survival in patients with angiographic cad according to tertiles of LPPLA2 activity
We investigated the proportion of patients without a fatal cardiac event over time and total survival rates in patients with angiographically CAD+ in relation to tertiles of LpPLA2 activity. The 2nd tertile (HR 1.76; 95% CI 1.26–2.46; P = 0.001) and the 3rd tertile (HR 1.85; 95% CI 1.27–2.69; P = 0.001) of LpPLA2 activity were significantly associated with increased cardiac death over time (Fig. 1A ). Similarly, the 2nd and 3rd tertiles of LpPLA2 activity gave HRs for total mortality of 1.37 (95% CI 1.05–1.77; P = 0.019) and 1.47 (95% CI 1.10–1.96; P = 0.010), respectively (Fig. 1B ).


Figure 1
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  		Figure 1. Percentage of patients without fatal cardiac event (A) and those who survived during the follow-up period (B) among the angiographically CAD+ group by tertiles of LpPLA2 activity (LpPLA2-act).

Survival rates were adjusted by age, sex, body mass index, type 2 diabetes mellitus, hypertension, smoking, use of lipid-lowering drugs and/or aspirin and/or other antiplatelet agents, LDL-C, HDL-C, logTG, logCRP, and logNT-pro-BNP.

cardiac mortality according to HSCRP and LPPLA2 activity
To investigate whether LpPLA2 activity may add to the prognostic information provided by hsCRP alone, we divided the study population into 3 groups according to clinically relevant concentrations of hsCRP: <3, 3 to 10, and >10 mg/L (1) (Fig. 2 ). For the hsCRP <3 mg/L group, adjusted HRs for cardiac death for the 2nd and 3rd tertiles compared with the 1st tertile of LpPLA2 activity were 2.38 (95% CI 1.36–4.16; P = 0.002) and 2.11 (95% CI 1.12–3.98; P = 0.022). Furthermore, in the hsCRP 3–10 mg/L group the 3rd tertile of LpPLA2 activity gave an HR for cardiac death of 1.93 (95% CI 1.04–3.59; P = 0.038) compared with the 1st tertile in this hsCRP group.


Figure 2
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  		Figure 2. HRs for cardiac death by hsCRP and LpPLA2 activity.

Individuals were broken down into clinically relevant groups of hsCRP (<3 mg/L, 3–10 mg/L, and >10 mg/L) (1) and further stratified into tertiles of LpPLA2 activity. Relative risks were calculated as HRs with the Cox proportional hazards regression model. HRs of tertiles of LpPLA2 activity were calculated separately in each stratum of hsCRP using the respective lowest tertile of LpPLA2 activity in each stratum as reference. Gray, unadjusted model; black, adjusted model including age, sex, body mass index, type 2 diabetes mellitus, hypertension, smoking, use of lipid-lowering drugs or aspirin and/or other antiplatelet agents, LDL-C, HDL-C, logTG, logNT-pro-BNP, and presence or absence of angiographically CAD+.


   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
This investigation adds to previous cross-sectional angiographic data of the LURIC trial (17). Continuation of data entry resulted in complete clinical and biochemical data sets for 3248 patients; 16 patients were lost to follow-up. Thus, 3232 patients (99.5%) were investigated in this study. Although methods assessing either LpPLA2 mass or LpPLA2 activity may differ and are not yet standardized, this study adds to numerous previous clinical studies and supports the theory that LpPLA2 is a proatherogenic risk marker. To establish LpPLA2 as a clinically relevant indicator, however, standardization of LpPLA2 methods is necessary. This study is the first cohort study to address long-term cardiac mortality associated with LpPLA2 and provides several new findings. First, LpPLA2 activity predicts cardiac mortality and all-cause mortality, adjusted for established risk factors, including NT-pro-BNP, hsCRP, and angiographic CAD status. Second, in patients with hsCRP concentrations <10 mg/L, the additional information of LpPLA2 activity increased the adjusted HR for cardiac death by 2-fold.

LpPLA2 activity is lower in women (17)(26) and may, in general, be related to the lower cardiovascular risk found in females. Therefore, we made data analysis adjusted for sex. LpPLA2 activity may be directly influenced by a variety of cardiovascular medication, with lipid-lowering drugs and aspirin showing the most pronounced effects (17). LpPLA2 has recently been shown to induce coronary endothelial dysfunction (27) and increased risk of stroke (28)(29). In our study, however, probably because of the low number of cases, the incidence rates of fatal stroke did not differ between tertiles of LpPLA2 activity either the CAD+ or the CAD– group (Table 1Up ).

Like LDL-C, NT-pro-BNP is an established biomarker not only for the diagnosis of heart failure (30) but also for the prediction of mortality in patients presenting with acute coronary syndromes (31)(32)(33) or stable coronary disease (34) and in asymptomatic individuals in the general population (35). In this study, however, with patients scheduled for coronary angiography, the association of LpPLA2 activity with cardiac and all-cause mortality adjusted for various established risk factors was robust even if NT-pro-BNP was included (Table 2Up ). On the basis of established risk factors such as patient clinical history, including angiographic status, drug history, and concentrations of lipoproteins, the addition of NT-pro-BNP was the most significant predictor of mortality, whereas hsCRP added prognostic value for total mortality only (Table 3Up ). Although NT-pro-BNP and hsCRP were already taken into account, the inclusion of LpPLA2 activity further increased the AUC of ROC curves for both cardiac and total mortality. The increased predictive power for cardiac death by LpPLA2 activity was similar to and the absolute AUC was greater (Table 3Up ) than those recently observed by Koenig et al. (21) for future cardiovascular events.

In patients with proven angiographic CAD, tertiles of LpPLA2 activity were associated with increased risk for cardiac and total mortality (Fig. 1Up ), whereas in patients without angiographic CAD, none of these associations were significant (data not shown). Therefore, on the basis of prevalent atherosclerosis, increased LpPLA2 activity may further propagate atherogenesis, but LpPLA2 activity does not behave as an acute phase marker and indicator of systemic inflammation (17).

In individuals with a moderate 10-year risk for cardiovascular morbidity of 10% to 20%, additional measurement of hsCRP is recommended because CRP concentrations >3 mg/L double estimated risk (1). We sought to determine whether the measurement LpPLA2 activity, in addition to hsCRP, in individuals undergoing coronary angiography would enhance the predictive power. Indeed, in patients with hsCRP concentrations <10 mg/L, the adjusted risk for cardiac death in the highest tertile of LpPLA2 activity was doubled. In general, hsCRP concentrations <3 mg/L are associated with low risk of CAD. If LpPLA2 activity is increased, however, the HR for cardiac death may be doubled even with hsCRP <3 mg/L. Therefore, the measurement of LpPLA2 activity in addition to hsCRP and other biomarkers such as NT-pro-BNP may be beneficial.

Limitations of this study include the fact that data were obtained only from middle-aged to elderly white Europeans referred for cardiac catheterization. Thus, the findings may not be generalized to younger individuals or individuals who are not white and of European descent. Although the referral bias associated with this design may be viewed as limitation of our study, this approach may also be seen as strength of this investigation. The prevalence of clinically asymptomatic coronary atherosclerosis has been reported to be very high in individuals 50 years old or older (36). Hence, angiography-based recruitment of controls rules out inadvertent allocation to the control group of individuals with major yet clinically inapparent CAD. Furthermore, our controls may be representative of a population-based control group, because the major cardiovascular risk factors occurred in our controls at frequencies similar to the general population and the prevalence of hypertension was close to that found in a random probability sample from Germany (37).


   Acknowledgments
 
Grant/funding support: None declared.

Financial disclosures: None declared.

Acknowledgments: We extend sincere appreciation to the participants in the LURIC study, without whose collaboration this article would not have been written. We also thank Gerta Rücker, Department of Biometry and Statistics, University of Freiburg, for statistical advice. The assistance of Doris Rockus, Gabi Herr, Silvia Behaim, Ursula Discher, and Brigitte Haas is gratefully acknowledged. We thank the members of the LURIC study team who were either temporarily or permanently involved in patient recruitment or sample and data handling, and the laboratory staff at the Ludwigshafen General Hospital and the Universities of Freiburg and Ulm, Germany. We also thank the German registration offices and local public health departments for their assistance. The corresponding author had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.


   Footnotes
 
1 Nonstandard abbreviations: hsCRP, high-sensitivity C-reactive protein; PAF, platelet-activating factor; AH, acetylhydrolase; LpPLA2, lipoprotein-associated phospholipase A2; CAD, coronary artery disease; LDL-C, cholesterol associated with LDLs; LURIC, Ludwigshafen Risk and Cardiovascular Health; CAD+, proven CAD; CAD–, absence of angiographic CAD; NT-pro-BNP, N-terminal pro-B-type natriuretic peptide; GLM, general linear model; HR, hazard ratio; TG, triglycerides; logCRP, logarithmically transformed hsCRP; logNT-pro-BNP, logarithmically transformed NT-pro-BNP; logTG, logarithmically transformed triglycerides; HDL-C, cholesterol associated with HDLs; AUC, area under the curve.


   References
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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
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