Published online before print February 15, 2007, doi: 10.1161/ATVBAHA.107.139352
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© 2007 American Heart Association, Inc.
Atherosclerosis and Lipoproteins |
Circulating Secretory Phospholipase A2 Activity and Risk of Incident Coronary Events in Healthy Men and Women
The EPIC-NORFOLK Study
From INSERM (Z.M., A.T.), U689, Centre de Recherche Cardiovasculaire Lariboisière, Paris, France; Department of Pharmacology (T.S.), AP-HP, Hôpital Saint-Antoine-URCEST, and Université Pierre et Marie Curie (UPMC), Paris, France; Centre d’Investigation Clinique et Centre de Ressources Biologiques (J.B., C.S.-A., V.H.), AP-HP, Hôpital Bichat, Paris, France; Department of Cardiology (S.E.), UPMC and Hôpital Saint-Antoine, Paris, France; Medical Research Council (N.J.W.), Epidemiology Unit, Cambridge, UK; Department of Public Health and Primary Care (R.L., K.-T.K.), University of Cambridge, Cambridge, UK; Departments of Cardiology and Vascular Medicine (M.B.), Academic Medical Center, Amsterdam, The Netherlands.
Correspondence to Ziad Mallat, MD, PhD, Inserm U689, Hôpital Lariboisière, 75010, Paris, France. E-mail ziad.mallat{at}larib.inserm.fr
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Abstract |
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Objective— To assess the association between secretory phospholipase A2 (sPLA2) activity, which encompasses several types of sPLA2, and cardiovascular disease (CAD) in healthy individuals.
Methods and Results— We investigated this association in a nested case-control study among the 25 663 participants in EPIC-Norfolk cohort. Cases (n=991) were subjects in whom CAD developed during the 6 years of mean follow-up. Controls (n=1806) matched by age, sex, and enrollment time remained free of any CAD during follow-up. The risk of incident CAD was associated with increasing quartiles of sPLA2 activity (P<0.001). After adjustment for risk factors, C-reactive protein and sPLA2 type IIA concentration, the odds ratios of incident CAD in the second, third, and fourth quartiles of sPLA2 activity were 1.41, 1.33, and 1.56 (P=0.003), compared with the lowest quartile. sPLA2 activity and CRP were poorly correlated (r=0.15), and their combined values were more informative for incident risk of CAD than either biomarker alone. Subjects in the highest quartiles of sPLA2 activity and CRP had an adjusted odds ratio of 2.89 (95% confidence interval, 1.78 to 4.68; P<0.001) for CAD compared with those with the lowest quartiles of both markers.
Conclusions— Measurement of serum sPLA2 activity provides additive prognostic value to traditional risk factors and CRP levels, and identifies a subgroup of individuals at high risk for incident CAD. Measurement of sPLA2 type II concentration had little added prognostic utility.
In a nested case-control study among 25 663 healthy participants of EPIC-Norfolk cohort, the risk of incident coronary artery disease was associated with increasing quartiles of serum sPLA2 activity. sPLA2 activity and CRP levels provided better prediction of risk than either biomarker alone. The odds ratio of risk was 2.89 (95% CI, 1.78 to 4.68; P<0.001) in the highest quartiles of sPLA2 activity and CRP, compared with those in the lowest quartiles of both markers.
Key Words: biomarker • coronary artery disease • phospholipase A2 • prevention • risk factors
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Introduction |
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Inflammation plays a key role in the pathophysiology of vulnerable plaque and coronary events. Measurement of circulating markers of inflammation has attracted considerable interest in the past decade. Among them, C-reactive protein (CRP) is the strongest "novel" biomarker identified for predicting atherothrombotic events in apparently healthy individuals and for adding predictive value at all levels of risk based on Framingham score.1 Recent guidelines have recommended that CRP measurement should be considered for patients at intermediate risk of coronary artery disease (CAD),2 but there is still substantial room for improvement. A current interest has emerged for evaluating the impact of potential associations of inflammatory markers to improve the prediction of absolute CAD risk in the general population.3,4
Phospholipase A2 (PLA2) enzymes hydrolyze phospholipids at the sn-2 position to generate lysophospholipids and fatty acids,5 leading to the activation of various immunoinflammatory processes related to the pathogenesis and complications of atherosclerosis.6 One of the most studied PLA2 is a low-molecular-weight (14 kDa) group IIA secretory PLA2 type IIA (sPLA2 type IIA), expressed in normal and atherosclerotic human arteries,7 and associated with enhanced susceptibility to atherogenesis in animals.8 Increased plasma concentration of sPLA2 type IIA has been associated with the risk of coronary events in stable9 patients. Plasma concentration of sPLA2 type IIA has been shown to be increased in unstable CAD patients10 and was associated with recurrent events during follow-up.11 We showed recently that the direct and accurate measurement of circulating sPLA2 enzyme activity, which encompasses several types of sPLA2, including sPLA2 type IIA, V, and X, was an independent predictor of death and new or recurrent myocardial infarction in patients with acute coronary syndrome, and provided a better prognostic value than the measurement of sPLA2 type IIA concentration or CRP levels.12
The relationship between plasma sPLA2 activity and the risk of incident CAD in people free of disease is unknown. Therefore, we examined whether serum sPLA2 activity was associated with the risk of incident CAD in apparently healthy individuals and whether the combined measurement of CRP and sPLA2 activity improved the prediction of CAD.
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Methods |
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Study Population
We performed a nested-case control study among participants in the EPIC-Norfolk study.13,14 Briefly, 25 663 healthy men and women, aged between 45 and 79 years, were recruited from age–sex registers of general practices in Norfolk. The participants completed a baseline questionnaire survey between 1993 and 1997, attended a clinic visit, and were followed-up for an average of 6 years. Case ascertainment has been described previously.14 Cases were those having fatal or nonfatal CAD during follow-up. We excluded all individuals who reported a history of heart attack or stroke at the baseline visit. Controls were subjects who remained free of cardiovascular disease during follow-up. We matched 2 controls to each case by sex, age (within 5 years), and time of enrollment (within 3 months). All individuals have been flagged for death certification at the UK Office of National Statistics, with vital status ascertained for the entire cohort. In addition, participants admitted to hospital were identified using their National Health Service number by data linkage with the East Norfolk Health Authority database, which identifies all hospital contacts throughout England and Wales for Norfolk residents. The study was approved by the Norwich Health Authority Ethics Committee, and all participants provided written informed consent.
Study Measurements
Blood samples were stored at –80°C at the Department of Clinical Biochemistry, University of Cambridge. All samples were identified by number only and analyzed in random order.
Serum levels of total cholesterol, high-density lipoprotein cholesterol, and triglycerides were measured on fresh samples with the RA 1000 (Bayer Diagnostics, Basingstoke, UK), and low-density lipoprotein cholesterol levels were calculated with the Friedewald formula.15 Serum concentrations of sPLA2 were measured with a sandwich-type enzyme-linked immunosorbent assay as previously described.16 The measurement has no cross-reactivity with type I, IV, V, or type X sPLA2. The mean intra-assay variation between duplicates was 9.2% and the lower detection limit was 0.4 ng/mL. Plasma concentrations of CRP were measured with a sandwich-type enzyme-linked immunosorbent assay as previously described.17 Results were related to a standard consisting of commercially available CRP (Behringwerke AG, Marburg, Germany). The lower detection limit was 0.1 mg/L.
Serum sPLA2 activity was measured by a selective fluorometric assay14,18,19 by using fluorescent substrate 1-hexadecanoyl-2-(1-pyrenedecanoyl)-sn-glycero-3 phosphomethanol, sodium salt (Interchim, Montluçon, France), as previously described.12 One-hundred percent hydrolysis of the fluorescent substrate was measured using 0.1 U PLA2 from bee venom (Sigma Chemical Co). The hydrolysis of substrate in the absence of plasma was used as negative control and deduced from PLA2 activity. All samples were tested in duplicate and plasma activity was expressed as nmol/min per mL. The minimum detectable activity was 0.10 nmol/min per mL. It is noteworthy that recombinant Lp-PLA2 was unable to hydrolyze the fluorescent substrate. Moreover, sPLA2 activity was not affected by the addition of Pefabloc, a potent irreversible inhibitor of Lp-PLA2 (3.54±0.4 versus 3.57±0.6 with or without Peflaboc, respectively; P=0.83), indicating that our assay does not measure Lp-PLA2 activity.
Statistical Analysis
Baseline characteristics were compared between cases and controls taking into account the matching between them. Because triglycerides, CRP, sPLA2 type IIA levels, and sPLA2 activity had a skewed distribution, values were log-transformed before being used as continuous variables; however, in the Tables, untransformed medians and corresponding interquartile ranges are shown. To determine relationships between plasma sPLA2 activity and cardiovascular risk factors, we calculated mean risk factor levels per sPLA2 activity quartile. Quartiles were based on the distribution in the controls. In addition, Pearson correlation coefficients were calculated to assess the relationship between sPLA2 activity as a continuous variable and other continuous biomarkers of risk. Sex-specific quartiles were used for sex-specific analyses and quartiles based on the sexes combined for pooled analyses.
Odds ratios (ORs) and corresponding 95% confidence intervals (CIs), as an estimate of the relative risk of incident CAD, were calculated using conditional logistic regression analysis. The lowest sPLA2 activity quartile was used as reference category. Adjustments were performed with body mass index, diabetes, systolic blood pressure, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and smoking (never, previous, current). ORs were also calculated after additional adjustment for plasma levels of CRP and sPLA2 type IIA concentration. The trend across the quartiles of sPLA2 activity and CRP was tested by entering a single ordinal term for the quartile in the logistic regression model. The deviation from linearity was tested by comparing models containing quartile indicators with those containing a linear term in a likelihood-ratio test with 2 degrees of freedom (df). We also tested the additional prognostic contribution of quartiles of sPLA2 activity to models containing the other variables with a likelihood ratio test. To assess whether sPLA2 activity levels had predictive value on top of the Framingham risk score, we calculated ORs for future CAD per sPLA2 activity quartile, simultaneously adjusting for the Framingham risk score20 as a continuous variable.
Statistical analyses were performed using SPSS software (version 12.0.1; Chicago, Ill). P<0.05 was considered significant.
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Results |
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Baseline Characteristics
The baseline characteristics of cases and controls are shown in Table 1. In both men and women, the patients in whom CAD developed were more likely to have a previous history of diabetes, hypertension, smoking, and dyslipidemia than those who remained free of event. Higher blood pressure, low-density lipoprotein cholesterol levels, CRP levels, sPLA2 activity, and lower high-density lipoprotein cholesterol levels were observed in cases than in controls. sPLA2 activity was significantly associated with traditional cardiovascular risk factors, with the exception of diabetes (Table 2). The results were similar for men and women when analyzed separately.
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sPLA2 Activity and Risk of Incident CAD
In the multivariate model, diabetes, smoking status, systolic blood pressure, low-density lipoprotein cholesterol, CRP, sPLA2 type IIA concentration, and sPLA2 activity were independent predictors of incident CAD, whereas high-density lipoprotein cholesterol was associated with a reduced risk of CAD. The OR of incident CAD associated with an increase of 1 nmol/min per mL of sPLA2 activity was 1.10 (1.02 to 1.18; P=0.01). An increase of 1 ng/m1 of sPLA2 type IIA concentration was associated with an OR of 1.02 (1.01 to 1.03; P=0.003) for CAD risk similar to the risk with an increase of 1 mg/L of CRP (1.01 to 1.03; P=0.02).
Table 3 presents adjusted ORs of incident CAD according to increasing quartiles of baseline sPLA2 activity or CRP. After adjustment for all traditional risk factors, CRP and sPLA2 type IIA concentration, the ORs of incident CAD in the second, third, and fourth quartiles of sPLA2 activity were 1.41, 1.33, and 1.56 (P=0.003), compared with the lowest quartile. Similar effects were observed in men or women when analyzed separately. The corresponding ORs associated with increasing quartiles of CRP, adjusted for traditional risk factors, sPLA2 type IIA concentration, and sPLA2 activity were 0.93, 1.19, and 1.43 (P=0.001). Increasing quartiles of sPLA2 type IIA concentration were associated with a modest increase in the risk of incident CAD after adjustment for traditional risk factor, CRP, and sPLA2 activity (1.02, 1.12, and 1.29; P=0.04).
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Comparison of Predictive Models Based on sPLA2 Type IIA Concentration or on sPLA2 Activity
sPLA2 activity showed weak correlation with sPLA2 type IIA concentration (r=0.20), reinforcing that measurement of sPLA2 activity encompasses several types of sPLA2. Moreover, the predictive model based on sPLA2 activity adjusted for classical cardiovascular risk factors and CRP had a better discrimination than a predictive model based on sPLA2 type IIA concentration, adjusted for the same variables. The likelihood ratio 
2 statistic was higher for the model based on sPLA2 activity than the model based on sPLA2 type IIA concentration (236.3, P=0.0002 versus 229, P=0.007, respectively; both with df=11). In addition, in likelihood ratio tests of the contribution of each variable, the addition of sPLA2 activity to the model based on sPLA2 type IIA concentration was stronger (2=12.89, df=1; P<0.01) than the addition of sPLA2 type IIA concentration to the model based on sPLA2 activity (2=7.93, df=1; P<0.02).
sPLA2 Activity and the Framingham Risk Score
sPLA2 activity levels had predictive value on top of the Framingham risk score. After adjustment for components of the Framingham risk score, increasing quartiles of sPLA2 activity remained associated with the risk of future CAD (1.0, chosen as reference; 1.4 [1.1 to 1.8]; 1.3 [1.0 to 1.7]; and 1.6 [1.3 to 2.1]; P=0.001). The corresponding ORs for increasing quartiles of CRP were 1.0 (chosen as reference), 1.0 (0.8 to 1.3), 1.3 (1.0 to 1.6), and 1.8 (1.4 to 2.3; P<0.001).
Combined Measurement of sPLA2 Activity and CRP Levels and Risk of Incident CAD
sPLA2 activity and CRP levels were poorly correlated (r=0.15), suggesting that each biomarker identifies different high-risk groups. The ability of the model based on sPLA2 activity to discriminate events from nonevents was similar to that of the model based on CRP levels (likelihood ratio 2 statistic was 220 and 225, with df=10, for the model based on sPLA2 activity and CRP, respectively).
The addition of sPLA2 activity, but not sPLA2 type IIA concentration, to the model based on CRP significantly increased the ability of the model to predict the occurrence of incident CAD (2=14.4, 1 df; P<0.001). Increasing quartiles of sPLA2 activity remained associated with the risk of future CAD in subjects with low CRP levels (<0.70 mg/L; Table 4) who were otherwise considered at low risk for CAD, but also in those with the highest CRP levels (
3.10 mg/L; Table 4). In contrast, increasing quartiles of sPLA2 type IIA concentration were not associated with a further increase in the risk of CAD in people with high CRP levels (Table 5). Subjects in the highest quartiles of sPLA2 activity (4.95 nmol/min per mL) and CRP (3.10 mg/L; n=309) had an adjusted OR of 2.89 (95% CI, 1.78 to 4.68; P<0.001), as compared with those in the lowest quartiles of both markers (n=176; Table 4).
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Discussion |
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Our results suggest that a single measurement of sPLA2 activity that encompasses several types of sPLA2, including type IIA, V, and X, is useful and provides little additive value for assessing the risk of future CAD in apparently healthy men and women, regardless of traditional risk factors and CRP. Furthermore, the combined measurement of sPLA2 activity and CRP allows a better assessment of the risk of incident CAD than either biomarker alone. Measurement of sPLA2 type II concentration had little added prognostic utility.
The phospholipase A2 family includes >19 intracellular and secreted enzymes that catalyze the hydrolysis of the sn-2 ester bond of glycerophospholipids.6 Among them, the calcium-dependent sPLA2 and the serine-dependent, calcium-independent enzyme, lipoprotein-associated (Lp)-PLA2, originally named platelet activating factor acetyl hydrolase, have been more investigated. Levels of Lp-PLA2 are either downregulated or upregulated after inflammatory stimuli.21,22 Increased levels of Lp-PLA2 have been associated with cardiovascular risk.23–25 However, 2 major studies have shown that the association of Lp-PLA2 with CAD was not significant after adjustment for low-density lipoprotein cholesterol, the main carrier of Lp-PLA2 in humans.26,27
Several experimental and clinical studies suggest a pro-atherogenic role for sPLA2. sPLA2 type II A is synthesized by smooth muscle cells in the normal arterial wall,7,28 and its expression is upregulated by inflammatory stimuli.29–32 sPLA2 type II A is also expressed in atherosclerotic lesions by vascular and inflammatory cells.28,33 It hydrolyzes phospholipids and generates free fatty acids and lysophospholipids, leading to the production of high concentrations of pro-inflammatory compounds in the milieu of the artery wall.6,20 sPLA2 type IIA leads to the generation of platelet activating factor, a potent cell activator and a proatherogenic factor.22 In addition, arachidonic acid release would generate eicosanoids and leukotrienes, potentially involved in atherogenesis.34 Clinical studies have shown increased plasma levels of sPLA2 type IIA concentration in patients with cardiovascular disease or in healthy individuals at risk of CAD.9,35,36 Other types of sPLA2 are suggested to play significant role in atherogenesis.37 Both sPLA2 –V38 and sPLA2-X39 are expressed in atherosclerotic lesions. sPLA2-V, but not type IIA, is active on lipoproteins in human serum and is induced in response to a Western diet in an experimental mouse model.38 Moreover, human sPLA2-X has the highest catalytic activity toward phosphatidylcholine, one of the major phospholipids species of cell membranes and low-density lipoprotein. These data suggest distinct roles for the various types of sPLA2 in the process of atherosclerosis.
Thus, we believe that sPLA2 activity, which encompasses several types of sPLA2 including type IIA, V, and X, may better-reflect the causative role of sPLA2s in the process of atherogenesis6,8 than either sPLA2 type alone. In the present study, sPLA2 activity in healthy individuals was a better predictor of future CAD than sPLA2 type IIA concentration. Moreover, high levels of sPLA2 activity were independently associated with increased risk of future CAD, similar to the risk associated with high levels of CRP. These results, as well as those in patients with acute coronary syndrome,12 strongly suggest the need for direct measurement of sPLA2 activity to better-account for the role of these enzymes in atherosclerosis.
CRP was poorly correlated with sPLA2 activity suggesting that the 2 biomarkers reflect distinct pathophysiological pathways. sPLA2 activity provided an additive value to the predictive model based on CRP. People in the highest quartiles of CRP and sPLA2 activity were those at the highest risk for future CAD. Therefore, screening for both markers may be more useful in identifying subgroups at high risk for clinical CAD than each marker alone. Further studies are needed, however, before these results can be translated into routine clinical practice.
The present study has strengths and limitations. Coronary events were identified by using hospital admission and mortality records. Exclusion of milder events without hospital admission may have underestimated absolute event rates. Moreover, a single measurement of sPLA2 activity at baseline does not rule out the possibility of variation of this activity over time. However, random measurement errors in both case ascertainment and exposure assessment would underestimate any relationship between sPLA2 activity and CAD risk, and therefore do not negate our findings. Strengths of the present study include the large number of participants followed-up and coronary events, the long length of follow-up (6 years), and its completeness for events.
In conclusion, a single measurement of sPLA2 activity provides additive value to traditional risk factors and CRP in predicting incident CAD.
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Acknowledgments |
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The authors are indebted to A. Rousseau of URC-EST, AP-HP for her help. The authors thank participants and general practitioners and the staff of EPIC-Norfolk cohort.
Sources of Funding
A.T. and Z.M. have received a Contrat d’Interface from AP-HP. T.S. was supported by LEEM-Recherche, Paris, France.
This study was supported by a grant from Assistance Publique-Hôpitaux de Paris (AP-HP, CIRC 2005) and by unrestricted grants from Astra-Zeneca and Sankyo Pharma. EPIC-Norfolk is supported by grant funding from Cancer Research UK and Medical Research Council, with additional support from the Stroke Association, British Heart Foundation, and Department of Health. Z.M. and A.T. are partners of the European Vascular Genomics Network (contract no. LSHM-CT-2003 503254).
Disclosure
Z.M., J.B., and A.T. are listed as coinventors on a patent filed by Inserm relating to "Cardiovascular prognostic and diagnostic marker."
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Footnotes |
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T.S. and J.B contributed equally to this work.
Original received November 29, 2006; final version accepted February 6, 2007.
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