Prognostic Utility of Lipoprotein-Associated Phospholipase A2 for Cardiovascular Outcomes in Patients With Stable Coronary Artery Disease
Objective— To determine the prognostic utility of lipoprotein-associated phospholipase A2 (Lp-PLA2) for specific adverse cardiovascular outcomes in patients with stable coronary artery disease (CAD), independent of traditional risk factors and high-sensitivity C-reactive protein (hs-CRP).
Methods and Results— We measured Lp-PLA2 in 3766 patients with stable CAD from the PEACE trial. Patients were followed for a median of 4.8 years for adverse cardiovascular events including death, myocardial infarction (MI), coronary revascularization, hospitalization for unstable angina (UA), and stroke. Multivariable Cox regression was used to adjust for traditional cardiovascular risk factors and to conduct multimarker analyses that included hs-CRP. After adjustment for baseline characteristics, patients in higher quartiles of Lp-PLA2 remained at significantly greater risk for the composite of cardiovascular death, MI, coronary revascularization, UA, or stroke (P<0.001 for trend, adj HR 1.41, 95% CI 1.17 to 1.70, for patients in 4th versus 1st quartile). The association was consistent regardless of a patient’s sex, cholesterol levels, or use of lipid-lowering therapy. When analyzed together, both hs-CRP and Lp-PLA2 were highly significant predictors of acute coronary syndromes (cardiovascular death, MI, or UA) (P for trend <0.001 for hs-CRP and 0.005 for Lp-PLA2), whereas only Lp-PLA2 was a significant predictor of coronary revascularization (P=0.01 for trend).
Conclusions— In stable CAD, an elevated level of Lp-PLA2 was a significant predictor of nonfatal adverse cardiovascular outcomes independent of traditional clinical risk factors and hs-CRP. Further investigation will be needed to establish whether therapies that lower Lp-PLA2 reduce cardiovascular risk.
Oxidatively modified lipoproteins are taken up by macrophages, thereby contributing to the genesis of foam cells, and can induce the expression of adhesion molecules, chemokines, and proinflammatory cytokines.1 Lipoprotein- associated phospholipase A2 (Lp-PLA2) is an enzyme that hydrolyzes oxidized phospholipids to generate bioactive proatherogenic lipids.2 Testing for circulating Lp-PLA2 levels is now available for routine clinical use, and is approved by the FDA as an aid in predicting risk of coronary heart disease and ischemic stroke. However, prior studies examining the prognostic utility of Lp-PLA2 have yielded conflicting results,3–7 and possible heterogeneity depending on the patient’s sex,3,4 cholesterol levels,5 and concomitant use of lipid-lowering therapy.3,8 Moreover, almost all of these studies were conducted in healthy individuals, with limited data available in individuals with established stable coronary artery disease (CAD)9–11 and limited data on the association with specific cardiovascular outcomes rather than just a composite end point.
We therefore investigated the prognostic utility of Lp-PLA2 for adverse cardiovascular events in 3766 patients with stable CAD. In particular, we ascertained the association with specific adverse cardiovascular outcomes, determined whether the associations were independent of traditional cardiovascular risk factors, assessed for effect modification by relevant baseline characteristics, and examined the relative prognostic strength of Lp-PLA2 in comparison to an established biomarker of inflammation, high-sensitivity C-reactive protein (hs-CRP).
Subjects consisted of 3766 patients with documented stable CAD who were enrolled in the PEACE trial, the design and main outcomes of which have been published.12 In brief, 8290 patients with documented stable CAD and preserved left ventricular systolic function were assigned at random to trandolapril or placebo. Median follow-up was 4.8 years. Cardiovascular death, myocardial infarction (MI), and stroke were adjudicated in a blinded fashion by an independent morbidity and mortality review committee using medical records. Coronary revascularization and hospitalization for unstable angina (UA) were classified by centrally-trained local adjudicators and confirmed by outcomes staff at the coordinating center. Both the parent clinical trial and this substudy were approved by the relevant institutional review boards, and informed consent was obtained from all patients.
As part of the study protocol, a sample of venous blood was obtained in EDTA-treated tubes at the time of enrollment in 3778 subjects. The plasma component was frozen and shipped to a central laboratory where samples were stored at −70°C or colder until thawed for determination of biomarkers. Lp-PLA2 mass measurements were performed using the PLAC Test at diaDexus Inc.13 The assay range is 1 to 1000 ng/mL, and the median value in healthy adults is 235 ng/mL.14 Twenty percent of the samples were assayed in duplicate; variation was <10% in 97% of the samples, and 11% to 15% in the remainder. Hs-CRP was measured at the TIMI Biomarker Laboratory using the CRP-Latex (II) immunoturbidimetric assay (Denka Seiken). This assay has a minimal detectable concentration of 0.03 mg/L, and a total imprecision of 5.1% and 2.5% at concentrations of 0.2 mg/L and 1.9 mg/L, respectively.15 All testing was performed by personnel blinded to clinical outcomes and treatment allocation.
Patients were divided into quartiles on the basis of the baseline Lp-PLA2 levels. In terms of baseline characteristics, differences between continuous variables were assessed using ANOVA and between categorical variables using chi-square tests. Cumulative event rate curves for each Lp-PLA2 quartile were calculated using the Kaplan-Meier method. Cox proportional hazards models were used to calculate hazard ratios adjusted only for randomized treatment arm and then also for age, sex, race, body mass index (BMI), history of hypertension or measured hypertension, history of diabetes, current smoking, total cholesterol, estimated glomerular filtration rate (GFR) using the abbreviated Modification of Diet in Renal Disease Study Group equation, prior MI, prior coronary revascularization, current β-blocker use, and current lipid-lowering therapy. Effect modification by baseline characteristics (sex, above or below median cholesterol level), use of lipid-lowering therapy, and randomized treatment arm was tested using formal interaction terms (2-way interaction terms for each Lp-PLA2 quartile×potential effect modifier). The overall significance for interaction for each potential effect modifier was tested by calculating the likelihood for models with and without the 2-way interaction terms and evaluating the likelihood ratio using a chi-square test with 3 degrees of freedom. Additional multivariable models were created in which hs-CRP (coded using the CDC/AHA recommended cut points of <1, 1 to 3, or >3 mg/L) was included.
Baseline Lp-PLA2 measurements were available in 3766 patients. There were no clinically relevant differences in the baseline characteristics of patients who did and did not participate in the biomarker study (data not shown). Per the protocol, all patients had stable CAD. Fifty-six percent of patients had a prior MI and 72% had undergone coronary revascularization (either PCI or CABG), both at a minimum of 3 months before enrollment. The median concentration of Lp-PLA2 was 222.4 ng/mL, and the 25th and 75th percentiles were 180.9 and 270.8 ng/mL, respectively.
Table 1 shows patient characteristics at enrollment by quartile of baseline Lp-PLA2 level. Higher baseline Lp-PLA2 levels were significantly associated with male sex, Caucasian race, current tobacco use, prior MI, lack of prior coronary revascularization, higher serum cholesterol level, and lack of lipid-lowering therapy (P≤0.002 for all).
Association With Cardiovascular Outcomes
There was a significant stepwise increase in the cumulative incidence of the composite of cardiovascular death, MI, coronary revascularization, hospitalization for UA, or stroke across Lp-PLA2 quartiles (Figure 1, P<0.001 for trend across quartiles), with a hazard ratio of 1.51 (95% CI 1.27 to 1.78, P<0.001) for patients in the fourth versus the first quartile. The association was also significant both for the PEACE primary end point (CV death, MI, or coronary revascularization; P<0.001) and for acute coronary syndromes (ACS; CV death, MI, or UA; P<0.001), and there was directional consistency for all of the components of the overall composite end point (Table 2), although the association with nonfatal stroke (87 events) was not statistically significant.
The association between Lp-PLA2 and the risk of the composite end point of cardiovascular death, MI, coronary revascularization, hospitalization for UA, or stroke remained significant after adjustment for baseline factors including age, sex, race, hypertension, diabetes, smoking, BMI, cholesterol, estimated GFR, prior MI, prior coronary revascularization, β-blocker use, and lipid-lowering therapy. There was a significant stepwise increase in the adjusted risk of the composite end point by quartile of baseline Lp-PLA2 (P<0.001 for trend), although the magnitude of the association was somewhat lessened with an adjusted hazard ratio of 1.41 (95% CI 1.17 to 1.70, P<0.001) for patients in the fourth versus the first quartile of Lp-PLA2 levels (Table 3). The association also remained significant for the PEACE primary end point (P=0.005 for trend) and for ACS (P=0.002 for trend). Analyses using sex and race specific quartiles produced virtually identical results (data not shown).
With regard to the individual elements of the composite end point, Lp-PLA2 levels remained significantly associated with the likelihood of coronary revascularization (P=0.01 for trend) and of hospitalization for UA (P<0.001 for trend), and effect estimates were largely unaffected by multivariable adjustment. In contrast, after adjusting for the aforementioned covariates the association with nonfatal MI was partially attenuated (adj HR 1.36, 95% CI 0.88 to 2.11, for fourth quartile versus first quartile) and the association with cardiovascular death was rendered null (adj HR 0.88, 95% CI 0.51 to 1.53), albeit with wide confidence intervals. As was the case with coronary revascularization and UA, the association between Lp-PLA2 and nonfatal stroke was largely unaffected by multivariable adjustment.
Stratified Analyses and Effect Modification
Based on prior studies,3–5,8 we explored several potential interactions between baseline characteristics, Lp-PLA2 levels, and adverse cardiovascular events (Figure 2). The magnitude of the association between Lp-PLA2 and the composite end point were numerically greater in women than in men, and in those randomized to trandolapril than in those randomized to placebo, but there were no statistically significant interactions. Similarly, there was no evidence for effect modification based on cholesterol levels or lipid-lowering therapy use.
Lp-PLA2 and hs-CRP
We examined the simultaneous predictive ability of Lp-PLA2 and an established biomarker of inflammation, hs-CRP, by including both in Cox proportional hazards models. Measurements of both biomarkers were available in 3763 patients. The correlation between Lp-PLA2 and CRP was low (r=0.11, P<0.001). In multivariable models that adjusted for the previously listed clinical and laboratory covariates and included both inflammatory biomarkers (Figure 3), both biomarkers were highly significant predictors of ACS (P<0.001 for trend for CRP, P=0.005 for trend for Lp-PLA2). As noted above, though, for Lp-PLA2 the association was driven exclusively by non-fatal ACS, whereas hs-CRP demonstrated directional consistency for fatal (P=0.15) and nonfatal events (P=0.003 for MI, P=0.01 for UA). In contrast, Lp-PLA2 was a significant predictor of coronary revascularization (P=0.01 for trend) whereas hs-CRP was not (P=0.91).
In a large cohort of patients with stable CAD, we found that an elevated level of Lp-PLA2 was a significant independent predictor of the risk of subsequent adverse cardiovascular events. In terms of individual end points, whereas the associations with coronary revascularization, hospitalization for UA, and nonfatal stroke remained largely unaffected by multivariable adjustment, the association with nonfatal MI was attenuated and the association with cardiovascular death was rendered null. The association with Lp-PLA2 and cardiovascular events was consistent regardless of a patient’s sex, cholesterol levels, or use of lipid-lowering therapy. In a simultaneous multimarker approach, both hs-CRP and Lp-PLA2 remained independent predictors of ACS, whereas Lp-PLA2 but not hs-CRP predicted coronary revascularization.
Lp-PLA2 is an enzyme synthesized by macrophages and other inflammatory cells that can hydrolyze oxidized phospholipids to generate lysophosphatidylcholine and oxidatively-modified nonesterified fatty acids.16 Both bioactive lipids are proatherogenic, contributing to monocyte recruitment and macrophage proliferation, smooth muscle proliferation, increased expression of endothelial adhesion molecules, and endothelial cell dysfunction.17 For these reasons, Lp-PLA2 has been postulated to contribute directly to atherosclerosis. To that end, a recent study has demonstrated local production of Lp-PLA2 in coronary arteries that was correlated with the extent of atheroma.18 Furthermore, another study showed that Lp-PLA2 was more strongly expressed in vulnerable and ruptured plaques than in less advanced lesions.19
Prior studies examining the association between Lp-PLA2 levels and clinical events have been conducted primarily in healthy individuals without documented CAD and have generated mixed results. An early, seminal observation came from Packard and colleagues who reported an association between Lp-PLA2 levels and adverse cardiovascular outcomes in WOSCOPS,3 an exclusively male cohort with hyperlipidemia. In contrast, though, in the Women’s Health Study, Lp-PLA2 was not an independent predictor of cardiovascular events after adjustment for traditional cardiovascular risk factors.4 In a nested case-control study from ARIC, an independent association between Lp-PLA2 levels and cardiovascular outcomes was only seen in patients with lower cholesterol levels.5 In 2 other studies of patients at risk for CAD, Lp-PLA2 was associated with cardiovascular events, but this association was partially attenuated after adjustment for baseline characteristics.6,7
With regard to studies in patients with established CAD, Brilakis found Lp-PLA2 levels were associated with subsequent coronary events, but this observation was made in a cohort of patients undergoing angiography, one third of whom had ACS.9 This heterogeneity in the patient population potentially complicates interpretation as patients with ACS have a worse prognosis than those with stable CAD undergoing elective angiography and have higher Lp-PLA2 levels than those with stable CAD.20 Both Corsetti and Koenig have also reported an association between Lp-PLA2 levels and cardiovascular events, although their cohorts also included patients with recent ACS.10,11 In all 3 studies, the association persisted after adjustment for baseline characteristics, but because of the relatively small size of the studies (approximately 1000 or fewer subjects in each), there were relatively few cardiovascular events and thus analysis of the association between Lp-PLA2 and specific events was not possible. We have recently shown that Lp-PLA2 levels measured very early after ACS were not predictive of future cardiovascular events, an observation subsequently confirmed in 2 other ACS populations,21 whereas predictive ability did emerge when Lp-PLA2 was remeasured 30 days later.8
Our findings fill several gaps in our knowledge of the utility of Lp-PLA2 for cardiovascular risk prediction. First, we examined patients with stable CAD, a population in whom there was a paucity of prior data yet who are estimated to number over 13 million persons in the United States alone. Our analysis represents the largest published study to date in patients with stable CAD. Second, the large size of our study and in particular the large number of events during follow-up enabled us to examine the association between Lp-PLA2 and individual cardiovascular outcomes. In doing so, we found that Lp-PLA2 was not an independent predictor of cardiovascular death, but was of nonfatal events including coronary revascularization and UA, with trends for nonfatal MI and nonfatal stroke. The strong association with coronary revascularization is supported by our observations in another independent cohort.8 These findings are consistent with the hypothesized role of Lp-PLA2 as a direct causal mediator of atherosclerosis and plaque instability.22 Third, we were able to examine prospectively whether effect modification by sex, cholesterol levels, and lipid-lowering therapy, as postulated post-hoc by others,3–5,8 was present in this large dataset. We found no significant heterogeneity in the association between Lp-PLA2 levels and cardiovascular outcomes on the basis of any of these parameters.
We compared the predictive ability of Lp-PLA2 with hs-CRP, a well-established biomarker of inflammation. We found that after multivariable adjustment and simultaneous assessment of both biomarkers, both an elevated hs-CRP level and an elevated Lp-PLA2 were independent predictors of ACS, although for Lp-PLA2 the association was driven by nonfatal ACS, whereas hs-CRP demonstrated directional consistency for fatal and nonfatal events. In contrast, Lp-PLA2 was a significant predictor of coronary revascularization whereas CRP was not. These observations may reflect differences in the pathobiology represented by the 2 biomarkers. Lp-PLA2 is an enzyme that generates bioactive lipids that can contribute directly to atherogenesis and endothelial dysfunction and hence the need for coronary revascularization as well as ACS. In contrast, CRP is an acute phase reactant that not only may be a biomarker for a proinflammatory milieu, but may also be a direct risk factor for MI.23
Potential limitations of the study merit consideration. The study population was derived from a clinical trial, not a population cohort. As the PEACE trial excluded patients with heart failure, a left-ventricular ejection fraction ≤40%, or a serum creatinine >2.0 mg/dL, we cannot comment on the utility of Lp-PLA2 in patients with those characteristics. In general, however, the characteristics of patients in this study are typical of patients with stable CAD. Blood samples were obtained from only a subgroup of the participants in the overall PEACE trial. However, there were no clinically relevant differences between patients who did and did not participate in the biomarker substudy. Fasting blood samples were not mandated and this prevented us from measuring fasting lipoprotein levels including LDL and HDL, adjustments for which might have led to further attenuation of some of the observed associations. However, most studies have shown the correlation coefficients between total cholesterol and Lp-PLA2 and between LDL cholesterol and Lp-PLA2 to be similar (within 0.07),3,9,11,20,24–26 the correlation between HDL cholesterol and Lp-PLA2 to be modest, and the addition of HDL cholesterol to models to not materially change the effect estimate for Lp-PLA2.3,6,9,11 We found a monotonic relationship between increasing Lp-PLA2 quartiles and increasing risk of adverse cardiovascular outcomes. Further studies in additional cohorts would be helpful in minimizing any potential bias and in validating a similar risk relationship. Although there were large numbers of coronary revascularizations and hospitalizations for unstable angina in our cohort (>500 of each), there were fewer cardiovascular deaths and strokes (≈100 of each). Thus the confidence intervals surrounding the point estimates for the associations of Lp-PLA2 levels with these events were wider. Therefore, additional studies in independent cohorts will be important to validate our findings. Furthermore, a meta-analysis would help determine the magnitude of the associations with greater precision and clarify whether there is any heterogeneity with regard to the relation between Lp-PLA2 levels and different types of cardiovascular events.
In conclusion, we found that in stable CAD, an elevated level of Lp-PLA2 is a significant predictor of adverse cardiovascular outcomes, especially coronary revascularization and unstable angina. These associations were independent of traditional clinical risk factors and hs-CRP. To that end, Lp-PLA2 and hs-CRP appear to offer complementary information by predicting different cardiovascular outcomes. Whether a clinician should routinely measure Lp-PLA2 levels in patients with stable CAD will hinge on whether such a practice can be shown to improve clinical management. To that end, as Lp-PLA2 may not only be a risk marker, but also an actual risk factor given its putative direct role in atherogenesis, further investigation will be needed to determine whether using specific pharmacotherapies to lower Lp-PLA2 levels will reduce cardiovascular risk.
The authors gratefully acknowledge the efforts of the PEACE investigators, research coordinators, and committee members. A list of these individuals has been previously published (N Engl J Med 2004;351:2058–2068) and can be found at http://www.bsc.gwu.edu/peace/.
Sources of Funding
The PEACE trial was supported by a contract from the National Heart, Lung, and Blood Institute (N01HC65149) and by Knoll Pharmaceuticals and Abbott Laboratories, which also provided the study medication. Measurement of Lp-PLA2 was performed by diaDexus Inc. Drs Sabatine, Morrow, and O’Donoghue are supported in part by NIH grant U01 HL083-1341. Drs Jablonski and Rice are supported in part by NIH/NHLBI grant N01 HC065149 and a supplement from Knoll Pharmaceuticals and Abbott Laboratories.
Dr Sabatine reports having received research grants from diaDexus, Roche, Schering-Plough and honoraria from diaDexus. Dr Morrow reports having received research grants from Bayer, Beckman-Coulter, Biosite, GlaxoSmithKline, Ortho-Clinical Diagnostics, & Roche; having received honoraria from Bayer, Beckman-Coulter, Dade-Behring, Roche; and having served on advisory boards for Critical Diagnostics, GlaxoSmithKline, Beckman-Coulter, Ortho-Clinical Diagnostics. Dr O’Donoghue reports having received honoraria from GlaxoSmithKline. Drs Jablonski & Rice report having received research grants from Abbott Laboratories.
Original received May 17, 2007; final version accepted August 21, 2007.
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