Journal of Clinical Endocrinology & Metabolism
, doi:10.1210/jc.2004-2027
The Journal of Clinical Endocrinology & Metabolism Vol. 90, No. 5 3100-3105
Copyright © 2005 by The Endocrine Society
Lipoprotein-Associated Phospholipase A2, a Novel Inflammatory Biomarker and Independent Risk Predictor for Cardiovascular Disease
Krishnankutty Sudhir
Cardiovascular Core Analysis Laboratory, Stanford University Medical Center, Stanford, California 94305
Address all correspondence and requests for reprints to: Dr. Krishnankutty Sudhir, Room H3554, Cardiovascular Core Analysis Laboratory, Stanford University Medical Center, Stanford, California 94305-5637. E-mail: ksudhir{at}cvmed.stanford.edu.
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Abstract
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Lipoprotein-associated phospholipase A2 (Lp-PLA2) is a member of the phospholipase A2 superfamily, a family of enzymes that hydrolyze phospholipids. Circulating Lp-PLA2 is a marker of inflammation that plays a critical role in atherogenesis; its inhibition may have antiatherogenic effects. Epidemiological data have consistently demonstrated the association of increased levels of Lp-PLA2 with increased risk of coronary heart disease (CHD). In general, studies from the West of Scotland Coronary Prevention Study, Monitoring Trends and Determinants in Cardiovascular Diseases, and Rotterdam cohorts have shown that the association of Lp-PLA2 with CHD is not attenuated upon multivariate analysis with traditional risk factors and other inflammatory markers. In addition, in the Atherosclerosis Risk in Communities cohort, Lp-PLA2 was particularly useful in identifying CHD risk among patients with a baseline low-density lipoprotein less than 130 mg/dl. Studies in subjects with coronary artery disease have also shown associations between Lp-PLA2 and cardiovascular risk. Polymorphisms of the Lp-PLA2 gene have been reported, with varying significance, in Japanese and Caucasian populations. Overall, epidemiological studies suggest that measurement of Lp-PLA2 in plasma may be useful in identifying individuals at high risk for cardiac events.
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Introduction
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RECENT STUDIES HAVE demonstrated a major role for inflammation in the pathophysiology of vulnerable plaque and, consequently, of cardiovascular events. Circulating markers of inflammation have attracted considerable interest as predictors of cardiovascular risk. Lipoprotein-associated phospholipase A2 (Lp-PLA2) is a macrophage-derived enzyme that has recently been shown to be an independent predictor of coronary events. This review summarizes the epidemiological and clinical studies that have examined the role of Lp-PLA2 in cardiovascular disease and provides evidence for the potential use of this biomarker in risk prediction.
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Biology of Lp-PLA2
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Lp-PLA2 is a subtype of the phospholipase A2 superfamily, a family of enzymes that hydrolyze phospholipids. Lp-PLA2, also known as platelet activating factor acetylhydrolase (PAF-AH), is a 50-kDa Ca2+-independent phospholipase that is distinct from another macrophage product, secretory PLA2, a 14 kDa Ca2+-dependent enzyme (1). Increasing evidence suggests that Lp-PLA2 plays a critical role in the development of atherosclerosis and its clinical sequelae. Lp-PLA2 is up-regulated in atherosclerotic plaques (2) and strongly expressed in macrophages within the fibrous cap of rupture prone lesions (3); when released into circulation, Lp-PLA2 is transported in plasma predominantly (80%) associated with low-density lipoprotein (LDL) (4). The key to the role of Lp-PLA2 in atherogenesis is its hydrolysis of oxidized LDL (OxLDL), which is generated when LDL becomes oxidized in the milieu of the artery wall (5, 6, 7). The hydrolysis of OxLDL by Lp-PLA2 produces the proinflammatory, atherogenic by-products lysophosphatidylcholine (LysoPC) and oxidized fatty acids (OxFA) (6) (Fig. 1
). LysoPC plays a critical role in atherogenesis. It acts as a chemoattractant for monocytes, impairs endothelial function, causes cell death by disrupting plasma membranes, and induces apoptosis in smooth muscle cells and macrophages (6, 8, 9).
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FIG. 1. Schematic representation of Lp-PLA2, a macrophage-derived enzyme, in the vascular wall in atherosclerotic arteries. The hydrolysis of OxLDL by Lp-PLA2 in the milieu of the artery wall produces the proinflammatory, atherogenic by-products LysoPC and OxFA.
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Whereas human Lp-PLA2 is mainly associated with LDL (4), in mice, Lp-PLA2 or PAF-AH is predominantly associated with high-density lipoprotein (HDL) (10); this difference may explain the antiatherosclerotic effect of PAF-AH in mouse models. Transgenic apolipoprotein (apoE)-deficient, apoAI-overexpressing mice have increased plasma PAF-AH activity (11); adenovirus-mediated gene transfer of PAF-AH resulted in increased PAF-AH activity, decreased phospholipid oxidation, and reduced recruitment of macrophages to lesion-prone sites in the aortic root of apoE-deficient mice (11). Furthermore, in another study, adenovirus-mediated gene transfer of human PAF-AH prevented injury-induced neointima formation and reduced spontaneous atherosclerosis in apoE–deficient mice (12). These data suggested that in species such as mice, in which Lp-PLA2 or PAF-AH is predominantly associated with HDL, it may protect against atherosclerosis.
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Modulation of Lp-PLA2
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Data from preclinical studies suggest that inhibition of Lp-PLA2 could have antiatherogenic effects. The addition of an Lp-PLA2 inhibitor to cell culture systems abolished OxLDL-induced chemoattraction for monocytes and attenuated its ability to induce the apoptotic death of human monocytes (6, 9). Significant decreases in concentrations of both LysoPC and OxFA were observed (6). Additionally, the inhibition of Lp-PLA2 in Watanabe heritable hyperlipidemic rabbits led to a significant reduction in atherogenesis (5). Azetidinones, a new class of compounds being evaluated in the clinical setting for their ability to specifically inhibit the enzymatic activity of Lp-PLA2, appear to be a promising class of agents for the modification of Lp-PLA2 and the treatment of atherosclerosis. Additionally, clinical studies have demonstrated that statins and fibrates, both agents known to decrease cardiovascular events, reduce plasma Lp-PLA2 levels (13, 14, 15).
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Assessment of Lp-PLA2 Levels
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Clinical data obtained from recent epidemiological studies suggest that the determination of Lp-PLA2 levels may aid in the identification of individuals at high risk for coronary heart disease (CHD). Lp-PLA2 mass is measured by an enzyme immunoassay (the PLAC test) developed for the quantitative determination of Lp-PLA2 in human plasma (1). Results are reliable and reproducible when the assay procedure is carried out with adherence to good laboratory practice (1). In addition, Lp-PLA2 activity can also be measured in human plasma (16).
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Evidence from Clinical and Epidemiological Studies Showing Lp-PLA2 Is a Risk Predictor (Table 1)
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The West of Scotland Coronary Prevention Study (WOSCOPS)
WOSCOPS was a primary prevention trial designed to evaluate the use of pravastatin in 6595 hypercholesterolemic men who had not had a coronary event (17). In a nested case-control study that examined various predictors of risk in the WOSCOPS study population, 580 men who had suffered a cardiac event (myocardial infarction (MI), revascularization, or death from cardiac disease) were compared with 1160 age- and smoking-matched controls. A 2-fold greater risk of CHD was observed for patients in the highest quintile of Lp-PLA2 levels compared with those in the lowest quintile. In the WOSCOPS analysis, a large panel of inflammatory markers was evaluated, which included C-reactive protein (CRP), white-cell count, fibrinogen, and Lp-PLA2. Univariate analysis demonstrated that increased levels of all four inflammatory markers were associated with a significantly greater risk of heart disease (P < 0.001). Similar to Lp-PLA2, the risk of CHD was 2-fold greater in the highest quintile of CRP levels and white-cell count compared with the lowest quintile. However, on multivariate analysis, risk associated with CRP levels and white-cell counts was attenuated, only remaining significant for the highest quintile. In contrast, the association of Lp-PLA2 with risk of CHD remained significant for all quintiles (P = 0.005), demonstrating the strength of Lp-PLA2 as an independent marker of CHD. Furthermore, Lp-PLA2 was the only marker of inflammation whose levels were not affected by smoking. The results of WOSCOPS demonstrated that Lp-PLA2 is a novel risk factor that predicts risk independent of other markers of inflammation, including CRP, fibrinogen, and white-cell count, and classic risk factors, such as smoking.
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TABLE 1. Epidemiological and clinical studies showing an association between Lp-PLA2 (mass or activity) and cardiovascular events or other endpoints
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The Atherosclerosis Risk in Communities (ARIC) study
Findings from the ARIC study further support the hypothesis that Lp-PLA2 is independently associated with CHD (18). This was a prospective, case-cohort study designed to evaluate atherosclerosis over a period of 6 yr in 12,819 apparently healthy middle-aged men and women. A coronary event was reported in 608 patients. These patients were compared with 740 matched controls from the study. Mean levels of Lp-PLA2 and CRP were higher in patients who had experienced a CHD event compared with those who had not. A hazard ratio (HR) of 1.78 [95% confidence interval (CI) 1.33–2.38] for the highest tertile of Lp-PLA2 (
422 µg/liter) and 2.53 (1.88–3.40) for the highest tertile of CRP (>3.0 mg/liter) was reported. In patients with LDL levels below the median (<130 mg/dl), both Lp-PLA2 and CRP levels were significantly and independently associated with CHD, even in fully adjusted models. Those individuals with increased levels of both Lp-PLA2 and CRP were found to have the greatest risk for a CHD event [2.95 (1.47–5.94)], suggesting that these inflammatory markers are complementary in identifying high-risk individuals.
The Monitoring Trends and Determinants in Cardiovascular Diseases (MONICA)—Augsburg Cohort Study
In a Southern German study examining subjects from the MONICA population, the relationship between Lp-PLA2 levels and risk of coronary events was evaluated in 934 apparently healthy men aged 45–64 yr who were followed for 14 yr, from 1984–1998 (19). During this period, 97 men suffered a coronary event, diagnosed according to the MONICA protocol. Mean baseline levels of Lp-PLA2 were significantly higher in men who had suffered an event compared with men who had not (295 ± 113 vs. 263 ± 79 µg/liter; P = 0.01). In addition, a 1 SD increase in Lp-PLA2 mass was associated with a 37% (16–62%) increase in risk of future coronary events, and this risk remained statistically significant after controlling for potentially confounding factors [23%, (2–47%)] and CRP [21% (1–45%)]. Finally, the combination of a high Lp-PLA2 (>290.8 µg/liter) and a high CRP (>3 mg/liter) was consistently associated with a statistically significantly increased risk for future coronary events and was superior to either marker alone in predicting risk, with a HR of 1.93 (1.09–3.40) in the fully adjusted model. Thus Lp-PLA2 and CRP may be complementary in identifying high-risk subjects and therefore, the combination of both markers may further improve risk assessment.
The Rotterdam study
The Rotterdam Study was a population-based follow-up study in 7983 subjects aged 55 yr and over. Oei et al. (20) performed a case-cohort study, including 308 CHD cases and a random sample of 1822 subjects. Compared with the first quartile of Lp-PLA2 activity, multivariate-adjusted HR for CHD for the second, third, and fourth quartile were 1.38 (95% confidence interval 0.90–2.14), 1.99 (1.29–3.07), and 1.96 (1.25–3.09), respectively (P trend = 0.02). The Rotterdam study thus provides additional evidence for an association between Lp-PLA2 and CHD, independent of other risk factors.
One study failed to show an association between Lp-PLA2 levels and risk of CHD. Blake et al. (21) conducted a prospective, nested case-control study in a small number of apparently healthy middle-aged women (123 with CHD and 123 controls) to assess the risk of death from CHD, nonfatal MI, and stroke associated with baseline levels of Lp-PLA2 over a mean follow-up of 3 yr. In univariate analysis, mean levels of Lp-PLA2 were significantly higher at baseline among cases than controls. However, the predictive value of Lp-PLA2 was attenuated after adjustment for other cardiovascular risk factors. The small numbers in this study and confounding effects of hormonal therapy (Lp-PLA2 levels were lower among women using hormone replacement therapy), may explain the disparate observations in this study compared with others showing a relationship between Lp-PLA2 levels and risk of CHD.
Studies of Lp-PLA2 in patients with evidence of coronary artery disease (CAD) by angiography or computed tomography scan
Lp-PLA2 levels were evaluated by Caslake et al. (4) in a clinical study of 148 men, 48 with angiographically proven CAD, 46 who had suffered an MI at least 1 yr before the study, and 54 normal aged-matched controls. Significantly elevated levels of Lp-PLA2 were found in patients with angiographically proven CAD compared with the normal patients. A general linear multiple regression model suggested that this increase in Lp-PLA2 in patients with CAD was independent of LDL and other risk factors including smoking and systolic blood pressure.
Khuseyenova et al. (22) measured Lp-PLA2 concentrations in patients with angiographic evidence of CAD and in age- and gender-matched blood donors. Lp-PLA2 concentrations were significantly higher in cases than in controls (296.1 vs. 266.0 µg/liter, P < 0.0001). Multivariate logistic regression showed that the age and gender adjusted odds ratio (OR) for the presence of CAD was 1.61 (95% CI, 1.07–2.44) when the top quartile of the Lp-PLA2 distribution was compared with the bottom quartile. Adjustment for traditional cardiovascular risk factors and statin intake resulted in an OR of 2.04 (1.19–3.48). After additional adjustment for inflammatory and hemostatic parameters, the OR was slightly attenuated but still remained statistically significant [1.84(1.05–3.12)].
In another recent study performed at the Mayo Clinic, Brilakis et al. (23) measured Lp-PLA2 levels in patients undergoing clinically indicated coronary angiography. During a median follow-up of 4.0 yr, higher baseline Lp-PLA2 levels were associated with a greater risk of cardiovascular events: the relative risk increase per SD was 1.31 (P = 0.010), and remained significant after adjusting for clinical (age, gender, smoking, hypertension) and lipid (total and HDL cholesterol, Lp(a), and triglycerides) variables and CRP.
Finally, Iribarren and colleagues (24) examined the association between Lp-PLA2 (mass and activity), and coronary artery calcification (CAC) in young adults, in a nested case-control study using data from the year 15 examination (2000–2001) of the Coronary Artery Risk Development in Young Adults study. Lp-PLA2 mass and activity were significantly higher in cases than in controls. In age-adjusted conditional logistic regression, the relative risk increase of calcified coronary plaque per 1 SD increment was 1.40 (1.17–1.67) and 1.39 (1.14–1.70) for Lp-PLA2 mass and activity, respectively. After adjusting for multiple covariates including LDL and HDL cholesterol, triglycerides, and CRP, a statistically significant association remained for Lp-PLA2 mass (1.28; 95% CI, 1.03–1.60) but not for activity. No evidence was found for interaction between Lp-PLA2 mass or activity with LDL-C as predictors of calcified coronary plaque. Thus, Lp-PLA2 appears to be involved in early CAC, perhaps because of its direct role in atherosclerosis and its biologic association with lipoprotein particles.
These studies, in the aggregate, further support the hypothesis that Lp-PLA2 is an independent risk marker in patients with evidence of CAD. Whereas Lp-PLA2 predicts cardiovascular outcomes in patients with angiographic evidence of CAD, a more complex relationship may exist with CAC.
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Lp-PLA2 Activity in Acute Coronary Syndrome (ACS) and Stable Angina
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In addition to the finding of an association between Lp-PLA2 levels and risk of CHD, an association between Lp-PLA2 (PAF-AH) activity and risk of CHD has also been reported. Blankenberg et al. (25) measured Lp-PLA2 activity in the plasma of 496 men and women with CAD (220 with ACS and 276 with stable angina pectoris and 477 controls). Lp-PLA2 activity was increased in both men and women with ACS and stable angina compared with controls, with the greatest difference between controls and patients with ACS. Additionally, Lp-PLA2 levels were diminished in patients with hypertension or being treated with angiotensin converting enzyme-inhibitor therapy. Patients within the highest quartile of Lp-PLA2 activity had a statistically significant 1.8-fold increase in CAD risk (1.01 to 3.2; P = 0.048) compared with those in the lowest quartile after adjustment for clinical and metabolic factors. When individuals receiving statins or angiotensin converting enzyme inhibitor medication were excluded, patients within the highest quartile of Lp-PLA2 activity had a 3.9-fold (2.0–7.7; P < 0.0001) increase in CAD risk. No correlation was found between Lp-PLA2 activity and levels of common markers of inflammation.
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Lp-PLA2 as a Risk Predictor for Stroke
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Measurement of inflammatory markers such as CRP has been reported to identify individuals at increased risk for stroke (26); recently, the predictive value of Lp-PLA2 in stroke prediction was also explored. In a further analysis from the ARIC study, the relation between Lp-PLA2, CRP, traditional risk factors, and stroke over 6 yr was examined (27). Mean Lp-PLA2 and CRP levels were higher in the 223 cases (422 µg/liter and 3.75 mg/liter) than the 766 noncases (372 µg/liter and 3.04 mg/liter). Both Lp-PLA2 and CRP were associated with stroke after adjustment for age, sex, and race with a HR of 2.16 for the highest vs. the lowest tertile of Lp-PLA2 and 2.64 for CRP. In a model with all traditional risk factors, LDL and HDL, Lp-PLA2 levels in the highest tertile were associated with an HR of 1.97 (1.22–3.20, P = 0.01) and CRP levels more than 3 mg/liter with an HR of 1.91 (1.19–3.07, P < 0.01). In a model including CRP and Lp-PLA2 with traditional risk factors plus body mass index, triglycerides, and antihypertensive medication, the highest tertile of Lp-PLA2 had an HR of 2.04 (1.23–3.38, P < 0.01). Individuals with high levels of both CRP and Lp-PLA2 were at the highest risk (>8-fold) after adjusting for traditional risk factors compared with individuals with low levels of both, whereas others were at intermediate risk. Thus, both Lp-PLA2 and CRP may be complementary beyond traditional risk factors in identifying middle-aged individuals at increased risk for stroke. Recently, Oei et al. (20) compared 110 ischemic stroke cases with a random sample of 1822 subjects in a case-cohort analysis in the Rotterdam study, and also reported a significant association between Lp-PLA2 activity and ischemic stroke.
Of note, lipid profiles have weak and inconsistent associations with ischemic stroke (28); yet statins have been shown to lower the incidence of stroke even among individuals who do not have high cholesterol concentrations (29). Statins are known to lower levels of Lp-PLA2 (13, 15) and other proinflammatory markers including CRP (30); it is possible that inflammation plays a role in the etiology of stroke, reflected at least in some patients by elevated levels of inflammatory biomarkers. Furthermore, it is possible that the antiinflammatory properties of statins are crucial in their beneficial effects on stroke reduction.
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Lp-PLA2 in Diabetic Subjects
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Data on Lp-PLA2 in subjects with diabetes is limited. In a recent study in patients with type 2 diabetes (31), increasing Lp-PLA2 (PAF-AH) activity was significantly associated with a positive history of CAD, the OR estimate adjusted for age, gender, and body mass index of the highest quartile being 10.6 (P = 0.036). Lp-PLA2 activity was associated with the apolipoprotein B (apoB) content in dense LDL (LDL-5 and LDL-6) and with non-HDL cholesterol at baseline. However, after additional adjustment for apoB in dense LDL and non-HDL cholesterol, the OR increment for CAD across Lp-PLA2 quartiles was 2.09 (95% confidence interval, 1.02–4.29; P = 0.043). Additionally, in this group of patients, 8 wk of therapy with fluvastatin decreased Lp-PLA2 activity by about 23%. Whereas this study shows that Lp-PLA2 measurement may be useful in predicting CAD in diabetic subjects, further studies are needed to confirm this association.
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Genetic Polymorphisms
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The gene for Lp-PLA2 (PLA2G7) lies on chromosome 6p21-p12. Yamada et al. reported that the frequency of a Japanese PLA2G7 loss-of-function variant, V279F, was significantly higher in individuals who had suffered a myocardial infarct or a stroke (32), and more common in patients with occlusive atheroma than controls (33), suggesting a predominantly antiatherogenic role for Lp-PLA2. This variant has not been found in Caucasian populations (34); hence, the utility of Lp-PLA2 as a biomarker for risk prediction in Asian populations has been questioned. However, a second Caucasian variant, A379V, is also functional and results in a 2-fold decrease in the affinity of Lp-PLA2 for its substrate PAF, resulting in reduced degradation of PAF (34). This change in function is believed to underlie the association of the A379V variant allele with atopy in German and asthma in British populations (33). Clinical features associated with both the V279F and A379V variants suggest a predominantly antiinflammatory role for Lp-PLA2 which is compromised in the presence of either variant.
More recent studies have yielded conflicting results. Abuzeid et al. (35) investigated the association of the activity-reducing A379V variant with risk of MI in a large European case-control study, which compared 527 post-MI men with 566 age-matched controls from north and south Europe. Overall, the frequency of the V379 allele was 0.24 (95% CI 0.21–0.26). Homozygosity for the V379 allele was associated with lower risk of MI, (OR 0.56, 95% CI 0.32–0.98), maintained after adjustment for lifestyle factors and levels of inflammatory risk factors (CRP, fibrinogen, IL-6) (OR 0.46, 0.22–0.93). There was no evidence of heterogeneity of effect between the centers in the north and south of Europe. Because homozygosity for V379 occurs in only 5–6% of subjects, this genotype is not a major determinant of population genetic risk of CHD, but the association of this genotype with low levels of Lp-PLA2 in this study, strongly support the proinflammatory causative, and not consequential, role of Lp-PLA2 in CHD.
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Conclusions
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Lp-PLA2 is a marker of inflammation that plays a critical role in the development of atherosclerosis. Inhibition of Lp-PLA2 may have antiatherogenic effects. Clinical data have consistently demonstrated the association of increased levels of Lp-PLA2 with increased risk of CHD. In general, studies from the WOSCOPS and MONICA cohorts have shown that the association of Lp-PLA2 with CHD is not attenuated upon multivariate analysis with other inflammatory markers and traditional risk factors. Furthermore, in the ARIC cohort, Lp-PLA2 was particularly useful in identifying CHD risk among patients with a baseline LDL less than 130 mg/dl. Additionally, studies in patients with angiographic evidence of CAD, and subjects with type 2 diabetes, have also shown associations between Lp-PLA2 levels and cardiovascular risk. The clinical significance of various polymorphisms of the Lp-PLA2 gene requires further investigation. Measurement of Lp-PLA2 in plasma may be a valuable addition to the panel of tests used to identify individuals at high risk for cardiac events.
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Acknowledgments
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I thank Bob Wolfert, Ph.D., Vice-President, Diagnostics, at diaDiadexus, Inc., for reviewing the manuscript and providing helpful comments. I also acknowledge the outstanding work of all the investigators, including several colleagues and friends, whose contributions are quoted and referenced in this review.
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Footnotes
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STATEMENT OF CONFLICT OF INTEREST: Dr. Sudhir was previously Vice-President, Medical Affairs, at diaDexus, Inc., the company that manufactures the PLAC test, the commercially available assay for Lp-PLA2 mass.
First Published Online February 15, 2005
Abbreviations: ACS, Acute coronary syndrome; apoE, apolipoprotein E; CAC, coronary artery calcification; CAD, coronary artery disease; CHD, coronary heart disease; CI, confidence interval; CRP, C-reactive protein; HDL, high-density lipoprotein; HR, hazard ratio; LDL, low-density lipoprotein; Lp-PLA2, lipoprotein-associated phospholipase A2; LysoPC, lysophosphatidylcholine; MI, myocardial infarction; OR, odds ratio; OxFA, oxidized fatty acid; OxLDL, oxidized LDL; PAF-AH, platelet activating factor acetylhydrolase; WOSCOPS, West of Scotland Coronary Prevention Study.
Received October 14, 2004.
Accepted February 3, 2005.
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Abstract
Introduction
