| | Review of the Evidence for the Clinical Utility of Lipoprotein-Associated Phospholipase A2 as a Cardiovascular Risk MarkerA substantial body of peer-reviewed studies has been published validating the role of inflammation in atherogenesis and supporting lipoprotein-associated phospholipase A2 (Lp-PLA2) as a cardiovascular risk marker independent of and additive to traditional risk factors. As with elevated high-sensitivity C-reactive protein, an elevated Lp-PLA2 level approximately doubles the risk for primary and secondary cardiovascular events. Interestingly, when both inflammatory markers are increased together, they provide an even greater predictive capability to help identify very-high-risk individuals who would benefit most from aggressive lipid-lowering therapy. High levels of Lp-PLA2 are present in inflamed, rupture-prone plaques, and it appears that Lp-PLA2 is released from these plaques into the circulation. Over 25 prospective epidemiologic studies have demonstrated the association of elevated Lp-PLA2 levels with future coronary events and stroke—11 of 12 prospective studies have shown a statistically significant association between elevated Lp-PLA2 and primary coronary or cardiovascular events, 12 of 13 have shown a statistically significant association with recurrent coronary or cardiovascular events, and 6 studies have shown a positive association with stroke. Lp-PLA2 should be viewed today as an important cardiovascular risk marker whose utility is as an adjunct to the major risk factors to adjust absolute risk status and thereby modify low-density lipoprotein cholesterol goals. The low biologic fluctuation and high vascular specificity of Lp-PLA2 makes it possible to use a single measurement in clinical decision making, and it also permits clinicians to follow the Lp-PLA2 marker serially. Ultimately, Lp-PLA2 may also be classified as a risk factor, but this should not detract from its utility today as a risk marker. The goal of this article is to review the rapidly converging evidence for lipoprotein-associated phospholipase A2 (Lp-PLA2), a vascular inflammatory enzyme, as a clinically useful marker to improve identification of individuals whose level of risk is greater than clinically apparent for cardiovascular disease (CVD) events who may benefit from more intensive risk-reducing interventions. CVD risk assessment forms the basis for directing risk-reducing therapies in clinical practice, given the efficacy and safety of current pharmacologic agents targeting lipids, blood pressure, and blood glucose on a background of therapeutic lifestyle modification. Lipid-lowering therapies, specifically statins, are effective in the primary and secondary prevention of myocardial infarction (MI) and stroke. The availability of generic statins provides a cost-effective opportunity for CVD risk reduction and presents the challenge of identifying appropriate individuals in the general population who would most benefit from these agents. Accounting for established risk factors may explain only half of all coronary artery disease (CAD) events that occur.1 This shortcoming has fueled intense interest in identifying new biomarkers that may add to the predictive power of traditional risk factors. The guiding principle of the Adult Treatment Panel III (ATP III) guidelines is that the estimation of absolute 10-year CAD risk is used to stratify individuals to optimal low-density lipoprotein (LDL) cholesterol goals because intensity of treatment should be matched to absolute risk.2 ATP III also recognized that coronary heart disease (CHD) risk is not fully revealed by traditional risk factor assessment, noting that “when major risk factors are present, they account for only half of the variability in CHD risk in the US population”1 and proposed that emerging risk factors “be taken into consideration according to clinical judgment as optional modifiers of therapy but they should be used only as an adjunct to adjust the estimate of absolute risk status obtained with the major risk factors.” Within the past decade, evidence has accumulated that inflammation plays a critical role in the initiation and progression of atherosclerosis, suggesting that biomarkers of inflammation may aid in predicting an individual's risk for CVD events.1 High-sensitivity C-reactive protein (hs-CRP), an acute-phase reactant, has been well described as a useful inflammatory marker in predicting future CVD events, although hs-CRP was not recommended as a routine measurement in the ATP III guidelines. In 2003, a scientific statement published by the American Heart Association/Centers for Disease Control (AHA/CDC) reviewed inflammatory markers and recommended that “it is reasonable to measure hs-CRP as an adjunct to the major risk factors to further assess absolute risk for coronary disease primary prevention.”3 The hs-CRP measurement was considered optional, at the physician's discretion. The working group concluded that a high hs-CRP measurement in persons identified at intermediate risk by traditional risk factors alone “may allow for intensification of medical therapy to further reduce risk.”3 Subsequently, a substantial body of peer-reviewed studies has validated the role of inflammation in atherogenesis, as well as the risk predictive value of a variety of other inflammatory markers. Among these, Lp-PLA2 has been shown to be a cardiovascular risk marker independent of and additive to traditional risk factors.4 Similar to elevated hs-CRP, an elevated Lp-PLA2 approximately doubles the risk for first and recurrent CVD events. Interestingly, when both inflammatory markers are elevated, they have an even greater predictive capability.5, 6, 7 Conversely, low values of both markers reproducibly identify individuals with the lowest CVD risk. Lipoprotein–Associated Phospholipase A2: A Vascular-Specific Inflammatory Enzyme  It has been established that the Lp-PLA2 enzyme specifically hydrolyzes oxidized phospholipids on oxidized LDL particles within the arterial intima. The products of this reaction, oxidized free fatty acids and lysophosphatidylcholine, in turn stimulate expression of endothelial adhesion molecules and cytokines,8 which leads to recruitment of monocytes to the intima, where they activate to become macrophages, and ultimately, apoptotic foam cells. These activated macrophages and foam cells produce more Lp-PLA2, which appears to reenter the bloodstream.9 Lavi et al9 recently reported Lp-PLA2 blood concentrations sampled simultaneously in the human coronary os and the coronary sinus that demonstrated a net increase in Lp-PLA2 levels as blood traverses the coronary vascular bed with significant atherosclerotic plaque. However, when no coronary plaques are present, a decrease in Lp-PLA2 levels was found. This study also showed that the lysophosphatidylcholine produced by Lp-PLA2-mediated hydrolysis of oxidized LDL is highly associated with coronary artery endothelial dysfunction. High levels of Lp-PLA2 are also present in rupture-prone plaques,10 and it appears that Lp-PLA2 is released from these plaques into the circulation.9 Figure 1 contrasts the histopathologic characteristics of stable versus ruptured plaque. Staining of coronary and carotid tissue demonstrates the presence of Lp-PLA2 in the thin fibrous cap or rupture-prone plaques, but not in the early-stage plaques.10, 11, 12 Importantly, coronary and carotid tissue concentrations of Lp-PLA2 are very high in the rupture-prone shoulder region of thin fibrous cap atheromas. In addition, histopathologic stains reveal that Lp-PLA2 co-localizes with macrophages and oxidized LDL in atherosclerotic coronary and carotid plaques. In animal and human tissues, Hakkinen et al13 were able to show increasing levels of Lp-PLA2 messenger RNA expression in aortic samples with advanced atherosclerosis, where it is mainly confined to inflammatory cells. Having a marker that may signal that plaques are prone to rupture potentially meets an important unmet clinical need because >66% of MIs occur in persons with <50% stenosis on coronary angiography.14 Kolodgie et al10 found that 76% of 72 sudden coronary deaths at necropsy were attributable to plaque rupture and thrombosis. Tools available to physicians for CVD risk assessment include risk factor counting, lipid and lipoprotein measurement, carotid ultrasound imaging, stress testing ± echocardiography or nuclear imaging, coronary angiography, or coronary intravascular ultrasound, but none of these can assess whether a patient has vulnerable plaques. Risk assessment approaches have not included a noninvasive, inexpensive, and reliable means of identifying the potential of plaque rupture.15 Although emerging technologies, such as virtual histology intravascular ultrasound, intravascular ultrasound palpography and thermography, optical coherence tomography, or carotid magnetic resonance imaging, may help assess plaque composition and characteristics, these approaches are either invasive or very expensive for mass application. Review of the Epidemiologic Evidence Is the scientific evidence for the Lp-PLA2 biomarker as compelling for use in clinical practice as it has been for the other biomarkers, such as hs-CRP, brain natriuretic peptide, and troponin? In all, >25 prospective epidemiologic studies have investigated the association of Lp-PLA2 with future CAD events and stroke.5, 6, 7, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41 Of these, 10 of 11 studies have shown a statistically significant association between elevated Lp-PLA2 and primary coronary or cardiovascular events,5, 6, 16, 17, 18, 19, 20, 21, 22, 23, 24 12 of 13 have shown a statistically significant association with recurrent coronary or cardiovascular events,7, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 39 and 6 studies have shown a positive association with stroke.19, 36, 37, 38, 40, 41 Except for some attenuation in the elderly (the Prospective Study of Pravastatin in the Elderly at Risk [PROSPER],20 Cardiovascular Health Study [CHS],21 and the Rancho Bernardo Heart Study22) to a hazard ratio (HR) of 1.5, there is a consistent doubling of risk for Lp-PLA2 in the top quantile versus bottom quantile (Figure 2).5, 7, 16, 17, 18, 19, 20, 21, 22, 23, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 37, 38, 39 These results are fully adjusted for traditional risk factors and often for both body mass index (BMI) and other inflammatory markers, such as hs-CRP. In contrast to other inflammatory risk markers, the approximate doubling of risk associated with elevated Lp-PLA2 is not attenuated after adjusting for traditional risk factors, BMI, lipids, and other inflammatory markers. In addition, several studies illustrate the complementarity of Lp-PLA2 and hs-CRP in predicting the highest risk of a future cardiovascular event.5, 6, 7 In particular, in the Atherosclerosis Risk In Communities (ARIC) study, individuals who had increased levels of both Lp-PLA2 and hs-CRP were 3 times more likely to have a coronary event compared with individuals with low levels of Lp-PLA2 and hs-CRP.5 In the prospective stroke study of the same population, individuals who had increased levels of both Lp-PLA2 and hs-CRP had an 11-fold greater incidence of ischemic stroke compared with individuals with low levels of Lp-PLA2 and hs-CRP.37 Hypertension is a strong risk factor for stroke, but the high prevalence of hypertension in the US population reduces its predictive power. Because LDL cholesterol does not appear to be a reliable predictor of stroke, Lp-PLA2 may fill an important unmet need in the identification of persons at high risk for stroke.37 In the ARIC stroke study, individuals who had both Lp-PLA2 levels above the median and systolic blood pressure in the top tertile (>130 mm Hg) had a 6.8-fold increase in the risk for an ischemic stroke versus individuals in the bottom tertile for blood pressure with Lp-PLA2 below the median. Lp-PLA2 may therefore identify subjects with hypertension who are stroke-prone who might benefit from a lower LDL cholesterol goal, as supported by the results from the Anglo-Scandinavian Cardiac Outcomes Trial–Lipid-Lowering Arm (ASCOT-LLA) study,42 as well as meta-analyses that show statins lower the risk for stroke in both primary and secondary prevention populations. A recent meta-analysis showed that the risk ratios for Lp-PLA2 were similar whether mass or activity of the Lp-PLA2 enzyme was measured.4 Several study results suggest that Lp-PLA2 may serve best as a measure of plaque quality rather than of plaque burden. For instance, although a study showed that Lp-PLA2 was highly associated with coronary artery calcium score, this association was not significant in a second study.43, 44 Correlations of Lp-PLA2 levels and percent stenosis measured by quantitative coronary angiography, or the extent of carotid intima–media thickening by carotid ultrasound were also inconsistent. New CVD risk factors may or may not add significant predictive value to more traditional risk factors. A method to determine the incremental predictive value is the receiver operating characteristic (ROC). In high-risk patients, elevated Lp-PLA2 levels increase the area under the curve (AUC or c statistic) in ROC analysis, even when other markers, such as hs-CRP, cystatin C, or N-terminal pro–brain natriuretic peptide, are included in multivariate analysis.29, 31, 45 Figure 3, Figure 4 show the HRs and change in AUC for elevated Lp-PLA2 in high-risk populations in the Langzeiterfolge der Kardiologischen Anschlussheil-Behandlung (KAROLA)29 and Olmsted County Mayo Studies31 (Figure 3, Figure 4). In the ARIC study, which comprised an apparently healthy middle-aged population, elevated Lp-PLA2 raised the AUC significantly for the risk of coronary events, whereas 18 other cardiac markers, including hs-CRP, did not (Table 1).46 Although the c statistic improvement obtained by adding Lp-PLA2 to the traditional risk factors in the ARIC study was significant, the magnitude of this improvement was relatively modest, supporting the idea that inflammatory markers, including Lp-PLA2, should not be used as screening tests for coronary event risk in low-risk populations. For stroke risk, Lp-PLA2 performed better, raising the c statistic significantly by 0.02 over traditional risk factors, lipids, and hs-CRP combined, possibly because LDL cholesterol does not predict stroke (Table 2).47 Importantly, when hs-CRP and Lp-PLA2 were combined as predictors of stroke in the ARIC study, there was a significant increase in the c statistic over traditional risk factors by almost 0.05. These data further support that the 2 inflammatory markers, when combined, may provide additive information for CVD risk stratification over traditional risk factors. In low-risk populations, it is difficult for any risk marker (or factor) to add to the c statistic generated from just age and sex. For example, blood pressure adds 0.03 and LDL cholesterol adds 0.01 to the c statistic in an apparently healthy population, according to the Women's Health Study.48 However, the picture changes in intermediate- and higher-risk persons because these populations by definition already have traditional risk factors, so these factors have a much smaller net additional impact on the AUC versus their utility in screening low-risk populations. Therefore, it is in the moderate- or higher-risk person where an inflammatory marker could theoretically play a greater role in risk discrimination. This point is supported by a reexamination of the ARIC trial and the risk of stroke, where Lp-PLA2 and hs-CRP together were shown to reclassify the 5-year risk category in 37% of persons at moderate risk of stroke, but did not significantly reclassify the risk category for low-risk persons.46 Characteristics of the Lipoprotein–Associated Phospholipase A2 Marker Why do some inflammatory markers tend not to raise the AUC in ROC analysis? Markers that reflect systemic inflammation and not necessarily vascular inflammation may have a high false-positive rate, which tends to shift the ROC curve to the right with concomitant weakening of the c statistic. Lp-PLA2 appears to be highly specific for vascular inflammation such that it appears to be unaffected by common infections or arthritis, and it has low biologic variability, similar to lipids.49, 50 The low biologic fluctuation makes it possible to use a single measurement in clinical decision making and also permits clinicians to follow it serially. Most other markers of systemic inflammation, such as hs-CRP, show significant biologic fluctuation within an individual and are challenging to follow. Because the level of Lp-PLA2 is independent of traditional risk factors, its HR for cardiovascular risk is typically not attenuated after full multivariate adjustment in prospective studies.51 Furthermore, cardiovascular risk attributable to Lp-PLA2 is not attenuated when systemic markers of inflammation, such as hs-CRP, are included in the multivariate model. In fact, in an analysis of 312 patients with CAD and 479 age- and sex-matched controls, Khuseyinova et al28 reported that Lp-PLA2 in the top versus bottom quartile was associated with a 1.9-fold increased risk of CAD, even when fully adjusted for 24 lipid, lipoprotein, inflammatory, and hemostatic markers. Finally, a relatively unique characteristic of Lp-PLA2 is its independence from BMI and insulin resistance. In over a dozen studies where BMI was included in the multivariate analysis along with traditional risk factors, Lp-PLA2 persisted as a statistically significant CVD risk predictor. Unlike systemic inflammatory markers, which may be produced by the liver in response to cytokines produced in mesenteric adipose tissue, Lp-PLA2 is produced by macrophages and foam cells in atherosclerotic plaques.13 These findings are consistent with a study of women without diabetes mellitus, where insulin resistance was measured with a modification of the insulin suppression test, considered the “gold standard,” and insulin resistance was found not to be increased in association with an increased Lp-PLA2 concentration.51 In 2 recent prospective epidemiologic studies, ATP III–defined metabolic syndrome and Lp-PLA2 concentrations above the median were not only independent of each other, but they proved to be additive markers of CVD event risk.23, 52 In the Malmo Diet and Cancer Study, 4,480 subjects without diabetes were observed for 10 years, during which 261 CVD events developed. High Lp-PLA2 levels and the presence of the metabolic syndrome were independent and additive predictors of CVD risk (Figure 5).23 Similarly, in an angiographic cohort of 1,143 patients studied for 7.5 years, Carlquist et al53 found that the presence of the metabolic syndrome and elevated Lp-PLA2 were again independent and additive risk factors for cardiac mortality. Establishment of a Clinical Cut Point for Lipoprotein–Associated Phospholipase A2 Mass Concentrations To be a clinically useful tool, a biomarker must have an established cut point or decision value. In 2006, a national consensus panel recommended an Lp-PLA2 mass concentration cut point to be used with traditional risk factors to better identify high-risk patients.54 It was noted that Lp-PLA2 seems to exhibit a “risk threshold,” where CVD risk increases rather abruptly for Lp-PLA2 mass concentrations >200 ng/mL. This is evident on examination of the Kaplan-Meier CVD event-free survival curves in the Mayo Heart and KAROLA studies of high-risk CAD and acute coronary syndrome populations, where patients in the middle tertile for Lp-PLA2 have similar event rates as persons in the top tertile for Lp-PLA2.26, 29 In other words, an Lp-PLA2 mass concentration of 400 ng/mL does not seem to impart much more risk than 250 ng/mL. Similarly, when Lp-PLA2 enzyme activity is examined, instead of mass concentration, cardiovascular risk seems to increase at the second (middle) tertile (33rd percentile).45 The Ludwigshafen Risk and Cardiovascular Health Study (LURIC) study of Lp-PLA2 activity observed 2,513 patients with angiographically confirmed coronary atherosclerosis (>20% stenosis) and 719 patients without coronary atherosclerosis (<20% stenosis) for a median of 5.5 years. Absolute risk for cardiac death doubled in both the second and third tertiles for Lp-PLA2 activity compared with the bottom tertile whether coronary atherosclerosis was present or not, and after adjustment for N-terminal pro–brain natriuretic peptide and hs-CRP.45 Since the initial cut point recommendation, 2 prospective studies have examined and confirmed that risk seems to be low when the level of Lp-PLA2 is <200 ng/mL and that risk is high with a level >235 ng/mL. Gerber et al31 reported in a study of mortality risk 1 year after MI that 225 ng/mL seemed to be an appropriate cut point, and Mockel et al34 reported in a study of patients presenting with acute chest pain that a cut point of 210 ng/mL was appropriate for CVD risk over the next 42 days. Based on these reports, several commercial laboratories now recommend that Lp-PLA2 values <200 ng/mL be considered low, 200–235 ng/mL be considered borderline high, and >235 ng/mL be considered high. Lipoprotein–Associated Phospholipase A2 Is Not a Proven Treatment Target Lp-PLA2 levels are modified by lipid-lowering therapies, including statins, niacin, fenofibrate, omega-3 fatty acids, and ezetimibe. However, there are no data showing that targeting Lp-PLA2 levels with these agents improves clinical outcomes. Small molecule inhibitors of Lp-PLA2 are being developed and are currently undergoing evaluation in phase 2 and 3 clinical studies. Accordingly, Lp-PLA2 should be used as an adjunct to adjust absolute risk status to consider more intensive LDL cholesterol goals. Incorporating Lipoprotein–Associated Phospholipase A2 Testing into National Cholesterol and Inflammatory Marker Guidelines The 2001 ATP III guidelines outlined the following criteria to determine the clinical significance of emerging risk factors: (1) significant predictive power that is independent of other major risk factors; (2) a relatively high prevalence in the population (justifying routine measurement in risk assessment); (3) laboratory or clinical measurement that is widely available, well-standardized, inexpensive, has accepted population reference values, and is relatively stable biologically; and (4) preferably, but not necessarily, modification of the risk factor in clinical trials that has shown reduction in risk. Lp-PLA2 would appear to meet the proposed criteria: (1) there is substantial evidence published in peer-reviewed journals, including 25 prospective population-based studies, supporting Lp-PLA2 as a cardiovascular risk marker that provides incremental predictive ability over traditional risk factors; (2) Lp-PLA2 has a similar distribution in the population to LDL cholesterol; (3) a US Food and Drug Administration (FDA)–approved assay for measuring levels of Lp-PLA2 is commercially available through national, regional, and hospital reference laboratories, and is reimbursable by insurance companies and the Center for Medicare and Medicaid Services. As mentioned previously, a national consensus panel recommended a clinical decision value of 235 ng/mL as high, although some commercial laboratories now recommend levels <200 ng/mL as low, 200–235 ng/mL as borderline high, and >235 ng/mL as high. Lp-PLA2 has low biologic variability, similar to LDL cholesterol, and its low biologic fluctuation permits clinicians to follow levels serially; and (4) the results of ongoing studies to determine whether reducing Lp-PLA2 improves surrogate and/or clinical outcomes are eagerly awaited. Conclusion Lp-PLA2 testing appears to be useful as an adjunct to traditional CV risk assessment in moderate and high risk populations. Persons with elevated Lp-PLA2 levels who are appropriately reclassified as at higher risk would benefit from intensification of lipid lowering treatments, based on a substantial body of evidence that high risk patients benefit from incremental LDL-C reductions, regardless of baseline LDL-C levels. Author Disclosures The authors who contributed to this article have disclosed the following industry relationships. Marshall A. Corson, MD, is on the Speakers' Bureau for Abbott Laboratories, diaDexus, Inc., Forest Pharmaceuticals, Merck/Schering-Plough, Novartis, Oscient, and Pfizer, Inc.; his wife is an employee of diaDexus, Inc., and is a shareholder in Merck and Novartis. Peter H. Jones, MD, has received research grants from Abbott Laboratories, AstraZeneca; and serves as a consultant for Abbott Laboratories, AstraZeneca, Pfizer, Inc, and Merck/Schering-Plough. Michael H. Davidson, MD, is a member of the Speakers' Bureau for Abbott Laboratories, AstraZeneca Pharmaceuticals, Daiichi-Sankyo, Inc., diaDexus, Inc., Merck & Co., Inc., Merck/Schering-Plough, Oscient Pharmaceuticals, Pfizer, Inc, and Takeda Pharmaceuticals; serves as a consultant for Abbott Laboratories, AstraZeneca Pharmaceuticals, Daiichi-Sankyo, Inc., diaDexus, Inc., Merck & Co., Inc., Merck/Schering-Plough, Pfizer, Inc, Roche Pharmaceuticals, sanofi aventis, and Takeda Pharmaceuticals; has received grant/research support from Abbott Laboratories, AstraZeneca Pharmaceuticals, Daiichi-Sankyo, Inc., Merck & Co., Inc., Merck/Schering-Plough, Pfizer, Inc, Roche Pharmaceuticals, and Takeda Pharmaceuticals; is on the advisory board for Abbott Laboratories, Access Health, Atherogenics, AstraZeneca Pharmaceuticals, Daiichi-Sankyo, Inc., Merck & Co., Inc., Merck/Schering-Plough, Oscient Pharmaceuticals, Pfizer, Inc, Roche Pharmaceuticals, and Takeda Pharmaceuticals, and is on the Board of Directors for Angiogen and Sonogene, and is Chief Medical Officer of Professional Evaluation, Inc. 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a Division of Cardiology, Department of Medicine, University of Washington, Seattle, Washington, USA b Baylor Lipid and Atherosclerosis Clinic, Baylor College of Medicine, Houston, Texas, USA c University of Chicago, Pritzker School of Medicine, Chicago, Illinois, USA d Radiant Research, Chicago, Illinois, USA.  Address for reprints: Marshall Corson, MD, Division of Cardiology, Department of Medicine, Harborview Medical Center, University of Washington School of Medicine Box 359748, Rm 2EH-64, 325 9th Avenue, Seattle, Washington 98104.
Statement of author disclosure: Please see the Author Disclosures section at the end of this article. PII: S0002-9149(08)00715-7 doi:10.1016/j.amjcard.2008.04.018 © 2008 Elsevier Inc. All rights reserved. | |
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