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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptNIH Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
J Vasc Surg. Author manuscript; available in PMC Jun 23, 2009.
Published in final edited form as:
PMCID: PMC2700305
NIHMSID: NIHMS29832

The Association between Lipoprotein-associated Phospholipase A2 and CVD and Total Mortality in Vascular Medicine Patients

Abstract

Introduction

In some community-based studies, Lp-PLA2 has been shown to be independently predictive of future fatal and non-fatal cardiovascular disease (CVD) events. We tested the hypothesis that Lp-PLA2 is independently predictive of mortality in high risk patients from a vascular laboratory.

Methods

Between 1990 and 1994, patients seen in the previous 10 years for non-invasive lower extremity arterial testing were invited to return for a vascular examination of the lower extremities. By medical record review, we identified 2,265 eligible patients and of these, 508 returned for interviews, blood collection and arterial examination and represent those who had survived, could be located and were willing to participate. The 508 subjects were followed for an average of 6.7 years until the end of the study period on December 31, 2001. Vital status was ascertained by multiple searches of the social security death index. The primary outcomes for this study were time to any, CVD and coronary heart disease (CHD) mortality.

Results

The mean age was 68.2 years, 88% were male, 87% were non-Hispanic White, 39.1% were diagnosed with PAD only, 9.2% with other CVD only and 28.5% with both PAD and other CVD. Over the entire follow-up period, 299 (59.7%) patients died, 167 from CVD. Eighty-eight of the CVD deaths were due to CHD. With adjustment for CVD risk factors and baseline PAD and other CVD, a 1-SD increment in Lp-PLA2 activity was associated with a 40% higher risk for CHD mortality at 5-years of follow-up (p = 0.04). Additional adjustment for triglycerides, HDL and LDL cholesterol reduced this association to non-significance (HR: 1.12).

Conclusion

In a vascular laboratory patient population, higher levels of LpPLA2 mass and activity were not significantly associated with total, CVD or CHD mortality at 5 years of follow-up and after adjustment for traditional CVD risk factors and the presence of PAD and other CVD at baseline. An apparent elevated risk of CHD death associated with elevated Lp-PLA2 was largely explained by associated elevations in lipids and lipoproteins.

Introduction

Lipoprotein-associated phospholipase A2 (Lp-PLA2), also known as platelet activating factor acetylhydrolase, is a calcium-independent enzyme that cleaves oxidized and polar phospholipids.1, 2 In the circulation, Lp-PLA2 is bound predominately to LDL cholesterol and has also been shown to have an affinity for small, dense fractions of this class of cholesterol.3, 4 In the arterial wall, Lp-PLA2 is generated by monocytes, macrophages and T-lymphocytes and has been found in intimal atherosclerotic plaques.57 Importantly, Lp-PLA2 has been classified as a novel inflammatory marker due to the production of oxidized free fatty acids and lysophosphatidylcholines during oxidation of LDL.8

Since the rate of action of Lp-PLA2 on lipoproteins depends on the activity and mass of this enzyme, both of these measurements are required to understand its association to morbidity and mortality.9 In previous community-based studies, both Lp-PLA2 activity and mass have been shown to be independently predictive of future fatal and non-fatal coronary heart disease events.1015 However, no studies examining the potential association between mortality and both Lp-PLA2 activity and mass have been performed in a cohort of patients examined in a vascular laboratory. Accordingly, we conducted a study to compare the associations between both activity and mass of Lp-PLA2 and both total and CVD mortality in high risk patients from a vascular laboratory.

Methods

Subjects

Between 1990 and 1994, patients seen in the previous 10 years for non-invasive lower extremity arterial testing at the San Diego Veterans Administration Medical Center (VAMC) or the University of California, San Diego Medical Center (UCSDMC) vascular laboratories were invited to return for a vascular examination of the lower extremities using the same procedures as used previously. The invitations were derived from a listing of all patients who had visited our vascular laboratories in the previous 10 years, who had undergone a vascular examination and who had provided permission to be contacted. The order in which the participants were contacted was based on the timing of their original visit. Those seen furthest in the past were contacted first. Enrollment was not necessarily of consecutive patients.

Individuals who comprise the cohort were referred by specialist or primary care physicians and included patients with and without CVD comorbidities. Baseline CVD was defined as a history of myocardial infarction, stroke, percutaneous transluminal angioplasty or stent, coronary artery bypass graft or carotid artery surgery. Baseline peripheral arterial disease (PAD) was defined as an ankle-brachial index of < 0.9 in either lower extremity or a history of revascularization of the arteries in the lower extremities. The visits between 1990 and 1994 are baseline visits for these analyses. Of 2,265 patients with vascular laboratory visits in the 10-year time period before 1990 to 1994, 481 were deceased before 1990 and another 1,276 did not participate in the follow-up visit. Thus, 508 patients returned for interviews and represent those who had survived, could be located and were willing to participate. At the 1990 – 1994 visits, fasting venous blood was collected and stored at − 70°C. Subjects who agreed to undergo repeat testing for PAD signed a consent form approved by the University of California San Diego Human Research Protection Program and were interviewed in person using a structured questionnaire.

Vascular Assessment

At the follow-up visit, a non-invasive vascular examination including segmental blood pressures and flow velocities was performed. Systolic blood pressures were measured in both ankles and both arms by sphygmomanometry and photoplethysmography. Photoplethysmographic assessment has been shown to give essentially identical results to Doppler signal determination in both the arms and legs.16 The ankle/brachial index (ABI) for both legs was calculated using the arm with the higher systolic blood pressure. The subjects were categorized as normal or with PAD based on the ABI. PAD was defined as an ABI below 0.90, the conventional cut- point in vascular laboratories. The 95% confidence interval (CI) of ABI reproducibility has been reported to be in the 0.10 to 0.15 range.1719

Laboratory

Lipoproteins

Blood samples collected at the 1990 – 1994 visits were analyzed at that time for serum lipids and lipoproteins at a standardized lipid analytical laboratory using the Abbott VP “supersystem” bichromatic analyzer which employs direct enzymatic colorimetric assays.

Lp-PLA2

In 2006, the following assays were conducted using plasma samples from fasting venous blood obtained at the 1990 – 1994 and stored at −70°C.

Lp-PLA2 Activity (nmol/min/ml)

Lp-PLA2 activity was measured with a colorimetric activity method (CAM) provided by diaDexus Inc (South San Francisco, CA, USA). Samples, standards, or controls are added to wells of a non-binding 96-well microplate, followed by addition of CAM reaction buffer containing substrate. In the presence of Lp-PLA2 enzyme, the substrate is converted upon hydrolysis by the phospholipase enzyme. The change in absorbance is immediately measured at 405 nm over 60–180 seconds. The level of Lp-PLA2 activity in nmol/min/ml is calculated from the slope (OD405/min), based on a standard conversion factor from a p-Nitrophenol calibration curve. All samples were measured in duplicate. The intra-assay coefficient of variation (CV) was 4%. The inter-assay CV for six quality controls across plates was between 4 and 6%.

Lp-PLA2 Mass (ng/ml)

Lp-PLA2 mass was measured by the PLAC® test, a commercially available Lp-PLA2 ELISA kit supplied by diaDexus Inc. (South San Francisco, CA, USA). The assay is a sandwich enzyme immunoassay formulated with two specific monoclonal antibodies described by Caslake et al.20 The assay system utilizes monoclonal anti-Lp-PLA2 antibody (2C10) directed against Lp-PLA2 for solid phase immobilization on microwell strips. After addition of assay buffer to the antibody coated microplate, samples, calibrators, or controls are added to the wells and incubated for 2 hours. Following a washing step to remove any unbound antigen, a second monoclonal anti-Lp-PLA2 antibody (4B4) labeled with the enzyme horseradish peroxidase (HRP) is utilized to detect the immobilized antigen. The enzyme conjugate is incubated for 60 minutes followed by another washing step. Addition of the substrate, tetramethylbenzidine (TMB), results in the development of a blue color which is stopped appropriately with the addition of Stop Solution (1N HCL), changing the color to yellow. The absorbance of the enzymatic turnover of the substrate is determined spectrophotometrically at 450 nm and is directly proportional to the concentration of Lp-PLA2 present. A set of Lp-PLA2 Calibrators is used to plot a standard curve of absorbance versus Lp-PLA2 concentration from which the Lp-PLA2 concentration in the test sample can be determined. Duplicate assays were performed for 26% of the samples; the intra-assay coefficient of variation (CV) was 5%. The inter-assay CV for quality controls was between 6 and 10%.

Outcomes Ascertainment and Classification

The subjects were followed for an average of 6.7 years until the end of the study period on December 31, 2001. Between 1998 and 2001, the vital status of the 508 subjects who participated in the follow-up visit was ascertained by multiple searches of the social security death index. Of these, 501 had adequate blood samples available for the pertinent analysis. From this search, the place of death was recorded and then used to request the pertinent death certificate. Once received, the death certificate was reviewed and coded by a certified nosologist using the international classification of diseases, 9th edition. Mortality from coronary heart disease was defined using the ICD-9 code range of 410–414 while mortality from any CVD was defined as ICD-9 code range of 410–414 or 420–438. The coded underlying cause of death was used in these analyses.

Statistical Analysis

Continuous data are presented as means with standard deviations while categorical data are shown as frequencies with percents. All variables were examined for normality. Those independent variables that deviated from a Gaussian distribution were transformed to achieve normality (if possible). Those that were resistant to normalization were analyzed using nonparametric methods. Differences in age and sex adjusted mean values of the independent variables by high vs low Lp-PLA2 status were determined by ANCOVA. Correlations were conducted using the Spearman rank correlation method. To determine the risk for incident mortality, separate Cox proportional hazard models were constructed for Lp-PLA2 (i) activity and (ii) mass in a stepwise fashion. The first step in each analysis consisted of adjustments for age and sex as covariates of the Lp-PLA2 variable (i.e. activity or mass). The second step included the addition of traditional CVD risk factors and baseline PAD and other CVD; in the third step triglycerides were added; in the fourth step HDL cholesterol was added; and finally, in the fifth step LDL cholesterol was added to the model. Hazard ratios were determined for 5 years of follow-up. All analyses were conducted using SAS version 8.2 (Cary, NC). A two-tailed alpha of 0.05 was considered significant.

Results

The age of men and women in the study was not significantly different (68.2 years for men, 68.1 for women; p = 0.93). Sixty (12%) of the participants were women. One-hundred and ninety-six (39.1%) were diagnosed with PAD only, 46 (9.2%) were diagnosed with other CVD but not PAD and 143 (28.5%) were diagnosed with both PAD and other CVD. The mean duration of follow-up was 6.7 (3.2) years. Over the entire follow-up period, 299 (59.7%) patients died, of whom 167 died from CVD. Eighty-eight of the CVD deaths were due to coronary heart disease (CHD).

The mean (SD) Lp-PLA2 activity was 145.2 (33.5) nmol/min/ml while the corresponding mean for Lp-PLA2 mass was 377.9 (148.0) ng/ml. Those with an Lp-PLA2 activity level above the mean had significantly higher levels of both total and LDL cholesterol as well as triglycerides, while also having lower HDL cholesterol (Table 1). Notably, for the other CVD risk factors or inflammatory markers studied there were no other significant differences between those with an Lp-PLA2 activity above the mean compared to an Lp-PLA2 activity below the mean. For Lp-PLA2 mass, the associations were similar. Specifically, those above the mean for Lp-PLA2 mass had significantly higher total and LDL cholesterol levels and triglycerides. However, those above the mean did not have significantly different HDL cholesterol levels but they did have significantly higher levels of NT-pro-B-type natriuretic peptide and MCP-1 levels. There were also trends for higher C-reactive protein and PAI-1, which were of borderline significance (p = 0.08, and p=0.06 respectively)

Table 1
Age and Sex Adjusted Cohort Characteristics Stratified by Lp-PLA2 Activity and Mass above and Below the Mean

Levels of both Lp-PLA2 activity and mass were significantly different by sex and smoking status (Table 2). Compared with all other ethnic groups combined, Non-Hispanic Whites had significantly higher Lp-PLA2 activity (147.5 vs. 130.0 nmol/min/ml). Levels of Lp-PLA2 mass were also higher in non-Hispanic Whites, but these differences did not reach significance. Conversely, those with diabetes had significantly lower Lp-PLA2 mass but not activity levels. Interestingly, those with a family history of coronary heart disease or a personal history of CVD had significantly higher Lp-PLA2 activity but not mass levels. Mean Lp-PLA2 activity and mass levels were not significantly different by PAD status.

Table 2
Mean Lp-PLA2 Activity and Mass Levels for Different Cohort Characteristics

After adjustment for age and sex, Lp-PLA2 activity and mass were significantly correlated (r = 0.55, p < 0.01). Lp-PLA2 activity and mass were also significantly inversely correlated with the ABI (−0.12, p < 0.01 and −0.10, p 0.03; respectively). Table 3 shows the correlations between Lp-PLA2 activity and mass with the CVD risk factors and novel biomarkers. LDL cholesterol had the strongest age and sex-adjusted correlation with Lp-PLA2 activity (r = 0.45) followed by HDL cholesterol (−0.24) and triglycerides (0.19). The correlations between Lp-PLA2 activity and waist circumference and body weight were modest and of borderline significance. There were no significant associations between LP-PLA2 activity and fasting glucose and any of the novel risk factors such as C-reactive protein, interleukin-6 and D-dimer. With the same adjustment for age and sex, Lp-PLA2 mass was significantly correlated with LDL cholesterol (0.18) and triglycerides (0.19), but not HDL cholesterol. Lp-PLA2 mass was also significantly correlated with MCP-1 and PAI-1 (0.13 for both) but not with any of the other novel biomarkers.

Table 3
Age and Sex-Adjusted Correlations for Lp-PLA2 Mass and Activity

At 5 years of follow-up and in the Cox proportional hazards models, there were no significant associations between Lp-PLA2 mass or activity and total mortality or CVD mortality. Similarly, there was no significant association between Lp-PLA2 mass and CHD mortality. However, in a multivariable Cox proportional hazard model adjusted for age and sex, a 1-standard deviation increment of Lp-PLA2 activity was significantly associated with a 40% (p = 0.04) increased hazard for CHD mortality (Figure 1) that remained essentially unchanged with additional adjustment for smoking, hypertension, diabetes, family history of premature CHD, baseline PAD and other CVD (HR: 1.37, 95% CI: 1.00 – 1.89). Additional adjustment for triglycerides modestly attenuated this association (1.34, 0.97 – 1.86). However, when HDL cholesterol was added to the model, there was a substantial reduction in the hazard ratio (1.25, 0.90 – 1.75) which was further reduced with additional adjustment for LDL cholesterol (1.12, 0.78 – 1.60). Adding BMI and CRP to the models did not significantly change the nature of these associations.

Figure 1
5-Year Risks for Total, CVD and CHD Mortality Associated with Standardized Increments of Lp-PLA2 Activity

To determine if the mortality risks differed by baseline comorbidity status, we stratified the cohort into the following groups: 1) other CVD only, 2) PAD only, 3) CVD and PAD and 4) no CVD or PAD. We then conducted the same Cox regression analyses as described above for the entire cohort. In these exploratory analyses there were significant associations with Lp-PLA2 mass and both CVD and CHD mortality in the other CVD only group that was not further attenuated by adjustment for HDL and LDL cholesterol. For the PAD only and CVD + PAD groups, there were no significant associations with either Lp-PLA2 mass and activity with mortality. Since the sample size for these subsets was relatively small, these results should be interpreted with caution.

Discussion

In this cohort study of patients from a vascular laboratory and after adjustment for multiple CVD risk factors and baseline PAD and other CVD, higher levels of Lp-PLA2 activity were associated with significantly higher risks for CHD mortality. However, additional adjustment for HDL and LDL cholesterol significantly attenuated this association so that it was no longer statistically significant. We also note that among those with other CVD at baseline and after adjustment for the CVD risk factors, Lp-PLA2 mass was significantly associated with an increased hazard for CVD and CHD mortality. These associations were not attenuated with additional adjustment for HDL and LDL cholesterol. These results suggest a complex relationship between both Lp-PLA2 mass and activity and CVD events.

In our study, the lack of statistical significance between Lp-PLA2 activity and CHD mortality after adjustment for HDL and LDL cholesterol may be due to our relatively small cohort. The rationale for this assertion is that several other studies have found statistically significant associations between incident CVD events and Lp-PLA2 activity at 7 years of follow-up that were of similar magnitude to ours. Specifically, after adjustment for traditional CVD risk factors, a 1-SD increment in Lp-PLA2 was associated with hazard ratios of 1.30, 1.23 and 1.18 in the Mayo14, MONICA20 and WOSCOP9 studies, respectively. Combined with our findings, these results demonstrate a relatively consistent magnitude of association between higher levels of Lp-PLA2 and CVD risk across different study populations and which is independent of multiple risk factors.

Atherosclerosis is a chronic reparative inflammatory process21 and the underlying mechanism for the development the majority of CVD events. The immune/inflammatory pathway of this process is multifaceted and complex.22 A key step is the oxidation of lipoproteins in the intima of the arterial wall leading to an expansion of the inflammation by the recruitment of cells that elaborate vasoactive cytokines.23, 24 Lipoprotein-associated phospholipase A2 has been proposed as an inflammatory marker involved in the atherosclerotic process.2 Specifically, Lp-PLA2 participates in the oxidative modification of low density lipoprotein by cleaving oxidized phosphatidylcholines, generating lysophosphatidylcholine and oxidized free fatty acids. These free fatty acids promote inflammatory processes present at every stage of atherogenesis25 and result in diverse inflammatory effects on various cell types.26 These properties suggest that Lp-PLA2 would be a risk factor for the development and progression of atherosclerotic CVD.

From this context, some previous community-based studies have demonstrated Lp-PLA2 to be a significant risk marker for CVD events. For example, Oei and colleagues reported nearly two-fold higher relative risks for either incident CHD or stroke,14 that were independent of CVD risk factors and HDL cholesterol levels while other studies have demonstrated the risk associated with higher levels of Lp-PLA2 to be independent of both CVD risk factors and other inflammatory markers, such as C-reactive protein.13 However, in the Atherosclerosis Risk in Communities (ARIC) study, Lp-PLA2 was significantly associated with CHD events over 6 years only in those with an LDL cholesterol below 130 mg/dL12 and we did not observe an interaction between LDL cholesterol and Lp-PLA2 for incident CHD (data not shown). Finally, the Women’s Health Study (WHS) found no significant association between Lp-PLA2 and CVD events after adjustment for CVD risk factors.11

A significant association with CVD events has been demonstrated in clinical populations.15 In the PROVE IT-TIMI 22 trial, those in the highest quintile of Lp-PLA2 activity (but not mass) had a 33% higher risk for recurrent CVD events.27 Similarly, Brilakis and colleagues reported a 28% higher risk for major incident events over 4 years of follow-up in those undergoing clinically indicated angiography.15 The Thrombogenic Factors and Recurrent Coronary Events (THROMBO) postinfarction study reported significant associations between Lp-PLA2 activity and recurrent coronary events at a magnitude similar to our findings.28

Other studies have investigated the potential association between Lp-PLA2 and surrogate markers of CVD. Patients with endothelial dysfunction in the coronary arteries have been shown to have significantly higher levels of Lp-PLA2, while those with Lp-PLA2 in the highest tertile have over 3-times higher odds for having coronary artery endothelial dysfunction.29 Similarly, after adjustment for age, a 1-standard deviation increment of both Lp-PLA2 mass and activity has been associated with 40% higher odds for the presence of coronary artery calcium. With adjustment for covariates, including low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), triglycerides, and C-reactive protein, a statistically significant association remained for Lp-PLA2 mass (OR, 1.28; 95% CI, 1.03 to 1.60) but not for activity (OR, 1.09; 95% CI, 0.84 to 1.42).30 Finally, investigators from the Rotterdam study assessed the association between Lp-PLA2 and carotid intimal medial thickness, carotid plaques, calcified atherosclerosis of the abdominal aorta and the ankle brachial index. The age-adjusted odds ratio of having atherosclerosis at any site for the highest versus the lowest tertile of Lp-PLA2 activity was 1.86 (95% CI, 1.01 to 3.43) in men and 1.60 (95% CI, 1.08 to 2.37) in women. Notably, after additional adjustment for cholesterol, these associations attenuated to non-significance. The odds ratios of having atherosclerosis at specific sites followed a similar pattern.31

The participants in our study were a relatively small proportion of the cohort of individuals seen in the previous 10 years. Therefore, the results of this study may be influenced by selection and survival biases. A total of 92% of subjects who did not participate in the study (“non-participants”) were male, versus 87% of study subjects. The mean age of the non-participants at the midpoint of the study was 70 years, which was similar to the study subjects’ 68 years. In the non-participants group, the mean baseline ABI was 0.85 compared to 0.90 in the study subjects. These results suggest that the participants were modestly younger and had slightly less advanced disease than the non-participants, but were otherwise comparable.

In conclusion, our study in a vascular laboratory cohort concurs with the majority of earlier studies suggesting that Lp-PLA2 is a biomarker for and possibly plays a role in CVD events, as well as subclinical CVD. Similarly, our data suggest that some, but likely not all, of this risk can be attributed to correlations with lipoprotein cholesterol fractions. Finally, differences exist for the associations by Lp-PLA2 mass and activity, which at this time do not appear to follow a consistent pattern. Given the complexity of the findings to date, further studies are recommended to elucidate the relationship between this novel inflammatory marker and risk for future CVD morbidity and mortality.

Acknowledgments

This work was supported in part by a grant from the American Heart Association (Allison). Laboratory analysis was performed by GlaxoSmithKline, Research Triangle Park, NC.

Footnotes

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