Prospective Nested Case-Control Studies
Initial evidence for an association of Lp-PLA2 with cardiovascular risk came from the West of Scotland Coronary Prevention Study (WOSCOPS), a large primary prevention trial of men at high risk that was primarily initiated to evaluate the effect of pravastatin therapy on reduction of CHD (26). Of6595 middle-aged men with hypercholesterolemia and no preexisting CHD, 580 with subsequent coronary events (nonfatal myocardial infarction [MI], CHD death, or coronary revascularization procedure) that occurred during a 4.9-yr follow-up were enrolled as case subjects and compared with 1160 event-free participants, matched for age and smoking. Elevated Lp-PLA2 concentrations at baseline were associated with an increased risk of subsequent coronary events. The relative risk (RR) associated with an increase ofone standard deviation (SD) in Lp-PLA2 was 1.18 (95% confidence interval [CI]: 1.05-1.33; p = 0.005) after controlling for traditional risk factors and was independent of various other biomarkers such as C-reactive protein (CRP), fibrinogen, and white blood cell (WBC) count. By contrast, in similar multivariable analyses, the predictive values for CRP, fibrinogen, and WBC count were substantially attenuated after controlling for traditional risk factors and were no longer statistically significant after adjustment for each of the other inflammatory markers.
The predictive role of Lp-PLA2 was assessed within the Women's Health Study (WHS), a large cohort ofmiddle-aged normocholesterolemic women (27) representing a low-risk population for CVDs. Using a nested case-control design that included 123 cases and 123 controls, investigators found that baseline concentrations of Lp-PLA2 were significantly higher among women who subsequently developed cardiovascular events (such as MI, stroke, or death owing to CHD) compared with those who remained free of vascular disease (mean of 1.2 vs 1.05 mg/L, respectively; p = 0.016). However, although the RR in the top quartile compared with the bottom quartile was 1.73 (95% CI: 0.87-3.44), it was statistically nonsignificant and decreased further to 1.17 (95% CI: 0.45-3.05) after adjustment for various risk factors. This lack of association could be attributed to existing gender differences for Lp-PLA2. Indeed, several studies (28-30) have already reported on lower levels of Lp-PLA2 in women than in men, and experimental data may offer a possible explanation for these differences. It has been shown that administration of estrogen to rats inhibited secretion of the enzyme by hepatocytes, thereby reducing Lp-PLA2 levels (31,32). Other investigators have shown a decrease in PAF-AH activity in response to estrogen replacement therapy in postmenopausal women (33). Although the investigators had adjusted for hormonal replacement therapy in multivariable analysis, they found that gender differences nevertheless might represent a main source of confounding in the study by Blake et al.
The Atherosclerosis Risk in Communities (ARIC) study served as the database for another case-cohort study that included 608 men and women with incident CHD who were compared with 740 control subjects randomly drawn from the remaining cohort and followed for 6-8 yr (34). Again, Lp-PLA2 concentrations at baseline were higher in case subjects than in control subjects. In age- and gender-adjusted analysis, Lp-PLA2 was associated with an increased risk of CHD (hazard ratio [HR] in the top tertile compared with the bottom tertile was 1.78; 95% CI: 1.33-2.38), but statistical significance was lost after multivariable adjustments. By contrast, CRP was predictive in overall analysis even after controlling for multiple covariables (HR: 1.72; 95% CI: 1.24-2.39 comparing those with a CRP >3.0 mg/L with those with a CRP <1.0 mg/L). However, a significant interaction between Lp-PLA2 and LDL-C (<130 and ©130 mg/dL) was found. In subjects with low LDL-C, Lp-PLA2 significantly and independently predicted CHD (HR: 2.08; 95% CI: 1.20-3.62), suggesting that it could be a useful marker for identifying high-risk patients with relatively normal levels of LDL-C, a group in whom additional markers of risk are clearly needed.
Results from the MONICA (Monitoring of Trends and Determinants in Cardiovascular Disease)-Augsburg cohort study further support the hypothesis that Lp-PLA2 is independently associated with CHD (35). In this prospective study, the RR for a future coronary event associated with elevated Lp-PLA2 and with elevated CRP concentrations was directly compared in a cohort of 934 initially healthy middle-aged men with moderately increased total cholesterol who were drawn randomly from the general population in 1984 and followed until 1998. During a 14-yr follow-up, a total of 97 fatal and nonfatal coronary events, including sudden cardiac death, occurred. At baseline, both markers were elevated in subjects with a subsequent event compared with subjects in whom there were no events (295 ± 113 vs 263 ± 79 ng/mL,p < 0.01 for Lp-PLA2 and 2.62 ± 2.98 vs 1.53 ± 3.11 mg/L, p < 0.001 for CRP). In a Cox model, an increase of 1 SD in Lp-PLA2 was strongly and independently related to a first-ever event (HR: 1.23; 95% CI: 1.02-1.47), even after controlling for a variety of potential confounders, including the total cholesterol/HDL-C ratio as the strongest lipoprotein variable. Further inclusion of CRP in the model did not appreciably affect its predictive ability (HR: 1.21; 95% CI: 1.01-1.45). The considerably longer follow-up of14 yr extends the observations reported from the other studies regarding the time frame within which Lp-PLA2 might be a useful predictor for future cardiovascular events.
The discussed intriguingly consistent results have generated much interest in better defining the relationship between Lp-PLA2 and cardiovascular risk; Table 1 summarizes data from studies published so far, as well as preliminary data from several subsequent studies (8,26,27,34-43). For instance, in the setting ofpatients with manifest CHD, a cohort of consecutive patients undergoing coronary angiography was followed for an average of 4 yr, and Lp-PLA2 was found to represent an independent predictor of subsequent risk of CVD (36). Iribarren et al. (37) demonstrated an association between Lp-PLA2 mass and coronary artery calcification in young adults. In addition, Oei et al. (38) recently reported preliminary findings from the Rotterdam Study, a cohort of 7983 subjects age 55 yr and above. Multivariable Cox proportional hazard modeling showed an adjusted HR of 1.77 (95% CI: 1.19-2.64) for the top quartile ofthe Lp-PLA2 activity compared with the bottom quartile. The investigators further demonstrated that elevated levels of Lp-PLA2 were significantly associated with an increased risk ofstroke. Participants with the highest Lp-PLA2 levels (Q4) had a 75% increased risk of stroke (HR: 1.75; 95% CI: 1.08-2.84) compared with participants with the lowest levels (Q1) of Lp-PLA2. These findings were consistent with preliminary data from the ARIC cohort, in which the relationship among Lp-PLA2, CRP, and the incidence of stroke was studied in 223 case subjects who were compared with a random sample cohort of 766 individuals who remained free of disease during a 6-yr follow-up (39). The risk of stroke for individuals with the highest levels of Lp-PLA2 was twice as high as that for individuals with the lowest levels (HR: 2.04; 95% CI: 1.23-3.38, Q4 vs Q1;p < 0.01), even after taking into account other confounders, including lipid variables and CRP. By contrast, LDL-C concentrations did not predict the risk of stroke.
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