Lipoprotein-Associated Phospholipase A2 Activity, Ferritin Levels, Metabolic Syndrome, and 10-year Cardiovascular and Non-Cardiovascular Mortality: Results From the Bruneck Study

Sotirios Tsimikas; Johann Willeit; Michael Knoflach; Manuel Mayr; Georg Egger; Marlene Notdurfter; Joseph L. Witztum; Christian J. Wiedermann; Qingbo Xu; Stefan Kiechl

Disclosures

Eur Heart J. 2009;30(1):107-115. 

In This Article

Discussion

This prospective epidemiological study of unselected subjects followed for 10 years confirms that increased baseline Lp-PLA2 activity is associated with increased risk of future cardiovascular events. Importantly, it documents several novel observations consistent with the specific pathophysiological role of Lp-PLA2 in atherogenesis: first, it demonstrates a significant relationship with vascular death but not with non-CVD mortality consistent with a specific effect on the vessel wall; second, it identifies plasma ferritin levels, a measure of body and macrophage iron content and a potent pro-oxidant,[26,27] as a potential modulator of Lp-PAL2 activity; third, it demonstrates an inverse correlation between antioxidant levels (normalized to LDL-C) and HDL-C with Lp-PLA2 activity; fourth, it confirms a significant relationship of Lp-PLA2 with the metabolic syndrome (AHA-NHLBI criteria), the number of metabolic syndrome parameters and level of HOMA-IR. In total, these data support an integral role of Lp-PLA2 activity in lipid peroxidation and cardiovascular risk.

The totality of published reports on Lp-PLA2, measured either as mass or activity, suggest that it is significantly related to future CVD with hazard ratios of 1.5-2.0, but with a modest attenuation of risk following multivariable analysis. The current study, which adjusted for age, sex, previous CVD, systolic blood pressure, smoking, diabetes, ferritin, fibrinogen, LDL and HDL cholesterol, waist-to-hip ratio, alcohol consumption, social status, sports activity, HOMA-IR, lipoprotein(a), C-reactive protein, and urinary albumin, confirms a similar role of Lp-PLA2 in predicting CVD. Importantly, we also documented that baseline Lp-PLA2 activity was associated with vascular but not non-vascular death (Figure 1). The relationship between Lp-PLA2 and CVD risk was noted in most subgroups tested, including patients in various tertile groups for LDL-C and hs-C-reactive protein, and different FRS estimates. These data are consistent with studies in subjects with sudden death or undergoing carotid endarterectomy that have reported prominent expression of Lp-PLA2 within the necrotic core and surrounding macrophages of vulnerable and ruptured plaques and apoptotic cells.[28,29] Furthermore, a correlation of atheroma volume documented by IVUS with Lp-PLA2 mass measured in the coronary sinus has been documented.[30] These findings suggest that Lp-PLA2 is intimately associated with the transition of such plaques to clinical events.

Like with most other novel markers of vascular risk, no significant global increase in model performance (Figure 3) was observed upon addition of Lp-PLA2 activity to a standard prediction model (based on the Framingham risk function). The net reclassification improvement was 9.5% but fell short of significance. There is some promise, however, for a clinical utility in subgroups especially subjects at moderate risk or in combination with other novel risk markers. A large-scale meta-analysis is currently underway to resolve this issue.

The determinants of plasma Lp-PLA2 mass and activity levels are not fully known. In this study, variables primarily related to lipoproteins, oxidation, and insulin resistance were correlated with Lp-PLA2 activity. In particular, a positive association was noted between Lp-PLA2 activity and LDL-C, apoB-100, ferritin, and HOMA-IR, but an inverse association with HDL-C and anti-oxidant levels. Although a cause and effect relationship cannot be determined from this study, it does suggest that Lp-PLA2 activity may be influenced by the underlying atherogenic and pro-oxidant milieu. Interestingly, well-accepted risk factors such as hypertension, diabetes, and smoking and life-style behaviours all were not correlated with Lp-PLA2 activity.

There is compelling evidence that levels of LDL-C correlate with Lp-PLA2 mass and activity. Although it is known that Lp-PLA2 is released by inflammatory cells and then attaches itself to apoB-100 through a specific non-covalent interaction, the factors that mediate changes in Lp-PLA2 have not been determined. In most subjects, the majority of Lp-PLA2 mass is found on LDL-C and a relatively small amount (∼5%) is found on HDL.[31] Interestingly, lipoprotein(a) particles carry proportionally more Lp-PLA2 mass (1.5-fold) and activity (up to 7-fold) compared to equimolar amounts of LDL in the same subjects (reviewed by Tsimikas et al.[32]). In fact, a recent study from the Bruneck population showed that subjects in the highest tertile of both Lp-PLA2 activity and of oxidized phospholipids on apolipoprotein B-100 particles (OxPL/apoB) have nearly double the risk of future cardiovascular events compared to subjects in the highest tertile of each factor individually.[24] This suggests that a pro-oxidant environment where both substrate (OxPL) and enzyme (Lp-PLA2) activity levels are elevated results in a higher risk compared to each factor alone. Additionally, lipid lowering drugs have differential effects on LDL- and HDL-associated Lp-PLA2 activity. For example, whereas ezetimibe, rosuvastatin, and fenofibrate all reduce non-HDL-associated Lp-PLA2 mass and activity, only fenofibrate increases HDL-associated Lp-PLA2 mass and activity.[33] These data suggest that additional information on the pathophysiological role of Lp-PLA2 may be obtained by evaluating both its interaction with individual lipoproteins and makes a strong rationale for further research in this area.

This is the first study to document that ferritin levels positively correlate with Lp-PLA2 activity and that HDL-C and anti-oxidant levels are inversely associated. Additionally, this study confirms the strong association between Lp-PLA2 levels and the metabolic syndrome.[34,35] Ferritin is the main intracellular storage protein of iron. Heavy metal cations, such as iron and copper, are strong catalysts for oxidation of lipoproteins resulting in a large number of biological properties that could in principle make oxidized LDL proatherogenic.[36] Haem, an iron complex with protoporphyrin IX, is also a strong LDL-oxidizing agent, especially when activated by low concentrations of peroxides. Small amounts of haemoglobin are constantly leaking from damaged erythrocytes, particularly in the vascular regions with turbulent flow, such as vessel bifurcations and aortic curvatures. Haemoglobin-induced LDL oxidation has been suggested to significantly contribute to the increased levels of OxLDL found in the plasma of the patients on haemodialysis.[37]

Prior studies have primarily focused on Lp-PLA2 mass, which is now clinically available as an adjunct to clinical risk prediction.[38] In this study, we measured Lp-PLA2 activity, which is only available as a research assay. It has not been established whether Lp-PLA2 mass or Lp-PLA2 activity provide similar, complementary, or independent information. In published studies where both mass and activity were measured,[15,22,35] only a modest correlation was noted between Lp-PLA2 mass and activity. Future studies will be important to ascertain the role of each measure, particularly with the current clinical trials of Lp-PLA2 inhibitors to reduce cardiovascular risk.[39]

Limitations

Although this is a prospective study with 10-year follow-up, the number of events was limited. However, the cohort is extremely well characterized with 100% ascertainment of follow-up. Many of the associations with Lp-PLA2 were modest in strength, although highly statistically significant. These observations need to be verified in future studies.

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