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Lipoprotein-associated phospholipase (Lp-PLA2)

Lp-PLA2: An Inflammatory Biomarker

As previously stated, increasing evidence has suggested that cardiovascular and other metabolic diseases are inflammatory diseases. The enzyme Lp-PLA2 circulates in the blood, and attaches to LDL cholesterol particles in the bloodstream. Sometimes these particles containing the Lp-PLA2 adhere to the arterial walls, where a process known as oxidation takes place (Libby, Ridker, & Maseri, 2002; Macphee, et al., 2001; Suckling, et al., 2003; Tsimihodimos, et al., 2003). Oxidized LDL is susceptible to enzymatic attack, which promotes pro-inflammatory markers capable of triggering the atherogenic process. These inflammatory molecules help promote the build-up of fatty deposits (plaque) in the arteries, as well as produce molecules that attract immune cells to the arterial walls. These molecules bind to the cells called monocytes, which are large white blood cells, and are converted to macrophages, increasing the amount of atherosclerotic build-up.

Lp-PLA2: Risk Marker or Risk Factor

As previously stated, recent studies show that inflammation does play a role in cardiovascular disease (Castelli, et al., 1996; Libby, Ridker, & Maseri, 2002; Ridker, et al., 2000). It has been found that many persons with cardiovascular disease do not display traditional risk factors such as elevated cholesterol levels (Castelli, et al, 1996; Ridker, et al, 2000). Lp-PLA2 is considered currently considered a risk marker rather than a risk factor. However, the use of Lp-PLA2 in determining elevated risks for cardiovascular disease is relatively new. Two clinical studies have found that Lp-PLA2 to be independently linked to cardiovascular disease (Ballantyne, et al., 2003; Packard, et al., 2000). Several studies are underway regarding the importance of Lp-PLA2 as an inflammatory marker. However, very little is currently known regarding what role Lp-PLA2 plays in determining cardiovascular disease and what course of action is appropriate to improve Lp-PLA2 levels.

Lp-PLA2: The PLAC Test

Lp-PLA2 is measured through a simple blood test. The assay that is used is the Enzyme-linked sandwich immunosorbent assay (ELISA). This is called the PLAC test, and detects the presence of Lp-PLA2 in the blood. Currently Mayo Medical Laboratories, part of Mayo Clinic, support the PLAC test to determine Lp-PLA2 levels. The blood sample sent to one of their laboratories and the results are sent back to the physician.

The expected values are measured in ng/mL. Average value for females is 174 ng/mL (range 5th - 95th percentile: 120-342), and the average value for males is 251 (range 5th - 95th percentile: 131-376).

Lp-PLA2: Future Significance

Lp-PLA2 is not included in the CDC/AHA Expert Panel Recommendations for Inflammatory Markers that was published in 2003. The clinical research is still being evaluated as to the future significance of this inflammatory marker. Several studies have demonstrated the importance of CRP in the development of cardiovascular disease. More recently, the Lp-PLA2 has been linked to the atherogenic process. Two studies specifically have shown an associated between Lp-PLA2 with the development of cardiovascular disease (Both of these studies focused on Lp-PLA2 levels and found that those with elevated levels of Lp-PLA2 were at greater risk of an event compared to those with lower levels of Lp-PLA2 independent of traditional cardiovascular risk factors. Additionally, they found that Lp-PLA2 was individually and independently predictive of future cardiovascular events (Ballantyne, et al., 2003; Packard, et al., 2000).

CDC/AHA Expert Panel Recommendations for Inflammatory Markers

As a result of this increased interest in hs-CRP, the Centers for Disease Control and Prevention (CDC), and the American Heart Association (AHA) appointed a panel of experts (the Working Group) to examine inflammatory markers and their relevance to prevention and treatment practices (Pearson, Mensah, et al., 2003). One of the main objectives of this expert committee was to review measurement standards with respect to inflammatory markers and their potential for routine risk assessment. The Working Group published a scientific statement on markers of inflammation and cardiovascular disease summarizing their findings for clinical and public health strategies (Pearson, Mensah, et al., 2003). A summary of the Working Group’s findings are outlined below:

— The Working Group limited current assays to metabolically stable patients, using highly sensitive C-reactive Protein (hs-CRP), measured twice (ideally 2 weeks apart) with the average expressed in mg/L. The findings to be interpreted as follows …

Low risk < 1.0 mg/L
Average Risk 1.0 to 3.0 mg/L
High Risk >3.0 mg/L

The hs-CRP was chosen because it is a commercially available assay sensitive enough (low detection limit) for the detection of vascular disease (Pepys & Hirshfield, 2003; Pearson, Mensah , et al., 2003; Ridker, 2003).

— The Working Group recommended against general screening of adults, but suggested limiting the use of hs-CRP as an adjunct to major risk factors for primary prevention screening augmenting risk stratification. That is, physicians have the option to use hs-CRP to help detect an elevated risk in individuals with a low to moderate risk (defined as having between a 10% to 20% relative risk for coronary artery disease with the next 10 years).

— The Working Group concluded that in persons with stable cardiovascular disease or acute coronary syndromes, hs-CRP can be useful as an independent marker for identifying potential recurring events. However, physicians should not base secondary prevention strategies solely on the results of hs-CRP. Further, hs-CRP should not be the marker used to monitor effects of secondary treatment strategies.

— At this time, the Working Group cautioned against using hs-CRP in the absence of traditional risk factors, because of the limited data available to support its use as a sole marker. Further, it is not recommended in individuals with a high risk, defined as having greater than a 20% relative risk for cardiovascular disease within the next 10 years, because these individuals would already be targeted for intensive secondary or tertiary treatment (Parson, 2002).

— An untested future potential use of hs-CRP is as a motivational tool. The Working Group suggests that persons with an elevated risk need encouragement to change behaviors or comply with pharmacological therapies (Pearson, Mensah, et al., 2003). Future studies will need to be conducted to see if hs-CRP could be an effective tool during counseling in motivating behavioral change.

NOTE: The Working Group cautions professionals regarding these recommendations, because the scientific evidence is not yet fully adequate.

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