Lipoprotein-Associated Phospholipase A2 (Lp-PLA2)

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tulsa functional cardiology Lp-PLA2What is Lp-PLA2?

Lp-PLA2, also known as platelet-activating factor acetylhydrolase (PAF-AH), was initially identified as the enzyme responsible for hydrolyzing and inactivating the inflammatory phospholipid PAF (1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine).1-3

PAF is a biologically active phospholipid that expresses several inflammatory activities and is involved in various pathophysiological conditions including atherogenesis.1-3 PAF is hydrolyzed and inactivated by PAF-acetylhydrolase, a Ca2+-independent, phospholipase A2 (PLA2).3 PAF-acetylhydrolase circulates in plasma in active form bound to lipoproteins,4-6 and is thus known as lipoprotein-associated phospholipase A2 (Lp-PLA2).6

Approximately 80% of Lp-PLA2 circulates bound to low-density lipoprotein (LDL), whereas the other 20% is bound to high-density lipoprotein (HDL).7,8 Lp-PLA2 hydrolyzes the sn-2 ester bond in phospholipids of which the fatty acid moiety has been shortened or altered by oxidation to yield oxidized fatty acid and lysophosphatidylcholine (lysoPC).9 These metabolites have inflammatory properties,10 and lysoPC has been shown to have adverse effects on endothelial function.11-13

Lp-PLA2 could, therefore, play a direct role in the development of endothelial dysfunction and coronary artery disease (CAD). In addition, it may also serve as a useful biomarker for predicting coronary endothelial dysfunction.14

More recent evidence demonstrates that in addition to the lipoproteins, another carrier of Lp-PLA2 in human plasma is platelet-borne microparticles (PMPs).15,16 It is well-documented that Lp-PLA2 is a cardiovascular disease (CVD)-specific vascular inflammation biomarker which has been shown to be strongly predictive of CVD events, including stroke.

The precise pathophysiological role of the Lp-PLA2 enzyme in plasma as well as in the artery wall needs further clarification.

Several studies have suggested that the exact role of Lp-PLA2 may be differentiated according to the type of the lipoprotein carrier with which Lp-PLA2 circulates in plasma. Lp-PLA2 also plays a inflammatory role in coronary endothelial dysfunction and early atherosclerosis.14

Several population-based studies have shown that elevated lipoprotein-associated phospholipase A2 (Lp-PLA2) levels are associated with an increased risk of coronary heart disease and ischemic stroke.14,17-31

Rupture Prone Plaque & Lp-PLA2

Lp-PLA2 is a marker of vascular-specific inflammation and reflects the presence of rupture-prone plaque. Elevated levels of serum Lp-PLA2 are indicative of rupture-prone plaque and a strong independent predictor of cardiovascular risk, including CAD, myocardial infarction (MI), and stroke.18

Lp-PLA2 is clinically associated with an increased CHD risk, and there is a large body of published evidence from epidemiologic studies addressing the relationship of Lp-PLA2 and risk of cardiovascular disease.32-34

Although a small proportion of circulating Lp-PLA2 activity is associated with high-density lipoprotein (HDL), the majority (~80%) is associated with LDL. In particular, Lp-PLA2 is a potential marker for atherogenic small dense LDL (sdLDL), as most LDL-associated Lp-PLA2 (LDLLp-PLA2) is found complexed with sdLDL particles.16

The distribution of Lp-PLA2 between LDL and HDL is altered in various types of dyslipidemias (e.g., when plasma levels of lipoprotein (a) [Lp(a)] exceed 30 mg/dL)7,35; moreover, evidence suggests that the role of Lp-PLA2 in atherosclerosis may depend upon the type of lipoprotein particle with which it is associated.

For example, while several population-based studies have demonstrated independent association of plasma Lp-PLA2 levels—which largely reflect LDLLp-PLA2—with increased cardiovascular risk, HDL-associated Lp-PLA2 may be atheroprotective.7 Recent studies also indicate that oxidized phospholipids (oxPL) are preferentially sequestered by Lp(a), and subsequently degraded by Lp(a)-associated Lp-PLA2. These findings suggest that Lp(a) is a potential scavenger of oxPL, providing novel insight into the role of Lp(a) and Lp(a)-associated Lp-PLA2 in normal physiology as well as in inflammation and atherosclerosis.16

Elevated plasma Lp-PLA2 raises the risk of cardiovascular events by approximately 2 fold.16 Multiple prospective epidemiologic studies have demonstrated association of increased Lp-PLA2 levels with primary coronary or cardiovascular events, future coronary events, and stroke, suggesting that Lp-PLA2 has significant clinical utility as a cardiovascular risk marker.17

Further support for the proatherogenic role of LDLLp-PLA2 is derived from its preferential association with sdLDL,36 the most atherogenic LDL species.37 The enrichment of sdLDL with Lp- PLA2 enhances production of lysoPC during oxidation, in both normolipidemic and hypercholesterolemic patients.38 Other studies have demonstrated that Lp-PLA2 may significantly contribute to the atherogenicity of the electronegative LDL subfraction.39,40

Lp-PLA2 and Ethnicity

Emerging data suggest that metabolic and inflammatory factors impacting CVD risk differ across ethnic groups.26,32,33 There are several important differences between African-Americans and Caucasians with respect to Lp-PLA2. First, among subjects with CAD, Lp-PLA2 activity levels were higher among African- Americans. Second, the difference in Lp-PLA2 activity levels between CAD and non-CAD subjects was higher among African- Americans. Furthermore, the Lp-PLA2 index, a measure of enzymatic properties, was independently associated with the extent of CAD among African-Americans.41

Lp-PLA2 and Cardiovascular Disease

Functional medicine physicians seek the underlying problem. Cardiovascular disease is a complex process with over 400 different contributing risk factors. Understanding Lp-PLA2 helps us evaluate cardiovascular disease risk as well as where we should place our efforts to try to resolve the issue.

Lp-PLA2 is a vascular-specific proinflammatory enzyme that operates in the arterial intima.

Lp-PLA2 localizes to atherosclerotic plaque, particularly in those with a necrotic core and in ruptured plaques.42 High levels of Lp-PLA2 are found in rupture- prone plaques, and it appears that Lp-PLA2 is released from these plaques into the circulation. Lp-PLA2 is primarily produced by macrophages and then bound to various lipoproteins, including the apoB portion of LDLs and Lp(a).14

Staining of coronary and carotid tissue demonstrates the presence of Lp-PLA2 in the thin fibrous cap of rupture-prone plaques, but not in the early-stage plaques.43 Coronary and carotid tissue concentrations of Lp- PLA2 are notably very high in the rupture-prone shoulder region of thin fibrous cap atheromas, and histopathologic stains reveal that Lp-PLA2 colocalizes with macrophages and oxidized LDL in atherosclerotic coronary and carotid plaques.44

Lp-PLA2 hydrolyzes phospholipids on oxidized LDL particles in the subendothelial space. Lp-PLA2 hydrolyzes the center (n-2) ester bond of phospholipids, which yields oxidized fatty acids and lysoPC, a molecule with a range of potentially atherogenic effects, including chemoattraction of monocytes, increased expression of adhesion molecules, and inhibition of endothelial nitric oxide production.10,45

In this manner, a vicious cycle is set up that leads to the recruitment of monocytes to the intima, where they differentiate to become macrophages and, ultimately, foam cells, while at the same time locally producing more Lp-PLA2.

Furthermore, lysoPC has been found to be cytotoxic to vascular smooth muscle cells and can induce the local production of matrix metalloproteinases (MMPs), which can thin the fibrous cap and destabilize the architectural integrity of an atheromatous plaque, increasing its propensity to rupture.46

In terms of its utility as a circulating biomarker, Lp-PLA2 produced by activated macrophages and foam cells re- enters the bloodstream and can be measured. As reported by Lavi et al., Lp-PLA2 blood concentrations sampled simultaneously in the human coronary sinus demonstrated a net increase in Lp-PLA2 levels as blood traverses the coronary vascular bed with significant atherosclerotic plaque.14 However, when no coronary plaque is present, a decrease in Lp-PLA2 levels is found. This study also showed that the lysoPC produced by the Lp-PLA2-mediated hydrolysis of oxidized LDL is strongly associated with coronary artery endothelial dysfunction.

Summary of Lp-PLA2 Clinical Studies:

Lp-PLA2 is a Predictor of Cardiovascular and Stroke Events:

  1. An independent risk factor for CVD and stroke events14,18
    • 2x risk for CVD events when elevated
    • 5.5x risk for stroke events when elevated
  2. Predicts CVD in elderly men and women even with normal LDL-C levels19
  3. Additive risk with CRP18,20 or systolic blood pressure (SBP)20
    • When both Lp-PLA2 and CRP are very high—4x risk for CVD events
    • When both Lp-PLA2 and SBP are very high—6.4x risk for ischemic stroke
    • When both Lp-PLA2 and CRP are very high—11.4x risk for ischemic stroke
  4. Lp-PLA2 with CRP predicts recurrence and severity of second stroke event24
  5. Additive risk from Lp-PLA2 and CRP beyond carotid IMT results25
  6. Predicts angiographic finding of coronary atherosclerosis14,22
  7. Predicts coronary death22
  8. Predicts coronary endothelial dysfunction, which is a marker for early atherosclerosis and increased risk of ischemic cardiac events and stroke14
    • Lp-PLA2 is primarily associated with LDL (LDL-Lp-PLA2); a small amount of the enzyme activity is also associated with HDL.16
    • Most LDL-Lp-PLA2 is bound to atherogenic sdLDL particles and is a possible marker of sdLDL in plasma.16
    • Distribution of Lp-PLA2 between LDL and HDL is affected by various types of dyslipidemias.16
    • Lp-PLA2 levels may also be affected when Lp(a) plasma levels are greater than 30 mg/dL.16

How to reduce your Lp-PLA2:

A cross-sectional study of apparently healthy men and women demonstrated that Lp-PLA2 activity is influenced by a number of modifiable factors. Circulating levels of the enzyme were found to be positively associated with body weight and smoking, but inversely associated with increased consumption of alcohol and protein, and in women, with use of postmenopausal hormones.47

  • Decrease body fat
  • Do not smoke! Smoking increases Lp-PLA2
  • Appropriate alcohol intake – 1-2 glasses per day for men, and 1 for women
  • Consume appropriate amounts of protein
  • Hormone replacement therapy
  • Lp-PLA2 is lowered by statins and fenofibrate50-53
  • Niacin added to established statin therapy lowers Lp-PLA2 levels by additional 20%54
  • Lp-PLA2 cut-point values for patients with known CVD
    • Alert cut-point of > 235 ng/mL8,9,32
    • Goal cut-point of < 200 ng/mL8,9

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