[Does Lp-PLA2 determination help predict atherosclerosis and cardiocerebrovascular disease?]

Jadranka Sertić, Bosko Skorić, Jasna Lovrić, Tamara Bozina, Zeljko Reiner
Acta Medica Croatica: C̆asopis Hravatske Akademije Medicinskih Znanosti 2010, 64 (4): 237-45
Thorough control of risk factors is pivotal for cardiocerebrovascular diseases. As classic risk assessment accounts for only 50% of risk variability and due to the role of inflammatory processes in endothelial dysfunction and atherosclerotic plaque rupture, it is necessary to identify new biomarkers for risk prediction. In addition to the inflammatory marker high sensibility C-reactive protein (hs-CRP), lipoprotein associated phospholipase A2 (Lp-PLA2) is gaining increasing significance, since it is directly involved in the pathogenesis of atherosclerotic plaque progression. Lp-PLA2 is highly specific for vascular inflammation, has low biological variability, and plays a causative role in atherosclerotic plaque inflammation. It belongs to the group of intracellular and secretory phospholipase enzymes that can hydrolyze sn-2 phospholipid ester bond of cellular membranes and lipoproteins. Lp-PLA2 enzyme is formed by macrophages and foam cells in atherosclerotic plaque, and is associated primarily with LDL particles in blood. Lp-PLA2 that is bound to LDL is the sole enzyme responsible for hydrolysis of oxidized phospholipids (oxPL) on LDL particles. Lp-PLA2 hydrolyzes oxPL at the surface of lipoproteins, but has weak activity against non-oxPL. Lp-PLA2 is also the enzyme that hydrolyzes oxPL on HDL particles, where it may have a role in the antioxidative function of HDL. The distribution of Lp-PLA2 between LDL and HDL particles depends on the extent of Lp-PLA2 glycosylation, which may affect the activity of Lp-PLA2 in plasma. Stable atherosclerotic plaques contain few inflammatory cells and a small amount of Lp-PLA2. In contrast, unstable plaques most often do not have significant impact on arterial lumen but may be detected by its thin connective tissue cap, low collagen and high lipid content. A distinguishing factor between stable and unstable atherosclerotic plaque may also be the presence of activated inflammatory cells and increased Lp-PLA2 concentration in unstable plaque. These new insights indicate that Lp-PLA2 may be a risk factor, which is important for the formation of atherosclerotic plaque but also for its rupture. The purpose of applying markers of inflammation is to improve stratification of patients at risk, so that treatment intensity may be adjusted to the risk level. Lp-PLA2 inhibition is associated with decreased cytokines. Lipid-affecting drugs stabilize atherosclerotic plaque by reducing the central lipid core, decreasing macrophage infiltration, and thickening of the connective tissue cap. These drugs reduce Lp-PLA2 concentration and the frequency of cardiocerebrovascular events as well. Besides acting as a specific marker of atherosclerotic plaque inflammation, Lp-PLA2 has a significant prognostic value because of its direct role in the formation of rupture-prone atherosclerotic plaque, unlike classic risk factors, for example lipid measurement or vascular imaging, which do not directly estimate acute ischemic potential in the arterial wall. Studies have demonstrated correlation between increased Lp-PLA2 concentrations and enhanced risk of cardiocerebrovascular events, even after multivariate adjustment to classic risk factors. In addition to its high specificity for vascular inflammation, Lp-PLA2 concentration is stable in terms of time, unlike, for instance, CRP levels. Lp-PLA2 has been confirmed as an independent risk predictor, which is complementary to hsCRP. It could be used in clinical practice for improved risk assessment in patients with transient cardiocerebrovascular risk, particularly in those with metabolic syndrome (obese patients with mixed dyslipidemia, hyperglycemia, insulin resistance, and arterial hypertension). Lp-PLA2 levels allow for further risk stratification of high-risk patients into a very high risk group where more aggressive therapy is recommended, as well as the achievement of LDL-cholesterol levels < 2.5 or, even better, < 2.0 mmol/L as a feasible therapeutic target. Similar to hsCRP, the levels of Lp-PLA2 are reduced by lipid-affecting drugs, while its low concentrations are associated with a very low risk of cardiocerebrovascular events both in low- and high-risk population. According to recent American guidelines for assessing the risk of cardiovascular disease, Lp-PLA2 determination is recommended as an additional marker to the classic risk assessment in patients with moderate and high risk.

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