Received on March 23, 2006
Accepted on June 19, 2006

Lipids, Lipoproteins, and Cardiovascular Risk Factors

Lp-PLA₂: A New Kid on the Block

¹ GlaxoSmithKline, Cardiovascular Medicine Development Centre, Philadelphia, PA, and Thomas Jefferson University, Philadelphia, PA
² Worldwide Epidemiology, Philadelphia, PA
³ GlaxoSmithKline, Cardiovascular Medicine Development Centre, Philadelphia, PA
⁴ Center of Excellence for Drug Discovery, Philadelphia, PA

^* To whom correspondence should be addressed. E-mail: andrew.2.zalewski{at}gsk.com.

Background: Atherosclerosis is a systemic disease with focal rupture of vulnerable plaque responsible for major clinical events. Several population-based studies indicate an association between lipoprotein-associated phospholipase A₂ (Lp-PLA₂) and cardiovascular events. Lp-PLA₂ is emerging as a biomarker that may be viewed as the potential link between oxidized LDL cholesterol and multifocal plaque vulnerability.

Content: Lp-PLA₂ is produced by inflammatory cells of myeloid origin, is associated with circulating atherogenic lipoproteins (e.g., LDL), and is highly expressed in vulnerable plaques (de novo expression). Specificity of Lp-PLA₂ toward polar phospholipids in oxidized LDL may contribute to the formation of downstream products (e.g., lysophosphatidylcholine and nonesterified fatty acids) that mediate processes intimately involved in plaque vulnerability in situ, including proinflammatory cell phenotype and macrophage death. Recent studies in patients with acute coronary syndrome (ACS) demonstrate that Lp-PLA₂ and LDL measurements are not useful to assess the long-term cardiovascular risk shortly after the acute event. This is most likely a result of the acute drop in LDL values that is commonly observed in ACS. However, when measured at later time points, Lp-PLA₂ measurements emerge as an independent predictor of the long-term cardiovascular risk in the multivariate analysis.

Summary: Lp-PLA₂ is an intriguing marker of cardiovascular risk and may also be a marker of plaque activity/vulnerability. Despite these findings, unanswered questions still exist with respect to this enzyme and its biologic role in atherosclerosis. Addressing these questions will help clarify the clinical utility of measuring Lp-PLA₂ in routine clinical practice in the context of other approaches for identifying high-risk patients.