Lipoprotein-Associated Phospholipase A₂: A Risk Marker or a Risk Factor?

Lipoprotein-associated phospholipase A₂ (Lp-PLA₂) as a trigger of inflammation and rupture-prone plaque formation. The Lp-PLA₂ enzyme is produced by intraplaque macrophages and foam cells and is released by plaque into the circulation, where it binds to lipoproteins. Approximately 1 in 500 low-density lipoprotein (LDL) particles has an Lp-PLA₂ enzyme bound to it. On entry into the intimal space, the phospholipid surface of the LDL particle can oxidize. Lp-PLA₂ hydrolyzes oxidized phospholipids into oxidized fatty acids (oxFA) and lysophosphatidylcholine (lysoPC) products. These products stimulate adhesion molecule expression and release of cytokines, which recruit more leukocytes to the lesion. A vicious cycle of more Lp-PLA₂ production appears to ensue. (illustration by Scott Barrows, medical illustrator, University of Illinois at Chicago.)

Lipoprotein-associated phospholipase A₂ (Lp-PLA₂) enters the coronary circulation when coronary atherosclerosis (by intravascular ultrasound [IVUS]) is present. A total of 15 patients with early coronary atherosclerosis by IVUS were compared with 15 controls. Lp-PLA₂ levels in the coronary os (aorta) were compared with levels in the coronary sinus (vein), the difference reflecting either coronary production versus absorption of Lp-PLA₂. When coronary atherosclerosis was present, there was net production of Lp-PLA₂ as blood flowed across the coronary vascular bed. CRP = C-reactive protein; NS = not significant. (Courtesy of Amir Lerman, MD.)

Endothelial dysfunction in coronary arteries worsens as lipoprotein-associated phospholipase A₂ (Lp-PLA₂) increases. Unadjusted and adjusted association between percent change (±SE) in coronary blood flow in response to the maximal dose of intracoronary acetylcholine (microvascular endothelial function) and Lp-PLA₂ is shown. Values are adjusted for age, sex, body mass index, serum creatinine, total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglycerides, and the use of lipid-lowering medication. Analysis of variance for trend: p <0.001 for unadjusted and p = 0.008 for adjusted data. (Reprinted with permission from Arterioscler Thromb Vasc Biol.³³)

Odds ratio for coronary artery endothelial dysfunction for different lipid markers and lipoprotein-associated phospholipase A₂ (Lp-PLA₂). Elevated Lp-PLA₂ in the top tertile (>240 ng/mL) was associated with a statistically significant 3.3 odds ratio for coronary endothelial dysfunction (post acetylcholine challenge). Commonly measured lipids did not achieve significance as predictors of endothelial dysfunction in this cohort of 172 patients with <30% angiographic coronary stenosis. CI = confidence interval; HDL = high-density lipoprotein; LDL = low-density lipoprotein. For cholesterol, 1 mg/dL = 0.02586 mmol/L; for triglycerides, 1 mg/dL = 0.0113 mmol/L. (Courtesy of Amir Lerman, MD.)

Specificity and biologic variability of cardiac risk markers. Lipoprotein-associated phospholipase A₂ (Lp-PLA₂) has a higher specificity and lower biologic variability than other inflammatory markers and is specific to vascular inflammation. (A) Inflammatory markers were drawn in 90 young, healthy volunteers (average age, 34 years). Using roughly the top tertile of each biomarker, lipoprotein-associated phospholipase A₂ (Lp-PLA₂) was rarely elevated in these healthy individuals, whereas 46% of the individuals had elevated high-sensitivity C-reactive protein (hs-CRP). (B) Blood was drawn from 43 healthy adults 7 times for a 4-week period. Lp-PLA₂ is shown to exhibit low biologic variability (fluctuation within an individual over time) comparable to commonly measured lipids but in contrast to high biologic variability for hs-CRP. CV = cardiovascular; HDL = high-density lipoprotein; LDL = low-density lipoprotein; TG = triglycerides. (Adapted from Circulation.³⁷)

Apparent cardiovascular risk threshold above the bottom tertile for the elevation of lipoprotein-associated phospholipase A₂ (Lp-PLA₂) in high-risk patients. In 504 patients with angiographic coronary artery disease in the Mayo Heart Study (A), and in 1,051 patients post acute coronary syndromes or coronary revascularization in the Langzeiterfolge der Kardiologischen Anschlussheil-Behandlung (KAROLA) study (B), the risk for subsequent hard cardiovascular events increases steeply at the middle tertile for the Lp-PLA₂ biomarker. (Adapted from Eur Heart J³⁶ and Arterioscler Thromb Vasc Biol.³⁹)