Review of the Evidence for the Clinical Utility of Lipoprotein-Associated Phospholipase A₂ as a Cardiovascular Risk Marker

Contrasting histopathologic characteristics of a stable versus ruptured plaque. Most acute myocardial infarctions and sudden cardiac deaths occur from plaque rupture. Characteristics of ruptured plaques (right) include a high tissue concentration of lipoprotein-associated phospholipase A₂ (Lp-PLA₂) and inflammatory cells, and a thin fibrous cap that is <65 μm across, but there may be minimal stenosis. In contrast, stable plaque (left) has low concentrations of Lp-PLA₂ and inflammatory cell content, and thick fibrous caps, although there may be significant stenosis. Illustration by Scott Barrows, Medical Illustrator, University of Illinois at Chicago.

Elevated lipoprotein–associated phospholipase A₂ (Lp-PLA₂) is consistently associated with a doubling of risk for cardiovascular disease (CVD). Published prospective epidemiologic studies show the association of elevated Lp-PLA₂ (top quantile vs bottom quantile) with cardiovascular risk. A fairly consistent near doubling of risk is associated with elevated Lp-PLA₂. Results are fully adjusted for traditional risk factors, lipids, and often for body mass index and high-sensitivity C-reactive protein. ACS = acute coronary syndromes; ARIC = Atherosclerosis Risk in Communities; CAD = coronary artery disease; CHS = Cardiovascular Health Study; GUSTO/FRISC = Global Use of Strategies to Open Occluded Coronary Arteries/Fragmin During Instability in Coronary Artery Disease; KAROLA = Langzeiterfolge der Kardiologischen Anschlussheil-Behandlung; LDL = low-density lipoprotein cholesterol; LURIC = Ludwigshafen Risk and Cardiovascular Health Study; MI = myocardial infarction; NHS = Nurse's Health Study; NOBIS-II = North Wuerttemberg and Berlin Infarction Study–II; NOMAS = Northern Manhattan Study; PEACE = Prevention of Events with Angiotensin-Converting Enzyme Inhibition; PROSPER = Prospective Study of Pravastatin in the Elderly at Risk; PROVE-IT = Pravastatin or Atorvastatin and Infection Therapy; THROMBO = Thrombogenic Factors and Recurrent Coronary Events; WHI = Women's Health Initiative; WOSCOPS = West of Scotland Coronary Prevention Study.

Lipoprotein–associated phospholipase A₂ (Lp-PLA₂) adds to the area under the curve for traditional risk factors (TRF) and other biomarkers. The Langzeiterfolge der Kardiologischen Anschlussheil-Behandlung (KAROLA) study examined the risk of recurrent cardiovascular events in high-risk patients after acute coronary syndromes or revascularization associated with elevated Lp-PLA₂ (A). In receiver operating characteristic analysis, Lp-PLA₂ significantly raised the area under the curve (AUC) additively to TRF, lipids, and body mass index (BMI), even with other novel risk markers, such as cystatin C and N-terminal pro–brain natriuretic peptide (NT-proBNP) in the model (B). MI = myocardial infarction. *p = 0.03 fully adjusted for TRF, low-density lipoprotein and high-density lipoprotein, statin drugs, C-reactive protein, age, BMI, etc.; ^†TRF = age, sex, smoking status, history of MI, diabetes mellitus, rehabilitation, lipid-lowering drugs, angiotensin-converting enzyme inhibitor intake. (Adapted from Arterioscler Thromb Vasc Biol.²⁹)

Death rate 1 year after acute myocardial infarction (MI) was 5-fold higher, with elevated lipoprotein-associated phospholipase A₂ (Lp-PLA₂) in the Mayo Heart Study in Olmsted County, Minnesota (A). In receiver operating characteristic analysis, Lp-PLA₂ significantly raised the area under the curve (AUC) additively to traditional risk factors (TRF), lipids, diabetes mellitus, and obesity (B). *TRF = age, sex, hypertension, dyslipidemia, diabetes, smoking, and obesity. (Adapted from Arterioscler Thromb Vasc Biol.³¹)

High levels of lipoprotein-associated phospholipase A₂ (Lp-PLA₂) and metabolic syndrome (MS) are independent and additive risk factors in the Malmö study. CVD = cardiovascular disease. (Adapted from Arterioscler Thromb Vasc Biol.²³)