Clinical Utility of Inflammatory Markers and Advanced Lipoprotein Testing: Advice From an Expert Panel of Lipid Specialists

Conclusions:

The following are 10 points to remember about the clinical utility of inflammatory markers and advanced lipoprotein testing:

1. This report describes the consensus view of an expert panel convened by the National Lipid Association to evaluate the use of selected biomarkers to improve risk assessment, or to adjust therapy.

2. High-sensitivity C-reactive protein (CRP) is a marker of risk for cardiovascular (CV) events and reflects the inflammatory state. The hazard ratio for a 1-standard deviation change in CRP after adjustment for traditional risk factors is similar to non–high-density lipoprotein cholesterol (HDL-C) and systolic blood pressure, and consistent in men and women. CRP appears to have the potential to directly and indirectly activate inflammation and cytotoxicity, resulting in progressive vessel wall injury and atherosclerotic plaque formation.

3. CRP measurement is not recommended for routine use in low-risk (5% 10-year risk) patients, but may be of value in the metabolic syndrome. CRP is recommended routinely in intermediate-risk (5-20%) men beginning at 50 years of age and women at 60 years of age, especially when used with Reynolds risk scoring. CRP measurement is a reasonable option to help determine if therapy should be: 1) started in the case of premature family history, or 2) guide the intensity of therapy. Those with a CRP level >2.0 mg/L may benefit from intensification of both statin and lifestyle modification.

4. Lipoprotein-associated phospholipase A2 (Lp-PLA2) is an enzyme carried on lipid particles and an inflammatory biomarker produced in atherosclerotic plaques, linked to inflammation and presumably to plaque rupture. High levels are associated with an approximate twofold increase in risk for CV events (mortality, acute coronary syndrome, strokes), it is predictive independent of CRP, and has less variability than CRP. Lipid-lowering agents and lifestyle changes reduce Lp-PLA2.

5. Lp-PLA2 testing should not be performed in low-risk patients, but may be considered in intermediate-risk patients, as well as certain higher-risk subgroups (smokers and increased fasting blood sugar), in whom an elevated Lp-PLA2 level (>200 ng/ml) would reclassify them into high risk. It is not recommended for on-treatment risk management decisions.

6. Each lipoprotein particle secreted by the intestine or the liver contains one molecule of apolipoprotein (Apo) B that encircles the particle, provides external structural integrity, and is responsible for hepatic low-density lipoprotein (LDL) receptor binding. Apo B levels are a direct indication of the total number of circulating Apo B-containing lipoprotein particles. Like non–HDL-C, Apo B does not require a fasting blood draw. Considering published studies of lipids as outcome markers, the hierarchy is Apo B being the best predictor, LDL-C the worst, and non–HDL-C intermediate. Apo B superiority over non–HDL-C would be more likely in patients with elevated triglycerides and/or a low HDL-C, and in diabetes and the metabolic syndrome.

7. In patients at intermediate risk, a premature family history, and those with recurrent events, measurement of Apo B would enable the best possible management of modifiable factors for vascular risk. Once a patient with coronary heart disease (CHD) or CHD risk equivalent has achieved an LDL-C and/or non–HDL-C goal, an Apo B measurement might be useful for determining whether further intensification of lipid-lowering therapy is warranted. In patients at intermediate risk, with CHD or CHD risk equivalent, an Apo B target of <80 mg/dl is reasonable, with intensification to <70 mg/dl for those at very high risk.

8. LDL particles move into the arterial wall via a gradient-driven process; the greater the number of LDL particles (LDL-P), the greater the rate of diffusion into the arterial wall available to be oxidized and taken up by macrophages to form foam cells. Serum Apo B and LDL-P, as measured by nuclear magnetic resonance, are reflective of the particle number and indications for use are similar; diabetes, metabolic syndrome, and high triglycerides/low HDL-C in whom LDL particles are cholesterol poor and use of LDL-C is less predictive. Target values for LDL-P are below the 20th percentile (<1100 nmol/L) for very high- and high-risk patients, or the 50th percentile (<1440 nmol/L) for moderately high- and moderate-risk patients.

9. Lipoprotein (a) [Lp (a)] represents a modification of LDL by addition of a lipoprotein antigen, a protein made in the liver that binds to LDL in the plasma and forms a disulfide bond with Apo B. Because of a homology with plasminogen, it competitively binds with fibrin and reduces thrombolysis. Increasing levels (>30 mg/dl) are associated with an increase in CV events independent of other lipid parameters and risk factors. Lp (a) is genetically determined and is often elevated in persons with premature coronary disease. Intense lowering of LDL-C may reduce the risk attributable to an elevated Lp (a). Because there is no evidence that reducing Lp (a) is harmful, some lipidologists will use niacin in an effort to treat other lipoprotein abnormalities and to also achieve a lower Lp (a). Because elevated levels are additive to risk, one could argue that anyone presenting with vascular disease should have this measurement.

10. Using several analytic methods, LDL and HDL particles have been shown to be heterogeneous in size, density, and cholesterol/lipid content, each of which can affect their pro- and anti-atherogenic capacity. There is insufficient evidence to support LDL or HDL subfraction measurement in either initial or on-treatment management of persons in any risk category.

Perspective:

This is a very worthwhile article for those interested in biomarkers. While the recommendations are consistent with clinical practice of some cardiologists and lipid specialists including myself, there is little evidence to support specific targets for Apo B, LDL-P, nor best cut-points of risk for Lp (a) or Lp-PLA2.

Clinical Topics: Acute Coronary Syndromes, Diabetes and Cardiometabolic Disease, Dyslipidemia, Atherosclerotic Disease (CAD/PAD), ACS and Cardiac Biomarkers, Lipid Metabolism, Nonstatins, Novel Agents, Statins

Keywords: Inflammation, Coronary Artery Disease, Acute Coronary Syndrome, Stroke, Plaque, Atherosclerotic, Hypertriglyceridemia, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Lipoproteins, Blood Pressure, Metabolic Syndrome X, Cholesterol, C-Reactive Protein, Biological Markers, Plasminogen, Foam Cells, Fibrinolysis, Niacin, Fibrin, Risk Assessment, Magnetic Resonance Spectroscopy, Diabetes Mellitus


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