Measurement of low density lipoprotein (LDL) cholesterol and high density lipoprotein (HDL) cholesterol is the cornerstone of cardiovascular disease risk assessment. Yet few of us appreciate the potential for error due to imprecision and inaccuracy. Despite the widespread belief that the calculation or measurement of LDL or HDL cholesterol is standardized and reproducible, the data indicate that results can vary significantly with methods from different manufacturers, and calculated LDL cholesterol may not agree with measured LDL cholesterol. Problems with direct HDL-C assays also raise concerns about the reliability of calculated LDL cholesterol and non-HDL cholesterol measurement. Poor reliability of these assays relate to the ambiguity in the definition of both LDL and
HDL particles, and the heterogeneity of LDL and HDL particles (1).
For clinical research organizations (CROs), contract laboratories, and academic and pharmaceutical research laboratories developing next generation lipid therapies and diagnostics, choice of methods is vitally important. Clinical laboratories, especially those that specialize in lipid testing, should also consider assay reliability when choosing methods. This manuscript examines the reliability of current methodologies for measurement of LDL and HDL cholesterol and suggests that “old school” methods, such as dextran sulfate precipitation, perform better than newer homogeneous assays.

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Diabetes. 2009 Dec;58(12):2711-7.

Emerging evidence suggests that HDL function is not always accurately predicted by HDL cholesterol levels. The functions of HDL include reverse cholesterol transport and modulation of inflammation. These functions appear to have evolved as part of the innate immune system. In healthy individuals, in the absence of systemic oxidative stress and inflammation, HDL is anti-inflammatory. However, in those with chronic illnesses such as diabetes that are characterized by systemic oxidative stress and inflammation, HDL may actually promote the inflammatory response (i.e., it may become proinflammatory). HDL may be thought of as a shuttle. The size of the shuttle can be estimated by HDL cholesterol levels. The shuttle’s cargo can change dramatically from one that efficiently promotes reverse cholesterol transport and is anti-inflammatory to one that is less effective in promoting reverse cholesterol transport and is also proinflammatory without any change in the size of the shuttle (i.e., these changes in HDL cargo can occur without any change in HDL cholesterol levels). Understanding these issues may lead to improved use of HDL as a biomarker and may also lead to new therapeutic targets and therapies.

Clinical Chemistry. 2008;54:788-800

Background: Plasma concentrations of HDL cholesterol (HDL-C) and its major protein component apolipoprotein (apo) A-I are strongly inversely associated with cardiovascular risk, leading to the concept that therapy to increase HDL-C and apoA-I concentrations would be antiatherosclerotic and protective against cardiovascular events. The recent failure of the drug torcetrapib, a cholesteryl ester transfer protein inhibitor that substantially increased HDL-C concentrations, has brought focus on the issues of HDL heterogeneity and function as distinct from HDL-C concentrations.

Content: This review addresses the current state of knowledge regarding assays of HDL heterogeneity and function and their relationship to cardiovascular disease. HDL is highly heterogeneous, with subfractions that can be identified on the basis of density, size, charge, and protein composition, and the concept that certain subfractions of HDL may be better predictors of cardiovascular risk is attractive. In addition, HDL has been shown to have a variety of functions that may contribute to its cardiovascular protective effects, including promotion of macrophage cholesterol efflux and reverse cholesterol transport and antiinflammatory and nitric oxide–promoting effects.

Summary: Robust laboratory assays of HDL subfractions and functions and validation of the usefulness of these assays for predicting cardiovascular risk and assessing response to therapeutic interventions are critically important and of great interest to cardiovascular clinicians and investigators and clinical chemists.