Advanced Lipoprotein Testing and Subfractionation Are Not (Yet) Ready for Routine Clinical Use

Abstract

S tandard lipid tests measure the cholesterol or triglyceride content of lipoproteins, expressed as mg/dL (or mmol/L) of cholesterol or triglyceride. A standard lipid panel includes total cholesterol, low-density lipoprotein (LDL) cholesterol, highdensity lipoprotein (HDL) cholesterol, and triglycerides. These lipids are carried within lipoprotein particles that are heterogeneous in size, density, charge, core lipid composition, specific apolipoproteins, and function. 1 A variety of lipoprotein assays have been developed that subfractionate lipoprotein particles according to some of these properties such as size, density, or charge. 2 These lipoprotein assays have been proposed for improving assessment of risk of cardiovascular disease (CVD) and for guiding lipid-lowering therapies. They are mostly used today in specialized lipid clinics or research studies, and their general utility for clinical practice is not well delineated. 3 In this review, I first provide a summary of current guideline statements that address this topic. Then I give a brief overview of the different laboratory methods available for clinical use and discuss the literature evaluating these methods. Finally, I discuss current limitations to the widespread clinical application of these methods. Response by Superko on p 2404 Guideline RecommendationsThe Third Adult Treatment Panel of the National Cholesterol Education Program 4 and the American Heart Association 5 recommend measuring a standard lipid panel in adults and targeting lipid-lowering therapy on the basis of levels of LDL cholesterol, and non-HDL cholesterol in subjects with hypertriglyceridemia. European and Canadian guidelines recommend measuring standard lipids while also emphasizing the total/HDL cholesterol ratio in risk assessment. 6,7 Current guidelines do not recommend routine use of advanced lipoprotein tests, mainly because it is unclear how much incremental prognostic information is provided by these tests beyond that available from a standard lipid panel. 4,6,7 Recently, an international panel proposed that cardiovascular risk may be more closely related to atherogenic lipoprotein particle number than LDL cholesterol (the atherogenic lipoprotein particle paradigm). 8 This paradigm posits that lipid concentrations in lipoproteins do not equal the concentrations of the lipoproteins themselves and that measuring the concentration of lipoproteins may be superior to measuring their lipid concentrations for estimating CVD risk and determining the adequacy of statin therapy. 8 A subsequent consensus statement endorsed by the American Diabetes Association and the American College of Cardiology advocated measuring atherogenic particle concentration either as apolipoprotein B (apoB) or LDL particle concentration in subjects at high risk for cardiometabolic disorders for assessing CVD risk and guiding therapy, in conjunction with using LDL and non-HDL cholesterol. 9

Association of Apolipoprotein B and Nuclear Magnetic Resonance Spectroscopy–Derived LDL Particle Number with Outcomes in 25 Clinical Studies: Assessment by the AACC Lipoprotein and Vascular Diseases Division Working Group on Best Practices

“…Standardization was not claimed for any of the remaining 17 methods. As noted by several authors, a major concern about the use of apo B for assessment and treatment of CVD is the lack of rigorous standardization among methods and laboratories (49,52 ). Interestingly, this concern has not been shared for LDL-P, which is not standardized to any reference system, because it is measured in only one laboratory, thereby eliminating the problems of among-method and among-laboratory variability.…”

“…Based on the Medicare fee schedule, the incremental cost of adding an apo B or LDL-P test to a lipid panel is about $17 or $30 -$40, respectively, depending on the payer. There is some concern as to the cost benefit of the added testing given the additional expense (52 ). However, according to at least one US Expert Panel the incremental expense is warranted in certain patients (5 ).…”

Structure of HDL: Particle Subclasses and Molecular Components

“…HDL subfractionation on an analytical scale has been generally accomplished by the different techniques in academic laboratories; however, clinical interest in HDL heterogeneity has been growing in the last 10 years and a number of laboratory tests for determining HDL subclass distribution are now available, including GGE, NMR and 2D gel electrophoresis (Mora 2009). Whether evaluation of HDL subfractions is performed by academic or commercial laboratories, there are a number of factors that confound the interpretation of the results of such analyses.…”

2010 ACCF/AHA Guideline for Assessment of Cardiovascular Risk in Asymptomatic Adults

“…100 Thus, evidence that these more "advanced" lipid measures improve predictive capacity beyond standard lipid measurements is lacking. 101 The role of lipoprotein(a) [Lp(a)] in risk assessment has received attention as a potential additional risk marker. In the Emerging Risk Factors Collaboration, circulating concentration of Lp(a), a large glycoprotein attached to an LDL-like particle, was assessed for its relationship with risk of major vascular and nonvascular outcomes.…”