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............................................................................................................................................................................ 5.4.2 Lipid measurements In clinical practice, the concentration of plasma lipoproteins is not usually measured directly but is instead estimated by measuring their cholesterol content. TC in humans is distributed primarily among three major lipoprotein classes: VLDL, LDL, and HDL. Smaller amounts of cholesterol are also contained in two minor lipoprotein classes: IDL and Lp(a). A standard serum lipid profile measures the concentration of TC and HDL-C, as well as TG. With these values, the LDL-C concentration can be estimated.

Plasma LDL-C can be measured directly using enzymatic techniques or preparative ultracentrifugation, but in clinical medicine it is most often calculated using the Friedewald formula:

LDL-C 1⁄4 TC  HDL-C  (TG/2.2) in mmol/L or LDL-C 1⁄4 TC  HDL-C  (TG/5) in mg/dL Although convenient, the Friedewald calculated value of LDL-C has several well-established limitations: (i) methodological errors may accumulate since the formula necessitates three separate analyses of TC, TGs, and HDL-C; and (ii) a constant cholesterol/TG ratio in VLDL is assumed. With high TG values (>4.5 mmol/L or >400 mg/ dL) the formula cannot be used. This should especially be considered in non-fasting samples. To overcome the problems associated with calculated LDL-C, direct enzymatic methods for the measurement of LDL-C have been developed. These methods are commercially available as ready to use tools for automatic analysis. The definition of LDL-C by the Friedewald equation and by direct measurement is the same: non-HDL-C  VLDL-C, representing the sum of the cholesterol carried by the biochemically defined LDL, IDL, and Lp(a) subfractions. For the general population, calculated LDL-C and direct LDL-C show very strong correlations.8083 However, calculated LDL-C has been found to underestimate LDL-C at concentrations of TG >_2 mmol/L (177 mg/dL).81,82 Equally, at very low levels of LDL-C, calculated LDL-C may be misleading, especially in the presence of high TG.81,8486 To avoid some of the problems with the Friedewald formula, a number of modifications for the calculation of LDL-C have been suggested, but it remains to be proved whether these modifications are superior to Friedewald’s formula for the estimation of CV risk.81,8587 It is important to note that direct LDL-C measurements also have limitations, including systematic bias and inaccuracy in patients with dyslipidaemia, especially for high TG levels.8890 As an alternative calculated LDL-C, non-HDL-C can be calculated as TC  HDL-C and is a measure of the TC carried by all atherogenic ApoB-containing lipoproteins, including TG-rich particles in VLDL and their remnants.100 Several methods for the determination of Lp(a) are available. The complex molecular structure of Lp(a) and the variation in size of Apo(a) has been a challenge in the development of analytical methods for Lp(a). Available methods are, to a varying degree, influenced by the Apo(a) isoform.91 Furthermore, the concentration of Lp(a) is reported as either a molar concentration (nmol/L) or as a mass (mg/ dL) by the various assays, and conversion between molar and mass concentrations has been found to be both size- and concentrationdependent.9193 Therefore, standardization between assays is needed to establish a reliable and reproducible method for the quantification of Lp(a) mass or particle number.92

5.4.3 Fasting or non-fasting? Traditionally, blood sampling for lipid analyses has been recommended in the fasting state. Recent systematic studies comparing fasting and non-fasting samples have suggested that the difference is small for most lipid parameters.85,94100 Non-fasting sampling has been used in large population-based studies.100 In most studies, non-fasting samples display a higher TG level of 0.3 mmol/L (27 mg/ dL).100,101 On average, and for most individuals, this increment will be of no clinical significance. Indeed, a number of guidelines recommend non-fasting sampling.100,102,103 For general risk screening, non-fasting samples seem to have at least the same prognostic value as fasting samples.104 The practical advantages of non-fasting samples, including better patient acceptability, outweigh the potential imprecision in some patients, although the determination of some key analytes, such as fasting glucose, may be compromised. Furthermore, even if non-fasting sampling can be used in most cases, in patients with metabolic syndrome (MetS), DM, or hypertriglyceridaemia (HTG), calculated LDL-C should be interpreted with caution.

5.5 Recommendations for measuring

lipids and lipoproteins to estimate risk of atherosclerotic cardiovascular disease Measurement of plasma TC is needed to calculate risk using SCORE, while the inclusion of plasma HDL-C level can improve risk estimation using the online SCORE calculator. Therefore, both TC and HDL-C should be measured to estimate a person’s risk of ASCVD using SCORE, or one of the other risk calculators (almost all of which also include measurements of TC and HDL-C). Plasma LDL-C should be measured to estimate the risk of ASCVD that can be modified with LDL-C-lowering therapies, and to identify whether markedly elevated LDL-C levels are present that may suggest a lifetime high-risk of ASCVD due to lifelong cumulative exposure to high levels of atherogenic lipoproteins, such as in FH. Plasma LDL-C can be either calculated or measured directly. Plasma TG should be assessed to identify people who may have a greater modifiable risk of ASCVD than is reflected by LDL-C, due to the presence of an increased concentration of atherogenic ApoBcontaining TG-rich lipoproteins and their remnants, and to identify people in whom calculated and directly measured LDL-C may underestimate the risk of ASCVD by underestimating either the concentration of circulating LDL particles or the cholesterol content carried by those particles, such as those with very low levels of LDL. This may be especially relevant in patients with DM or MetS. In general, LDL-C, non-HDL-C, and ApoB concentrations are very highly correlated. As a result, under most circumstances, they provide very similar information about ASCVD risk.45,105108 However, under certain circumstances—including among people with elevated TG levels, DM, obesity, or very low achieved LDL-C levels—the calculated or directly measured LDL-C level may underestimate both the total concentration of cholesterol carried by LDL and, more importantly, underestimate the total concentration of ApoB-containing lipoproteins, thus underestimating the risk of ASCVD. In around Downloaded from academic.oup.com/eurheartj/article/41/1/111/5556353 by guest on 07 October 2026