There is universal agreement that low-density lipoprotein-cholesterol (LDL-C) plays a central role in the pathogenesis of atherosclerotic cardiovascular diseases (ASCVD) . It has been well described, however, that ASCVD risk is even more strongly associated by univariate analysis with small dense LDL-C (sdLDL-C) than LDL-C  and sdLDL-C is now considered an emerging risk factor by the National Cholesterol Education Program .
If sdLDL-C is superior to LDL-C as an ASCVD risk marker, why then it is not used more often for ASCVD risk assessment and why is it not recommended for routine screening by the most recent US 2018-2019 Multi-society guidelines on the management of blood cholesterol ? One explanation is the labor-intensive methods that were traditionally used to measure it. Recently, a direct sdLDL-C assay, which can be fully automated, has been developed and showed promising results in several large ASCVD outcome studies [1, 2]. Encouraged by these findings, we recently developed an equation for estimating sdLDL-C based on the standard lipid panel  and estimated LDL-C by the Sampson equation that is more accurate with hypertriglyceridemia .
Calculating sdLDL-C with our new method  consists of two steps: firstly, we calculate large buoyant LDL-C (lbLDL-C) based on total LDL-C an interaction term between LDL-C and the natural log of triglycerides (TG), and then lbLDL-C is subtracted from total LDL-C giving and estimate for sdLDL-C. Software for performing these calculations by the newly developed equations can be freely downloaded at the linked website.
We found that our sdLDL-C equation can identify additional high-risk patients in the National Heart and Nutrition Examination Survey (NHANES) not identified by other risk-enhancer tests, such us LDL-C, TG, apolipoprotein B or non-HDL-C, when using 80th percentile concentration of sdLDL-C (46 mg/dL) as a cut point. Moreover, after multivariate adjustment for other known ASCVD risk factors, our sdLDL-C equation used for estimating sdLDL-C in the Multi-Ethnic Study of Atherosclerosis (MESA) cohort gave results that were superior to all other lipid measures and even unexpectedly superior to the directly measured sdLDL-C.
Our findings suggest that sdLDL-C may be a biomarker of the “pro-atherogenic phenotype” observed in patients with hypertriglyceridemia, metabolic syndrome and diabetes, and other high-ASCVD risk groups . Given the relatively simplicity of the calculation and the fact that it does not involve additional laboratory testing beyond the standard lipid panel, estimated sdLDL-C could become a useful tool for ASCVD risk assessment but will require additional studies to establish its clinical utility and for determining how it can be best integrated into current guidelines.
This research was supported by the Intramural Research Program of the National Heart, Lung, and Blood Institute (NHLBI) at National Institutes of Health.
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- National Cholesterol Education Program Expert Panel on Detection, E. and A. Treatment of High Blood Cholesterol in, Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report. Circulation, 2002. 106(25): p. 3143-421.
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- Sampson, M., et al., A New Equation Based on the Standard Lipid Panel for Calculating Small Dense Low-Density Lipoprotein-Cholesterol and Its Use as a Risk-Enhancer Test. Clinical Chemistry, 2021. 67(7): p. 987-997.
- Sampson, M., et al., A New Equation for Calculation of Low-Density Lipoprotein Cholesterol in Patients With Normolipidemia and/or Hypertriglyceridemia. JAMA Cardiol, 2020. 5(5): p. 1-9.