Discrepant Risk Assessment between Low-Density Lipoprotein Cholesterol and Low-Density Lipoprotein Size

BACKGROUND: Low-density lipoprotein cholesterol (LDL-C) is directly associated with coronary artery disease (CAD) risk. Subfractionation of LDL enables differentiation between large-buoyant LDL (>20.5 nm) and small-dense LDL (≤20.5 nm). Small-dense LDL reportedly increases CAD risk, as do LDL-C and LDL particle (LDL-P) concentrations. Nuclear magnetic resonance spectroscopy (NMR) reports LDL-C, LDL-P, and LDL size (LDL-s). We investigated associations between these outputs and their agreement on CAD risk information. METHODS: Associations between LDL-P, LDL-C, and LDL-s measured by NMR were evaluated in serum from clinically ordered samples (n = 26 710), and a subset of patients with CAD evaluation from coronary angiography (n = 356). Correlations were determined using Spearman ρ, and clinical classifications were compared using the following thresholds for increased risk: LDL-C > 160 mg/dL, LDL-P > 1600 nmol/L, and LDL-S < 20.5 nm. RESULTS: The large laboratory NMR data set showed LDL-C was highly correlated with LDL-P (ρ = 0.87), and moderately with LDL-s (ρ = 0.51). Correlation between LDL-P and LDL-s was weakest (ρ = 0.21). When comparing pairwise high- and low-risk laboratory values, concordant values were observed in 99.8%, 43%, and 25% of cases for LDL-P/LDL-C, LDL-s/LDL-P, and LDL-C/LDL-s, respectively. In patients with angiography and NMR results, CAD was diagnosed in 40% (6/15) of patients with concordant high-risk LDL-C and small-dense LDL-s in the smaller patient cohort, but only 19% (6/31) of CAD-positive patients with high-risk LDL-C had small-dense LDL-s. CONCLUSIONS: LDL-s and LDL-C are frequently discordant at established LDL-C risk cutoffs. CAD diagnosis was found in similar numbers regardless of LDL-s phenotype.