Discordance analysis of estimated small dense LDL cholesterol and residual stroke risk in the CHARLS cohort

Epidemiological studies have yielded inconsistent findings regarding the relationship between conventional low-density lipoprotein cholesterol (LDL-C) and stroke, revealing limitations in its utility as a predictive biomarker. Small dense LDL-C (sdLDL-C), a highly atherogenic lipoprotein subclass, may better capture residual cardiovascular risk; however, direct measurement of sdLDL-C is restricted by limited assay standardization, and large prospective evidence for estimated sdLDL-C (esdLDL-C)—a practical surrogate derivable from standard lipid profiles—remains limited. This prospective analysis included 7,503 participants from the China Health and Retirement Longitudinal Study. esdLDL-C was calculated from standard lipid parameters using Sampson’s equation. Three analytical strategies were employed—percentile-based differences (≥ 15 percentile), cohort-derived and guideline-based clinical thresholds, and continuous model-based residual and percentage-threshold analyses—to evaluate the independent association of esdLDL-C with stroke risk relative to conventional LDL-C. The analysis was further extended to incorporate high-sensitivity C-reactive protein (hsCRP) for comprehensive risk stratification. Subgroup and sensitivity analyses validated the strength of the findings. Incremental predictive performance was assessed using C-statistics, integrated discrimination improvement, and net reclassification index (NRI). Over a median follow-up of 9.0 years, during which 860 incident stroke cases occurred, elevated esdLDL-C was modestly but significantly associated with an increase in stroke risk after full adjustment (hazard ratio [HR] per standard deviation increment: 1.26, 95% confidence interval [CI]: 1.05–1.50), with risk estimates exceeding those of other lipid parameters. Discordance analyses—percentile-based (HR: 1.40, 95% CI: 1.14–1.73), clinical threshold-based (HR: 1.46 at LDL-C < 130 mg/dL; HR: 1.06 at LDL-C < 100 mg/dL), and continuous model-based—generally demonstrated elevated stroke risk associated with high esdLDL-C relative to LDL-C, with graded risk observed across 2%–30% discordance (HRs: 1.23–1.40), although the association was not statistically significant at the more stringent LDL-C < 100 mg/dL threshold. Among individuals with optimal LDL-C (< 130 mg/dL) and low hsCRP (< 2 mg/L), high esdLDL-C (≥ 36 mg/dL) remained significantly associated with stroke risk (HR: 1.53, 95% CI: 1.23–1.89). Incorporation of esdLDL-C significantly enhanced risk reclassification (NRI: 0.1503; P < 0.001). esdLDL-C may confer incremental prognostic value for stroke risk beyond conventional LDL-C and hsCRP in Chinese adults. Derivable from routine lipid panels, it represents a practical adjunct marker for population-level risk assessment, pending external validation and head-to-head comparisons with directly measured sdLDL-C and apolipoprotein B.