ApoB/LDL-C discordance as a predictor of atherosclerotic cardiovascular disease in genetically confirmed heterozygous familial hypercholesterolemia: a hypothesis-generating cohort study

Genedy, Nader and Zouwail, Soha 2025. ApoB/LDL-C discordance as a predictor of atherosclerotic cardiovascular disease in genetically confirmed heterozygous familial hypercholesterolemia: a hypothesis-generating cohort study. Journal of Clinical Lipidology 10.1016/j.jacl.2025.11.008

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Abstract

Background In heterozygous familial hypercholesterolemia (HeFH), low-density lipoprotein cholesterol (LDL-C) remains the primary treatment target, yet emerging evidence suggests apolipoprotein B (apoB) may offer superior cardiovascular risk stratification. ApoB/LDL-C discordance occurs when apoB and LDL-C provide conflicting risk information, potentially identifying patients at heightened atherosclerotic cardiovascular disease (ASCVD) risk despite apparently controlled LDL-C levels. However, evidence in genetically confirmed HeFH cohorts is sparse. Objective To examine whether ApoB/LDL-C discordance associates with ASCVD events in a genetically confirmed HeFH cohort and to generate hypotheses for future validation studies. Methods This retrospective cohort study included 424 genetically confirmed HeFH patients (median age 51 years, 54.5% female) followed for a median of 9.1 years. Patients were classified as concordant (both apoB and LDL-C above or below sex-specific thresholds) or discordant. Cox proportional hazards models evaluated associations with ASCVD events (myocardial infarction, stroke, coronary revascularization), adjusting for age, sex, diabetes, hypertension, smoking, statin therapy, and baseline lipid parameters. Results Among 424 patients, 61 ASCVD events occurred (41 prevalent, 20 incident). ApoB/LDL-C ratio ≥0.31 g/mmol associated with higher event rates (27.6% vs 11.8%, p=0.0022). Adjusted hazard ratio was 38.55 (95% CI 3.72–399.36), though marked by extreme instability from sparse data stratification and small event counts. Additional exploratory analyses using R software revealed linear correlation patterns and threshold-based associations supporting the discordance hypothesis. Conclusion These preliminary findings suggest ApoB/LDL-C discordance may identify residual ASCVD risk in HeFH patients, warranting prospective validation in larger, independent cohorts before clinical application.

Item Type:	Article
Date Type:	Published Online
Status:	In Press
Schools:	Schools > Medicine
Publisher:	Elsevier
ISSN:	1933-2874
Date of First Compliant Deposit:	16 December 2025
Date of Acceptance:	11 November 2025
Last Modified:	16 Dec 2025 12:49
URI:	https://orca.cardiff.ac.uk/id/eprint/183285

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