Apolipoprotein B/LDL-C discordance and lipoprotein(a) as predictors of ASCVD risk in genetically confirmed heterozygous familial hypercholesterolemia (HeFH): A Retrospective Cohort Study (2005–2023)

Abstract Background Heterozygous familial hypercholesterolemia (HeFH) is characterized by elevated low-density lipoprotein cholesterol (LDL-C) levels and increased cardiovascular disease (CVD) risk. While LDL-C is the primary therapeutic target, apolipoprotein B (ApoB), reflecting the total burden of atherogenic lipoproteins, may be a superior risk predictor. ApoB/LDL-C discordance, where ApoB levels are disproportionately high relative to LDL-C, may indicate residual risk. Lipoprotein(a) [Lp(a)], an independent CVD predictor, further refines risk stratification. This study investigates the prevalence of ApoB/LDL-C discordance and its prognostic impact in a genetically confirmed HeFH cohort, emphasizing the role of Lp(a). Methods A retrospective cohort analysis was conducted on 425 genetically confirmed HeFH patients in Wales between 2005 and 2023. LDL-C was calculated using the Friedewald equation, and Lp(a) was measured in nmol/L. Patients were stratified by mutation type: LDLR (76.2%), APOB (13.5%), PCSK9 (5.9%), and structural variants (4.4%). ApoB/LDL-C discordance was determined using regression-derived thresholds, defining discordance as values outside ±0.3 standard deviations of expected ApoB for a given LDL-C. Multivariable Cox regression assessed associations between discordance, Lp(a), and major adverse cardiovascular events (MACE). Kaplan-Meier survival analysis compared MACE-free survival in patients with high (>60 nmol/L) versus low Lp(a) levels. Additionally, ROC analysis was performed to determine the optimal Lp(a) threshold for MACE prediction in mutation-positive patients. Results ApoB/LDL-C discordance was observed in 43.5% of patients, highest in LDLR carriers (48.3%), followed by APOB (39.7%) and PCSK9 (28.1%) (p=0.03). Discordant patients exhibited significantly higher Lp(a) levels (75.4 nmol/L, IQR: 28.2) compared to concordant individuals (32.1 nmol/L, IQR: 20.5, p<0.01). Cox regression identified ApoB/LDL-C discordance (HR=1.83, 95% CI: 1.27–2.64, p=0.001) and Lp(a) >50 nmol/L (HR=2.41, 95% CI: 1.72–3.35, p<0.001) as independent MACE predictors. Kaplan-Meier analysis demonstrated reduced MACE-free survival in patients with elevated Lp(a) (log-rank p<0.001). Furthermore, ROC analysis in mutation-positive patients identified an optimal Lp(a) threshold of 62 nmol/L for MACE prediction, with an AUC of 0.59, moderate sensitivity, and specificity. Conclusion Despite Lp(a) <60 nmol/L being generally considered normal, our findings suggest a lower Lp(a) distribution in mutation-positive patients. These results emphasize the need for personalized risk assessment beyond LDL-C in FH management. ApoB/LDL-C discordance and Lp(a) ≥62 nmol/L were significant predictors of MACE, reinforcing their role as critical biomarkers in this high-risk population. Further investigating these markers into routine clinical assessment may enhance cardiovascular risk stratification and guide therapeutic strategies in HeFH.Odds ratios comparison  Lp(a) ROC and Kaplan-Meire survival