Can the association between LDL-Cholesterol and incident coronary heart disease (CHD) be modulated by concomitant Lp(a) levels in the general population?
Authors: Arnold N , Blaum C , Gossling A , Zeller T , Soderberg S , Iacoviello L , Sans S , Veronesi G , Thorand B , Kee F , Salomaa V , Kuulasmaa K , Blankenberg S , Waldeyer C , Koenig W 
Published: November 2023

Abstract

Background
LDL-cholesterol (LDL-C), quantified by conventional methods, also includes the choles-terol attributable to Lipoprotein (a) (Lp(a)-C) due to their overlapping densities. The clinical relevance of this is still poorly investigated, since current attempts to estimate a true LDL-C (i.e. a LDL-C without its Lp(a)-C content, so called LDL-C-Lp(a)corr) remain challenging.

Aims
The aims of the present analysis were 1) to compare the association between LDL-C and LDL-C-Lp(a)corr with incident coronary heart disease (CHD) in the general population; 2) to determine the prognostic ability of LDL-C for future CHD events depending on concomitant Lp(a) levels.

Methods
Data from 68,748 subjects from eight European prospective population-based cohorts, who were free of CHD at baseline were used. LDL-C-Lp(a)corr was calculated as "LDL-C - Lp(a)-C", where Lp(a)-C was estimated as being 30% of the Lp(a) total mass. Fine and Gray competing risk-adjusted models were calculated for the association between LDL-C and LDL-C-Lp(a)corr (in quintiles (Q) with Q1 as REF) and future CHD events in the total study sample, as well as for LDL-C only after categorization of the study population according to Lp(a) mass (&lt;90th percentile (pctl.) (43,5 mg/dL) (n=61,861) and ≥90th pctl. (n=6,887)).

Results
Similar risk estimates for incident CHD were found for LDL-C and LDL-C-Lp(a)corr with sHRs of 2.69 (95% CI 2.30-3.15) and 2.49 (95% CI 2.13-2.90), respectively (both p&lt;0.001, comparing Q5 vs Q1; fully-adjusted models, including traditional cardiovascular risk factors and hsCRP). Categorization of the study sample according to Lp(a) mass revealed that the association between LDL-C and incident CHD was potentiated by higher Lp(a) mass (≥90th pctl) resulting in a sHR of 4.36 (95% CI 2.05-9.23; p&lt;0.001 for Q5 vs Q1; fully-adjusted model), which was approximately x1.5 higher than the risk estimate found in the total study sample (i.e. without categorization for Lp(a) mass). In contrast, in subjects with Lp(a) mass &lt;90th pctl. sHR for future CHD events was found to be 2.56 (95% CI 2.18-3.02) (for Q5 vs Q1 of LDL-C distribution; fully-adjusted model), being almost identical to the sHR obtained within the overall cohort (p for interaction between the categories of Lp(a) was 0.42).

Conclusion
Within the present analysis, correction of LDL-C for its Lp(a)-C content did not provide any meaningful additional information on CHD-risk estimation in the general population, thereby not confirming a clinically relevant value of LDL-C-Lp(a)corr. On the other hand, a simple categorization of Lp(a) mass with respect to high (≥90th pctl.) vs low (&lt;90th pctl.) values demonstrated that Lp(a) significantly modulates LDL-C-related risk for future CHD only at higher levels. So, for the vast majority of subjects (&lt;90th pctl. of Lp(a) distribution), no correction of LDL-C for its Lp(a)-C content is required.