Associations of plasma level of soluble LDL receptor with cardiovascular events and mortality in a large prospective cohort study

Soluble low-density lipoprotein receptor (sLDLR) is proteolytically cleaved from cell membranes and released into the circulation. Prior studies have linked plasma sLDLR to atherogenic lipids, but prospective evidence for its relation to cardiovascular outcomes is limited. This study aimed to evaluate associations between circulating sLDLR and risks of myocardial infarction (MI), heart failure (HF), and cardiovascular (CVD) mortality, as well as all-cause mortality. We analyzed data from 47,518 participants in the UK Biobank who were free of CVD at baseline, with a median follow-up of 12.8 years. Nested Cox proportional hazards models were used to estimate associations between Olink-based sLDLR levels and outcomes. Participants in the highest tertile of sLDLR were older, had higher BMI, and displayed more adverse lipid and inflammatory profiles. In models that included demographic and clinical data, each 1-SD increase of sLDLR was linked to higher MI risk but to lower risk of CVD mortality. With further adjustment for BMI, the association of sLDLR with MI remained significant (HR 1.32, [95% CI 1.17,1.50]), the inverse association with CVD mortality was further strengthened (HR 0.76 [0.64–0.90]), and significant inverse associations with HF and all-cause mortality also became apparent. Notably, HRs for all endpoints except CVD mortality were reduced to insignificance by adjustment for LDL-cholesterol (LDL-C). Time-dependent ROC analyses indicated consistent predictive performance across outcomes for up to 10 years of follow-up. sLDLR was associated with LDL-C-dependent MI risk but with protection from CVD mortality, and with LDL-C- and BMI-dependent inverse associations with HF and all-cause mortality. These findings point to sLDLR as a potential outcome-specific biomarker and indicate that LDL-C level and adiposity influence the observed associations.