Anatomy-Specific Association of Circulating Sortilin with Proximal Left Anterior Descending Artery Obstruction

Background: Sortilin (SORT1), linked to the 1p13.3 coronary risk locus, is implicated in lipid trafficking and atherogenesis; however, clinical studies of circulating SORT1 have produced inconsistent results. We evaluated whether circulating SORT1 is associated with angiographic burden and lesion localization in patients with premature or early clinical debut coronary atherosclerosis. Methods: This single-center, cross-sectional study analyzed a dataset collected from January to May 2023. Participants were classified as coronary atherosclerosis cases if the dataset contained an age of clinical debut of clinically significant atherosclerosis (n = 101). Controls had no recorded debut age and 0% stenosis in all assessed coronary segments (n = 27). Blood was collected in clot activator tubes; serum was stored at −40 °C until analysis. SORT1 (ng/mL) was measured using an Aviscera Bioscience ELISA. Coronary stenoses were recorded as percent diameter stenosis for left main (LM), proximal/mid/distal LAD, proximal/mid/distal LCx, and proximal/mid/distal RCA. Burden metrics included the number of segments with any stenosis (>0%), the number of obstructive segments (≥50%), the number of diseased vessels, and maximum stenosis. The prespecified primary endpoint was obstructive proximal LAD stenosis (≥50%). Nonparametric tests and Spearman correlations were used. Logistic regression evaluated the association between log2-transformed SORT1 and proximal LAD obstruction, adjusted for age, sex, LDL-C, statin use, and smoking/diabetes/hypertension durations. Results: SORT1 was higher in cases than controls (8.60 [2.60–17.10] vs. 2.30 [1.25–10.65] ng/mL; p = 0.0058). Within cases, SORT1 did not correlate with global angiographic burden (any-stenosis segments: ρ = −0.066, p = 0.513; obstructive segments: ρ = −0.060, p = 0.552; diseased vessels: ρ = −0.045, p = 0.652; maximum stenosis: ρ = −0.084, p = 0.403). Obstructive proximal LAD stenosis occurred in 44/101 (43.6%) and was associated with higher SORT1 (12.25 [4.18–17.45] vs. 4.10 [2.20–11.60] ng/mL; p = 0.0093). Each doubling of SORT1 was independently associated with proximal LAD obstruction (adjusted OR 1.48, 95% CI 1.12–1.95; p = 0.005). Conclusions: In this cross-sectional cohort, circulating SORT1 was associated with obstructive proximal LAD stenosis but not with global angiographic burden metrics. These findings are hypothesis-generating and warrant validation in independent cohorts with standardized preanalytics and prospective designs to assess temporal relationships and clinical utility.