Abstract Th0010: Apolipoprotein A-I Proteoforms in Large HDL are Associated with Incident Myocardial Infarction: Observations from Dallas Heart Study

Background: HDL dysfunction (reduced cholesterol efflux, anti-inflammatory and antioxidant activity) is linked to coronary artery disease (CAD), the leading cause of mortality. HDL particles have a diverse proteome that drives these functions in a subspecies-specific manner with particle size reflecting compositionally distinct HDL subspecies. Protein abundance alone does not adequately reflect HDL proteome complexity. Proteoforms are specific variants of a protein arising due to post transcriptional/translational modifications, affecting downstream phenotypes. Our previous studies demonstrated associations between ApoA-I proteoforms and cardiometabolic traits but links to actual CAD events remain unknown. Further, whether proteoform assessment in size-based subspecies provides additional insights is also a knowledge gap. Our objective is to identify the associations between ApoA-I proteoforms and incident myocardial infarction (MI) across size-based subspecies. Method: Using a nested case-control study deign, individuals with incident MI (N=33) and matched controls (N=32; age, sex, and race) were selected from the Dallas Heart Study (>3000 participants; no CVD at baseline). Pooled plasma from the baseline visit for each group was fractionated using size exclusion chromatography, and lipoproteins were characterized in plasma fractions using cholesterol, phospholipid, total protein, triglycerides, and ApoA-I assays. Top-down mass spectrometry was used to profile ApoA-I proteoforms in ApoA-I containing fractions across the size range. Results: Mean age was 56 years (45% women, 9% Hispanic and 66% Black). In large HDL plasma fractions, cholesterol and phospholipid were lower in incident MI cases versus controls (cholesterol: 16.9 vs 22.8; phospholipids: 34.5 vs 45.9; p<0.05). Total protein was similar between groups across the size range. Levels of truncated, minus water and canonical (unmodified) ApoA-I were higher in large HDL plasma fractions in incident MI cases versus controls (MI vs control: 9.6 vs 5.7; 9.9 vs 8.7; 59.7 vs 48.0; p<0.05 respectively). Conclusion: Some ApoA-I proteoforms associate with increased risk of incident MI, but only in large size fractions, not in whole plasma. These findings suggest clinical relevance of ApoA-I proteoforms and indicate improved insights by fractionating plasma by size. Further studies are needed to replicate these findings, understand mechanism, and test for clinical utility as risk markers and therapeutic targets.