Abstract 4357937: Lipid-Related Polygenic Risk Score and Its Association with Plaque Rupture versus Erosion: Insights into the Role of Lipids in the Pathogenesis of Unstable Plaque Morphologies

Background: Distinct plaque morphologies underlie the major causes of acute coronary syndrome (ACS) and sudden coronary death. We used polygenic risk scores (PRSs) for hypercholesterolemia and hypertriglyceridemia, two major risk factors for coronary artery disease (CAD), to evaluate the relative contributions of these risk factors to specific plaque morphologies that underly ACS. Hypothesis: Lipid-related PRS is associated with plaque rupture and/or plaque erosion. Methods: We extracted DNA from formalin-fixed paraffin-embedded heart tissues and genotyped 954 subjects from our sudden death autopsy registry, each of whom cause of death was determined by autopsy. Low-density lipoprotein (LDL)-specific and triglyceride (TG)-specific PRSs were constructed based on the Global Lipids Genetics Consortium genome-wide association study results, excluding single nucleotide polymorphisms with overlapping associations ( P <0.05) for both lipid traits. Results: Subjects in the highest quintile of LDL-specific PRS had significantly more plaque rupture, ≥75% lumen narrowing, thrombotic CAD, and CAD-related death compared to those in the lowest quintile. Even after adjusting for traditional risk factors, LDL-specific PRS remained significantly associated with rupture (odds ratio [OR]: 1.22 per standard deviation, 95%CI: 1.04–1.43, P =0.017), ≥75% lumen narrowing (OR: 1.33, 95%CI: 1.13–1.57, P <0.001), thrombotic CAD (OR: 1.21, 95%CI: 1.04–1.41, P =0.016), and CAD-related death (OR: 1.31, 95%CI: 1.13–1.52, P <0.001). In contrast, subjects within the highest TG-specific PRS had significantly higher prevalence of thrombotic CAD, and TG-specific PRS remained significantly associated with thrombotic CAD after adjustment (OR: 1.20, 95%CI: 1.03–1.40, P =0.020). No association was observed between LDL-/TG-specific PRS and plaque erosion. Conclusions: This is the first study to associate lipid PRSs with specific plaque morphologies, revealing distinct pathogenic mechanisms underlying plaque rupture and erosion. Early genetic risk stratification and subsequent lipid-lowering interventions may provide substantial clinical benefits in mitigating cardiovascular risk and preventing sudden coronary death, especially in relation to plaque rupture. Our data raises questions about the effectiveness of such strategies in preventing plaque erosion, suggesting the need for further investigation to better understand the pathogenesis of plaque erosion.