HDL function and composition in atherothrombotic cardiovascular disease with very high HDL ‐C

BACKGROUND: Emerging evidence demonstrates a J-shaped relationship between HDL-C levels and atherosclerotic cardiovascular disease (ASCVD) with very high HDL-C concentrations paradoxically associated with increased ASCVD events. This study aims to determine whether individuals with very high HDL-C (>80 mg/dL) and ASCVD exhibit altered HDL composition and impaired HDL functionality. METHODS: We investigated the HDL profile and functionality in 49 subjects (mean age: 62 ± 2 years, 83% female) with very high HDL-C levels (>80 mg/dL), including 23 with ASCVD. All ASCVD patients and 46% of those without ASCVD (non-ASCVD) were on lipid-lowering treatment. RESULTS: Plasma atherogenic lipoprotein-cholesterol levels were significantly lower in ASCVD patients than in those without ASCVD, despite matched HDL-C levels. CEC differences were evident after tertile stratification, with ASCVD participants overrepresented in the lowest tertile and showing lower median IQR CEC than non-ASCVD (p = 0.030). Total radical-trapping antioxidative potential showed no significant group differences in HDL ability to inhibit copper-induced LDL oxidation. However, basal HDL oxidative level was significantly higher in the ASCVD compared with the non-ASCVD group (p = 0.007). Inflammatory glycoproteins were inversely associated with CEC and HDL-C levels in ASCVD patients, but not in non-ASCVD patients. By NMR, mean HDL particle diameter did not differ between groups, yet ASCVD patients had fewer percent of large HDL particles compared to the non-ASCVD (0.84 ± 0.02% vs. 0.91 ± 0.02%; p = 0.034) and a trend toward more small particles. HDL-C content increased with particle size in ASCVD (p = 0.008; r = 0.531), but not in non-ASCVD, while HDL-TG levels did not differ across tertiles. Functional cell-based assays showed attenuated endothelial proliferation (normalized Cell-Index) in ASCVD compared with non-ASCVD, most evident in the largest HDL particle tertile. CONCLUSIONS: These findings suggest that HDL functionality and particle distribution may offer more clinically relevant insights into cardiovascular risk than plasma HDL-C concentrations alone, particularly in individuals with very high HDL-C levels.