Electronegative HDL remodeling is independently associated with angiographic obstructive coronary artery disease

Background

Conventional lipid parameters such as LDL-C and HDL-C do not fully reflect lipoprotein functional heterogeneity related to inflammation, oxidative stress, and endothelial dysfunction.

Electronegative HDL subfractions, particularly H5, represent a dysfunctional HDL phenotype and may capture residual atherosclerotic risk beyond cholesterol concentration.

Purpose

To evaluate whether the most electronegative HDL subfraction (H5) is independently associated with angiographically confirmed obstructive coronary artery disease (CAD) and provides incremental predictive value beyond conventional risk factors.

Methods

We prospectively enrolled 261 patients presenting with typical chest pain and noninvasive testing suggestive of CAD. Fasting blood samples were obtained prior to coronary angiography. HDL was isolated by sequential ultracentrifugation and separated into five charge-based subfractions (H1–H5) using anion-exchange fast protein liquid chromatography. The proportion of the most electronegative subfraction (H5%) was quantified. Associations with obstructive CAD were assessed using multivariable logistic regression and receiver operating characteristic (ROC) analysis.

Results

The median age was 67 years (IQR 60–75), and 71.6% were male. Obstructive CAD patients were older and had higher prevalence of diabetes, end-stage renal disease, and hyperlipidemia.

Compared with non-obstructive CAD, patients with obstructive disease exhibited a shift toward a more electronegative HDL distribution, characterized by lower H1% and higher H3–H5%, including significantly higher H5% (2.15% vs 1.84%). As a continuous predictor, H5% demonstrated an area under the ROC curve of 0.63 for obstructive CAD. An optimal cut-off of 2.0% provided the best sensitivity–specificity balance. In multivariable analysis, H5 >2.0% remained independently associated with obstructive CAD (adjusted OR 2.06, 95% CI 1.01–4.24), together with diabetes and reduced estimated glomerular filtration rate.

Conclusions

Electronegative HDL remodeling, reflected by elevated H5%, is independently associated with angiographic obstructive CAD. H5 identifies dysfunctional HDL not captured by conventional lipid measurements and may serve as a biomarker of residual atherosclerotic risk.H5 level and AUCLogistic regression