High-density lipoprotein subclass measurements improve mortality risk prediction, discrimination and reclassification in a cardiac catheterization cohort

Abstract

Background and Aims Recent failures of HDL cholesterol (HDL-C)-raising therapies to prevent cardiovascular disease (CVD) events have tempered the interest in the role of HDL-C in clinical risk assessment. Emerging data suggest that the atheroprotective properties of HDL depend on specific HDL particle characteristics not reflected by HDL-C. The purpose of this study was to determine the association of HDL particle concentration (HDL-P) and HDL subclasses with mortality in a high-risk cardiovascular population and to examine the clinical utility of these parameters in mortality risk discrimination and reclassification models. Methods Using nuclear magnetic resonance spectroscopy, we measured HDL-P and HDL subclasses in 3972 individuals enrolled in the CATHGEN coronary catheterization biorepository; tested for association with all-cause mortality in robust clinical models; and examined the utility of HDL subclasses in incremental mortality risk discrimination and reclassification. Results Over an average follow-up of eight years, 29.6% of the individuals died. In a multivariable model adjusted for ten CVD risk factors, HDL-P [HR, 0.71 (0.67-0.76), p= 1.3e-24] had a stronger inverse association with mortality than did HDL-C [HR 0.93 (0.87-0.99), p=0.02]. Larger HDL size conferred greater risk and the sum of medium- and small-size HDL particles (MS-HDL-P) conferred less risk. Furthermore, the strong inverse relation of HDL-P levels with mortality was accounted for entirely by MS-HDL-P; HDL-C was not associated with mortality after adjustment for MS-HDL-P. Addition of MS-HDL-P to the GRACE Risk Score significantly improved risk discrimination and risk reclassification. Conclusion HDL-P and smaller HDL subclasses were independent markers of residual mortality risk and incremental to HDL-C in a high-risk CVD population. These measures should be considered in risk stratification and future development of HDL-targeted therapies in high-risk populations.

A Novel Protein Glycan–Derived Inflammation Biomarker Independently Predicts Cardiovascular Disease and Modifies the Association of HDL Subclasses with Mortality

“…In our cohort, HDL particle size is associated with mortality risk—larger HDL size confers a higher risk of mortality and a sum of small- and medium-size HDL particles (MS-HDL-P) confers a lower risk (7). In studies from other groups the antiinflammatory properties of HDL become proinflammatory during the acute-phase response (22); this suggests a potential interaction between HDL and inflammation that could influence mortality risk.…”

“…Lipoprotein subclass particle concentrations and size are also measurable by NMR spectroscopy and are independent markers of CVD (6, 7). Emerging preclinical and clinical data suggest a biological interaction between inflammation and HDL.…”

Relationship of baseline HDL subclasses, small dense LDL and LDL triglyceride to cardiovascular events in the AIM-HIGH clinical trial

“…These findings confirm that total HDL-C level does not necessarily reflect the athero-protective properties of HDL. Interestingly, one study published this year concluded that smaller, denser HDL3-C levels are primarily responsible for the inverse association between HDL-C and incident CHD (23) and the other concluded that the small and medium size HDL particle measurements improve mortality risk prediction (24). These studies lend further support to the concept that the smaller, denser HDL subpopulation is superior to total HDL in risk prediction.…”

Metrics of high-density lipoprotein function and hospital mortality in acute heart failure patients

“…Furthermore, pharmacological interventions aimed at raising HDL-cholesterol levels failed to reduce cardiovascular events [3,4]. Determination of HDL particle concentrations and HDL subclasses as well as determination of HDL functionality have proved more appropriate to test and quantify the beneficial atheroprotective properties of HDL [5,6]. HDL-mediated atheroprotection has been ascribed to the attenuation of endothelial adhesion molecule expression, protection of low-density lipoprotein (LDL) from oxidation, inhibiton of inflammatory response in macrophages, stimulation of endothelial nitric oxide production and promotion of vasodilatation [7][8][9][10][11].…”