title: High-density lipoprotein subclass measurements improve mortality risk prediction, discrimination and reclassification in a cardiac catheterization cohort.
abstract: OBJECTIVE
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Division of Cardiology, Department of Medicine, Durham, NC, USA; Duke Molecular Physiology Institute, Duke University Medical Center, Durham, NC, USA. Electronic address: robert.mcgarrah@dm.duke.edu.
authors.forename: Robert W
authors.initials: RW
authors.lastname: McGarrah
authors.affiliation: Duke Molecular Physiology Institute, Duke University Medical Center, Durham, NC, USA.
authors.forename: Damian M
authors.initials: DM
authors.lastname: Craig
authors.affiliation: Duke Molecular Physiology Institute, Duke University Medical Center, Durham, NC, USA.
authors.forename: Carol
authors.initials: C
authors.lastname: Haynes
authors.affiliation: Duke Molecular Physiology Institute, Duke University Medical Center, Durham, NC, USA.
authors.forename: Z Elaine
authors.initials: ZE
authors.lastname: Dowdy
authors.affiliation: Division of Cardiology, Department of Medicine, Durham, NC, USA; Duke Molecular Physiology Institute, Duke University Medical Center, Durham, NC, USA; Duke Clinical Research Institute, Durham, NC, USA.
authors.forename: Svati H
authors.initials: SH
authors.lastname: Shah
authors.affiliation: Division of Cardiology, Department of Medicine, Durham, NC, USA; Duke Molecular Physiology Institute, Duke University Medical Center, Durham, NC, USA.
authors.forename: William E
authors.initials: WE
authors.lastname: Kraus
mesh_terms: D000368:Aged; D015415:Biomarkers / Q000097:blood; D006328:Cardiac Catheterization; D002318:Cardiovascular Diseases / Q000097:blood* / Q000175:diagnosis; D002423:Cause of Death; D016009:Chi-Square Distribution; D016002:Discriminant Analysis; D005260:Female; D006801:Humans; D016013:Likelihood Functions; D008075:Lipoproteins, HDL / Q000097:blood* / Q000145:classification; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D019906:Nuclear Magnetic Resonance, Biomolecular; D011237:Predictive Value of Tests; D011379:Prognosis; D016016:Proportional Hazards Models; D018570:Risk Assessment; D012307:Risk Factors; D013997:Time Factors
chemical_list: D015415:Biomarkers; D008075:Lipoproteins, HDL
keywords: Biomarkers; HDL; HDL subclasses; Mortality; Risk prediction