Paul T Williams1, Xue-Qiao Zhao2, Santica M Marcovina3, James D Otvos4, B Greg Brown2, Ronald M Krauss5. 1. Life Sciences Division, Lawrence Berkeley Laboratory, Berkeley, CA, USA. 2. Department of Medicine, Division of Cardiology, University of Washington, Seattle, WA, USA. 3. Department of Medicine, Northwest Lipid Research Laboratories, University of Washington, Seattle, WA, USA. 4. LipoScience, Inc., Raleigh, NC, USA. 5. Children's Hospital Oakland Research Institute, 5700 Martin Luther King Jr Way, Oakland, CA 94609, USA. Electronic address: rkrauss@chori.org.
Abstract
BACKGROUND: Compare gradient gel electrophoresis (GGE), vertical auto profile ultracentrifugation (VAP-II), nuclear magnetic resonance spectroscopy (NMR), and ion mobility for their ability to relate low- (LDL), intermediate- (IDL), very-low-density (VLDL) and high-density lipoprotein (HDL) subfraction concentrations to atherosclerotic progression. METHODS AND RESULTS: Regression analyses of 136 patients who received baseline and follow-up coronary angiographies and subfraction measurements by all four methods in the HDL Atherosclerosis Treatment Study. Prior analyses have shown that the intervention primarily affected disease progression in proximal arteries with <30% stenoses at baseline. Three-year increases in percent stenoses were consistently associated with higher on-study plasma concentrations of small, dense LDL as measured by GGE (LDLIIIb, P=10(-6); LDLIVa, P=0.006; LDLIVb, P=0.02), VAP-II (LDL4, P=0.002), NMR (small LDL, P=0.001), and ion mobility (LDL IIb, P=0.04; LDLIIIa, P=0.002; LDLIIIb, P=0.0007; LDLIVa, P=0.05). Adjustment for triglycerides, HDL-cholesterol, and LDL-cholesterol failed to eliminate the statistical significance for on-study GGE estimated LDLIIIb (P=10(-5)) and LDLIVa (P=0.04); NMR-estimated small LDL (P=0.03); or ion mobility estimated large VLDL (P=0.02), LDLIIIa (P=0.04) or LDLIIIb (P=0.02). All methods show that the effects were significantly greater for the on-study than the baseline small, dense LDL concentrations, thus establishing that the values concurrent to the progression of disease were responsible. The rate of disease progression was also related to individual VLDL, IDL, and HDL subclasses to differing extents among the various analytic methods. CONCLUSION: Four methodologies confirm the association of small, dense LDL with greater coronary atherosclerosis progression, and GGE, NMR, and ion mobility confirm that the associations were independent of standard lipid measurements. CLINICAL TRIAL REGISTRATION: clinicaltrials.gov/ct2/show/NCT00000553.
BACKGROUND: Compare gradient gel electrophoresis (GGE), vertical auto profile ultracentrifugation (VAP-II), nuclear magnetic resonance spectroscopy (NMR), and ion mobility for their ability to relate low- (LDL), intermediate- (IDL), very-low-density (VLDL) and high-density lipoprotein (HDL) subfraction concentrations to atherosclerotic progression. METHODS AND RESULTS: Regression analyses of 136 patients who received baseline and follow-up coronary angiographies and subfraction measurements by all four methods in the HDL Atherosclerosis Treatment Study. Prior analyses have shown that the intervention primarily affected disease progression in proximal arteries with <30% stenoses at baseline. Three-year increases in percent stenoses were consistently associated with higher on-study plasma concentrations of small, dense LDL as measured by GGE (LDLIIIb, P=10(-6); LDLIVa, P=0.006; LDLIVb, P=0.02), VAP-II (LDL4, P=0.002), NMR (small LDL, P=0.001), and ion mobility (LDL IIb, P=0.04; LDLIIIa, P=0.002; LDLIIIb, P=0.0007; LDLIVa, P=0.05). Adjustment for triglycerides, HDL-cholesterol, and LDL-cholesterol failed to eliminate the statistical significance for on-study GGE estimated LDLIIIb (P=10(-5)) and LDLIVa (P=0.04); NMR-estimated small LDL (P=0.03); or ion mobility estimated large VLDL (P=0.02), LDLIIIa (P=0.04) or LDLIIIb (P=0.02). All methods show that the effects were significantly greater for the on-study than the baseline small, dense LDL concentrations, thus establishing that the values concurrent to the progression of disease were responsible. The rate of disease progression was also related to individual VLDL, IDL, and HDL subclasses to differing extents among the various analytic methods. CONCLUSION: Four methodologies confirm the association of small, dense LDL with greater coronary atherosclerosis progression, and GGE, NMR, and ion mobility confirm that the associations were independent of standard lipid measurements. CLINICAL TRIAL REGISTRATION: clinicaltrials.gov/ct2/show/NCT00000553.
Keywords:
Angiography; Coronary artery disease; High density lipoproteins; Lipoprotein subfractions; Low-density lipoproteins; Prevention; Very low density lipoproteins
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