title: Very-Low-Density Lipoprotein-Associated Apolipoproteins Predict Cardiovascular Events and Are Lowered by Inhibition of APOC-III.
abstract: BACKGROUND
  Routine apolipoprotein (apo) measurements for cardiovascular disease (CVD) are restricted to apoA-I and apoB. Here, the authors measured an unprecedented range of apolipoproteins in a prospective, population-based study and relate their plasma levels to risk of CVD.
  
  
  OBJECTIVE
  This study sought to measure apolipoproteins directly by mass spectrometry and compare their associations with incident CVD and to obtain a system-level understanding of the correlations of apolipoproteins with the plasma lipidome and proteome.
  
  
  METHODS
  Associations of 13 apolipoproteins, 135 lipid species, and 211 other plasma proteins with incident CVD (91 events), defined as stroke, myocardial infarction, or sudden cardiac death, were assessed prospectively over a 10-year period in the Bruneck Study (N = 688) using multiple-reaction monitoring mass spectrometry. Changes in apolipoprotein and lipid levels following treatment with volanesorsen, a second-generation antisense drug targeting apoC-III, were determined in 2 human intervention trials, one of which was randomized.
  
  
  RESULTS
  The apolipoproteins most significantly associated with incident CVD were apoC-II (hazard ratio per 1 SD [HR/SD]: 1.40; 95% confidence interval [CI]: 1.17 to 1.67), apoC-III (HR/SD: 1.38; 95% CI: 1.17 to 1.63), and apoE (HR/SD: 1.31; 95% CI: 1.13 to 1.52). Associations were independent of high-density lipoprotein (HDL) and non-HDL cholesterol, and extended to stroke and myocardial infarction. Lipidomic and proteomic profiles implicated these 3 very-low-density lipoprotein (VLDL)-associated apolipoproteins in de novo lipogenesis, glucose metabolism, complement activation, blood coagulation, and inflammation. Notably, apoC-II/apoC-III/apoE correlated with a pattern of lipid species previously linked to CVD risk. ApoC-III inhibition by volanesorsen reduced plasma levels of apoC-II, apoC-III, triacylglycerols, and diacylglycerols, and increased apoA-I, apoA-II, and apoM (all p < 0.05 vs. placebo) without affecting apoB-100 (p = 0.73).
  
  
  CONCLUSIONS
  The strong associations of VLDL-associated apolipoproteins with incident CVD in the general community support the concept of targeting triacylglycerol-rich lipoproteins to reduce risk of CVD.
authors.affiliation: Department of Neurology, Medical University Innsbruck, Innsbruck, Austria.
authors.forename: Raimund
authors.initials: R
authors.lastname: Pechlaner
authors.affiliation: University of California San Diego, La Jolla, California; Ionis Pharmaceuticals, Carlsbad, California.
authors.forename: Sotirios
authors.initials: S
authors.lastname: Tsimikas
authors.affiliation: King's British Heart Foundation Centre, King's College London, London, United Kingdom.
authors.forename: Xiaoke
authors.initials: X
authors.lastname: Yin
authors.affiliation: Department of Neurology, Medical University Innsbruck, Innsbruck, Austria; Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Peter
authors.initials: P
authors.lastname: Willeit
authors.affiliation: King's British Heart Foundation Centre, King's College London, London, United Kingdom.
authors.forename: Ferheen
authors.initials: F
authors.lastname: Baig
authors.affiliation: Department of Laboratory Medicine, Hospital of Bruneck, Bruneck, Italy.
authors.forename: Peter
authors.initials: P
authors.lastname: Santer
authors.affiliation: Department of Laboratory Medicine, Hospital of Bruneck, Bruneck, Italy.
authors.forename: Friedrich
authors.initials: F
authors.lastname: Oberhollenzer
authors.affiliation: Department of Internal Medicine, Hospital of Bruneck, Bruneck, Italy.
authors.forename: Georg
authors.initials: G
authors.lastname: Egger
authors.affiliation: University of California San Diego, La Jolla, California.
authors.forename: Joseph L
authors.initials: JL
authors.lastname: Witztum
authors.affiliation: Ionis Pharmaceuticals, Carlsbad, California.
authors.forename: Veronica J
authors.initials: VJ
authors.lastname: Alexander
authors.affiliation: Department of Neurology, Medical University Innsbruck, Innsbruck, Austria.
authors.forename: Johann
authors.initials: J
authors.lastname: Willeit
authors.affiliation: Department of Neurology, Medical University Innsbruck, Innsbruck, Austria. Electronic address: stefan.kiechl@i-med.ac.at.
authors.forename: Stefan
authors.initials: S
authors.lastname: Kiechl
authors.affiliation: King's British Heart Foundation Centre, King's College London, London, United Kingdom. Electronic address: manuel.mayr@kcl.ac.uk.
authors.forename: Manuel
authors.initials: M
authors.lastname: Mayr
mesh_terms: D000368:Aged; D053305:Apolipoprotein C-III / Q000037:antagonists & inhibitors*; D001053:Apolipoproteins / Q000097:blood*; D002318:Cardiovascular Diseases / Q000097:blood* / Q000453:epidemiology* / Q000517:prevention & control; D005260:Female; D006801:Humans; D015994:Incidence; D008079:Lipoproteins, VLDL / Q000097:blood*; D008297:Male; D013058:Mass Spectrometry; D008875:Middle Aged; D011446:Prospective Studies
chemical_list: D053305:Apolipoprotein C-III; D001053:Apolipoproteins; D008079:Lipoproteins, VLDL
keywords: lipidomics; mass spectrometry; proteomics; triglycerides