期刊
JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY
卷 69, 期 7, 页码 789-800出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.jacc.2016.11.065
关键词
lipidomics; mass spectrometry; proteomics; triglycerides
资金
- BHF
- Heart Research UK
- Pustertaler Verein zur Pravention von Herz-und Hirngefaesserkrankungen
- Gesundheitsbezirk Bruneck
- Sudtiroler Sanitatsbetrieb
- Province of Bolzano, Italy
- excellence initiative (Competence Centers for Excellent Technologies - COMET) of the Austrian Research Promotion Agency FFG: Research Center of Excellence in Vascular Ageing - Tyrol, VASCage - BMVIT [843536]
- BMWFW
- Wirtschaftsagentur Wien
- Standortagentur Tirol
- National Institute for Health Research (NIHR) Biomedical Research Centre based at Guy's and St Thomas' NHS Foundation Trust and King's College London in partnership with King's College Hospital
- Ionis Pharmaceuticals
- NIH [R01-HL119828, P01-HL088093, P01 HL055798, R01-HL106579, R01-HL078610, R01-HL124174]
- British Heart Foundation [CH/16/3/32406, RG/16/14/32397, FS/13/2/29892] Funding Source: researchfish
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. OBJECTIVES 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. (C) 2017 The Authors. Published by Elsevier on behalf of the American College of Cardiology Foundation.
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