Susceptibility of low-density lipoprotein particles to aggregate depends on particle lipidome, is modifiable, and associates with future cardiovascular deaths

Maija Ruuth, Su Duy Nguyen, Terhi Vihervaara, Mika Hilvo, Teemu D Laajala, Pradeep Kumar Kondadi, Anton Gisterå, Hanna Lähteenmäki, Tiia Kittilä, Jenni Huusko, Matti Uusitupa, Ursula Schwab, Markku J Savolainen, Juha Sinisalo, Marja-Liisa Lokki, Markku S Nieminen, Antti Jula, Markus Perola, Seppo Ylä-Herttula, Lawrence RudelAnssi Öörni, Marc Baumann, Amos Baruch, Reijo Laaksonen, Daniel F J Ketelhuth, Tero Aittokallio, Matti Jauhiainen, Reijo Käkelä, Jan Borén, Kevin Jon Williams, Petri T Kovanen, Katariina Öörni

    Forskningsoutput: TidskriftsbidragArtikelVetenskapligPeer review

    116 Citeringar (Scopus)



    Low-density lipoprotein (LDL) particles cause atherosclerotic cardiovascular disease (ASCVD) through their retention, modification, and accumulation within the arterial intima. High plasma concentrations of LDL drive this disease, but LDL quality may also contribute. Here, we focused on the intrinsic propensity of LDL to aggregate upon modification. We examined whether inter-individual differences in this quality are linked with LDL lipid composition and coronary artery disease (CAD) death, and basic mechanisms for plaque growth and destabilization.

    Methods and results

    We developed a novel, reproducible method to assess the susceptibility of LDL particles to aggregate during lipolysis induced ex vivo by human recombinant secretory sphingomyelinase. Among patients with an established CAD, we found that the presence of aggregation-prone LDL was predictive of future cardiovascular deaths, independently of conventional risk factors. Aggregation-prone LDL contained more sphingolipids and less phosphatidylcholines than did aggregation-resistant LDL. Three interventions in animal models to rationally alter LDL composition lowered its susceptibility to aggregate and slowed atherosclerosis. Similar compositional changes induced in humans by PCSK9 inhibition or healthy diet also lowered LDL aggregation susceptibility. Aggregated LDL in vitroactivated macrophages and T cells, two key cell types involved in plaque progression and rupture.


    Our results identify the susceptibility of LDL to aggregate as a novel measurable and modifiable factor in the progression of human ASCVD.

    Sidor (från-till)2562–2573
    TidskriftEuropean Heart Journal
    StatusPublicerad - 2018
    MoE-publikationstypA1 Tidskriftsartikel-refererad


    • Sphingomyelin
    • Atherosclerosis
    • low-density lipoprotein receptor-related protein 1
    • Lipidomics

    Citera det här