Susceptibility of low-density lipoprotein particles to aggregate depends on particle lipidome, is modifiable, and associates with future cardiovascular deaths
Open accessAbstract
Aims: 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 vitro activated macrophages and T cells, two key cell types involved in plaque progression and rupture. Conclusion: Our results identify the susceptibility of LDL to aggregate as a novel measurable and modifiable factor in the progression of human ASCVD.
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Decreased aggregation susceptibility could be achieved through a diet rich in vitamin E, such as the Mediterranean diet.
“In a very elegant study using data from the Healthy Nordic diet group, Ruuth et al. were able to demonstrate that decreased aggregation susceptibility could be achieved through a diet rich in vitamin E, such as the MD [51].”
From Mediterranean Diet as an Antioxidant: The Impact on Metabolic Health and Overall Wellbeing (2021) · cites this paper as [51]
Oxidative, proteolytic, and lipolytic modifications induce LDL aggregation, and LDL aggregation susceptibility is associated with risk of cardiovascular death.
“Oxidative, proteolytic and lipolytic modifications induce LDL aggregation46, and the aggregation susceptibility of LDL was shown to be associated with the risk of cardiovascular death55.”
From Inflammation and its resolution in atherosclerosis: mediators and therapeutic opportunities (2019) · cites this paper as [55]
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- Authors
- Ruuth, M., Nguyen, S. D., Vihervaara, T., Hilvo, M., Laajala, T. D., Kondadi, P. K., Gisterå, A., Lähteenmäki, H., Kittilä, T., Huusko, J., Uusitupa, M., Schwab, U., Savolainen, M. J., Sinisalo, J., Lokki, M.-L., Nieminen, M. S., Jula, A., Perola, M., Ylä-Herttula, S., Rudel, L., Öörni, A., Baumann, M., Baruch, A., Laaksonen, R., Ketelhuth, D. F. J., Aittokallio, T., Jauhiainen, M., Käkelä, R., Borén, J., Williams, K. J., Kovanen, P. T., & Öörni, K.
- Affiliations
- University of Helsinki (FI)
- Wihuri Research Institute (FI)
- Zora Biosciences (Finland) (FI)
- University of Gothenburg (SE)
- Karolinska University Hospital (SE)
- University of Eastern Finland (FI)
- Oulu University Hospital (FI)
- Finnish Institute for Health and Welfare (FI)
- Department of Biotechnology and Molecular Medicine, A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Yliopistonranta 1, P.O. Box 1627, 70211 Kuopio, Finland
- Wake Forest University Health Sciences (US)
- Åbo Akademi University (FI)
- Genentech (US)
- Tampere University (FI)
- Corresponding author
- Öörni, Katariina
- ORCID
- Ruuth, Maija
- Vihervaara, Terhi
- Hilvo, Mika
- Laajala, Teemu D
- Gisterå, Anton
- Lähteenmäki, Hanna
- Uusitupa, Matti
- Schwab, Ursula
- Savolainen, Markku J
- Sinisalo, Juha
- Lokki, Marja-Liisa
- Nieminen, Markku S
- Jula, Antti
- Perola, Markus
- Öörni, Anssi
- Baumann, Marc
- Baruch, Amos
- Laaksonen, Reijo
- Ketelhuth, Daniel F J
- Aittokallio, Tero
- Jauhiainen, Matti
- Käkelä, Reijo
- Borén, Jan
- Williams, Kevin Jon
- Kovanen, Petri T
- Öörni, Katariina
- Venue
- European Heart Journal
- Publisher
- Oxford University Press (OUP)
- Published
- 2018-07-04
- Volume
- 39
- Issue
- 27
- Pages
- 2562-2573
- ISSN
- 0195-668X (ISSN-L)
- 1522-9645
- PMC
- PMC6047440
- OpenAlex
- W2884473360
- Cited by
- 180
- References
- 46
- Citations by year
- 2026: 9 · 2025: 22 · 2024: 22 · 2023: 24 · 2022: 26 · 2021: 18 · 2020: 24 · 2019: 28 · 2018: 7
- FWCI
- 20.01
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- European Heart Journal (publishedVersion, cc-by-nc)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- Tampere University Institutional Repository (Tampere University) (publishedVersion, cc-by-nc)
- UEF eRepo (University of Eastern Finland) (submittedVersion, cc-by-nc)
- UTUPub (University of Turku) (submittedVersion)
- UTUPub (University of Turku) (submittedVersion, cc-by-nc)
- Åbo Akademi University Research Portal (submittedVersion)
- Tampere University Institutional Repository (Tampere University) (submittedVersion, cc-by-nc)
- STM:n Hallinnonalan avoin julkaisuarkisto (Julkari) (submittedVersion)
- WOS
- Funders
- Antti Wihuri Foundation
- Finnish Foundation for Cardiovascular Research
- Academy of Finland (265940, 295504 to T.A.)
- Magnus Ehrnrooth Foundation
- Jane and Aatos Erkko Foundation
- Swedish Heart-Lung Foundation
- Topics
- Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
- Life Sciences › Immunology and Microbiology › Immunology › Atherosclerosis and Cardiovascular Diseases
- Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
- Keywords
- low-density lipoprotein, LDL aggregation, sphingolipids, phosphatidylcholine, lipolysis, coronary artery disease mortality, atherosclerosis, PCSK9 inhibition, dietary intervention, macrophage activation, T cell activation, plaque rupture, cardiovascular risk prediction
- MeSH terms
- Adult, Animals, Coronary Artery Disease, Female, Humans, Lipids, Lipoproteins, LDL, Male, Middle Aged, Prognosis, Risk Assessment, Mice
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