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Circulating soluble IL-6 receptor associates with plaque inflammation but not with atherosclerosis severity and cardiovascular risk

Edsfeldt, Andreas LU ; Gonçalves, Isabel LU orcid ; Vigren, Isa ; Jovanović, Anja ; Engström, Gunnar LU ; Shore, Angela C. ; Natali, Andrea ; Khan, Faisel and Nilsson, Jan LU (2023) In Vascular Pharmacology 152.
Abstract

Background: The residual cardiovascular risk in subjects receiving guideline-recommended therapy is related to persistent vascular inflammation and IL-6 represents a target for its treatment. IL-6 binds to receptors on leukocytes and hepatocytes and/or by forming complexes with soluble IL-6 receptors (sIL-6R) binding to gp130 which is present on all cells. Here we aimed to estimate the associations of these two pathways with risk of cardiovascular disease (CVD). Methods: IL-6 and sIL-6R were analyzed using the proximity extension assay. Baseline plasma samples were obtained from participants in the prospective Malmö Diet and Cancer (MDC) study (n = 4661), the SUMMIT VIP study (n = 1438) and the Carotid Plaque Imaging Project (CPIP, n =... (More)

Background: The residual cardiovascular risk in subjects receiving guideline-recommended therapy is related to persistent vascular inflammation and IL-6 represents a target for its treatment. IL-6 binds to receptors on leukocytes and hepatocytes and/or by forming complexes with soluble IL-6 receptors (sIL-6R) binding to gp130 which is present on all cells. Here we aimed to estimate the associations of these two pathways with risk of cardiovascular disease (CVD). Methods: IL-6 and sIL-6R were analyzed using the proximity extension assay. Baseline plasma samples were obtained from participants in the prospective Malmö Diet and Cancer (MDC) study (n = 4661), the SUMMIT VIP study (n = 1438) and the Carotid Plaque Imaging Project (CPIP, n = 285). Incident clinical events were obtained through national registers. Plaques removed at surgery were analyzed by immunohistochemistry and biochemical methods. Results: During 23.1 ± 7.0 years follow-up, 575 subjects in the MDC cohort suffered a first myocardial infarction. Subjects in the highest tertile of IL-6 had an increased risk compared to the lowest tertile (HR and 95% CI 2.60 [2.08–3.25]). High plasma IL-6 was also associated with more atherosclerosis, increased arterial stiffness, and impaired endothelial function in SUMMIT VIP, but IL-6 was only weakly associated with plaque inflammation in CPIP. sIL-6R showed no independent association with risk of myocardial infarction, atherosclerosis severity or vascular function, but was associated with plaque inflammation. Conclusions: Our findings show that sIL-6R is a poor marker of CVD risk and associated vascular changes. However, the observation that sIL-6R reflects plaque inflammation highlights the complexity of the role of IL-6 in CVD.

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author
; ; ; ; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Atherosclerosis, Atherosclerotic plaque, IL-6, Myocardial infarction, Soluble IL-6 receptor
in
Vascular Pharmacology
volume
152
article number
107214
publisher
Elsevier
external identifiers
  • pmid:37634789
  • scopus:85169804872
ISSN
1537-1891
DOI
10.1016/j.vph.2023.107214
language
English
LU publication?
yes
id
de4b0246-4c3e-4e8c-8f78-d4aa17ad14f4
date added to LUP
2023-10-25 15:50:41
date last changed
2024-04-19 03:55:08
@article{de4b0246-4c3e-4e8c-8f78-d4aa17ad14f4,
  abstract     = {{<p>Background: The residual cardiovascular risk in subjects receiving guideline-recommended therapy is related to persistent vascular inflammation and IL-6 represents a target for its treatment. IL-6 binds to receptors on leukocytes and hepatocytes and/or by forming complexes with soluble IL-6 receptors (sIL-6R) binding to gp130 which is present on all cells. Here we aimed to estimate the associations of these two pathways with risk of cardiovascular disease (CVD). Methods: IL-6 and sIL-6R were analyzed using the proximity extension assay. Baseline plasma samples were obtained from participants in the prospective Malmö Diet and Cancer (MDC) study (n = 4661), the SUMMIT VIP study (n = 1438) and the Carotid Plaque Imaging Project (CPIP, n = 285). Incident clinical events were obtained through national registers. Plaques removed at surgery were analyzed by immunohistochemistry and biochemical methods. Results: During 23.1 ± 7.0 years follow-up, 575 subjects in the MDC cohort suffered a first myocardial infarction. Subjects in the highest tertile of IL-6 had an increased risk compared to the lowest tertile (HR and 95% CI 2.60 [2.08–3.25]). High plasma IL-6 was also associated with more atherosclerosis, increased arterial stiffness, and impaired endothelial function in SUMMIT VIP, but IL-6 was only weakly associated with plaque inflammation in CPIP. sIL-6R showed no independent association with risk of myocardial infarction, atherosclerosis severity or vascular function, but was associated with plaque inflammation. Conclusions: Our findings show that sIL-6R is a poor marker of CVD risk and associated vascular changes. However, the observation that sIL-6R reflects plaque inflammation highlights the complexity of the role of IL-6 in CVD.</p>}},
  author       = {{Edsfeldt, Andreas and Gonçalves, Isabel and Vigren, Isa and Jovanović, Anja and Engström, Gunnar and Shore, Angela C. and Natali, Andrea and Khan, Faisel and Nilsson, Jan}},
  issn         = {{1537-1891}},
  keywords     = {{Atherosclerosis; Atherosclerotic plaque; IL-6; Myocardial infarction; Soluble IL-6 receptor}},
  language     = {{eng}},
  publisher    = {{Elsevier}},
  series       = {{Vascular Pharmacology}},
  title        = {{Circulating soluble IL-6 receptor associates with plaque inflammation but not with atherosclerosis severity and cardiovascular risk}},
  url          = {{http://dx.doi.org/10.1016/j.vph.2023.107214}},
  doi          = {{10.1016/j.vph.2023.107214}},
  volume       = {{152}},
  year         = {{2023}},
}