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

Vascul Pharmacol. 2023 Oct:152:107214. doi: 10.1016/j.vph.2023.107214. Epub 2023 Aug 25.


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.

Keywords: Atherosclerosis; Atherosclerotic plaque; IL-6; Myocardial infarction; Soluble IL-6 receptor.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Atherosclerosis* / diagnosis
  • Cardiovascular Diseases* / diagnosis
  • Heart Disease Risk Factors
  • Humans
  • Inflammation / diagnosis
  • Interleukin-6
  • Myocardial Infarction*
  • Prospective Studies
  • Receptors, Interleukin-6
  • Risk Factors


  • prostaglandin-inositol cyclic phosphate
  • Interleukin-6
  • Receptors, Interleukin-6