Discovery of four plasmatic biomarkers potentially predicting cardiovascular outcome in peripheral artery disease
Open accessAbstract
Peripheral artery disease (PAD) patients have an increased cardiovascular risk despite pharmacological treatment strategies. Biomarker research improving risk stratification only focused on known atherothrombotic pathways, but unexplored pathways might play more important roles. To explore the association between a broad cardiovascular biomarker set and cardiovascular risk in PAD. 120 PAD outpatients were enrolled in this observational cohort study. Patients were followed for one year in which the composite endpoint (myocardial infarction, coronary revascularization, stroke, acute limb ischemia and mortality) was assessed. Patient data and blood samples were collected upon inclusion, and citrated platelet-poor plasma was used to analyze 184 biomarkers in Olink Cardiovascular panel II and III using a proximity extension assay. Fifteen patients reached the composite endpoint. These patients had more prior strokes and higher serum creatinine levels. Multivariate analysis revealed increased plasma levels of protease-activated receptor 1 (PAR1), galectin-9 (Gal-9), tumor necrosis factor receptor superfamily member 11A (TNFRSF11A) and interleukin 6 (IL-6) to be most predictive for cardiovascular events and mortality. Positive regulation of acute inflammatory responses and leukocyte chemotaxis were identified as involved biological processes. This study identified IL-6, PAR1, Gal-9, TNFRSF11A as potent predictors for cardiovascular events and mortality in PAD, and potential drug development targets.
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Exercise-induced muscle-derived IL-6 is thought to preferentially activate the classical signaling pathway via membrane-bound receptors, which is associated with anti-inflammatory and cardioprotective effects.
“exercise-induced muscle-derived IL-6 is thought to preferentially activate the “classical signaling” pathway via membrane-bound receptors based on indirect evidence from human studies and mechanistic data from cell models; this pathway is associated with anti-inflammatory and cardioprotective effects [34,35].”
From Exercise-Induced Myokines in Obesity-Related Metabolic Disorders and Cardiovascular Protection: A Narrative Review (2026) · cites this paper as [35]
The Discussion describes IL-6 as pro-inflammatory and pro-atherogenic in atherosclerosis, but does not address exercise-induced, muscle-derived IL-6. Searches for classical signaling, membrane-bound receptors, and anti-inflammatory or cardioprotective effects found no passage assessing the claimed pathway. (LLM, conf=0.76)
Experimental — accuracy not yet measuredThe pulsatile IL-6 signal induces expression of anti-inflammatory cytokines IL-10 and IL-1 receptor antagonist in skeletal muscle and adipose tissue, initiating a systemic acute anti-inflammatory response.
“this pulsatile IL-6 signal induces expression of anti-inflammatory cytokines such as IL-10 and IL-1 receptor antagonist (IL-1Ra) in skeletal muscle and adipose tissue, initiating a systemic acute anti-inflammatory response [34,35].”
From Exercise-Induced Myokines in Obesity-Related Metabolic Disorders and Cardiovascular Protection: A Narrative Review (2026) · cites this paper as [35]
The Discussion describes IL-6 as pro-inflammatory in atherosclerosis and says it induces CRP and fibrinogen. Searches for pulsatile IL-6 signaling and for IL-10, IL-1Ra, skeletal muscle, adipose tissue, and an acute anti-inflammatory response found no passage addressing the claimed mechanism. (LLM, conf=0.77)
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- Authors
- Kremers, B. M. M., Posma, J. N., Heitmeier, S., Glunz, J., ten Cate, H., Pallares Robles, A., Daemen, J. H. C., ten Cate-Hoek, A. J., Mees, B. M. E., & Spronk, H. M. H.
- Affiliations
- Maastricht University (NL)
- Bayer (Germany) (DE)
- Maastricht University Medical Centre (NL)
- Corresponding author
- Kremers, B. M. M.
- Venue
- Scientific Reports
- Published
- 2022-11-01
- Volume
- 12
- Issue
- 1
- Pages
- 18388-18388
- ISSN
- 2045-2322 (ISSN-L)
- PMC
- PMC9626632
- OpenAlex
- W4308025750
- Cited by
- 17
- References
- 41
- Citations by year
- 2026: 5 · 2025: 4 · 2024: 4 · 2023: 4
- FWCI
- 2.87
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Scientific Reports (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Research Publications (Maastricht University) (publishedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Research Publications (Maastricht University) (submittedVersion, other-oa)
- Funders
- European Union's Horizon 2020 research and innovation program under the Marie Sklodowska-Curie agreement (813409)
- Topics
- Health Sciences › Medicine › Surgery › Peripheral Artery Disease Management
- Life Sciences › Immunology and Microbiology › Immunology › Atherosclerosis and Cardiovascular Diseases
- Health Sciences › Medicine › Oncology › Inflammatory Biomarkers in Disease Prognosis
- Keywords
- peripheral arterial disease, cardiovascular risk prediction, plasma biomarkers, protease-activated receptor 1, galectin-9, RANK, interleukin-6, cardiovascular events, mortality, acute inflammation, leukocyte chemotaxis, proximity extension assay
- MeSH terms
- Humans, Risk Factors, Biomarkers, Interleukin-6, Treatment Outcome, Stroke, Receptor, PAR-1, Peripheral Arterial Disease
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