suPAR: A New Biomarker for Cardiovascular Disease?

doi:10.1016/j.cjca.2015.03.023

Canadian Journal of Cardiology

Volume 31, Issue 10, October 2015, Pages 1293-1302

https://doi.org/10.1016/j.cjca.2015.03.023 Get rights and content

Abstract

The fundamental role of inflammation in cardiovascular disease (CVD) has prompted interest in numerous biomarkers that detect subclinical levels of inflammation. Soluble urokinase plasminogen activator receptor (suPAR) is a novel biomarker that correlates significantly with cardiovascular events and outperforms traditional markers of inflammation such as C-reactive protein (CRP) in prognosticating a range of CVDs. Furthermore, of particular interest is the suggestion that suPAR reflects a pathophysiological pathway more closely linked with subclinical organ damage than CRP. We provide the first comprehensive review of suPAR in CVD and explore its function and usefulness in predicting cardiovascular events.

Résumé

Le rôle fondamental de l’inflammation dans la maladie cardiovasculaire (MCV) a suscité l’intérêt pour de nombreux biomarqueurs qui détectent les degrés subcliniques d’inflammation. Le récepteur soluble de l’activateur du plasminogène de l’urokinase (suPAR : soluble urokinase plasminogen activator receptor) est un nouveau biomarqueur qui corrèle de façon significative avec les événements cardiovasculaires et surpasse les marqueurs traditionnels de l’inflammation tels que la protéine C réactive (CRP : C-reactive protein) dans le pronostic de nombreuses MCV. De plus, la suggestion selon laquelle le suPAR reflète une voie physiopathologique plus étroitement liée à la lésion subclinique de l’organe que le CRP revêt un intérêt particulier. Nous présentons la première étude exhaustive sur le suPAR dans les MCV, et explorons son fonctionnement et son utilité dans la prédiction des événements cardiovasculaires.

Section snippets

suPAR Pathophysiology

Urokinase-type plasminogen activator receptor (uPAR) is a membrane-linked protein found in several cell types, including immunologically active cells and vascular endothelial cells.⁵ Several biological functions have been described for this versatile receptor. These include several physiological pathways (many of which regulate atherogenesis), such as the plasminogen activating pathway, cell signalling through integrins, modulation of cell adhesion, migration, and proliferation.5, 6, 7, 8

Biomarkers in CVD

The rapid rise in the number of cardiovascular biomarkers has been driven by attempts to further risk-stratify individuals beyond that achievable with traditional risk factors. Although the predictive value of the established risk factors is substantial, up to 20% of those experiencing CVD have no traditional risk factors.¹⁸

CVD pathogenesis is multifactorial in origin, and several complex biological pathways are implicated that emphasize the central role of inflammation in mediating various

suPAR and CRP

CRP is an acute-phase protein, produced by hepatocytes in response to the inflammatory cytokine, interleukin-6. In this context, it is worthy of note that up to 30% of circulating interleukin-6 in humans originates from adipose tissue.²³ CRP is the best-studied marker of inflammation in CVD and, as discussed, has been used to stratify cardiovascular risk, linked to subclinical inflammation.² Although no causal link has been established, strong evidence suggests that elevated CRP can reliably

Future Work

suPAR is consistently shown to be a reliable predictor of adverse events in populations of generally “healthy” middle-aged individuals and those with established CAD. However, there are several limitations. First, the literature search reveals few papers on suPAR and CVD (see Table 1). In addition, although a recent paper has investigated suPAR in a black African population,³⁴ much of the literature is derived from the same 3 population-based cohorts in Denmark and Sweden (the MONICA health

Conclusive Remarks

Although there is limited literature relating to suPAR and CVD, and few clinical trials, suPAR has proven to be a versatile prognostic marker and appears to reflect atherosclerosis and other SOD better than traditional inflammatory markers; however, its clinical impact has yet to be proven. The possibility that suPAR represents an alternative inflammatory pathway to CRP has the potential to be exploited in multimarker approaches to risk stratification. Further research is needed to elucidate

Acknowledgements

The views expressed are those of the authors and not an official position of the institution or funder.

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Cited by (83)

Establishing reference intervals for soluble urokinase plasminogen activator receptor in Northern European adults
2024, Practical Laboratory Medicine
Soluble urokinase plasminogen activator receptor (suPAR) may have untapped potential in clinical diagnostics. Previous studies determined reference intervals using an enzyme-linked immunoassay, but there is a need for reference intervals using a faster assay if the analysis is to be used in emergency medicine. The current study aims to determine reference intervals for suPAR using a fully automated particle-enhanced turbidimetric immunoassay (PETIA) according to the Clinical and Laboratory Standards Institute guideline A28-A3c.
Blood samples were prospectively collected from Danish blood donors. Plasma suPAR was analyzed on the cobas 8000 module c502 in an open channel using a PETIA. Sex-partitioned reference intervals were determined using a parametric quantile approach.
The study included 241 participants—123 females and 118 males. The common reference interval for suPAR was 1.56–4.11 ng/mL (95% confidence intervals (CI) for the lower and upper limits were 1.56–1.63 and 3.81–4.47, respectively). The reference interval for females was 1.59–4.65 ng/mL (95% CIs 1.48–1.70 and 4.09–5.48, respectively) and for males, 1.56–3.59 ng/mL (95% CIs 1.47–1.65 and 3.31–3.93, respectively).
Our results support using sex-partitioned reference intervals for suPAR and provide a basis for future studies using the PETIA method.
Discrimination and Inflammation in Adolescents of Color
2023, Biological Psychiatry Global Open Science
This study examined how experiences with discrimination relate to inflammation, a key biological pathway in mental and physical illnesses, and whether associations are moderated by gender across two samples of adolescents of color.
Study 1 was a longitudinal study of 419 African American adolescents assessed on discrimination (ages 19–20), with trajectories of biomarkers of low-grade inflammation (C-reactive protein and soluble urokinase plasminogen activator receptor) measured from ages 25 to 29. Study 2 was a cross-sectional study of 201 eighth graders of color assessed on discrimination and mechanistic indicators of a proinflammatory phenotype: 1) in vitro studies of immune cells’ inflammatory cytokine responses to stimuli; 2) in vitro studies of cells’ sensitivity to anti-inflammatory agents; 3) circulating numbers of classical monocytes, key cellular drivers of low-grade inflammation; and 4) a composite of six biomarkers of low-grade inflammation.
Interactions of discrimination by gender were found across both studies. In study 1, African American males experiencing high discrimination showed increasing trajectories of soluble urokinase plasminogen activator receptor over time (p < .001). In study 2, adolescent boys of color experiencing greater discrimination evinced a more proinflammatory phenotype: larger cytokine responses to stimuli (p = .003), lower sensitivity to anti-inflammatory agents (p = .003), higher numbers of classical monocytes (p = .008), and more low-grade inflammation (p = .003). No such associations were found in females.
Discrimination is a pressing societal issue that will need to be addressed in efforts to promote health equity. This study suggests that adolescent males of color may be particularly vulnerable to its effects on mental health–relevant inflammatory processes.
New Biomarkers in Heart Failure: The Bar is High
2023, Journal of Cardiac Failure
Prospective associations between neighborhood violence and monocyte pro-inflammatory transcriptional activity in children
2022, Brain, Behavior, and Immunity
Individuals exposed to persistent neighborhood violence are at increased risk for developing mental and physical health problems across the lifespan. The biological mechanisms underlying this phenomenon are not well understood. Thus, we examined the relationship between children’s exposure to neighborhood violence and inflammatory activity, a process involved in the pathogenesis of multiple health problems. 236 children from the Chicago area participated in a two-year longitudinal study (mean age at baseline, 13.9 years; 67% female; 39% White, 34% Black, 33% Hispanic). Neighborhood violence was measured as the homicide frequency in a child’s Census block group in the five years before study entry. Fasting blood was drawn at study entry and two years later (in eighth and tenth grade). The blood was used to quantify protein biomarkers of systemic inflammatory activity and perform genome-wide expression profiling of isolated monocytes. Neighborhood violence was associated with higher systemic inflammatory activity at both assessments. It also was associated with a monocyte transcriptional profile indicative of increased signaling along the nuclear factor-kappa B (NF-κB) and activator protein 1 (AP-1) control pathways, which are key orchestrators of pro-inflammatory effector functions. Neighborhood violence also was associated with transcriptional indications of higher beta-adrenergic and lower glucocorticoid signaling, which could function as neuroendocrine conduits linking threatening experiences with inflammatory activity. Neighborhood violence was not associated with two-year changes in protein biomarkers, although it did presage a transcriptional profile indicative of increasing AP-1 and declining glucocorticoid signaling over follow-up. Collectively, these observations highlight cellular and molecular pathways that could underlie health risks associated with neighborhood violence.
suPAR: A newer biomarker of systemic chronic inflammation
2021, Brain, Behavior, and Immunity
Prognostic Value of Soluble Urokinase-Type Plasminogen Activator Receptor and High-Sensitivity C-Reactive Protein on Postoperative Mortality in Patients Undergoing Elective On-Pump Cardiac Surgery
2021, Journal of Cardiothoracic and Vascular Anesthesia
Elevated soluble urokinase-type plasminogen activator receptor (suPAR) and high-sensitivity C-reactive protein (hsCRP) have been associated with increased mortality in patients with cardiovascular disease. The aim of the present study was to explore the relationship between suPAR and hsCRP values and associated mortality after elective cardiac surgery. A secondary aim was to assess whether a combined risk model of European System for Cardiac Operative Risk Evaluation (EuroSCORE II), suPAR, and/or hsCRP would improve the prognostic accuracy compared with EuroSCORE II alone.
Retrospective observational study.
Single-center, university hospital.
Adult patients admitted for elective on-pump cardiac surgery were included. Biobank blood samples were obtained from previous research projects at a tertiary heart center from 2012 to 2018.
None.
A total of 931 patients were included. Kaplan-Meier and Cox proportional hazard analyses were used to explore a potential association between preoperative suPAR and hsCRP values and all-cause mortality up to one year after surgery. Thirty-day mortality was predicted from suPAR, hsCRP, and EuroSCORE II by logistic regression and compared using area under the receiver operating characteristics curve and Brier scores. After adjustment for known confounders, a doubling of suPAR and hsCRP corresponded to a hazard ratio for all-cause mortality of 2.27 (95% confidence interval 1.65-3.11; p < 0.001) and 1.26 (95% confidence interval 1.07-1.49; p = 0.005), respectively. However, adding the biomarkers to EuroSCORE II did not improve prediction/discrimination with respect to 30-day mortality.
Elevated preoperative levels of suPAR and hsCRP were associated with all-cause mortality in elective cardiac surgery patients. However, inclusion of biomarkers did not improve the prognostic accuracy of EuroSCORE II.

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: See editorial by Arbel and Strauss, pages 1223-1224 of this issue.

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ReviewsuPAR: A New Biomarker for Cardiovascular Disease?

Abstract

Résumé

Section snippets

suPAR Pathophysiology

Biomarkers in CVD

suPAR and CRP

Future Work

Conclusive Remarks

Acknowledgements

Int J Cardiol

FEBS Lett

Int J Cardiol

Am J Cardiol

Atherosclerosis

Clin Biochem

Can J Cardiol

Atherosclerosis

Mayo Clin Proc

Atherosclerosis

Atherosclerosis

Clin Biochem

J Am Soc Echocardiogr

Lancet

Cardiovasc Pathol

Thromb Res

Thromb Res

Kidney Int

Thromb Res

Anti-inflammatory therapies for cardiovascular disease

Eur Heart J

Soluble urokinase plasminogen activator receptor levels are elevated and associated with complications in patients with type 1 diabetes

J Intern Med

Usefulness of suPAR as a biological marker in patients with systemic inflammation or infection: a systematic review

Intensive Care Med

suPAR: the molecular crystal ball

Dis Markers

The urokinase receptor: focused cell surface proteolysis, cell adhesion and signaling

FEBS Lett

Regulation of cell signalling by uPAR

Nature Rev

Proteolytic cleavage of the urokinase receptor substitutes for the agonist-induced chemotactic effect

EMBO J

Review
suPAR: A New Biomarker for Cardiovascular Disease?