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. 2024 Mar 27;31(5):521-528.
doi: 10.1093/eurjpc/zwad311.

Soluble urokinase Plasminogen Activator Receptor (suPAR) mediates the effect of a lower education level on adverse outcomes in patients with coronary artery disease

David Füller  1   2 , Chang Liu  1   3 , Yi-An Ko  4 , Ayman A Alkhoder  1 , Shivang R Desai  1 , Zakaria Almuwaqqat  1 , Shivani A Patel  3 , Kiran Ejaz  1 , Tanveer Kauser  1 , Mohamed Afif Martini  1 , Zain Alvi  1 , Puja K Mehta  1 , Laurence S Sperling  1 , Arshed A Quyyumi  1
Affiliations

Soluble urokinase Plasminogen Activator Receptor (suPAR) mediates the effect of a lower education level on adverse outcomes in patients with coronary artery disease

David Füller et al. Eur J Prev Cardiol. .

Abstract

Aims: To investigate whether the adverse impact of lower educational attainment on mortality risk in patients with coronary artery disease (CAD) is mediated by the activation of inflammatory and immune pathways, estimated as elevated soluble urokinase plasminogen activator receptor levels.

Methods and results: In 3164 patients undergoing coronary angiography, we investigated multivariable associations between suPAR and educational attainment and assessed the relationship between a lower educational level (defined as a high-school degree or less as the highest educational qualification) and outcomes using Cox proportional hazard and Fine and Gray's subdistribution competing risk models. The potential mediating effect through suPAR and high-sensitivity C-reactive protein (hs-CRP) was assessed using mediation analysis. A total of 1814 patients (57.3%) had achieved a higher (≥college) education level and 1350 patients (42.7%) a lower (≤high school) education level. Soluble urokinase plasminogen activator receptor levels were 9.0% [95% confidence interval (CI) 6.3-11.8, P ≤ 0.0001] higher in patients with lower educational qualifications than in those with higher educational qualifications after covariate adjustment. Lower educational attainment was associated with a higher risk of cardiovascular death after adjustment for demographic, clinical, and behavioural covariates, including CAD severity and heart failure history, medication use, and hs-CRP levels [hazard ratio 1.26 (95% CI 1.02-1.55, P = 0.03)]. However, after adjustment for suPAR levels, the effect of a lower educational level on cardiovascular death became insignificant. Values were similar for all-cause death. Soluble urokinase plasminogen activator receptor levels mediated 49% and hs-CRP levels 17% of the cardiovascular death risk attributable to lower educational attainment.

Conclusion: Circulating suPAR levels importantly mediate the effects of lower educational attainment on mortality, indicating the importance of systemic inflammation and immune dysregulation as biologic mediators of adverse social determinants of health.

Keywords: Biology of adversity; CAD outcomes; Education; Social determinants of health; suPAR.

Plain language summary

In patients with coronary artery disease (CAD), we demonstrate that nearly half of the higher risk of all-cause and cardiovascular mortality associated with lower educational attainment as a measure of socioeconomic status is mediated by systemic inflammation and immune dysregulation, which can be estimated by measuring the circulating soluble urokinase plasminogen activator receptor (suPAR) levels. Even after accounting for differences in cardiovascular risk factors, lower educational attainment is associated with higher mortality risk in patients with CAD and there is activation of inflammatory pathways and immune dysregulation in those with lower (≤high school) educational attainment than in those with higher (≥college) educational attainment, estimated as higher circulating suPAR levels.Almost half of the higher risk for adverse outcomes observed in those with lower educational attainment appears to be due to systemic inflammation and immune dysregulation and can be estimated from measuring suPAR levels.

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Conflict of interest statement

Conflict of interest: None declared.

Figures

Graphical Abstract
Graphical Abstract
Figure 1
Figure 1
Plasma levels of the soluble urokinase plasminogen activator receptor through six different categories of educational attainment assessed in the Emory Cardiovascular Biobank. Based on the linear regression model, every one level higher of education is associated with lower levels of soluble urokinase plasminogen activator receptor by 5.3% (95% CI −6.3, −4.3%), P ≤ 0.0001.
Figure 2
Figure 2
Effect of a low educational qualification, defined as elementary/middle school, some high school, or high-school graduate as having the highest educational qualification, on adverse outcomes. Reference high educational qualification defined as some college education, a college degree, graduate education, or a degree as the highest educational qualification. Model 1: adjusted for age, sex, race (White vs. non-White), diabetes, hypertension, history of myocardial infarction, heart failure, previous percutaneous coronary intervention, previous coronary artery bypass graft, ejection fraction, obstructive coronary artery disease defined as ≥50% stenosis in ≥1 epicardial artery, smoking, use of aspirin daily, P2Y12-receptor inhibitors, statins, beta-blockers, angiotensin antagonists, alcohol consumption, body mass index, estimated glomerular filtration rate, total cholesterol, LDL-C, HDL-C, and triglycerides. Model 2: adjusted for covariates in Model 1 and high-sensitivity C-reactive protein. Model 3: adjusted for covariates in Model 1 and soluble urokinase plasminogen activator receptor.
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