ORIGINAL RESEARCH article
Front. Cardiovasc. Med.
Sec. Cardiovascular Epidemiology and Prevention
This article is part of the Research TopicThe Role of Environmental and Metabolic Factors in Global Cardiovascular HealthView all 11 articles
Allostatic Load-Cardiovascular Disease Associations and the Mediating Effect of Inflammatory Factors: A Prospective Cohort Study
Provisionally accepted
Shuai Xu1*
Ge Zhang2
Yudi Xu2Chaoyang Yu2
Ruhao Wu2
Zhengrui Li3
Teng Li2Xinyue Cui2
Xufeng Huang4
Shujing Zhou4Yahui Han5
Haonan Zhang2Shiqian Zhang6
Yufeng Jiang7- 1Orthopaedic Institute, Soochow University, Suzhou, China
- 2The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- 3Shanghai Jiao Tong University School of Medicine, Shanghai, China
- 4Debreceni Egyetem, Debrecen, Hungary
- 5Naval Medical University School of Pharmacy, Shanghai, China
- 6The Affiliated Hospital of Nankai University, Tianjin, China
- 7The Fourth Affiliated Hospital of Soochow University, Suzhou, China
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Background: Allostatic load (AL) captures multisystem dysregulation that accrues with chronic stress and may shape cardiovascular disease (CVD) risk through neuroendocrine and immune pathways. Robust population-scale evidence clarifying the exposure-response pattern and the extent of inflammatory mediation remains limited. Methods: In the UK Biobank, we analyzed 205,504 adults free of CVD at baseline from 502,366 recruited. An AL score was assembled from 12 routinely measured biomarkers. Incident CVD was ascertained via linkage to hospital and mortality records. We estimated adjusted hazard ratios (HRs) using Cox models and assessed nonlinearity with restricted cubic splines; robustness was evaluated in prespecified subgroups and sensitivity analyses. We also investigated the role of the mediating effect of inflammatory factors in the AL-CVD relationship. Results: Higher AL tracked with progressively greater CVD risk in a graded, non-linear pattern. Relative to AL=0, AL>=6 was associated with HR 2.15 (95% CI 1.99-2.33). Eight inflammatory markers met retention criteria for mediation; neutrophil count mediated 4.73% of the AL-CVD association. Group contrasts across AL tertiles indicated Cohen's d near 0.5 for several markers, largest for no-AL vs high-AL. Conclusion: Elevated AL is linked to higher incident CVD with a non-linear exposure-response, and neutrophil-centric inflammation accounts for a measurable portion of the association. These findings support integrating stress-biology constructs and inflammatory profiling into cardiovascular risk assessment and prevention frameworks.
Keywords: allostatic load, cardiovascular disease, UK Biobank, Inflammatory factors, Prospective
Received: 14 Oct 2025; Accepted: 20 Nov 2025.
Copyright: © 2025 Xu, Zhang, Xu, Yu, Wu, Li, Li, Cui, Huang, Zhou, Han, Zhang, Zhang and Jiang. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Shuai Xu, xs325803896@163.com
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