Frontiers in Cardiovascular Medicine
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.
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.
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.
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.
Text reproduced verbatim from Version of Record (source); DOI; CC-BY-4.0.
Shuai Xu, Ge Zhang, Yudi Xu, Chaoyang Yu, Ruhao Wu, Zhengrui Li, Teng Li, Xinyue Cui, Xufeng Huang, Shujing Zhou, Yahui Han, Haonan Zhang, Shiqian Zhang, Yufeng Jiang. Allostatic load-cardiovascular disease associations and the mediating effect of inflammatory factors: a prospective cohort study. Frontiers in Cardiovascular Medicine. 2026;12:1724572. https://doi.org/10.3389/fcvm.2025.1724572
Allostatic load-cardiovascular disease associations and the mediating effect of inflammatory factors: a prospective cohort study
Baseline multisystem biomarkers were associated with subsequent cardiovascular events in an observational analysis. Adjusted associations and statistical mediation do not establish prevention by lowering the score or an inflammatory marker, or a validated clinical prediction model.
How is biomarker-defined allostatic load associated with incident cardiovascular disease, and what statistical mediation is attributed to inflammatory markers in the analyzed UK Biobank cohort?
This observational analysis relates baseline multisystem biomarkers to subsequent cardiovascular events. Its adjusted associations and mediation estimates inform epidemiological hypotheses; they do not demonstrate that lowering the score or an inflammatory marker prevents events. It is not a validated clinical prediction model.
The analytic sample is not the entire UK Biobank recruitment population. The reported 13-year period is not described here as a mean or median follow-up.
| Measure | Value |
|---|---|
| analytic participants | 205,504 |
| incident CVD events | 18,542 |
| article reported follow up period | 13 years |
Source locator: Results: Baseline characteristics; Fig. 1
HDL and IGF-1 used the low-value risk direction. This biomarker score is not a direct measurement of psychological stress, a neuroendocrine response or an inflammatory intervention.
| Measure | Value |
|---|---|
| baseline biomarkers | 12 |
| score range | 0–12 |
| risk scoring | Quartile-based; low-value direction for HDL and IGF-1 |
Source locator: Methods: Assessment of allostatic load
AL = 0 is the reference group. This relative hazard association is not a 115% absolute-risk increase or a treatment effect.
| Measure | Value |
|---|---|
| comparison | AL ≥6 versus AL = 0 |
| model | Model 3 |
| hazard ratio | 2.15 |
| reported 95 percent CI | 1.99–2.33 |
Source locator: Results: Associations of AL with CVD; Fig. 2A
No additional precise hazard ratios from supplementary tables are supplied here, and this sensitivity analysis does not fully exclude reverse causation.
| Measure | Value |
|---|---|
| nonlinearity P | <0.001 |
| sensitivity exclusion | Events in the first 3 years after baseline |
Source locator: Results: Associations of AL with CVD; Fig. 2B
This is model-based decomposition using baseline indicators, not a proven causal pathway or evidence that lowering neutrophils or an inflammatory marker prevents CVD.
| Measure | Value |
|---|---|
| candidate mediators | 8 |
| neutrophil count mediation estimate | 4.73% |
Source locator: Results: Mediation analyses of inflammatory factor on associations of AL with CVD; Fig. 4E
| Cohort | Role | n | Relationship |
|---|---|---|---|
| UK Biobank analytic cohort | analytic population without cardiovascular disease at baseline | 205,504 | Independent cohort |
An analytic cohort of 205,504 participants had 18,542 incident CVD events during the article-reported 13-year period; Model 3 compared AL ≥6 with AL = 0 at HR 2.15 (95% CI 1.99–2.33). These are observational relative-hazard findings, not a treatment effect.
Twelve baseline biomarkers formed a 0–12 score using quartile-based risk scoring, with the low-value direction for HDL and IGF-1. It is not a direct psychological-stress measure or an intervention.
Evidence: KF2
Nonlinearity P<0.001 and directionally similar results after excluding first-three-year events were reported in the main text. This does not fully exclude reverse causation.
Evidence: KF4
Among eight candidate mediators in the correlation analysis, the neutrophil-count mediation estimate was 4.73%. Baseline model decomposition does not establish a causal pathway or drug benefit.
Evidence: KF5
| Row ID | Component | Context | Finding | Evidence Level | Scope | Source Locator | Evidence refs |
|---|---|---|---|---|---|---|---|
| evidence-al-1 | Analytic population and incident cardiovascular outcomes | The analytic sample is not the entire UK Biobank recruitment population. The reported 13-year period is not described here as a mean or median follow-up. | The analytic cohort comprised 205,504 participants and 18,542 incident CVD events during an article-reported 13-year follow-up period. | Human observational exposure–outcome and exploratory mediation evidence | Describes the analytic population and reported follow-up period, not all recruited UK Biobank participants. | Results: Baseline characteristics; Fig. 1 | KF1 |
| evidence-al-2 | Multisystem biomarker exposure scoring | HDL and IGF-1 used the low-value risk direction. This biomarker score is not a direct measurement of psychological stress, a neuroendocrine response or an inflammatory intervention. | Allostatic load was operationalized using 12 baseline biomarkers with quartile-based risk scoring and a score range of 0–12. | Human observational exposure–outcome and exploratory mediation evidence | Defines the biomarker exposure; it does not validate a psychological-stress measurement or an intervention. | Methods: Assessment of allostatic load | KF2 |
| evidence-al-3 | Adjusted high-versus-zero allostatic-load association | AL = 0 is the reference group. This relative hazard association is not a 115% absolute-risk increase or a treatment effect. | In adjusted Model 3, AL ≥6 versus AL = 0 was associated with incident CVD at HR 2.15 (95% CI 1.99–2.33). | Human observational exposure–outcome and exploratory mediation evidence | Supports an adjusted relative-hazard association only, not absolute-risk change or treatment efficacy. | Results: Associations of AL with CVD; Fig. 2A | KF3 |
| evidence-al-4 | Exposure-response nonlinearity and sensitivity analysis | No additional precise hazard ratios from supplementary tables are supplied here, and this sensitivity analysis does not fully exclude reverse causation. | The AL–CVD association was nonlinear, and the main text reported directionally similar results after excluding events in the first three years after baseline. | Human observational exposure–outcome and exploratory mediation evidence | Supports a nonlinear association and a specified sensitivity check, without eliminating reverse causation. | Results: Associations of AL with CVD; Fig. 2B | KF4 |
| evidence-al-5 | Neutrophil-count statistical mediation | This is model-based decomposition using baseline indicators, not a proven causal pathway or evidence that lowering neutrophils or an inflammatory marker prevents CVD. | Eight candidate mediators entered the correlation analysis; the neutrophil-count mediation estimate was 4.73%. | Human observational exposure–outcome and exploratory mediation evidence | Supports exploratory statistical mediation, not causal prevention or anti-inflammatory drug efficacy. | Results: Mediation analyses of inflammatory factor on associations of AL with CVD; Fig. 4E | KF5 |
The analytic cohort comprised 205,504 participants and 18,542 incident CVD events during an article-reported 13-year follow-up period. The analytic sample is not the entire UK Biobank recruitment population. The reported 13-year period is not described here as a mean or median follow-up.
Evidence: KF1
Allostatic load was operationalized using 12 baseline biomarkers with quartile-based risk scoring and a score range of 0–12. HDL and IGF-1 used the low-value risk direction. This biomarker score is not a direct measurement of psychological stress, a neuroendocrine response or an inflammatory intervention.
Evidence: KF2
In adjusted Model 3, AL ≥6 versus AL = 0 was associated with incident CVD at HR 2.15 (95% CI 1.99–2.33). AL = 0 is the reference group. This relative hazard association is not a 115% absolute-risk increase or a treatment effect.
Evidence: KF3
The AL–CVD association was nonlinear, and the main text reported directionally similar results after excluding events in the first three years after baseline. No additional precise hazard ratios from supplementary tables are supplied here, and this sensitivity analysis does not fully exclude reverse causation.
Evidence: KF4
Eight candidate mediators entered the correlation analysis; the neutrophil-count mediation estimate was 4.73%. This is model-based decomposition using baseline indicators, not a proven causal pathway or evidence that lowering neutrophils or an inflammatory marker prevents CVD.
Evidence: KF5
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