# Implications of inflammation and sex in lower extremity arterial disease

## TL;DR

This paper explores how inflammation and sex differences affect lower extremity arterial disease, highlighting key biomarkers and the need for personalized treatment strategies.

## Contribution

The paper identifies sex-specific differences in inflammatory biomarkers and their associations with LEAD progression and outcomes.

## Key findings

- Men with LEAD show stronger associations between CRP and disease, while women present with more advanced disease at older ages.
- Inflammatory markers like CRP, IL-6, and D-dimer are linked to LEAD progression and adverse outcomes.
- Sex-specific lesion patterns and comorbidities suggest the need for tailored diagnostic and treatment approaches.

## Abstract

Lower extremity arterial disease (LEAD) affects over 200 million people globally and is largely driven by chronic vascular inflammation. However, the complex interplay between inflammatory pathways, their prognostic value and potential sex‐specific differences remains insufficiently understood.

Literature indicates that elevated inflammatory markers—such as (high‐sensitivity) C‐reactive protein, fibrinogen, D‐dimer, interleukin‐6, α‐defensins and soluble adhesion molecules as well as newly arising parameters such as neutrophil counts and markers of clonal haematopoiesis—may predict both the onset and progression of LEAD, from declining ankle–brachial indices and impaired walking performance to higher rates of amputation, cardiovascular events and mortality. Moreover, women with LEAD frequently present at older ages with more advanced disease, exhibit distinct lesion patterns and greater functional impairment, and often have higher baseline CRP levels than men, although the strength of association between inflammatory markers and adverse outcomes may be attenuated in women. However, it remains unclear how inflammatory markers can guide (sex) specific patient stratification in LEAD or which markers provide the most clinical utility in general.

Together, these findings underscore the need for comprehensive inflammatory profiling in LEAD risk stratification and highlight the importance of joining sex‐specific analyses, new (bio)markers and machine learning to integrate clinical, genomic, proteomic and functional data into future studies to inform patient‐tailored prevention and treatment strategies.

The graphical abstract illustrates the role of inflammation and sex‐related differences in lower extremity artery disease (LEAD). Key inflammatory biomarkers associated with LEAD include C‐reactive protein (CRP), fibrinogen, interleukin‐6 (IL‐6), and D‐dimer, which contribute to vascular inflammation and atherosclerotic plaque formation in lower limb arteries. Sex‐specific differences are observed, with men showing higher prevalence of smoking, more typical symptoms, a stronger CRP‐LEAD association, and more frequent iliac or infragenicular lesions. Women, on the other hand, are more likely to present with hypertension, older age at diagnosis, more asymptomatic disease courses, and predominantly femoropopliteal lesions. Associations with diabetes, prevalence, outcome, and dyslipidemia remain uncertain for both sexes.