Implications of inflammation and sex in lower extremity arterial disease.

BACKGROUND: 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. METHODS AND RESULTS: 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. CONCLUSION: 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.