Beyond function: supervised exercise therapy may target inflammatory gene expression in patients with symptomatic peripheral artery disease.

Background: Supervised exercise therapy (SET) is a first-line treatment for patients with symptomatic peripheral artery disease (PAD). However, its impact on inflammation, as well as the relationship between inflammation and functional improvements, remain poorly understood. Patients and methods: In this prospective, single-arm study, 51 patients with symptomatic PAD underwent a 12-week multimodal SET program. Limb perfusion, walking ability, and estimated muscle power were assessed before and after SET. Inflammatory gene expression in peripheral blood mononuclear cells was evaluated by real-time quantitative PCR. Response to SET was defined as an improvement of >46 m in the six-minute walking distance (6MWD). Results: Following SET, mRNA expression levels significantly decreased for polymorphonuclear (PMN)-elastase (-48%; p=.003) and myeloperoxidase (MPO) (-39%; p=.002). Trends toward reduction were also observed for matrix metalloproteinase-9 (MMP-9) (-42%; p=.070), neutrophil gelatinase-associated lipocalin (NGAL) (-37%; p=.069), and protein-arginine deiminase type 4 (PAD4) (-29%; p=.052). Linear mixed models indicated similar changes between responders and non-responders. After adjusting the model for baseline gene expression levels and clinically relevant covariates, a significant post-SET reduction was observed in both responders and non-responders for PMN-elastase (p=.027 and p<.001, respectively), MMP-9 (both p=.003), and MPO (p=.016 and p=.003, respectively). PAD4 expression significantly decreased only in non-responders (p=.045). Regression analyses revealed no associations between inflammatory gene expression and perfusion, walking ability, or muscle power. Conclusions: SET may reduce the expression of several inflammatory markers in patients with symptomatic PAD, independently of functional gains. Further studies are needed to confirm these findings and to explore whether reducing systemic inflammation translates into improved cardiovascular outcomes in this population.