Peripheral artery disease (PAD) is a chronic atherosclerotic condition characterized by reduced blood flow to the lower extremities, leading to significant morbidity and increased cardiovascular (CV) risk. Despite its high prevalence, the underlying molecular mechanisms contributing to PAD progression and its systemic inflammatory component remain incompletely understood. This thesis explores novel molecular pathways involved in PAD, focusing on neutrophil activation as a key inflammatory process and assessing the impact of supervised exercise therapy (SET) on inflammatory biomarker modulation.
The first study investigates circulating biomarkers of neutrophil activation in patients with chronic symptomatic PAD, comparing their plasma levels to those of healthy controls. The findings reveal significantly elevated levels of polymorphonuclear (PMN)-elastase, myeloperoxidase (MPO), and neutrophil gelatinase-associated lipocalin (NGAL) in PAD patients, underscoring the role of neutrophil-driven inflammation in disease pathophysiology. Furthermore, both PMN-elastase and MPO were found to be predictive of adverse CV outcomes at six months, suggesting their potential utility as biomarkers for risk stratification. These results highlight the relevance of neutrophil activation in PAD progression and the need for novel therapeutic strategies targeting inflammation.
The second study examines the effects of a multimodal SET program on the gene expression of inflammatory biomarkers in peripheral blood mononuclear cells from PAD patients. A significant reduction in PMN-elastase expression was observed following exercise therapy, while MPO and protein-arginine deiminase 4 (PAD4) exhibited non-significant downward trends. These findings suggest that supervised exercise may exert beneficial anti-inflammatory effects, contributing to improved vascular health in PAD patients. Notably, individuals with higher baseline inflammation markers tended to experience the greatest reductions in biomarker expression, despite limited improvements in functional walking capacity. Additionally, metabolic factors such as elevated body mass index and hemoglobin A1c levels were associated with attenuated walking ability gains, emphasizing the importance of a personalized approach to PAD rehabilitation.
Overall, this research provides novel insights into the inflammatory mechanisms underlying PAD and supports the integration of neutrophil biomarkers into clinical practice for enhanced CV risk assessment. The observed modulation of inflammatory markers through exercise therapy highlights the therapeutic potential of physical activity in managing PAD-related inflammation and preventing disease progression. By bridging molecular insights with clinical applications, these findings contribute to the development of targeted interventions aimed at reducing CV risk and enhancing quality of life in PAD patients.