Our previous work shows that men and women with lower extremity peripheral arterial disease (PAD) have poorer lower extremity functioning, poorer leg strength, and greater functional decline than persons without PAD. However, pathophysiologic mechanisms underlying these relationships are not well understood. Chronic inflammation has been proposed as a biological mechanism underlying the decline in physical function that occurs with aging. This study will build on our previous work by defining interrelationships between mediators of inflammation, D-dimer, C-reactive protein (CRP), homocysteine, and viscosity with pathophysiologic findings in calf skeletal muscle in persons with and without PAD. We will also study associations between inflammatory mediators, D-dimer, CRP, homocysteine and viscosity with functional decline. Inflammatory mediators will consist of interleukin-6 (IL-6), soluble vascular cell adhesion molecule (VCAM-1), and soluble intracellular adhesion molecule-1 (ICAM-1). This proposed study is ancillary to our ongoing NHLBI-funded study of functional outcomes among men and women with PAD, the Walking and Leg Circulation Study II (R01-HL71223). WALCS II is a prospective observational study of 500 men and women with PAD and 290 men and women without PAD that is identifying relationships between PAD, pathophysiologic findings in lower extremity skeletal muscle, and functional decline. WALCS II data collection includes measurement of lower extremity functional performance, calf skeletal muscle cross-sectional area, fat composition of calf skeletal muscle, leg strength, and leg power. We request additional funds to study associations between inflammatory factors, D-dimer, homocysteine, and viscosity with these important outcomes in PAD. In our cross-sectional aims, we will test the hypotheses that higher levels of inflammatory factors, D-dimer, homocysteine, and viscosity are associated with greater pathophysiologic impairments of lower extremity muscle and poorer lower extremity functioning. In our longitudinal aims, we will test the hypotheses that higher levels of the proposed blood factors and viscosity are associated with greater progression of skeletal muscle pathophysiologic findings and greater functional decline. Results will be used to develop interventions to improve functioning and prevent functional decline in PAD.
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