This study will prospectively assess associations between hemostatic and inflammatory blood factors and progression of lower extremity arterial ischemia and cardiovascular events in 499 men and women with lower extremity peripheral arterial disease (PAD) and 241 men and women without PAD. The proposed study is ancillary to an NHLBI funded prospective study of functional and cardiovascular outcomes in men and women with PAD, the Walking and Leg Circulation Study (WALCS). The blood factors we will study, fibrinogen, PAI-1, TPA antigen, d-dimer, prothrombin 1.2, and C-reactive protein (CRP), are associated with progression of coronary atherosclerosis in proposed models of the pathogenesis of coronary atherosclerosis, but are not well studied in PAD. Our primary specific aims are as follows. First, we will determine whether higher baseline blood factor levels are associated with a) progression of lower extremity arterial ischemia (decline in ankle brachial index >= 0.15, lower extremity gangrene, ulcer, revascularization, or amputation);, b) functional decline over 48 month follow-up. Second, we will determine whether higher baseline blood factor levels are associated with new cardiovascular events over 48 month follow-up. We hypothesize that higher blood factor levels at baseline will be associated with PAD progression, functional decline, and higher rates of cardiovascular morbidity and mortality Pilot data from the Cardiovascular Health Study (CHS) show that relative risks of fibrinogen, D-dimer and CRP levels for cardiovascular events are highest for events occurring more proximate to baseline blood factor measurements. Therefore, we will also determine whether blood factor levels measured at the most recent examination prior to cardiovascular events or PAD progression are higher than the levels that do not immediately precede cardiovascular events or PAD progression. We hypothesize that blood factor levels at the most recent examination prior to cardiovascular events or PAD progression will be higher than blood factor levels that do not immediately precede cardiovascular events or PAD progression.
The specific aims of this study cannot be answered by the CHS, the Women's Health Study or the Atherosclerosis Risk in Community study. Unique comparisons of the proposed study include the wide spectrum of PAD severity in the WALCS cohort, the large number of PAD participants, the breadth of functional assessments, and the inherent generalizability of our findings to patients routinely encountered by practicing physicians. Much of the data collection is currently funded as part of the WALCS, reducing the marginal cost of our application. Results are expected to lead to subsequent studies identifying mechanisms of any associations demonstrated and lead to interventions that prevent progression of lower extremity arterial ischemia, functional decline, and cardiovascular events in men and women with PAD.
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