Potential Vascular Mechanisms of Ramipril Induced Increases in Walking Ability in Patients With Intermittent Claudication

Abstract

Rationale: We recently reported that ramipril more than doubled maximum walking times in patients with peripheral artery disease with intermittent claudication. Objective: Our aim was to conduct exploratory analyses of the effects of ramipril therapy on circulating biomarkers of angiogenesis/arteriogenesis, thrombosis, inflammation, and leukocyte adhesion in patients with intermittent claudication. Methods and Results: One hundred sixty-five patients with intermittent claudication (mean, 65.3 [SD, 6.7] years) were administered ramipril 10 mg per day (n=82) or matching placebo (n=83) for 24 weeks in a randomized, double-blind study. Plasma biomarkers of angiogenesis/arteriogenesis (vascular endothelial growth factor-A, fibroblast growth factor-2), thrombosis (D-dimer, von Willebrand factor, thrombin-antithrombin III), inflammation (high-sensitivity C-reactive protein, osteopontin), and leukocyte adhesion (soluble vascular cell adhesion molecule-1, soluble intracellular adhesion molecule-1) were measured at baseline and 24 weeks. Relative to placebo, ramipril was associated with increases in vascular endothelial growth factor-A by 38% (95% confidence interval [CI], 34%–42%) and fibroblast growth factor-2 by 64% (95% CI, 44–85%; P <0.001 for both), and reductions in D-dimer by 24% (95% CI, −30% to −18%), von Willebrand factor by 22% (95% CI, −35% to −9%), thrombin-antithrombin III by 16% (95% CI, −19% to −13%), high-sensitivity C-reactive protein by 13% (95% CI, −14% to −9%), osteopontin by 12% (95% CI, −14% to −10%), soluble vascular cell adhesion molecule-1 by 14% (95% CI, −18% to −10%), and soluble intracellular adhesion molecule-1 by 15% (95% CI, −17% to −13%; all P <0.001). With the exception of von Willebrand factor, all the above changes correlated significantly with the change in maximum walking time ( P =0.02−0.001) in the group treated with ramipril. Conclusions: Ramipril is associated with an increase in the biomarkers of angiogenesis/arteriogenesis and reduction in the markers of thrombosis, inflammation, and leukocyte adhesion. This study informs strategies to improve mobility in patients with intermittent claudication. Clinical Trial Registration Information: URL: http://clinicaltrials.gov . Unique identifier: NCT00681226.