Potential Vascular Mechanisms of Ramipril Induced Increases in Walking Ability in Patients with Intermittent Claudication
Rationale: We recently reported that ramipril more than doubled walking times in peripheral artery disease patients with intermittent claudication.
Objective: 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: 165 patients with intermittent claudication (mean (SD), 65.3 (6.7) years), were administered ramipril 10mg/d (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, VEGF-A; fibroblast growth factor, FGF-2), thrombosis (D-dimer; von Willebrand Factor, vWF; thrombin-antithrombin III, TAT), inflammation (high sensitivity C-reactive protein, hsCRP; osteopontin, OPN), and leukocyte adhesion (soluble vascular cell adhesion molecule-1, sVCAM-1; soluble intracellular adhesion molecule-1, sICAM-1) were measured at baseline and 24 weeks. Relative to placebo, ramipril was associated with increases in VEGF-A by 38% (95% CI, 34 to 42%) and FGF-2 by 64% (44 to 85%; P<0.001 for both), and reductions in D-dimer by 24% (-30 to -18%), vWF by 22% (-35 to -9%), TAT by 16% (-19 to -13%), hsCRP by 13% (-14 to -9%), OPN by 12% (-14 to -10%), sVCAM-1 by 14% (-18 to -10%), and sICAM-1 by 15% (-17 to -13 %; all P<0.001). With the exception of vWF 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 biomarkers of angiogenesis/arteriogenesis and reduction in markers of thrombosis, inflammation and leukocyte adhesion. This study informs strategies to improve mobility in patients with intermittent claudication.
- Received October 9, 2013.
- Revision received January 2, 2014.
- Accepted January 7, 2014.