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Circ Res. 2014 Mar 28;114(7):1144-55. doi: 10.1161/CIRCRESAHA.114.302420. Epub 2014 Jan 7.

Potential vascular mechanisms of ramipril induced increases in walking ability in patients with intermittent claudication.

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  • 1From Baker IDI Heart and Diabetes Institute and Department of Cardiovascular Medicine, Alfred Hospital, Melbourne, Australia (A.A.A., C.L., A.K.N., M.R., B.A.K.); Queensland Research Centre for Peripheral Vascular Disease, James Cook University, Townsville, Queensland, Australia (J.G.); and Department of Vascular and Endovascular Surgery, Townsville Hospital, Queensland, Australia (J.G.).



We recently reported that ramipril more than doubled maximum walking times in patients with peripheral artery disease with intermittent claudication.


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.


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.


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.


http://clinicaltrials.gov. Unique identifier: NCT00681226.


biological markers; inflammation; peripheral arterial disease; thrombosis

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