Effect of Cilostazol Endothelial Progenitor Cells and Collateral Formation in Peripheral Occlusive Artery Disease (PAOD)

Cilostazol Enhances the Number and Functions of Circulating Endothelial Progenitor Cells and Collateral Formation Assessed by Dual-energy 128-row CT Angiography Mediated Through Multiple Mechanisms in Patients With Mild-to-moderate PAOD

1. The number and function of circulating endothelial progenitor cells (EPCs) are inversely associated with coronary risk factors and atherosclerotic diseases such as PAOD.
2. This double-blind, randomized, placebo-controlled trial to evaluate the effects of cilostazol on human early EPCs and angiogenesis as well as the potential mechanisms of action in patients with mild-to-moderate PAOD.

1. titration of drugs

   1. run-in period: eligible subjects are screened and baseline blood samples are obtained

   2. study period: 12 weeks

      • 24 subjects with cilostazol and 20 subjects with dummy placebo
      • On the first day after the end of the study period, the follow-up data are obtained by the same procedure

   3. blood sampling and measurement of serum biomarkers

      • obtained from peripheral veins in all study subjects at the run-in period and the end of the treatment period of the study
      • sent for isolation, cell culture, and assays of human EPCs
      • also stored for enzyme-linked immunosorbent assay (Stromal cell derived factor-alfa1, adiponectin, soluble thrombomodulin, vascular endothelial growth factor)

2. assays of human EPCs

   1. colony formation by EPCs
   2. quantification of EPCs and apoptotic endothelial cells
   3. chemotactic motility, proliferation/viability and apoptosis assays

3. collateral vessels formation and distal run-off assessed by dual-energy multi-slice computed tomography angiography

4. echocardiographic examinations to evaluate left ventricular functions

Inclusion Criteria:

• ankle-brachial index (ABI) less than 0.9 in one or both legs but no obvious symptoms of intermittent claudication

Exclusion Criteria:

• obvious symptoms of intermittent claudication
• severe PAD (Fontaine grading > 3) or critical limb ischemia in at least one leg
• severe liver dysfunction (transaminases >10 times of upper normal limit, history of liver cirrhosis, or hepatoma)
• > stage 4 chronic kidney disease (end-stage renal disease with chronic dialysis not excluded)
• left ventricular ejection fraction <50% by echocardiography
• documented active malignancy
• chronic inflammatory disease
• planned coronary intervention or endovascular therapy or bypass surgery within 3 months
• known drug allergy history for cilostazol
• current use of cilostazol or any other cAMP-elevator
• premenopausal women