Effect of Cilostazol on Endothelial Progenitor Cells and Endothelial Function in High Risk for Cardiovascular Disease

Cilostazol Enhances the Number and Functions of Circulating Endothelial Progenitor Cells Mediated Through Multiple Mechanisms in Patients With High Risk for Cardiovascular Disease

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

1. titration of drugs

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

   2. study period: 12 weeks

      • subjects with cilostazol and 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. measurement of flow-mediated dilatation (FMD) of left brachial artery by sonography

Inclusion Criteria: high-risk patients who have at least one of the following situations without pre-existing cardiovascular disease including peripheral artery disease or coronary artery disease:

• type 2 diabetes mellitus
• metabolic syndrome
• stage 3 (or more advanced) chronic kidney disease
• 2 or more coronary risk factors (male > 45 years or female > 55 years, hypertension, tobacco smoking, hyperlipidemia, family history of cardiovascular disease)

Exclusion Criteria:

• ankle-brachial index less than 0.9 or more than 1.3 in one or both legs
• significant stenosis (more than 50% as compared to reference vessel) in peripheral artery on image study
• symptoms suggesting peripheral artery disease in at least one leg
• clinical or electrocardiographic evidence of coronary artery disease
• clinical evidence of cerebrovascular disease
• severe liver dysfunction (transaminases >10 times of upper normal limit, history of liver cirrhosis, or hepatoma)
• left ventricular ejection fraction (<50% by echocardiography)
• documented active malignancy
• chronic inflammatory disease
• known drug allergy history for cilostazol
• current use of cilostazol or any other cAMP-elevator
• premenopausal women