Previous studies found that cilostazol has a favorable effect on glucose and lipid homeostasis, endothelial function, atherosclerosis, and vasculo-angiogenesis. However, it is poorly understood whether these effects can translate into better clinical outcomes. This study investigated the outcome effect of cilostazol in patients with coronary artery disease (CAD) or at a high risk of cardiovascular (CV) disease. We conducted a randomized, double-blind, placebo-controlled trial involving 266 patients who received cilostazol, 200 mg/day (n = 134) or placebo (n = 132). Pre-specified clinical endpoints including composite major adverse cardiovascular events (MACE) (CV death, non-fatal myocardial infarct, non-fatal stroke, hospitalization for heart failure, or unplanned coronary revascularization), the composite major coronary event (MCE) and major adverse CV and cerebrovascular event (MACCE), were prospectively assessed. The mean duration of follow-up was 2.9 years. Relative to placebo, cilostazol treatment had a borderline effect on risk reduction of MACE (hazard ratio [HR], 0.67; 95% confidence interval (CI), 0.34–1.33), whereas the beneficial effect in favor of cilostazol was significant in patients with diabetes mellitus or a history of percutaneous coronary intervention (p for interaction, 0.02 and 0.06, respectively). Use of cilostazol, significantly reduced the risk of MCE (HR, 0.38; 95% CI, 0.17–0.86) and MACCE (HR, 0.47; 95% CI, 0.23–0.96). A significantly lower risk of angina pectoris (HR, 0.38; 95% CI, 0.17–0.86) was also observed in the cilostazol group. After multi-variable adjustment, cilostazol treatment independently predicted a lower risk of MCE. In conclusion, these results suggest cilostazol may have beneficial effects in patients with CAD or at a high risk of CV disease.

Pulmonary arterial hypertension (PAH) is a progressive cardiopulmonary disorder characterized by extensive pulmonary vascular remodeling and right ventricular dysfunction. Recent investigations have identified microRNA-21-5p (miR-21-5p) as a key driver of pulmonary artery smooth muscle cells (PASMCs) phenotypic transformation and extracellular matrix (ECM) dysregulation, thereby exacerbating disease pathology. In this study, we investigated the therapeutic potential of Plumbagin (PL), a natural naphthoquinone compound, in attenuating PAH progression via modulation of the miR-21-5p and ECM remodeling. Using a monocrotaline (MCT)-induced PAH mouse model along with cultured human PASMCs, we evaluated the effects of PL on miR-21-5p expression, bone morphogenetic protein receptor type 2 (BMPR2) levels, and ECM-related factor expression. PL treatment significantly mitigated pulmonary vascular remodeling in the animal model. Mechanistically, PL suppressed miR-21-5p levels, restored BMPR2 expression, and reversed PASMC phenotypic switching, while modulating key ECM regulators including matrix metalloproteinase (MMP)-7, MMP-19, and tissue inhibitor of metalloproteinases-3 (TIMP-3). Clinical validation using serum samples from patients with PAH revealed that elevated miR-21-5p and MMP-7 levels correlated with increased disease severity, whereas higher MMP-19 and TIMP-3 levels were inversely associated. Collectively, these findings highlight targeting the miR-21-5p and ECM dynamics as a promising therapeutic strategy for PAH management and underscore the translational potential of PL in improving patient outcomes.

Yeh JK, et al. Right Heart J. 2025 Dec;1(1):e3. https://doi.org/10.65721/rhj.2026.1.e3