Cilostazol use and calf muscle pathophysiology in people with peripheral artery disease

Cilostazol is a phosphodiesterase 3 (PDE3) inhibitor and is one of the only approved medications shown to improve walking performance in patients with peripheral artery disease (PAD). However, its effects on skeletal muscle pathophysiology are poorly understood. Because skeletal muscle dysfunction contributes to mobility impairment in PAD, this study aimed to evaluate whether patients taking cilostazol exhibit differences in skeletal muscle pathophysiology compared to those not taking cilostazol.

We conducted a cross-sectional analysis of 50 patients with PAD, including 15 patients taking cilostazol and 35 not taking cilostazol. Calf muscle strength was assessed via isometric dynamometry. Gastrocnemius muscle biopsies were analyzed for myofiber morphology, mitochondrial function using high-resolution respirometry, and gene expression via RNA sequencing.

No significant differences were observed in calf muscle strength (p = 0.49), myofiber cross-sectional area (Type I: p = 0.53; Type IIa: p = 0.59), or capillary density (p = 0.74) between groups. However, mitochondrial oxygen consumption under physiological energy demand was significantly higher in cilostazol-treated patients (p = 0.0137), although oxidative phosphorylation conductance (p = 0.38) and mitochondrial hydrogen peroxide emission were not different. RNA sequencing revealed transcriptomic overlap between groups, but gene set enrichment analysis identified upregulation of pathways related to mitochondrial gene expression and downregulation of inflammatory signaling in patients taking cilostazol.

Cilostazol use in patients with PAD is associated with increased skeletal muscle mitochondrial oxygen consumption and modest transcriptomic changes, but it does not appear to alter muscle strength, fiber size, or capillarization. These findings suggest a limited impact of cilostazol on skeletal muscle structure, although potential metabolic effects warrant further investigation.