Pathogenic mechanism of paclitaxel coated balloons and protective effects of dexamethasone


Cardiovascular disease (CVD) is the world’s first leading cause of death contributing to 18.8 million global deaths worldwide. Lower extremity peripheral artery disease (PAD) stems from CVD and is the third leading cause of atherosclerotic morbidity. The prevalence of PAD increases significantly with age, and complications can lead to ischemia, non-healing wounds, gangrene, and amputation. Percutaneous transluminal angioplasty (PTA) and stenting are the mainstream techniques used to treat severe PAD. Due to high risk of restenosis within 12 months of the procedure, drug-coated balloons (DCB) and drug eluting-stents (DES) have become the standard of care since the early 2000s. Paclitaxel (PTX) is an extremely potent anti-restenotic agent used to coat balloons and stents to inhibit the assembly of microtubules, thereby inhibiting cell division. A recent systemic review and meta-analysis examined the all-cause of death rates at 1-year, 2-year, and 5-years of PCB and PES in the femoral and/or popliteal arteries versus control. The authors demonstrated a significantly increased risk of death in the PTX arm, which resulted in a warning from the FDA and a halt in the use of PTX devices. The massive release of PTX following balloon or stent application on the vessel wall and into systemic circulation may attribute to delayed systemic toxicity. Dexamethasone (DEX) is a glucocorticoid what may serve as an alternative anti-restenotic agent. In this study, we examined PTX induced toxicity in endothelial cells using cell biological assays and migration assay. This study showed that PTX significantly reduced EC survival, proliferation, and migration. DEX was able to partially rescue the EC functions but was unable to abrogate PTX-induced inhibition of EC migration. RNA sequencing was used to examine differentially expressed genes modulated by PTX and DEX. Protein expression of MCP-1, CKS-2, CD137, and BMF were analyzed with western blots and found that DEX was able to abrogate the PTX induced effects. Overall, this study was the first to examine the potential mechanism(s) of PTX induced systemic toxicity in CVD and may serve as a stepping stone for future investigations to abrogate the adverse effects of PTX mediated devices

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