Plastic Surgery Research Council
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PSRC 60th Annual Meeting

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Pharmacologic Inhibition of Phosphodiesterase 5 as a Strategy to Improve Outcomes in Microvascular Surgery
Marc Soares, MD, Piul Rabbani, PhD, April Duckworth, MD, Nick Rao, MD, Jessica Chang, BA, Pierre B. Saadeh, MD, Karan Mehta, BA, Amanda Kua, BA, Daniel Ceradini, MD.
NYU, New York, NY, USA.

PURPOSE:
Ischemic microvascular injury compromises the endothelial barrier that maintains tissue homeostasis and initiates the inflammatory cascade. Following reperfusion, vascular injury is exacerbated and poses a critical clinical challenge to microsurgery, particularly with regards to vascularized composite allotransplantation. Phosphodiesterase 5 inhibitors (PDE5i), most commonly represented by the FDA-approved drug sildenafil citrate (trade-name Viagra), can potentiate vasodilation in ischemic vasculature and suppress inflammatory pathways. If ischemic injury to the endothelium initiates a pathologic cascade leading to impaired revascularization, persistent tissue hypoxia, and accelerated inflammation, then we hypothesize that pharmacologic treatment microvascular flaps with sildenafil will improve tissue physiology and survival in the context of prolonged ischemia.
METHODS:
Using in vitro and in vivo models of ischemia-reperfusion injury (IRI), we characterized the effect of FDA-recommended doses of sildenafil (10nM and 100nM) on vascular inflammatory markers. Functionally, an adhesion assay was performed to assess the effect of PDE5i on the ability of the vascular endothelium to reduce allogenic lymphocyte adherence. In vivo, using an established rat model of VCA, composite flaps were perfused with sildenafil-containing perfusate and transplanted into allogenic rats. Laser doppler assess tissue perfusion in the immediate post-operative period.
RESULTS:
PDE5-inhibition decreased endothelial expression of vascular inflammatory markers ICAM-1 and MCP-1 following ischemia reperfusion injury (3.4-fold, and 8.1-fold reduction from non-treated controls, respectively p<0.01), while increasing vasculoprotective expression of VEGF and eNOS (2-fold & 4.5-fold respectively compared to non-treated controls p<0.05). Functionally, PDE5i-treatment correlated with a 23% decrease in allogenic lymphocyte adhesion compared to non-PDE5i controls (p =0.04). In the immediate post-operative period, PDE5i-allografts demonstrated a 3-fold increased vascular perfusion compared to non-treated allografts (310 FU v.s. 117 FU, p=0.01). Ongoing studies are evaluating the role of PDE5 inhibition on graft survival and rejection.
CONCLUSION:
PDE5 inhibition using an FDA-approved compounds can attenuate vascular inflammation associated with ischemia-reperfusion injury and may be a rapidly-translatable therapy to improve outcomes in microvascular surgery and allotransplantation.


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