Adenovirus-mediated expression of β-adrenergic receptor kinase C-terminus reduces intimal hyperplasia and luminal stenosis of arteriovenous polytetrafluoroethylene grafts in pigs

Background - Hemodialysis vascular access dysfunction is the single most important cause of morbidity in kidney hemodialysis patients. Failure of an arteriovenous polytetrafluoroethylene ( PTFE) graft, the most common form of hemodialysis access, is primarily due to intimal hyperplasia and thrombosis at the venous anastomosis. Methods and Results - This study was aimed at evaluating the efficacy and safety of an adenoviral vector (Ad2/beta ARKct) encoding the carboxyl terminus of beta-adrenergic receptor kinase (beta ARKct) in a pig model of arteriovenous PTFE graft failure. Transduction of the external jugular vein with Ad2/beta ARKct (5E9, 5E10, or 5E11 particles per vein) did not result in systemic toxicity, as measured by clinical and pathological assessments. Ad2/beta ARKct significantly reduced neointimal hyperplasia in the graft/vein anastomosis. It also improved the graft patency rate and angiographic score, as measured histologically and angiographically, compared with vehicle or empty viral vector controls. Conclusions - Our results suggest that local administration of adenoviral vectors encoding beta ARKct into the jugular vein represents a viable strategy to treat AV graft hemodialysis vascular access failure.