title: Ethanol-mediated perivascular renal sympathetic denervation: preclinical validation of safety and efficacy in a porcine model.
abstract: OBJECTIVE
  We report the use of a novel endovascular approach using chemical neurolysis, via periadventitial injection of dehydrated ethanol (EtOH) to perform renal artery denervation.
  
  
  RESULTS
  A novel, three-needle delivery device was introduced into the renal arteries of adult swine using fluoroscopic guidance. EtOH was injected bilaterally with one injection per artery, via the three needles into the adventitial and periadventitial space, using EtOH doses 0.15 ml/artery; n=3, 0.30 ml/artery; n=3, and 0.60 ml/artery; n=3, with saline injection as a sham control (0.4 ml/artery; n=3), and naive subjects (n=7) as a true negative control. The renal parenchymal norepinephrine (NE) concentration at two-week follow-up was the primary efficacy endpoint. The mean renal NE reduction was 54%, 78% and 88% at doses of 0.15 ml, 0.30 ml and 0.60 ml, respectively (p<0.0001 vs. controls). Histological examination revealed marked, and deep, circumferential renal nerve injury at depths of 2-8 mm from the intimal surface. There was no evidence of device-related or EtOH-induced injury to the intimal layers. In some samples at the higher EtOH doses, there was focal loss of smooth muscle cells in the outer media. Angiography at 45 days demonstrated normal appearing renal arteries with no detectable stenoses (n=8).
  
  
  CONCLUSIONS
  Circumferential adventitial delivery of very low doses of EtOH may be a promising alternative to energy-based systems to achieve dose-dependent, and predictable renal denervation. Further study is warranted.
authors.affiliation: Michigan State University, Borgess Heart Institute, Kalamazoo, MI 49048, USA. tafisc@gmail.com
authors.forename: Tim A
authors.initials: TA
authors.lastname: Fischell
authors.forename: Felix
authors.initials: F
authors.lastname: Vega
authors.forename: Narayan
authors.initials: N
authors.lastname: Raju
authors.forename: Eric T
authors.initials: ET
authors.lastname: Johnson
authors.forename: Darrin J
authors.initials: DJ
authors.lastname: Kent
authors.forename: Robert R
authors.initials: RR
authors.lastname: Ragland
authors.forename: David R
authors.initials: DR
authors.lastname: Fischell
authors.forename: Steven L
authors.initials: SL
authors.lastname: Almany
authors.forename: Vartan E
authors.initials: VE
authors.lastname: Ghazarossian
mesh_terms: D055011:Ablation Techniques; D000818:Animals; D004305:Dose-Response Relationship, Drug; D057510:Endovascular Procedures; D000431:Ethanol / Q000008:administration & dosage*; D007668:Kidney / Q000098:blood supply* / Q000294:innervation* / Q000378:metabolism / Q000473:pathology; D023421:Models, Animal; D009638:Norepinephrine / Q000378:metabolism; D012077:Renal Artery; D013552:Swine; D013563:Sympathectomy, Chemical / Q000379:methods*; D013997:Time Factors
chemical_list: D000431:Ethanol; D009638:Norepinephrine