"Preclinical safety and efficacy of a novel extravascular bi-lateral renal denervation instrument." Rami Tzafriri, Peter Markham, Misty Williams-Fritze, John Keating, Jay Budrewicz, Chang-Wook Jeong

Aims: Intravascular catheter-based renal denervation (RDN) is limited to accessible renal arteries (≥3mm). The aim of this study was to preclinically evaluate the chronic safety of a novel extravascular radiofrequency (RF) instrument that is applied laparoscopically under CT guidance and whose electrode assembly circumferentially wraps the renal artery. Three models of the renal denervation laparoscopic instrument are available, offering coverage diameters than span small (2-5 mm), medium (5-8 mm) and large (8-11 mm) arteries. All three models were evaluated in pigs.

Methods and Results: All animal experiments were performed at CBSET, Inc. (AAALAC accredited) and adhered to the Guide for the Care and Use of Laboratory Animals under an Institutional Animal Care and Use Committee-approved protocol. Thirty pigs underwent bilateral extravascular RDN at proximal and distal sites using the Hyperburner™ RDN System (DeepQure Inc., Seoul, Republic of Korea), with at least one nominal dose (50oC/70sec) and one elevated dose (53oC/70sec) per artery. Abdominal CT scans were performed pre and post procedure to evaluate renal arteries, kidneys, and adjacent organs. For each artery, the size of the treating instrument was selected based on preprocedure CT scans, which confirmed the availability renal arteries with outer diameters in the 2-10 mm range. The renal artery diameter at the planned denervation site was confirmed using a laparoscopic ruler following artery dissection and immediately prior to treatment. Acute performance was evaluated by 3 surgeons. Animal health was regularly monitored. Animals were euthanized 7, 28, 84 and 168 days post treatment, and subjected to a comprehensive necropsy. Tissues were collected for histology (H&E and tyrosine hydroxylase (TH)) and two portions of each kidney (cranial and caudal pole) were analyzed for Norepinephrine D6 (NEPI) content. All treatments achieved the highest average acute performance scores with no observed post-treatment arterial injuries or spasms. All animals exhibited good health. CT scans showed minimal to absent stenosis of post treatment renal arteries, regardless of diameter. There were no perfusion deficits in the liver, spleen, jejunum, and large intestines in any of the animals, and no evidence of thrombus in the aorta, caudal vena cava and visible portions of the portal vein Acceptable arterial and periarterial/adventitial tissue responses were observed grossly and histologically, including presence of nerve response to treatment, absence of adverse events, and complete healing and extensive remodeling of arterial and periarterial tissues by 84 and 168 days. Renal artery medial necrosis/smooth muscle cell loss was negligible across artery sizes, with no mural injury/disruption, luminal occlusion or thrombosis. Adventitial/perivascular findings were consistent with initial RF-induced responses resolving over time. Histologic renal nerve responses decreased over time, being notable in TH-stained sections at Days 7 and 28, with prominent subsequent decrease in incidence at Days 84 and 168, attributed to repair/regeneration. Relative to historical baseline levels, NEPI concentration declined by ≥50% at Days 7-84 and 26% at Day 168.

Conclusions: Extravascular RDN of large, medium and small arteries via laparoscopic access was safe and efficacious in pigs over the course of 24 weeks.