Rationale for Radiation Therapy for Nerve Denervation Ron Waksman, Issi Barbash Washington Hospital Center

Ron Waksman, MD Consulting Fee Abbott Laboratories Biotronik, Inc. Boston Scientific Corporation Medtronic, Inc. Merck and Company, Inc.

Honoraria Abbott Laboratories Boston Scientific Corporation Medtronic, Inc. Consulting Fee Merck and Company, Inc.

Background Renal sympathetic efferent and afferent lie immediately adjacent to the wall of the renal arteries Historical experience of radical surgical approaches for sympathetic denervation were successful in lowering BP with the cost of high rates of morbidity and mortality Renal sympathetic denervation was achieved more recently with a percutaneous catheter based approach utilizing radio frequency ablation

Limitations of RF-ablation mediated-renal denervation Potential damage to vascular endothelium with late vascular stenosis Inconsistent Efficacy Localized effect to the location of ablation and need for multiple ablations Long procedure time Pain during treatment

Alternative approaches for renal denervation High intensity ultrasound energy therapy Kona Medical Local administration of Guanethidine by micro-infusion catheter Mercator MedSystems Inc. CyberKnife radiosurgery Baroreceptor activation

Clinical and histologic (arrows) neuropathies were Radiation-mediated nerve damage was initially identified after intraoperative radiotherapy. Clinical and histologic (arrows) neuropathies were documented after a dose of only 35 Gy LeCouteur et al. Int J Rad Oncol Biol Phys 1989

Gamma knife radiosurgery is used routinely for nerve ablation in trigeminal neuralgia Clinical use of radiation dosages of 80-90 Gy in a 4-mm isocenter. Clinical studies showed long term effects of up to 3 years f/u. Animal histology indicates that gamma knife radiosurgery creates localized, irreversible nerve damage. Delayed enhancement by MRI indicates fibrosis of the trigeminal nerves Park et al. J Clinical Neuro 2011, Kondziolka et al. Neurosurg 2000

β-radiation has been used to treat ISR in the renal arteries Patient Age Dose (Gy) F/U (mo) Adverse events 1 65 20.7 7 None 2 5 3 71 16.9 4 70 22.15 62 21.00 Jahraus et al. Southern Med J 2003

A novel approach for renal denervation by β-radiation using Beta-Cath™ 3.5F System (Novoste) Potential “sparing” of endothelial injury Localized effect Small sheath size Short procedure time

Preclinical study of β-radiation for creating linear myocardial lesions The isthmus was irradiated by beta-cath catheter ([Sr/Y]-90, Novoste) in 8 dogs. High dose radiation created effective bidirectional block: High dose radiation was safe: Did not damage the endothelium Created localized transmural lesion 25 Gy 50 Gy n 2 6 Conduction block Immediate None Late (>1 week) 1/2 6/6 lesion Guerra & Bonan, Circulation 2004

Brachytherapy for renal denervation preclinical safety study 10 naïve Yorkshire swine were treated for sympathetic renal denervation by vascular brachytherapy using a β-emitting radiation source A beta-emitting radiation dose of 25 or 50 Gy was delivered in the proximal renal artery Animals were followed up to 1- or 2 months Safety endpoints: Angiography IVUS Histology* Efficacy endpoint: * Data available for 1 month follow up

Dosimetry calculations

Renal artery angiography 2 months post brachytherapy showed wide patency of the renal arteries with no angiographic adverse findings (stenosis aneurysm) Baseline angio BetaCath 50 Gy 2 mo f/u

IVUS showed no endothelial or adventitial damage

Nerve injury pathology assessment

Nerve injury pathology assessment Perivascular nerve fascicles with mild cellular degeneration, perineural chronic inflammation and fibrosis (H&E) High power showing hypocellular fascicles with cellular degeneration (black arrow) and perineural inflammation (H&E)

Vascular injury pathology assessment

Vascular injury Pathology assessment Focal adventitial fibrosis with myxoid change (H&E) High power showing arteriolar fibrinoid necrosis periarteriolar chronic inflammation (Russell-Movat stain)

No arterial injury except for minimal smooth muscle cell loss and periadventitial fibrosis (area between lines) (H&E) High power showing nerve fascicles with minimal perineural chronic inflammation (black arrow) (H&E) Periadventitial fibrosis

Conclusions Renal denervation using β-emitting radiation is feasible β-emitting radiation can cause renal nerve damage In the tested dosages (25-50 Gy) there is minimal vascular damage Further clinical studies are required to assess efficacy