Vascular Brachytherapy Renal Denervation for Resistant Hypertension Ron Waksman, MD Director, Cardiovascular Research Advanced Education Professor of Medicine, Georgetown University MedStar Heart Institute

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

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 Depends on accurate targeting the renal nerve 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 5-8 minutes per artery

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

β-Radiation for the Creation of Linear Lesions in the Canine Atrium C and D, Recorded 1 week after β-radiation, show clockwise and counterclockwise block when pacing septal and lateral to line of block respectively. 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 Minimum and maximum doses (Gy) for the inner and outer vessel wall surfaces and at 0.5mm and 1mm beyond the outer vessel surfaces

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

Percentage of damaged renal nerves

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

Future Clinical Study

VBT for RDN Study Flow Patients with resistant hypertension Defined as: Systolic BP ≥ 160 mmHg (≥ 150 mmHg for DM) while maxed on 3 meds Renal Angiography Exclude: treatable length <20 mm ≥20% by stenosis Multiple main renal arteries Randomized 1:1 Dose: 25 Gy @ 2 mm 10 patients Dose: 50 Gy @ 2 mm 10 patients Clinical Office Visit Follow up 1 and 3 months Angiographic and Duplex Follow up 6months Clinical Office Visit Follow up 12 months

Endpoints Primary Secondary Safety: Clinical: any need for renal artery intervention to treat renal artery injury induced by the catheter of radiation within 6 months. Angiographic: late loss at 6 months by offline QCA. Efficacy: Clinical: decrease in systolic and diastolic blood pressure of ≥10 mmHg at six months following the procedure. Secondary Short term effects on blood pressure Acute procedural safety; renal artery dissection or perforation requiring intervention serious groin complications specifically. eGFR drop >25% or new renal artery stenosis > 60% by angiogram at 6 months.

Next Steps… Conditional FDA approval for a feasibility study granted 22 Feb 2013 Currently being submitted to local IRB First patient enrolled is slated for Q2 2013

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