Renal Artery Brachytherapy for Sympathetic Renal Denervation for the Treatment of Resistant Hypertension: Preclinical safety study Ron Waksman, Issi Barbash, Renu Virmani MedStar Washington Hospital Center

I/we have no real or apparent conflicts of interest to report. Israel M. Barbash, MD I/we have no real or apparent conflicts of interest to report.

Background Renal sympathetic efferent and afferent nerves 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 And play significant role in pathophysiology of HTN

SYMPLICITY HTN-2: Office BP was reduced in resistant HTN patients In patients with RHTN, Data from Showed At 6 mo f/u SYMPLICITY HTN-2, Lancet 2010

SYMPLICITY HTN-1, 2 year follow-up: In patients with resistant hypertension, catheter-based renal sympathetic denervation results in a substantial reduction in BP sustained out to 2 years 2 yr f/u from Showed paersistent decrease Up to 24 mo And data from other RF systems continue to accumulate showing comparable efficacy SYMPLICITY HTN-1, Hypertension 2011

Limitations of RF-ablation mediated-renal denervation Potential damage to vascular endothelium with late vascular stenosis Pain associated with the ablation Need for multiple ablations resulting in long procedure time RF energy

A novel approach for renal denervation by β-radiation using Beta-Cath™ 3.5F System (Novoste) Potential “sparing” of endothelial injury Limited perivascular effect Small sheath size Short procedure time Our purpose was to test a .. No pain

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 Theoretical support for this approach comes from studies like this, showing that LeCouteur et al. Int J Rad Oncol Biol Phys 1989

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

β-radiation induces 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 With regards to safety lesion Guerra & Bonan, Circulation 2004

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 We have a lot of experience with brachytherapy in the coronaries Jahraus et al. Southern Med J 2003

Methods 10 naïve Yorkshire swine β -emitting radiation dose of 25 or 50 Gy was delivered to the main renal artery Follow-up of 1-2 months: Angiography IVUS Histology* * Data available for 1 month follow up

Renal artery angiography showed no angiographic stenosis up to 2 months follow-up Baseline angio BetaCath location 2 mo f/u

IVUS showed no endothelial or adventitial damage Baseline 1 month 2 months

Nerve injury assessment Perivascular nerve fascicles with mild cellular degeneration, inflammation and fibrosis Hypocellular fascicles with cellular degeneration and perineural inflammation In terms of efficacy, these are 2 H&E slides 2nd: High power mag showing

Nerve injury assessment This slide summarize the histolgy quantification of the Dose response effect

Vascular injury assessment Focal adventitial fibrosis with myxoid change Arteriolar fibrinoid necrosis periarteriolar chronic inflammation In terms of And damage only to With sparing of the endothelium of the main vessel

Vascular injury assessment This slide summarize the histolgy quantification of the

Conclusions Renal denervation using β-emitting radiation is feasible In the tested dosages (25-50 Gy) there is minimal vascular damage β-emitting radiation can cause renal nerve damage Further clinical studies are required to assess efficacy If proven effective, dedicated device should be developed Our preliminary results indicate