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

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

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

4. 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

5. 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

6. 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

7. 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

8. Gamma knife radiosurgery is used routinely for nerve ablation in trigeminal neuralgia
Clinical use of radiation dosages of 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

9. 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

10. 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

11. 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

12. 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

13. Dosimetry calculations

14. 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

15. IVUS showed no endothelial or adventitial damage

16. Nerve injury pathology assessment

17. 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)

18. Vascular injury pathology assessment

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

20. 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

23. 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