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

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

3. 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

4. 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

5. 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

6. 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

7. 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

8. 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

9. 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

10. 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

11. 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

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
Minimum and maximum doses (Gy) for the inner and outer vessel wall surfaces and at 0.5mm and 1mm beyond the outer vessel surfaces

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. Percentage of damaged renal nerves

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

21. 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

22. Future Clinical Study

23. 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 2 mm
10 patients
Dose: 50 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

24. 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.

25. 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

26. 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