1. Pre-Clinical Evaluation of Renal Denervation with RF Technologies Meital Mazor, PhD Vessix Vascular, Boston Scientific

2. Meital Mazor, PhD
Within the past 12 months, I have had a financial interest/arrangement or affiliation with the organization(s) listed below.
Vessix Vascular, Inc.
Employee and stockholder
Boston Scientific
Employee

3. In human arteries…. many parameters are involved in the efficacy of renal denervation

4. Significantly more nerves in hypertensive patient vs
Significantly more nerves in hypertensive patient vs. normotensive subjects
Hypertensive Patient
Normotensive Patient
32 renal human arteries included. The number of nerves per mm2 within the 0.5 mm ring area from the adventitia was 2.5±1.8 in N vs. 3.5±1.4 in H (p<0.04) while no difference was detected above 0.5 mm (1.5±0.9 in N vs. 1.2±0.7 in H, p=0.3). Giuseppe Sangiorgi et al. J Am Coll Cardiol. 2012;60(17_S)

5. In renal arteries, atherosclerosis increases the distance between the catheter and the nerves
64% of the arteries included in this analysis are atherosclerotic
Histology images and figure were taken from Renu Virmani, LINC 2013

6. In healthy porcine…..

7. No hypertension, No hypertensive medications, No atherosclerosis, Thinner arteries (Tunica media thickness is about half of humans)

8. RF Renal Denervation Systemsa
Medtronic Symplicity™
St. Jude
EnligHTN™
Covidien (Maya)
OneShot™
Boston Scientific
Vessix™
Energy RF
Monopolar
Bipolar
Catheter Design
Catheter with single electrode
Basket with four electrodes
Balloon with helical electrode and irrigation
Balloon with four to eight electrode pairs
Guidewire No
0.014”
(0.36 mm)
0.014” or 0.018”
(0.36 mm or 0.46 mm)
Power (watts)
5 - 8 6 25 ~1
Generator Control
Power
Temperature
System Single Activation Time
2 minb
6 minc
2 mind
30 sec
Total Denervation Time
24 min
4 min
2 min
a None of these devices are available for sale in the US.
b Medtronic Website.
c St. Jude Website.
d Covidien (Maya) Presentation; Ormiston et al. EuroIntv
*The Vessix™ Renal Denervation System is not available for sale in the US.
N/A= Not Reported
RF=Radiofrequency

9. Monopolar RF (Single or Multiprobe)
Grounding Pad
Surrounding Tissue
Blood Vessel Wall
Blood Flow
Dissipated Energy
RF energy is dispersed through the body and terminates into a grounding pad placed on patient’s thigh.
Requires perfusion of blood in the artery to cool the catheter.
Significant power (6 to 8 watts) is required to reach an effective temperature.
Significant heat is lost into the bloodstream requiring long therapy “dwell times” ( minutes) in order to get depth of penetration into the adventitia.
Arteries <4.0 mm cannot be treated, since there is not enough perfusion of blood to cool catheter.
Long treatment times extends possible pain for the patient.
Per Dr. M, Have reviewed by Prabodh Mathur

10. Symplicity Released Energy maximum 8 Watt Temperature between 40-75°
• The generator automatically switch off if temperature is higher than 75 °

11. Sievert H. et al ICI

12. Swine artery at 10 day post MP RDN
Endothelization almost complete
Full media thickness was constituted with fibrotic tissue
Pronounced adventitial inflammation
Amount of microfilament stained nerves was reduced by 45%.
Steigerwald K, et al. Morphological assessment of renal arteries after radiofrequency catheter-based sympathetic denervation in a porcine model. J Hypertens Nov;30(11):

13. Mono-polar RDN- 180 days
The RF-induced lesions were well healed and devoid of any significant inflammatory component.
The lesions consisted of fibrosis, and minimal to mild disruption of the external elastic lamina.
Minimal intimal thickening and minimal disruption of the internal elastic lamina were seen in all treated renal arteries
Rippy MK et al. Clin Res Cardiol Dec;100(12):

14. Nerve injury at 180 days
The renal nerve injury was characterized primarily as healing fibrosis causing a thickening of the surrounding perineurium in affected nerves.
Rippy MK et al. Clin Res Cardiol Dec;100(12):

15. ESC 2008, Henry Krum

16. Bipolar RF on a Balloon
Surrounding Tissue
Blood Vessel Wall
No Blood Flow
Bipolar RF energy travels only from a positive to negative pole located on each electrode thereby localizing the energy and eliminating the necessity of a grounding pad.
Balloon occludes blood flow; no heat is lost to bloodstream, thus creating an efficient environment to deliver energy.
Since perfusion of the blood is not needed to cool catheter, small diameter balloons allow treatment in accessory renal arteries.
Allows delivery of very low power (0.5 to 1 watt).
Allows for simultaneous delivery of energy to multiple electrodes and very fast treatment times (in the case of The Vessix™ Renal Denervation System total of 30 seconds for all 8 electrodes).
Fast treatment time may mitigate pain for the patient.

17. Vessix V2 Renal Denervation System
Low pressure non-compliant balloon (3 atm) with offset helical pattern of bi-polar electrodes
Custom RF Generator controls temperature at precisely 68◦C and delivers RF energy to all electrodes simultaneously.
Very low power (typically <1.0 Watt/electrode) needed to reach and maintain target temperature
Generator confirms apposition via impedance. Electrodes not properly apposed to tissue are automatically turned off 17

18. Porcine artery 7 days post bipolar RF treatment
4 mm long electrodes, 680C for 30 seconds, Day 7. Representative low magnification image of renal artery 7 days post 68°C RF treatment. Note two separate zones of treatment (brackets) circumferentially around the artery, as evidenced by transmural coagulative necrosis of the arterial wall and extension of the zones of treatment into the adjacent adventitia (within dashed lines).

19. Zone of RF Treatment
Treatment zone was evidenced by transmural coagulative necrosis of the arterial wall and extension of the zones of treatment into the adjacent adventitia (within dashed lines). Susceptible nerves are nerves adjacent to or within the zone of treatment (within dashed line), while non-susceptible nerves are nerves outside of zone of treatment.
Note: hemorrhage within adventitia is an artifact related to histology processing
Each RF treated and sham artery was trimmed to yield six cross-sections
Trimmed specimens were processed for paraffin-embedding to yield hematoxylin and eosin-stained slide for light microscopy.
Nerve analysis were done on cross-sections with zone of treatment.

20. Degenerate/reactive nerve within zone of treatment
Loss of normal fiber morphology characterized by:
Disorganized hypercellularity
Vacuolization
Perineural fibroplasia/fibrosis

21. Single treatment per artery (n=3)

22. Treatment of full artery length (n=3)

23. Single treatment with horizontally placed electrodes (n=3)

24. RF treatment throughout the entire artery length affected more nerves within the zone of treatment (p<0.05), and caused the highest decrease in NEPI levels.
-46% NEPI
-78% NEPI
-41% NEPI
The group with surgical denervation showed a 75% reduction in NEPI, compared to the endogenous NEPI level of the untreated controls.
The group with surgical denervation showed a 75% reduction in NEPI, similar to the group treated for the full artery length.
The group with surgical denervation showed a 75% reduction in NEPI, similar to the group treated for the full artery length.

25. Full artery length treatment affected significantly higher percentage of overall nerves (in and outside the zone of treatment).
Affected nerves= susceptible nerves and affected unsusceptible nerves

26. NEPI correlation to percentage of affected nerves
The decrease in NEPI concentration is dependent on the percentage of total affected nerves. While NEPI is decreased with the number of affected nerves, this decrease is more pronounced when higher percentage of the total artery nerves is affected.
Affected nerves (%)

27. Vascular Safety in Treated Swine Renal Arteries is Demonstrated through 180 Days
Pre Treatment
180 Days Post Treatment
Histology confirms no adverse effect on surrounding tissue
All treated arteries were patent
No dissections, aneurysms, or changes in blood or urine chemistry
Endothelialization by 7 days
Significant reduction in norepinephrine through 180 days
Balloon Location
Vessix™ data on file
*The Vessix™ Renal Denervation System is not available for sale in the US.
Swine model results not necessarily indicative of clinical performance

28. Thank you