1. Medtronic Cardiovascular,
Preclinical Insights Into the Optimal Ablation Location for Renal Denervation Procedures
Robert J. Melder, ScD
Senior R&D Director
Medtronic Cardiovascular,
Santa Rosa, CA
Authors: Robert J. Melder, Stefan Tunev, Jennifer Ruwart, Paul Coates, Julie Trudel, Daniel Schulz-Jander and Martin Rothman

2. Disclosure Statement of Financial Interest
Within the past 12 months, I or my spouse/partner have had a financial interest/arrangement or affiliation with the organization(s) listed below.
Affiliation/Financial Relationship
Company
Grant/Research Support
Consulting Fees/Honoraria
Major Stock Shareholder/Equity
Royalty Income
Ownership/Founder
Intellectual Property Rights
Other Financial Benefit (Employee)
None
Medtronic Inc.

3. Historical Review of Past Performance: Review of 66 treated and 64 Naïve Swine
Mean
N = 238
Average of four RF ablations in each artery
Significant (P<0.05) increase in non-functional axonal area along artery
Significant drop (P<0.05) in sympathetic axonal density measured by immuno-histochemistry in the renal cortex
Significant drop (P<0.05) in tissue norepinephrine (NE) values measured in the renal cortex
Catheter-based Renal Denervation has a significant impact on sympathetic nerve function and viability but with substantial variability

4. Our view of renal nerve distribution has changed: Can we do better with new methodological approaches to denervation with the existing technology?
Renal nerves may have a positional bias : distal nerves are closer to the arterial lumen
Histological analysis by Sakakura1 and others2,3 suggest that a more distal approach could increase the frequency of successful ablations
Distal ablation strategies can be executed with the existing catheters
2 mm radial intervals per ring
1Sakakura K et al. J Am Coll Cardiol Aug 19;64(7):
2Tzafriri ARJ Am Coll Cardiol Sep 16;64(11):
3Mahfoud F EuroPCR2014

5. Experimental Approach
Part 1: Main Renal Artery Dose Response
Hypothesis- Increasing the net ablative dose of RF by increasing number of lesions will increase the degree of renal nerve ablation
Method-
Three treatment arms of animals were randomized for unilateral RDN treatment with Symplicity Spyral in the Main Renal artery using 1, 2 or 3 treatment cycles, producing 4, 8 or 12 lesions in the treated artery
The contra-lateral kidney was used as the “in-animal” control
Study terminated at 7 days and tissues sampled for histology and renal NE analysis
Part 2: Distal Main and Branch Treatment
Hypothesis- Focusing treatment on the most vulnerable segments of renal artery will provide an optimal ablative response
Method-
Two treatment arms of animals were randomized for unilateral RDN treatment with Symplicity catheters; Spyral was used to treat only the renal artery branches (1 cycle), Flex was used to treat only the Distal Main artery (6 lesions)
The contra-lateral kidney was used as the “in-animal” control
Study terminated at 7 days and tissues sampled for histology and renal NE analysis

6. Renal Tissue Norepinephrine Analysis
4 lesions
8 lesions
12 lesions
4 lesions/
branch
6 lesions
All treatments significantly reduced tissue NE
No meaningful dose response to multi-cycle Spyral treatment could be observed in the Main Renal Artery
Branch and Distal Main treatments showed decreased variability

7. A closer look at response: Greater levels of NE reduction with increased uniformity of response
Branch treatment reduced mean tissue NE by 84% with 2 outliers
Distal Main treatment with reduced Mean tissue NE by 84%, also with 2 outliers but most values near zero
47%
Decrease
84%
Decrease
84%
Decrease

8. Renal Tissue Analysis – Cortical Axon Density
4 lesions
8 lesions
12 lesions
Treatments closely paralleled renal NE response
No meaningful dose response to multi-cycle Spyral treatment could be observed in the Main Renal Artery
Branch and Distal Main treatments showed decreased variability

9. A closer look at response: Greater levels axon reduction with increased uniformity of response
Branch treatment reduced mean axon area by 82%
Distal Main treatment reduced mean axon area by 88%
40%
Decrease
82%
Decrease
88%
Decrease

10. I V Y Optimization of the Treatment Methodology:
a combined target approach to renal denervation I
RF treatment of the Main Artery V
RF treatment of each Branch Y
RF treatment of the Main Artery
and Branches

11. Branch & Main Artery Treatment Highly Effective in Reducing Renal NE
Untreated or undertreated branches can give rise to outliers (red circle) in response
Combination treatment of renal artery branches and main artery seem to be optimal in reducing outlier impact
2-cycles of treatment in the main artery do not improve response more than 1 cycle of treatment

12. Histology of Branch Treatment (near branch point)
Dotted lines=RF injury areas, arrows=necrotic nerves in RF area, arrowheads=intact nerves, M=psoas muscle, V=vein, U=ureter, Ad=adrenal gland, Cr=cranial edge
Necropsy and histology indicate Branch Artery and Main Renal Artery treatment appear to show similar safety profile as conventional RF treatment in the main artery with minimal non-target involvement

13. Summary
Prior experience with renal denervation responses in swine indicates that the placement of the lesions may be a source of variability in the response
Histological analysis of human renal arteries suggests that zones of closest approach of renal nerves to the renal artery provide ideal ablation sites
Increasing the number of ablations along the main renal artery reduces variability of response but not does not significantly increase the degree of renal nerve ablation
Targeted renal nerve ablation in zones of nearest approach (distal main and branches) can maximize the denervation response
Treating the renal artery branches in combination with the main renal artery significantly increases the net amount of nerve ablation and decreases the variability of the response
Treating the renal artery branches and main renal artery shows a similar safety profile as conventional treatment in the main artery, although clinical confirmation of the safety and efficacy of this approach is needed