1. Renal Denervation: the St. Jude experience
Vasilios Papademetriou, MD
Professor of Medicine
Georgetown University

2. <First Name> <Last Name>, <Degree(s)>
I have no relevant financial relationships

3. Renal Denervation: the St. Jude experience
Vasilios Papademetriou, MD
Professor of Medicine
Georgetown University

4. EnligHTN Renal Denervation System
Multi-electrode ablation catheter
Non-occluding, Nitinol basket design
8F 4 electrode deflectable atraumatic tip
Predictable 4 lesion ablation pattern
Simultaneous 60 second ablation
Touch-screen pole-mounted RF generator
Default Settings
Time
60 seconds simultaneous
Impedance Ω
Maximum Power
8 Watts
Temperature
70 degrees C

5. Circumferential renal nerve ablation with the enlightn system1 2 3 4 5 6

6. Variability of the procedure
EnligHTN

7. Lesion progression using the enlighten catheter
Adventitial
Surface: Acute
Transmural lesions
Theoretical lesion pattern
Luminal Surface
5 Days Healing Progression
Luminal Surface
90 Days Healing Progression
Luminal Surface: Acute TTC Stained Renal Artery
Luminal Surface
30 Days Healing Progression
Papademetriou V, Euro PCR 2014

8. Lesions dimensions using the enlighten device
Depth
Papademetriou et al CRT 2017

9. Optimal number of lesions for optimal four quadrant ablation
Lesions Dimensions
Optimal # lesions
Diameter of Renal Artery (mm)
Optimal Number of ablations 4
4.5 5
5.5 6
6.5
Av. RA diameter in humans: 5.6 mm
Optimal # lesions: >7/renal artery or >14 total
Papademetriou et al Euro PCR 2014

10. Depth is important

11. Immunohistochemisty – 30 day post treatment
ATH
ATH 10X
H&E MT
  Two RF ablation sites (red arrows)
Nerve runs parallel to the artery outside of the treatment area (circle) stained strongly positive for TH. 
Nerve parallel to the artery (rectangle) stains negative for TH in the treatment zone (solid black arrow) but positive for TH outside of the RF treatment zone (broken arrow).
Tyrosine hydroxylase (TH) immunohistochemistry (IHC) staining demonstrates marked reduction in the presence of TH in individual nerves in areas aligned with the RF ablation sites.  The loss of TH indicates focal alteration of nerve function. 
Papademetriou V, Euro PCR 2014

12. Tissue Norepinephrine Reduction
random lesion placement, domestic swine model
8 lesions /side
54% reduction in NEPI
Papademetriou Euro PCR 2014

13. Distribution of Renal Sympathetic Nerves

14. Renal nepi change

15. Is Branch Treatment Necessary?
Mahfoud, et al; Comparative Branch vs. Distally Focused Main Renal Artery Denervation with Two RF Catheters in a Preclinical Model, TCT 2015

16. EnligHTN I: Study design
WorthleyEuropean, Tsioufis…Papademetriou et al Eur Heart J 2013;34:2132
Papademetriou,Tsioufis,..Worthley et al: Hyperten sion 2014;64:565
Tsioufis,Papademetriou..Worthley et al: J Hyper 2015;

17. Demographics Characteristic N(%) or mean(SD) Gender (female) 15 (33%)
Ethnic origin (white)
45 (98%)
Body Mass Index (kg/m2)
32 (±5)
Coronary Artery Disease
9 (20%)
Hyperlipidemia
27 (59%)
Type II Diabetes Mellitus
Sleep Apnea
14 (30%)
eGFR (mL/min/1.73m2)
87 (±19)
Serum Creatinine (mmol/L)
78 (±17)
Cystatin C (mg/L)
1.14 (±0.29)
Urine Albumin-to-Creatinine Ratio (mg/g)
169.4 (±492)
Number of Anti-Hypertensive Medications
4.8 (±1.1)
Office Systolic Blood Pressure (mmHg)
176 (±16)
Office Diastolic Blood Pressure (mmHg)
96 (±14)
Heart Rate (bpm)
71 (±12)

18. EnligHTN I: Change in Blood pressure with Renal Denervation
Office BP Reduction
ABPM Reduction
Worthley, Tsioufis…Papademetriou et al Eur Heart J 2013;34:2132
Papademetriou,Tsioufis,..Worthley et al: Hypertension 2014;64:565
Tsioufis,Papademetriou..Worthley et al: J Hyper 2015;

19. Home BP Reduction Through 24 Months
WorthleyEuropean, Tsioufis…Papademetriou et al Eur Heart J 2013;34:2132
Papademetriou,Tsioufis,..Worthley et al: Hyperten sion 2014;64:565
Tsioufis,Papademetriou..Worthley et al: J Hyper 2015;

20. Change in Office, Ambulatory and Home BP measurements
Systolic BP
Diastolic BP

21. Average Number of Anti-Hypertensive Medications by Visit
Summary mean±SD (n) (min, max)]
Baseline
4.7 ± 1.0 (46) (3.0, 8.0)
1 Month
4.7 ± 0.9 (46) (3.0, 7.0)
3 Month
4.6 ± 1.1 (46) (1.0, 7.0)
6 Month
4.7 ± 1.1 (45) (1.0, 7.0)
12 Month
4.8 ± 1.3 (45) (1.0, 8.0)
18 Month
4.9 ± 1.4 (44) (1.0, 8.0)
24 Month
4.8 ± 1.5 (44) (0.0, 8.0)

22. LV Mass Index changes after RDN
Echo Sub-Study: N=20
LV Mass Index changes after RDN
Tsioufis C, Papademetriou V…. J Hum Hypert 2016
22 CONFIDENTIAL-Do not distribute

23. Mitral Lateral E/E’ changes after RDN
Echo Sub-Study: N=20
Mitral Lateral E/E’ changes after RDN
Diastolic LV function
Tsioufis C, Papademetriou V…… J Hum Hypertension 2016
23 CONFIDENTIAL-Do not distribute

24. EnligHTN™ Clinical Series: An Update for St Jude
EnligHTN I: First-in-Human Clinical Trial (24M DATA PUBLISHED)
Single arm, FIH trial of 46 pts. to establish initial Safety & Efficacy of the Gen 1 EnligHTN™ System, Resistant HTN; two-year year follow-up
EnligHTN II: International Clinical Trial (ENROLLING)
Non-Randomized trial of 500 pts. to further evaluate safety and long-term efficacy of the market released EnligHTN™ system in the broader HTN population, five-year follow-up (n= 344 to date)
EnligHTN III: Gen 2 First-in Human Trial (6M DATA PUBLISHED 24M manuscript drafted)
Single arm, FIH trial of 39 pts in Australia, Resistant HTN; two-year follow-up

25. The EnligHTNed Trial -Global IDE
Update from st jude
& beyond
EnligHTN Regional Observational Studies (ENROLLING)
Non-Randomized registry(s) to further establish outcomes and support regional reimbursement in European geographies. ~1300 planned patients total with 12M follow-up (n=87)
Renal Denervation + Atrial Fibrillation (ENROLLING)
Post-market, prospective, multi-center, randomized feasibility trial to evaluate the effect of concomitant renal denervation and cardiac ablation on AF recurrence; two-year follow-up (n=54)
Metabolic Syndrome Pilot RCT (FOLLOW UP)
RCT, FIH trial of 17 pts, Assessing muscle sympathetic nerve activity & insulin resistance in res HTN pts; 12M follow-up (n = 17)
The EnligHTNed Trial -Global IDE
In discussions with FDA, final stages
Sham control
Triple drug regimen
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26. Issues with experience so far
Experimental data
Circumferential lesioning? YES
Depth, up to 5 mm, may not be enough
Fiber interruption- axon may stay intact
Reduction in tissue NEPI 47-80% may not be enough
Clinical Data: Confounders
Lack of appropriate controls
Early studies, unintentional exaggeration of baseline office BP?
Discrepancy of change in Office BP with home and ABPM

27. In Summary
Clinical results seen so far, including data out to 24 months from EnligHTN I & III, are encouraging
Ongoing clinical trials, continue to demonstrate Efficacy and safety
Clinical data so far and pre-clinical insights from the last year have influenced the procedure and next steps.
SJM is in the final stages of discussion with FDA regarding the design of a new randomized, sham-controlled clinical trial.
The study has been suspended indefinitely
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