1. Pre-Clinical Models and Clinical Studies to
Assess Sympathetic Renal Denervation
Jie Wang MD PhD
Disclosure: JW was a consultant and shareholder of Ardian
Consultant: Respicardial (Cardiac Concepts), Backbeat Medical

2. Renal Afferent and Efferent Nerves
Renal Sympathetic Afferent /Efferent Nerves: Kidney as Recipient and Origin of Central Sympathetic Drive
Vasoconstriction
Atherosclerosis
Hypertrophy
Arrhythmia
Oxygen Consumption
Heart Failure
Renal Afferent and Efferent Nerves
Insulin
Resistance
↑ Renin Release  RAAS activation
↑ Sodium Retention
↓ Renal Blood Flow
↓ Urine Output

3. Three Different Diseases, One Common Pathway
Hypertension, Congestive Heart Failure, and Chronic Renal Failure all have multiple origins
Physiologic changes, initiated by the kidney, accelerate progression of these conditions due to:
Abnormal hormone secretions (renin, aldosterone, norepi)
Renal and pulmonary vasoconstriction
Salt and water retention
The Common Pathway:
Renal Sympathetic Nerve Hyperactivity

4. Change in Blood Pressure (mmHg)
Targeting Renal Sympathetic Nerve to Treat Hypertension: Renal Denervation
Change in Blood Pressure (mmHg) 4 4

5. Opportunities and Competitors
RDN market opportunity: $700M by 2016, $2.3B by 2020**
**JP Morgan, Renal Denervation: The Next Big Thing in CV Devices, Oct, 2011
Confidential

6. Proof-of-Concept Studies: Proper Measurements and Models
Blood Pressure
Cardiac Function: CO, LVdP/dt, LV loops
Urine Output
Acute Animal Models
Chronic Animal Models
Human Studies

7. Proof-Of-Concept study: Experimental Designs
Heart failure (acute or chronic) was created
A nerve blocking drug (Marcaine) was injected (Needle) or infused (Implanted catheter) into the periarterial space outside of the renal artery (Gerota’s fascia)
Renal nerve activity was temporarily blocked
Urine output (every 15 min) was measured in normal status, before and after Marcain in heart failure status

8. Coronary Artery Microembolization –induced Canine Heart Failure Models
Surgical Preparation
Aortic Pressure
Mean Diameter
Coronary Diameter
LV Pressure
LV dP/dt
Coronary Flow
Mean Flow
Coronary Catheter

9. Acute Heart Failure: Acute Experiment
Obtained data from the 11 dogs with micro-embolization model of Acute HF: anesthetized status
8 dogs had Renal Nerve Block (RNB) created by direct injecting 10 ml of Marcaine (bupivicaine) inside Gerota’s fascia
3 dogs served as controls: saline injection inside Gerota’s fascia
Urine output (Urine output/every 15 min) significantly increased compared to controls
Both naturesis and diuresis were observed confirming physiologic basis for the effect

10. Microembolization Created
(mmHg)
LVP 0-
100-
Aortic Flow.
(L/min)
Aortic Pres.
time 200 msec
assist
baseline
Mild HF (<30%)
Mod. HF (30-60%)
Sev. HF (>60%)
10-
Microembolization Created
Severe Heart Failure

11. Acute Heart Failure : Urinary output (UOP) in the Treated Kidney (A) and in both Kidneys (Total)
(B) after Unilateral Renal Nerve Block (URNB) and Bilateral Renal Nerve Block (BRNB). A significant reduction
in UOP was seen after Acute Heart Failure, but UOP was increased significantly after URNB. No additional
increase in UOP was seen after BRNB (* p<0.05 vs. Baseline, † p<0.05 vs. AHF).

12. Chronic Canine Model: Acute Experiment
Instrumentation surgery
Induce stable heart failure
daily coronary embolizations for 4-8 weeks
~50,000 ( um in diameter) beads/day x days
Terminal experimental: anesthetized status
Urine output before and after direct injection of Marcaine into Gerota’s Fascia
Similar results to acute heart failure: 6 dogs with chronic heart failure

13. Hemodynamics

14. Congestive Heart Failure : Urinary Output (UOP) in the Treated Kidney and in both Kidneys
(Total) after Unilateral Renal Nerve Block (URNB) and Bilateral Renal Nerve Block (BRNB). A
significant increase in UOP was seen after URNB compared to the CHF state (* p<0.05 vs. CHF),
but BRNB failed to produce a significant increase in UOP compared to URNB alone.

15. Summary
Renal nerve blockade achieves significant increases in urine output in both acute and chronic heart failure
Urine output can be used index of renal nerve blockade

16. Acute Human Feasibility Study in Patients
Class III-IV CHF patients refractory to diuretics or patients with BP > 140/90 on medication
Injection of drug to block RN using CT guided technique
Comparison of urine volume, urine and serum electrolytes, hemodynamic and neurohormonal effects from 6 hours pre- to 12 hours post- injection

17. Intervention Performed In 5 Patient
Successful test of RN blocking technique
Performed under CAT Scan Guidance
Needle placed at the hilum of the kidney
Single injection of Marcaine resulted as predicted in:
Nerve block for 12 hours
Increase in urine output
Reduction in blood pressure

18. What Are the Best Models Should be?
Heart Failure vs Hypertension
Urine Output vs Blood Pressure/Cardiac Function
Large Animals vs Small Animals