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

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

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

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

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

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

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

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

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

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

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).

Chronic Canine Model: Acute Experiment Instrumentation surgery Induce stable heart failure daily coronary embolizations for 4-8 weeks ~50,000 (90-120 um in diameter) beads/day x 20-60 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

Hemodynamics

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.

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

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

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

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