SensingMapping Renal Nerve Activity Before During and After

Sensing/Mapping Renal Nerve Activity Before, During and After Denervation Jie Wang, MD, Ph. D Jiangsu Province Hospital, Nanjing, China Columbia University, USA Yue. Hui Yin, MD The 2 nd Affiliated Hospital, Chongqing Medical University Chongqing, China Washington DC, Feb 23, 2020

Disclosure Statement of Financial Interest Within the past 12 months, I have had a financial interest/arrangement or affiliation with the organization(s) listed below. Affiliation/Financial Relationship • • • Consulting Fees/Honoraria Major Stock Shareholder/Equity Ownership/Founder Company • • • Sy. Map Medical Ltd, Coridea, Axon Sy. Map Medical Ltd, Park Medical All TCT 2020 faculty disclosures are listed online and on the App.

Renal Nerve Mapping/Selective Denervation Is A Unmet Clinical Need Renal Never Stimulation to Map Renal Nerves for Selective RDN Has Solid: Ø Anatomy Bases Ø Physiology Bases Ø Histology Evidences

Anatomy Bases for Renal Nerve Mapping and Selective Ablation üSympathetic(73. 5%): Hot Spot üParasympathetic(17. 9%): Cold Spot üAfferent/ No Sym/Parasym(8. 7%): Neutral Spot

Physiology Bases for Renal Nerve Mapping and Selective Ablation SP: thoracic sphlancnic nerves; Coe: celiac ganglion; Pg: renal posterior ganglion; Ig: renal inferior ganglion; Lo: contribution of the lumbar chain to the renal plexus; Mompeo et al, Clin Anat. 2016 ; 29(5): 660 -664. Neural Control of Renal Function DIBONA GF AND KOPP UC: PHYSIOLOGICAL REVIEWS. Vol. 77, No. 1, January 1997 In Responses to Electronic Stimulation ü Hot Spot: Increases in BP/HR ü Cold Spot: Decreases in BP/HR ü Neutral Spot: No changes in BP/HR van Amsterdam, et al, Annals of Anatomy 204 (2016) 71 -79

Clinical Evidences: Hot Spot 200 67 Second Stimulation before Ablation BP Increasing 100 0 81 Second Stimulation After Ablation 200 100 0 No BP Increasing

Clinical Evidence: Cold Spot 51 Second Stimulation BP Decreasing 200 120 40

Histological Evidence For Renal Nerve Mapping ü SRS: Strong response site ü WRS: Weak response site üMasson trichrome to locate mapping/ablating sites üHistology: TH(tyrosine hydroxylase): Efferent CGRP(calcitonin gene-related peptide): Afferent Sensory n. NOS(Neuronal NO synthase): Parasympathetic nerve fibers Distance from the luminal surface of renal arteries to each nerve, the area and number of nerves.

Systolic Blood Pressure in Responses To Renal Never Stimulation at Strong Response Site and Weak Response Site

Histological Evidences for Renal Mapping and Selective Ablation

Renal Mapping/Ablation System “ 5 in 1”Catheter ‒ ‒ Equipped with 8 CPU, mutual feedback to ensure that the stimulation / ablation parameters are correct Accurate low temperature control, automatic adjustment of ablation energy Ruhr joints Handle Connector ‒ Pipe Body Connecting Cables Five functions as one, easy to operate ü guide ü Angiography ü Mapping ü Temperature control ablation ü Manual Irragation Electrode

Using A Novel System to Map and Ablate Renal Sympathetic Nerves • In renal artery site-by-site: Stimulation, Ablation, Stimulation • Deliver an intra-renal artery stimulation • Monitor changes in blood pressure/heart rate • Increases in blood pressure/heart rate: ABLATION; otherwise, move to next site Hot Spot: BP; Cold Spot: BP; Neutral Spot: No Change in BP 1, Mapping renal sympathetic/parasympathetic innervations BEFORE the procedure 2, Monitoring an effective renal sympathetic ablation DURING the procedure 3, Assessing an effective renal sympathetic denervation AFTER the procedure

A Prospective, Multicenter, Single Blind, Randomized and Controlled Trial of Renal Sympathetic Denervation Using Sy. Map. Cath I™ Catheter and SYMPIONEER S 1™ Stimulator/Generator for the Treatment of Hypertension Sympathetic Mapping/Ablation of Renal Nerves Trial (SMART Study) Clinical. Trials. gov ID: NCT 02761811 CFDA Registration Trial 19 Hospitals/220 Patients

Patient Population § Patients with uncontrolled hypertension for at least 6 Months, after standardized drug therapy (at least 2 drugs) for at least 28 days, Office SBP ≧ 150 mm. Hg, ≤ 180 mm. Hg

Primary Efficacy Endpoints Ø The Control rate of office SBP ( SBP<140 mm. Hg) at 6 month after the treatment Ø The composite index of anti-hypertension drugs at 6 months after the treatments Drug composite Index: based on the class numbers and doses of medications: = Weights X (sum of doses) Weight: # Classes Dose: Half Dose: 0. 5; One Standard Dose: 1; Double Dose: 2 Examples: Two classes of drugs were taken: double doses were used for one class and one dose was used for another class: The Index = 2*（2+1）= 6 Changes of antihypertensive drugs should an Endpoint Antihypertensive drugs are allowed to justify in order to achieve SBP<140 mm. Hg

Standardization of Anti-hypertension Drug Regimen Standardized Drugs, Doses and Manufactures Class Name Commercial Name 1 ARB Irbesartan Aprovel 2 CCB Amlodipine Norvasc Β Receptor Metoprolol Blocker Sustained Release 3 4 5 6 Diuretic Hydrochlorothiazid e α Receptor Terazosin Blocker Hydrochloride Combination Irbesartan+ Drug Hydrochlorothiazide Betaloc 氢氯噻嗪片 Coaprovel Standard Dose Maximum Dose 150 mg/Day 300 mg/Day 5 mg/Day 10 mg/Day 47. 5 mg/Day 95 mg/Day 25 mg/Day 50 mg/Day Abbott (Shanghai) 2 mg/Day 4 mg/Day Sanofi（Hanzhou, Irbesartan 150 mg+ China ） Hydrochlo. 12. 5 mg/Day Manufacture Sannofi（Hanzhou, China） Pfizer（Dalian, China） Astra. Zeneca Changzhou Pharmaceutical Irbesartan 300 mg+Hydrochlo 25 mg/Day

A Rigorios Regimen for Post-randomization Medication Changes Order to Add Drugs Irbesartan Amlodipine Metoprolol Hydrochlorothiazide Terzzosin Hydrochloride Order to Reduce Drugs Drug adherence is monitored by HPLC- MS/MS (urine) 17

Renal Arterial Stimulation Percentage of Hot Spots vs. Total Mapping Sites (“Hot Spots”: Pressor Response) N=10 Total Mapped Sites Average Maps/kidney Total Hot Sites Identified (% of total maps) Average Hot Sites/kidney (ablated) 2 nd Ablation Required (%) Renal Mapping Results Left Renal A Right Renal A Total 82 8. 2 75 7. 5 157 15. 7 41 (50%) 44 (59%) 85 (54%) 4. 1 4. 4 8. 5 16 (39%) 18 (41%) 34 (40%) Cold Spots: 16%; Neutral Spots: 29%

We propose that renal mapping and selective renal denervation of excitatory nerves will avoid removal of the sympathetic inhibitory fibers and maximize clinical benefits and safety.

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