1. 강동경희대학교병원 심장혈관센터 김종진 Renal Nerve Denervation in Resistant Hypertension

2.  M/41  PMHx  DM / HTN / Hep / Tb ( - / + / - / - )  HTN: 1 yrs (not-controlled) + medication for 4 yr  Medications  amlodipine 10mg / olmesartan 40mg / nebivolol 5mg / indapamide 1.5mg  160/95 mmHg (for 6 months)  Lab. Findings  AST/ALT: 41/92 IU/L  ECG: LVH with strain pattern  Chest PA: normal CASE 1

3.  F/53  PMHx  DM / HTN / Hep / Tb ( + / + / - / - )  HTN: medication for 10 yrs  Medications  amlodipine 5mg / losartan 100mg / carvedilol 25mg / indapamide 1.5mg  160/90 mmHg (for 6 months)  Lab. Findings  HbA1C: 8.0%  ECG: NSR  Chest PA: mild cardiomegaly CASE 2

4.  M/56  PMHx  DM / HTN / Hep / Tb ( - / + / - / - )  HTN: 15 yrs (not-controlled) + medication for 1 yr  Medications  nifedipine oros 60mg / hydrochlorthiazide 25mg / perindopril 8mg / nebivolol 2.5mg / doxazosin 2mg  165/85 mmHg (for 7 months)  Lab. Findings  Cr 1.4 mg/dL  GFR by MDRD: 52 ml/min/1.73 m 2 / Hb 12.7 g/dL  ECG: biatrial enlargement / LVH with strain pattern  Chest PA: cardiomegaly CASE 3

5.  M/50  PMHx  DM / HTN / Hep / Tb ( + / + / - / - )  HTN: medication for 15 yrs  Medications  tenormin 50mg / amlodipine 10mg / olmesartan 40mg  160/100 mmHg (6 months)  Lab. Findings  FBS: 104 mg/dL  ECG: incomplete RBBB  Chest PA: no abnormality CASE 4

6.  F/69  PMHx  DM / HTN / Hep / Tb ( - / + / - / - )  HTN: medication for 6 months  Medications  amlodipine 5mg / omesartan 20mg / indapamide 1.5mg / bisoprolol 5mg  193/126 mmHg (for 1months)  Lab. Findings  ECG: NSR, LVH  Chest PA: no abnormality CASE 5

7.  F/59  PMHx  DM / HTN / Hep / Tb ( - / + / - / - )  HTN: medication for 20yrs  Medications  nisoldipine 20mg bid / indapamide 1.5mg qd / diovan 80mg bid / bisoprolol 5mg bid  169/95 mmHg (for 2yrs)  Lab. Findings  ECG: sinus bradycardia  Chest PA: no abnormality CASE 6

8. Blood pressure lowering -Goals often not reached Combination therapy -Mandatory in most cases Compliance -Poor Organ protection -Incomplete Healing -An illusion? Unmet needs in hypertension therapy

9. HYPERTENSION A MAJOR PUBLIC HEALTH BURDEN 9

10. Astonishing prevalence –1 in 3 adults –1 B people worldwide  1.6 B by 2025 Single largest contributor to death Dramatically increases risk of heart attack, stroke, heart failure, kidney failure & insulin resistance Source: American Heart Association, World Health Organization A Major Public Health Burden 10

11. Prevalence, Awareness and Therapy Hypertensives in Germany Hypertensives,kno wing that to be affe cted treated hypertensives controlled * and treated hyperten sives 16 millions 12 millions 8 millions 2 millions * = < 140/90 mmHg don´t know don´t do do little problem: 4 Mio. 4 Mio. 6 Mio.

12. Current approach failing –Physician inertia –Patient compliance –Resistant HTN Drugs Work, But Not as Well as You May Think 35% Treated & Controlled 30% Untreated 35% Treated but Uncontrolled 12

13. Current ESH/ESC Guidelines - Combinations of Antihypertensive Drugs- Diuretics ACE Inhibitors Calcium Channel Blocke r ß-Blocker The preferred combinations in the general hypertensive population are represented as thic k lines. The frames indicate classes of agents proven to beneficial in controlled intervention trials. AT 1 -Receptor Blocker  -Blocker Aldosterone- Antagonist !

14. Bakris et al., Am J Kidney Dis 2000; 36: 646 1 No of antihypertensive drug classes 234 UKPDS (RR diast. <85 mmHg) ABCD (RR diast. <75 mmHg) MDRD (MAP <92 mmHg) HOT (RR diast. <80 mmHg) AASK (MAP <92 mmHg) Blood pressure control: Takes > 2 antihypertensives Standard therapy: 2.3 drug classes Intensive therapy: 3.5 drug classes N Engl J Med 2010 N Engl J Med 2010

15. 2/3 of patients requires combination therapy Patients (%) 312311 3 MONOtherapy 100% 32 37 20 8 39 14 7 39 32 20 7 33 36 21 6 40 38 16 4 50 33 13 3 30 38 22 8 3 drugs- combination 2 drugs- combination 4 drugs- combination > 4 drugs- combination USAJapanFranceGermanyItalySpainUK 210 26 2928 224 Fix combination in % 47 61 35 383228 66 Free combination in %

16. AHA Statement Circulation 2008;117:e510ff Definition of Resistant Hypertension Resistant hypertension –RR > 140/90 mmHg, despite treatmant with 3 drug classes i ncluding a diuretic

17. AHA Statement Circulation 2008;117:e510ff Predictors of resistant hypertension Advanced age High sodium intake Obesity Renal condition Sleep apnea Diabetes LVH

18. Non-pharmacological & p harmacological therapy Strategy in resistant hypertension Screening for secondary causes Sleep apnea Renal failure Renal artery stenosis Hyperaldosteronism Pheochromocytoma Coarctation of the aorta Renal denervationBaroreflex stimulation Identification of modifiable l ife style factors Reduction of drugs that may i ncrease blood pressure Exclusion of pseudoresistenc e Specific therapy

19. For distribution only in markets where the Symplicity renal denervation system is approved. Not for distribution in the USA or Japan. Trademarks may be registered and are the property of their respective owners. © 2012 Medtronic, Inc. All rights reserved. UC201205566EE Catheter-Based Renal Denervation (RDN)

20. WELL ESTABLISHED SCIENTIFIC FOUNDATION 20

21. Renal Sympathetic Connection Role of kidneys & sympathetic nervous system in development & progression of HTN is well established Pharmaceuticals modify physiology at intermediate steps in pathway RDN attempts to break the cycle at its source 21

22. ↑ Contractility ↑ Heart rate Afferent Nerves Schlaich et al. Hypertension. 2009;54(6):1195-1201. Vasoconstriction ↑ Renin Release  RAAS activation ↑ Sodium Retention ↓ Renal Blood Flow Efferent Nerves Blood Pressure 22 Renal Sympathetic Nerve Activity Kidney as Origin & Recipient of Central Sympathetic Drive

23. ↑ Contractility ↑ Heart rate Hypertrophy Arrhythmia Heart Failure Afferent Nerves Vasoconstriction Atherosclerosis ↑ Renin Release  RAAS activation ↑ Sodium Retention ↓ Renal Blood Flow ↓ Kidney function Efferent Nerves Blood Pressure 23 + Increase co-morbidities Schlaich et al. Hypertension. 2009;54(6):1195-1201. Renal Sympathetic Nerve Activity Kidney as Origin & Recipient of Central Sympathetic Drive

24. Disrupts Renal Nerves, Lowering SNS Activity Afferent Nerves ↑ Contractility ↑ Heart rate Hypertrophy Arrhythmia Heart Failure Vasoconstriction Atherosclerosis ↑ Renin Release  RAAS activation ↑ Sodium Retention ↓ Renal Blood Flow ↓ Kidney function Efferent Nerves Blood Pressure -- Renal Denervation (RDN)-- ↑ Contractility ↑ Heart rate Hypertrophy Arrhythmia Heart Failure Vasoconstriction Atherosclerosis ↑ Renin Release  RAAS activation ↑ Sodium Retention ↓ Renal Blood Flow ↓ Kidney function 24 - Decrease co-morbidities + Increase co-morbidities Schlaich et al. Hypertension. 2009;54(6):1195-1201.

25. Norepinephrine Spillover Muscle Sympathetic Nerve Activity (MSNA) Central Sympathetic Nerve Activity Renal Sympathetic Nerve Activity Proof of Principle

26. Reduction of Renal Contribution to Central Sympathetic Drive: MSNA in Resistant Hypertension Patient Baseline 1 mo 12 mo MSNA (burst/min) BP (mmHg) 56  161/107 41 (-27%)  141/90 (-20/-17) 19 (-66%)  127/81 (-34/-26) * Improvement in cardiac baroreflex sensitivity after renal denervation (7.8  11.7 msec/mmHg) * 59 year old male on 7 HTN meds Schlaich et al. NEJM. 2009; 36(9): 932-934.

27. baseline MSNA: 46 burst/min 3 Months FU MSNA: 33 burst/min ESRD patient with MSNA over 33 months FU post bilateral denervation (submitted for publication) 12 Months FU MSNA: 21 burst/ min 33 Months FU MSNA: 19 burst/min Normal MSNA between 15-20 bursts/min Sobotka Euro-PCR 2011

28. Proof of Principle: Related Changes in Underlying Physiology Baseline1 mo∆ Office BP (mmHg) 161/107141/90 Renal NE spillover (ng/min) - left kidney7237-48% - right kidney7920-75% Total body NE spillover (ng/min) 600348-42% Plasma Renin (μg/l/hr) 0.30.15-50% Renal Plasma flow (ml/min) 719112657% Schlaich et al. NEJM. 2009; 36(9): 932-934. LV Mass (cMRI) dropped 7% (from 78.8 to 73.1 g/m 2 ) from baseline to 12 months

29. Renal Norepinephrine Spillover: 10 cases Example Case: Left: 75 % reduction Right: 85 % reduction Esler et al. J Htn. 2009;27(suppl 4):s167. Schlaich et al. J Htn. 2009;27(suppl 4):s154. Mean total renal norepinephrine spillover ↓ 47%, p=0.023 (95% CI: 28–65%) Mean total body NE spillover ↓ 28%, p=0.043 (95% CI: 4–52%)

30. ESRD patient (M; 37 yrs) Submitted for publication Medication at baseline: Tritace 10 mg Avapro 300 mg Zanidip 20 mg Noten 50 mg Minoxidil 5 mg 156 133 95 81 ESRD (FSGS), RRT since 04/2006 Dry Weight: 81 kg no change in HD regimen NTx August 2008 Medication at 33 M FU: Noten 50 mg Sobotka Euro-PCR 2011

31. Trans-catheter Renal Denervation at least modulates central sympathetic over-drive It might be a physiological treatment modality to treat sympathetic over-drive related disease –Hypertension –Sleep disturbances –Type 2 diabetes mellitus –…. Renal Denervation – Summary of Background & Physiology-

32. 1952 Concept Validated by Surgical History Effective, but significant morbidity 32

33. A common question … Blaufox et al. N Engl J Med. 1969;280(2):62-66. How will the kidney function without sympathetic control? Transplanted kidneys lack innervation Yet effectively maintain fluid and electrolyte balance Establishes that sympathetic component of control represents “overdrive” system, rather than foundation of basic renal function 33

34. A SIMPLER, MORE ELEGANT SOLUTION 34

35. Arise from T10-L2 Follow the renal artery to the kidney Primarily lie within the adventitia The only location that renal efferent & afferent nerves travel to gether Renal Anatomy Allows a Catheter-Based Approach Vessel Lumen Media Adventitia Renal Nerves 35

36. Symplicity® Catheter System™ Low profile, electrode tipped catheter Delivers RF energy to treatment site Proprietary RF generator - Low power - Automated - Built-in safety control algorithms Standard interventional technique 40-minutes from first to last RF delivery In the United States: Caution: Investigational Device. Limited by Unite d States law to investigational use.

37. Standard interventional technique 4-6 two-minute treatments per artery Proprietary RF Generator −Automated −Low-power −Built-in safety algorithms Anatomy of Renal Nerve Catheter-Based Approach

38. In the United States: Caution: Investigational Device. Limited by Unite d States law to investigational use.

39. Extensive research in >300 swines Angiography and pathology at 7, 30, 60 & 180 days No stenosis or luminal reduction seen in treated arteries RF Generator algorithm optimized to minimize vascular injury Vascular Safety Predicted by Preclinical Studie s 39

40. Symplicity Catheter Tip Features Be familiar with the dimensions at the distal end of the catheter Flexible Tip (self-orienting) 5mm 12mm Deflectable Shaft

41. Symplicity Catheter Handle Features Orange section of handle rotates shaft, and trigger flexes the catheter tip Deflect tip by pulling lever towards back of handle Straighten tip by pushing lever towards front of handle Handle rotator has tactile “click” every 45 degrees Dot on rotator gives relative rotational reference

42. 42 Targeting Renal Nerves Treat distal to proximal 4-6 focal treatments 2 min per treatment ≥ 5 mm between locations Stable, unique locations Circumferential coverage Common strategy (dependent on renal a natomy): Distal: Inferior and inferolateral locations Proximal: Superior and superolateral locations Avoid purely lateral treatments (possible electr ode movement with respiration) PULL, ROTATE, ASSESS new location and prior treatment site

43. Procedure Overview

44. Areas To Avoid Avoid to treat the areas of visible disease –Such as atherosclerosis, calcification, and fibromuscular dysplasia Atherosclerosis (Ostial Stenosis) Avoid treating in segment with stenosis Calcification Avoid energy delivery to area with visible calcification Fibromuscular Dysplasia (FMD) Avoid treating in segment with FMD There is no clinical experience treating near areas of visible disease, or in vessels with renal artery aneurysms

45. Angiographic Appearance – Typical Pre-Procedure Acute Post-Procedure 1 Month Follow-Up Typical appearance to expect at one month post-procedure

46. SUMMARY -TECHNIQUE OF RENAL DENERVATION- The generation 2 Symplicity catheter facilitates the procedure and increases procedure safety Better catheter navigation Less traumatic catheter tip Better vessel wall adaption of the tip Limitations: Hostile aorta Bended course of the renal artery trunk Short renal artery trunk Renal artery diameter < 4mm Atherosclerotic plaques or FMD

47. CLINICAL RESULTS 47

48. First-in-Man (AU) Series of Pilot Studi es (EU, US & AU) Series of Pilot Studi es (EU, US & AU) Symplicity HTN-2 Initial RCT (EU & AU) Symplicity HTN-2 Initial RCT (EU & AU) SYMPLICITY HTN-3 US Pivotal Trial (US) SYMPLICITY HTN-3 US Pivotal Trial (US) Global SYMPLICITY Registry (Approved Regions) Global SYMPLICITY Registry (Approved Regions) Expand HTN Indicati on (Approved Regions) Expand HTN Indicati on (Approved Regions) Post-Market Registry (US) Post-Market Registry (US) SYMPLICITY HF Symplicity HTN-1 Pilot Studies in New Indications (Approved Regions) Pilot Studies in New Indications (Approved Regions) Trials under way Comprehensive SYMPLICITY Clinical Trial Program follows over 5000 patients across multiple indications This report

49. Results Recognized for their Importance 49 Lancet. 2010. published electronically on Nov 17, 2010

50. Symplicity HTN-1 Initial Cohort – Reported in the Lancet, 2009: -First-in-man, non-randomized -Cohort of 45 patients with resistant HTN (SBP ≥160 mmHg on ≥3 anti-HTN drugs, including a diuretic; eGFR ≥ 45 mL/min) - 12-month data \ Expanded Cohort – This Report (Symplicity HTN-1): -Expanded cohort of patients (n=153) -24-month follow-up Lancet. 2009;373:1275-1281 Sievert et al. European Society of Cardiology. 2010.

51. Symplicity HTN-1: Groundbreaking series of Non-Randomised studies First in Man Cohort: 45 patients, EU, Australia Non-Randomised First patient enrolled: June, 2007 12-month initial report in The Lancet, 2009 Expanded Cohort* (this report): 153 patients, EU, Australia, USA Non-Randomised 36-month follow-up *Expanded results presented at the American College of Cardiology Annual Meeting 2012 (Krum, H.) Office SBP ≥160 mmHg Stable drug regimen of 3+ more anti-HTN medications eGFR ≥45 mL/min/1.73m 2 Key Inclusion Criteria

52. Sievert et al. European Society of Cardiology. 2010. DemographicsAge (years) 57 ± 11 Gender (% female) 39% Race (% non-Caucasian) 5% Co-morbiditiesDiabetes Mellitus II (%) 31% CAD (%) 22% Hyperlipidemia (%) 68% eGFR (mL/min/1.73m 2 ) 83 ± 20 Blood PressureBaseline BP (mmHg) 176/98 ± 17/15 Number of anti-HTN meds (mean) 5.0 ± 1.4 ACE/ARB (%) 90% Beta-blocker (%) 82% Calcium channel blocker (%) 75% Vasodilator (%) 19% Diuretic (%) 95% Spironolactone (%) 21% Baseline Patient Characteristics

53. Procedure Detail & Safety 38 minute median time from first to last ablation –Average of 4 ablations per artery Intravenous narcotics & sedatives used to manage pain during delivery of RF energy No catheter or generator malfunctions No major complications Minor complications 4/153: – 1 renal artery dissection during catheter delivery (prior to RF energy), no sequelae – 3 access site complications, treated without further sequelae Sievert et al. European Society of Cardiology. 2010.

54. Chronic Safety (Through 3-Year Follow-up) 81 patients with 6-month renal CTA, MRA, or Duplex No vascular abnormalities at any site of RF delivery One progression of a pre-existing stenosis unrelated to RF treatment (stented without further sequelae) Three deaths within the follow-up period; both unrelated to the device or therapy Two hypotensive events that required hospitalization Unrelated to device or therapy (sepsis and hypovolemia, each) No electrolyte disturbances No change in renal function (∆ eGFR) 12 Months: -2.9 mL/min/1.73m 2 (n.s.) Sievert et al. European Society of Cardiology. 2010.

55. Significant, Sustained BP Reduction BP change (mmHg) Sievert et al. European Society of Cardiology. 2010.

56. Significant, Sustained Blood Pressure Reductions to at Least 3 Years Expanded results presented at the American College of Cardiology Annual Meeting 2012 (Krum, H.) p <0.01 for  from baseline for all time points

57. Percentage Responders Increases Over Time Responder was defined as an office SBP reduction ≥10 mmHg (n=143)(n=148)(n=144) (n=130) (n=107) (n=59) (n=24) Expanded results presented at the American College of Cardiology Annual Meeting 2012 (Krum, H.)

58. Response Rate Among 1-Month Non-responders ( n=45) (n=17) *Non-responder defined as a SBP reduction of <10 mmHg ( n=44) ( n=39) ( n=8)(n=45) Expanded results presented at the American College of Cardiology Annual Meeting 2012 (Krum, H.)

59. Symplicity HTN-1: SBP Distribution Significantly Improves After Renal Denervation – Lowering Risk of CV Events Baseline (n=150) 1 year (n=132) 2 years (n=105) 3 years (n=34*) Expanded results presented at the Transcatheter Cardiovascular Therapeutics Annual Meeting 2012 (Schlaich, M.)

60. Lancet. 2010. published electronically on November 17, 2010 Symplicity HTN-2 Investigators. The Lancet. 2010. Purpose: To demonstrate the effectiveness of catheter-based renal denervation for reducing blood pressure in patients with uncontrolled hypertension in a prospective, randomized, controlled, clinical trial Patients: 106 patients randomized 1:1 to treatment with renal denervation vs. control Clinical Sites: 24 centers in Europe, Australia, & New Zealand (67% were designated hypertension centers of excellence) Symplicity HTN-2

61. Inclusion Criteria: –Office SBP ≥ 160 mmHg (≥ 150 mmHg with type II diabetes mellitus) –Stable drug regimen of 3+ more anti-HTN medications –Age 18-85 years Exclusion Criteria: –Hemodynamically or anatomically significant renal artery abnormalities or prior renal artery intervention –eGFR < 45 mL/min/1.73m 2 (MDRD formula) –Type 1 diabetes mellitus –Contraindication to MRI –Stenotic valvular heart disease for which reduction of BP would be hazardous –MI, unstable angina, or CVA in the prior 6 months Symplicity HTN-2 Investigators. The Lancet. 2010. Symplicity HTN-2

62. Assessed for Eligibility (n=190) Excluded During Screening, Prior to Randomisation (n=84)  BP < 160 at Baseline Visit (after 2-weeks of medication compliance confirmation) (n=36; 19%)  Ineligible anatomy (n=30; 16%)  Declined participation (n=10; 5%)  Other exclusion criteria discovered after consent (n=8; 4%) Randomised (n=106) Allocated to RDN n=52 Treated n=49 Analysable 6-month Pr imary End- Point Screening Allocated to Control n=54 Control n=51 Analysable 12-month Post- Randomisation 12-month post-RDN n=47 Per protocol, 6-mo Post-RDN (Crossover) n=35 Not-per-protocol*, 6- mo Post-RDN (Crossover) n=9 * Crossed-over with ineligible BP (<160 mmHg) Symplicity HTN-2: Patient disposition Crossover n=46 2 LTFU 18-month post-RDN n=43 18-mo Post-RDN (Crossover) n=31

63. RDN and Control Populations Well-matched, Severe Treatment Resistant Hypertensives RDN (n = 52) Control (n = 54) p-Value Baseline systolic BP (mmHg) 178 ± 18178 ± 16 0.97 Baseline diastolic BP (mmHg) 97 ± 1698 ± 17 0.80 Number anti-HTN medications5.2 ± 1.55.3 ± 1.80.75 Age 58 ± 12 0.97 Gender (female) (%)35%50%0.12 Race (Caucasian) (%)98%96%>0.99 BMI (kg/m 2 ) 31 ± 5 0.77 Type 2 diabetes40%28%0.22 Coronary artery disease19%7%0.09 Hypercholesterolemia52% >0.99 eGFR (MDRD, ml/min/1.73m 2 ) 77 ± 1986 ± 20 0.013 Serum creatinine (mg/dL) 1.0 ± 0.30.9 ± 0.2 0.003 Urine alb/creat ratio (mg/g) * 128 ± 363109 ± 254 0.64 Cystatin C (mg/L) † 0.9 ± 0.20.8 ± 0.2 0.16 Heart rate (bpm)75 ± 1571 ± 150.23 * n = 42 for RDN and n = 43 for Control. Wilcoxon rank-sum test for two independent samples used for between-group comparisons of UACR. † n = 39 for RDN and n = 42 for Control. Expanded results presented at the American College of Cardiology Annual Meeting 2012 (Esler, M.)

64. Primary Endpoint: 6-Month Office BP Symplicity HTN-2 Investigators. The Lancet. 2010. ∆ from Baseline to 6 Months (mmHg) 33/11 mmHg difference between RDN and Control (p<0.0001) 84% of RDN patients had ≥ 10 mmHg reduction in SBP 10% of RDN patients had no reduction in SBP Systolic Diastolic SystolicDiastolic

65. Superior to Medical Management, Reductions Sustained to 12M ∆ from Baseline to 6 Months (mmHg) Expanded results presented at the American College of Cardiology Annual Meeting 2012 (Esler, M.) RDN (n= 49) ∆ from Baseline to 12 Months (mmHg) Systolic Diastolic Latest Follow-up (12M post Randomisation) Latest Follow-up: Control crossover (n = 35): -24/-8 mmHg (Analysis on patients with SBP ≥ 160 mmHg at 6 M) p <0.01 for  from baseline Primary Endpoint: 84% of RDN patients: ≥10 mmHg reduction i n SBP 10% of RDN patients: no reduction in SBP Systolic Diastolic SystolicDiastolic Primary Endpoint (6M post Randomisation) p <0.01 for difference between RDN and Control

66. Superior to Medical Management, Reductions Sustained to 18M ∆ from Baseline to 18 Months (mmHg) Systolic Diastolic Latest Follow-up (18M post Randomisation) p <0.01 for  from baseline RDN (n=43) Primary Endpoint: 84% of RDN patients: ≥10 mmHg reduction i n SBP 10% of RDN patients: no reduction in SBP Systolic Diastolic SystolicDiastolic Primary Endpoint (6M post Randomisation) p <0.01 for difference between RDN and Control ∆ from Baseline to 6 Months (mmHg)

67. Systolic BP (mmHg) Control Group Also Benefited From RDN After Crossover Control Crossover RDN n = 49 n = 47 n = 43 n = 51 n = 37 n = 35 n = 33 n = 31 Baseline 18M Post-RDN

68. RDN GroupCrossover Group 6 Months 12 Months 18 Months 6 Months 12 Months 18 Months n = 49 n = 47 n = 43 n = 35 n = 33 n = 31 n = 43 n = 31 n = 74 18-Month BP Reduction RDN Crossover Pooled ∆ in BP from Baseline (mmHg) p <0.01 for  from baseline Sustained to 18 Months for RDN, Crossover, and Pooled Groups Systolic Diastolic

69. Medication Changes Censoring BP after medication increases: Renal Denervation  Reduction of 31/12 ± 22/11 mmHg (p<0.0001 for SBP & DBP) Control  Change of 0/-1 ± 20/10 mmHg (p=0.90 & p=0.61 for SBP & DBP, respectively) RDN (n=49) Control (n=51) P-value # Med Dose Decrease (%)10 (20%)3 (6%)0.04 # Med Dose Increase (%)4 (8%)6 (12%)0.74 Symplicity HTN-2 Investigators. The Lancet. 2010. Despite protocol guidance to maintain medications, some medication c hanges were required:

70. Office Systolic BP Distribution Symplicity HTN-2 Investigators. The Lancet. 2010.

71. BP Change (mmHg) Symplicity HTN-2 Investigators. The Lancet. 2010. Home & 24 Hour Ambulatory BP Home BP Change (mmHg) 24-h ABPM: Analysis on technically sufficient (>70% of readings) paired baseline and 6-month RDN (n=20): -11/-7 mmHg (SD 15/11; p=0.006 SBP change, p=0.014 for DBP change) Control (n=25): -3/ -1 mmHg (SD 19/12; p=0.51 for systolic, p=0.75 for diastolic) Systolic Diastolic Systolic Diastolic

72. Time Course of Office BP Change Symplicity HTN-2 Investigators. The Lancet. 2010. † p<0.0001 for between-group comparisons †† p=0.002 for between-group comparisons ††† p=0.005 for between-group comparisons Two-way repeated measures ANOVA, p=0.001 RDN ∆ from Baseline (mmHg) Control ∆ from Baseline (mmHg) † † † † †† †††

73. Procedural Safety No serious device or procedure related adverse events (n=52) Minor adverse events 1 femoral artery pseudoaneurysm treated with manual compression 1 post-procedural drop in BP resulting in a reduction in medication 1 urinary tract infection 1 prolonged hospitalization for evaluation of paraesthesias 1 back pain treated with pain medications & resolved after one month 6-month renal imaging (n=43) No vascular abnormality at any RF treatment site 1 MRA indicates possible progression of a pre-existing stenosis unrelated to RF treatment (no further therapy warranted) Symplicity HTN-2 Investigators. The Lancet. 2010.

74. Other Safety RDN (n=49) Control (n=51) Composite CV Events Hypertensive event unrelated to non-adherence to medication32 Other CV events00 Other Serious AEs Transient ischemic attack12 Hypertensive event after abruptly stopping clonidine10 Hypotensive episode resulting in reduction of medications10 Coronary stent for angina11 Temporary nausea/edema10 Symplicity HTN-2 Investigators. The Lancet. 2010.

75. Renal Function Δ Renal Function (baseline - 6M) RDN Mean ± SD (n) Control Mean ± SD (n) Difference (95% CI) p-value eGFR (MDRD) (mL/min/1.73m 2 ) 0 ± 11 (49) 1 ± 12 (51) (-5, 4) 0.76 Serum Creatinine (mg/dL) 0.0 ± 0.2 (49) 0.0 ± 0.1 (51) 0.0 (-0.1, 0.1) 0.66 Cystatin-C (mg/L) 0.1 ± 0.2 (37) 0.0 ± 0.1 (40) 0.0 (-0.0, 0.1) 0.31 Symplicity HTN-2 Investigators. The Lancet. 2010.

76. Baseline 6M post-RDN 12M post-RDN Crossover RDN eGFR (mL/min/1.73m 2 ) Stage I Stage II Stage III Stage IV ESRD Stage V n = 49 n = 35n = 49 n = 35n = 45 n = 31 Renal Function

77. Symplicity RDN Safety Record Continues to be Strong in Expanded Results Symplicity HTN-2 Investigators. The Lancet. 2010. Baseline6 month12 months eGFR (ml/min/1.73m 2 ) 76.9 ±19.3 (n= 49)77.1±18.8 (n=49)78.2±17.4 (n=45) Cystatin C (mg/L) 0.91±0.25 (n=38)0.98±0.36 (n=40)0.98±0.30 (n=38) RDN N=47 Baseline6 month12 months eGFR (ml/min/1.73m 2 ) 88.8 ± 20.7 (n = 35) 89.3±19.5 (n = 35)85.2±18.3 (n = 35) Cystatin C (mg/L) 0.78 ± 0.17 (n=27) 0.82±0.16 (n=26)0.89±0.20 (n=26) Crossover N=35 Treated at Randomisation Treated after 6-mo follow-up

78. Medication Changes at 6 and 12 Months Post-Renal Denervation RDN (n=47)6 month12 months Decrease (# Meds or Dose)20.9% (9/43)27.9% (12/43) Increase (# Meds or Dose)11.6% (5/43)18.6% (8/43) Crossover (n=35)6 months post-RDN Decrease (# Meds or Dose)18.2% (6/33) Increase (# Meds or Dose)15.2% (5/33) Physicians were allowed to make changes to medications Once the 6 month primary endpoint was reached* *Further analysis of Medications is ongoing

79. Impressive Safety Record No device-related SAEs and vascular complications No clinically significant changes to eGFR Two hypotensive events that required hospitalisation One in crossover cohort and 1 in RDN cohort Ten hypertensive events requiring hospitalisation through 18 months post RDN in combined cohort One mild transient acute renal failure Two deaths within the follow-up period All unrelated to the device or therapy

80. Lancet Conclusions Catheter-based renal denervation, done in a multicentre, randomised trial in patients with treatment-resistant essential hypertension, resulted in significant reductions in BP. The magnitude of BP reduction can be predicted to affect the development of hypertension-related diseases and mortality The technique was applied without major complications. This therapeutic innovation, based on the described neural pathophysiology of essential hypertension, affirms the crucial relevance of renal nerves in the maintenance of BP in patients with hypertension. Catheter-based renal denervation is beneficial for patients with treatment-resistant essential hypertension. Symplicity HTN-2 Investigators. The Lancet. 2010.

81. Symplicity HTN-1 Three Year and Symplicity HTN-2 One Year Summary Sustained BP Reductions to Three Years First Symplicity HTN-1 patient treated June 2007 Three year reporting shows no diminishment of effect and impressive long term safety For patients that have completed 3 year follow up, 100% have been classified as responders (>10 mmHg reduction), while at 6 months 71% of patients were classified as responders. Superior Results Confirmed in Randomised Study Symplicity HTN-2 treatment population shows sustained treatment effect at 12 month follow-up Control cross-over patients also show significant BP reduction Only the Symplicity™ renal denervation system has proven safe, superior and sustained BP reductions

82. RENAL DENERVATION & INSULIN RESISTANCE

83. Effects of Renal Denervation on Glucose Handling in Patients with Resistant HTN 25 Treatment, 11 Control Age 56.9 ± 10 years BMI 31.4 ± 5.5 kg/m² Type 2 DM on oral medication, n=15 No patients on insulin treatment Baseline BP: 178/94 ± 16/13 mmHg 5.6 ± 1.4 antihypertensive meds Mahfoud et al. European Society of Cardiology. 2010.

84. Reduction in HOMA Index at 1 & 3 Months following Renal Denervation *significant reduction (p<0.05) compared to baseline HOmeostasisModelAssessment-InsulinResistance (HOMA-IR) = (FPI x FPG)/405 Treatment Group Fasting Glucose (mg/dl) Fasting Insulin (mU/l) C-peptide (µg/l)HOMA-IR Baseline (25)118 ± 2020.7 ± 11.86.1 ± 3.66.1 ± 4.3 1 month (25)110 ± 14*12.9 ± 7.3*3.3 ± 1.5*3.5 ± 1.8* 3 months (25)106 ± 12*11.1 ± 4.8*3.1 ± 1.1*2.9 ± 1.3* Mahfoud et al. European Society of Cardiology. 2010.

85. Changes in Glucose Tolerance Testing at 3 Months following Renal Denervation Mahfoud et al. European Society of Cardiology. 2010.

86. Change in Status: Diabetes (DM)  Glucose Intolerance (GIT)  Normal Worsening of diabetic status: (normal  glucose intolerance  diabetes) - Renal Denervation: 0/25 - Control: 2/11 (18%) Improvement in diabetic status: (diabetes  glucose intolerance  normal) - Renal Denervation: 4/25 (16%) - Control: 0/11 Mahfoud et al. European Society of Cardiology. 2010.

87. Can Excessive NeuroStimulation Cause Heart Disease? Can excessive sympathetic drive contribute to –Atrial fibrillation High ventricular response to atrial fibrillation Low conversion success –Ventricular tachyarrhythmias Electrical Storm Long QT pathology Can sympathetic drive cause functional ventriular abn ormalities or systolic or diastolic function? Is sympathetic stimulation related to overall cardiovascular death?

88. Equipment and Medication Set-Up Equipment Symplicity Catheter and Generator Dispersive electrode (Ground pad) 6 French renal guide catheter (45-55cm, RDC-1 or LIMA) and introducer sheath Tuohy (RHV) Non-ionic contrast (dilute to 50:50) Heparinized saline flush bag Radiopaque ruler (optional) Key equipment and medication for procedure preparation It is important physician provides pain medication/amnesiac first, as procedure can be painful It is important physician provides pain medication/amnesiac first, as procedure can be painful Medications  Common medications to have available for procedure –Midazolam (Dormicum, Versed) or similar –Heparin –Fentanyl / Morphine or similar –Nitroglycerine –Atropine

89. Manifold Set-Up Dilute to 50:50 Monitor IA pressures via groin sheath sidearm Know the manifold set-up and contrast management needs Heparinized Saline Contrast Control Syringe Stopcock Symplicity Catheter Tuohy Side Arm Adapter (RHV) 6F RDC-1 (or LIMA)

90. Symplicity™ Renal Denervation System Low-profile, electrode tipped catheter Delivers RF energy to treatment site Proprietary RF generator –Low power –Automated –Built-in safety control algorithms Standard renal artery access technique 40 minutes from first to last RF delivery

91. Soft key label Symplicity Catheter Generator model G2 generates the radio frequency (RF) waves needed for the procedure Front Panel Power Switch Grounding Stud AC Power Connector Volume Adjust Back Panel Generator – Overview Be familiar with the front and back panels

92. Using the Generator – Basic and Advanced Settings The advanced display shows time, temperature, power and the percentage of impedance drop Basic SettingAdvanced Setting Use “soft keys” to toggle between Basic and Advanced displays Impedance is the ratio of voltage to current measured in ohms In layman’s terms: impedance measures tissue resistance Larger relative starting impedance indicates better wall contact During energy delivery, the impedance decrease correlates to tissue heating Bigger impedance drops generally indicate better energy delivery

93. Using the Generator – Important Screens View summary of last 5 treatments by using a “soft key” This screen will be displayed following routine treatments  Starting Impedance ------------  % Impedance Drop ------------  Max Temp ( C) ------------------  Max Power (Watts) ------------  End Power (Watts) ------------  Ablation Time (Sec) ----------  Check Status Messages ----- Know the commonly viewed screens °

94. The Symplicity™ Renal Denervation System A larger electrode set at a higher power may heat a larger area an d cause unwanted damage to tis sues surrounding the nerves Symplicity electrode, 8WLarger electrode, >8W The above figures are for illustrative use only and do not represent actual numerical modeling The Symplicity electrode is desi gned and matched with specific time and power outputs to optimi ze temperature and ablation of t he renal nerves ILLUSTRATIVE Use Only

95. Angiographic Appearance: TypicalPre-Procedure Acute Post-Procedure “notches” 1 Month Follow-Up

96.  Medications  amlodipine 10mg / olmesartan 40mg / nebivolol 5mg / indapamide 1.5mg  160/95 mmHg (for 6 months)  F/U; 2 weeks after RDN  147/87mmHg at office  D/C amlodipine  much improved subjective symptoms CASE 1 3/304/257/2710/26

97.  Medications  amlodipine 5mg / losartan 100mg / carvedilol 25mg / indapamide 1.5mg  160/90 mmHg (for 6 months)  F/U; 1 month after RDN  116/73mmHg at home  154/87mmHg at office  D/C amlodipine CASE 2 3/145/148/1310/1512/03

98.  Medications  nifedipine 60mg / hydrochlorthiazide 25mg / perindopril 8mg / nebivolol 2.5mg / doxazosin 2mg  165/85 mmHg (for 7 months)  F/U; 2 weeks after RDN  admission due to suicide (drug intoxication)  same medication  normal BP CASE 3 3/155/307/229/25

99.  Medications  tenormin 50mg / amlodipine 10mg / olmesartan 40mg  160/100 mmHg (6 months)  F/U; 1 month after RDN  normal BP at home  160/90mmHg at office  same medications CASE 4 5/2 7/5 1/23 10/24

100.  Medications  amlodipine 5mg qd / omesartan 20mg qd / indapamide 1.5mg qd / concor 5mg qd  193/126 mmHg (for 1months)  F/U; 2wks after RDN  141/77mmHg at office  same medications CASE 5 6/46/259/24

101.  Medications  nisoldipine 20mg bid / indapamide 1.5mg qd / diovan 80mg bid / bisoprolol 5mg bid  169/95 mmHg (for 2yrs)  F/U; 1 month after RDN  occasionally high BP at home  138/84mmHg at office  D/C nisodipine CASE 6 3/266/137/511/142/20

102.  Medications  Amlodipine 10mg / olmesartan 40mg / nebivolol 5mg / indapamide 1.5mg  160/95 mmHg (for 6 months)  F/U; 2 weeks after RDN  147/87mmHg at office  D/C amlodipine  much improved subjective symptoms CASE 1

103.  Medications  amlodipine 5mg / losartan 100mg / carvedilol 25mg / indapamide 1.5mg  160/90 mmHg (for 6 months)  F/U; 1 month after RDN  116/73mmHg at home  154/87mmHg at office  D/C amlodipine CASE 2

104.  Medications  Nifedipine 60mg / hydrochlorthiazide 25mg / perindopril 8mg / nebivolol 2.5mg / doxazosin 2mg  165/85 mmHg (for 7 months)  F/U; 2 weeks after RDN  admission due to suicide (drug intoxication)  same medication  normal BP CASE 3

105.  Medications  Tenormin 50mg / amlodipine 10mg / olmesartan 40mg  160/100 mmHg (6 months)  F/U; 1 month after RDN  normal BP at home  160/90mmHg at office  same medications CASE 4

106.  Medications  Amlodipine 5mg qd / omesartan 20mg qd / indapamide 1.5mg qd / concor 5mg qd  193/126 mmHg (for 1months)  F/U; 2wks after RDN  141/77mmHg at office  same medications CASE 5

107.  Medications  Nisodipine 20mg bid / indapamide 1.5mg qd / diovan 80mg bid / bisoprolol 5mg bid  169/95 mmHg (for 2yrs)  F/U; 1 month after RDN  Occasionally high BP at home  138/84mmHg at office  D/C nisoldipine CASE 6

108.  Renal Sympathetic Nerve Denervation 1.Safe and effective in resistant hypertension treatment. 2.In the future, will be a promising interventional procedure for other territories with hypertension or for diseases with over-drive sympathetic activity.Conclusion