1. RDN for hypertension: Physiological rationale Dr.C.Venkata S.Ram

2. Prevalence Map of Raised Lesions of Right Coronary Artery by Age and Hypertension NormotensiveHypertensiveAge 15-24 25 - 34 0-2 2-4 4-6 6-8 8-10 10+ n=1067n=185 n=1134n=233 Dr.C.Venkata S.Ram

3. TEXAS BLOOD PRESSURE INSTITUTE CVD Risk Is High In RH (Redon HTN 1998;31:712) 86 Pts, 49 Months f/u CV Events = 24.6% CV Events/100 pt years 2.2 9.5 13.6 Low Tertile ADBP IntHigh Dr.C.Venkata S.Ram

4. HYPERTENSION – WHY INTERVENTIONAL THERAPIES ? Chronic condition Asymptomatic Complications → serious Poor compliance Adverse effects: * Diuretics * β – blockers * CCBs * RAAS blockers * Central α-agonists * Hydralazine * Minoxidil Cumulative costs Drug-drug interactions Intercurrent problems Dr.C.Venkata S.Ram

5. Sympathetic Nervous System and Adrenergic Excess The autonomic nervous system and its sympathetic arm play an important role in the regulation of BP Short term regulation of BP especially in responses to transient changes in arterial BP via baroreflex mechanisms is well known Role of SNS in longer term BP regulation has been debated for many years Dr.C.Venkata S.Ram

6. 6 vagal efferents sympathetic efferents NE Ach EPI Stress Renal afferents Chemoreceptors Cardiac afferents NTS Baroreceptors Ang II renin NE Dr.C.Venkata S.Ram

7. 7 Grassi G et al., Hypertension 50:537, 2007 White Coat & Masked HTN MSNA, b / 100hb Dr.C.Venkata S.Ram

10. Consequences of SNS Activation Mancia, G: http://www.sns-web.org/pdf/slideset_07.pdf Dr.C.Venkata S.Ram

11. “RAUWOLFIA SERPENTINA TREATMENT OF HIGH BLOOD PRESSURE” BY RUSTOM JAL VAKIL ACTA MEDICA SCANDINAVICA 1955;152:107-114 Dr.C.Venkata S.Ram

12. Am J Surg 75:48-68, 1948 Long Term Effect of Renal Denervation in Human Hypertension Dr.C.Venkata S.Ram

13. one nerve fiber contacting multiple effectors Juxtaglomerular granular cell: renin Am J Physiol 279:R1517-1524, 2000  Renin secretion rate  1 - adrenoceptor  Tubular sodium reabsorption  1B - adrenoceptor  Renal blood flow  1A - adrenocepto r  RSNA DiBona GF, Kopp UC. Physiol Rev 77:75-197, 1997 Effects of Renal Sympathetic Nerve Activity on Renal Function Dr.C.Venkata S.Ram

15. Overactive SNS is Driver for Resistant HTN 10.20.2013TZeller @ TCT2013 15 G. Sangiorgi et al., TCT 2012 Significantly more nerves in hypertensive patients nerves Dr.C.Venkata S.Ram

16. Renal Denervation by RF Ablation Related Changes in Underlying Physiology Office BP Renal NE spillover - left kidney - right kidney Total body NE spillover Plasma Renin Renal Plasma flow (mmHg) (ng/min) (µg/l/hr) (ml/min) Baseline 161/107 72 79 600 0.3 719 1 mo 141/90 37 20 348 0.15 1126 ∆ -48% -75% -42% -50% 57% LV Mass (cMRI) dropped 7% (from 78.8 to 73.1 g/m 2 ) from baseline to 12 months Schlaich et al. NEJM. 2009; 36(9): 932-934. 17 Dr.C.Venkata S.Ram

17. For distribution only in markets where the Symplicity TM renal denervation system is approved. Symplicity is a trademark of Medtronic, Inc. and is registered in one or more countries of the world. Not for distribution in the USA or Japan. © 2012 Medtronic, Inc. All rights reserved. MKG025 3/12 Renal Denervation Preclinical Efficacy and Safety Extensive research in >300 swine Effectiveness: –Statistically significant reduction in renal tissue NE Safety: –Verification testing included angiography, gross pathology, histopathology, & clinical pathology at 7, 30, 60, and 180 days –Intact endothelium by 7 days –Vascular healing observed at 30 and 60 days; by 180 days, arteries were well healed (no inflammatory cells) – treatment sites were considered sterile and stable –No stenosis or luminal reduction seen in any treated artery through 180 days Renal Tissue NE (pg/mg) P<0.0001 P=1.0 Data on file. Medtronic, Inc. Dr.C.Venkata S.Ram

18. Am J Physiol 238: R353-R358, 1980 Renal NE Concentration After Renal DNX Residual renal NE concentration 29% of control at 24-32 days after DNX Dr.C.Venkata S.Ram

19. Renal DNX : prevents reflex induced renin secretion Am J Physiol 232:H500-H507, 1977 Dr.C.Venkata S.Ram

20.  Innervated  Denervated J Appl Physiol 33: 649-655, 1972 Renal DNX : decreases renal renin content Dr.C.Venkata S.Ram

21. Assessing Sympathetic Activation Muscle Sympathetic Nerve Activity (MSNA) Emma Hart Julian Paton Dr.C.Venkata S.Ram

22. Schlaich et al. NEJM 2009;36:932-934 Baseline12 M FU30 days FU ECG BP MSNA 56 bursts/min41 bursts/min 19 bursts/min Ablation of Renal Afferent Nerves: effect on muscle sympathetic nerve activity in a patient with Resistant hypertension Dr.C.Venkata S.Ram

23. Targeting Renal Nerves Nerves arise from T10-L2 The nerves arborize around the artery and primarily lie within the adventitia Vessel Lumen Media Adventitia Renal Nerves Dr.C.Venkata S.Ram

24. Catheter-based RDN Therapy: Ardian and more 10.20.2013TZeller @ TCT2013 Slide 24 COV: One Shot STJ: EnligHTN RECOR BSX: Vessix KONA and more… Dr.C.Venkata S.Ram

25. The Landmark Trial: Symplicity HTN-1 M. Schlaich TCT 2012 10.20.2013TZeller @ TCT2013 Slide 25 Reduction in Office BP is significant and sustained over 3 year follow up Dr.C.Venkata S.Ram

26. Porcine Histology at 7 and 90 days TZeller @ TCT2013 7-days: Circumferential nerve damage with minimal effect on artery; Less injury with NW 2013 formulation 90-days: Nerves covered in fibrous connective tissue; arteries look healthy 7 DAYS 90 DAYS Slide 26 10.20.2013 Dr.C.Venkata S.Ram