RDN for hypertension: Physiological rationale

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

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

3. 86 Pts, 49 Months f/u CV Events = 24.6% 13.6 9.5 CV Events/100 pt years 2.2 Low Tertile ADBP Int High TEXAS BLOOD PRESSURE INSTITUTE CVD Risk Is High In RH (Redon HTN 1998;31:712) 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 andAdrenergic 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. Ang II Chemoreceptors renin Renal afferents Stress NTS vagal efferents Baroreceptors Ach NE Cardiac afferents NE EPI NE sympathetic efferents Dr.C.Venkata S.Ram

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

8. Evidence for Sympathetic Activation in “Essential” Hypertension Dr.C.Venkata S.Ram

9. Sympathectomy (Denervation) and Vascular Morphology Dr.C.Venkata S.Ram

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

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

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

14. Dr.C.Venkata S.Ram

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

16. Renal Denervation by RF Ablation Related Changes in Underlying Physiology Baseline 161/107 72 79 600 0.3 719 1mo 141/90 37 20 348 0.15 1126 ∆ -48% -75% -42% -50% 57% OfficeBP RenalNEspillover -leftkidney -rightkidney TotalbodyNEspillover PlasmaRenin RenalPlasmaflow (mmHg) (ng/min) (ng/min) (µg/l/hr) (ml/min) LVMass(cMRI)dropped7%(from78.8to73.1g/m2)frombaselineto12months Schlaichetal.NEJM.2009;36(9):932-934. Dr.C.Venkata S.Ram 17

17. Renal Denervation Preclinical Efficacy and Safety P<0.0001 • 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 P=1.0 Renal Tissue NE (pg/mg) Data on file. Medtronic, Inc. Dr.C.Venkata S.Ram

18. Renal NE Concentration After Renal DNX Residual renal NE concentration 29% of control at 24-32 days after DNX Am J Physiol 238: R353-R358, 1980 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. Renal DNX : decreases renal renin content • Innervated •  Denervated J Appl Physiol 33: 649-655, 1972 Dr.C.Venkata S.Ram

21. Assessing Sympathetic Activation  Muscle Sympathetic Nerve Activity (MSNA) EmmaHart JulianPaton Dr.C.Venkata S.Ram

22. Ablation of Renal Afferent Nerves: effect onmuscle sympathetic nerve activity in a patient with Resistant hypertension Baseline 30 days FU 12 M FU ECG BP MSNA 56 bursts/min 41 bursts/min 19 bursts/min Schlaich et al. NEJM 2009;36:932-934 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 COV: One Shot STJ: EnligHTN RECOR BSX: Vessix KONA and more… TZeller @ TCT2013 Dr.C.Venkata S.Ram

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

26. Porcine Histology at 7 and 90 days • 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 TZeller @ TCT2013 Dr.C.Venkata S.Ram

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