Stefan Bertog, Laura Vaskelyte, Ilona Hofmann, Sameer Gafoor, Simon Lam, Horst Sievert

1. CSI-TRENDS Taipei 2013 The Importance of the Sympathetic Nervous System in Hypertension: Human data Including early Human Experience with renal Denervation (MSNA, NE spillover, renin etc.) Stefan Bertog, Laura Vaskelyte, Ilona Hofmann, Sameer Gafoor, Simon Lam, Horst Sievert CardioVascular Center Frankfurt

2. No disclosures relevant to this topic

3. Renal denervation • We now understand: • Basic anatomy and physiology of the renal sympathetic nervous system • That interruption of the renal sympathetic nervous system (efferent and/or afferent) in an animal model of sympathetic overactivity may prevent hypertension

4. Sympathetic nervous system activity • How do we measure sympathetic nervous system activity in humans? • Is the sympathetic nervous system activity higher in hypertensive individuals? • What happens after renal denervation?

5. Sympathetic nervous system activity • How do we measure it in humans? • Urinary and plasma cathecholamines • Muscle sympathetic nervous system activity (MSNA) • Norepinephrine spillover measurement • Total body • Organ specific

6. Urinarycathecholamines • Problems with urinary cathecholamines • Provides only a “static picture”of sympathetic function and is too sluggish to detect momentary changes • Subject to variabilities in cathecholamine metabolism and clearance (e.g. renal function determines clearance)

7. Plasma Norepinephrine • Physiological conditions of increased sympathetic nervous system activity are accompanied by increased plasma NE • However, it has limited sensitivity to detect increased sympathetic drive • Depends on secretion, metabolism and reuptake • Circulating NE accounts for only 5-10% of NE secreted from the nerve terminal

8. Sympathetic nervous system activity • How do we measure it in humans? • Urinary and plasma cathecholamines • Muscle sympathetic nervous system activity (MSNA, microneurography) • Norepinephrine spillover measurement • Total body • Organ specific

9. Sympathetic nervous system activity • How do we measure it in humans? • Muscle sympathetic nervous system activity (MSNA, microneurography) • Norepinephrine spillover measurement • Total body • Organ specific

10. Guyunet. Nature reviews. Neuroscience 2006 vol:7 iss:5 pg:335 -346

11. Renal denervation • Human experience • Proofofprincipledata • How do wemeasureoverall and renal sympatheticnervoussystemactivity? • Microneurography* • The onlyavailabledirectmethodtomeasuresympatheticnervousactivity in humans • Hair thintungstenelectrodeispositioned in closeproximityto a bundleofunmyelinatedsympatheticfiberswithin a superficial nerve (e.g. peroneal, median or radial nerve) • Signal frequency and amplitudecorrelatewithsympatheticfiberactivity • Cannotbeusedtomeasurethesympatheticactivitytointernalorgans *Hagbartt, Vallbo Acta Physiol Scand 1968; 74: 96-108 Mano et al. Clinical Neurophysiology 2006; 17(11): 2357-84

12. Sympathetic nervous system activity • How do we measure it in humans? • Muscle sympathetic nervous system activity (MSNA, microneurography) • Norepinephrine spillover measurement • Total body • Organ specific

13. Renal denervation • Human experience • Proofofprincipledata • How do wemeasureoverallsympatheticnervoussystemactivity and renal sympatheticnervousactivity? • Norepinephrine (NE) spillover(Eslerat al. ClinExpHypertens A 1984;6:507-21 -H2158, 2004) • Indirectlymeasuresorganspecificsympatheticactivity • NE releasedatthe nerve endingof a specificorganismeasured Wendell S. Akers and Lisa A. Cassis Am J Physiol Heart Circ Physiol 286:H2151-H2158, 2004

14. NE spillover • This method assumes that there is insignificant NE recycling within the neuron • Metabolism by O-Methylation in non-neuronal cells is not taken into account • Diffusion rates (that are dependent on regional blood flow) are not taken into account

15. NE spillover = ([venous NE] – [arterial NE]) X Renal plasma flow U 1 α 2 AT 1 FE NE X [arterial NE] X Renal plasma flow + 0.5 β 1 β 2 • (Esler at al. Clin Exp Hypertens A 1984;6:507-21 -H2158, 2004)

16. NE spillover = ([venous NE] – [arterial NE]) X Renal plasma flow U 1 α 2 AT 1 FE NE X [arterial NE] X Renal plasma flow + β 1 β 2 • (Esler at al. Clin Exp Hypertens A 1984;6:507-21 -H2158, 2004)

17. Sympathetic nervous system activity • How do we measure sympathetic nervous system activity in humans? • Is the sympathetic nervous system activity higher in hypertensive individuals? • What happens after renal denervation?

18. MSNA in essential HTN Schlaich et al. Hypertension 2004;43:169–175

19. NE spillover in normotensive (NT) and hypertensive (ET) individuals Schlaich et al. Hypertension 2004 Feb;43(2):169-75. Epub 2003 Nov 10.

20. Sympathetic nervous system activity • How do we measure sympathetic nervous system activity in humans? • Is the sympathetic nervous system activity higher in hypertensive individuals? • What happens after renal denervation?

21. Renal denervation • Catheter-based human experience • Proof of concept data 10 cases • 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%) Esler et al. J Htn. 2009;27(suppl 4):s167. Schlaich et al. J Htn. 2009;27(suppl 4):s154.

22. Renal denervation • Human experience • Proof of concept data • Microneurography Baseline 30 D 12 Mo Schlaich MP, Sobotka PA, Krum H, Lambert E, Esler MD. NEJM. 2009; 36(9): 932-934.

23. Conclusion Sympathetic nervous system activity is currently best measured by MSNA and spillover methods Renal sympathetic nervous system activity is increased in essential hypertension Catheter-based renal sympathetic denervation causes a reduction in sympathetic nervous system activity