CardioVascular Center Frankfurt 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

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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

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?

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

Urinary cathecholamines 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)

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 Plamsa norepinephrine does not allow distinction between secretion and clearance Does not allow regional SNS acivity measurement

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

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

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

Renal denervation Human experience Proof of principle data How do we measure overall and renal sympathetic nervous system activity? Microneurography* The only available direct method to measure sympathetic nervous activity in humans Hair thin tungsten electrode is positioned in close proximity to a bundle of unmyelinated sympathetic fibers within a superficial nerve (e.g. peroneal, median or radial nerve) Signal frequency and amplitude correlate with sympathetic fiber activity Cannot be used to measure the sympathetic activity to internal organs These are fibres that supply the muslce vasculature. There are single and multiple nerve fibre recordings. Generally, they correlate, but there is variability in multifibre recording depending on the location of the electrode with respect to the fibre. These variations are not problamatic in single fibre recordings. The procedure can cause mild local paraesthesias (in 10% of patients) which generallyy resolve within a few days *Hagbartt, Vallbo Acta Physiol Scand 1968; 74: 96-108 Mano et al. Clinical Neurophysiology 2006; 17(11): 2357-84

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

Renal denervation Human experience Proof of principle data How do we measure overall sympathetic nervous system activity and renal sympathetic nervous activity? Norepinephrine (NE) spillover (Esler at al. Clin Exp Hypertens A 1984;6:507-21 -H2158, 2004) Indirectly measures organ specific sympathetic activity NE released at the nerve ending of a specific organ is measured Wendell S. Akers and Lisa A. Cassis Am J Physiol Heart Circ Physiol 286:H2151-H2158, 2004

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 Tricyclic antidepressants which inhibit reuptake can be used to minimize recycling

NE spillover = ([venous NE] – [arterial NE]) X Renal plasma flow + AT 1 U 1 α 2 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)

NE spillover = ([venous NE] – [arterial NE]) X Renal plasma flow + AT 1 U 1 α 2 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)

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?

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

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

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?

Renal denervation Catheter-based human experience 10 cases 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.

Renal denervation Human experience Proof of concept data Microneurography Strokes are the leading cause of disability in the world today as well as the third leading cause of death. Current estimates suggest a stroke incidence of 780 000 annually in the US. Baseline 30 D 12 Mo Schlaich MP, Sobotka PA, Krum H, Lambert E, Esler MD. NEJM. 2009; 36(9): 932-934.

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