stefan bertog, laura vaskelyte, ilona hofmann, sameer gafoor, simon lam, horst sievert...

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

Horst SievertHorst SievertCardioVascular Center FrankfurtCardioVascular Center Frankfurt

CSI-TRENDS Taipei 2013

The Importance of the Sympathetic Nervous The Importance of the Sympathetic Nervous System in Hypertension: Human data Including System in Hypertension: Human data Including

early Human Experience with renal early Human Experience with renal Denervation (MSNA, NE spillover, renin etc.)Denervation (MSNA, NE spillover, renin etc.)

No disclosures relevant No disclosures relevant to this topicto this topic

Renal denervationRenal denervation• We now understand:We now understand:

- Basic anatomy and physiology of the renal Basic anatomy and physiology of the renal sympathetic nervous systemsympathetic nervous system

- That interruption of the renal sympathetic That interruption of the renal sympathetic nervous system (efferent and/or afferent) in nervous system (efferent and/or afferent) in an an animal model animal model of sympathetic of sympathetic overactivity may prevent hypertensionoveractivity may prevent hypertension

Sympathetic Sympathetic nervous system activitynervous system activity

• How do we measure sympathetic How do we measure sympathetic nervous system activity in nervous system activity in humanshumans??

• Is the sympathetic nervous system Is the sympathetic nervous system activity activity higherhigher in hypertensive in hypertensive individuals?individuals?

• What happens after renal denervation?What happens after renal denervation?


• How do we measure it in humans?How do we measure it in humans?- Urinary and plasma cathecholaminesUrinary and plasma cathecholamines- Muscle sympathetic nervous system Muscle sympathetic nervous system

activity (MSNA)activity (MSNA)- Norepinephrine spillover measurementNorepinephrine spillover measurement

• Total bodyTotal body• Organ specificOrgan specific

UrinaryUrinary cathecholaminescathecholamines

• Problems with urinary cathecholaminesProblems with urinary cathecholamines- Provides only a “static picture” Provides only a “static picture” of of

sympathetic function and is too sluggish to sympathetic function and is too sluggish to detect momentary changesdetect momentary changes

- Subject to variabilities in cathecholamine Subject to variabilities in cathecholamine metabolism and clearance metabolism and clearance (e.g. renal (e.g. renal function determines clearance)function determines clearance)

Plasma NorepinephrinePlasma Norepinephrine

• Physiological conditions Physiological conditions of increased of increased sympathetic nervous system activity are sympathetic nervous system activity are accompanied by increased plasma NEaccompanied by increased plasma NE

• However, it has However, it has limited sensitivity to limited sensitivity to detect increased sympathetic drivedetect increased sympathetic drive- Depends on Depends on secretion, metabolism and secretion, metabolism and

reuptakereuptake- Circulating NE accounts for only 5-10% of NE Circulating NE accounts for only 5-10% of NE

secreted from the nerve terminalsecreted from the nerve terminal


• How do we measure it in humans?How do we measure it in humans?- Urinary and plasma cathecholaminesUrinary and plasma cathecholamines- Muscle sympathetic nervous system Muscle sympathetic nervous system

activity (MSNA, microneurography)activity (MSNA, microneurography)- Norepinephrine spillover measurementNorepinephrine spillover measurement



• How do we measure it in humans?How do we measure it in humans?- Muscle sympathetic nervous system Muscle sympathetic nervous system



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

Renal denervationRenal denervation• Human experienceHuman experience

- Proof of principle dataProof of principle data• How do we measure overall and renal sympathetic How do we measure overall and renal sympathetic

nervous system activity?nervous system activity?- Microneurography*Microneurography*

• The only available The only available directdirect method to measure sympathetic nervous method to measure sympathetic nervous activity in humansactivity in humans

• Hair thin tungsten electrode is positioned in close proximity to a Hair thin tungsten electrode is positioned in close proximity to a bundle of unmyelinated sympathetic fibers within a superficial bundle of unmyelinated sympathetic fibers within a superficial nerve (e.g. peroneal, median or radial nerve)nerve (e.g. peroneal, median or radial nerve)

• Signal Signal frequencyfrequency and and amplitudeamplitude correlate with sympathetic fiber correlate with sympathetic fiber activityactivity

• Cannot be used to measure the sympathetic activity to internal Cannot be used to measure the sympathetic activity to internal organsorgans

*Hagbartt, Vallbo Acta Physiol Scand 1968; 74: 96-108*Hagbartt, Vallbo Acta Physiol Scand 1968; 74: 96-108

Mano et al. Clinical Neurophysiology 2006; 17(11): 2357-84Mano et al. Clinical Neurophysiology 2006; 17(11): 2357-84


• How do we measure it in humans?How do we measure it in humans?- Muscle sympathetic nervous system Muscle sympathetic nervous system




- Proof of principle dataProof of principle data• How do we measure overall sympathetic nervous How do we measure overall sympathetic nervous

system activity and renal sympathetic nervous system activity and renal sympathetic nervous activity?activity?

- Norepinephrine (NE) spillover Norepinephrine (NE) spillover ((Esler at al. Clin Exp Hypertens A 1984;6:507-21 -H2158, 2004)Esler at al. Clin Exp Hypertens A 1984;6:507-21 -H2158, 2004)

• IndirectlyIndirectly measures organ specific sympathetic activity measures organ specific sympathetic activity• NE released at the nerve ending of a specific organ is measuredNE released at the nerve ending of a specific organ is measured

Wendell S. Akers and Lisa A. Cassis Wendell S. Akers and Lisa A. Cassis Am J Physiol Heart Circ Physiol Am J Physiol Heart Circ Physiol 286:H2151-H2158, 2004286:H2151-H2158, 2004

NE spilloverNE spillover• This method assumes that there is This method assumes that there is

insignificant NE recycling within the insignificant NE recycling within the neuron neuron

• Metabolism by O-Methylation in non-Metabolism by O-Methylation in non-neuronal cells is not taken into accountneuronal cells is not taken into account

• Diffusion rates (that are dependent on Diffusion rates (that are dependent on regional blood flow) are not taken into regional blood flow) are not taken into accountaccount

α 2

β 1 β 2

AT 1 U 1

((Esler at al. Clin Exp Hypertens A 1984;6:507-21 -H2158, 2004)Esler at al. Clin Exp Hypertens A 1984;6:507-21 -H2158, 2004)

([venous NE] – [arterial NE]) X Renal plasma flow([venous NE] – [arterial NE]) X Renal plasma flow

NE spillover = NE spillover =

FE NE X [arterial NE] X Renal plasma flowFE NE X [arterial NE] X Renal plasma flow0.5

+

α 2

β 1 β 2

AT 1 U 1

((Esler at al. Clin Exp Hypertens A 1984;6:507-21 -H2158, 2004)Esler at al. Clin Exp Hypertens A 1984;6:507-21 -H2158, 2004)

([venous NE] – [arterial NE]) X Renal plasma flow([venous NE] – [arterial NE]) X Renal plasma flow

NE spillover = NE spillover =

FE NE X [arterial NE] X Renal plasma flowFE NE X [arterial NE] X Renal plasma flow

+

MSNA in essential HTNMSNA in essential HTN

Schlaich et al. Schlaich et al. Hypertension 2004;43:169–175Hypertension 2004;43:169–175

NE spillover inNE spillover in

normotensive (NT)normotensive (NT)

andand

hypertensive (ET)hypertensive (ET)

individualsindividuals

Schlaich et al. HypertensionSchlaich et al. Hypertension 2004 Feb;43(2):169-75. Epub 2003 Nov 10. 2004 Feb;43(2):169-75. Epub 2003 Nov 10.

Renal denervationRenal denervation• Catheter-based human experienceCatheter-based human experience

- Proof of concept dataProof of concept data

10 cases10 cases

Esler et al. J Htn. 2009;27(suppl 4):s167.Esler et al. J Htn. 2009;27(suppl 4):s167.

Schlaich et al. J Htn. 2009;27(suppl 4):s154.Schlaich et al. J Htn. 2009;27(suppl 4):s154.

• Mean total renal norepinephrine spillover ↓ 47%Mean total renal norepinephrine spillover ↓ 47%

• p=0.023 (95% CI: 28–65%)p=0.023 (95% CI: 28–65%)

• Mean total body NE spillover ↓ 28%Mean total body NE spillover ↓ 28%

• p=0.043 (95% CI: 4–52%)p=0.043 (95% CI: 4–52%)


- Proof of concept dataProof of concept data• MicroneurographyMicroneurography

Schlaich MP, Sobotka PA, Krum H, Lambert E, Esler MD. NEJM. 2009; 36(9): 932-934. Schlaich MP, Sobotka PA, Krum H, Lambert E, Esler MD. NEJM. 2009; 36(9): 932-934.

Baseline 30 D 12 Mo

ConclusionConclusionSympathetic nervous system activity is Sympathetic nervous system activity is currently best measured by MSNA and currently best measured by MSNA and spillover methodsspillover methods

Renal sympathetic nervous system activity is Renal sympathetic nervous system activity is increased in essential hypertensionincreased in essential hypertension

Catheter-based renal sympathetic Catheter-based renal sympathetic denervation causes a reduction in denervation causes a reduction in sympathetic nervous system activitysympathetic nervous system activity

stefan bertog, laura vaskelyte, ilona hofmann, sameer gafoor, simon lam, horst sievert...

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