0. 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

1. No disclosures relevant to this topic

2. 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

3. 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?

4. 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

5. 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)

6. 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

7. 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

8. 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

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

10. 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:
Mano et al. Clinical Neurophysiology 2006; 17(11):

11. 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

12. 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: 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

13. 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

14. 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: H2158, 2004)

15. 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: H2158, 2004)

16. 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?

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

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

19. 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?

20. 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.

21. 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 annually in the US.
Baseline
30 D
12 Mo
Schlaich MP, Sobotka PA, Krum H, Lambert E, Esler MD. NEJM. 2009; 36(9):

22. 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