Autonomic Neuroscience from Bench to Bedside

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Autonomic Neuroscience from Bench to Bedside

• Ann Arbor
• May 14, 2004

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Mentoring Advice

• Become a skilled clinician
• Use the best methodology
• Know everything about something
• Work hard
• John B. Youmans, John A. Oates and Victor A.
  McKusick

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How Dysautonomias Teach Us
Amplification of Signal
Phenomena
Unique Pathophysiologic Models afferent lesion
(BF) efferent lesion (AF) central lesion
(MSA/SDS) gene-specific disorders
Mechanisms
Top 7 Lessons A Personal Perspective
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Cardiovascular Continuum
LBP
POTS
Normotension
Labile HBP
HBP
NMS
Bradycardia/hypotension 500,000 Americans
Orthostatic tachycardia
500,000 Americans
Orthostatic hypotension
100,000 Americans
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Top 7 Lessons From Dysautonomias

• You can live without norepinephrine (NE)
• Dopamine can be important in BP control
• Baroreflex failure (BF) can present as Pheo
• BF can present as malignant vagotonia
• Food and water powerfully affect BP
• Orthostatic tachycardia (POTS) is common
• Too much NE can be bad for you

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DBH Deficiency

• Severe orthostatic hypotension
• Ptosis of the eyelids
• Complicated perinatal course
• Shock
• Hypoglycemia
• Hypothermia
• Nasal stuffiness
• Retrograde ejaculation

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Are pressor reflexes intact ?
mm Hg
Noradrenergic system is nonfunctional
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Are Adrenergic Receptors Present?(Phenylephrine)
Adrenergic receptors are functional
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Are Sympathetic Nerves Present?
bursts/min
Noradrenergic nerves are electrically active
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Is Plasma Norepinephrine Present?
pg/ml
No Norepinephrine
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Catecholamine Synthesis
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Is Plasma Dopamine Present?
pg/ml
Dopamine is greatly increased
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Plasma DA gtgt NE
pg/ml
DA replacing NE ?
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Catecholamine Synthesis
DBH
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DBH Deficiency Genetics

• IVS12TgtC is causative in both patients.
• Missense mutation in exon 2.
• Missense mutations in exons 1 and 6.

Kim K-S, Am J Hum Gen 2002 108 140
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Effect of the mutation IVS12T on DBH splicing
Exon1
Exon2
Exon3
Exon4
A
Normal
CMV promoter
Mutant
B
Mutant
Normal
Exon1
Exon2
1,018
Exon 1
Intron 1
Exon 2
GACACTGCCTATTTTGCG gcgagt-108bp-gtttga-380bp-agca
g GACGCCTGGAGTGACCAG D T A Y F A A S
------- V stop
517
396
298
Exon1
Exon2
220
Exon 1
Exon 2
...GACACTGCCTATTTTGCG GACGCCTGGAGTGACCAG... D
T A Y F A D A W S D Q
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D?H-Deficiency
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DOPS Therapy
DOPS
DOPS
DOPS
NE
NE
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DOPS Restores NE to Normal
pg/ml or seconds
Norepinephrine-COOH
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Catechols in DBH Deficiency

• Normal cognitive and psychiatric faculties
• Completely absent in blood, CSF, urine
• Norepinephrine
• Epinephrine
• Normetanephrine
• Metanephrine
• DHPG
• VMA

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Top 7 Lessons From Dysautonomias

• You can live without norepinephrine (NE)
• Dopamine can be important in BP control
• Baroreflex failure (BF) can present as Pheo
• BF can present as malignant vagotonia
• Food and water powerfully affect BP
• Orthostatic tachycardia (POTS) is common
• Too much NE can be bad for you

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• Why is BP low in DBH Deficiency ?
• because NE is absent ?
• or because DA is raised ?
• ..Otto Kuchel, Montreal

Metyrosine blocks tyrosine hydroxylase causing
hypotension by lowering NE
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The TH-antagonist metyrosine lowers DA and raises
BP
pg/ml or mm Hg
Weight rose 1 kg DA was an endogenous diuretic
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Top 7 Lessons From Dysautonomias

• You can live without norepinephrine (NE)
• Dopamine can be important in BP control
• Baroreflex failure (BF) can present as Pheo
• BF can present as malignant vagotonia
• Food and water powerfully affect BP
• Orthostatic tachycardia (POTS) is common
• Too much NE can be bad for you

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Normal Baroreflex
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Baroreflex Failure
Resting quietly
Excitation
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Top 7 Lessons From Dysautonomias

• You can live without norepinephrine (NE)
• Dopamine can be important in BP control
• Baroreflex failure (BF) can present as Pheo
• BF can present as malignant vagotonia
• Food and water powerfully affect BP
• Orthostatic tachycardia (POTS) is common
• Too much NE can be bad for you

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Selective Baroreflex Failure
Excitation
Resting Quietly
Jens Jordan et al, Hypertension 1997301072
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Top 7 Lessons From Dysautonomias

• You can live without norepinephrine (NE)
• Dopamine can be important in BP control
• Baroreflex failure (BF) can present as Pheo
• BF can present as malignant vagotonia
• Food and water powerfully affect BP
• Orthostatic tachycardia (POTS) is common
• Too much NE can be bad for you

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Water and BP in Autonomic Failure
Jens Jordan et al. Circulation 2000101504
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Effect of Nn-Nicotinic Blockade (Trimethaphan) on
Waters Pressor Action
mmHg
Autonomic Function Necessary for Pressor Action
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500 ml Oral vs Intravenous Fluid
mmHg
The oral route is key to waters pressor effect
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Does Oral Water Suppress Sympathetic Activity
bursts/min
Water increases sympathetic activity
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Water and BP Many questions

• Pressor when baroreflex fails
• Must be oral for effect
• Causes increased sympathetic activity

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Water in normal subjects

• Water raises BP 11 mmHg in older normal
  subjects

Is water ingestion a source of noise in clinic
BP determinations?
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Water Improves Tolerance of Head-Up Tilt
1.0
0.8
Cumulative Survival of Tilt Testing
Water
0.6
P 0.007
No Water
0.4
50
40
30
20
10
0
n22 normal subjects
Time (min)
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Top 7 Lessons From Dysautonomias

• You can live without norepinephrine (NE)
• Dopamine can be important in BP control
• Baroreflex failure (BF) can present as Pheo
• BF can present as malignant vagotonia
• Food and water powerfully affect BP
• Orthostatic tachycardia (POTS) is common
• Too much NE can be bad for you

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Postural Tachycardia Syndrome(POTS)

• Symptoms of sympathetic activation x 6 mo
• Orthostatic tachycardia gt 30 bpm
• No orthostatic hypotension (DBP gt 20/10)
• Plasma NE gt 600 pg/ml

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Postural Tachycardia SyndromeMany Names

• Orthostatic Intolerance (OI)
• Effort Syndrome
• Hyperdynamic ß-Adrenergic State
• Idiopathic Hypovolemia
• Irritable Heart
• Mitral Valve Prolapse Syndrome
• Neurocirculatory Asthenia
• Orthostatic Tachycardia Syndrome
• Soldiers Heart
• Vasoregulatory Asthenia

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Postural Tachycardia (POTS)

• Not a disease !
• A syndrome
• Like anemia or fever

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Top 7 Lessons From Dysautonomias

• You can live without norepinephrine (NE)
• Dopamine can be important in BP control
• Baroreflex failure (BF) can present as Pheo
• BF can present as malignant vagotonia
• Food and water powerfully affect BP
• Orthostatic tachycardia (POTS) is common
• Too much NE can be bad for you

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Proband with POTS

• Palpitations
• Dizziness or lightheadedness
• Slowed thinking on standing
• Reduced exercise capacity
• Fatigue
• Near-fainting often and rarely fainting

John R. Shannon NEJM 2000342541
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Plasma NE and Sympathetic Activity (SA)
of supine value
An electrical/chemical dissociation ?
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Tritiated NE Clearance
NE clearance is impaired
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Evidence of NET Deficiency

• NE/MSA Dissociation
• Impaired NE Clearance
• Tyramine Insensitivity
• Yohimbine Hypersensitivity
• Low DHPG/NE Ratio

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NET Deficiency
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Identified Coding Variants in the Human
Norepinephrine Transporter
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The A457P Mutant Fails to Demonstrate NE Uptake
in Several Heterologous Expression Systems
3HNE Uptake (percent hNET wt)
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How dysfunctional is A457P ?

• A457P has virtually no NE transport function.
• Little A457P actually gets into the cell
  surface.
• A457P interferes with WT NET getting to surface.

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Conclusions

• Autonomic disorders lead us to discovery of both
  phenomena and mechanisms.
• Autonomic disorders like POTS are heterogeneous
  and will lead to discovery of many new genetic
  and acquired pathophysiologies.
• These discoveries will be enabled by bedside
  interventions and imaging capabilities which
  allow us to visualize physiology in real time.

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Tyramine Responsiveness(NE release into plasma)
Impaired tyramine release
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Yohimbine (a2-antagonist)
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Therapy of Severe Dysautonomias

• FIRST LINE
• Water (40 mmHg!)
• Food (-30mmHg!)

• SECOND LINE
• Physical Maneuvers
• Exercise (in water)

• THIRD LINE
• Fludrocortisone Salt
• Pressor Drugs (midodrine)

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Audience Question

• I wondered if youd comment on the other major
  pressor system, rigination intensive system,
  either in the DBH defiency or during the water
  logging?

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Audience Question

• Theres another system that involves
  anti-diuretic hormone is there some sort of
  paradoxical DBH response to water in these
  individuals?

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Audience Question

• I was kind of puzzled about the fact that the
  absence of norepinephrine has little effects on
  brain function and also knowing that
  norepinephrine plays a significant role on
  appetite regulation because some of the
  anorexgenic drugs actually cause an increase in
  norepinephrine or norepinephrine ???
  inhibitors. Was there any subtle effects that you
  could see whether these people tested by
  cognitive function or some other way?

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Audience Question

• So other neurotransmitters must be compensated
  for the absence of norepinephrine?

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Audience Question

• There has been a lot of interest in the pain
  field very recently in the COMT enzyme and that
  polymorphisms might be responsible for
  differences in pain sensitivity. But I am not
  aware of works that been done looking at the
  consequences on classic text of autonomic
  function. Are any of those polymorphisms
  associated with differences in autonomic function
  as we know it?

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Audience Question

• Its always striking to me that patience with
  the ?????????? dysfunction are not orthostatic
  at all as compared to the puromotic failure. Do
  you have good explanations for the clinical
  evidence for the no orthostatis whatsoever in
  these patience?