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Autonomic Neuroscience from Bench to Bedside. Ann Arbor May 14, 2004. 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. How Dysautonomias Teach Us. Amplification of Signal.
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Autonomic Neuroscience from Bench to Bedside Ann Arbor May 14, 2004
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
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
Cardiovascular Continuum LBP POTS NMS Normotension Labile HBP HBP Bradycardia/hypotension ~500,000 Americans Orthostatic tachycardia ~500,000 Americans Orthostatic hypotension ~100,000 Americans
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
DBH Deficiency • Severe orthostatic hypotension • Ptosis of the eyelids • Complicated perinatal course • Shock • Hypoglycemia • Hypothermia • Nasal stuffiness • Retrograde ejaculation
Are pressor reflexes intact ? mm Hg Noradrenergic system is nonfunctional
Are Adrenergic Receptors Present?(Phenylephrine) Adrenergic receptors are functional
Are Sympathetic Nerves Present? bursts/min Noradrenergic nerves are electrically active
Is Plasma Norepinephrine Present? pg/ml No Norepinephrine
Is Plasma Dopamine Present? pg/ml Dopamine is greatly increased
Plasma DA >> NE pg/ml DA replacing NE ?
DBH Deficiency Genetics • IVS1+2T>C 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
Effect of the mutation IVS1+2T 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 …GACACTGCCTATTTTGCGgcgagt-108bp-gtttga-380bp-agcagGACGCCTGGAGTGACCAG D T A Y F A A S ------- V stop 517 396 298 Exon1 Exon2 220 Exon 1 Exon 2 ...GACACTGCCTATTTTGCGGACGCCTGGAGTGACCAG... D T A Y F A D A W S D Q
DOPS Therapy DOPS DOPS DOPS NE NE
DOPS* Restores NE to Normal pg/ml or seconds *Norepinephrine-COOH
Catechols in DBH Deficiency • ‘Normal’ cognitive and psychiatric faculties • Completely absent in blood, CSF, urine: • Norepinephrine • Epinephrine • Normetanephrine • Metanephrine • DHPG • VMA
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
“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
The TH-antagonist metyrosine lowers DA and raises BP pg/ml or mm Hg Weight rose 1 kg: DA was an endogenous diuretic
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
Baroreflex Failure Resting quietly Excitation
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
Selective Baroreflex Failure Excitation Resting Quietly Jens Jordan et al, Hypertension 1997;30:1072
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
Water and BP in Autonomic Failure Jens Jordan et al. Circulation 2000;101:504
Effect of Nn-Nicotinic Blockade (Trimethaphan) on Water’s Pressor Action mmHg Autonomic Function Necessary for Pressor Action
500 ml Oral vs Intravenous Fluid mmHg The oral route is key to water’s pressor effect
Does Oral Water Suppress Sympathetic Activity bursts/min Water increases sympathetic activity
Water and BP: Many questions • Pressor when baroreflex fails • Must be oral for effect • Causes increased sympathetic activity
Water in normal subjects • Water raises BP ~11 mmHg in older normal subjects Is water ingestion a source of noise in clinic BP determinations?
Water Improves Tolerance of Head-Up Tilt 1.0 0.8 Cumulative Survival of Tilt Testing Water 0.6 P = 0.007 NoWater 0.4 0 10 20 30 40 50 n=22 normal subjects Time (min)
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
Postural Tachycardia Syndrome(POTS) • Symptoms of sympathetic activation x 6 mo • Orthostatic tachycardia > 30 bpm • No orthostatic hypotension (DBP > 20/10) • Plasma NE > 600 pg/ml
Postural Tachycardia Syndrome:Many Names • Orthostatic Intolerance (OI) • Effort Syndrome • Hyperdynamic ß-Adrenergic State • Idiopathic Hypovolemia • Irritable Heart • Mitral Valve Prolapse Syndrome • Neurocirculatory Asthenia • Orthostatic Tachycardia Syndrome • Soldier’s Heart • Vasoregulatory Asthenia
Postural Tachycardia (POTS) Not a disease ! A syndrome Like “anemia” or “fever”
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
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 2000;342:541
Plasma NE and Sympathetic Activity (SA) % of supine value An electrical/chemical dissociation ?
Tritiated NE Clearance NE clearance is impaired
Evidence of NET Deficiency • NE/MSA Dissociation • Impaired NE Clearance • Tyramine Insensitivity • Yohimbine Hypersensitivity • Low DHPG/NE Ratio
Identified Coding Variants in the Human Norepinephrine Transporter
The A457P Mutant Fails to Demonstrate NE Uptake in Several Heterologous Expression Systems [3H]NE Uptake (percent hNET wt)
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.
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.