Autonomic Neuroscience from Bench to Bedside

1. Autonomic Neuroscience from Bench to Bedside Ann Arbor May 14, 2004

2. 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

3. 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

4. Cardiovascular Continuum LBP POTS NMS Normotension Labile HBP HBP Bradycardia/hypotension ~500,000 Americans Orthostatic tachycardia ~500,000 Americans Orthostatic hypotension ~100,000 Americans

5. 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

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

7. Are pressor reflexes intact ? mm Hg Noradrenergic system is nonfunctional

8. Are Adrenergic Receptors Present?(Phenylephrine) Adrenergic receptors are functional

9. Are Sympathetic Nerves Present? bursts/min Noradrenergic nerves are electrically active

10. Is Plasma Norepinephrine Present? pg/ml No Norepinephrine

11. Catecholamine Synthesis

12. Is Plasma Dopamine Present? pg/ml Dopamine is greatly increased

13. Plasma DA >> NE pg/ml DA replacing NE ?

14. Catecholamine Synthesis DBH

15. 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

16. 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

17. DH-Deficiency

18. DOPS Therapy DOPS DOPS DOPS NE NE

19. DOPS* Restores NE to Normal pg/ml or seconds *Norepinephrine-COOH

20. Catechols in DBH Deficiency • ‘Normal’ cognitive and psychiatric faculties • Completely absent in blood, CSF, urine: • Norepinephrine • Epinephrine • Normetanephrine • Metanephrine • DHPG • VMA

21. 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

22. “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

23. The TH-antagonist metyrosine lowers DA and raises BP pg/ml or mm Hg Weight rose 1 kg: DA was an endogenous diuretic

24. 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

25. Normal Baroreflex

26. Baroreflex Failure Resting quietly Excitation

27. 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

28. Selective Baroreflex Failure Excitation Resting Quietly Jens Jordan et al, Hypertension 1997;30:1072

29. 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

30. Water and BP in Autonomic Failure Jens Jordan et al. Circulation 2000;101:504

31. Effect of Nn-Nicotinic Blockade (Trimethaphan) on Water’s Pressor Action mmHg Autonomic Function Necessary for Pressor Action

32. 500 ml Oral vs Intravenous Fluid mmHg The oral route is key to water’s pressor effect

33. Does Oral Water Suppress Sympathetic Activity bursts/min Water increases sympathetic activity

34. Water and BP: Many questions • Pressor when baroreflex fails • Must be oral for effect • Causes increased sympathetic activity

35. Water in normal subjects • Water raises BP ~11 mmHg in older normal subjects Is water ingestion a source of noise in clinic BP determinations?

36. 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)

37. 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

38. 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

39. 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

40. Postural Tachycardia (POTS) Not a disease ! A syndrome Like “anemia” or “fever”

41. 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

42. 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

43. Plasma NE and Sympathetic Activity (SA) % of supine value An electrical/chemical dissociation ?

44. Tritiated NE Clearance NE clearance is impaired

45. Evidence of NET Deficiency • NE/MSA Dissociation • Impaired NE Clearance • Tyramine Insensitivity • Yohimbine Hypersensitivity • Low DHPG/NE Ratio

46. NET Deficiency

47. Identified Coding Variants in the Human Norepinephrine Transporter

48. The A457P Mutant Fails to Demonstrate NE Uptake in Several Heterologous Expression Systems [3H]NE Uptake (percent hNET wt)

49. 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.

50. 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.