2012 AAS Program Abstracts CAR

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23rd INTERNATIONAL SYMPOSIUM ON THE AUTONOMICNERVOUS SYSTEM

Atlantis Resort

Paradise Island, Bahamas

October 31November 3, 2012

Preliminary Program

WEDNESDAY, OCTOBER 31, 2012

6:007:00 PM Registration

Imperial Foyer South I

7:007:15 PM WelcomeDr. Michael Joyner, President

Imperial Ballroom CD

Autonomic Failure: PAF, MSA, Parkinsons DiseaseChairs: Eduardo Benarroch & Steven Vernino

7:157:30 PM Alpha synuclein as a cutaneous biomarker of Parkinson disease

C.H. Gibbons, N. Wang, J. Lafo, R. Freeman

Boston, MA, USA

7:307:45 PM CSF biomarkers of central and peripheral catecholamine deficiency in synucleinopathies

D.S. Goldstein, L. Sewell, C. Holmes, C. Sims-ONeil, Y. SharabiBethesda, MD, USA

7:458:00 PM Prognostic indicators and clinical spectrum of MSA based on autopsy-confirmed cases

J.J. Figueroa, A.K. Parsaik, W. Singer, P. Sandroni, E.E. Benarroch, P.A. Low, J.H. Bower

Rochester, MN, USA

8:008:15 PM Mechanical stimulation of the feet improves gait and increases cardiac vagal profile in Parkinsons disease

F. Barbic, M. Galli, M. Canesi, A. Porta, V. Cimolin, V. Bari, L. Dalla Vecchia, F. Dipaola, V. Pacetti, F. Meda,

I. Bianchi, E. Brunetta, R. Furlan

Milan, Italy

8:158:30 PM Profound myocardial catecholamine depletion in Lewy body diseases

D.S. Goldstein, P. Sullivan, T. Jenkins, C. Holmes, M. Basile, D.C. Mash, I.J. Kopin, Y. Sharabi

Bethesda, MD, USA

8:308:45 PM Autonomic dysfunction in Parkinsonian LRRK2 mutation carriers

B. Tijero, J.C. Gomez Esteban, K. Berganzo, V. Llorens, H.J.J. Zarranz

Bilbau, Spain

8:459:00 PM Comparison of techniques for non-invasive assessment of systemic hemodynamics in autonomic function testing

C. Sims-ONeil, S. Pechnik, L. Sewell, L. Nez, D.S. Goldstein

Bethesda, MD, USA

THURSDAY, NOVEMBER 1, 2012

7:308:00 AM Breakfast & Exhibits

Imperial Ballroom B

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8:008:45 AM Plenary Lecture

Master and commander: the brain and the autonomic nervous system

Vaughan G. Macefield, Ph.D

University of Western Sydney & Neuroscience Research Australia Sydney, Australia

Cerebral Blood Flow, Neuroimaging in Brain and Heart & Pediatric Autonomic DisordersChairs: Lucy Norcliffe-Kaufmann & Jens Tank

8:459:00 AM The middle cerebral artery dilates to sodium nitroprusside: a combined transcranial Doppler and near infrared

spectroscopy study

J.M Stewart, C.E. Schwartz, Z.R. Messer, C. Terilli, M.S. Medow,

Valhalla, NY, USA

9:009:15 AM Cerebral oxygenation, heart rate & blood pressure responses in congenital central hypoventilation syndrome (CCHS)

during exogenous ventilatory challenges: PHOX2B genotype/CCHS phenotype association

M.S. Carroll, P.P. Patwari, T.M. Stewart, C.D. Brogadir, A.S. Kenny, C.M. Rand, D.E. Weese-Mayer

Chicago, IL, USA

9:159:30 AM Time course of cardiac sympathetic denervation in Parkinson disease

D.S. Goldstein

Bethesda, MD, USA

9:309:45 AM Parental attribution of symptoms in adolescents with postural tachycardia syndrome and its relation to child

functioning and psychological variables

E.M. Keating, R.M. Antiel, K.E. Weiss, D. Wallace, P.R. Fischer, C. Harbeck-Weber

Rochester, MN, USA

9:4510:00 AM Cardiovagal sensitivity and orthostatic heart rate response in young patients with orthostatic intolerance

W. Singer, A.K. Parsaik, E.E. Benarroch, P. Sandroni, P.A. Low

Rochester, MN, USA

10:0010:15 AM Parental response to pain: the impact on functional disability, depression, anxiety, and pain acceptance in adolescents

with chronic pain and orthostatic intolerance

R.M. Antiel, E.M. Keating, K.E. Weiss, D.P. Wallace, P.R. Fischer, C. Harbeck-Weber

Rochester, MN, USA

10:1510:30 AM Coffee Break

Imperial Ballroom B

Autonomic Regulation: Basic Science & Animal StudiesChairs: David Jardine & Imad Jarjour

10:3010:45 AM Relationship between ganglionic long-term potentiation (LTP) and homeostatic synaptic plasticity in experimental

autoimmune autonomic ganglionopathy (EAAG)

Z. Wang, S. Vernino

Dallas, TX, USA

10:4511:00 AM Methionine sulfoxide reductase A: a novel molecular determinant of baroreflex sensitivity, blood pressure and

hypertensive end-organ damage

R. Sabharwal, R. El Accaoui, M.K. Davis, J.A. Goeken, R. Weiss, F.M. Abboud, D. Meyerholz, M.W. Chapleau

Iowa City, IA, USA

11:0011:15 AM Baroreflex induced changes in stressed blood volume, not cardiac output curve, is the central mechanism preventing

volume load induced pulmonary edema

T. Sakamoto, T. Kakino, K. Sunagawa

Fukuoka, Japan

11:1511:30 AM Prostaglandin D synthase is critical for development of chronic angiotensin II-salt hypertension in the rat

G.D. Fink, N. Asirvatham-Jeyaraj

East Lansing, MI, USA

11:3011:45 AM The central chemoreflex activation induces sympathoexcitation and resets the arterial baroreflex without

compromising its pressure stabilizing function

K. Saku, K. Sunagawa

Fukuoka, Japan

11:4512:00 PM Advanced techniques and pitfalls of autonomic function assessment and arrhythmia analysis in the mouse model

C.M. Welzig, J.B. Galper

Charleston, SC, USA

12:001:30 PM Lunch & Poster Session I

Imperial Ballroom B

1:303:30 PM Free Time

3:304:00 PM AAS Busin ess meeting

Imperial Ballroom CD

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Awards SessionChairs: Michael Joyner & Wouter Wieling

4:004:45 PM Streeten Lecture

The ups and downs of blood pressure & baroreflex sensitivitya historical and personal perspective

Mark Chapleau, Ph.D

University of Iowa and Veterans Affairs Medical Center, Iowa City, IA, USA

4:455:00 PM Streeten Travel Fellowship AwardBlunted osmopressor response in familial dysautonomia

N. Goulding, L. Norcliffe-Kaufmann, J. Martinez, D. Roncevic, L. Stok, F. Axelrod, H. Kaufmann

New York, NY, USA

5:005:15 PM FMS/Penaz Wesseling Award

Paradox elevations in angiotensin II, independent of plasma renin activity, contribute to the supine hypertension of

primary autonomic failure

A.C. Arnold, L.E Okamoto, C. Shibao, A. Gamboa, S.R. Raj, D. Robertson, I. Biaggioni

Nashville, TN, USA

5:155:30 PM FMS/Penaz Wesseling Award

Chronic effects of aliskiren versus hydrochlorothiazide on sympathetic neural responses to head-up tilt in hypertensive

seniors

Y. Okada, S.S. Jarvis, S.A. Best, T.B. Bivens, R.L. Meier, B.D. Levine, Q. Fu

Dallas, TX, USA

5:305:45 PM AAS Travel Award

Association between cerebral autoregulation and white matter hyperintensities in elderly individualsS. Purkayastha, B. Paccha, I. Iloputaife, D.K. Kiely, F.A. Sorond, L.A. Lipsitz

Roslindale, MA, USA

5:456:00 PM AAS Travel Award

The change in arterial stiffness during ganglionic blockade is associated with sympathetic nerve activity in women

J.N. Barnes, R.E. Harvey, E.C. Hart, N. Charkoudian, T.B. Curry, J.H. Eisenach, W.T. Nicholson, M.J. Joyner,

D.P. Casey

Rochester, MN, USA

FRIDAY, NOVEMBER 2, 2012


Imperial Ballroom B

7:308:15 AM Plenary Lecture

Autonomic responses to pregnancyQi Fu, M.D., Ph.D

Institute for Exercise and Environmental Medicine, Texas Health Presbyterian Hospital Dallas, and UT Southwestern

Medical Center, Dallas, TX, USA

Microneurography & Cardiovascular Control in Humans/Cardiovascular Disease, Diabetes, Obesity & AgingChairs: Jill Barnes & Qi Fu

8:158:30 AM Catheter based renal nerve ablation does not elicit a central sympatholytic response in difficult to control hypertensive

patients

J. Brinkmann, K. Heusser, B.M. Schmidt, J. Menne, G. Klein, H. Haller, A. Diedrich, J. Jordan, J. Tank

Hanover, Germany

8:308:45 AM Methodological considerations for assessing resting spontaneous baroreflex control of muscle sympathetic nerve

activity in humans

S.W. Holwerda, H. Yang, J.R. Carter, P.J. Fadel

Columbia, MO, USA

8:459:00 AM Sleep deprivation augments cardiovascular reactivity to acute stress in humans

H. Yang, J.J. Durocher, R.A. Larson, J.P. DellaValla, J.R. Carter

Houghton, MI, USA

9:009:15 AM Susceptibility to inducible ventricular arrhythmia in type I diabetic Akita mice is dependent on abnormalities of Ca2+

handling

H. Jin, M. Rajab, M. Aronovitz, B. Wang, K. Picard, H. Park, M. Link, J.B. Galper

Boston, MA, USA

9:159:30 AM Sympathetic hyper-responsiveness In takotsubo cardiomyopathy

L. Norcliffe-Kaufmann, J. Martinez, H. Kaufmann, H. Reynolds

New York, NY, USA

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9:309:45 AM Improvement of obesity-associated insulin resistance during autonomic blockade

A. Gamboa, L. Okamoto, A. Arnold, S. Raj, A. Diedrich, N. Abumrad, I. Biaggioni

Nashville, TN, USA

9:4511:15 AM Coffee & Poster Session II

Imperial Ballroom B

Postural Orthostatic Tachycardia Syndrome (POTS)

Chairs: Satish Raj & Wolfgang Singer

11:1511:30 AM Beta-2 adrenergic receptor polymorphism and hemodynamics in patients with postural orthostatic tachycardia

syndrome and healthy controls

M.N. Manento, L.R. Gullixson, K.K. Nickander, P.A. Low, J.H. Eisenach

Rochester, MN, USA

11:3011:45 AM The pathophysiology of neuropathic and non-neuropathic postural tachycardia syndrome

C. Gibbons, I. Bonyhay, A. Benson, R. Freeman

Boston, MA, USA

11:4512:00 PM Deconditioning in patients with orthostatic intolerance

A. Parsaik, T.G. Allison, W. Singer, D.M. Sletten, M.J. Joyner, E.E. Benarroch, P.A. Low, P. Sandroni

Rochester, MN, USA

12:0012:15 PM Preliminary data on the durability of improved symptoms, functioning, and psychological distress in adolescents with

POTS treated in a multidisciplinary treatment program

B.K. Bruce, T.E. Harrison, K.E. Weiss, P.R. Fischer, S.P. Ahrens, W.N. TimmRochester, MN, USA

12:1512:30 PM Objective measures of sleep in patients with POTS

S.J. Kizilbash, P.R. Fischer, R.M. Lloyd

Rochester, MN, USA

12:3012:45 PM Reduced alpha-adrenergic vascular response: the physiological link between postural orthostatic tachycardia

syndrome and neurally mediated syncope

N. Mehta, M. Tavora-Mehta, J.C. Guzman, C.A. Morillo

Hamilton, ON, Canada

12:457:00 PM Free Time

7:0010:00 PM Presidential Dinner

Ripples Pool Deck

SATURDAY, NOVEMBER 3, 2012


Imperial Ballroom B

Diabetic, Autoimmune & Other Autonomic NeuropathiesChairs: Christopher Gibbons & Christoph Schroeder

8:008:15 AM Multi-scale glycemic variability affects brain structure and functional outcomes in type 2 diabetes mellitus

X. Cui, A. Galica, B. Manor, A. Abduljalil, C.-K. Peng, V. Novak

Boston, MA, USA

8:158:30 AM The laser Doppler imaging axon-reflex flare areaa novel regression thresholding based technique to assess

neurovascular function

T. Siepmann, B.M. Illigens, R. Freeman, C. Gibbons

Boston, MA, USA

8:308:45 AM Long-term outcomes in autoimmune autonomic ganglionopathy

S. Muppidi, E.B. Spaeth, C. Gibbons, S. VerninoDallas, TX, USA

8:459:00 AM Type I diabetic Akita mice demonstrate decreased heart rate variability and increased inducibility of ventricular

tachycardia which are reversed by statins

C.M. Welzig, H.-J. Park, M. Rajab, M. Aronovitz, H. Jin, M.S. Link, J.B. Galper

Charlston, SC, USA

9:009:15 AM The quantification of sudomotor nerve fibers: a multicenter study in diabetes

C.H. Gibbons, J. Lafo, G. Smith, R. Singleton, R. Freeman

Boston, MA, USA

9:1510:45 AM Coffee & Poster Session III

Imperial Ballroom B

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Orthostatic Hypotension and SyncopeChairs: Rasna Sabharwal & Darren Casey

10:4511:00 AM Treatment of neurogenic orthostatic hypotension (NOH) with droxidopa: results from a multicenter, double-blind,

randomized, placebo-controlled, parallel group, induction design study

H. Kaufmann, P. Low, I. Biaggioni, C.J. Mathias, R. Freeman, L.A. Hewitt

New York, NY, USA

11:0011:15 AM What is MSNA doing at the onset of syncope?

D.L. Jardine

Christchurch, New Zealand11:1511:30 AM A meta-analysis of pharmacologic treatments of orthostatic hypotension

C.H. Gibbons, S. Raj

Boston, MA, USA

11:3011:45 AM Increasing cardiac output does not change middle cerebral artery blood velocity in the hyperthermic human

C.G. Crandall, T. Seifert, T.E. Wilson, M. Bundgaard-Nielsen, N.H. Secher

Dallas, TX, USA

11:4512:00 PM Patterns of diagnosis and intervention in neurogenic orthostatic hypotension (NOH): a patient-flow study

H. Kaufmann, R.E. Paquette

New York, NY, USA

12:0012:30 PM Open Discussion & Adjourn

POSTER SESSION IThursday, November 1, 201212:001:30 PM

Autonomic Failure: PAF, MSA, Parkinsons Disease

Poster #1 A randomized, double-blind, placebo-controlled clinical trial of Rifampicin in multiple system atrophy

P.A. Low, S. Gilman, D. Robertson, I. Biaggioni, W. Singer, H. Kaufmann, S. Perlman, W. Cheshire, S. Vernino,

R. Freeman, R.A. Hauser, S. Lessig

Rochester, MN, USA

Poster #2 Orthostatic hypotension in Parkinson disease: passive tilt vs. active standing

J. Martinez, J.C. Esteban Gomez, B. Tijero Merino, K. Berganzo, H. Kaufmann

New York, NY, USA

Poster #3 Cerebellar and parkinsonian phenotypes in multiple system atrophy (MSA). Similarities and differences

D. Roncevic, J. Martinez, L. Norcliffe-Kaufmann, H. Kaufmann

New York, NY, USA

Poster #4 A novel quantitative index of baroreflex-sympathoneural function: application to patients with chronic autonomic

failure

F. Rahman, D.S. Goldstein

Bethesda, MD, USA

Poster #5 Loss of cerebral blood flow rhythm in Parkinsons disease and vascular parkinsonism

S.-J. Yeh, B.-W. Chang, B.-Y. Liau, C.-C. Chiu

Taichung, Taiwan

Pediatric Autonomic Disorders

Poster #6 Temperature profile in congenital central hypoventilation syndrome (CCHS) and rapid-onset obesity with

hypothalamic dysfunction, hypoventilation, and autonomic dysregulation (ROHHAD): ibutton measures of

peripheral skin temperature

R. Saiyed, C.M. Rand, M.S. Carroll, P.P. Patwari, T. Stewart, C. Koliboski, D.E. Weese-Mayer

Chicago, IL, USAPoster #7 Heart rate variability in hospitalized children: autonomic response to laughter and engagement

P.P. Patwari, M.S. Carroll, K. Gray, M.K. Janda, A.S. Kenny, T.H. Stewart, C. Brogadir, S.H. Wang, D.M. Steinhorn

Chicago, IL, USA

Poster #8 Cardiac stroke volume and sympathetic/parasympathetic measurements increase the sensitivity and specificity of

HUTT in children and adolescents

M.T. Numan, J.E. Lankford, A. Gourishankar, I.J. Butler

Houston, TX, USA

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Autonomic Regulation: Basic Science & Animal Studies

Poster #9 Biogenic amine metabolism in juvenile neurocardiogenic syncope with dysautonomia

I.J. Butler, J.E. Lankford, M.T. Numan

Houston, TX, USA

Poster #10 The iceman revisited: autonomic function tests during performance of the Asian Tummo meditation technique

J.T. Groothuis, M.T.E. Hopman

Nijmegen, The Netherlands

Poster #11 Evidence for central sensitization in bladder pain syndrome from the ICEPAC trial (Interstitial Cystitis: Elucidation

of Psychophysiologic and Autonomic Characteristics)preliminary psychometric findingsJ.W. Janata, F. Daneshgari, C.A.T. Buffington, G. Chelimsky, M.D. Louttit, D. Zhang, T.C. Chelimsky

Cleveland, OH, USA

Novel Therapies & Clinical Trials

Poster #12 The antiemetic efficacy of carbidopa: a randomized, double-blind, placebo-controlled crossover study in patients with

familial dysautonomia

L. Norcliffe-Kaufmann, J. Martinez, F. Axelrod, H. Kaufmann

New York, NY, USA

Poster #13 Comparative efficacy between the norepinephrine transporter blocker, atomoxetine, against midodrine for the

treatment of orthostatic hypotension

C.E. Ramirez, L.E. Okamoto, A. Gamboa, S.R. Raj, A. Diedrich, D. Robertson, I. Biaggioni, C. Shibao

Nashville, TN, USA

Poster #14 Beneficial effects of oral rehydration solution on orthostatic intoleranceM.S. Medow, D. Tewari, A. Aggarwal, Z. Messer, J.M. Stewart

Valhalla, NY, USA

Gastrointestinal & Urogenital Systems, IBS, Cystitis

Poster #15 Musculoskeletal evaluation of patients with interstitial cystitis

T.V. Sanses, G. Chelimsky, D. Zhang, J. Janata, T. Mahajan, B. Fenton, A. Askari, R. Elston, T. Chelimsky, ICEPAC

Study Group

Milwaukee, WI, USA

Poster #16 Heart rate variability in pelvic pain

P. Singh, J. Thayer, G. Chelimsky, T. Chelimsky

Milwaukee, WI, USA

Poster #17 Study of the P2X2 a n d 7 receptors in the enteric glial cells of ileum rat subjected to ischemia and reperfusion

C.E. Mendes, K. Palombit, W. Tavares de Lima, P. Castelucci

Sao Paulo, BrazilPoster #18 Brainstem neuropeptides and vagal protection of the gastric mucosal against injury: role of prostaglandins, nitric

oxide and calcitonin-gene related peptide in capsaicin afferents

Y. Tache

Los Angeles, CA, USA

Poster #19 Autonomic dysfunction and esophageal dysmotility in persons with spinal cord injury

G.J. Schilero, M. Radulovic, C. Renzi, C. Yen, W.A. Bauman, M. Korsten

Bronx, NY, USA

Poster #20 Real time change of prefrontal cortex activity related to normal and abnormal bladder filling in Parkinson disease:

a functional near-infrared spectroscopy (fNIRS) study

C. Yamaguchi, T. Uchiyama, T. Yamamoto, R. Sakakibara, M. Fuse, M. Yanagisawa, T. Kamai, T. Ichikawa,

K. Hirata, S. Kuwabara, T. Yamanishi

Tochigi, Japan

Poster #21 Effect of Brilliant Blue G on P2X7 receptor after intestinal ischemia and reperfusion

K. Palombit, C.E. Mendes, W. Tavares de Lima, P. Castelucci

Sao Paulo, BrazilPoster #22 Photo-stimulating effects of low reactive level laser on bladder dysfunction in neurological disease rats

T. Uchiyama, C. Yamaguchi, T. Yamamoto, R. Sakakibara, M. Fuse, M. Yanagisawa, T. Kamai, T. Ichikawa,

K. Hirata, S. Kuwabara, T. Yamanishi

Tochigi, Japan

Cerebral Blood Flow Regulation

Poster #23 Cerebral blood flow in autonomic failure

L. Rivera Lara, P. Novak

Worcester, MA, USA

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Poster #24 Added clinical value of cerebral blood flow in juveniles and young adults with neurocardiogenic syncope and

dysautonomia as measured by near-infrared spectroscopy

J.E. Lankford, M.T. Numan, A. Gourishankar, I.J. Butler

Houston, TX, USA

POSTER SESSION IIFriday, November 2, 20129:4511:15 AM

Microneurography & Cardiovascular Reflexes in Humans

Poster #25 Do the chronic heart failure patients have limited sympathetic response to a transient baroreflex stress?

P. Zubin Maslov, T. Breskovic, J.K. Shoemaker, Z. Dujic

Split, Croatia

Poster #26 Assessment of cardiovascular adrenergic function using the Valsalva maneuverreproducibility and validity of

indices

T.L. Gehrking, J.A. Gehrking, J.D. Schmelzer, P.A. Low, W. Singer

Rochester, MN, USA

Poster #27 Sex differences in limb vascular reactivity to mental stress in humans

J.R. Carter, H. Yang, T.D. Drummer

Houghton, MI, USA

Poster #28 Melatonin does not alter skin sympathetic nerve responses to mental stress

C.A. Ray, C.L. Sauder, M.D. MullerHershey, PA, USA

Poster #29 The arterial baroreflex resets with orthostasis

C.E. Schwartz, J.M. Stewart

Hawthorne, NY, USA

Poster #30 Carotid chemoreflex and muscle metaboreflex interactions in humans

H. Edgell, M.K. Stickland

Edmonton, AB, Canada

Poster #31 Do multi-unit sympathetic discharge patterns change with age and cardiovascular disease?

D.N. Brewer, P. Zubin Maslov, Z. Dujic, J.K. Shoemaker

London, Ontario, Canada

Cardiovascular Disease, Obesity & Aging: Human Studies

Poster #32 Acute baroreflex sensitivity impairment due to insulin-induced experimental hypoglycemia

A. Rao, I. Bonyhay, S. Ballatori, G. Adler, R. Freeman

Boston, MA, USA

Poster #33 Autonomic contribution to blood pressure and resting energy expenditure in obese hispanics

L.E. Okamoto, C. Shibao, A. Gamboa, A. Diedrich, G. Farley, S. Paranjape, I. Biaggioni

Nashville, TN, USA

Poster #34 The impact of injury to autonomic pathways on cardiovascular disease risk after spinal cord injury

H.J.C. Ravensbergen, I.S. Sahota, S.A. Lear, V.E. Claydon

Burnaby, British Columbia, Canada

Poster #35 What is the best marker for obesity in individuals with spinal cord injury?

H.J.C. Ravensbergen, M.C. Keenleyside, S.A. Lear, V.E. Claydon

Burnaby, British Columbia, Canada

Poster #36 Central arterial stiffness and autonomic modulation in active women

P. Latchman, G. Gates, J. Pereira, R. Axtell, M. Bartels, R. De Meersman

New Haven, CT, USA

Poster #37 Impaired autonomic modulation in acute stroke improves with clinical recovery within 72 hours

M.J. Hilz, H. Marthol, S. Moeller, J. Koehn, A. Akhundova, P. De Fina, S. SchwabErlangen, Germany & New York, NY, USA

Poster #38 Relation of cardiovagal baroreflex sensitivity to impaired carotid artery elastic function in patients with tetralogy of

Fallot

A. Pinter, T. Horvath, A. Sarkozi, D. Cseh, M. Kollai

Budapest, Hungary

Poster #39 Features of vascular neurogenic regulation in patients with atrial fibrillation and heart failure

O.V. Mamontov, A.V. Kozlenok, E.R. Bernhard, E.V. Parmon, E.V. Shlyakhto

Saint-Petersburg, Russian Federation

Poster #40 Calcitonin gene related peptide level and endocannabinoid system activity in patients with abdominal obesity and

arterial hypertension

E. Shlyakhto, E. Bazhenova, O. Belyaeva, A. Berezina, O. Berkovich, E. Baranova


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Poster #41 Heart rate variability and high sensitivity C-reactive protein: influence of coronary artery lesions

N.Y. Tamburus, V.C. Kunz, R.F.L. Paula, M.R. Salviati, T.A.G. Nery, E. da Silva

Sao Paulo, Brazil

Sympathovagal Balance & Spectral Analysis

Poster #42 Oligofiber recordings detail single-fiber sympathetic nerve discharge

C.-K. Su, C.-H. Chiang, C.-M. Ho, C.-M. Lee, Y.-P. Fan

Taipei, Taiwan

Poster #43 Cardiovascular autonomic control in the first year after spinal cord injuryJ. Inskip, M. McGrath, B. Kwon, V. Claydon

Burnaby, BC, Canada

Poster #44 Sympathovagal balancea thermodynamic perspective

R. Schondorf, J. Benoit, M.J. Lafitte

Montreal, QC, Canada

Poster #45 The autonomic testing of normal subjects

G. Chelimsky, S.M. Ialacci, T.C. Chelimsky

Milwaukee, WI, USA

Blood Flow & Autonomics

Poster #46 Alpha-adrenergic blockade unmasks a greater compensatory vasodilation in hypoperfused contracting muscle

D.P. Casey, M.J. Joyner

Rochester, MN, USA

Poster #47 COMPASS 31a refined and abbreviated composite autonomic symptom score

D.M. Sletten, G.A. Suarez, P.A. Low, J. Mandrekar, W. SingerRochester, MN, USA

Poster #48 Autonomic, Blood Flow and Sensory Small Fiber Scale (ABSS)

P. Novak

Worcester, MA, USA

Poster #49 Systemic dysautonomia in complex regional pain syndromea feasibility study

K.R. Chemali, K. McNeeley, L. Zhou, T. Chelimsky

Norfolk, VA, USA

POSTER SESSION IIISaturday, November 3, 20129:1510:45 AM

Exercise, Temperature Regulation & Hypoxia

Poster #50 Thermophysiological consequences of an absent evening melatonin release in spinal cord injury

H. Jones, J.T. Groothuis, T.M.H. Eijsvogels, J. Nyakayiru, R.J.M. Verheggen, A. Thompson, E.J.W. van Someren, G.

Atkinson, M.T.E. Hopman, D.H.J. Thijssen

Nijmegen, The Netherlands

Poster #51 Post-exercise recovery period in patients with idiopathic ventricular arrhythmias

E. Parmon, T. Tulintseva, E. Berngardt, E. Panova, E. Shlaykto

Saint Petersburg, Russian Federation

Postural Orthostatic Tachycardia Syndrome

Poster #52 Regulation of circulation during exercise in adolescents with postural orthostatic tachycardia syndrome (POTS)

A. Goodloe, D. Soma, C.K. Brands, P.R. Fischer, P.T. Pianosi

Rochester, MN, USA

Poster #53 Neuropsychological profiles in adolescents with postural tachycardia syndrome (POTS)

K.D. Evankovich, L.K. Jarjour, A.M. Hernandez, I.T. JarjourHouston, TX, USA

Poster #54 How important is the T in POTS using pediatric versus adult diagnostic criteria for postural tachycardia?

I.T. Jarjour, A.M. Hernandez, L.K. Jarjour

Houston, TX, USA

Poster #55 Palpitations in postural tachycardia syndrome: what do they tell?

R.K. Khurana

Baltimore, MD, USA

Poster #56 The spectrum of neuropathic orthostatic tachycardia

W. Singer, T.L. Gehrking, P.A. Low

Rochester, MN, USA

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Poster #57 Origins of cognitive dysfunction in postural tachycardia syndrome

A.C. Arnold, K. Haman, E.M. Garland, S.Y. Paranjape, C.A. Shibao, I. Biaggioni, D. Robertson, S.R. Raj

Nashville, TN, USA

Poster #58 Pharmacological I(f) pacemaker current inhibition in a human postural tachycardia syndrome (POTS) model

C. Schroeder, K. Heusser, D. Rieck, F.C. Luft, J. Tank, J. Jordan

Hannover, Germany

Poster #59 Cardiovascular autonomic response to nitric oxide inhibition in POTS patients

I. Bonyhay, C. Gibbons, A. Benson, R. Freeman

Boston, MA, USA

Poster #60 Postural tachycardia syndrome: optimal duration of diagnostic orthostatic challenge

W.B. Plash, V. Nwazue, A. Diedrich, I. Biaggioni, E.M. Garland, S.Y. Paranjape, B.K. Black, W.D. Dupont, C.

Shibao, S.R. Raj

Nashville, TN, USA

Poster #61 Uncoupling of serum interleukin-6 and C-reactive protein in lean patients with postural tachycardia syndrome

L.E. Okamoto, S.R. Raj, A. Gamboa, C. Shibao, A.C. Arnold, A. Diedrich, G. Farley, D. Robertson, I. Biaggioni

Nashville, TN, USA

Orthostatic Hypotension & Syncope

Poster #62 Blood pressure effect of droxidopa in hypotensive individuals with spinal cord injury

J. Wecht, D. Rosado-Rivera, C. Yen, M. Radulovic, W. Bauman

Bronx, NY, USA

Poster #63 Prevalence of orthostatic hypotension in asymptomatic veterans

J. Wecht, C. Yen, S. Pena, A. Ivan, W. BaumanBronx, NY, USA

Poster #64 Combination ergotamine and caffeine for the treatment of orthostatic hypotension

C. Shibao, C.E. Ramirez, L.E. Okamoto, A.C. Arnold, A. Gamboa, P. Muppa, S.R. Raj, A. Diedrich, D. Robertson, I.

Biaggioni

Nashville, TN, USA

Poster #65 Abnormal autonomic findings in chronic subjective dizziness: sympathetic dysfunction or hyperactivity

H. Lee, H.A. Kim

Daegu, South Korea

Poster #66 Neurogenic mechanisms and venous physiology in patients with orthostatic intolerance

L. Saju, Z. Sun, R. Shields, F. Fouad-Tarazi

Cleveland, OH, USA

Poster #67 Mechanisms underlying the relationships between cardiovascular dysfunction and fall susceptibility in older adults

B.H. Shaw, S.N. Robinovitch, V.E. Claydon

Burnaby, BC, Canada

Poster #68 Arterial baroreflex asymmetry: an additional mechanism of orthostatic insufficiency in patients with non-cardiacsyncope

O.V. Mamontov, M.I. Bogachev, E.V. Shlyakhto


Poster #69 Myoclonic jerks in syncope are probably generated in the cortex

J.G. van Dijk, R.D. Thijs, J. van Niekerk, W. Wieling, D.G. Benditt

Leiden, The Netherlands

Diabetic, Autoimmune & Other Autonomic Neuropathies

Poster #70 Glucoregulation and autonomic function in older male patients with diabetes mellitus and obstructive sleep apnea

J.L. Gilden, J. Cheng, B. Theckedath, P. Hung, J. Stoll

North Chicago, IL, USA

Poster #71 A case of paraneoplastic autonomic failure preceding Hodgkins lymphoma

P. Muppa, C.E. Ramirez, B. Black, D. Robertson, A. Peltier, S.R. Raj, C. Shibao, I. BiaggioniNashville, TN, USA

Poster #72 11-year follow-up of a case of autoimmune autonomic ganglionopathy

W. Singer, D.M. Sletten, T.L. Gehrking, A.K. Parsaik, P.A. Low

Rochester, MN, USA

Poster #73 Autonomic function test outcomes in diabetes mellitus

L.B. Tay, S. Srinivasan, C. Kang, T. Umapathi

Singapore

Clin Auton Res (2012) 22:207258 215

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Wednesday, October 31, 2012

Oral Presentations

Alpha-synuclein as a cutaneous

biomarker of Parkinson disease

C.H. Gibbons, N. Wang, J. Lafo, R. FreemanDepartment of Neurology, Beth Israel Deaconess Medical Center,

Harvard Medical School, Boston, MA, USA

Background: Parkinsons disease is a multisystem neurodegenerative

disease characterized by the deposition ofa-synuclein in the central,

peripheral and enteric nervous system. Although the most prominent

manifestations of Parkinsons disease are due to central, motor system

neurodegeneration, there is widespread peripheral, autonomic and

enteric nervous system degeneration with associated clinical features.

Objective: To develop a biomarker for Parkinson disease.

Methods: Fourteen patients with Parkinson disease and 10 age and

gender matched control subjects underwent skin biopsies at the distal

leg, distal thigh and proximal thigh. Skin biopsies were stained for

PGP9.5, tyrosine hydroxylase, vasoactive intestinal peptide and

a-synuclein. The density of nerve fibers within specific dermal

organelles (pilomotor muscles and sweat glands) was calculated.

Because normal subjects have low levels ofa-synuclein and Parkin-

sonian subjects have autonomic nerve degeneration, we chose a

primary outcome as the proportion of these nerve fibers that contained

a-synuclein (determined by a-synuclein overlap with PGP 9.5),

defined as the a-synuclein ratio.Results: Patients with PD had a distal sensory and autonomic neu-

ropathy expressed by loss of intra-epidermal, pilomotor and

sudomotor fibers (P\0.05 vs. controls). Patients with PD had higher

a-synuclein ratios compared to controls within pilomotor nerves at the

distal leg (0.76 0.19 vs. 0.26 0.13, P\ 0.001), distal thigh

(0.78 0.16 vs. 0.28 0.18; P\ 0.001) and proximal thigh

(0.80 0.13 vs. 0.32 0.15; P\0.001). Patients with PD had

higher a-synuclein ratios compared to controls within sudomotor

nerves at the distal leg (0.20 0.11 vs. 0.02 0.01, P\0.005),

distal thigh (0.18 0.12 vs. 0.02 0.01, P\0.005) and proximal

thigh (0.20 0.14 vs. 0.02 0.01, P\ 0.005).

Discussion: We have developed novel techniques to quantify the

density of autonomic nerve fiber innervation within specific dermal

organelles, and have quantified the ratio ofa-synuclein deposition

within these nerve fibers. We found significantly elevateda-synuclein

deposition ratios within both sympathetic adrenergic pilomotor and

sympathetic cholinergic sudomotor fibers in patients with Parkinson

disease. These findings suggest the a-synuclein ratio may be a bio-

marker in patients with Parkinson disease.

Acknowledgement: Study supported by NIH NINDS K23NS050209

(CHG) and the RJG Foundation (CHG).

CSF biomarkers of central and peripheral

catecholamine deficiency in synucleinopathies

D.S. Goldstein, L. Sewell, C. Holmes, C. Sims-ONeil, Y. Sharabi

Clinical Neurocardiology Section, NINDS/NIH, Bethesda, MD, USA

Background: Central catecholamine deficiency characterizes primary

chronic autonomic failure syndromes, including alpha-synucleinopa-

thies such as multiple system atrophy (MSA), pure autonomic failure

(PAF), and Parkinson disease (PD). We hypothesized that cerebro-

spinal fluid levels of neuronal metabolites of catecholamines provide

neurochemical biomarkers of these disorders.

Methods: We measured cerebrospinal fluid levels of catechols includ-

ing dopamine, norepinephrine, and their main respective neuronal

metabolites dihydroxyphenylacetic acid and dihydroxyphenylglycol in

MSA, PAF, and PD. Cerebrospinal fluid catechols were assayed in 146

subjects54 MSA, 20 PAF, 34 PD, and 38 controls. In 14 patients

cerebrospinal fluid wasobtainedbefore or within 2 years after theonset

of Parkinsonism.

Results: The MSA, PAF, and PD groups all had lower cerebrospinal

fluid dihydroxyphenylacetic acid [1.32 (SEM) 0.12 nmol/l,

0.86 0.09, 1.00 0.09] than controls (2.15 0.18 nmol/l;

p\ 0.0001, p = 0.0002, p\ 0.0001). Dihydroxyphenylglycol was

also lower in the three synucleinopathies (7.75 0.42, 5.82 0.65,

8.82 0.44 nmol/l) than controls (11.0 0.62 nmol/l; p = 0.009,

p\ 0.0001, p\ 0.0001). Dihydroxyphenylacetic acid was lower and

dihydroxyphenylglycol higher in PD than in PAF. Dihydroxyphen-

ylacetic acid was 100 % sensitive at 89 % specificity in separating

patients with recent onset of Parkinsonism from controls but was of

no value in differentiating MSA from PD.

Conclusions: Synucleinopathies feature cerebrospinal fluid neuro-

chemical evidence for central dopamine and norepinephrine

deficiency. PD and PAF involve differential central dopaminergic

versus noradrenergic lesions. Cerebrospinal fluid dihydroxyphenyl-

acetic acid seems to provide a sensitive means to identify even

early PD. (Ref.: Goldstein et al., Brain 2012; Mar 26. [Epub ahead of

print])

Prognostic indicators and clinical spectrum of MSA

based on autopsy-confirmed cases

J.J. Figueroa, A.K. Parsaik, W. Singer, P. Sandroni, E.E. Benarroch,

P.A. Low, J.H. Bower

Department of Neurology, Mayo Clinic, Rochester, MN, USA

Multiple system atrophy (MSA) is a progressive neurodegenerative

disorder characterized by motor dysfunction with autonomic failure.

The goal of our study was to evaluate phenotype at presentation, rate of

motor deterioration, and survival time after onset of motor and auto-

nomic symptoms in a cohort of autopsy confirmed MSA patients. We

retrospectively studied the Mayo Clinic cohortof 49 autopsy confirmed

MSA patients comprised of 33 (67 %) men and 16 (33 %) women.

Disease duration from motor symptom onset (age 55.8 7.1 years) to

death (age 65.5 8.6 years) was 9.7 4.7 years. Clinical phenotype

at first evaluation was MSA-P in 29 (60 %), MSA-C in 16 (32 %),

MSA-PC in 2 (4 %), and pure autonomic failure in 2 (4 %). At pre-

sentation, patients had symmetric parkinsonism (27/32), retropulsion

(12/14), absent resting tremor (37/44), poor levodopa responsiveness

(18/22) and antecollis (5/7). Gait impairment was present at onset ofmotor symptoms in 80 %. Time from onset of motor symptoms to first

fall, wheelchair dependency and dysphagia was 1.5 0.8, 4.4 2.9

and 6.1 2.2 years respectively. Dysphagia requiring intervention

was associated with the shortest survival time (1.4 1.2 years), fol-

lowedby wheelchairdependency (4.4 2.9 years), fecalincontinence

(6.0 3.8 years), presyncope and syncope (6.2 4.3 years), need

for bladder catheterization (6.4 4.1 years) and erectile dysfunction

(8.9 5.0 years). This study reveals important clinical characteris-

tics and indicators of prognosis of MSA based on the natural history

of a large cohort of well-characterized autopsy-confirmed cases of

MSA.

216 Clin Auton Res (2012) 22:207258

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Mechanical stimulation of the feet improves gait

and increases cardiac vagal profile in Parkinsons

disease

F. Barbic1, M. Galli2, M. Canesi3, A. Porta4, V. Cimolin2, V. Bari4,

L. Dalla Vecchia5, F. Dipaola1, V. Pacetti1, F. Meda1, I. Bianchi1,

E. Brunetta1, R. Furlan1

1Unita Sincopi e Disturbi della Postura, Clinica Medica-IRCCS

Istituto Clinico Humanitas, Rozzano (MI), Universita di Milano,

Milano, Italy; 2Laboratorio per lanalisi della postura e del

movimento L. Divieti, Politecnico di Milano, Milano, Italy;3Centro Parkinson, CTO, Milano, Italy; 4Dipartimento di Tecnologie

per la Salute, Istituto Ortopedico Galeazzi, Universita di Milano,

Milano, Italy; 5IRCCS, Fondazione Maugeri, Milano, Italy

Background: Alterations in sensorimotor central integration and/or

peripheral sensory function might play a role in movement disorders

in Parkinsons disease (PD). Body mechanical stimulations was

recently found to improve gait in PD. In addition, alterations in car-

diovascular autonomic control are common in PD, although their

relationships with movement disorders have not been fully addressed.

Aims: We tested the hypothesis that bilateral plantar stimulation can

improve gait and autonomic control of heart rate up to 24 h.Methods: We studied 13 patients with idiopathic PD (mean age

66 2 years, BMI 23 1 kg/m2, HoehnYahr scale 24) on their

habitual pharmacological treatment. Every subject underwent

mechanical pressure (0.8 kg/mm2) at the big toe tip and at the big toe

metatarsal joint (plantar stimulation, PL) on both feet. Gait analysis

and spectral analysis of heart rate variability provided quantitative

indexes to assess movement disorders and cardiac autonomic profile

(HFRR, marker of cardiac vagal modulation) before and 24 h after

plantar stimulation.

Results: Twenty-four hour after PL step mean length and gait velocity

increased (23.3 6.2 from 537.7 40.8 mm and 0.06 0.02 from

0.93 0.09 m/s, respectively) and clock-wise rotation time

decreased (-1.8 0.8 from 8.8 1.2 s). In addition, HFRRincreased (1.2E-04 2.7E-04 from 4.5E-04 1.9E-04 m/sec2)

compared to baseline, suggesting an enhancement of the cardiac vagalmodulation.

Conclusions: 24 h after plantar stimulation, PD patients showed

changes in step length, gait velocity and body rotation time consistent

with an improvement of their movement disorder. Plantar stimulation

induced a concomitant increase in the vagal modulatory activity of

heart rate.

Profound myocardial catecholamine depletion in Lewy

body diseases

D.S. Goldstein, P. Sullivan, T. Jenkins, C. Holmes, M. Basile,

D.C. Mash, I.J. Kopin, Y. Sharabi


Background: Striatal dopamine depletion is a neurochemical hallmark

of Parkinson disease (PD) and a major cause of the characteristic

movement disorder. Accumulating evidence indicates that PD and

other Lewy body diseases also feature loss of cardiac sympathetic

nerves, with decreased tyrosine hydroxylase, the rate-limiting enzyme

in catecholamine biosynthesis, measured by semi-quantitative

immunohistochemistry. We applied a quantitative neurochemical

method to test whether Lewy body diseases characteristically involve

loss of catecholaminergic neurons both in the striatum and the heart,

by assaying putamen and left ventricular apical concentrations of

catecholamines and the catecholamine precursor DOPA, the imme-

diate product of tyrosine hydroxylation, in post-mortem tissue from

patients with PD, pure autonomic failure (PAF, a rare Lewy body

disease that does not involve clinical evidence of central neurode-

generation), or multiple system atrophy (MSA, a non-Lewy body

form of alpha-synucleinopathy).

Methods: Putamen and apical myocardial tissue were obtained at

autopsy within several hours of death in patients with end-stage PD,

PAF, or MSA, and control patients (N = 4, 1, 1, and 6 as of this

writing).

Results: PD patients had strikingly decreased myocardial norepi-

nephrine and dopamine contents (by 93 and 94 %) compared to

controls (p = 0.008, p = 0.001). Decreased myocardial catechol-

amine contents were also evident in the PAF patient but were normal

in the MSA patient. Myocardial and putamen DOPA were decreased

in PD but to a lesser extent (about 2/3) than were the catecholamines.

Post-mortem findings confirmed neuroimaging and neurochemical

data in the same patients during life.

Conclusions: Lewy body diseases are associated with drastic myo-

cardial catecholamine depletion, demonstrating that PD is not only a

brain disease and movement disorder but is a more generalized dis-

ease that involves a form of dysautonomia. The decreases in

norepinephrine and dopamine in the putamen and myocardium seem

greater than explained by denervation alone, consistent with

decreased vesicular storage in residual nerves.

Autonomic dysfunction in Parkinsonian LRRK2

mutation carriers

B. Tijero1, J.C. Gomez Esteban1, K. Berganzo1, V. Llorens2,

H.J.J. Zarranz1

1Movement Disorders and Autonomic Unit, Neurology Service,

Cruces Hospital, Basque Health Service (Osakidetza), Department

of Neurociences, University of the Basque Country, Spain;2NuclearMedicine Service, Cruces Hospital, Baracaldo, Spain

Introduction: The aim of this study is to compare autonomic function

in carriers of the LRRK2 (G2019S and R1441S) mutations and those

with idiopathic Parkinsons Disease (iPD) Patients.

Patients and methods: We studied 25 patients with a diagnosis of PD

according to the UK Parkinsons Disease Society clinical diagnosis

criteria (6 had the G2019S and 6 R1441G, and 13 had iPD without

genetic mutations). All patients completed the SCOPA autonomic

questionnaire, underwent blood pressure and heart rate monitoring

during head up tilt with measurements of plasma norepinephrine,

Valsalva maneuver and deep breathing, recording of sympathetic skin

response (SSR), and cardiac MIBG scintigraphy.

Results: Scores of the SCOPA questionnaire were similar in patients

with and without the LRRK2 mutations. Three of the iPD and one of

the LRRK2 carriers have orthostatic hypotension. During passive tilt,

iPD patients have minor Blood pressure increase than LRRK patients.

Arterial pressure overshoot during phase IV of the Valsalva

maneuver was less pronounced in patients with iPD than LRRK2

mutation carriers. MIBG late (4 h) myocardial/mediastinal uptake

ratios are higher in LRRK2 mutation carriers than iPD patients

(1.51 0.28 vs. 1.32 0.25, p = 0.05) Discussion: Carriers of the

LRRK2 gene mutation had less autonomic impairment than those

with iPD as shown by higher cardiac MIBG uptake and less impair-

ment of autonomic non-invasive test.

Clin Auton Res (2012) 22:207258 217

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Comparison of techniques for non-invasive assessment

of systemic hemodynamics in autonomic function

testing

C. Sims-ONeil, S. Pechnik, L. Sewell, L. Nez, D.S. Goldstein


Background: Neurogenic orthostatic hypotension is a cardinal mani-festation of chronic autonomic failure (CAF). Systemic hemodynamic

measurements include cardiac output (stroke volume times heart rate)

and total peripheral resistance (TPR, mean arterial pressure divided

by cardiac output). Normally, orthostasis decreases stroke volume,

and heart rate and TPR increase reflexively. In CAF, TPR should fail

to increase during orthostasis, because of baroreflex failure. This

study compared three non-invasive methods for measuring orthostatic

hemodynamic changes in CAF-impedance cardiography (BioZ), fin-

ger pulse contour (Nexfin), and gas rebreathing (Innocor).

Methods: A total of 78 subjects, 29 with and 49 without CAF,

underwent simultaneous hemodynamic measurements by BioZ,

Nexfin, or Innocor during supine rest and at 5 min of head-up tilt.

Results: Among supine subjects individual values by the three tech-

niques agreed for stroke volume and TPR. CAF patients had higher

TPR than did controls. During orthostasis, stroke volume decreasedby all three measurements. Clear differences emerged for calculated

orthostatic changes in TPR in CAF patients: BioZ reported a fall,

Nexfin no change, and Innocor an increase. In some patients, the

Innocor rebreathing maneuver itself decreased stroke volume as

indicated by the Nexfin device, especially during orthostasis.

Conclusions: All three non-invasive methods for tracking systemic

hemodynamics yield similar results for TPR in supine subjects, and

TPR during supine rest is increased in CAF. Impedance cardiography

underestimates the orthostatic fall in stroke volume in CAF patients,

resulting in a calculated orthostatic fall in TPR. Gas diffusion over-

estimates the orthostatic fall in stroke volume, resulting in a

calculated orthostatic increase in TPR, due to artifactual effects of the

rebreathing maneuver required for the cardiac output measurement.

Of the three methods, the finger pulse contour approach seems to

track most validly effects of orthostasis on TPR in CAF.

Thursday, November 1, 2012

Oral Presentations

Plenary Lecture

Master and commander: the brain and the autonomic

nervous system

Vaughan G. Macefield, Ph.D.

School of Medicine, University of Western Sydney; Neuroscience

Research Australia, Sydney, Australia

The autonomic nervous system, so named because it operates automat-

icallywithout the need for conscious controlis very much a

delegated system: it faithfully follows a set of instructions to bring

about homeostasis, and attempts to maintain a stable internal environ-

mentin the presenceof disease,yet these presets canbe over-ridden by

the requirements of higher-order control. We have all experienced the

racing heart rate, and the cold, clammy palms associated with anxiety.

Some of us may be in a state of chronic stress and are experiencing an

increasein blood pressure thatwe maybe worriedabout.The point hereis

that the delegated systemthe Commandercan operate without

higher-order control to maintain our blood pressure, our heart rate, our

temperature essentially constant. Yet, the Master can exert higher-order

control that is either volitionally generated, such as during exercise or is

the product of cognitive or affective processes, such as worrying or the

experience of pain. In this talk, I will consider recent neuroimaging data

that highlight the different roles o f cortical and subcortical structures in

the generation of sympathetic outflow related to cardiovascular control.

In particular, I will discuss the advantages of concurrent microneurog-

raphy and functional magnetic resonance imaging (fMRI) in the

identification of functional roles for various bulbar and suprabulbar

structures, with particular reference to medullary and hypothalamic

nuclei, the insula, precuneus and prefrontal cortex.

The middle cerebral artery dilates to sodium

nitroprusside: a combined transcranial Doppler

and near infrared spectroscopy study

J.M Stewart1,2, C.E. Schwartz1, Z.R. Messer2, C.Terilli2,

M.S. Medow1,21Department of Physiology, New York Medical College, Valhalla,

NY, USA; 2Department of Pediatrics, New York Medical College,

Valhalla, NY, USA

Prior studies indicate that the middle cerebral artery (MCA) does not

dilate in response to moderate orthostatic stress or changes in carbon

dioxide. Thus, measurements of cerebral blood flow velocity (CBFv) by

transcranial Doppler ultrasound (TCD) are sufficient to estimate relative

changes in cerebral blood flow under these conditions. Systemically

administered nitric oxide (NO) donors decrease CBFv. However, NO

dilates cerebral arteries of all sizes in primate models. We investigated

whether systemic bolus injection of the NO donor sodium nitroprusside

(SNP) dilates the MCA and whether bolus phenylephrine constricts the

MCA in 10 supine healthy volunteer subjects 1824 years old. WecombinedTCD of the MCAwith nearinfrared spectroscopy(NIRS) over

the frontal cortex. Cerebral oxygenation and total hemoglobin increased

by14 1and15 1 lM/L with 100 lg SNP despite hypotension,and

were reduced by 6 1 and 7 1 lM with 150 lg phenylephrine

despite hypertension. SNP increased NIRS derived cerebral blood flow

estimates by approximately 40 % from baseline, while TCD derived

CBFv decreased by 15 %. Phenylephrine decreased NIRS derived

cerebral blood flow estimates by approximately 11 % from baseline,

while TCDderived CBFvincreased by 5 %. Studies using upright tiltand

lower body negative pressure were performed for comparison with the

literature and demonstrated similar relative changes in NIRS derived

cerebral blood flow and TCD derived CBFv as orthostatic stress pro-

gressed. We conclude that the middle cerebral artery dilates to sodium

nitroprusside and constricts to phenylephrine but does not dilate during

orthostatic stress.

Cerebral oxygenation, heart rate & blood pressure

responses in congenital central hypoventilation

syndrome (CCHS) during exogenous ventilatory

challenges: PHOX2B genotype/CCHS phenotype

association

M.S. Carroll, P.P. Patwari, T.M. Stewart, C.D. Brogadir, A.S. Kenny,

C.M. Rand, D.E. Weese-Mayer

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Center for Autonomic Medicine in Pediatrics, Ann and Robert H.

Lurie Childrens Hospital, Northwestern University Feinberg School

of Medicine, Chicago, IL, USA

Congenital central hypoventilation syndrome (CCHS) is a disorder of

respiratory and autonomic regulation, characterized by hypoventila-

tion and diminished/absent ventilatory responses to hypoxia/

hypercarbia. However, ventilatory responses in CCHS have not been

evaluated subsequent to identification of PHOX2B as the disease-defining gene, and recognition that the longer polyalanine repeat

expansion mutations (PARMs) are typically associated with more

severe clinical features. We therefore hypothesized that cerebral

oxygenation and cardiovascular metrics in response to exogenous

ventilatory challenges (EVC) would show a graded deficit correlated

with PHOX2B genotype among CCHS patients with PARMs. Thirty-

one children and young adults (5 months27 years; 14 female) with

CCHS were tested during wakefulness with 45 separate clinical EVCs

(each with 4 distinct gas mixtures) during continuous comprehensive

physiological monitoring. Three-minute challenges were adminis-

tered between 3 min room-air periods, with minimal ventilatory

support: Hyperoxia (100 % O2), hyperoxia-hypercarbia (95 % O2/

5 % CO2) and hypoxia-hypercarbia (14 % O2/7 % CO2). The fourth

challenge, hypoxia, consisted of 5 or 7 tidal breaths of N2. A com-

parison group of 4 young men (1821 years) were monitored whilereceiving all but the hypoxia challenge. Percent change from baseline

(SEM) was calculated during each challenge for the cerebral near

infrared spectroscopy (cNIRS) channel, mean blood pressure, and

heart rate. Significance was assessed at p\ 0.05 (paired ttest). The 3

most common PARM genotypes were compared to assess genotype-

phenotype association. Though the cNIRS response was not consis-

tently associated with polyalanine repeat length, it was impaired/

attenuated in CCHS versus controls during the hypoxia-hypercarbia

challenge. Blood pressure responses were variable, but showed a

CO2-dependent increase in CCHS. Heart rate was suppressed by

hyperoxia in CCHS, but increased in the combined hypoxia-hyper-

carbia challenge. The heart rate response to the hypoxia-hypercarbia

challenge was consistently correlated with polyalanine repeat length

(blunted response with increasing PARM length). Overall, compre-

hensive physiological evaluation during ventilatory challengesindicated residual responsiveness in CCHS, providing a potential

fulcrum for therapeutic interventions.

Time course of cardiac sympathetic denervation

in Parkinson disease

D.S. Goldstein


Background: Parkinson disease entails not only nigrostriatal dopa-

minergic but also cardiac noradrenergic denervation, which can occur

before clinical onset of the movement disorder. The neuropathologic

process in the heart appears to proceed retrogradely and centripetally.

Localized denervation in the left ventricular myocardial free wall

progresses to diffuse denervation, with late loss of interventricular

septal innervation. We analyzed neuroimaging data from patients with

localized denervation to estimate the loss rate of cardiac catechol-

aminergic neurons in Parkinson disease.

Methods: Serial 18F-dopamine positron emission tomographic scan-

ning data in Parkinson disease patients were reviewed and 4 patients

identified who had localized followed by diffuse denervation.

Localized denervation was defined by free wall18F-dopamine-derived

radioactivity more than 2 standard deviations below the normal mean

and septal radioactivity within 2 standard deviations of the normal

mean. Diffuse denervation was defined by both septal and free wall

radioactivity more than 2 standard deviations below the normal mean.

Results: The time between localized and diffuse denervation averaged

2.5 (SEM) 0.8 years. The mean change in septal radioactivity

during this interval was -56 10 %, corresponding to 22 % loss per

year. In one patient followed over more than 12 years, cardiac sym-

pathetic innervation was normal for 6 years, with subsequent rapid

loss of free wall radioactivity and then equally rapid loss of septal

radioactivity with a delay of about 2 years.

Conclusions: In Parkinson disease, once there is evidence for loss of

sympathetic nerves in the left ventricular free wall, septal denervation

rapidly ensues, resulting in remarkably swift diffuse denervation by

23 years later. Follow-up cardiac sympathetic neuroimaging in

patients with localized cardiac denervation therefore may be a basis

for a novel, quantitative means to assess potential treatments to retard

the loss of catecholaminergic neurons that characterizes Parkinson

disease.

Parental attribution of symptoms in adolescents

with postural tachycardia syndrome and its relation

to child functioning and psychological variables

E.M. Keating1, R.M. Antiel2, K.E. Weiss3, D. Wallace4,

P.R. Fischer5, C. Harbeck-Weber3

1Mayo Medical School, Mayo Clinic, Rochester, MN, USA;2Department of General Surgery, Mayo Clinic, Rochester, MN, USA;3Department of Psychiatry and Psychology, Mayo Clinic, Rochester,

MN, USA; 4Integrative Pain Management, Childrens Mercy

Hospital, Kansas City, MO, USA; 5Department of Pediatric

and Adolescent Medicine, Mayo Clinic, Rochester, MN, USA

Background: Chronic pain is a common symptom in adolescents with

postural orthostatic tachycardia syndrome (POTS), and it is frequently

associated with impairment in functioning. The manner in which

parents respond to childrens pain may predict childrens functional

disability, and parental responses to the pain are related to parental

beliefs about the causes of the pain. The Parent Attribution Ques-

tionnaire (PAQ) was developed to assess these parental attributions

regarding their childs pain. We evaluated parent attributions of

symptoms in adolescents with POTS in order to determine how they

are related to their childs functioning.

Methods: 141 adolescent patients with chronic pain and clinical

symptoms suggestive of POTS were seen in a multidisciplinary

chronic pain clinic at Mayo Clinic. Of these patients, 37 were iden-

tified as having POTS with a postural heart range change of at least 40

beats per minute on tilt table testing. Parents of 114 of these patients

completed a demographic questionnaire and PAQ. The PAQ is a

19-item questionnaire that asks parents to indicate the extent they

believe medical (9 items) and psychosocial factors (10 items) account

for their childs health condition.

Results: In patients with chronic pain who have symptoms suggestive

of possible autonomic dysfunction, higher parental attribution of

symptoms to medical causes was associated with increased levels

of functional disability (r = 0.33, p\ 0.001). Parental attribution of

symptoms to psychological causes was linked to depression only in

patients without POTS (r = 0.53, p\ 0.01) but not in those with

POTS.

Conclusions: Functional disability in adolescents with POTS relates

to the degree to which parents attribute the childs symptoms to a

medical problem. It is likely that helping parents avoid over-accep-

tance of incurable medical problems as causing pain could help

children attain better functioning.

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Cardiovagal sensitivity and orthostatic heart rate

response in young patients with orthostatic intolerance

W. Singer, A.K. Parsaik, E.E. Benarroch, P. Sandroni, P.A. Low

Department of Neurology, Mayo Clinic, Rochester, MN, USA

Background and Objective: Orthostatic intolerance (OI) is increas-

ingly recognized among adolescents but pathophysiologic

mechanisms underlying this condition remain poorly understood.

These patients typically have normal autonomic function as assessed

using standardized autonomic testing. We frequently see high or very

high values for cardiovagal indices in these patients and made the

observation that those with unusually high HR responses to deep

breathing (HRDB) and Valsalva maneuver (VM, Valsalva

ratio = VR) also seem to have the most excessive HR responses to

tilt. Such relationshipif presentwould be intriguing in terms of

mechanisms underlying the magnitude of HR responses to tilt and of

OI; factors such as excessive cardiac vagal modulation and baroreflex

sensitivity might be implicated. We therefore sought to evaluate

whether the magnitude of cardiovagal indices predicts the orthostatic

rise in HR and whether the pattern of findings reveals insights into the

pathophysiology underlying adolescent OI.

Methods: 100 adolescent patients were randomly selected from a

large cohort of patients referred to our laboratory for evaluation of

symptoms of OI. HRDB and VR were quantified using standard

techniques. Vagal baroreflex sensitivity (vBRS) was defined as slope

between systolic blood pressure (BP) decline during phase II and

resulting change in RR interval. HR and BP responses to tilt were

assessed using 30 s data averages, BP responses to the VM were

assessed using systolic BP at the different phases of the maneuver.

Correlations between different parameters were tested using Pear-

sons r.

Results: HRDB and vBRS were not correlated with DHR or DBP

during tilt. However, VR was significantly correlated with DHR

(p = 0.001). While VR was also strongly correlated with the BP

changes during early phase II and phase IV of the VM, as well as the

sum of both, only one of these BP indices (phase IV) was weakly

correlated with DHR during tilt. No correlations were seen between

BP and HR responses to tilt.

Conclusions: These findings argue against excessive cardiac vagal

modulation or excessive BRS underlying the excessive orthostatic rise

in HR in adolescents with OI. The pattern of findings would rather

suggest that the mechanism underlying the excessive orthostatic rise

in HR also results in excessive BP responses to the VM and conse-

quently excessive VR. This putative mechanism remains subject to

further study. Supported by NIH (K23NS075141, U54NS065736,

UL1RR24150) and Mayo Funds.

Parental response to pain: the impact on functional

disability, depression, anxiety, and pain acceptancein adolescents with chronic pain and orthostatic

intolerance

R.M. Antiel1, E.M. Keating2, K.E. Weiss3, D.P. Wallace4,

P.R. Fischer5, C. Harbeck-Weber3

1Department of General Surgery, Mayo Clinic, Rochester, MN, USA;2Mayo Medical School, Rochester, MN, USA;3Department of Psychiatry and Psychology, Mayo Clinic, Rochester,

MN, USA; 4Integrative Pain Management, Childrens Mercy

Hospital, Kansas City, MO, USA; 5Department of Pediatric

and Adolescent Medicine, Mayo Clinic, Rochester, MN, USA

Background: Parental responses to pain may have an important

impact on adolescent pain outcomes. Approximately 10 % of

adolescents suffer from autonomic dysfunction marked by ortho-

static intolerance, severe fatigue, and chronic pain. We sought to

examine if parental responses to these symptoms are related to

their childs functioning, psychological well-being, and pain

acceptance.

Methods: Participants included 141 adolescents with chronic pain

and symptoms of orthostatic intolerance who were seen in a mul-

tidisciplinary pain clinic at the Mayo Clinic. Of the 141 patients, 37

(26 %) had excessive postural tachycardia (PT) with a heart rate

change of at least 40 bpm on tilt table testing. Participants com-

pleted the Functional Disability Inventory, the Center of

Epidemiological StudiesDepression Scale, the Spence Childrens

Anxiety Scale, and the Chronic Pain Acceptance Questionnaire,

adolescent version. Parents of 103 of these patients completed the

Parent Response to Pain QuestionnaireRevised, which measures 4

theoretically driven parental factors: solicitous behaviors, secondary

gain, promoting adaptive behavior, and encouragement of specific

pain management.

Results: Parent solicitous behaviors were significantly related to

anxiety (r = 0.21, p\ 0.05). Parent report of secondary gain was

correlated with depression (r = 0.57, p\ 0.01) and negatively related

to acceptance (r = -0.40, p\ 0.05). Upon further examination of the

sub-sample of patients with excessive PT, parent report of secondary

gain was related to functional disability (r = 0.39, p\ 0.05) and

parent encouragement to use specific pain management skills was

inversely associated with depression (r = -0.069, p\0.05).

Conclusions: Differential parental responses to pain are significantly

related to adolescent anxiety, depression, and pain acceptance. Fur-

thermore, in patients with co-morbid orthostatic intolerance parental

responses are associated with functional disability and depression.

These findings suggest that parental responses to adolescent pain are

related to patient outcomes and could have implications for effective

interventions.

Relationship between ganglionic long-term potentiation(LTP) and homeostatic synaptic plasticity

in experimental autoimmune autonomic

ganglionopathy (EAAG)

Z. Wang, S. Vernino

UT Southwestern University, Dallas, TX, USA

The autonomic nervous system must be able to adapt to maintain

homeostasis. Plasticity of ganglionic synaptic transmission repre-

sents one important mechanism of autonomic adaptation. We have

shown that homeostatic plasticity of ganglionic neurotransmission

occurs in EAAG. In EAAG, there is a reduction in synaptic gan-

glionic AChRs followed by a compensatory increase in

neurotransmitter release to help offset the deficit in synaptic trans-mission. Homeostatic plasticity is quite different from classical use-

dependent LTP. Both types of plasticity occur in autonomic ganglia,

so the ganglionic synapse is an ideal system in which to study the

interrelationship between these two forms of synaptic plasticity. We

studied synaptic transmission in isolated mouse superior cervical

ganglia using microelectrode and patch clamp electrophysiology

methods. High frequency stimulation (HFS) of the preganglionic

nerve (20 Hz for 20 s) in control ganglia induces a long-lasting

increase in synaptic transmission due to increased probability of

synaptic release. A second HFS does not produce further enhance-

ment. Ganglia from mice with EAAG fail to show LTP. Inhibitors

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of nitric oxide synthase prevent the induction of LTP in control

ganglia and also cause a normalization of presynaptic release in

EAAG ganglia. These findings indicate that homeostatic plasticity of

synaptic transmission (as occurs in the EAAG model) shares com-

mon molecular mechanism with use-dependent plasticity (ganglionic

LTP). The implication is that pharmacological manipulation of

ganglionic LTP may be a useful therapeutic option for patients with

autonomic disorders.

Methionine sulfoxide reductase A: a novel molecular

determinant of baroreflex sensitivity, blood pressure

and hypertensive end-organ damage

R. Sabharwal, R. El Accaoui, M.K. Davis, J.A. Goeken, R. Weiss,

F.M. Abboud, D. Meyerholz, M.W. Chapleau

The University of Iowa and Veterans Affairs Medical Center,

Iowa City, IA, USA

Methionine sulfoxide reductase-A (MsrA) selectively reverses oxi-

dation of methionine residues in proteins, thereby protecting against

oxidative stress-induced cellular damage and dysfunction. We

hypothesized that MsrA is required for normal autonomic and blood

pressure (BP) regulation, and protects against hypertension-induced

end-organ damage. BP, heart rate (HR) and locomotor activity were

measured in MsrA deficient (n = 13) and control C57BL/6 (n = 7)

mice by telemetry, before and during infusion of angiotensin II (Ang

II) (1,000 ng/kg/min for 4 weeks). Under basal conditions, MsrA-/-

mice exhibited mild hypertension (117 3 vs. 107 2 mmHg) and

decreased locomotor activity. During periods when activity levels

were similar, the hypertension in MsrA-/- mice was exacerbated

(135 2 vs. 103 2 mmHg). MsrA-/- mice also exhibited

decreases in spontaneous baroreflex sensitivity (BRS, sequence

technique) (0.9 0.1 vs. 2.2 0.1 ms/mmHg) and cardiovagal tone

(HR response to cholinergic receptor blocker methylatro-

pine = +32 5 vs. +100 17 bpm); and increases in BP variability

(BPV) and sympathetic tone (HR response to beta adrenergic receptor

blocker propranolol) (P\0.05). Ang II increased mean BP, BPV and

sympathetic tone; and decreased BRS and vagal tone, with MsrA-/-

mice exhibiting markedly enhanced responses (P\0.05). Adminis-

tration of the antioxidant tempol (1 mM, drinking water) reversed the

Ang II-induced hypertension and autonomic dysregulation. Ang II-

infused MsrA-/- mice (n = 10) exhibited left ventricular dysfunc-

tion, increased diameter of the ascending aorta (echocardiography),

and abdominal aortic aneurysms. We conclude that MsrA: (1) is

required for normal BP, BRS and sympathovagal balance under basal

conditions; (2) protects against Ang II-induced hypertension, auto-

nomic dysfunction and end-organ damage; and (3) is a novel

therapeutic target in hypertension. (HL14388, VA)

Baroreflex induced changes in stressed blood volume,not cardiac output curve, is the central mechanism

preventing volume load induced pulmonary edema

T. Sakamoto, T. Kakino, K. Sunagawa

Department of Cardiovascular Medicine, Kyushu University,

Fukuoka, Japan

Background: We previously demonstrated that baroreflex failure

predisposes volume induced pulmonary edema. Since the baroreflex

changes both cardiac and vascular properties, how exactly the

baroreflex failure causes volume intolerance remains unknown. The

aim of this investigation is to examine the mechanism of baroreflex

failure induced volume intolerance.

Method: In 6 anesthetized dogs, we isolated carotid sinuses and

controlled intra-carotid sinus pressure (CSP), while measuring the left

(PLA) and right (PRA) atrial pressure, arterial pressure (AP) and

aortic flow (CO). We closed the baroreflex feedback loop by matching

CSP to instantaneous AP, whereas opened by maintaining CSP con-

stant independent of AP. We infused total of 22.5 ml/kg of dextran in

an increment of 2.5 ml/kg. In each step, we measured PLA, PRA and

CO in both open and closed loop conditions. We fitted the CO curve

to a logarithmic function and determined its functional slope S, as a

measure of cardiac performance, for the left (SL) and right (SR)

ventricle. We determined stressed blood volume and mean circulatory

filling pressure (Pmcf).

Results: Increases in PLA was lower in the closed loop than in the

open loop condition (9 3 vs. 12 5 mmHg, p\0.05). Both SL

and SR were lower in the closed loop than in the open loop condition

(SL: 23 5 vs. 27 6 ml/kg/min, p\0.01, SR: 23 5 vs.

27 6 ml/kg/min, p\ 0.01) indicating that the baroreflex lowers

cardiac performance against volume overload. Pmcf after infusion of

22.5 ml/kg of dextran was lower in the closed loop than in the open

loop condition (10.8 0.5 vs. 12.8 1.1 mmHg, p\ 0.005).

Conclusion: In response to volume challenge, the baroreflex lowered

cardiac performance and prevented the increases in Pmcf. Although

those two responses have antagonizing impact on PLA, the fact that

the baroreflex lowered PLA indicates that the baroreflex induced

changes in stressed volume is the central mechanism preventing

pulmonary edema.

Prostaglandin D synthase is critical for development

of chronic angiotensin II-salt hypertension in the rat

G.D. Fink, N. Asirvatham-Jeyaraj

Department of Pharmacology and Toxicology, Michigan State

University, East Lansing, MI, USA

Chronic infusion of angiotensin II (150 ng/kg/min, sc) into rats

ingesting a high salt diet (4.0 % NaCl) produces sustained hyper-

tension (AngII-salt HT) caused in part by increased splanchnic

sympathetic nerve activity. Previous work suggests that cyclooxy-

genase products generated in the brain during the first few days of

exposure to angiotensin II are necessary for these effects. Analyses of

eicosanoid pathway gene expression in the brain during the early

phase of AngII-salt HT highlighted lipocalin-type prostaglandin D

synthase (L-PGDS) as a possible critical element in the response. To

test that idea we continuously administered the highly selective

L-PGDS inhibitor AT-56 into the brain of rats via intracerebroven-

tricular (icv) infusion (6.6 lmol/h). We then induced our standard

14-day model of AngII-salt HT starting 5 days after icv AT-56

administration had begun. Rats receiving only icv vehicle served as

controls. Blood pressure was measured continuously throughout theexperiment by radiotelemetry. Sympathetic control of blood pressure

was estimated from the depressor response to acute ganglion blockade

with hexamethonium (30 mg/kg, ip). Control rats showed typical

elevations in blood pressure during AngII infusion and a significantly

enhanced depressor response to ganglion blockade on day 8 after

starting AngII. Rats receiving icv AT-56 exhibited no change in basal

blood pressure but had a markedly and significantly reduced blood

pressure and sympathetic response to AngII infusion compared to

control rats. Systemic administration of AT-56 via continuous sub-

cutaneous infusion (6.6 lmol/h) also completely prevented the

increases in blood pressure and sympathetic pressor activity normally

Clin Auton Res (2012) 22:207258 221

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observed during AngII infusion. These studies reveal that L-PGDS,

likely in the brain, is a necessary component of AngII-salt HT and

sympathoexcitation. Since systemic inflammation, sleep deprivation

and obesity are all associated with increased brain levels of prosta-

glandin D and sympathoexcitation, our results may have broad

implications for understanding neurogenic forms of hypertension.

The central chemoreflex activation inducessympathoexcitation and resets the arterial baroreflex

without compromising its pressure stabilizing function

K. Saku, K. Sunagawa

Department of Cardiovascular Medicine, Kyushu University,

Fukuoka, Japan

Background: The augmented chemoreflex and impaired baroreflex in

heart failure result in excessive sympathoexcitation and poor prog-

nosis. However, how the chemoreflex interacts with the baroreflex

remains unknown. The purpose of this investigation was to examine

the impact of chemoreflex on the baroreflex function under the open-

loop condition.

Methods and Results: In 7 vagotomized rats, we vascularily isolated

the bilateral carotid sinuses, controlled carotid sinus pressure (CSP)

and measured SNA at the celiac ganglia and arterial pressure (AP).

We activated the central chemoreflex by hypercapnia (inhalation of

3 % CO2). Under the open baroreflex loop, we compared the changes

in AP and SNA in response to CSP with/without hypercapnia.

Increasing CSP stepwise from 60 to 170 mmHg sigmoidally sup-

pressed SNA, whereas the SNA suppression linearly decreased AP.

Hypercapnia markedly increased SNA (DSNA = 53.4 7.1 %,

p\0.01) irrespective of CSP indicating the resetting of the CSP

SNA relationship (the neural arc). Hypercapnia increased the setpoint

pressure (168.6 8.2 vs. 188.3 8.1 mmHg, p\ 0.01) of neural

arc, whereas did not alter the SNAAP relationship (peripheral arc).

The total loop gain from CSP to AP at the operating point remained

unchanged (-1.09 0.13 vs. -1.43 0.18, p = ns). Random per-

turbation of CSP with binary white noise sequences indicated that

hypercapnia did not affect the transfer functions of the neural or

peripheral arcs. Therefore, the chemoreflex activation did not impact o n

the baroreflex dynamic characteristics of pressure stabilizing function.

Conclusion: Hypercapnia resets the baroreflex neural arc upward and

increases arterial pressure, while does not affect baroreflex pressure

stabilizing characteristics. We conclude that the central chemoreflex

modifies hemodynamics via sympathoexcitation without compro-

mising baroreflex function. The augmented chemoreflex in heart

failure cannot be responsible for the baroreflex dysfunction. How

chemoreflex induced changes in hemodynamics contribute to CO2homeostasis remains to be seen.

Advanced techniques and pitfalls of autonomic function

assessment and arrhythmia analysis in the mouse model

C.M. Welzig1, J.B. Galper2

1Department of Neurosciences, Medical University of South Carolina,

Charleston, SC, USA; 2Molecular Cardiology Research Institute,

Tufts Medical Center, Boston, MA, USA

Background: Mice are very frequently employed as a mammalian

research model and are used in a wide spectrum of experimental

protocols. However, the study of autonomic function and disorders as

well as cardiac arrhythmia is relatively uncommon compared to larger

animals or humans, since high quality continuous long term ECG and

arterial blood pressure (APB) recordings as well as the techniques for

analysis of heart rate (HR), heart rate variability (HRV) and

arrhythmia detection in the mouse present technical and computa-

tional challenges.

Methods: We present data from several studies involving murine ECG

and ABP signals from implanted wireless radiofrequency transmitters.

We describe and compare different methods of digital signal pro-

cessing, heart beat and arrhythmia detection and classification,

computation of baroreflex sensitivity, time domain and frequency

domain HRV parameters, construction of composite plots for

dynamics of HR and HRV data over time during interventional

studies from an aspect specific to the mouse model. We illustrate

technical challenges, common mistakes and solutions throughout the

process from telemetry to the analysis results presentation.

Results: During a decade of experience with murine ECG signal

analysis, we have developed a toolbox of techniques specifically

tailored to the mouse model. Here we demonstrate the technical

requirements for signal quality and processing, how wavelet based

visualizations and spectrograms can significantly aid in the charac-

terization of dynamic changes and the detection of anomalies and

artifacts and how specific plotting techniques can reveal unexpected

findings such as multiple transient atrial pacemakers during carbachol

challenge experiments. We show the use of machine learning algo-

rithms for the automatic detection and reliable subclassification of

ventricular tachycardia and premature contractions after myocardial

infarction with pattern recognition techniques such as artificial neural

networks in large data sets from long term ECG signals. Finally, we

show that parallel processing and general-purpose computing on

graphics processing units allow for accelerated analysis of continuous

mouse ECG recordings over days with millions of heart beats as well

as for providing near real-time computation of advanced analysis

output during experiments.

Streeten Lecture

The ups and downs of blood pressure & baroreflex

sensitivitya historical and personal perspective

Mark W. Chapleau, Ph.D.

University of Iowa and Veterans Affairs Medical Center, Iowa City,

IA, USA

The baroreceptor reflex is a powerful regulator of blood pressure

(BP). Increases and decreases in BP are buffered by baroreflex-

mediated autonomic and circulatory adjustments. By minimizing BP

variability, the baroreflex protects against ischemia, syncope and end-

organ damage (e.g., vascular and cardiac hypertrophy, renal failure,

stroke). The baroreflex also favorably influences cardiac sympath-

ovagal balance, and consequently affects the electrical properties ofthe heart. Decreased baroreflex sensitivity (BRS) for control of heart

rate (HR) predicts future arrhythmias and decreased survival in

patients with myocardial infarction, heart failure and diabetes;

increased BRS is protective. In my presentation, I will review

experimental approaches and key discoveries related to the physiol-

ogy and pathophysiology of the baroreceptor reflex, with emphasis on

studies leading up to and including work in my laboratory. Results

obtained using a variety of approaches will be presented including

recordings of baroreceptor afferent and sympathetic efferent nerve

activity; telemetry-based measurements of cardiovascular and derived

autonomic indices in conscious, genetically modified mice; electro-

physiological and imaging studies of isolated baroreceptor neurons in

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culture; and viral vector-mediated gene transfer. Topics to be dis-

cussed include: (1) Ion channels determining the mechanosensitivity

and excitability of baroreceptor afferents; (2) Modulation of afferent

BRS by autocrine/paracrine factors; (3) Sensory and central mecha-

nisms mediating adaptation and resetting of the baroreflex in

hypertension; (4) Mechanisms of dysautonomia in mouse models of

disease and aging; and (5) Future directions for research. (NIH

HL14388, US Dept Vet Aff, AHA)

Blunted osmopressor response in familial dysautonomia

N. Goulding, L. Norcliffe-Kaufmann, J. Martinez, D. Roncevic,

L. Stok, F. Axelrod, H. Kaufmann

Dysautonomia Center, New York University School of Medicine,

New York, NY, USA

Drinking pure water markedly increases blood pressure in patients with

chronic autonomic failure because water-induced hypo-osmolarity,

sensed by peripheral osmoreceptors, triggers sympatho-excitation likely

arising from a spinal mechanism. Osmosensory transduction involves

transient receptor potential vanilloid 4 channels (TRPV4) expressed onafferent neurons with their cell bodies in the dorsal root ganglia (DRG).

Patients with familial dysautonomia (FD, hereditary sensory and auto-

nomic neuropathy type-III) havea reduced number of afferent neurons in

the DRG. The aim of our study was to investigate whether a pronounced

osmopressor response was alsopresent in patientswith FD. Ninepatients

withFD and 6 withchronic autonomic failureparticipated in thisstudy (5

with MSA and 1 with PAF). Beat-to-beat BP was recorded in a supine

position before and following the ingestion of 500 ml of room temper-

ature water for 30 min. As expected, in patients with autonomic failure,

mean blood pressure (MBP) increased significantly after water ingestion

(from 104 13 to 128 20 mmHg, p\0.05, max response

D19 9 mmHg, p\0.01). In contrast, in patients with FD, water

ingestion did not increase MBP significantly over the 30 min period

(90 13to94 13 mmHg, NS, max responseD7 11 mmHg, NS,).

Thus, the response to water drinking differed significantly between thetwo groups (2-way ANOVA: p\0.0001). These findings suggest an

absence of functional peripheral osmoreceptors in FD patients and may

have therapeutic implications.

Paradox elevations in angiotensin II, independent

of plasma renin activity, contribute to the supine

hypertension of primary autonomic failure

A.C. Arnold, L.E Okamoto, C. Shibao, A. Gamboa, S.R. Raj,

D. Robertson, I. Biaggioni

Division of Clinical Pharmacology, Vanderbilt University School

of Medicine, Nashville, TN, USA

At least 50 % of primary autonomic failure [AF] patients exhibit

supine hypertension, despite profound impairments in sympathetic

activity. Plasma renin activity is often undetectable in AF suggesting

renin mechanisms are not involved. However, since aldosterone levels

are preserved, we examined the status and contribution of the renin-

angiotensin [Ang] system in AF. Supine plasma Ang peptides were

measured in hypertensive AF patients [AF-HT, n = 18], normoten-

sive patients [AF-NT, n = 11] and matched healthy subjects

[n = 10]. Despite suppressed renin activity, total renin concentration

was intact [16 5 AF-HT vs. 11 4 AF-NT vs. 7 1 pg/mL

healthy; p = 0.29], and plasma prorenin was selectively elevated in

hypertensive AF patients [2.0 0.5 AF-HT vs. 0.7 0.1 AF-NT vs.

0.6 0.1 ng/mL healthy; p\ 0.05]. While levels of Ang I were

similar among groups, Ang II was paradoxically elevated [39 4

AF-HT vs. 42 6 AF-NT vs. 27 4 pg/mL healthy; p\ 0.05] in

AF. In contrast, Ang-(17) was suppressed in AF patients [7 1 AF-

HT vs. 4 1 AF-NT vs. 22 6 pg/mL healthy; p\ 0.05]. The Ang

II AT1 receptor antagonist losartan [50 mg, PO] significantly reduced

supine systolic blood pressure [25 15 mmHg at 6 h after admin-

istration; p\0.05] in 9 AF-HT patients. These findings suggest an

imbalance in Ang II and Ang-(17) activity in AF independent of

hypertensive status. The source of Ang II in the absence of plasma

renin activity is still under investigation. The loss of renin activity is

not due to reduced renin content but may result from low substrate

availability or defective enzyme activation. Prorenin levels are ele-

vated in hypertensive AF patients, which could stimulate Ang II

generation and actions. Regardless, Ang II appears to contribute to the

supine hypertension of AF. Collectively, these patients offer a unique

model to study cardiovascular regulation and Ang II production in the

absence of autonomic and traditional renin influences.

Chronic effects of aliskiren versus hydrochlorothiazide

on sympathetic neural responses to head-up tilt

in hypertensive seniors

Y. Okada1,2, S.S. Jarvis1,2, S.A. Best1,2, T.B. Bivens1, R.L. Meier1,

B.D. Levine1,2, Q. Fu1,2

1Institute for Exercise and Environmental Medicine, Texas Health

Presbyterian Hospital Dallas, TX, USA; 2UT Southwestern Medical

Center, Dallas, TX, USA

The cardiovascular risk remains high in hypertensives even with ade-

quate blood pressure (BP) control. One possible mechanism may be

persistent sympathetic activation via the baroreflex. We tested thehypothesis that a direct renin inhibitor, aliskiren, would reduce BP

without sympathetic activation, contrary to a diuretic, hydrochlorothia-

zide (HCTZ), in elderly hypertensives. Twelve hypertensives [stage I

hypertension, 64 1 (SE) years] were treated either with aliskiren

(n = 7, 300 mg daily) or HCTZ (n = 5, 25 mg daily) for 6 months.

Muscle sympathetic nerve activity (MSNA), BP, heart rate (HR) and

cardiac output (Qc) were measured supine and during a graded head-up

tilt (HUT; 5-min 30 and20-min 60) before and after treatment. Plasma

norepinephrine and aldosterone were also assessed. Both groups had

similar reductions in 24 h am

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