clinical autonomic research, issue 22, 2012

ABSTRACTS

23rd INTERNATIONAL SYMPOSIUM ON THE AUTONOMICNERVOUS SYSTEM

Atlantis ResortParadise Island, BahamasOctober 31–November 3, 2012

Preliminary Program

WEDNESDAY, OCTOBER 31, 2012

6:00–7:00 PM Registration

Imperial Foyer South I

7:00–7:15 PM Welcome—Dr. Michael Joyner, President

Imperial Ballroom CD

Autonomic Failure: PAF, MSA, Parkinson’s DiseaseChairs: Eduardo Benarroch & Steven Vernino

7:15–7:30 PM Alpha synuclein as a cutaneous biomarker of Parkinson diseaseC.H. Gibbons, N. Wang, J. Lafo, R. Freeman

Boston, MA, USA

7:30–7:45 PM CSF biomarkers of central and peripheral catecholamine deficiency in synucleinopathiesD.S. Goldstein, L. Sewell, C. Holmes, C. Sims-O’Neil, Y. Sharabi

Bethesda, MD, USA

7:45–8:00 PM Prognostic indicators and clinical spectrum of MSA based on autopsy-confirmed casesJ.J. Figueroa, A.K. Parsaik, W. Singer, P. Sandroni, E.E. Benarroch, P.A. Low, J.H. Bower

Rochester, MN, USA

8:00–8:15 PM Mechanical stimulation of the feet improves gait and increases cardiac vagal profile in Parkinson’s diseaseF. 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

8:15–8:30 PM Profound myocardial catecholamine depletion in Lewy body diseasesD.S. Goldstein, P. Sullivan, T. Jenkins, C. Holmes, M. Basile, D.C. Mash, I.J. Kopin, Y. Sharabi

Bethesda, MD, USA

8:30–8:45 PM Autonomic dysfunction in Parkinsonian LRRK2 mutation carriersB. Tijero, J.C. Gomez Esteban, K. Berganzo, V. Llorens, H.J.J. Zarranz

Bilbau, Spain

8:45–9:00 PM Comparison of techniques for non-invasive assessment of systemic hemodynamics in autonomic function testingC. Sims-O’Neil, S. Pechnik, L. Sewell, L. Nez, D.S. Goldstein

Bethesda, MD, USA

THURSDAY, NOVEMBER 1, 2012

7:30–8:00 AM Breakfast & ExhibitsImperial Ballroom B

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Clin Auton Res (2012) 22:207–258

DOI 10.1007/s10286-012-0175-5

8:00–8:45 AM Plenary LectureMaster and commander: the brain and the autonomic nervous systemVaughan 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

8:45–9:00 AM The middle cerebral artery dilates to sodium nitroprusside: a combined transcranial Doppler and near infraredspectroscopy studyJ.M Stewart, C.E. Schwartz, Z.R. Messer, C. Terilli, M.S. Medow,

Valhalla, NY, USA

9:00–9:15 AM Cerebral oxygenation, heart rate & blood pressure responses in congenital central hypoventilation syndrome (CCHS)during exogenous ventilatory challenges: PHOX2B genotype/CCHS phenotype associationM.S. Carroll, P.P. Patwari, T.M. Stewart, C.D. Brogadir, A.S. Kenny, C.M. Rand, D.E. Weese-Mayer

Chicago, IL, USA

9:15–9:30 AM Time course of cardiac sympathetic denervation in Parkinson diseaseD.S. Goldstein

Bethesda, MD, USA

9:30–9:45 AM Parental attribution of symptoms in adolescents with postural tachycardia syndrome and its relation to childfunctioning and psychological variablesE.M. Keating, R.M. Antiel, K.E. Weiss, D. Wallace, P.R. Fischer, C. Harbeck-Weber

Rochester, MN, USA

9:45–10:00 AM Cardiovagal sensitivity and orthostatic heart rate response in young patients with orthostatic intoleranceW. Singer, A.K. Parsaik, E.E. Benarroch, P. Sandroni, P.A. Low

Rochester, MN, USA

10:00–10:15 AM Parental response to pain: the impact on functional disability, depression, anxiety, and pain acceptance in adolescentswith chronic pain and orthostatic intoleranceR.M. Antiel, E.M. Keating, K.E. Weiss, D.P. Wallace, P.R. Fischer, C. Harbeck-Weber

Rochester, MN, USA

10:15–10:30 AM Coffee BreakImperial Ballroom B

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

10:30–10:45 AM Relationship between ganglionic long-term potentiation (LTP) and homeostatic synaptic plasticity in experimentalautoimmune autonomic ganglionopathy (EAAG)Z. Wang, S. Vernino

Dallas, TX, USA

10:45–11:00 AM Methionine sulfoxide reductase A: a novel molecular determinant of baroreflex sensitivity, blood pressure andhypertensive end-organ damageR. Sabharwal, R. El Accaoui, M.K. Davis, J.A. Goeken, R. Weiss, F.M. Abboud, D. Meyerholz, M.W. Chapleau

Iowa City, IA, USA

11:00–11:15 AM Baroreflex induced changes in stressed blood volume, not cardiac output curve, is the central mechanism preventingvolume load induced pulmonary edemaT. Sakamoto, T. Kakino, K. Sunagawa

Fukuoka, Japan

11:15–11:30 AM Prostaglandin D synthase is critical for development of chronic angiotensin II-salt hypertension in the ratG.D. Fink, N. Asirvatham-Jeyaraj

East Lansing, MI, USA

11:30–11:45 AM The central chemoreflex activation induces sympathoexcitation and resets the arterial baroreflex withoutcompromising its pressure stabilizing functionK. Saku, K. Sunagawa

Fukuoka, Japan

11:45–12:00 PM Advanced techniques and pitfalls of autonomic function assessment and arrhythmia analysis in the mouse modelC.M. Welzig, J.B. Galper

Charleston, SC, USA

12:00–1:30 PM Lunch & Poster Session IImperial Ballroom B

1:30–3:30 PM Free Time3:30–4:00 PM AAS Business meeting

Imperial Ballroom CD

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Awards SessionChairs: Michael Joyner & Wouter Wieling

4:00–4:45 PM Streeten LectureThe ‘‘ups and downs’’ of blood pressure & baroreflex sensitivity—a historical and personal perspectiveMark Chapleau, Ph.D

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

4:45–5:00 PM Streeten Travel Fellowship AwardBlunted osmopressor response in familial dysautonomiaN. Goulding, L. Norcliffe-Kaufmann, J. Martinez, D. Roncevic, L. Stok, F. Axelrod, H. Kaufmann

New York, NY, USA

5:00–5:15 PM FMS/Penaz Wesseling AwardParadox elevations in angiotensin II, independent of plasma renin activity, contribute to the supine hypertension ofprimary autonomic failureA.C. Arnold, L.E Okamoto, C. Shibao, A. Gamboa, S.R. Raj, D. Robertson, I. Biaggioni

Nashville, TN, USA

5:15–5:30 PM FMS/Penaz Wesseling AwardChronic effects of aliskiren versus hydrochlorothiazide on sympathetic neural responses to head-up tilt in hypertensiveseniorsY. Okada, S.S. Jarvis, S.A. Best, T.B. Bivens, R.L. Meier, B.D. Levine, Q. Fu

Dallas, TX, USA

5:30–5:45 PM AAS Travel AwardAssociation 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

5:45–6:00 PM AAS Travel AwardThe change in arterial stiffness during ganglionic blockade is associated with sympathetic nerve activity in womenJ.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


7:30–8:15 AM Plenary LectureAutonomic 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

8:15–8:30 AM Catheter based renal nerve ablation does not elicit a central sympatholytic response in difficult to control hypertensivepatientsJ. Brinkmann, K. Heusser, B.M. Schmidt, J. Menne, G. Klein, H. Haller, A. Diedrich, J. Jordan, J. Tank

Hanover, Germany

8:30–8:45 AM Methodological considerations for assessing resting spontaneous baroreflex control of muscle sympathetic nerveactivity in humansS.W. Holwerda, H. Yang, J.R. Carter, P.J. Fadel

Columbia, MO, USA

8:45–9:00 AM Sleep deprivation augments cardiovascular reactivity to acute stress in humansH. Yang, J.J. Durocher, R.A. Larson, J.P. DellaValla, J.R. Carter

Houghton, MI, USA

9:00–9:15 AM Susceptibility to inducible ventricular arrhythmia in type I diabetic Akita mice is dependent on abnormalities of Ca2+

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

Boston, MA, USA

9:15–9:30 AM Sympathetic hyper-responsiveness In takotsubo cardiomyopathyL. Norcliffe-Kaufmann, J. Martinez, H. Kaufmann, H. Reynolds

New York, NY, USA

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9:30–9:45 AM Improvement of obesity-associated insulin resistance during autonomic blockadeA. Gamboa, L. Okamoto, A. Arnold, S. Raj, A. Diedrich, N. Abumrad, I. Biaggioni

Nashville, TN, USA

9:45–11:15 AM Coffee & Poster Session IIImperial Ballroom B

Postural Orthostatic Tachycardia Syndrome (POTS)Chairs: Satish Raj & Wolfgang Singer

11:15–11:30 AM Beta-2 adrenergic receptor polymorphism and hemodynamics in patients with postural orthostatic tachycardiasyndrome and healthy controlsM.N. Manento, L.R. Gullixson, K.K. Nickander, P.A. Low, J.H. Eisenach

Rochester, MN, USA

11:30–11:45 AM The pathophysiology of neuropathic and non-neuropathic postural tachycardia syndromeC. Gibbons, I. Bonyhay, A. Benson, R. Freeman

Boston, MA, USA

11:45–12:00 PM Deconditioning in patients with orthostatic intoleranceA. Parsaik, T.G. Allison, W. Singer, D.M. Sletten, M.J. Joyner, E.E. Benarroch, P.A. Low, P. Sandroni

Rochester, MN, USA

12:00–12:15 PM Preliminary data on the durability of improved symptoms, functioning, and psychological distress in adolescents withPOTS treated in a multidisciplinary treatment programB.K. Bruce, T.E. Harrison, K.E. Weiss, P.R. Fischer, S.P. Ahrens, W.N. Timm

Rochester, MN, USA

12:15–12:30 PM Objective measures of sleep in patients with POTSS.J. Kizilbash, P.R. Fischer, R.M. Lloyd

Rochester, MN, USA

12:30–12:45 PM Reduced alpha-adrenergic vascular response: the physiological link between postural orthostatic tachycardiasyndrome and neurally mediated syncopeN. Mehta, M. Tavora-Mehta, J.C. Guzman, C.A. Morillo

Hamilton, ON, Canada

12:45–7:00 PM Free Time

7:00–10:00 PM Presidential Dinner

Ripples Pool Deck

SATURDAY, NOVEMBER 3, 2012


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

8:00–8:15 AM Multi-scale glycemic variability affects brain structure and functional outcomes in type 2 diabetes mellitusX. Cui, A. Galica, B. Manor, A. Abduljalil, C.-K. Peng, V. Novak

Boston, MA, USA

8:15–8:30 AM The laser Doppler imaging axon-reflex flare area—a novel regression thresholding based technique to assessneurovascular functionT. Siepmann, B.M. Illigens, R. Freeman, C. Gibbons

Boston, MA, USA

8:30–8:45 AM Long-term outcomes in autoimmune autonomic ganglionopathyS. Muppidi, E.B. Spaeth, C. Gibbons, S. Vernino

Dallas, TX, USA

8:45–9:00 AM Type I diabetic Akita mice demonstrate decreased heart rate variability and increased inducibility of ventriculartachycardia which are reversed by statinsC.M. Welzig, H.-J. Park, M. Rajab, M. Aronovitz, H. Jin, M.S. Link, J.B. Galper

Charlston, SC, USA

9:00–9:15 AM The quantification of sudomotor nerve fibers: a multicenter study in diabetesC.H. Gibbons, J. Lafo, G. Smith, R. Singleton, R. Freeman

Boston, MA, USA

9:15–10:45 AM Coffee & Poster Session IIIImperial Ballroom B

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Orthostatic Hypotension and SyncopeChairs: Rasna Sabharwal & Darren Casey

10:45–11:00 AM Treatment of neurogenic orthostatic hypotension (NOH) with droxidopa: results from a multicenter, double-blind,randomized, placebo-controlled, parallel group, induction design studyH. Kaufmann, P. Low, I. Biaggioni, C.J. Mathias, R. Freeman, L.A. Hewitt

New York, NY, USA

11:00–11:15 AM What is MSNA doing at the onset of syncope?D.L. Jardine

Christchurch, New Zealand

11:15–11:30 AM A meta-analysis of pharmacologic treatments of orthostatic hypotensionC.H. Gibbons, S. Raj

Boston, MA, USA

11:30–11:45 AM Increasing cardiac output does not change middle cerebral artery blood velocity in the hyperthermic humanC.G. Crandall, T. Seifert, T.E. Wilson, M. Bundgaard-Nielsen, N.H. Secher

Dallas, TX, USA

11:45–12:00 PM Patterns of diagnosis and intervention in neurogenic orthostatic hypotension (NOH): a patient-flow studyH. Kaufmann, R.E. Paquette

New York, NY, USA

12:00–12:30 PM Open Discussion & Adjourn

POSTER SESSION IThursday, November 1, 201212:00–1:30 PM

Autonomic Failure: PAF, MSA, Parkinson’s Disease

Poster #1 A randomized, double-blind, placebo-controlled clinical trial of Rifampicin in multiple system atrophyP.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 standingJ. 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 differencesD. 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 autonomicfailureF. Rahman, D.S. Goldstein

Bethesda, MD, USA

Poster #5 Loss of cerebral blood flow rhythm in Parkinson’s disease and vascular parkinsonismS.-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 withhypothalamic dysfunction, hypoventilation, and autonomic dysregulation (ROHHAD): ibutton measures ofperipheral skin temperatureR. Saiyed, C.M. Rand, M.S. Carroll, P.P. Patwari, T. Stewart, C. Koliboski, D.E. Weese-Mayer

Chicago, IL, USA

Poster #7 Heart rate variability in hospitalized children: autonomic response to laughter and engagementP.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 ofHUTT in children and adolescentsM.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 dysautonomiaI.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 techniqueJ.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: Elucidationof 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 withfamilial dysautonomiaL. 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 thetreatment of orthostatic hypotensionC.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 cystitisT.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 painP. Singh, J. Thayer, G. Chelimsky, T. Chelimsky

Milwaukee, WI, USA

Poster #17 Study of the P2X2 and 7 receptors in the enteric glial cells of ileum rat subjected to ischemia and reperfusionC.E. Mendes, K. Palombit, W. Tavares de Lima, P. Castelucci

Sao Paulo, Brazil

Poster #18 Brainstem neuropeptides and vagal protection of the gastric mucosal against injury: role of prostaglandins, nitricoxide and calcitonin-gene related peptide in capsaicin afferentsY. Tache

Los Angeles, CA, USA

Poster #19 Autonomic dysfunction and esophageal dysmotility in persons with spinal cord injuryG.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) studyC. 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 reperfusionK. Palombit, C.E. Mendes, W. Tavares de Lima, P. Castelucci

Sao Paulo, Brazil

Poster #22 Photo-stimulating effects of low reactive level laser on bladder dysfunction in neurological disease ratsT. 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 failureL. 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, 20129:45–11:15 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 maneuver—reproducibility and validity ofindicesT.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 humansJ.R. Carter, H. Yang, T.D. Drummer

Houghton, MI, USA

Poster #28 Melatonin does not alter skin sympathetic nerve responses to mental stressC.A. Ray, C.L. Sauder, M.D. Muller

Hershey, PA, USA

Poster #29 The arterial baroreflex resets with orthostasisC.E. Schwartz, J.M. Stewart

Hawthorne, NY, USA

Poster #30 Carotid chemoreflex and muscle metaboreflex interactions in humansH. 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 hypoglycemiaA. 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 hispanicsL.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 injuryH.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 womenP. 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 hoursM.J. Hilz, H. Marthol, S. Moeller, J. Koehn, A. Akhundova, P. De Fina, S. Schwab

Erlangen, Germany & New York, NY, USA

Poster #38 Relation of cardiovagal baroreflex sensitivity to impaired carotid artery elastic function in patients with tetralogy ofFallotA. 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 failureO.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 andarterial hypertensionE. 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 lesionsN.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 dischargeC.-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 balance’’—a thermodynamic perspectiveR. Schondorf, J. Benoit, M.J. Lafitte

Montreal, QC, Canada

Poster #45 The autonomic testing of normal subjectsG. 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 muscleD.P. Casey, M.J. JoynerRochester, MN, USA

Poster #47 COMPASS 31—a refined and abbreviated composite autonomic symptom scoreD.M. Sletten, G.A. Suarez, P.A. Low, J. Mandrekar, W. Singer

Rochester, 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 syndrome—a feasibility studyK.R. Chemali, K. McNeeley, L. Zhou, T. Chelimsky

Norfolk, VA, USA

POSTER SESSION IIISaturday, November 3, 20129:15–10:45 AM

Exercise, Temperature Regulation & Hypoxia

Poster #50 Thermophysiological consequences of an absent evening melatonin release in spinal cord injuryH. 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 arrhythmiasE. 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. Jarjour

Houston, 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 tachycardiaW. Singer, T.L. Gehrking, P.A. Low

Rochester, MN, USA

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Poster #57 Origins of cognitive dysfunction in postural tachycardia syndromeA.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) modelC. 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 patientsI. Bonyhay, C. Gibbons, A. Benson, R. Freeman

Boston, MA, USA

Poster #60 Postural tachycardia syndrome: optimal duration of diagnostic orthostatic challengeW.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 syndromeL.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 injuryJ. Wecht, D. Rosado-Rivera, C. Yen, M. Radulovic, W. Bauman

Bronx, NY, USA

Poster #63 Prevalence of orthostatic hypotension in asymptomatic veteransJ. Wecht, C. Yen, S. Pena, A. Ivan, W. Bauman

Bronx, NY, USA

Poster #64 Combination ergotamine and caffeine for the treatment of orthostatic hypotensionC. 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 hyperactivityH. Lee, H.A. Kim

Daegu, South Korea

Poster #66 Neurogenic mechanisms and venous physiology in patients with orthostatic intoleranceL. 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 adultsB.H. Shaw, S.N. Robinovitch, V.E. ClaydonBurnaby, BC, Canada

Poster #68 Arterial baroreflex asymmetry: an additional mechanism of orthostatic insufficiency in patients with non-cardiacsyncopeO.V. Mamontov, M.I. Bogachev, E.V. Shlyakhto


Poster #69 Myoclonic jerks in syncope are probably generated in the cortexJ.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 apneaJ.L. Gilden, J. Cheng, B. Theckedath, P. Hung, J. StollNorth Chicago, IL, USA

Poster #71 A case of paraneoplastic autonomic failure preceding Hodgkin’s lymphomaP. Muppa, C.E. Ramirez, B. Black, D. Robertson, A. Peltier, S.R. Raj, C. Shibao, I. Biaggioni

Nashville, TN, USA

Poster #72 11-year follow-up of a case of autoimmune autonomic ganglionopathyW. Singer, D.M. Sletten, T.L. Gehrking, A.K. Parsaik, P.A. Low

Rochester, MN, USA

Poster #73 Autonomic function test outcomes in diabetes mellitusL.B. Tay, S. Srinivasan, C. Kang, T. Umapathi

Singapore

Clin Auton Res (2012) 22:207–258 215

123

Wednesday, October 31, 2012

Oral Presentations

Alpha-synuclein as a cutaneous

biomarker of Parkinson disease

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

Department of Neurology, Beth Israel Deaconess Medical Center,

Harvard Medical School, Boston, MA, USA

Background: Parkinson’s disease is a multisystem neurodegenerative

disease characterized by the deposition of a-synuclein in the central,

peripheral and enteric nervous system. Although the most prominent

manifestations of Parkinson’s 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 of a-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 of a-synuclein deposition

within these nerve fibers. We found significantly elevated a-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-O’Neil, 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

subjects—54 MSA, 20 PAF, 34 PD, and 38 controls. In 14 patients

cerebrospinal fluid was obtained before or within 2 years after the onset

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 cohort of 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 of

motor 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-

lowed by wheelchair dependency (4.4 ± 2.9 years), fecal incontinence

(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) 22:207–258

123

Mechanical stimulation of the feet improves gait

and increases cardiac vagal profile in Parkinson’s

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 l’analisi 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 Parkinson’s 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, Hoehn–Yahr scale 2–4) 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, HFRR

increased (1.2E-04 ± 2.7E-04 from 4.5E-04 ± 1.9E-04 m/sec2)

compared to baseline, suggesting an enhancement of the cardiac vagal

modulation.

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; 2Nuclear

Medicine 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 Parkinson’s Disease (iPD) Patients.

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

according to the UK Parkinson’s 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) 22:207–258 217

123

Comparison of techniques for non-invasive assessment

of systemic hemodynamics in autonomic function

testing

C. Sims-O’Neil, 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 decreased

by 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-

ically—without the need for conscious control—is very much a

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

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

ment in the presence of disease, yet these ‘‘presets’’ can be 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

increase in blood pressure that we may be worried about. The point here is

that the delegated system—the Commander—can 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 of 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. Medow1,2

1Department 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 18–24 years old. We

combined TCD of the MCA with near infrared spectroscopy (NIRS) over

the frontal cortex. Cerebral oxygenation and total hemoglobin increased

by 14 ± 1 and 15 ± 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 TCD derived CBFv increased by 5 %. Studies using upright tilt and

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

218 Clin Auton Res (2012) 22:207–258

123

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

Lurie Children’s 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 months–27 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 (18–21 years) were monitored while

receiving 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 t test). 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 challenges

indicated 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 wall 18F-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

2–3 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, Children’s 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 children’s pain may predict children’s 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 child’s pain. We evaluated parent attributions of

symptoms in adolescents with POTS in order to determine how they

are related to their child’s 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 child’s 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 child’s 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.

Clin Auton Res (2012) 22:207–258 219

123

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


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 relationship—if present—would 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-

son’s 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 acceptance

in 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, Children’s 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 child’s 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 Studies—Depression Scale, the Spence Children’s

Anxiety Scale, and the Chronic Pain Acceptance Questionnaire,

adolescent version. Parents of 103 of these patients completed the

Parent Response to Pain Questionnaire—Revised, 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

220 Clin Auton Res (2012) 22:207–258

123

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 the

experiment 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) 22:207–258 221

123

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 induces

sympathoexcitation 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 SNA–AP 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 on

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 CO2

homeostasis 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

sensitivity—a 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 of

the 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

222 Clin Auton Res (2012) 22:207–258

123

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 on

afferent neurons with their cell bodies in the dorsal root ganglia (DRG).

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

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

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

osmopressor response was also present in patients with FD. Nine patients

with FD and 6 with chronic autonomic failure participated in this study (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 ± 13 to 94 ± 13 mmHg, NS, max response D7 ± 11 mmHg, NS,).

Thus, the response to water drinking differed significantly between the

two 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-(1–7) 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-(1–7) 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 the

hypothesis 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� and 20-min 60�) before and after treatment. Plasma

norepinephrine and aldosterone were also assessed. Both groups had

similar reductions in 24 h ambulatory BP after treatment (aliskiren:

128 ± 3/72 ± 2 post vs. 143 ± 4/78 ± 3 mmHg pre; HCTZ: 128 ± 3/

74 ± 1 vs. 144 ± 3/81 ± 2 mmHg; all p \ 0.01). HR increased and Qc

decreased during HUT in both groups with no change after treatment.

MSNA was greater supine and during HUT after HCTZ treatment

(supine, 75 ± 11 post vs. 63 ± 6 pre; 60� HUT, 86 ± 6 vs. 78 ± 6

bursts/100 beats; p = 0.02 for treatment). Conversely, after aliskiren

treatment, supine MSNA remained unchanged, but upright MSNA was

lower (supine, 69 ± 13 vs. 64 ± 8; 60� HUT, 75 ± 11 vs. 82 ± 11

bursts/100 beats; p = 0.01 for interaction of treatment 9 posture).

Plasma norepinephrine concentration and aldosterone level during HUT

were greater after HCTZ treatment (60� HUT; 844 ± 225 vs.

638 ± 175 pg/ml, p = 0.04 and 18.0 ± 3.5 vs. 9.2 ± 3.1 ng/dl,

p = 0.02), but were unchanged after aliskiren treatment. Thus, aliskiren

effectively lowered BP and reduced upright MSNA in elderly hyper-

tensives. HCTZ evoked sympathetic activation and enhanced the renin-

angiotensin-aldosterone system during orthostasis.

Clin Auton Res (2012) 22:207–258 223

123

Association between cerebral autoregulation and white

matter hyperintensities in elderly individuals

S. Purkayastha1, B. Paccha1, I. Iloputaife1, D.K. Kiely1, F.A. Sorond2,

L.A. Lipsitz1

1Institute for Aging Research, Hebrew SeniorLife, Roslindale, MA,

USA; 2Neurology, Brigham and Women’s Hospital, Boston, MA,

USA

Aim: Cerebral autoregulation (CA) maintains a relatively constant

cerebral blood flow despite changes in perfusion pressure. Abnor-

malities in CA may threaten cerebral perfusion and result in ischemic

damage to watershed regions in the periventricular white matter.

Cerebral white matter hyperintensities (WMH) are prevalent among

elderly people and are associated with chronic cerebral hypoperfusion

and ischemic injury. The purpose of the study was to examine the

association between CA and total cerebral WMH volume in elderly

individuals.

Methods: Thirty-seven subjects (79 ± 6 years) from the MOBILIZE

Boston study were recruited for assessment of total cerebral WMH

using magnetic resonance imaging (MRI). Subjects were divided at

median into low (N = 18) and high (N = 19) WMH groups based on

total cerebral WMH obtained from the MRI images. Beat-to-beat

blood pressure and middle cerebral artery blood velocity (MCAV)

measurements were obtained from finger plethysmography and

transcranial Doppler ultrasonography while subjects were seated

upright for 5 min. Transfer function analyses of beat-to-beat MCAV

and blood pressure variability were evaluated to determine CA.

Lower transfer function gains between blood pressure and MCAV in

the low frequency range (0.07–0.20 Hz) are considered better CA.

Results: The variability in MCAV at low frequency was greater in the

high compared to the low WMH group (2.39 ± 0.6 vs. 1.02 ± 0.2,

P = 0.04) despite no differences in blood pressure variability

between the two groups. Low frequency transfer function gain was

also significantly greater in the high compared to the low WMH group

(0.88 ± 0.08 vs. 0.64 ± 0.05, P = 0.04).

Conclusion: Our results suggest that a high total cerebral WMH

burden is associated with impairment in CA in elderly individuals.

Abnormal CA may predispose older people to cerebral hypoperfusion

and ischemic damage to white matter in the brain.

The change in arterial stiffness during ganglionic

blockade is associated with sympathetic nerve activity

in women

J.N. Barnes1, R.E. Harvey1, E.C. Hart2, N. Charkoudian3, T.B.

Curry1, J.H. Eisenach1, W.T. Nicholson1, M.J. Joyner1, D.P. Casey1,4

1Department of Anesthesiology, Mayo Clinic, Rochester, MN, USA;2School of Physiology and Pharmacology, University of Bristol,

Bristol, England, UK; 3Thermal and Mountain Medicine Division,

U.S. Army Research Institute of Environmental Medicine, Natick,

MA, USA; 4Department of Physiology and Biomedical Engineering,

Mayo Clinic, Rochester, MN, USA

Arterial stiffness is an independent risk factor for hypertension.

Sympathetic overactivity may contribute to the age-related increase in

arterial stiffness. Previously, it has been shown that arterial stiffness is

associated with muscle sympathetic nerve activity (MSNA) in men.

However, this has not been investigated in women. Accordingly, our

purpose was to examine the association between arterial stiffness and

MSNA in women. Furthermore, we sought to determine if the change

in arterial stiffness, after eliminating the influence of the autonomic

nervous system using ganglionic blockade, is associated with basal

sympathetic tone. Nine healthy young women (24 ± 3 years) and ten

healthy older women (61 ± 7 years) participated in this study. Heart

rate, arterial pressure, and pulse wave velocity (PWV) were moni-

tored before and during ganglionic blockade with trimethaphan.

MSNA measured during quiet rest was greater in older women when

expressed as both burst incidence (54 ± 6 vs. 23 ± 3 bursts/100 hb;

p \ 0.01) and burst frequency (32 ± 3 vs. 14 ± 2 bursts/min;

p \ 0.01). Aortic PWV was also higher in older women (9.0 ± 0.6

vs. 6.4 ± 0.3 m/s; p \ 0.01) at baseline and during ganglionic

blockade (7.6 ± 0.4 vs. 6.5 ± 0.2 m/s; p \ 0.05). MSNA burst

incidence and burst frequency were positively associated with base-

line aortic PWV (r = 0.55, p \ 0.05; r = 0.63, p \ 0.01,

respectively), but not peripheral PWV. Aortic PWV values during

ganglionic blockade were not associated with baseline MSNA (BI:

r = 0.38, p = 0.10; BF: r = 0.40, p = 0.09); however the change in

aortic PWV after ganglionic blockade was inversely associated with

MSNA (BI: r = -0.54, p \ 0.05; BF: r = -0.61, p \ 0.01). Taken

together, these data suggest that increased sympathetic nerve activity

may contribute to the development of arterial stiffness.

Friday, November 2, 2012

Oral Presentations

Plenary Lecture

The autonomic responses to pregnancy

Qi Fu, M.D., Ph.D.

Institute for Exercise and Environmental Medicine, Texas Health

Presbyterian Hospital Dallas, and UT Southwestern Medical Center,

Dallas, TX, USA

In humans, pregnancy is associated with dramatic changes in maternal

hemodynamics. These changes are detectable by 4 weeks of gesta-

tion,1,2 and reach a plateau in the second trimester of pregnancy.3–6 It

has been proposed that hemodynamic changes during pregnancy

occur through autonomic control mechanisms,7 but the actual role of

the sympathetic nervous system in normal pregnancy as well as in

hypertensive disorders of pregnancy is poorly understood. With the

microneurographic technique, Greenwood et al8,9 found that muscle

sympathetic nerve activity (MSNA) increased in normotensive

pregnant women and was even greater in women with gestational

hypertension and preeclampsia during the third trimester. They

thereby concluded that sympathetic hyperactivity during the latter

months of normal pregnancy helped to return the arterial pressure to

non-pregnant levels, but when the increase in sympathetic activity

was excessive, hypertension ensued. This notion was supported by the

findings of Schobel et al10 and Fischer et al11 showing that pre-

eclampsia was in a state of sympathetic overactivity, which

normalized after delivery. The key question that must be addressed

then is whether sympathetic overactivity develops early during

pregnancy, remaining high throughout gestation, or whether this

sympathetic activation only occurs at term, providing the substrate for

preeclampsia and other pregnancy associated cardiovascular compli-

cations. Recent work from our laboratory showed that resting MSNA

increased markedly during early pregnancy (i.e., B8 weeks of ges-

tation), remained elevated throughout the entire gestation, and was

suppressed shortly after delivery in healthy normotensive women.

These results suggest that sympathetic activation is a common phe-

nomenon during pregnancy in humans. Conversely, total peripheral

224 Clin Auton Res (2012) 22:207–258

123

resistance was lower during pregnancy compared to non-pregnancy,

indicating blunted sympathetic vasoconstriction. We also found that

race may affect sympathetic neural control during pregnancy. For

example, Asian women had a much less prominent sympathetic

activation to the skeletal muscle and the heart, but a greater activation

of the renin-aldosterone system during pregnancy compared to White

women. On the other hand, MSNA appeared to be comparable

between Black and White pregnant women, but Blacks had greater

sympathetic activation to the heart and the kidney early on during

pregnancy. These different responses may contribute importantly to

racial differences in the prevalence of gestational hypertension and

preeclampsia in humans. Overactivation of the sympathetic nervous

system can lead to an impairment of vasodilatation by a-adrenergic

mechanisms.12,13 Thus, sympathetic overactivity may be a key factor

in the development of hypertensive disorders during pregnancy.

Indeed, we found some early signs of excessive sympathetic over-

activity in one woman with gestational hypertension during the first

trimester. If these preliminary observations can be confirmed in more

women with hypertensive pregnancies, it would provide invaluable

information regarding the pathophysiology of gestational hyperten-

sion and preeclampsia. With this knowledge, early prevention or

treatment targeted to the appropriate pathophysiology may be initi-

ated, which may reduce maternal and fetal death or morbidity, as well

as cardiovascular risks in women later in life.

References:1. Phippard AF, et al., J Hypertens. 1986;4(6):773–779.

2. Chapman AB, et al., Am J Physiol. 1997;273(5 Pt 2):F777–782.

3. Robson SC, et al., Am J Physiol. 1989;256(4 Pt 2):H1060–1065.

4. Capeless EL, Clapp JF. Am J Obstet Gynecol. 1989;161(6 Pt

1):1449–1453.

5. Clapp JF, 3rd, Capeless E. Am J Cardiol. 1997;80(11):

1469–1473.

6. Duvekot JJ, et al., Am J Obstet Gynecol. 1993;169(6):

1382–1392.

7. Ekholm EM, et al., Clin Auton Res. 1994;4(4):161–165.

8. Greenwood JP, et al., Circulation. 2001;104(18):2200–2204.

9. Greenwood JP, et al., J Hypertens. 1998;16(5):617–624.

10. Schobel HP, et al., N Engl J Med. 1996;335(20):1480–1485.

11. Fischer T, et al., Eur J Clin Invest. 2004;34(6):443–448.

12. Hijmering ML, et al., J Am Coll Cardiol. 2002;39(4):683–688.

13. Sverrisdottir YB, et al., PLoS One.2010;5(2):e9257.

Catheter based renal nerve ablation does not elicit

a central sympatholytic response in difficult to control

hypertensive patients

J. Brinkmann1, K. Heusser1, B.M. Schmidt2, J. Menne2, G. Klein3,

H. Haller2, A. Diedrich4, J. Jordan1, J. Tank1

1Institute of Clinical Pharmacology, Hanover Medical School,

Hanover, Germany; 2Division of Nephrology and Hypertension,

Department of Medicine, Hanover Medical School, Hanover,

Germany; 3Department of Electrophysiology, Division

of Cardiovascular Medicine, Hanover Medical School, Hanover,

Germany; 4Vanderbilt Autonomic Dysfunction Center, Division

of Clinical Pharmacology, Nashville, TN, USA

Background. Endovascular renal nerve ablation has been developed to

treat resistant hypertension. Renal denervation may attenuate central

sympathetic outflow through decreased renal afferent nerve traffic as

evidenced by a recently published case report. We tested the

hypothesis that renal nerve ablation is accompanied by reduced

central sympathetic nerve traffic in a larger sample.

Materials and methods: We studied 12 not preselected patients with

difficult to control arterial hypertension (ages 45–74 years) who had

been admitted for renal nerve ablation. All patients were on C3

antihypertensive medications at full doses, including a diuretic. ECG,

respiration, brachial and finger arterial blood pressure, and muscle

sympathetic nerve activity (MSNA) were recorded before and

3–6 months after renal nerve ablation. Heart rate- (HRV) and blood

pressure variability (BPV) were analyzed in the time and frequency

domain. Pharmacological baroreflex slopes were determined using the

modified Oxford-bolus technique. Spontaneous sympathetic barore-

flex sensitivity was analyzed by the Kienbaum method.

Results: Resting heart rate (pre: 61 ± 9, post 58 ± 8 bpm; p = 0.66)

and supine blood pressure (pre: 157 ± 20/85 ± 12 mmHg; post:

157 ± 20/84 ± 12 mmHg; p = 1.0) were similar on both study days.

Resting MSNA was similar before and after renal nerve ablation (pre:

34 ± 8, post: 31 ± 10 bursts/min; p = 0.50). In one case, blood

pressure reduction of 66/30 mm Hg was not associated with a

reduction in MSNA (40 vs. 41 bursts/min). Renal nerve ablation had

no influence on HRV and BPV. Baroreflex mediated heart rate control

and baroreflex mediated control of sympathetic nerve traffic (pre:

-4.8 ± 4, post: -4.6 ± 3 %/mm Hg; p = 0.7) did not change.

Conclusion: Our data suggest that reduction in centrally generated

sympathetic activity may be the exception rather than the rule fol-

lowing renal nerve ablation in unselected patients with difficult to

control arterial hypertension. The large proportion of non responders

in terms of blood pressure reduction is a matter of concern.

Methodological considerations for assessing resting

spontaneous baroreflex control of muscle sympathetic

nerve activity in humans

S.W. Holwerda1, H. Yang2, J.R. Carter2, P.J. Fadel1

1Department of Medical Pharmacology & Physiology, Dalton

Cardiovascular Research Center, University of Missouri, Columbia,

MO, USA; 2Department of Kinesiology and Integrative Physiology,

Michigan Technological University, Houghton, MI, USA

Spontaneous measurements for the estimation of baroreflex control of

muscle sympathetic nerve activity (MSNA) are increasingly being

used to assess sympathetic baroreflex sensitivity at rest primarily due

to the relative ease of relating spontaneously occurring changes in

MSNA and diastolic blood pressure (DBP). However, a thorough

examination of this methodology for assessing spontaneous baroreflex

sensitivity in humans under resting conditions has not been per-

formed. Indeed, although spontaneous measurements have been

shown to correlate with MSNA baroreflex sensitivity derived using

the modified Oxford, the impact of bin size, baseline time duration,

diastolic blood pressure range, and MSNA burst frequency remain

unknown. This becomes important because published results have not

used standard analyses methods. Thus, to comprehensively examine

the influence of varying analyses procedures on estimates of spon-

taneous MSNA baroreflex sensitivity, weighted linear regression

analysis between MSNA and DBP was performed in 100 subjects.

First, intra-class correlation coefficients for varying bin sizes (1, 2,

and 3 mmHg) and segment durations (1, 2, 5, and 10 min) were

calculated to examine reliability of spontaneous MSNA baroreflex

sensitivity. Next, the influence of the DBP range and MSNA burst

frequency on the validity of the relationship between MSNA and DBP

were considered. Interestingly, despite similar burst incidence MSNA

baroreflex sensitivity across all bin sizes, the reliability was weak for

2- and 1-min baseline durations. The diminished reliability appeared

to be due to a significant reduction in the DBP range across baseline

time durations (e.g., 10 min, 25 ± 1 vs. 1 min, 15 ± 1 mmHg;

Clin Auton Res (2012) 22:207–258 225

123

P \ 0.001); whereas MSNA burst frequency was similar across

baseline time durations (P = 0.949). Overall, these findings question

the validity of using baseline period durations \5 min for assessing

resting spontaneous MSNA baroreflex sensitivity; an effect that

appears to be related, in part, to smaller DBP ranges with shorter

baseline periods.

Sleep deprivation augments cardiovascular reactivity

to acute stress in humans

H. Yang1, J.J. Durocher1, R.A. Larson1, J.P. DellaValla2, J.R. Carter1

1Department of Kinesiology and Integrative Physiology, Michigan

Technological University, Houghton, MI, USA; 2Center for Sleep

Medicine, Androscoggin Valley Hospital, Berlin, NH, USA

Exaggerated cardiovascular reactivity to mental stress (MS) and cold

pressor test (CPT) have been linked to increased risk of cardiovas-

cular disease. Recent epidemiological studies identify sleep

deprivation as an important risk factor for hypertension, yet the

relations between sleep deprivation and cardiovascular reactivity

remain equivocal. We hypothesized that 24 h total sleep deprivation

(TSD) would augment cardiovascular reactivity to MS and CPT, and

blunt MS-induced forearm vasodilation. Because associations

between sleep deprivation and hypertension have been reported to be

stronger in women, a secondary aim was to probe for sex differences.

Mean arterial pressure (MAP) and heart rate (HR) were recorded

during a 5 min MS trial and 2 min CPT trial in 28 young healthy

subjects (14 men and 14 women) after normal sleep (NS) and TSD

(randomized, crossover design). Forearm vascular conductance

(FVC) was determined for the MS trial. MS increased MAP, HR, and

FVC during both NS and TSD (p \ 0.001). HR reactivity during the

final 3 min of MS was augmented with TSD (D17 ± 2 vs. D14 ± 1

beats/min; p \ 0.05), and these augmented HR responses persisted

during the 5 min recovery (D4 ± 1 vs. D1 ± 1 beats/min; p \ 0.01).

Increases in MAP and FVC during MS were not different between NS

and TSD. Similar to the MS trial, CPT increased MAP and HR during

both NS and TSD (p \ 0.001), but only HR reactivity was augmented

during TSD (D12 ± 2 vs. D9 ± 1 beats/min; p \ 0.05). The aug-

mented HR persisted during the CPT recovery (D1 ± 1 vs. D-1 ± 1

beats/min; p \ 0.05). When analyzed for sex differences, cardiovas-

cular responses to MS and CPT were not different between sexes or

conditions (condition 9 time 9 sex, p [ 0.05). We conclude that

TSD potentiates HR reactivity during and after both MS and CPT.

These findings provide new mechanistic insight regarding emerging

links between sleep deprivation, stress, and cardiovascular risk.

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

Tufts Medical Center, MCRI, Tufts University, Boston, MA, USA

Introduction: Diabetes mellitus is associated with increased risk of

sudden cardiac death. Little evidence exists to support specific

mechanisms to account for this association. Furthermore, there is no

animal model which demonstrates arrhythmogenesis in the Type I

diabetic heart. The Akita mouse has been shown to be a useful model

for the study of the pathogenesis of secondary effects of type I

diabetes. Here, we study the inducibility of ventricular tachycardia

(VT) in the Akita mice by programmed ventricular electrical stimu-

lation and investigate the ionic and cellular mechanism of

arrhythmogenesis.

Methods: Programmed ventricular electrical stimulation was per-

formed in Akita and wild type (WT) mice. Left ventricular myocytes

were isolated for electrophysiology and calcium imaging studies.

Voltage and current clamp were used to record Ca2+ currents and

action potentials. Sarcomere shortening and Ca2+ transient were

measured using the Ionoptix system. Ca2+ sparks were recorded by

confocal microscopy.

Results: Inducibility of VT in Akita mice was significantly increased

(78.6 %, 11 of 14) compared to WT (28.6 %, 4/14, p = 0.006).

Action potential duration at 90 % repolarization at 1 Hz was pro-

longed in Akita myocytes (61.5.1 ± 7.7 ms, n = 7) versus WT

(30.5 ± 1.3 ms, n = 7, p \ 0.05). We determined whether these

effects were associated with abnormalities of Ca homeostasis. L type

Ca2+ current densities were unchanged compared to WT. However,

Ca2+ transient decay time was increased in Akita (170.9 ± 10.3 ms,

n = 23) vs WT (138.6 ± 7.3 ms, n = 20, p \ 0.05) while SERCA2a

expression was decreased in the Akita heart. Furthermore, frequency

of Ca2+ sparks was significantly increased compared to WT

(0.266 ± 0.022, n = 36 vs. 0.043 ± 0.003 sparks/lm/s, n = 13,

p \ 0.001) consistent with increased Ca2+ leak. Consequently, cy-

stolic Ca2+ concentration was significantly elevated in Akita

myocytes, leading to the occurrence of early and delayed after

depolarizations which predispose to arrhythmia.

Conclusions: The type 1 diabetic Akita mouse demonstrated a high

level of inducibility of VT which may be due to prolongation of APD

and abnormalities of Ca2+ handling.

Sympathetic hyper-responsiveness in takotsubo

cardiomyopathy

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

New York University Dysautonomia Center, New York, NY, USA

Takotsubo cardiomyopathy primarily strikes post-menopausal women

after an emotional shock or intense physical stress. Both stimuli

trigger a powerful increase in sympathetic outflow and the release of

norepinephrine, which is unusually high during an episode, suggest-

ing a hyperadrenergic mechanism for the disorder. The role of the

baroreflex in predisposing to takotsubo cardiomyopathy is uncertain.

We studied 10 women who had a past episode of takotsubo cardio-

myopathy and 10 age/BMI matched healthy women. Blood pressure

and RR intervals were measured continuously and plasma catechol-

amines were sampled through an indwelling venous catheter.

Sympathetic activation was provoked by hemodynamic (Valsalva),

cognitive (stroop test) and emotional (event recall) stimuli. Para-

sympathetic function was assessed during slow paced breathing (E:I

ratio). Baroreflex sensitivity was measured using spectral and

sequence techniques. Participants also underwent 24 h ambulatory

blood pressure monitoring. Sympathetic responsiveness to hemody-

namic, cognitive and emotional stimuli was exaggerated in the

women with history of takotsubo compared to controls: Phase IV

overshoot in BP after the release of the Valsalva strain was both

amplified (DSBP: +31 ± 6 vs. +10 ± 4 mmHg, p \ 0.01) and pro-

longed (duration: 25 ± 4 vs. 11 ± 1 s); stroop test produced a greater

increase in SBP (DSBP 40 ± 6 vs. 28 ± 3 mmHg, p \ 0.05). Com-

pared to cognitive arousal, recalling the event that triggered their

episode evoked an even greater pressor response in takotsubo women

(+D 62 ± 8 mmHg, p \ 0.04). Heart rate fluctuations with paced

breathing were significantly lower in the takotsubo women (E:I ratio

226 Clin Auton Res (2012) 22:207–258

123

1.15 vs. 1.42, p \ 0.01). Spectral and sequence analysis showed that

baroreflex gain was significantly lower than normal. Women with

takotsubo had higher peak SBP values captured during ambulatory

monitoring (156 ± 5 vs. 128 ± 1 mmHg, p \ 0.05). No differences

in catecholamine levels were apparent. Our findings suggest that

subtle abnormalities in baroreflex function leading to exaggerated

sympathetic responsiveness might play a role in predisposing women

to takotsubo cardiomyopathy.

Improvement of obesity-associated insulin resistance

during autonomic blockade

A. Gamboa, L. Okamoto, A. Arnold, S. Raj, A. Diedrich,

N. Abumrad, I. Biaggioni.

Department of Medicine, Vanderbilt University, Nashville, TN, USA

A hallmark of obesity is the development of insulin resistance.

Increased secretion of insulin is an initial compensatory mechanism

and is thought to contribute to sympathetic activation in an attempt to

restore energy balance. We have previously shown, however, that

sympathetic activity has no beneficial effect on resting energy

expenditure in obesity. On the contrary, we hypothesize that sym-

pathetic activation contributes to insulin resistance providing a

negative feedback loop. To test this hypothesis, we determined insulin

sensitivity (hyperinsulinemic euglycemic clamp) in obese subjects

(30 \ BMI \ 40 kg/m2) during intact and during pharmacologically

induced autonomic blockade (trimethaphan 4 mg/min IV infusion).

Blood pressure was clamped during autonomic blockade by con-

comitant titrated IV infusion of the NOS inhibitor L-NMMA. Eleven

obese subjects (41 ± 3.6 years, 35 ± 0.8 kg/m2, 144 ± 4/

90 ± 4 mm Hg) were studied on two separate occasions randomly

assigned. Seven were found to be insulin resistance and four to be

insulin sensitive (Glucose Infusion Rate, GIR [ 4.5 mg/kg/min).

There were no differences in age, total fat percentage, blood pressure

or muscle sympathetic activity between groups. GIR increased during

autonomic blockade only among subjects with insulin resistance

(2.96 ± 0.54 to 4.03 ± 0.67 mg/kg/min for the intact and blocked

days, p = 0.018). No improvement was seen in the insulin sensitive

group (6.08 ± 0.88 to 5.99 ± 1.34 mg/kg/min for the intact and

blocked days, p = 0.5). Our results support the concept that sympa-

thetic activation has a detrimental effect on glucose utilization in

obesity, and provides the rational to explore it as a therapeutic target.

Beta-2 adrenergic receptor polymorphism

and hemodynamics in patients with postural orthostatic

tachycardia syndrome and healthy controls

M.N. Manento1, L.R. Gullixson1, K.K. Nickander2, P.A. Low2,

J.H. Eisenach1

1Department of Anesthesiology, Mayo Clinic, Rochester, MN, USA;2Department of Neurology, Mayo Clinic, Rochester, MN, USA

Previous studies suggest that polymorphisms in the beta-2 adrenergic

receptor gene (ADRB2) influence hemodynamics in postural tachy-

cardia syndrome (POTS). To replicate these findings in a large cohort

of POTS patients and healthy controls who underwent head-up tilt

(HUT), we tested the hypothesis that two common single nucleotide

polymorphisms (SNPs) in the coding region of ADRB2 (Arg16/Gly

and Gln27/Glu) influence the hemodynamic and catecholamine

responses to HUT.

Methods: Hemodynamics and venous catecholamines were collected

from POTS patients undergoing autonomic screening (n = 153, mean

age 29 ± 1 year, 129 females), and compared to healthy controls

(n = 145, age 26 ± 1 year, 87 females) who participated in Clini-

calTrials.gov: ‘‘High Resolution Phenotyping in Healthy Humans’’

which included arterial pressure and catecholamines. Dominant,

additive, and recessive linear models were performed with separate

analyses for each variable and SNP.

Results: Consistent with prior reports, norepinephrine (NE) was

increased in POTS versus controls while supine and upright

(P \ 0.05) but interestingly the epinephrine levels were decreased in

POTS. Within controls, Arg16 homozygotes displayed greater HR

and NE levels while supine and during HUT. Gln27 homozygotes

displayed greater HR while supine and during HUT. In POTS, Arg16

homozygotes had a blunted increase in HR during HUT, and the

Glu27 homozygotes had a greater NE response to HUT. Taken

together, there was a HR-by-genotype interaction for position 16

during HUT at min 1 (P = 0.05) and min 5 (P = 0.04). We conclude

that Arg16/Gly may inversely affect HR in POTS compared to con-

trols, and there was evidence to suggest that Gln27/Glu influenced

catecholamines within POTS during HUT. We were unable to repli-

cate previously reported effects of genotype on blood pressure in

POTS. While these findings lend additional evidence that ADRB2

polymorphisms influence hemodynamics and catecholamines in

POTS, definitive implications for management remain undetermined.

The pathophysiology of neuropathic and non-

neuropathic postural tachycardia syndrome

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



Objective: To define the clinical characteristics, fatigue severity,

autonomic function and differentiating features in individuals with

neuropathic and non-neuropathic POTS.

Background: The postural tachycardia syndrome (POTS) is defined as

an exaggerated heart rate in the upright position with orthostatic

intolerance. Some patients with POTS have an underlying small fiber

neuropathy.

Methods: Twenty-one subjects (17F) with POTS and 10 healthy

control subjects (7F) had skin biopsy analysis of intra-epidermal

nerve fiber density (IENFD), quantitative sensory testing (QST) and

autonomic testing. Subjects completed quality of life, fatigue and

disability questionnaires. Subjects were divided into neuropathic

and non-neuropathic POTS, defined by abnormal IENFD and/or heat

and heat-pain detection thresholds. Differences in autonomic function

and symptom questionnaires were analyzed by ANOVA with cor-

rections for multiple analyses. Significance was set at P \ 0.05.

Results: POTS subjects had significantly greater fatigue, anxiety,

physical impairment, orthostatic intolerance and perceived disability

than controls (P \ 0.0001 all questionnaires). Individuals with non-

neuropathic POTS had greater anxiety, orthostatic intolerance and

perceived disability than those with neuropathic POTS. Neuropathic

POTS subjects had higher supine blood pressures (P \ 0.05), higher

heart rates (P \ 0.05), lower 30:15 ratios (P \ 0.05) and lower Val-

salva ratios (P \ 0.05). POTS subjects had lower IENFD at the distal

leg than controls (P \ 0.05) but those with non-neuropathic POTS

were similar to controls. Neuropathic POTS subjects had higher levels

of distal sympathetic adrenergic innervation than those with non-

neuropathic POTS or healthy control subjects.

Discussion: POTS subtypes can only be distinguished by evaluation

for small fiber neuropathy. Patients with non-neuropathic POTS have

Clin Auton Res (2012) 22:207–258 227

123

greater anxiety, orthostatic intolerance and perceived disability

despite better overall autonomic function than those with neuropathic

POTS. These findings suggest that neuropathic and non-neuropathic

POTS have different pathophysiological mechanisms that underlie the

postural tachycardia. These findings have implications for therapeutic

interventions to treat this disorder.

Acknowledgement: Study supported by NIH NINDS K23NS050209

(CHG) and NIH RO1 HL059459 (RF).

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

Mayo Clinic, Rochester, MN, USA

Objective: To study the frequency and degree of deconditioning,

clinical features and the relationship between deconditioning and

autonomic parameters in patients with orthostatic intolerance.

Methods: We retrospectively studied all patients seen for orthostatic

intolerance at Mayo Clinic between January 2006 and June 2011, who

underwent both standardized autonomic and exercise testing.

Results: One hundred and eighty four patients [84 Postural Orthostatic

Tachycardia Syndrome (POTS), 100 without orthostatic tachycardia

(OI)] fulfilled inclusion criteria. Eighty nine percent were females;

median age was 27.5 years (IQR22–37). Symptoms duration was

4 years (IQR 2–7.8). Ninety three percent of patients had decondi-

tioning (reduced maximum oxygen uptake with VO2 max% \85 %)

during exercise. This finding was unrelated to age, gender, and

duration of illness. The prevalence of deconditioning was similar

between POTS (95 %) and OI (91 %). VO2 max% had a weak cor-

relation with a few autonomic and laboratory parameters, but

adequate predictors of VO2 max% could not be identified.

Conclusion: Reduced VO2 max% consistent with deconditioning is

present in almost all patients with orthostatic intolerance and may

play a central role in pathophysiology. This finding provides a strong

rationale for retraining in the treatment of orthostatic intolerance.

None of the autonomic indices are reliable predictors of

deconditioning.

Preliminary data on the durability of improved

symptoms, functioning, and psychological distress

in adolescents with POTS treated in a multidisciplinary

treatment program

B.K. Bruce1, T.E. Harrison2, K.E. Weiss1, P.R. Fischer3, S.P. Ahrens3,

W.N. Timm4

Departments of Psychology and Psychiatry,1 Anesthesiology,2

Pediatric and Adolescent Medicine,3 and Physical Medicine

and Rehabilitation,4 Mayo Clinic, Rochester, MN, USA

Postural orthostatic tachycardia syndrome (POTS) can result in signifi-

cant disability and psychological distress in adolescents. Symptoms of

POTS can include sweating, dizziness, shortness of breath, and presyn-

cope which can lead to the avoidance of many activities. Often school

attendance is significantly impacted, as well as participation in sports,

social activities, and family participation. In the most severe patients,

POTS can result in patients who are essentially home-bound. Treatment

to date has focused primarily upon pharmacological treatment. An initial

study showed significant improvement in functioning, depression, and

anxiety in patients with POTS following multidisciplinary treatment. The

present study was designed to examine the durability of this intervention

in improving symptoms, functioning and psychological distress in a

sample of adolescents with POTS who had failed standard intervention.

Fifteen adolescents, ages 13–18, diagnosed with POTS were participants

in this study. The majority of patients were female (73 %) and Caucasian

(100 %). All of the patients also reported chronic pain in addition to their

POTS symptoms. Measures included a questionnaire that assessed POTS

symptoms, the Functional Disability Index, the Center for Epidemio-

logical Studies-Depression-Child questionnaire, and the

Multidimensional Anxiety Questionnaire. Measures were completed at

admission and discharge from the 3 week multidisciplinary rehabilita-

tion program and at 3 month follow-up. Using repeated measures

ANOVA analyses, patients demonstrated significant improvements

across three time points (baseline, after treatment, and 3 months follow-

up) on measures of depression (F = 15.46, p \ 0.001), anxiety

(F = 4.82, p \ 0.05), and functional disability (F = 35.71, p \ 0.001).

Patients also demonstrated significant improvements in POTS symptoms

which included rapid heart rate, nausea, dizziness, blurred vision,

weakness, shakiness, anxiety, pale, clammy (F = 8.63, p \ 0.01). These

data suggest that the improvements initially made at the end of multi-

disciplinary treatment are maintained at 3 month follow-up.

Objective measures of sleep in patients with POTS

S.J. Kizilbash1, P.R. Fischer1, R.M. Lloyd1,2

1Department of Pediatrics and Adolescent Medicine, Mayo Clinic,

Rochester, MN, USA; 2Center for Sleep Medicine, Division

of Pulmonary and Critical Care, Mayo Clinic, Rochester, MN, USA

Background: Sleep disturbance is a common symptom reported by

patients with Postural Orthostatic Tachycardia Syndrome (POTS).

However, there are no studies investigating the objective measures of

sleep.

Objective: To analyze the objective measures of sleep in patients with

POTS.

Method: A retrospective chart review of pediatric patients presenting

to Mayo Clinic for a multidisciplinary evaluation of chronic symp-

toms who were diagnosed with POTS based on[30 beats/min change

in heart rate during a tilt table test. They also underwent sleep eval-

uation with one or more objective studies of sleep; Polysomnography

(PSG), Actigraphy and/or Multiple Sleep Latency Test (MSLT)

between 3/2000 and 3/2012.

Results: Fifty-eight patients fulfilled the inclusion criterion. The mean

age at onset of symptoms was 12.9 years and 71 % were females.

Fatigue was reported by 92 %, subjective insomnia by 54 % and

hypersomnia by 40 % of patients. PSG showed increased initial sleep

latency [15 min) in 47 % and increased arousal ([12/h) in 43.1 %.

Increased periodic limb movement index was seen in 45.1 % (normal

B5 in pediatrics) indicating periodic limb movement disorder

(PLMD). There was no statistically significant difference in the mean

ferritin values of patients with and without PLMD (27.5 vs. 24.7 mcg/

L, p 0.51). Sleep architecture was relatively preserved. Mean Apnea/

Hypopnea Index was 1.9 events per hour (normal B1 in pediatrics).

Actigraphy demonstrated delayed sleep phase tendencies in 88.8 %

and day time napping in 77.7 %. Ten of the 17 patients who under-

went actigraphy had findings consistent with erratic sleep pattern. Of

the 10 patients who underwent MSLT, 6 had evidence of central

hypersomnolence including 4 with idiopathic hypersomnia and 2 with

narcolepsy.

Conclusion: Patients with POTS have objective evidence of primary

sleep disorders including periodic limb movement disorder, circadian

rhythm disturbance and central hypersomnia.

228 Clin Auton Res (2012) 22:207–258

123

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

Department of Cardiology, McMaster University,

Hamilton, ON, Canada

Introduction: The purpose of this study was to test the hypothesis that

impaired alpha (a) adrenergic vascular response may be a common

pathophysiological link between Postural Orthostatic Tachycardia

Syndrome (POTS) and neurally mediated syncope (NMS).

Methods: Fifteen POTS and 15 NMS patients who had a positive

head-up tilt test (HUT) at 70�, during 15 min drug free, were com-

pared to 15 patients with suspected NMS with a negative HUT with

isoproterenol provocation (Neg-HUT). The alpha-adrenergic sensi-

tivity (D blood pressure-phenylephrine) and activity (D blood

pressure-phentolamine) and catecholamine levels in supine and at 5

and 10 min of HUT were analyzed. Cardiac hemodynamic parameters

obtained from the Task Force Monitor were measured at supine and

during a 15 min drug free HUT.

Results: Mean a-adrenergic sensitivity was reduced in all three groups

compared to healthy volunteers from literature data (Normal values:

107 ± 38). a-adrenergic sensitivity was lower in POTS patients

compared to Neg-HUT patients (32.3 ± 28.5 vs. 54.0 ± 33.3;

p = 0.04). No differences were observed in a-adrenergic activity.

Stroke index (SI) was similar between groups in supine and during

HUT. Compared to Neg-HUT, POTS patients had higher norepi-

nephrine levels at 10 min of HUT and higher heart rate delta (D)

changes (from supine to HUT). Conversely, POTS had lower Dchanges in total peripheral resistance index (TPRI) (-163.3 ± 773.0

vs. 230.4 ± 825.3 vs. 644.2 ± 542.9 dyn s m/cm5, respectively;

p \ 0.05).

Conclusions: Alpha receptor sensitivity was significantly impaired in

POTS patients compared to patients with a negative HUT. TPRI response

to orthostatic challenge was also primarily impaired in POTS patients.

Impaired a-adrenergic receptor sensitivity may share a common patho-

physiological pathway in orthostatic intolerance syndromes.

Saturday, November 3, 2012

Oral Presentations

Multi-scale glycemic variability affects brain structure

and functional outcomes in type 2 diabetes mellitus

X. Cui1,2, A. Galica3, B. Manor3, A. Abduljalil4, C.-K. Peng1,5,

V. Novak3

1Division of Interdisciplinary Medicine and Biotechnology, Beth

Israel Deaconess Medical Center, Harvard Medical School, Boston,

MA, USA; 2School of Information Engineering, Wuhan University

of Technology, Wuhan, Hubei, China; 3Division of Gerontology,

Beth Israel Deaconess Medical Center, Harvard Medical School,

Boston, MA, USA; 4Center for Advanced Magnetic resonance

Imaging, The Ohio State University, OH, USA; 5Center

for Dynamical Biomarkers and Translational Medicine, National

Central University, Chungli, Taiwan

Background: Diabetes mellitus (DM) increases the risk for dementia.

However, complex interactions between chronic hyperglycemia and

glycemic variability are not well understood. We studied the

relationships between glycemic variability, brain tissue and functional

measures.

Methods: Forty-three T2DM and twenty-six non-DM subjects aged

50–85 years completed continuous glucose monitoring (CGM) for

3 days. Glycemic variability was quantified using a novel approach

based on the ensemble empirical mode decomposition algorithm

(EEMD). EEMD enables decomposition of the raw GCM time-series

into multiple ‘‘glycemic variability cycles (GVCs)’’ linked to physi-

ological rhythms: e.g., autonomic and hormonal (0.5–2 h), meal

(4–5 h); sleep/wake (10–12 h) and diurnals. Regional brain volumes

were quantified from 3T MRIs. Numerous laboratory, cognitive and

functional assessments were completed.

Results: The DM group demonstrated greater glycemic variability

than controls at multiple time-scales (GVCs: 2 h, meal, sleep/awake,

diurnal, p \ 0.0001), which were correlated with higher HbA1c

(p \ 0.05). In diabetics, greater GVC for sleep/wake cycle was

associated with worse verbal learning scores (r2 = 0.24, p \ 0.015)

and depression (r2 = 0.18, p \ 0.014). For all subjects, GVCs were

associated with slower normal and dual task walking (r2 = 0.1–0.37,

p \ 0.05). GVCs (0.5–2 h) were linked to lower regional gray matter

volumes in learning and memory circuits, insular cortex and regions

for motor and visuospatial processing, mainly in the temporal and

parietal lobes (r2 = 0.26–0.74, p \ 0.05). GVCs (0.5–2 h) were

linked with less blood pressure dipping at night, worse sleep effi-

ciency and atrophy of the insular cortex.

Conclusions: Multi-scale GV is a promising measure of glycemic

control that may be sensitive to underlying influences associated with

different physiological rhythms; e.g. hormonal modulation, cardio-

vascular autonomic rhythms, meal and sleep/wake cycle. In diabetics,

increased GV is associated with worse cognition, more depression

and brain atrophy. DM-related increases in glycemic variability

associated with multiple physiological rhythms may be independent

predictors of brain atrophy and functional decline.

The laser Doppler imaging axon-reflex flare area—a

novel regression thresholding based technique to assess

neurovascular function

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

Department of Neurology, Carl Gustav Medical School, Dresden,

Germany

Background: Laser Doppler Imaging (LDI) can measure neurovas-

cular function in patients with small fiber neuropathy through

assessment of the vasomotor axon-reflex. However, previous studies

show conflicting results in patients with neuropathy, in part, because

no standard LDI data analysis method has been established. This

study reports the efficacy of a novel LDI image analysis technique in

the detection of vasomotor C-fiber function changes in a capsaicin

model of small fiber neuropathy.

Methods: Eighteen healthy subjects ages 21–27 underwent occlusive

application of 0.1 % capsaicin cream on the lateral thigh over 48 h to

cause local small fiber nerve damage. Placebo was applied on the contra-

lateral thigh under randomized conditions. Axon-reflex mediated flare

was induced through iontophoresis of 10 %-acetylcholine. Post-capsai-

cin and placebo LDI measurements were taken from both thighs for

4 weeks on day 3, 10, 17, 24 and 31. LDI axon-reflex flare area assess-

ment was performed using our regression thresholding technique and the

results were compared to two previously reported LDI methods. Skin

biopsies were performed to measure intra-epidermal nerve fiber density

(IENFD) in the capsaicin and placebo treated regions.

Results: IENFD was reduced in capsaicin treated skin (2.8 ± 2.9

fibers/mm capsaicin vs. 17.4 ± 5.7 fibers/mm placebo: p \ 0.0001).

The axon-reflex flare area as measured by our regression method was

Clin Auton Res (2012) 22:207–258 229

123

reduced on all evaluation days in capsaicin treated skin (p \ 0.05) but

not in control treated skin. Our regression threshold method proved

more sensitive than the two previously reported LDI methods in

showing differences between capsaicin treated and control skin on all

testing days (p \ 0.05)

Discussion: This study demonstrates that regression thresholding based

LDI measurements of the axon-reflex flare area can detect neurovascular

dysfunction due to small nerve fiber damage. This technique appears to

differentiate neuropathic and non-neuropathic cutaneous regions more

effectively than previously reported methods. This test may supplement

the clinical assessment of small fiber neuropathy

Long-term outcomes in autoimmune autonomic

ganglionopathy

S. Muppidi 1, E.B. Spaeth1, C. Gibbons2, S. Vernino1

1Department of Neurology and Neurotherapeutics, UT Southwestern

Medical Center, Dallas, TX, USA; 2Department of Neurology, Beth

Israel Deaconess Medical Center, Boston, MA, USA

Objective: To assess the long-term outcome in patients with auto-

immune autonomic ganglionopathy (AAG).

Methods: We identified AAG patients from two medical centers from

2003 to present. We reviewed clinical manifestations, comprehensive

autonomic evaluation, ganglionic acetylcholine receptor (gnAChR)

antibody titers and immunosuppressive therapy. Some patients com-

pleted an Activities of Daily Living (ADL) questionnaire related to

their autonomic dysfunction at onset and at present.

Results: Thirteen patients during the study period (nine women; mean age

of 54.3 years) were identified. Twelve were seropositive (gnAChR titer

[0.05). Three patients had acute onset (\4 weeks), five had subacute

onset (4–8 weeks), and five had chronic onset ([8 weeks). At onset, all

but one patient had orthostatic hypotension and GI hypomotility. Eleven

patients had decreased sweating, saliva production, and bladder urgency.

All four men had erectile dysfunction. Four patients complained of limb

sensory symptoms. All but one patient had severe global autonomic

failure and eight had pupillary dysfunction on objective testing. Com-

posite Autonomic Severity Score was[8/10 in eight patients. Autonomic

function improved in some patients with decrease in antibody titer. For

initial therapy, twelve patients received prednisone, eight received IVIG

and/or plasma exchange. For maintenance immunosuppression, patients

were on prednisone and either azathioprine or mycophenolate mofetil

and some were on regular plasma exchange therapy. Mean duration of

follow up was 6 years and during the follow up, one patient developed

diffuse Large B Cell Lymphoma after treatment with mycophenolate

mofetil. One patient was diagnosed with rectal adenoma carcinoma at the

onset of AAG symptoms. Five patients completed a questionnaire

regarding ADL, and all but had a significant improvement.

Conclusions: In our series, AAG patients responded to immunosup-

pressive therapy, with dramatic improvement in their ADLs and some

improvement in objective measures of autonomic function. Two

patients had malignancy, but the relationship to AAG is unclear.

Type I diabetic Akita mice demonstrate decreased heart

rate variability and increased inducibility of ventricular

tachycardia which are reversed by statins

C.M. Welzig1, H.-J. Park2, M. Rajab2, M. Aronovitz2, H. Jin2,

M.S. Link2, J.B. Galper2

1Department of Neurosciences, Medical University of South Carolina,

SC, USA; 2Molecular Cardiology Research Institute, Tufts Medical

Center, Boston, MA, USA

Introduction: Diabetes mellitus is associated with an impaired

response of the heart to parasympathetic stimulation and increased

cardiovascular mortality and sudden death. Decreased heart rate

variability (HRV) has been shown to be a risk factor for cardiovas-

cular disease and has been associated with sudden cardiac death in

young type I diabetics, while parasympathetic stimulation has been

shown to be protective against ventricular tachycardia (VT). We

previously demonstrated that patients treated with pravastatin had

increased parasympathetic activity and decreased ventricular ectopy.

We also previously demonstrated that the Type I diabetic (Akita)

mouse has a markedly decreased response to parasympathetic stim-

ulation. Here we determine whether pravachol treatment reverses the

abnormality in HRV and heart rate response to parasympathetic

stimulation in Akita mice and whether this effect is associated with

decreased inducibility of VT via programmed ventricular stimulation

in the Akita mouse.

Methods: Heart rate was determined using implantable ECG trans-

mitters. The increase in the normalized high frequency component of

HRV (HF) determined as HF fraction, was calculated over time after

injection of propranolol in placebo and pravachol treated Akita mice.

For programmed stimulation, an intracardiac octapolar catheter was

placed in the right ventricle via the jugular vein followed by drive

trains of 8 beats at 100 with up to 3 premature extrastimuli at pro-

gressively shorter cycle lengths until refractoriness. These were

repeated at drive trains of 90 and 80 ms. VT was defined as C4 beats.

Results: HF fraction at 15 min after propranolol was decreased in

Akitas, 48.6 ± 5.2 % versus 70.9 ± 4.8 % in WT (n = 10,

P = 0.005) and increased from 58.2 ± 2.5 % in placebo to

68.8 ± 3.6 % (n = 7, P = 0.033) in pravachol (10 mg/kg) treated

mice. The decrease in heart rate in response to carbamylcholine was

also significantly increased in Pravachol treated mice. Akita mice

were significantly more vulnerable to stimulation of VT 78.57 % (11

of 14), compared to WT 28.57 % (4 of 14, P = 0.006). Pravastatin

treated Akita mice were less vulnerable to VT 36.84 % (7 of 19),

compared to placebo treated Akita mice 75 % (12 of 16, P = 0.023).

Conclusion: These data support the hypothesis that statins might

protect the diabetic heart from arrhythmias via an increase in HRV.

The quantification of sudomotor nerve fibers:

a multicenter study in diabetes

C.H. Gibbons1, J. Lafo1, G. Smith2, R. Singleton2, R. Freeman1

1Beth Israel Deaconess Medical Center, Harvard Medical School,

Boston, MA, USA; 2University of Utah, Salt Lake City, UT, USA

Background: We have recently reported techniques to quantify the

sweat gland nerve fiber density (SGNFD) in healthy subjects and

patients with diabetes. We sought to validate these findings against a

well established cohort of healthy controls and patients with diabetes

and to develop novel methods to improve collaborative efforts on the

structural investigation of autonomic nerve fibers.

Methods: We compared the sweat gland nerve fiber density (SGNFD)

of a cohort of 36 patients with diabetes and 72 healthy controls

studied in Boston to a group of 151 patients with diabetes and 30

healthy controls studied at the University of Utah. Tissue was

reviewed from existing skin biopsies taken for evaluation of intra-

epidermal nerve fiber density (IENFD) and stained with PGP 9.5.

Every sweat gland was digitally captured by light microscopy with an

in focus, and blurred image. Images were transferred digitally from

Utah to Boston for analysis using automated and manual counting as

previously reported (Gibbons, Muscle & Nerve 2010).

Results: There were significant differences between control sweat

glands and diabetic sweat glands in the Utah group using the

230 Clin Auton Res (2012) 22:207–258

123

automated SGNFD counting technique at the proximal thigh

(13.4 ± 4.9 % vs. 8.5 ± 4.8 %, P \ 0.001), distal thigh (13.3 ±

7.2 % vs. 9.3 ± 7.7 %, P \ 0.05) and distal leg (12.5 ± 7.4 % vs.

6.8 ± 6.8 %, P \ 0.001). There were significant differences between

control sweat glands and diabetic sweat glands in the Utah group

using the manual SGNFD counting technique at the proximal thigh

(53.9 ± 15.1 % vs. 33.8 ± 9.6 %, P \ 0.001), distal thigh (48.6 ±

17.2 % vs. 34.5 ± 19.7 %, P \ 0.05) and distal leg (40.1 ± 17.4 %

vs. 16.8 ± 15.5 %, P \ 0.001). There were no significant differences

in SGNFD by group (control or diabetes) or biopsy location obtained

from the Utah and Boston cohorts (P = NS).

Discussion: Both the automated and manual sweat gland counting

methods could detect differences between groups of control subjects

and individuals with diabetes. The manual counting technique more

clearly discriminates individual subjects, but is more labor intensive.

Our data highlight the ability to analyze SGNFD from existing skin

biopsy databases and demonstrate a simple method suitable for col-

laborative studies via electronic transfer of images for analysis.

Treatment of neurogenic orthostatic hypotension

(NOH) with droxidopa: results from a multicenter,

double-blind, randomized, placebo-controlled, parallel

group, induction design study

H. Kaufmann1, P. Low2, I. Biaggioni3, C.J. Mathias4, R. Freeman5,

L. A. Hewitt6

1New York University Dysautonomia Center, New York, NY, USA;2Mayo Clinic, Rochester, MN, USA; 3Vanderbilt University,

Nashville, TN, USA; 4Imperial College London, London, UK; 5Beth

Israel Deaconess Medical Center, Boston, MA, USA; 6Chelsea

Therapeutics Inc., Charlotte, NC, USA

Objective: Assess the clinical effect of droxidopa in subjects with

symptomatic NOH.

Background: Symptoms of NOH (e.g, lightheadedness, falls, and

syncope) result from low blood pressure (BP) upon standing due to

impaired norepinephrine release from sympathetic nerve terminals.

Droxidopa, an orally active synthetic amino acid, may improve

standing BP and NOH symptoms by augmenting norepinephrine

levels.

Methods: Multinational trial evaluated safety and efficacy of drox-

idopa in 263 symptomatic NOH patients. Primary efficacy variable

was the Orthostatic Hypotension Questionnaire (OHQ) composite

score. After an open-label droxidopa dose-optimization phase

(100–600 mg tid) and 7-day washout, patients were randomized in

double-blind fashion to receive droxidopa or placebo for 7 days.

Results: Responders (C1 point improvement on OHQ item 1 and

C10 mmHg increase in standing systolic BP [SBP] during the open-

label phase) were randomized to treatment with their optimized

droxidopa dose (n = 82) or placebo (n = 80). Underlying diseases

and age were similar in the droxidopa and placebo groups: age 57

versus 56 years, 51 versus 53 % male, Parkinson’s disease 43 versus

38 %, multiple system atrophy 17 versus 15 %, primary autonomic

failure 32 versus 35 %, and nondiabetic autonomic neuropathy 3

versus 7 %, respectively, and other diagnoses 5 % in both groups.

The mean change in OHQ composite score showed a statistically

significant, clinically meaningful improvement in patients taking

droxidopa vs those taking placebo (-1.83 ± 2.07 vs. -0.93 ± 1.69,

respectively, p = 0.003). Standing SBP increased 11.2 mmHg with

droxidopa versus 3.9 mmHg with placebo (p \ 0.001). Supine

hypertension (SBP [ 180 mmHg) occurred in 4 (5 %) droxidopa-

treated versus 2 (3 %) placebo-treated patients. The most frequent

adverse events (AEs) in droxidopa-treated versus placebo-treated

patients were headache 11 versus 0 %, dizziness 8 versus 1 %, nausea

5 versus 0 %, and fatigue 4 versus 3 %.

Conclusions: Droxidopa significantly improved symptoms and raised

BP in the standing position in symptomatic NOH patients. The drug

was well-tolerated and caused no serious AEs.

What is MSNA doing at the onset of syncope?

D.L. Jardine

Department of General Medicine, Christchurch Hospital,

Christchurch, NZ

Background: The mechanism of vasovagal syncope has traditionally

been thought to consist of vasodilatation (mediated by peripheral

sympathetic withdrawal) and bradycardia, secondary to increased

vagal activity on the heart. Recent MSNA studies have challenged not

only vasodilatation as the key mechanism, but also sympathetic

withdrawal.

Aim: To review all recordings of tilt-induced syncope in our labora-

tory with satisfactory BP, HR and MSNA recordings in order to

clarify the sequence of events particularly during the final minute of

presyncope.

Methods: All patients selected were being investigated for symptoms

of vasovagal syncope and underwent 60� head-up tilt testing with

continuous monitoring of BP (intra-arterial or FINAPRES), HR and

MSNA. In addition, stroke volume, cardiac output and total peripheral

resistance were derived from the arterial waveform using MODEL-

FLOW. If patients remained normotensive after 20 min of tilt, GTN

spray was administered, as per tilt protocol.

Results: 65 patients (mean age 46.1 ± 2 years, 37 females) were

selected from 340 tilts undertaken between January 1995 and Sep-

tember 2005. During presyncope, MBP fell from 101 ± 2 to

62 ± 2 mmHg [p \ 0.001]; HR from 82 ± 2 to 78 ± 3 bpm; cardiac

output from 89 ± 2 to 77 ± 3 % baseline [p \ 0.001]; and TPR from

114 ± 4 to 92 ± 3 [p \ 0.001]. During the last minute, MSNA

[bursts/min] fell in 56 patients [88 %], but only below baseline levels

in 14 [22 %]. MSNA burst size [burst area per beat] increased in 24

[38 %]. MSNA recording fields only included recovery from syncope

in 32 [50 %].

Conclusion: Measurement of MSNA during the last stages of pre-

syncope is difficult and results may be affected by field loss, sampling

intervals and variation in the onset of hypotension and bradycardia

between individuals. During the last minute of presyncope, MSNA

burst frequency falls in most patients, and this is not all mediated by

the ‘‘bradycardia effect’’. Burst size is more variable and may fall

later or even increase in some patients.

A meta-analysis of pharmacologic treatments

of orthostatic hypotension

C.H. Gibbons1, S. Raj2

1Department of Neurology, Beth Israel Deaconess Medical Center,

Harvard Medical School, Boston, MA, USA; 2Department

of Neurology, Vanderbilt University Medical Center, Nashville,

TN, USA

Background: A number of pharmacologic therapies are widely uti-

lized for the treatment of orthostatic hypotension, although the

benefits are not fully established.

Objective: To identify and evaluate the benefits and harms of all

pharmacologic treatments for postural hypotension.

Clin Auton Res (2012) 22:207–258 231

123

Methods: We conducted a review of all available literature from the

Cochrane central register of controlled trials, Medline (1966–2010)

and EMBASE (1980–2010) using the following search terms:

orthostatic hypotension, postural hypotension, orthostatic intolerance,

neurally mediated hypotension and autonomic hypotension. We

searched for randomized, double blind, placebo controlled trials. Our

primary outcome was the change in mean systolic and or diastolic

pressure in the upright position pre and post-treatment. Secondary

outcomes included change in symptom scores, chronic change in

upright blood pressure and adverse events due to treatment.

Results: We reviewed [3,000 abstracts and identified 62 articles

appropriate for review. Although several articles suggest a benefit of

drug treatment, none of the articles reported complete outcome data,

blinding or randomization and none of the data was available from the

authors of the articles.

Discussion: After an exhaustive review of the literature on orthostatic

hypotension, we conclude that there is insufficient data to make

conclusions about the effectiveness of any pharmacologic treatments.

All studies reported information in a limited and diverse fashion, with

many outcome values only included in figure format. Some studies

only reported diastolic, systolic or mean blood pressures, or mean

change in blood pressures. We were unable to obtain actual data from

any study. We conclude that the American Autonomic Society should

take a lead role in defining outcomes for studies of orthostatic

hypotension.

Increasing cardiac output does not change middle

cerebral artery blood velocity in the hyperthermic

human

C.G. Crandall1, T. Seifert2, T.E. Wilson3, M. Bundgaard-Nielsen2,

N.H. Secher2

1University of Texas Southwestern Medical Center and Institute

for Exercise and Environmental Medicine, Texas Health Presbyterian

Hospital Dallas, TX, USA; 2Risghospitalet, University

of Copenhagen; 3Ohio University College of Osteopathic Medicine

Hyperthermia severely compromises lower-body negative pressure

(LBNP) tolerance, while tolerance in this thermal condition is pre-

served if preceded by rapid volume infusion (Keller et al. J Phyisol2009). In normothermic individuals, volume infusion increases

cerebral blood flow, reportedly due to increases in cardiac output

(Ogoh et al. J Phyisol 2005). The present study tested the hypothesis

that rapid volume infusion in hyperthermic individuals increases

cerebral perfusion, which may contribute to the aforementioned

preservation of LBNP tolerance. In 8 healthy male subjects

(29 ± 5 years), middle cerebral artery blood velocity (transcranial

Doppler), arterial blood pressure (cannulation of radial artery), car-

diac output (thermodilution), and PaCO2 (arterial blood gas) were

measured while subjects were normothermic, passively heat stressed

(i.e., hyperthermic), and hyperthermic after rapid infusion of 500 ml

synthetic colloid plus saline (12 ml/kg total volume infused).

Hyperthermia increased pulmonary artery blood temperature

(36.6 ± 0.3 to 37.7 ± 0.3 �C; P \ 0.01) and cardiac output

(6.4 ± 0.9 to 10.7 ± 2.1 l/min; P \ 0.01), while decreasing cerebral

blood velocity (59 ± 7 to 53 ± 12 cm/s; P \ 0.01) and mean arterial

pressure (91 ± 8 to 80 ± 7 mmHg; P \ 0.01). Subsequent volume

infusion, while remaining hyperthermic, further increased cardiac

output (to 13.8 ± 2.4 l/min; P \ 0.01 relative to normothermia and

hyperthermia), without changing cerebral blood velocity

(55 ± 12 cm/s; P = 0.4) or mean arterial pressure (82 ± 5 mmHg;

P = 0.3). PaCO2 was unchanged throughout all conditions and per-

turbations. Thus, cerebral perfusion was unchanged despite *3 l/min

increase in cardiac output due to volume infusion. These data indicate

that, unlike normothermia, increases in cardiac output via volume

infusion do not increase cerebral perfusion in hyperthermic individ-

uals. Therefore, the preservation of LBNP tolerance while

hyperthermic, following rapid volume infusion, is not due to increases

in cerebral perfusion prior to the LBNP challenge.

Patterns of diagnosis and intervention in neurogenic

orthostatic hypotension (NOH): a patient-flow study

H. Kaufmann1, R.E. Paquette2

1New York University, Dysautonomia Center, New York, NY, USA;2Copernicus, Boston, MA, USA

Objective: To elucidate current patterns of treatment for neurogenic

orthostatic hypotension (Neurogenic OH or NOH), especially roles of

different specialties, factors governing treatment decisions, and

interventions utilized.

Methods: For this patient-flow study, 110 neurologists, 110 cardiol-

ogists, and 110 primary-care physicians (PCPs) were interviewed. All

had C120 patients per month, including C8 with NOH (C10 for

neurologists) in Parkinson’s disease (PD), multiple system atrophy

(MSA), or pure autonomic failure (PAF). Each interview included 3

chart reviews for a total of 990 unique patient charts.

Results: Clinicians’ roles: By monthly average, neurologists were

seeing the most NOH patients (48, including 35 with PD). However,

substantial numbers were seen by PCPs (41, including 22 with PD and

10 with MSA) and cardiologists (37, including 16 with PD and 14

with PAF). Treatment decisions: At diagnosis, neurologists had pre-

scribed medications for 83 % of NOH patients, cardiologists for

80 %, and PCPs for 57 %. For changing therapy, 95 % of neurolo-

gists, 91 % of cardiologists, and 74 % of PCPs considered themselves

the primary decision-maker, and 67, 58, and 59 % felt ‘‘somewhat’’ to

‘‘completely’’ confident in treating NOH. However, only 5 % of NOH

patients had undergone any change of therapy during the past 2 years.

Interventions: Among the chart reviews, 67 % of NOH patients ini-

tially received monotherapy, 9 % received combination therapies, and

24 % received no pharmacotherapy. Among monotherapy users,

53 % took fludrocortisone and 33 % midodrine. Neurologists were

the most likely to prescribe monotherapy, to prescribe medication

plus lifestyle modification, and to consider their patients’ NOH ‘‘very

well’’ to ‘‘extremely well’’ controlled (52 % of neurologists’ cases,

48 % of cardiologists’ cases, and 36 % of PCPs’ cases).

Conclusions: Although neurologists see the most NOH, especially in

PD, cardiologists and PCPs have substantial numbers of patients and

often act autonomously. Across specialties, physicians appear to do

little to alter NOH management over time.

Poster Session I

Poster #1

A randomized, double-blind, placebo-controlled clinical

trial of Rifampicin in multiple system atrophy

P.A. Low1, S. Gilman2, D. Robertson3, I. Biaggioni3, W. Singer1,

H. Kaufmann4, S. Perlman5, W. Cheshire6, S. Vernino7; R. Freeman8,

R.A. Hauser9, S. Lessig10

1Mayo Clinic, Rochester, MN, USA; 2University of Michigan, Ann

Arbor, MI, USA; 3Vanderbilt University, Nashville, TN, USA; 4New

York University Dysautonomia Center, New York, NY, USA;

232 Clin Auton Res (2012) 22:207–258

123

5UCLA Medical Center, Los Angeles, CA, USA; 6Mayo Clinic,

Jacksonville, FL, USA; 7University of Texas Southwestern Medical

Center, Dallas, TX, USA; 8Beth Israel Deaconess Medical Center,

Boston, MA, USA; 9University of South Florida, Tampa, FL, USA;10University of California, San Diego, San Diego, CA, USA

Objective: To describe a Phase III study intended to determine

whether Rifampicin slows or reverses the progression of multiple

system atrophy (MSA).

Background: MSA is a rapidly progressive disorder characterized by

autonomic failure with parkinsonism and/or cerebellar ataxia. It is

defined neuropathologically by glial cytoplasmic inclusions consisting of

aggregated misfolded alpha-synuclein with widespread neuronal

degeneration. In a transgenic mouse model of MSA, Rifampicin, a bac-

tericidal antibiotic, inhibits formation of alpha-synuclein fibrils and

disaggregates already formed fibrils, thereby improving behavioral

abnormalities and halting or reversing neuropathological changes.

Methods: We initiated a randomized, double-blind, placebo-con-

trolled 12 months clinical safety/efficacy study of 100 pts with

possible or probable MSA, 50 % consigned to active drug (Rifam-

picin 300 mg twice daily), 50 % to placebo (Riboflavin capsules

twice daily). Subjects recruited from 10 US sites. Inclusion criteria

include subjects of either gender; ages 30–80 years; \4 years from

time of diagnosis; expected survival at least 3 years; able to give

informed consent; MMSE [ 24. Exclusion criteria include modified

UMSARS 1 score [17; tetrabenazine, rasagiline or selegiline;

abnormal liver function tests; medications affecting autonomic

function; neuroleptics; dementia. Primary outcome measure will be

rate of change from baseline to 12 months in total UMSARS 1 score.

Secondary outcome measures will include change from baseline to

completion in total UMSARS score; slope analysis of rate of pro-

gression in total UMSARS score from baseline to 12 months; change

from baseline to 12 months in UMSARS subscores.

Results: The original study was funded by NINDS as a 2 center study. It

was subsequently expanded under the Autonomic Rare Disease Con-

sortium to a multicenter (10 sites) study confined to the United States of

America. Recruitment commenced in April 2011 with the goal of

recruiting 100 subjects over 2 years. By April 2012 we had completed

recruitment. Subjects were predominantly white (90 %) and elderly

(60.9 ± 8.4 years), with a slight predominance of males (M:F, 62:38)

and a ratio of MSA-C:MSA-P of 58:42 %. Ratio of Probable:possible

MSA was 57:43 %. UMSARS Score: UMSARS I (excluding Q11) was

12.5 ± 3.6, indicating mild-moderate symptoms and impairment of

activities of daily living. UMSARS II was 15.9 ± 4.6. UMSARS IV was

2.1 ± 0.8. COMPASS_select was 14.7 ± 11.8. Most severely affected

domains were those of orthostatic intolerance, bladder dysfunction and

sleep disorder. Dropouts thus far have comprised 4 subjects. There have

been 1 death and 3 completions.

Conclusions: The goal of recruiting 100 subject with relatively mild-

moderate MSA within 24 months has been accomplished in

12 months. We chose 10 centers with a heavy research interest and

strong autonomic emphasis. Patients were evenly distributed between

possible and probable MSA. There was a slight predominance of

MSA-C over MSA-P. It is feasible to recruit early MSA. Rifampin

has been well-tolerated and its toxicity has been manageable. Patient

compliance has been high with only 4 subjects dropping out to date.

Poster #2

Orthostatic hypotension in Parkinson disease: passive

tilt vs. active standing

J. Martinez1, J.C. Esteban Gomez2, B. Tijero Merino2, K. Berganzo2,

H. Kaufmann1

1New York University Medical Center, New York, NY, USA;2Hospital de Cruces, Bilboa, Spain

Orthostatic hypotension (OH) defined as a reduction of systolic blood

pressure of at least 20 mmHg or diastolic blood pressure of at least

10 mmHg within 3 min of active standing or head-up-tilt (HUT) is

common in Parkinson disease (PD). We compared the frequency of

OH when assessed by head-up-tilt test (HUT) versus active standing

in 233 patients with PD. 116 patients (73 men and 43 women)

underwent a 60� HUT and 117 patients (62 men and 53 women)

underwent an active standing procedure. Blood pressure and heart rate

were measured before and after 3 min in the upright position. The

average dose of levodopa and direct dopaminergic agonists and the

frequency of other medications was similar in both cohorts. The

prevalence of OH was 70 % in those undergoing HUT and 41 % in

those undergoing active standing (p \ 0.001). However, patients

undergoing HUT were significantly older (72.1 vs. 61.2 years,

p \ 0.001) and had higher systolic blood pressure while supine (151

vs. 134 mmHg, p \ 0.001). Prevalence of OH by age showed that the

40–50 years old group (n:15) had 20 % prevalence of OH with HUT

versus 40 % with active standing (NS); in the 50–60 years old group

(n:38), 33 % had OH with HUT versus 47 % with active standing

(NS), in the 60–70 years old group (n:67), 78 % had OH with HUT

versus 43 % with active standing (p \ 0.004), and in the 70–80 years

old group (n:85), 60 % had OH with HUT and 36 % with active

standing (p \ 0.04). Thus, in younger patients with PD active

standing and HUT showed similar prevalence of OH. However,

among PD patients 60 years and older the prevalence of OH was

significantly higher with HUT than active standing. These findings

have practical implication for diagnosis and clinical management.

Poster #3

Cerebellar and parkinsonian phenotypes in multiple

system atrophy (MSA). Similarities and differences

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


Based on the predominant motor abnormality, two MSA clinical

phenotypes are identified: parkinsonian (MSA-P) and cerebellar

(MSA-C). It is unclear whether in addition to the motor deficit there

are other significant differences between these phenotypes. We

reviewed clinical data from 97 patients with possible (12 %) or

probable (88 %) MSA based on Consensus criteria, from the database

of the NYU Dysautonomia Center. Of these, 60 % were classified as

MSA-P and 40 % as MSA-C. Age at first visit was similar in MSA P

and C (both 61). Brain MRIs were more frequently abnormal in MSA-

C than MSA-P patients (93 vs. 51 %; p \ 0.001), the predominant

abnormality being cerebellar and pontine atrophy. Autonomic

symptoms preceded motor abnormalities in 59 % of MSA-C versus

44 % of MSA-P patients. Autonomic symptoms were felt

2.8 + 2.4 years before motor deficits in both phenotypes. Forty-four

patients had an appropriate trial of levodopa; 70 % had poor or no

motor response, while 30 % had an initial, but short-lived good

response to levodopa. Of those with good response, 93 % had MSA-

P. Orthostatic hypotension, at least 20/10 mmHg within 3 min of tilt,

occurred in 85 % of MSA-C and 79 % of MSA-P patients, while a

fall of 30/15 mmHg occurred in 69 %, both in MSA-C and MSA-P.

Heart rate variability was similarly reduced in both phenotypes.

Absence of blood pressure overshoot during phase IV of Valsalva

maneuver was recorded in 86 % of MSA-C versus 66 % of MSA-P

Clin Auton Res (2012) 22:207–258 233

123

(p \ 0.05). Plasma concentration of norepinephrine, supine and

upright was similar in both phenotypes. In sum, MSA-C and MSA-P

patients had similar gender distribution, age of first visit, and fre-

quency of OH. MSA-C patients more often had autonomic symptoms

as the first abnormality. They also had more abnormal MRIs, more

frequently abnormal Valsalva maneuver and less response to

levodopa.

Poster #4

A novel quantitative index of baroreflex-

sympathoneural function: application to patients

with chronic autonomic failure

F. Rahman1, D.S. Goldstein2

1Internal Medicine Residency Program, Boston University, Boston,

MA, USA; 2Clinical Neurocardiology Section, NINDS/NIH,

Bethesda, MD, USA

Background: Beat-to-beat blood pressure and heart rate recordings

during the Valsalva maneuver can be used to evaluate baroreflex

function without pharmacological manipulations. One can calculate

baroreflex-cardiovagal gain (BCG) from the slope of the relationship

between cardiac interbeat interval and systolic blood pressure during

the fall in pressure in Phase II. Failure of blood pressure to increase

from its nadir at the end of Phase II and lack of a pressure overshoot

in Phase IV constitute qualitative means to assess baroreflex-sym-

pathoneural function. Here we report a simple quantitative index of

baroreflex-sympathoneural function based on beat-to-beat systolic

pressure during and after the Valsalva maneuver and application of

this method in patients with chronic autonomic failure syndromes.

Low frequency power of heart rate variability from power spectral

analysis has been proposed as an index of the ability to modulate

autonomic outflows by baroreflexes.

Method: Using the trapezoid rule, we calculated areas below the

baseline systolic pressure in Phases II and IV of the Valsalva

maneuver in a total of 288 subjects, including patients with chronic

autonomic failure manifested by orthostatic hypotension in Parkinson

disease, multiple system atrophy, or pure autonomic failure. BCG and

the log of low frequency power were measured in the same subjects.

Orthostatic fractional changes in plasma norepinephrine provided a

neurochemical index of baroreflex-sympathoneural function.

Results: The sum of baroreflex areas in Phases II and III-IV was

higher in patients with Parkinson disease with orthostatic hypoten-

sion, pure autonomic failure, or multiple system atrophy than

in controls (p \ 0.00001 each). Individual values for the log of

baroreflex total area correlated negatively with the log of BCG

(r = -0.47, p \ 0.0001), the log of low frequency power (r = -0.47,

p \ 0.0001), and the orthostatic fractional increase in plasma nor-

epinephrine (r = -0.35, p \ 0.0001). Interpretation: The baroreflex

areas method provides a quantitative index of baroreflex-sympatho-

neural function.

Poster #5

Loss of cerebral blood flow rhythm in Parkinson’s

disease and vascular parkinsonism

S.-J. Yeh1, B.-W. Chang2, B.-Y. Liau2, C.-C. Chiu3

1Department of Neurology, Cheng-Ching Hospital, Taichung,

Taiwan; 2Hong-Kong University, Taichung, Taiwan; 3Department

of Automatic Control Engineering, Feng Chia University, Taichung,

Taiwan

Objectives: Differential diagnosis between vascular parkinsonism

(vP) and idiopathic Parkinson’s Disease (PD) is often difficult, due to

the overlap in clinical presentation. The aim of the study was to use

cerebral blood flow (CBF) regulation study to distinguish the two

conditions and the mechanism of control of CBF.

Materials and methods: We studied fourteen PD (6 female and 8

male; age = 58.3 + 12.2 years), 16 vP (2 female and 14 male;

age = 71.3 + 8.9 years) and 10 normal subjects (NL) (3 female and 8

male; age = 56.5 + 8.6 years) as control group, who had undergone a

simultaneously continuous TCD and beat-to-beat BP (CBP) moni-

toring. Several TCD markers and cross-correlation analysis (CCF) of

CBF and BP were used to establish the status of CBF regulation.

Results: The TCD PI resulted significantly higher in VP

(PI = 1.05 + 0.28) than in NL (0.79 + 0.16) but higher compared to

PD (0.85 + 0.18). The percentage of decrease of CBF velocity in

TCD during tilting resulted significantly higher in vP (23.8 + 15.3 %)

than in NL (8.5 + 12.7 %) but higher compared to PD

(18.2 + 8.2 %). We found that a cut-off of PI[1.2 could differentiate

PD from VP with a 100 % specificity and a 60 % sensitivity. CCF

coherence (the percentage of number with correlation [0.5) was

significantly higher in NL (90 %) compared to PD (61.5 %) and vP

(37.5 %). Phase shift in CCF showed good coupling in NL with

1.9 + 0.8 beats shift but graded loss of coupling on CBF and BP in PD

and vP (phase shift = 3.4 + 1.0 and 2.8 + 1.1 beats respectively).

Conclusions: PI and dynamic change of CBF in tilting can be used to

differentiate vP and PD with a good degree of certainty. In healthy

subjects, the CBF regulation is active even during the steady equi-

librium state between normal physiological BP range. Graded loss of

coupling between CBF and BP is positively related to PD and vP.

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

Ann and Robert H Lurie Children’s Hospital of Chicago,

Chicago, IL, USA

Rationale: Human body temperature results from a balance of heat

production/loss, varies diurnally, and is driven by an endogenous

circadian rhythm. Peripheral skin temperature, measured at distal

extremities, is inversely related to core body temperature but typically

offset by 1 h. Preliminary data suggest altered temperature/circadian

regulation patterns in CCHS and ROHHAD, both disorders of

respiratory and autonomic control. These data, coupled with anec-

dotal observations of cool extremities in both disorders, led us to

hypothesize that children with CCHS and ROHHAD will have

reduced peripheral skin temperature (vs. controls) and that children

with ROHHAD will demonstrate an augmented variability in tem-

perature patterns (vs. controls).

Methods: Study subjects included 14 cases (7 PHOX2B mutation-

confirmed CCHS cases, 7 phenotypically confirmed ROHHAD cases)

and 9 healthy controls. Peripheral skin temperature was measured

with the Thermochron iButton, (Maxim, Dallas), affixed to a cotton

234 Clin Auton Res (2012) 22:207–258

123

wrist-band, with temperature measures every 3 min, for a period of

*96 h.

Results: Compared to controls, CCHS cases had significantly lower

daytime (31.8 vs. 32.5, p \ 0.01) and nighttime (32.5 vs. 33.6,

p \ 0.001) mean peripheral skin temperature. Compared to controls,

children with ROHHAD had a trend toward lower mean daytime

peripheral skin temperature (32.1 vs. 32.5, NS) and a significantly

higher nighttime mean peripheral skin temperature (34.1 vs. 33.6

p \ 0.01).

Conclusions: These results confirm our hypotheses of altered

peripheral temperature regulation patterns in CCHS and ROHHAD.

CCHS cases exhibited lower overall temperatures with an attenuated

diurnal variation, while wide fluctuations in peripheral temperatures

were characteristic of ROHHAD cases. These data serve to compre-

hensively characterize temperature profiles and related dysregulation

in this cohort and begin to unravel the distinct mechanisms of tem-

perature regulation in these related disorders of respiratory and

autonomic regulation.

Poster #7

Heart rate variability in hospitalized children:

autonomic response to laughter and engagement

P.P. Patwari1, M.S. Carroll1, K. Gray2, M.K. Janda2, A.S. Kenny1,

T.H. Stewart1, C. Brogadir1, S.H. Wang3, D.M. Steinhorn3

1Center for Autonomic Medicine in Pediatrics, Children’s Memorial

Hospital in Chicago, IL, USA; 2Pediatrics, Children’s Memorial

Hospital in Chicago, IL, USA; 3Pediatric Critical Care, Children’s

Memorial Hospital in Chicago, IL, USA

Introduction: With growing evidence of autonomic nervous system

(ANS) function as a biomarker in disease and the importance of

environment in recovery, we proposed that effects of enjoyable

intervention (affecting hospital environment) in children could be

quantified through the ANS measure of heart rate variability (HRV).

We hypothesized that the induction of laughter from clown exposure

would relieve stress, distinct from quiet engagement with measurable

changes in the ANS response resulting in increased parasympathetic

(PSNS) and decreased sympathetic (SNS) tone.

Methods: Hospitalized children without fear of clowns, heart rate

altering medication, or hearing/visual/development impairment were

recruited. Primary dependent variables were State-Trait Anxiety

Inventory (STAI) for children and adolescents and HRV metrics (non-

invasive monitoring; NOX-T3;CareFusion,CA). Subjects were

exposed to active engagement (Clown Care, Big Apple Circus) and

quiet engagement (quiet project with volunteer) with cardiorespira-

tory monitoring prior to, during, and after intervention. Waveforms

were exported and analyzed with custom MATLAB software to

calculate normalized measures for a 3-min segment of each condition.

Values for HRV included: standard deviation of the N–N interval

(SDNN), high frequency (HF, 0.15–0.4 Hz) reflecting PSNS tone, and

low frequency (LF, 0.04–0.15 Hz) ratio [LF/(HF + LF)] reflecting

SNS tone.

Results: The Pilot Cohort included 48 subjects: mean age 10.5 years

(range: 5.3–17.9). Mean STAI scores reflect a significant reduction in

anxiety after both interventions (mean ± SD: Baseline 50 ± 14;

Post-clown 44 ± 10; Post-volunteer 44 ± 10; p \ 0.05 pre/post

t test). We found a reduction in mean SDNN with only volunteer-

intervention (Baseline 60.5 ± 5.3; post-volunteer 44.8 ± 4.2;

p \ 0.05), significant increase in SNS with only clown-intervention

(Baseline 0.488 ± 0.018; post-clown 0.514 ± 0.017; p \ 0.05). No

significant change in PSNS tone with either intervention.

Conclusion: These findings demonstrate an important difference in a

child’s response to variable stimuli. While anxiety was reduced fol-

lowing clown-intervention, the SNS tone increased contrary to our

hypothesis—suggesting that similar, unexpected findings may be

present in other activities involving environmental stimuli in hospi-

talized children.

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

Department of Pediatric Cardiology, Center of Dysautonomia,

University of Texas, Houston, TX, USA

Head up tilt table test (HUTT) is gold standard in evaluating auto-

nomic dysfunction and syncope in children and adolescents.

Limitations of conventional HUTT, cycling blood pressure (BP)

every one to 2 min, with heart rate (HR) correlated with patient

symptoms, has low sensitivity and specificity. Investigators have

evaluated more reliable and sensitive physiological parameters to

increase predictability of HUTT. From May 2009 to May 2012 we

performed 422 HUTT evaluations on children and adolescents. The

first group of 152 patients had conventional HUTT, including HR,

arm cuff BP, and oxygen saturation recorded every minute for 10 min

while supine, for 30 min while head up 70o and for 10 min with

supine reposition while recording patient symptoms. The second

group included 270 patients with HUTT using Task Force Monitor�

with display and storage of continuous BP, HR, cardiac stroke volume

(SV) by trans-thoracic impedance and calculated sympathetic and

parasympathetic activity correlated with symptoms and signs. Median

ages were 12.5 and 13.2 years in group one and two, respectively.

Patients from both groups were referred by pediatric neurologists,

cardiologists, gastroenterologists and rheumatologists with syncope

(63 %), dizziness (88 %), lightheadedness and headaches (52 %),

chronic nausea and stomach pains (32 %), chronic fatigue (42 %),

convulsions (6 %), fibromyalgia (2 %), palpitations and chest tight-

ness (12 %) and metabolic disorders (10 %). A positive test was

defined in group one as severe symptoms of syncope, blackout,

vomiting, severe headache, excessive fatigue and tremors or con-

vulsions accompanied by changes in HR (tachycardia, bradycardia)

and/or blood pressure. In group two, similar symptoms were

accompanied by significant changes in HR, BP, cardiac SV and

sympathetic/parasympathetic activity. There was increased ability to

correlate clinical manifestations with physiological abnormalities on

HUTT in the second cohort of subjects and also an increased sensi-

tivity of the test to determine whether there was orthostatic

intolerance

Poster #9

Biogenic amine metabolism in juvenile

neurocardiogenic syncope with dysautonomia

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

Department of Pediatric Neurology, Center for Dysautonomia,

University of Texas at Houston Medical School, Houston, TX, USA

Clin Auton Res (2012) 22:207–258 235

123

In a cohort of children and adolescents with neurocardiogenic syn-

cope and dysautonomia with physiological abnormalities on head up

tilt table testing (HUTT), seventeen youngsters had a diagnostic

lumbar puncture to evaluate persistent daily headaches. In addition to

opening cerebrospinal fluid (CSF) pressure and routine analyses,

biogenic amine and biopterin metabolites were quantified by high

performance liquid chromatography (Medical Neurogenetics, Atlanta,

GA). There were seventeen subjects (14 females), aged

12.5–20.5 years and one subject had two lumbar punctures 5 years

apart. Serotonin metabolite levels of 5-hydroxyindoleacetic acid

(5HIAA) were decreased in eleven subjects and dopamine metabolite

levels of homovanillic acid (HVA) were decreased in eleven subjects.

Twelve subjects had a defect in either 5HIAA and/or HVA metabo-

lites. Neopterin was decreased in one only subject with normal

biogenic amine metabolites and one subject had a low CSF 5-meth-

yltetrahydrofolate level (cerebral folate deficiency with folate

receptor antibodies). Patients with deficient 5HIAA and HVA levels

showed more severe clinical symptoms during HUTT and were less

tolerant of upright posture. Defects in peripheral catecholamines have

been evaluated in adults with dysautonomia and defects in peripheral

serotonin levels have been observed in migraine patients. This study

indicates that there are defects in dopamine and serotonin in the

central nervous system in juvenile onset neurocardiogenic syncope

with dysautonomia. Normal CSF levels of biopterin metabolites

(neopterin and tetrahydrobiopterin) in subjects with defective bio-

genic amine levels do not indicate a metabolic defect in biogenic

amine biosynthesis. One subject showed a severe decrement in HVA

levels over an interval of 5 years. A neurodevelopmental defect in

biogenic amines in the central nervous system should be further

evaluated in juvenile onset neurocardiogenic syncope and dysauto-

nomia. Clinical correlation with severity of orthostatic intolerance

and biogenic amine deficits is an interesting observation.

Poster #10

The iceman revisited: autonomic function tests

during performance of the Asian Tummo meditation

technique

J.T. Groothuis1,2, M.T.E. Hopman1

1Department of Physiology, Radboud University Nijmegen Medical

Centre, Nijmegen, The Netherlands; 2Department of Rehabilitation,

Radboud University Nijmegen Medical Centre, Nijmegen,

The Netherlands

Background: The world record holder of full-body ice immersion

claims he can influence his autonomic nervous system through the

Asian Tummo meditation technique. We previously demonstrated

(AAS 2010) that he did not demonstrate the typical immediate blood

pressure or heart rate elevation during submersion into ice (water). To

assess whether he can actually influence his autonomic nervous sys-

tem, we performed autonomic function tests with and without

meditation.

Methods: We performed different autonomic function tests, i.e. Val-

salva maneuver, forced respiration, head-up tilt and a cold pressure

test of the hand, on a 53 year old male (the Iceman) on two different

days; once in a normal control situation without any meditation

technique, whilst during the other occasion he was performing the

Asian Tummo meditation technique. Blood pressure and heart rate

were measured continuously using an automatic blood pressure

device (Nexfin).

Results: Without mediation, the cardiovascular reactions on the

autonomic function tests were completely normal. During the

performance of the Asian Tummo meditation technique a deep

breathing pattern with a Valsalva-like pattern was evidently visible in

the blood pressure and heart rate recordings. With meditation, the

cardiovascular reactions during the forced respiration, Valsalva

maneuvers and cold pressure test were all normal, although the

responses were more evident compared to the control situation.

During the head-up tilt the Valsalva-like pattern in blood pressure and

heart rate was more pronounced which resulted in large shifts in blood

pressure and heart rate during the head-up tilt with phases of severe

hypotension followed by recovery phases.

Conclusions: During the performance of the Asian Tummo medita-

tion, the breathing pattern combined with whole body tensing results

in a Valsalva-like pattern in blood pressure and heart rate. No actual

influence of the meditation technique on the autonomic nervous

system nor on the responses during the autonomic function tests was

observed.

Poster #11

Evidence for central sensitization in bladder pain

syndrome from the ICEPAC trial (interstitial cystitis:

elucidation of psychophysiologic and autonomic

characteristics)—preliminary psychometric findings

J.W. Janata1, F. Daneshgari1, C.A.T. Buffington2, G. Chelimsky3,

M.D. Louttit1, D. Zhang4, T.C. Chelimsky3

1University Hospitals Case Medical Center, Cleveland, OH, USA;2The Ohio State University, Columbus, OH, USA; 3Medical College

of Wisconsin, Milwaukee, WI, USA; 4Case Western Reserve

University, Cleveland, OH, USA

Background: Interstitial cystitis (IC—Bladder Pain Syndrome), is

characterized by pain in the bladder worse when full and better when

empty along with urgency and frequency. Despite extensive research,

the pathophysiology is unknown and there is no effective treatment.

ICEPAC aims to evaluate psychophysiologic contributions to this

disorder in general and to elucidate the role of central processing in

particular.

Methods: ICEPAC completed enrollment will include 76 women with

IC, 76 women with myofascial pelvic pain disorder (MPP), 38 1st

degree female relatives of IC subjects without pelvic pain, and 38

healthy age-matched women. Subjects complete comprehensive

psychological measures of pain, function, catastrophizing, childhood

trauma, PTSD, somatization, anxiety and stress. A subset of patients

also undergo a Trier stress test, with assessment of the resulting

catecholaminergic and hypothalamic-pituitary response.

Results: Initial recruitment has included 50 subjects: 22 with IC/MPP,

7 with MPP alone and 21 healthy controls. Ages ranged from 18 to

62. Compared to healthy controls, the pain groups show elevated

levels of somatization, depression, anxiety, PTSD symptoms, pain

catastrophizing and childhood trauma, and both groups show

impairment of function. However, the IC/MPP group compared to the

MPP group has significantly higher scores on childhood emotional

abuse (mean = 12.4 vs. 9.0), PTSD symptoms (13.3 vs. 5.1), and pain

catastrophizing (28.0 vs. 16.6).

Conclusion: These results are consistent with early exposure to

trauma and subsequent central nervous system sensitization evidenced

by PTSD symptoms and increased emotional processing of nocicep-

tive input. These promising early findings require the confirmation

that additional recruitment will provide. Evidence for autonomic

signatures or correlates is pending continued recruitment.

236 Clin Auton Res (2012) 22:207–258

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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


One of the most disabling features of patients with familial dysau-

tonomia (Riley Day syndrome, hereditary autonomic and sensory

neuropathy type III) are recurrent vomiting attacks that can last for

hours and are associated with high levels of circulating dopamine.

None of the available treatments are effective. To determine whether

treatment with carbidopa, a competitive inhibitor of the enzyme dopa

decarboxylase that blocks the synthesis of dopamine outside the brain,

can improve symptoms we enrolled 12 patients with FD in an open-

label titration and treatment study. This was followed by a random-

ized, double-blind, placebo-controlled crossover study to evaluate its

antiemetic efficacy. Symptoms severity was measured daily on a

validated patient reported outcome scale (Rhodes Index) and at

scheduled office visits (Global Clinical Impression of Severity Scale).

Vomiting was prevented by previous fundoplication surgery in each

case, but all patients experienced severe cyclical nausea and uncon-

trollable retching that was refractory to standard treatments. Average

daily dose of carbidopa was 480 mg (range 325–600 mg/day) and

was well tolerated. Twenty-four hour urinary dopamine excretion was

significantly lower while on carbidopa (147 ± 32 ug/g crt) than at

baseline (271 ± 41 ug/g crt, p \ 0.0001). In the double-blind phase,

patients experienced significantly less nausea and retching each day

while on carbidopa than while on placebo (composite Rhodes Index

score: carbidopa 6.9 ± 2.2 vs. placebo 9.7 ± 2.5, p \ 0.0001).

Patients also reported that their symptoms were less severe on car-

bidopa compared with placebo at scheduled study visits (Global

Clinical Impression of Severity: 2 ± 0.5 vs. 4 ± 1 units, p \ 0.02).

We conclude that carbidopa inhibits the formation of dopamine in the

periphery and is a safe, effective antiemetic in patients with FD.

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

Department of Medicine, Division of Clinical Pharmacology,

Vanderbilt University School of Medicine, Nashville, TN, USA

Orthostatic hypotension is the hallmark of autonomic failure. Patients

usually require medication to prevent the blood pressure fall and pre-

syncopal symptoms on standing position. We have previously reported

that atomoxetine, a norepinephrine transporter blocker that potentiates

residual sympathetic tone, has a pressor effect in autonomic failure. The

aim of this study was to test the hypothesis that for the same pressor

response, atomoxetine is more effective on improving blood pressure on

standing and reducing pre-syncopal symptoms compared with the alpha-

1 adrenergic agonist, midodrine. We studied 34 patients who had a

similar pressor response to atomoxetine (18 mg) and midodrine

(5–10 mg), defined a priori as an increase in at least 15 mm Hg in seated

systolic blood pressure (SBP), 60 min after drug administration. Both,

atomoxetine and midodrine increased seated SBP by 32 (95 % CI:

23.4–40.9, P \ 0.001) and 30 mm Hg (95 % CI: 21.1–39.1, P \ 0.001),

respectively compared with placebo. No difference in seated SBP was

observed between atomoxetine and midodrine. In contrast, atomoxetine

had a greater pressor response on standing. Atomoxetine increased

standing SBP by 12 mm Hg (95 % CI: 0.6–22.4, P = 0.039), compared

with midodrine. Of note, both atomoxetine and midodrine significantly

improved pre-syncopal symptoms. Atomoxetine reduced the lighthead-

edness score by 2 points (95 % CI: 0.07–3.53, P = 0.04), compared to

baseline. Similarly, midodrine reduced the lightheadedness score by 2

points (95 % CI: 0.49–3.51, P = 0.01), compared to baseline score. In

conclusion, atomoxetine has a greater effect on orthostatic tolerance as

defined by standing systolic blood pressure compared with midodrine.

Poster #14

Beneficial effects of oral rehydration solution

on orthostatic intolerance

M.S. Medow, D. Tewari, A. Aggarwal, Z. Messer and J.M. Stewart

Department of Pediatrics, New York Medical College, Valhalla, NY,

USA

Background and Aim: OI can cause excessive upright heart rate (HR),

and blood pressure (BP) decreases, initiated by postural contraction of

central blood volume (CBV) by translocation of blood from the upper

to lower body. Intravenous isotonic saline (IVS) CVB expansion

effectively reduces OI regardless of etiology; oral hydration fails to

provide similar benefit. ORS (glucose + sodium) efficiently rehy-

drates cholera patients, suggesting it can increase CBV. We propose

that equal volumes of ORS or IVS can improve orthostatic tolerance

by mitigating changes in HR and BP in fainting patients.

Methods: We studied subjects with OI (N = 4), with 3 postural faints

during the past year or Postural Orthostatic Tachycardia Syndrome,

and healthy controls (N = 4), and separately evaluated baseline (no

treatment), IVS and ORS. Orthostasis using Lower Body Negative

Pressure (LBNP) was applied sequentially at -15, -30, -40 mmHg

for 5 min each, and -55 mmHg for 1 h or until OI was elicited.

Results: While controls tolerated -55 mmHg, fainters could not.

Controls became tachycardiac with decreased pressure (32.4 % HR

increase from baseline), but fainter’s HR remained unchanged during

LBNP. In fainters, IV saline and ORS resulted in heart rate increases

at -40 mmHg, significantly greater (p \ 0.05) than baseline. In

controls, mean arterial pressure (MAP) remained unchanged from

baseline to -40 mmHg, but decreased significantly (43.7 %,

p \ 0.01) in fainters. Following IV saline in fainters, MAP fell sig-

nificantly comparing baseline to 40 mmHg (76.5 ± 7.2 vs.

54.9 ± 2.4, [p \ 0.05]). In contrast, ingestion of ORS by fainters

prevented this decrease as MAP remained unchanged (78.1 ± 9.2 vs.

75.5 ± 5.5 mmHg, baseline vs. -40 mmHg).

Conclusion: This pilot study suggests ORS may be beneficial in

decreasing orthostasis in fainters, possibly afforded by allowing

appropriate increases in HR and BP maintenance, thereby avoiding

syncope. ORS may be a practical, cost-effective alternative to IVS for

OI management.

Clin Auton Res (2012) 22:207–258 237

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Poster #15

Musculoskeletal evaluation of patients with interstitial

cystitis

T.V. Sanses1, G. Chelimsky2, D. Zhang3, J. Janata1, T. Mahajan1,

B. Fenton4, A. Askari1, R. Elston3, T. Chelimsky2, ICEPAC Study

Group3

1University Hospitals Case Medical Center, Cleveland, OH, USA;2Medical College of Wisconsin, Milwaukee, WI, USA; 3Case

Western Reserve University, Cleveland, OH, USA; 4SUMMA Health

System, Akron, OH, USA

Objectives: To determine the distribution and correlations of pain

across five body locations in women with Interstitial Cystitis (IC) and

healthy age-matched women.

Background: We hypothesized that deep muscular pelvic pain in

patients with IC is due to a generalized pain disorder with altered

afferent signaling. Therefore, the pain is not limited to the pelvic area,

but rather a more centralized disorder.

Methods: Interstitial Cystitis Elucidation of Psychophysiologic and

Autonomic Characteristics study (ICEPAC) is a multicenter pro-

spective cohort trial. Subjects underwent muscular tender point

assessment in 5 areas: general body, abdomen, inguinal, inner thigh,

and pelvic area. Pain was assessed using a 0–10 Numeric Rating Scale

(NRS). We calculated the overall intraclass correlation (ICC), where

the classes are the body locations, and the 10 pairwise correlations

across the 5 locations of pelvic, body, lower extremity, abdominal and

inguinal tender points. Positive pairwise correlations and overall ICC

would support our hypothesis.

Results: We examined 17 patients with IC and 20 healthy age-mat-

ched women. We found no difference in age and weight between the

groups. The range of mean NRS pain scores for different body

locations in subjects with IC was 4.1–5.2 and in healthy controls

0.2–1.0. The mean pelvic NRS pain score in subjects with IC was

higher 4.91 ± 3.34 than in healthy controls 0.19 ± 0.31, p \ 0.01.

The ICC coefficients for women with IC and healthy age-matched

controls were positive 0.58 and 0.541, respectively. Within the group

of women with IC, the pairwise correlation coefficients were high

between pelvic and abdominal (0.70), and between pelvic and

inguinal (0.73) muscle groups. Similar but smaller correlations were

noticed in healthy controls.

Conclusions: Muscular, including pelvic, pain in women with IC

could be due to a generalized pain disorder with altered afferent

signaling. These results will be confirmed after the final enrollment is

completed.

Poster #16

Heart rate variability (HRV) in pelvic pain

P. Singh1, J. Thayer2, G. Chelimsky3, T. Chelimsky3

1Case Western Reserve University, Cleveland, OH, USA; 2The Ohio

State University, Columbus, OH, USA; 3The Medical College

of Wisconsin, Milwaukee, WI, USA

Background: HRV has not been studied in pelvic pain.

Hypothesis: Based on other pain syndrome literature, HRV should

reflect heightened sympathetic and diminished parasympathetic

function.

Methods: This IRB-approved prospective study compared HRV in the

supine and upright positions in 14 healthy females [18 years

screened for diseases with autonomic abnormalities, and 20 subjects

with either interstitial cystitis or myofascial pelvic pain. The tilt study

was divided into 5 min of supine rest, 10 min upright epochs, and the

last 5 min of supine rest. The study compared the 2 periods of supine

rest with the first upright epoch. Standard time and frequency domain

measures were compared using student’s t test for groups with

unequal variance.

Results: Demographic variables were not different in the 2 popula-

tions. Mean RR interval supine in pelvic pain subjects was

849 ± 170 ms (71 bpm) compared to 1,000 ± 218 ms (60 bpm) in

healthy subjects (p = 0.004), and upright 733 ± 134 ms (82 bpm)

versus 853 ± 135 (70 bpm, p = 0.05). RMSSD was 44 ± 42 versus

76 ± 59 (p = 0.02) supine, and 23 ± 15 versus 44 ± 39 upright

(p = 0.07).

Conclusion: Women with pelvic pain have significantly higher heart

rates at rest and standing compared to healthy women with signif-

icantly less variability. Their values at rest are nearly identical to the

those of healthy women standing suggesting that their resting

sympathetic tone may be at the level of standing healthy sympa-

thetic tone.

Poster #17

Study of the P2X2 and 7 receptors in the enteric glial cells

of ileum rat subjected to ischemia and reperfusion

C.E. Mendes1, K. Palombit1, W. Tavares de Lima2, P. Castelucci1

1Department of Anatomy, University of Sao Paulo, Brazil;2Department of Pharmacology, University of Sao Paulo, Brazil

Intestinal ischemia/reperfusion (I/R-i) injury is a common problem

in hospitalized patients, and is associated with high morbidity and

mortality in both surgical and trauma patients. The enteric neurons

and glial cells are affected in the ischemia. The aim was to study the

effect of I/R-i on enteric glial cells, neurons and P2X2 and 7

receptors. The ileal artery was occluded for 35 min with an atrau-

matic vascular clamp. The animals were sacrificed after 0 h (h),

24 h, and 14 days (d) after ischemia. Sham-operated groups were

subjected to identical manipulations without the arterial occlusion.

The tissues were prepared for double marking of P2X2 and 7

receptors with anti-Hu (pan-neuronal), S100 (glial marker), and glial

fibrillary acidic protein (GFAP/glial marker). The P2X2 receptor-IR

cells co-localized 90 % with anti-Hu-IR neurons and 30 % with

S100-IR glial cells in all groups. P2X7 receptor-IR co-localized

100 % with anti-Hu-IR neurons and S100-IR glial cells in all

groups. S100-IR co-localized 70 % with GFAP-IR glial cells, and

anti-Hu-IR not co-localize with GFAP in all groups. The density

(cell/cm2) of P2X2-IR/cm2 decreased by 18, 13, 3 %, and P2X7-IR/

cm2 decreased by 8, 10 and 4 % in the 0, 24 h and 14 days I/R-i

groups, respectively. Hu-IR/cm2 neurons decreased by 23 % (0 h),

21 % (24 h) and 13 % (14 days). S100-IR/cm2 decreased by 13 %

only I/R-i 14d group, and GFAP-IR/cm2 increased by 19 % (0 h)

5 % (24 h) and 7 % (14 days) in the I/R-i groups. The prolife area

(lm2) of anti-Hu-IR neurons did not differ statistically, and S100-IR

glial cells decreased by 9 % in all groups. Our findings indicate that

the I/R-i is associated with alterations in the P2X2 and 7 receptors,

enteric neurons and enteric glial cells that may result in changes

motility intestinal.

238 Clin Auton Res (2012) 22:207–258

123

Poster #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

Cure: Digestive Diseases Research Center and Center for Neuro-

visceral Sciences & Women’s Health, Digestive Diseases Division,

David Geffen School of Medicine at UCLA and VA Greater Los

Angeles Healthcare System, Los Angeles, CA, USA

Earlier studies indicated that the integrity of vagal pathway was required

to confer gastric protection against damaging agents. Several peptides

located in the brainstem initially identified to influence vagal outflow to

the stomach, as assessed by electrophysiological approach or by vagal-

dependent alterations of gastric secretory and motor function, were

investigated for their influence in the vagal regulation of gastric mucosa

resistance to injury in conscious rats. Thyrotropin releasing hormone

(TRH), or the stable TRH agonist, RX-77368, injected at low doses into

the cisterna magna (ic) or the dorsal motor nucleus (DMN) protects the

gastric mucosa against intragastric ethanol-induced gastric injury

through stimulation of vagal cholinergic pathways, inducing the release

of gastric prostaglandins/nitric oxide (NO) and the recruitment of efferent

function of capsaicin sensitive afferent fibers containing calcitonin-gene

related peptide (CGRP). TRH antibody injected bilaterally into the DMN

or ic prevented the adaptive gastric protection induced by intragastric

administration of mild irritants (0.35 N HCl or 20 % ethanol) before

strong irritants (0.6 N HCl, 60 % ethanol). Microinjection of TRH

antibody bilaterally into the DMN abrogates the gastroprotection against

60 % ethanol induced by kainic acid microinjected into the raphe pallidus

indicative that activation of endogenous TRH containing raphe-DMN

projections play a role in adaptive gastric protection. Peptide YY, CGRP,

adrenomedullin and corticotripin releasing factor injected intracister-

nally also protect against ethanol injury largely through similar peripheral

effectors mechanisms than TRH. Synergistic interaction between RX-

77368 and PYY agonist [Pro34]PYY to confer gastroprotection against

ethanol are observed when injected ic at subthreshold doses Therefore

gastric prostaglandins and CGRP/NO pathways represent a commonfinal

mechanism through which brain peptides confer vagally mediated gas-

troprotection against injury. A better understanding of brain circuitries

through which these peptides are released will provide new strategies to

recruit integrated and multifaceted gastroprotective mechanisms.

Poster #19

Autonomic dysfunction and esophageal dysmotility

in persons with spinal cord injury

G.J. Schilero1,2, M. Radulovic1,2, C. Renzi1, C. Yen1,

W.A. Bauman1,2,3, M. Korsten1,2

1Rehabilitation Research and Development Center of Excellence

for the Medical Consequences of Spinal Cord Injury, The James J.

Peters Veterans Affairs Medical Center, Bronx, NY, USA;2Department of Medicine, The Mount Sinai School of Medicine, New

York, NY, USA; 3Department of Rehabilitation Medicine, The Mount

Sinai School of Medicine, New York, NY, USA

Background: Parasympathetic innervation of the esophagus provides

motor innervation to the muscular layer and secreto-motor innerva-

tion to glands. Sympathetic input arising from cervical and thoracic

chains is involved in regulation of esophageal sphincter contraction,

muscular wall relaxation, blood vessel constriction, and augmented

peristaltic activity. Little is known, however, regarding the effects of

spinal cord injury (SCI) upon esophageal motility.

Objective: To compare differences in esophageal motility between

persons with SCI and able-bodied (AB) controls using high resolution

manometry (Given Imaging, Duluth, GA).

Methods: After fasting 12 h, a catheter containing multiple pressure

sensors was introduced into the esophagi of subjects to a height-

indexed depth to enable visualization of both upper and lower

esophageal sphincters. Each subject performed 10 wet swallows while

esophageal pressure topography and impedance were recorded at 116

different detection points along the probe. The mean amplitude of the

propagating pressure wave (PPW), and the percentage of observed

double peaked swallows (%DS) were recorded.

Results: SCI group included 11 subjects. Duration of injury

1–42 years; mean age, 48 ± 12 years. Mean PPW amplitude was

significantly decreased in the SCI group compared to the AB group

(75 ± 23 mmHg versus 140 ± 61, respectively; p = 0.0171). %DS

was significantly increased in the SCI group compared to the AB

group (28 ± 19 and 5 ± 8; p = 0.0169).

Conclusion: The inability to generate adequate esophageal peristalsis

in the SCI cohort suggests loss of esophageal autonomic control. The

increase in %DS noted in the SCI group suggests a compensatory

mechanism for bolus clearance. The clinical consequences of the

observed non-specific esophageal motility disorder (NEMD) are not

well understood, although limited studies in the able-bodied have

demonstrated progression to achalasia in over 50 %. NEMD might

therefore predispose to tracheobronchial aspiration and pneumonia in

the SCI population. Studies are ongoing to examine the role of NEMD

upon airway inflammation and aspiration risk.

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. Yamaguchi1, T. Uchiyama1,2, T. Yamamoto2, R. Sakakibara3,

M. Fuse1,4, M. Yanagisawa4, T. Kamai5, T. Ichikawa4, K. Hirata6,

S. Kuwabara2, T. Yamanishi1

1Continence Centre & Department Neuro-urology, Dokkyo Medical

University; 2Department of Neurology, Chiba University Graduate

School of Medicine; 3Neurology Division, Department of Internal

Medicine, Sakura Medical Center, Toho University; 4Department

of Urology, Chiba University Graduate School of Medicine;5Department of Urology, Dokkyo Medical University; 6Department

of Neurology, Dokkyo Medical University

Patients with Parkinson’s disease (PD) frequently have lower urinary

tract dysfunction (LUTD). However, the mechanism of LUTD in PD has

not been clarified yet. We noninvasively showed the real time change of

oxy-Hb in prefrontal cortex in patients with PD and evaluated the asso-

ciation between prefrontal cortex and LUTD in PD. We recruited 6

patients with PD, who were informed consent and different from the

subjects in preliminary study last year; 3 women and 3 men; mean age

60 years (55–61), untreated and 4 patients had detrusor overactivity

during bladder filling. The fNIRS prove was placed on two area (right and

left) of the subject’s frontal head, and we measured oxy-Hb concentration

in bilateral anterior parts of prefrontal cortex (may be Brodmann’s area 9,

10) during bladder filling in cystometry by fNIRS (NIRO 200,

Clin Auton Res (2012) 22:207–258 239

123

Hamamatsu Photonics Inc, Japan). The oxy-Hb concentration was cal-

culated by the Beer-Lambert method. In patients with PD, oxy-Hb

concentration gradually increased in bilateral anterior parts of prefrontal

cortex from the start to end of bladder filling. However, regardless of the

appearance of detrusor overactivity, this rate was smaller than our data in

other subjects without detrusor overactivity. And the rate in patients with

detrusor overactivity was smaller than that without detrusor overactivity.

Furthermore, the specific change of oxy-Hb concentration was shown

under detrusor overactivity during bladder filling in real time; oxy-Hb

spontaneously increased at the beginning of detrusor overactivity and

oxy-Hb concentration remarkably decreased under detrusor overactivity

occurring. There was no significant difference in oxy-Hb concentration

between right and left prefrontal cortex. We showed the specific changes

of oxy-Hb concentration synchronised with normal and abnormal bladder

filing in bilateral prefrontal cortex of patients with PD by using fNIRS. In

patients with PD, dysfunction of prefrontal cortex may be involved in

LUTD, in particular detrusor overactivity.

Poster #21

Effect of Brilliant Blue G on P2X7 receptor

after intestinal ischemia and reperfusion

K. Palombit1, C.E. Mendes1, W. Tavares de Lima2, P. Castelucci1

1Department of Anatomy, University of Sao Paulo, Brazil;2Department of Pharmacology, University of Sao Paulo, Brazil

In pathological conditions including ischemia, the extracellular ATP can

reach high levels, activating the P2X7 receptor. Several studies have shown

that injury can be attenuated by the antagonist of P2X7 receptor, the Bril-

liant Blue G (BBG). In the present work, we analyzed the effects of the BBG

on the P2X7 receptor and ileum myenteric plexus of rats after intestinal

ischemia and reperfusion (I/R). The ileal artery was occluded for 45 min

with an atraumatic vascular clamp. BBG (50 and 100 mg/kg) or saline

(vehicle) was given subcutaneous 1 and 24 h after injury (I/R 24 h group).

In the I/R 14 days group, BBG was given 1 h and once daily for the next

5 days. We too analyzed I/R 0 h group (not reperfusion). Myenteric neu-

rons were evaluated for immunoreactivity against the P2X7 receptor, nitric

oxide synthase (NOS), neurofilament (NF) and choline acetyl transferase

(ChAT) (n = 5). P2X7 receptor-IR was observed to co-localize 100 %

with NOS-IR, NF-IR and ChAT-IR neurons in all groups. The neuronal

density (neurons/cm2) of the I/R 0 h group was decreased by40 %of P2X7-

IR, NOS-IR, NF-IR and ChAT-IR neurons. In the I/R 24 h saline group the

density of P2X7-IR, NOS-IR, NF-IR and ChAT-IR neurons was decreased

by 19, 46, 59 and 30 %, respectively, and in the BBG50 and BBG100 I/R

24 h groups was reduced by 19, 33, 41 and 30 %, respectively. The density

of P2X7-IR, NOS-IR, NF-IR and ChAT-IR neurons was reduced by 16, 56,

37 and 45 % in the I/R 14d saline group, respectively, and in the BBG50 and

BBG100 I/R 14 days groups the densities was reduced by 3, 35, 27 and

21 %, respectively. This work indicates that I/R causes myenteric neuronal

loss in I/R 0 h, saline 24 h and 14 days groups, and BBG treatment

appeared to be effective in protecting neuronal class studied.

Poster #22

Photo-stimulating effects of low reactive level laser

on bladder dysfunction in neurological disease rats

T. Uchiyama1,2, C. Yamaguchi1, T. Yamamoto2, R. Sakakibara3,

M. Fuse1,4, M. Yanagisawa4, T. Kamai5, T. Ichikawa4, K. Hirata6,

S. Kuwabara2, T. Yamanishi1

1Continence Center and Department Neuro-urology, Dokkyo Medical

University; 2Department of Neurology, Chiba University Graduate

School of Medicine; 3Neurology Division, Department of Internal

Medicine, Sakura Medical Center, Toho University; 4Department

of Urology, Chiba University Graduate School of Medicine;5Department of Urology, Dokkyo Medical University; 6Department

of Neurology, Dokkyo Medical University

Photo-stimulation using low reactive level laser was reported to

have neurobiological effects. As these effects, inhibition of Ad- and

C- fibre nerve conductions, activation of central descending inhibi-

tory system, and suppression of local synaptic neurotransmission

were reported. Micturition reflex is constructed by activation of

peripheral Ad- and C- fibre afferent nerves, and which is controlled

by central descending inhibitory system. Then, the photo-stimulation

will be applicable to modulate these neural controls. Therefore, we

investigate the photo-stimulating effect of low reactive level laser on

bladder dysfunction in neurological disease rats. Experiments were

performed on adult male Sprague–Dawley rats with bilateral injec-

tions to substantia nigra of 6OHDA (PD model), spinal injury (SP

model) or saline (Normal model). Cystometric investigation was

performed, and interval time between voids, urine volume per void,

and maximum bladder pressure during voiding were investigated.

After 30–60 min’ baseline recording, photo-stimulation using low

reactive level laser or sham stimulation via prove was irradiated to

bilateral L6/S1 intervertebral foramen transcutaneously via the probe

contacted to body or directly via the probe non-contacted to body.

Recording after the stimulation was continued for several hours until

micturition cycle returned to baseline. Compared with the baseline

record, in indirect and direct sham-stimulated groups in each model,

interval time between voids and urine volume per void were not

unchanged. Both in indirect and direct photo-stimulated groups in

each model, interval time between voids and urine volume per void

was significantly increased. These changes were stimulation-time

dependent. In any groups, maximum bladder pressure was unchan-

ged. Photo-stimulation using low reactive level laser to bilateral L6/

S1 root modulated storage function but not voiding function in each

model. These effects may be considered to be inhibition of afferent

nerve conduction, activation of central descending inhibitory system,

and suppression of local synaptic neurotransmission, as well as

analgesic effect.

Poster #23

Cerebral blood flow in autonomic failure

L. Rivera Lara, P. Novak

Department of Neurology, University of Massachusetts, MA, USA

Background: Autonomic failure (AF), especially adrenergic, can be

associated with orthostatic symptoms that are due cerebral hypoper-

fusion. Usually, the orthostatic blood pressure changes are used as a

proxy for status of cerebral perfusion. However, the relationship

between the cerebral blood flow velocity, that is more direct marker

of cerebral perfusion and AF, is not well understood.

Methods: 228 subjects, 136/92 women/men, mean age 53 years, sd

17.6 years, with orthostatic symptoms, and 40 healthy controls, under-

went standardized autonomic testing (deep breathing, Valsalva

maneuver, tilt test, QSART, skin biopsy). Cerebral blood flow velocity

(CBv) from the left middle cerebral artery was monitored during the

supine baseline and tilt using transcranial doppler. Composite autonomic

240 Clin Auton Res (2012) 22:207–258

123

severity score (CASS) has been used for grading AF into mild, moderate

and severe.

Results: Mild/moderate/severe AF was detected in 119/76/33 sub-

jects. ANOVA showed significant difference in mean CBv in graded

AF, both in supine and tilt. The reduction of CBv was proportional to

severity of AF, being the most abnormal in severe AF. There was also

supine hypertension in severe AF. The drop of CBv during the tilt test

was not significant among all AF groups. The correlation between

orthostatic hypotension and drop of the CBv during the tilt test was

not significant.

Conclusion: CBv abnormalities are associated with AF. Baseline CBv

is inversely proportional to degree of AF. The lowest baseline CBv

was seen in severe AF group (in spite of supine hypertension in that

group) indicating the presence of intracranial vasoconstriction.

Chronic hypoperfusion can be associated with AF irrespectively of

position of the body, e.g. supine or standing.

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

Department of Pediatric Neurology, Center for Dysautonomia,

University of Texas at Houston Medical School, Houston, TX, USA

Transcranial Doppler ultrasonography (TCD) has been utilized as a

surrogate measure of cerebral blood flow with demonstrated impair-

ments in cerebral blood flow in patients with orthostatic intolerance

(OI). In our institution, near-infrared spectroscopy (NIRS) has been

utilized as a method of measuring cerebral blood flow. During the

period July 2010 to January 2012, we reviewed 71 adolescents and

young adults diagnosed with neurocardiogenic syncope and dysau-

tonomia who underwent bilateral cerebral perfusion monitoring with

NIRS during head up tilt test (HUTT). Data was analyzed by visu-

alization of contour changes in NIRS values. We used previously

described phases of HUTT: dynamic tilt phase (early in tilt test), static

phase (during tilt test), and post-tilt phase (return to supine). We

found three variations in the dynamic tilt phase (gradual decrement,

steep decline and no change), six variations in the static phase

(constant throughout test, constant until onset of a steep decline,

gradual decline throughout test, gradual decline until onset of a steep

decline, waxing and waning throughout test, waxing and waning until

onset of steep decline), and three variations in the post-tilt phase

(mild, moderate, and severe overshoot). We also observed a distinc-

tion between the two cerebral hemispheres with respect to NIRS

values during HUTT in 22 patients. Finally, 42 patients were unable

to complete the HUTT (30 min duration) due to severe clinical pos-

tural intolerance. These results confirmed a decrease in cerebral blood

flow as assessed by NIRS in patients with OI and autonomic dys-

function. Distinctly, we have profiled the cerebral blood flow contours

throughout the phases of HUTT and compared the values in both

hemispheres. Discovery of such variations in cerebral blood flow may

add insight into the clinical spectrum of this condition and physio-

logical changes observed enable correlation with severity of postural

intolerance.

Poster Session II

Poster #25

Do the chronic heart failure patients have limited

sympathetic response to a transient baroreflex stress?

P. Zubin Maslov1, T. Breskovic1, J.K. Shoemaker2,3, Z. Dujic1

1Department of Physiology, University of Split School of Medicine,

Split, Croatia; 2Neurovascular Research Laboratory, School

of Kinesiology, Western University, London, Ontario, Canada;3Department of Physiology and Pharmacology, Western University,

London, Ontario, Canada

Diastolic blood pressure (DBP) fall resulting from premature ven-

tricular contraction (PVC) causes baroreceptor unloading and increase

in the amplitude and duration of multi-unit sympathetic bursts sug-

gesting an increase in axonal recruitment in that cardiac cycle. These

larger bursts and their axonal content may reflect the ability of the

sympathetic nervous system to respond to hypotension. Chronic

sympathetic hyperactivation characterizes heart failure (CHF) raising

a question regarding the ability of these patients to further enhance

sympathetic drive. We quantified the action potential (AP) content

within multi-unit muscle sympathetic nerve activity (MSNA) from

microneurographic recordings during sinus rhythm and during PVCs,

quantifying the APs per burst and classifying these APs into clusters

based on their peak-to-peak amplitude. Sympathetic neurograms were

obtained from 4 moderate CHF patients, providing 188 sinus rhythm-

related bursts and 38 post-PVC bursts, and from two similarly aged

control individuals, providing 129 sinus rhythm-related bursts and 36

post-PVC bursts. Compared to controls (10 ± 3 APs/burst) the CHF

group had higher AP content per burst during sinus rhythm (15 ± 9

APs/burst P = 0.01) as well as higher number of active clusters per

burst (4 ± 1 vs. 3 ± 1 clusters/burst, CHF patients vs. controls,

respectively, P = 0.01). In both GROUPS, post-PVC bursts had

higher AP frequency, number of APs, and number of active AP

clusters (P = 0.05) compared with sinus-rhythm bursts. Our data

indicate that despite their chronic sympathetic hyperactivity, CHF

patients demonstrate the ability to enhance sympathetic outflow fur-

ther through increased number of APs/burst. The higher cluster

number in the post-PVC bursts suggests CHF patients retain the

ability to recruit additional, larger APs.

Poster #26

Assessment of cardiovascular adrenergic function using

the Valsalva maneuver—reproducibility and validity

of indices

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


Background: The Valsalva maneuver (VM) has a long tradition as

integral component of standardized autonomic function testing. While

heart rate responses to the VM provide information about cardiovagal

integrity, blood pressure (BP) responses during certain phases of the

maneuver provide valuable information about cardiovascular adren-

Clin Auton Res (2012) 22:207–258 241

123

ergic function. Various adrenergic indices derived from the VM have

been described, but comparative assessment of their reproducibility

and validity is lacking. We therefore sought to systematically evaluate

previously described indices of cardiovascular adrenergic function

derived from the VM in a cohort of subjects with graded adrenergic

impairment.

Methods: Using a large autonomic research database, we randomly

selected three age-matched groups of 30 subjects: group one with

severe adrenergic impairment defined as the presence of neurogenic

orthostatic hypotension, group two with mild to moderate adrenergic

impairment based on abnormal BP responses to the VM and/or bor-

derline orthostatic BP drop, and group three consisting of healthy

control subjects. Nine adrenergic indices were derived for each sub-

ject from two technically adequate VMs: BP drop and pulse pressure

compression during early phase II, BP recovery during late phase II

(calculated from baseline and from early phase II), BP overshoot

during phase IV (magnitude and duration), BP recovery time (PRT),

50 % PRT, and a baroreflex sensitivity index calculated from PRT.

Reproducibility and validity of each parameter was assessed using

correlation analysis and between group comparisons.

Results: Significant within parameter correlations were seen for all

indices, but the most reproducible parameters were BP recovery

during late phase II related to baseline, PRT, and BP drop during early

phase II (Pearson’s r = 0.91–0.96). The best separation of groups was

achieved using BP recovery during late phase II (related to baseline

and early phase II) as well as PRT (all perfect or near perfect sepa-

ration between groups 1 and 3). BP drop and pulse pressure

compression during early phase II and parameters related to phase IV

overshoot showed the most overlap between groups.

Conclusions: Parameters used to assess adrenergic function derived

from the VM show considerable differences in reproducibility and

validity. Superior parameters are those assessing late phase II BP

recovery and PRT, while other parameters are less reproducible and/

or show greater overlap between normal and abnormal. Supported by

NIH (NS44233, U54NS065736, K23NS075141, UL1RR24150) and

Mayo Funds.

Poster #27

Sex differences in limb vascular reactivity to mental

stress in humans

J.R. Carter1, H. Yang1, T.D. Drummer2

1Department of Kinesiology and Integrative Physiology, Michigan

Technological University, Houghton, MI, USA; 2Department

of Mathematical Sciences, Michigan Technological University,

Houghton, MI, USA

Mental stress (MS) elicits a robust and consistent forearm vasodila-

tion, but vascular reactivity in the calf remains inconsistent. MS has

been reported to induce calf vasodilation more frequently in women

(Butt et al., Clin Auto Res, 1999). Muscle sympathetic nerve activity

(MSNA) is an important contributor to calf blood flow, yet the rela-

tions between sex, limb blood flow, and MSNA reactivity to MS have

not been adequately explored. We hypothesized that MS would elicit

more dramatic vasodilation of the calf in women, and that this might

be explained by reduced MSNA reactivity and/or blunted sympathetic

vascular transduction. We measured heart rate (HR), mean arterial

pressure (MAP), calf blood flow (CBF), and forearm blood flow

(FBF) in 18 men (age, 23 ± 2 years) and 15 women (age,

22 ± 1 years) during 5 min of supine baseline and 5 min of MS

(serial subtraction). Calf (CVC) and forearm (FVC) vascular

conductance were calculated as limb blood flow divided by MAP. MS

elicited similar increases in MAP D10 ± 1 vs. D11 ± 1 mmHg), HR

(D16 ± 2 vs. D17 ± 2 beats/min), FBF (D81 ± 16 vs. D82 ± 15 %)

and FVC (D62 ± 13 vs. D64 ± 13 %) in men and women, respec-

tively. In contrast, CBF (D16 ± 8 vs. D42 ± 8 %; p = 0.016) and

CVC (D4 ± 7 vs. D29 ± 8 %; p = 0.012) responses to MS were

exaggerated in women compared to men. Changes in FVC were

significantly correlated with changes in CVC in women (r = 0.674;

p = 0.004), but not men. MSNA reactivity to MS tended to be aug-

mented in men (D6 ± 1 vs. D3 ± 1 bursts/min; p = 0.11), and the

changes in CVC were negatively correlated with increases of MSNA

in men (r = -0.411; p = 0.045), but not women. In conclusion, our

data suggest different patterns of calf vascular reactivity to MS in men

and women that might relate, in part, to MSNA reactivity and/or

altered vascular transduction of MSNA.

Poster #28

Melatonin does not alter skin sympathetic nerve

response to mental stress

C.A. Ray, C.L. Sauder, M.D. Muller

Penn State Heart & Vascular Institute, Penn State University College

of Medicine, Hershey, PA, USA

Melatonin attenuates muscle sympathetic nerve activity (MSNA)

responses to sympathoexcitatory stimuli (e.g., orthostatic stress and oto-

lithic stimulation). It is not known if melatonin has the same effect on skin

sympathetic nerve activity (SSNA). Because melatonin has been reported

to alter thermoregulation in which SSNA also contributes, it was

hypothesized that melatonin would attenuate SSNA to a sympathoexcit-

atory stimulus. Therefore, the purpose of this study was to examine if

melatonin alters SSNA responses to mental stress. Cognitive stress elicits

marked increases in SSNA thus allowing us to observe potential attenu-

ation in SSNA by melatonin. Nine young healthy subjects (6 men, 3

women) underwent experimental testing on two separate days. Three

minutes of mental stress (i.e., mental arithmetic) were conducted before

and after ingestion of melatonin (3 mg) or placebo. Participants were

dressed in a water-perfused suit to maintain skin temperature at 35 �C.

Mental stress elicited comparable increases in mean arterial pressure

(17 ± 4 vs. 13 ± 3 mmHg) and heart rate (28 ± 6 vs. 25 ± 5 beats/min)

before and after melatonin ingestion. Both early (i.e., first 10 s) and sus-

tained (i.e., entire 3 min) responses for SSNA to mental stress were

analyzed. Before ingestion of melatonin, mental stress elicited increases

in SSNA within the first 10 s (D218 ± 24 %) and over the entire 3 min

(D125 ± 17 %). After ingestion of melatonin, SSNA responses were

comparable in the first 10 s (D203 ± 16 %) and over the entire 3 min

(D83 ± 6 %). Mean skin temperature and sweat rate did not change with

melatonin. Responses on the placebo day were not different between the

two trials. In summary, unlike its effect on MSNA, melatonin did not alter

SSNA responses to sympathoexcitation, as elicited by mental stress. This

finding indicates that melatonin has contrasting effects on muscle and skin

sympathetic nerve activity in humans. Supported by NIH (HL109952).

Poster #29

The arterial baroreflex resets with orthostasis

C.E. Schwartz, J.M. Stewart

Department of Physiology, New York Medical College, Hawthorne,

NY, USA

242 Clin Auton Res (2012) 22:207–258

123

The arterial baroreflexes, located in the coronary sinus and along the

arch of the aorta, are essential to the rapid short term autonomic

regulation of blood pressure. In the past, they were believed to be

inactivated during exercise because blood pressure, heart rate and

sympathetic activity were so radically changed from their resting

functional relationships with blood pressure. However, it was dis-

covered that all relationships between coronary sinus pressure and

either HR or sympathetic vasoconstriction maintained their curvilin-

ear sigmoidal shape but were reset, or shifted, so as to best maintain

BP during exercise. We examined the resetting of the arterial ba-

roreflexes during orthostasis comparing upright tilt with supine

relationships between systolic BP and HR (the cardiovagal barore-

flex), mean BP and ventilation (the ventilatory baroreflex) and

diastolic BP and sympathetic nerve activity (the sympathetic baro-

reflex). We used the modified Oxford method in which BP was

rapidly varied with bolus injections of sodium nitroprusside followed

1 min later by phenylephrine. Both the cardiovagal and ventilatory

baroreflexes were ‘‘reset’’ with no change in gain or response range.

In contrast, the sympathetic baroreflex was augmented as well as

shifted causing a similar increase in peripheral resistance that opti-

mally defended the subject against hypotension. Increased peripheral

resistance is not present in active skeletal muscles during exercise.

This difference is likely selective for exercising muscle and may

represent the actions of functional sympatholysis by which exercise

metabolites interfere with adrenergic vasoconstriction.

Poster #30

Carotid chemoreflex and muscle metaboreflex

interactions in humans

H. Edgell, M.K. Stickland

Department of Medicine, University of Alberta, Edmonton, AB,

Canada

Both metaboreceptors and chemoreceptors play a role in the sympa-

thetic response to exercise, and interactions between these reflexes

have been shown previously. The purpose of this study was to isolate

the muscle metaboreflex while stimulating/inhibiting the carotid

chemoreceptor to better understand their interactions. Nine young

healthy men (Height: 179.9 ± 7.4 cm, Weight: 91.5 ± 22.1 kg, Age:

24.0 ± 3.7, VO2: 51.3 ± 13.0 mL/kg/min) performed three trials of

40 % maximal voluntary contraction handgrip for 2 min, followed by

3 min of post-exercise circulatory occlusion (PECO). In random

order, subjects either breathed room air, hypoxia (target

SpO2 = 85 %), or hyperoxia (FIO2 = 1.0) during the PECO in order

to modulate the chemoreflex. Following these trials, a resting hypoxia

trial was conducted without handgrip or PECO. Ventilation (VE),

heart rate (HR), blood pressure (BP) and muscle sympathetic nervous

activity (MSNA) data were continuously obtained. As expected,

exercise increased all variables, and PECO in normoxia reduced all

variables compared to exercise; however all except HR remained

above baseline. Hyperoxia resulted in a greater reduction in MSNA

during PECO as compared to both normoxia and hypoxia (Hyper:

-18.0 ± 6.2 bursts/min, Norm: -11.2 ± 10.0 bursts/min, Hypo:

-11.3 ± 6.2 bursts/min; n = 6; P = 0.02). Hypoxia attenuated the

reduction in HR during PECO as compared to both normoxia and

hyperoxia (Hyper: -31.1 ± 6.2 bpm, Norm: -26.6 ± 7.2 bpm,

Hypo: -3.8 ± 7.1 bpm; n = 9; P \ 0.001), while there was a ten-

dency for the reduction in VE during PECO to be less in hypoxia

(Hyper: -4.9 ± 6.8L/min; Norm: -3.8 ± 2.9L/min; Hypo:

+2.0 ± 7.8L/min; n = 9; P = 0.08). There was no change in the

reduction of BP during PECO with hyperoxia or hypoxia (Hyper:

-4.5 ± 7.4 mmHg; Norm: -4.5 ± 3.9 mmHg; Hypo:-5.2 ±

5.5 mmHg; n = 8; P = 0.89). These preliminary results demonstrate

a reduction in MSNA during PECO with suppression of the chemo-

receptors, suggesting that the metaboreflex sensitizes the chemoreflex,

and that the chemoreflex may play a role in the integrated MSNA

response to handgrip exercise.

Poster #31

Do multi-unit sympathetic discharge patterns change

with age and cardiovascular disease?

D.N. Brewer1, P. Zubin Maslov2, Z. Dujic2, J.K. Shoemaker1

1School of Kinesiology, Western University, London, Ontario,

Canada; 2School of Medicine, University of Split, Split, Croatia

Burst frequency in integrated muscle sympathetic nerve activity

(MSNA) suggests increased sympathetic outflow with age and car-

diovascular disease (CVD). Assessment of burst frequency alone

ignores the action potential (AP) content of each burst causing

potential error in assessing sympathetic outflow. This study tested the

hypothesis that age and CVD increase MSNA by contrasting MSNA

burst patterns of the integrated signal with AP content patterns.

MSNA (microneurography) was recorded in Young, Older healthy,

metabolic syndrome (MET), coronary artery disease (CAD) and

congestive heart failure (CHF; Class II) (n = 7 per group) individu-

als. A significant MANOVA, F(32,108) = 2.088, p \ 0.05, g2 = 0.9

suggested that variables of MSNA were different between groups.

Univariate analysis using Tukey’s HSD post hoc suggested that,

compared with Young (17 ± 6 b/min), burst frequency increased in

Older (31 ± 6), MET (34 ± 10) and CAD (34 ± 8) (P \ 0.001) and

more in CHF (55 ± 9 b/min; P \ 0.05 vs. all groups). APs per burst

were similar across groups: young (11 ± 6 APs/b), Older (7.7 ± 2)

and CHF (13 ± 6) (NS; effect size = 0.92). Compared to Young

(187 ± 112 APs/min), APs per min were not different in Older

(235 ± 92), MET (305 ± 103) or CAD (299 ± 105) patients (NS)

but increased to 746 ± 367 APs/min in CHF (P \ 0.05 vs. all

groups). Therefore, increased MSNA burst frequency with age or with

moderate CVD disease or risk (CAD and MET) does not translate to

more total AP discharge until severe cardiovascular disease (CHF)

when a small increase in APs/burst compounds the elevated burst

incidence to produce greater sympathetic outflow. These results

challenge the use of burst frequency alone as a discriminator between

groups of varying age and health status. Supported by CIHR and

NSERC funding.

Poster #32

Acute baroreflex sensitivity impairment due to insulin-

induced experimental hypoglycemia

A. Rao2, I. Bonyhay1, S. Ballatori1, G. Adler2, R. Freeman1

1Department of Neurology, Beth Israel Deaconess Medical Center,

Harvard Medical School, Boston, MA, USA; 2Division

of Endocrinology, Diabetes, and Hypertension, Brigham

and Women’s Hospital, Harvard Medical School, Boston, MA, USA

Background: In our previous studies, we demonstrated that baroreflex

sensitivity (BRS) was impaired 16 h after antecedent hypoglycemia.

Clin Auton Res (2012) 22:207–258 243

123

However, it is not known when this BRS impairment begins after the

exposure of hypoglycemia and whether other acute hemodynamic

changes occur with the baroreflex change.

Objective: To test the hypothesis that BRS impairment occurs during

the hypoglycemia exposure.

Methods: Hyperinsulinemic hypoglycemic clamp studies were per-

formed in 15 healthy study participants (age 25 ± 5 years, BMI:

23 ± 4; 12 men) not taking any medications. The night before study

procedures, study participants were admitted to the Clinical Research

Center at Brigham and Women’s Hospital and were asked to fast and

remain supine after midnight. Hypoglycemic clamps were performed

in the morning with insulin (80 mU/m2 body surface area/min)

infused for 150 min. Dextrose (20 %) was infused to maintain glu-

cose levels at 50 mg/dL for 120 min. Modified Oxford baroreflex

tests were performed in duplicate immediately before initiating the

clamp (euglycemia) and during the final 30 min of hypoglycemia: a

bolus injection of 100 lg sodium nitroprusside (vasodilator) was

administered, followed 60 s later by a bolus injection of 150 lg

phenylephrine hydrochloride (vasoconstrictor). The sequential

administration of these agents produces a drop followed by a rise in

blood pressure over a short time course. Changes in autonomic

measures, blood pressure response and baroreflex sensitivity (BRS),

were analyzed by repeated measures ANOVA.

Results: Blood pressure prior to each modified Oxford was not dif-

ferent between euglycemic (E) and hypoglycemic (H) states (MAP:

E: 86 ± 4 vs. H: 84 ± 5 mmHg), whereas heart rate significantly

increased during hypoglycemia (E: 58 ± 6 vs. H: 71 ± 8 bpm,

P \ 0.001). Blood pressure response to phenylephrine was signifi-

cantly blunted during hypoglycemia (E: 32 ± 15 vs. H:

20 ± 9 mmHg, P \ 0.01), which was also accompanied by a sig-

nificant decrease in BRS (E: 36 ± 16 vs. H: 19 ± 8 ms/mmHg,

P \ 0.005).

Conclusion: The present study demonstrates that hypoglycemia

acutely decreases BRS, suggesting ongoing hypoglycemia reduces

vagal control of the heart. These findings could have clinical impli-

cations in patients experiencing ongoing hypoglycemia.

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


Vanderbilt University, Nashville, TN, USA

Compared to Caucasians, obese Hispanics are at higher risk for dia-

betes and metabolic syndrome but have lower prevalence of

hypertension, suggesting different mechanisms of obesity hyperten-

sion. To assess the autonomic contribution to blood pressure (BP) and

resting energy expenditure (REE), we induced autonomic withdrawal

with the ganglionic blocker trimethaphan in 10 lean (BMI

23.8 ± 0.5 kg/m2, 33 ± 3 years.) and 9 obese (BMI 35.1 ± 1.2 kg/

m2, 42 ± 3 years.) mestizo Hispanics, and 7 obese (BMI

35.4 ± 0.9 kg/m2, 37 ± 3 years.) Caucasians. Baseline supine sys-

tolic BP was higher in obese Hispanics compared to lean Hispanics

(116 ± 5 vs. 96 ± 2 mmHg; P \ 0.01). After autonomic blockade,

systolic BP fell more in obese Hispanics compared to lean Hispanics

(-25 ± 5 vs. -3 ± 3 mmHg; P \ 0.01), and the ‘‘intrinsic’’ BP in

the absence of autonomic influences was similar between the two

groups (93 ± 5 vs. 93 ± 3 mmHg; P [ 0.05). Trimethaphan lowered

BP selectively by reducing autonomic function because it decreased

BP by only 15 ± 4 mmHg in a control group of patients with pure

autonomic failure and severe supine hypertension. Baseline REE was

higher in obese Hispanics than in lean Hispanics (1,836 ± 128 vs.

1,321 ± 37 kcal/d; P \ 0.01), but the difference disappeared after

adjusting for fat-free mass (FFM). Furthermore, the fall in REE

adjusted for FFM after trimethaphan was similar in both groups (lean

-59 ± 15 vs. obese -54 ± 22 kcal/day adjusted by FFM; p [ 0.05).

Compared to obese Hispanics, obese Caucasians had similar baseline

and intrinsic BP and REE, which fell by a magnitude similar to that of

obese Hispanics with trimethaphan. In conclusion, sympathetic acti-

vation induced by obesity is an important factor of BP elevation in

both obese Hispanics and Caucasians, but does not contribute to the

increase in REE.

Poster #34

The impact of injury to autonomic pathways

on cardiovascular disease risk after spinal cord injury

H.J.C. Ravensbergen1,2, I.S. Sahota1,2, S.A. Lear1,3, V.E. Claydon1,2

1Department of Biomedical Physiology and Kinesiology, Simon

Fraser University, Burnaby, British Columbia, Canada; 2International

Collaboration On Repair Discoveries, Department of Medicine,

University of British Columbia (ICORD), Vancouver, British

Columbia, Canada; 3Faculty of Health Sciences, Simon Fraser

University, Burnaby, British Columbia.

Introduction: The leading cause of morbidity and mortality in indi-

viduals with spinal cord injury (SCI) is cardiovascular disease. The

mechanisms underlying the high risk of cardiovascular disease after

SCI are unclear. Leading a sedentary lifestyle after SCI has been

proposed to be the main contributing factor. However, we propose

that direct injury to cardiovascular autonomic pathways plays an

important role. We, therefore, aimed to compare risk factors for

cardiovascular disease between individuals with autonomically

complete SCI, autonomically incomplete SCI, and able-bodied

controls.

Methods: Completeness of injury to cardiovascular autonomic path-

ways was determined by level of injury (above T5), low plasma

noradrenaline, and decreased power of low frequency oscillations in

systolic blood pressure. Classic cardiovascular risk factors were

evaluated (glucose tolerance, insulin sensitivity, fasting lipid profiles

and measures of obesity). Physical activity was determined using

questionnaires. We tested 19 able-bodied controls, and 29 individuals

with SCI (13 autonomically complete and 16 autonomically

incomplete).

Results: Glucose tolerance and insulin sensitivity were impaired only

in the autonomically complete SCI group. HDL cholesterol and the

HDL/total cholesterol ratio were lower in both SCI groups compared

to controls. We did not find any differences in LDL cholesterol

between groups. Physical activity scores were similar in all groups.

Severity of impairment in glucose tolerance was positively correlated

with severity of autonomic injury.

Conclusion: These results are compatible with an independent rela-

tionship between autonomic dysfunction after SCI and impaired

glucose handling. Impairments in lipid profiles were observed in both

SCI groups. These findings support the need to target treatment

towards autonomic dysfunction after SCI, in addition to lifestyle

modification, in order to reduce morbidity and mortality due to car-

diovascular disease.

244 Clin Auton Res (2012) 22:207–258

123

Poster #35

What is the best marker for obesity in individuals

with spinal cord injury?

H.J.C. Ravensbergen1,2, M.C. Keenleyside1, S.A. Lear1,3,

V.E. Claydon1,2


Fraser University, Burnaby, British Columbia, Canada; 2International

Collaboration on Repair Discoveries (ICORD), Vancouver, British

Columbia, Canada; 3Faculty of Health Sciences, Simon Fraser

University, Burnaby, British Columbia

Cardiovascular disease is now the leading cause of morbidity and

mortality in individuals with spinal cord injury (SCI). Obesity is well

known to be a major predictor for cardiovascular disease risk. A

simple and widely used marker for obesity in the able-bodied popu-

lation is body mass index (BMI), but it has some major limitations. In

the SCI population, current cut-off values for BMI lead to an

underestimation of obesity, probably because BMI is not sensitive to

the altered contributions of fat and fat free mass to body weight after

SCI. As such, improved measures of obesity that are more accurate in

this population are needed. We aimed to identify the best marker of

obesity after SCI, considering both practically of use, and ability to

detect adiposity and cardiovascular disease risk. We measured BMI,

waist circumference (WC), waist-to-hip ratio (WHR), waist-to-height

ratio (WHtR) and neck circumference (NC) as known markers of

obesity. We investigated relationships between these measures and

total body and abdominal fat percentages as measured using dual

energy X-ray absorptiometry. We also determined correlations

between the obesity markers and a cardiovascular disease risk score

incorporating fasting levels of glucose, insulin, triglycerides, ratio of

total cholesterol to high density lipoprotein (HDL) cholesterol (TC/

HDL) and glucose 120 min after an oral glucose load. Measurements

were conducted in 30 individuals with SCI. We identified significant

correlations between WC, WHR and WHtR and fat percentages,

individual risk parameters, and the sum of risk score, indicating these

are strong markers for obesity and cardiovascular risk after SCI.

Importantly, each of these markers is easy to measure in this popu-

lation, unlike BMI which requires a wheelchair scale to determine

body weight. We propose that these measures could provide simple

but more sensitive alternatives to BMI that are easy to use in general

medical practice or at home.

Poster #36

Central arterial stiffness and autonomic modulation

in active women

P. Latchman1, G. Gates2, J. Pereira1, R. Axtell1, M. Bartels3,

R. De Meersman4

1Southern Connecticut State University, New Haven, CT, USA; 2The

Children Hospital at Montefiore, Bronx, NY, USA; 3Columbia

University Medical Center, Columbia University, New York, NY,

USA; 4Alfaisal University, College of Medicine, Riyadh,

Saudi Arabia

Introduction: Hypertension is one of the most common health prob-

lems in the United States. Of any group in the United States, African

American (AA) women have the greatest propensity for hypertension.

Loss of baroreflex sensitivity (BRS), autonomic dysfunction and

increased central arterial stiffness could be implicated in the etiology

of hypertension. Sedentary AA women have been shown to have

significantly higher levels of autonomic dysfunction, significantly

lower levels of BRS and significantly higher levels of arterial stiffness

versus their Caucasian (C) counterparts. Regular physical activity by

individuals at high risk for developing hypertension has been shown

to reduce the rise in blood pressure that occurs over time.

Aim: To determine if there are differences in BRS, autonomic func-

tion and central arterial stiffness between very active AA women and

matched C women.

Materials and methods: We compared 8 very active AA women to 17

age, height, weight and blood pressure matched C women. Autonomic

modulation and BRS were assessed using spectral density analysis

and transfer function analysis of the electrocardiogram and beat-to-

beat blood pressure. Central arterial stiffness was determined via

pulse wave velocity.

Results: No significant differences existed between groups in BRS

(AA = 19.6 ± 4.6 vs. C = 16.4 ± 10.7 ms/mmHg, p = 0.4); sympa-

thetic vasomotor activity (LFSBP) (AA = 3.6 ± 2.0 vs. C = 3.8 ±

2.0 mmHg2, p = 0.8); parasympathetic nervous activity (HFln)

(AA = 7.3 + 1.0 vs. 7.3 ± 1.2 ms2, p = 0.90) or central arterial stiff-

ness (AA = 5.6 + 0.90 vs. C = 5.5 ± 1.2 m/s, p = 0.80).

Discussion: These findings are suggestive that very active AA women

may not be at higher risk for developing hypertension versus their C

counterparts.

Conclusions: BRS, autonomic function and central arterial stiffness is

similar in very active AA and C women.

Poster #37

Impaired autonomic modulation in acute stroke

improves with clinical recovery within 72 hours

M.J. Hilz1,2, H. Marthol1, S. Moeller1, J. Koehn1, A. Akhundova1,

P. De Fina3, S. Schwab1

1Department of Neurology, University of Erlangen-Nuremberg,

Erlangen, Germany; 2Departments of Neurology, Medicine,

and Psychiatry, New York University, New York, NY, USA;3International Brain Research Foundation, Flanders, NJ, USA

Background and aim: In acute stroke, there is compromised cardio-

vascular autonomic modulation (CAM) that correlates with stroke

severity as assessed by the National Institutes of Health Stroke Scale

(NIHSS) (Hilz MJ, et al. Stroke. 2011). Autonomic dysfunction has

not yet been correlated with clinical changes in stroke severity during

the initial 72 h after stroke-onset. We therefore assessed CAM and

baroreflex sensitivity (BRS) within the first 24 h and after 72 h upon

stroke-onset.

Methods: In 48 patients with middle cerebral artery ischemic stroke

(24 women, 68 ± 14 years), we assessed NIHSS-scores and CAM

parameters within 24 and 72 h after stroke-onset. From 5 min RR-

interval (RRI) and blood pressure (BP) recordings, we calculated

spectral powers of RRI oscillations in mainly sympathetically medi-

ated low- (LF: 0.04–0.15 Hz) and parasympathetically mediated high-

frequency (HF: 0.15–0.5 Hz) ranges, and BRS as gain between sys-

tolic BP- and RRI-oscillations for coherence [0.7. We compared

cardiovascular parameters of both measurements using t tests and

NIHSS-scores using the Wilcoxon-test (significance: p \ 0.05).

Results: From the first to the second assessment, there was a decrease

in NIHSS-scores [median (inter-quartile range): 5 (4–11) vs. 3

(1–10)], systolic and diastolic BPs, and increase in RRI-LF-powers,

RRI-HF-powers and BRS [5.4 ± 5.3 vs. 9.4 ± 6.6 ms mmHg-1].

Clin Auton Res (2012) 22:207–258 245

123

Conclusion: After 72 h, decrease in NIHSS scores and increase in LF-

and HF-RRI-modulation and in BRS show an association between

CAM recovery and clinical stroke improvement.

Acknowledgement: The study was supported by Bayer Healthcare

Pharmaceuticals, Germany, the Rolf- and Hubertine-Schiffbauer-

Foundation, Hof, Germany, and the International Brain Research

Foundation Inc., 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

Semmelweis University, Institute of Human Physiology and Clinical

Experimental Research, Budapest, Hungary

Sudden cardiac death (SCD) is a common late complication in

patients with tetralogy of Fallot (ToF). Reduced cardiovagal barore-

flex sensitivity (BRS) was found to be an independent predictor of

SCD. Reduced BRS was reported in ToF patients, but the underlying

mechanism is not clear. Our laboratory has shown earlier that BRS is

related to carotid artery distensibility (DC) in healthy subjects and

that DC is reduced in ToF. Considering all above, we aimed to test the

hypothesis that reduced BRS is related to impaired carotid artery

elastic function. We studied 36 ToF patients (21 ± 11 years) and 50

age- and gender-matched healthy control subjects. Carotid artery

diastolic diameter and pulsatile distension was determined by echo

wall tracking and carotid blood pressure was measured by tonometry.

DC was calculated subsequently. Spontaneous blood pressure fluc-

tuations coupled with adequate heart rate responses were used to

calculate spontaneous BRS (sBRS). Intravenous phenylephrine-

induced blood pressure elevation followed by heart rate reduction was

used to determine BRSphe.

Results: (mean ± SD) BRS indices were markedly reduced in

patients compared with controls (sBRS 9.3 ± 9.2 vs. 17.5 ± 6.8 ms/

mmHg; BRSphe 16.8 ± 10.2 vs. 32.6 ± 11.4 ms/mmHg). DC also

showed significant difference between groups (5.1 ± 1.8 vs.

6.8 ± 2.8 9 10-3/mmHg). DC correlated significantly and positively

with BRS across patients and control subjects as well (sBRS

r = 0.49� vs. r = 0.42*; BRSphe r = 0.31 vs. r = 0.73*). Multiple

regression analysis indicated that DC is an independent determinant

of BRS indices in ToF patients. (�p \ 0.05; *p \ 0.01) Our data

demonstrate that reduced DC can contribute to impairment of BRS in

ToF patients. Lifestyle modifications, such as moderate aerobic

exercise, sodium restriction and omega-3-fatty acid intake, appear to

be efficient interventions in preventing and treating carotid artery

stiffness and—indirectly—impaired baroreflex function.

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

Almazov Federal Heart, Blood and Endocrinology Centre,


Atrial fibrillation (AF) deteriorates the prognosis in patients with

chronic heart failure (CHF). Probably it is due to peculiarities of

hemodynamic control. The goal was to evaluate the neural peculiar-

ities of vascular control and orthostatic tolerance in patients suffering

both AF and CHF.

Patients and methods: The study included totally 61 patients with

CHF II-IV NYHA class, with ejection fraction (EF) 35.0 ± 10.1 %,

including 25 ones having AF and 36 persons with sinus rhythm (SR).

According to clinical and nosological characteristics, both groups

were comparable. In addition to general clinical surveys, several

special investigations were performed: 1—tilt-test, 2—forearm blood

flow (FBF) by occlusion plethysmography to Dohn as well as its

dynamics during cold stress (CS), 3—cardiopulmonary baroreflex

testing (CPBR) when creating a vacuum in the lower part of the body

-10 mm Hg, and 4—to assess the metaboreflex hand-grip test was

executed. Hemodynamic parameters were recorded by using a con-

tinuous non-invasive BP monitor Finometer-PRO, (FMS,

Amsterdam).

Results: Patients with AF were older: 60.1 ± 9.0 and 54.5 ±

8.0 years, p \ 0.05 and had a larger left atrial volume index:

69.8 ± 23.7 and 54.2 ± 15.6 sm3/m2, p \ 0.05. Sizes of the other

cavities of the heart and contractility were not different. Patients with

AF had higher total peripheral vascular resistance (TPR): 1.34 ± 0.42

and 1.00 ± 0.30 MU, p \ 0.005 and lower FBF: 3.1 ± 1.5 and

4.8 ± 2.4 ml/100 sm3 min., P \ 0.05, between which observed an

inverse correlation: r = -0.34, p \ 0.05. The reaction in response to

sympatho-activation tests was also different: an increase in diastolic

blood pressure (DBP) during hand-grip test in patients with AF was

greater, 14.9 ± 5.9 and 11.1 ± 5.9, p \ 0.05, whereas the vasocon-

striction in response to CS: 0.24 ± 0.14 and 0.31 ± 0.13, p \ 0.05

and reduced venous return (CPBR): 0.16 ± 0.17 and 0.29 ± 0.11

rel.units., p \ 0.05—were lower. In addition, in patients with AF was

more frequently observed decrease in DBP in the standing position:

-2.1 ± 5.2 mm Hg, whereas in the SR- its natural growth:

2.0 ± 6.3 mm Hg, p \ 0.05, and the dynamics of DBP in orthostasis

was directly related to the initial TPR: r = 0.43, p \ 0.001 and

CPBR, r = -0.49, p \ 0.001.

Conclusion: In patients with CHF simultaneously suffering AF a more

pronounced increase in vascular tone related with a reduction of

peripheral blood flow, as well as enhanced metaboreflex. It is

accompanied with weakening of vasomotor reactivity to cold stress

and reducing venous return that is connected with diminishing of

tolerance to orthostasis.

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

Department of Cardiology, Almazov Federal Centre of Heart, Blood

and Endocrinology, Saint-Petersburg, Russian Federation

Hypothesis: Calcitonin gene-related peptide (CGRP)—vasoactive

neuropeptide implicated in physiological processes. Endocannabinoid

system activates in patients with abdominal obesity (AO) and arterial

hypertension (AH) and stimulates CGRP release in experiments.

Aim: To evaluate serum CGRP and plasma endocannabinoid (ECs)

levels (anandamide (AEA) and 2-arachidonoylglycerol (2-AG)) in

obese patients with AH.

246 Clin Auton Res (2012) 22:207–258

123

Materials and methods: We examined 56 patients (42.0 ± 0.8 years

old) with AO (IDF, 2005) and 24 non-obese (NO) subjects. 50 % of

obese patients had AH. Level of CGRP was evaluated by EIA method

(Peninsula Laboratories, LLC, USA), levels of ECs—by chromato-

mass-spectrometry.

Results. CGRP level didn’t differ in patients with AO (n = 31) and

NO-subjects (n = 12) (0.26 ± 0.04 ng/ml and 0.18 ± 0.03 ng/ml;

p [ 0.05), and in obese patients with AH and obese patients without

AH (0.30 ± 0.07 ng/ml and 0.21 ± 0.07 ng/ml; p [ 0.05). AEA and

2-arachidonoylglycerol 2-AG levels were higher in obese patients

(n = 24) versus NO-subjects (n = 20)—AEA: 16.0 ± 2.2 ng/ml and

7.1 ± 1.1 ng/ml; p \ 0.0001; 2-AG: 0.9 ± 0.1 ng/ml and

0.5 ± 0.1 ng/ml; p = 0.005. AEA level were higher in patients with

AO and AH versus patients with AO and without AH (0.9 ± 0.1 ng/

ml and 0.6 ± s0.1 ng/ml; p = 0.002). 2-AG level didn’t differ in

patients with AO and AH and patients with AO and without AH

(16.5 ± 3.3 ng/ml and 10.0 ± 1.6 ng/ml; p [ 0.05). We revealed

correlations between AEA level and duration of obesity (DO)

(r = 0.6; p = 0.02), BMI (r = 0.6; p = 0.0001), waist circumference

(WS) (r = 0.6; p = 0.0001), systolic blood pressure (SBP) (r = 0.5;

p = 0.001) and diastolic BP (DBP) (r = 0.5; p = 0.001). We

revealed correlations between 2-AG level and DO (r = 0.5;

p = 0.001), BMI (r = 0.4; p = 0.002), WS (r = 0.4; p = 0.004),

SBP (r = 0.3; p = 0.004) and DBP (r = 0.3; p = 0.005). We didn’t

find correlations between CGRP level and all investigating

parameters.

Conclusions: We didn’t find changes of CGRP level in obese

hypertensive patients. ECs levels associated with DO, antropometric

parameters, blood pressure in patients with AO and AH.

Poster #41

Heart rate variability and high sensitivity C-reactive

protein: influence of coronary artery lesions

N.Y. Tamburus1, V.C. Kunz1, R.F.L. Paula2, M.R. Salviati2,

T.A.G. Nery2, E. da Silva1,2

1Department of Physiotherapy, Laboratory of Cardiovascular

Physiotherapy, Federal University of Sao Carlos, Sao Carlos, Sao

Paulo, Brazil; 2Department of Physiotherapy, College of Health

Sciences, Methodist University of Piracicaba, Piracicaba, Sao Paulo,

Brazil

Introduction: High level of C-reactive protein and decreased HRV

(heart rate variability) are considered important indicators of systemic

inflammation and autonomic dysfunction, both have been associated

with risk of coronary artery disease (CAD). However, it is unknown

the relationship of HRV indexes and high sensitivity C-reactive

protein (hs-CRP) with progression of CAD.

Objective: The aim of the study was to evaluate and compare plasma

levels of hs-CRP and HRV indexes in patients with only coronary risk

factors for CAD and with coronary artery disease.

Methods: A sample of 163 men (mean age 56.54 ± 6.87 years) was

divided into two groups: CAD group (obstructive CAD C 50 % -

DAC+ n = 87) and coronary risk factor group, without significant

obstruction (DAC- n = 76). Heart rate (HR) and R-Ri was measured

using a Polar�S810i for 15 min in supine rest. The HRV analysis was

performed using frequency (high [HF] and low frequencies [LF]—

normalizes units; LF/HF ratio) and time domain (RMSSD and

SDNN—ms). The hs-CRP was determined by nephelometry. Statis-

tical analysis: Mann–Whitney test, with level of significance = 5 %.

Results: The CAD + presented lower RMSSD, SDNN and AFnu

values (14.12 ± 7.04, 21.63 ± 9.67 and 0.34 ± 0.18, respectively)

and higher BFnu and hs-CRP (0.65 ± 0.18 and 0.50 ± 0.68) than

CAD- (RMSSD = 30.73 ± 15.93; SDNN = 37.66 ± 15.65; AFnu =

0.44 ± 0.19; BFnu = 0.55 ± 0.19; LF/HF = 1.78 ± 1.60; hs-

CRP = 0.26 ± 0.33).

Conclusion: These results indicate that autonomic heart dysfunction

and inflammation are related with progression of CAD.

Poster #42

Oligofiber recordings detail single-fiber sympathetic

nerve discharge

C.-K. Su 1, C.-H. Chiang1,2, C.-M. Ho2, C.-M. Lee1,3, Y.-P. Fan1

1Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan;2Department of Anesthesiology, Taipei Veterans General Hospital

and National Yang-Ming University, Taipei, Taiwan; 3Department

of Molecular & Cell Biology, University of California at Berkeley,

Berkeley, CA, USA

Whole-bundle nerve recording is an easy technique to gauge central

sympathetic outflow. However, this conventional technique fails to

detail individual fiber activities. Aiming for a signal resolution at the

single-fiber level, we established a novel experimental model so-

called ‘oligofiber recordings’. In vitro splanchnic sympathetic nerve-

thoracic spinal cord preparations were obtained from Sprague–Daw-

ley neonatal rats. Whole-bundle nerves were incubated in a glass

micropipette containing 0.5 % collagenase for 90 min. The dissoci-

ated nerve fascicles were then brought into a small caliber

micropipette for electrical signal recordings. Oligofiber activities that

displayed several distinct spike potential waveforms were often

achieved. Automation of spike sorting was primarily based on spike

waveform features using a series of custom-made LabVIEW pro-

grams incorporated with MATLAB scripts. Data clusters were

automatically selected by j-means clustering algorithms followed by

verification of the waveform homogeneity by principal component

analysis (PCA). Dissimilar waveforms unselected by PCA were

retrieved by a subtraction algorithm (SA), which partially resolved

overlapped spikes. Both PCA-selected and SA-retrieved spikes were

combined as unit activities. To evaluate if unit activities truly origi-

nated from single fibers, we examined the probability distribution of

interspike intervals (ISIs) and determined if a change of waveform

features was a function of their preceding ISIs. 77 unit activities

collected from 30 experiments were confirmed as single-fiber activ-

ities. Using the oligofiber recording techniques, we could

simultaneously examine, on average, *3 single fiber activities per

experiment. After some modifications, these techniques should be

applicable to any peripheral nerve recordings.

Poster #43

Cardiovascular autonomic control in the first year

after spinal cord injury

J. Inskip1,2, M. McGrath, B. Kwon2,3, V. Claydon1,2


Fraser University, Burnaby, BC, Canada; 2International Collaboration

on Repair Discoveries (ICORD), Vancouver BC, Canada; 3Combined

Neurosurgical and Orthopaedic Spine Program, Department

of Orthopaedics, University of British Columbia, Vancouver, Canada

Clin Auton Res (2012) 22:207–258 247

123

Autonomic pathways that travel in the spinal cord are susceptible to

spinal cord injury (SCI) and their disruption can result in a range of

cardiovascular dysfunctions. The development and evolution of these

complications remains poorly understood. Here we sought to evaluate

cardiovascular function in the first year after traumatic SCI using

spectral analyses. Resting supine beat-to-beat blood pressure and

3-lead electrocardiography were recorded during supine rest for

15 min at several time points in the first year post-injury. Here we

present results from recordings performed in the first 2 weeks post-

injury, and again at 1 year, on the same eight subjects: four with

cervical SCI and four with low thoracic or lumbar SCI. Autonomic

function was quantified using spectral analysis of heart rate variability

(HRV) and blood pressure variability (BPV). Individuals also com-

pleted a questionnaire at each visit evaluating symptoms of

cardiovascular dysfunction after SCI. All subjects showed increased

total HRV at 1 year post-injury compared to the first time point. Our

initial BPV analyses show two different patterns. Individuals with low

level lesions show frequency domain analyses that are essentially

normal and do not show significant changes over time post-injury.

Individuals with cervical SCI show evidence of impaired cardiovas-

cular autonomic function that spontaneously improves over time. It

remains to be determined whether this reflects autonomically com-

plete lesions that recover, or incomplete lesions with altered

autonomic function associated with the initial trauma. The early

period after SCI appears to be a time when autonomic control of the

cardiovascular system can change significantly. Clinically, it may be

wise to assess the cardiovascular system at several stages in the first

year after injury in order to get a clearer picture of the level of

cardiovascular autonomic control.

Poster #44

‘‘Sympathovagal balance’’—a thermodynamic

perspective

R. Schondorf1, J. Benoit1, M.J. Lafitte2

1Department of Neurology, Jewish General Hospital, McGill

University, Montreal, QC, Canada; 2DyAnsys, Geneva, Switzerland

We have previously applied a novel time domain method to provide

kinematic descriptors of vagal and sympathetic responses of cardiac

autonomic activity during well-characterized physiologic maneuvers.

This method essentially considers each component in isolation and

provides little insight into the overall impact of these responses.

Thermodynamics considers energy changes within a system in terms

of heat entering the system and macroscopic work done by the sys-

tem. Usually the latter is regarded as meaningful by an outside

observer. We adapted our analytic method to obtain an index of

energy balance from the original phase space representation of our

beat-to-beat responses. We have found that the directionality and

magnitude of our index coheres well with expected changes in RR

intervals (RRI) in normal subjects at rest, during head-up tilt (HUT)

and during dynamic neck suction and in patients with POTS during

HUT and following MAST pants inflation. Conversely, patients fol-

lowing cardiac transplantation manifest little modification in RRI

despite significant changes in energy transfer. During neurally med-

iated syncope (NMS) an intermediate condition is observed. During

supine and early HUT, changes in energy translate as changes in RRI.

However, in the minutes prior to syncope there is a transition to a

state where even large swings in energy are essentially ineffective at

changing RRI. Finally, at syncope there is an abrupt change in

responsivity once again to a large directionally appropriate energy

change with resultant bradycardia. It would appear therefore that

analogous to other thermodynamic systems not all energy transfers

cause changes in RRI. In some instances heat production that does not

result in meaningful work appears to dominate. Therefore, changes in

RRI cannot be predicted or derived solely from isolated descriptors of

cardiac autonomic activity without simultaneously considering over-

all effective energy transfer.

Poster #45

The autonomic testing of normal subjects

G. Chelimsky1, S.M. Ialacci2, T.C. Chelimsky1

1Medical College of Wisconsin, Milwaukee, WI, USA; 2Case

Western Reserve University, Cleveland, OH USA

Background: The prevalence of abnormalities in autonomic testing

(ANS) in the general healthy population is unknown.

Hypothesis: Syncope can occur in a healthy population, but other

orthostatic syndromes and neuropathy are usually not present.

Methods: IRB prospective study evaluating results of autonomic

testing in healthy female [18 years who were well screened for

diseases known to be associated with autonomic abnormalities, had

BMI \ 35, not pregnant or breast feeding and no recent history of

surgeries. The subject underwent a detailed neurological and tender

point examination for fibromyalgia. Exclusion included: pin sensation

\8 in hands and/or feet, C8 sites rated C4/10 for fibromyalgia, have

history of pelvic pain, psychological state is unstable, pregnancy or

breastfeeding. All subjects underwent autonomic testing including:

cardiac response to deep breathing (DB), cardiac response to Valsalva

maneuver (VM), 70� head up tilt test (TTT) for 30 min and sudo-

motor axon reflex (QSART).

Results: 14 females were enrolled (mean 31 years, 20–55 years), BMI

of 22.9 ± 3.3. DB was normal in all subjects. 1 had decreased VM.

None reported any orthostatic symptoms during TTT. One subject had

a heart rate increase of 35 from baseline in the first 10 min (age 24)

and 5 had a heart rate increase of 32–42 bpm from baseline after

10 min. One subject had a syncopal episode without postural tachy-

cardia or orthostatic hypotension. In QSART, 9/13 had decreased or

absent sweating in the forearm. 6 had decreased or absent QSART in

C2 locations.

Conclusion: Healthy females may have an asymptomatic heart rate

increase during tilt and demonstrate abnormal QSARTs, particularly

in the forearm and abnormal sudomotor function in the absence of

other abnormalities. Supported by NIH grant R01DK083535

Poster #46

Alpha-adrenergic blockade unmasks a greater

compensatory vasodilation in hypoperfused contracting

muscle

D.P. Casey, M.J. Joyner

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

We previously demonstrated that acute hypoperfusion in exercising

human muscle causes an immediate increase in vascular resistance

that is followed by a partial restoration (\100 % recovery) of flow. In

the current study, we examined the contribution of a-adrenergic

vasoconstriction in the initial changes in vascular resistance at the

248 Clin Auton Res (2012) 22:207–258

123

onset of hypoperfusion as well as in the recovery of flow over time.

Nine healthy male subjects (29 ± 2) performed rhythmic forearm

exercise (20 % of maximum) during hypoperfusion evoked by intra-

arterial balloon inflation. Each trial included: baseline, exercise prior

to inflation, exercise with inflation, and exercise after deflation (3 min

each). Forearm blood flow (FBF; ultrasound), local (brachial artery),

and systemic arterial pressure (MAP; Finometer) were measured. The

exercise bout was repeated during phentolamine infusion (a-adren-

ergic receptor blockade). Forearm vascular conductance (FVC;

ml min-1 100 mmHg-1) and resistance (mmHg ml min-1) was cal-

culated from BF (ml min-1) and local MAP (mmHg). Recovery of

FBF and FVC (steady state inflation plus exercise value – nadir)/

[steady state exercise (control) value-nadir] with phentolamine was

enhanced compared with the respective control (no drug) trial

(FBF = 97 ± 5 % vs. 81 ± 6 %, P \ 0.05; FVC = 126 ± 9 % vs.

91 ± 5 %, P \ 0.01). However, the absolute (0.05 ± 0.01 vs.

0.06 ± 0.01 mmHg ml min-1; P = 0.17) and relative (35 ± 5 % vs.

31 ± 2 %; P = 0.41) increase in vascular resistance at the onset of

balloon inflation was not different between the a-adrenergic receptor

inhibition and control (no drug) trials. Therefore, our data indicate

that a-adrenergic mediated vasoconstriction restricts compensatory

vasodilation during forearm exercise with hypoperfusion, but is not

responsible for the initial increase in vascular resistance at the onset

of hypoperfusion.

Poster #47

COMPASS 31—a refined and abbreviated composite

autonomic symptom score

D.M. Sletten1, G.A. Suarez1, P.A. Low1, J. Mandrekar2, W. Singer1

1Department of Neurology, Mayo Clinic, Rochester, MN, USA;2Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN,

USA

Objectives: The autonomic symptom profile (ASP) is a well-estab-

lished questionnaire evaluating severity and distribution of autonomic

symptoms. Using a subset of questions, we have generated a validated

scoring instrument, the composite autonomic symptom score

(COMPASS). An error-prone scoring algorithm, time-consuming

administration, and lack of internal consistency necessitated a rede-

sign to an updated, more concise, statistically solid, and broadly

applicable tool for autonomic symptom quantification.

Methods: We assessed the internal consistency of COMPASS using

Cronbach alpha coefficients based on the ASP of 405 healthy control

subjects. Applying a simplified scoring algorithm, we then used

exploratory factor analysis with orthogonal rotation and Eigenvalue

calculations to extract internally consistent domains and to reduce

dimensionality. This was followed by expert revisions to eliminate

redundant content and to retain clinically important questions, and

final assessment of the new instrument.

Results: The new, simplified scoring algorithm alone resulted in

higher Cronbach alpha values in all domains. Factor analysis revealed

7 domains with a total of 54 questions retained. Expert revisions

resulted in further reduction of questions and domains with a

remaining total of 31 questions in 6 domains (COMPASS 31).

Measures of internal consistency were much improved compared to

COMPASS. Following appropriate weighting, this instrument pro-

vides an autonomic symptom score from 0 to 100.

Conclusions: COMPASS 31 is a refined, internally consistent, and

markedly abbreviated quantitative measure of autonomic symptoms.

It is based on the original ASP and COMPASS, applies a much

simplified scoring algorithm, and is suitable for widespread use in

autonomic research and practice.

Poster #48

Autonomic, blood flow and sensory small fiber scale

(ABSS)

P. Novak

Department of Neurology, University of Massachusetts, Worcester,

MA, USA

Background: There is a need for objective, fully quantitative and

clinically relevant instrument for scoring of autonomic, cerebral blood

flow and sensory small fiber domains. The only available clinically

validated scale is Composite Autonomic Severity Score (CASS) that

scores autonomic functions. The objective of this study was to vali-

date a new scale—Autonomic, Cerebral Blood Flow and Sensory

Small Fiber Scale (ABSS).

Methods: ABSS is based on CASS and defines the following domains:

(1) Cardiovagal; (2) Heart rate at rest and tilt; (3) Adrenergic; (4)

Sudomotor; (5) Sensory and (6) Intracranial blood flow. Cardiovagal

domain uses deep breathing test only. Heart rate domain uses heart

rate at supine and tilt test. Adrenergic domain has 3 separate subdo-

mains: adrenergic failure -Valsalva maneuver, adrenergic failure-tilt,

adrenergic hyperactivity-tilt. Sudomotor domain has 2 subdomains:

functional (identical to CASS) and morphological (using sweat glands

nerve fiber density). Sensory domain uses epidermal nerve fiber

density (ENFD). The intracranial blood flow (CBf) domain uses blood

flow velocity from the middle cerebral artery obtained during supine

period, tilt test and Valsalva maneuver. ABSS was validated pro-

spectively in 545 subjects with the following diagnoses: diabetes (53),

Parkinson disease (63), autonomic neuropathy (389), healthy controls

(40). CASS has been used as a gold standard for grading of autonomic

failure (AF) into mild, moderate and severe.

Results: ANOVA showed overall significance in ABSS scores among

diagnostic groups as well as graded AF. ENFD and CBf also corre-

lated with diagnostic groups and graded AF. Specificities and

sensitivities were above 90 % is separation of normal from abnormal

responses. ABSS classified 12 % of subjects as having adrenergic

failure that were classified as having normal response using CASS.

Conclusion: ABSS is compatible with CASS in both separations of

diagnostic groups as well as in grading of AF. ABSS is more sensitive

to detect adrenergic failure, it is able to detect autonomic overactivity,

provides expanded dynamic range, and defines new domains.

Poster #49

Systemic dysautonomia in complex regional pain

syndrome—a feasibility study

K.R. Chemali1, K. McNeeley1, L. Zhou2, T. Chelimsky3

1Department of Neurology, Sentara-EVMS, Norfolk, VA, USA;2Department of Neurology, Mount Sinai School of Medicine, New

York, NY, USA; 3Department of Neurology, Medical College

of Wisconsin, Milwaukee, WI, USA

Objectives: To assess the autonomic nervous system (ANS) in CRPS

at the affected limb and other sites.

Clin Auton Res (2012) 22:207–258 249

123

Background: CRPS is thought to be perpetuated by somatic-auto-

nomic coupling. Some reports suggested a cardiovascular

dysautonomia in CRPS, raising the possibility that CRPS is a local

manifestation of a widespread disorder of the ANS. In this study, we

assessed the ANS at the pupil, the cardiovascular and sudomotor

systems.

Methods: 5 patients with CRPS type I of a lower limb, with no sys-

temic symptoms of dysautonomia underwent pupillometry, heart rate

variability to deep breathing (HRDB), Valsalva maneuver (VM), tilt

table (HUT), QSART and skin biopsy (SB).

Results: a. Pupillometry: One patient displayed relative loss of sym-

pathetic tone, and the second showed abnormalities in both

sympathetic and parasympathetic parameters. A 3rd patient displayed

equivocal findings. b. HRDB: 1 patient showed decreased HR vari-

ability, suggesting cardiac parasympathetic abnormality. c. VM:

Valsalva ratios and blood pressures were normal in all patients. d.

HUT: none of the patients displayed abnormalities. e. QSART: 2

patients showed sudomotor abnormalities at the affected foot and 1

patient showed abnormalities at both the affected and unaffected feet.

f. Skin biopsy: 4 patients showed reduction of somatic and sudomotor

small fibers at the site of maximal allodynia and 1 patient showed a

reduction of these fibers in both limbs.

Conclusions: a. Skin biopsy remains the most sensitive test in con-

firming the diagnosis of CRPS b. A mild degree of subclinical

dysautonomia far from the affected limb seems to be present in some

patients with CRPS. The exact percentage of patients who have a

generalized dysautonomia cannot be concluded based on this small

sample. However, this study is feasible and a larger sample of patients

is necessary.

Poster Session III

Poster #50

Thermophysiological consequences of an absent evening

melatonin release in spinal cord injury

H. Jones1, J.T. Groothuis2,3), T.M.H. Eijsvogels2, J. Nyakayiru2,

R.J.M. Verheggen2, A. Thompson1, E.J.W. van Someren4, G.

Atkinson1, M.T.E. Hopman2, D.H.J. Thijssen 1,2

1Research Institute for Sport and Exercise Science, Liverpool John

Moores University, Liverpool, United Kingdom; 2Department

of Physiology, Radboud University Nijmegen Medical Centre,

Nijmegen, The Netherlands; 3Department of Rehabilitation, Radboud

University Nijmegen Medical Centre, Nijmegen, The Netherlands;4Department of Sleep and Cognition, Netherlands Institute

for Neuroscience, Amsterdam, The Netherlands

Background: Individuals with a spinal cord injury (SCI), especially

tetraplegics, experience poor sleep quality. Recently, we demon-

strated that, in tetraplegia, there is an absence of evening release of

melatonin and altered circadian rhythmicity of core body temperature.

Melatonin is an important hormone for the initiation of sleep, possibly

via thermoregulatory changes. Here, we examine the core and skin

thermoregulatory consequences of alterations in melatonin release in

SCI individuals.

Methods: Between 7 and 11 PM, we examined core body temperature

(telemetry system), skin temperature above and below the SCI

(temperature sensors) in 15 SCI individuals (AIS A), 9 paraplegic and

6 tetraplegic, and 10 age- and gender matched able-bodied controls.

Eight salivary melatonin samples were obtained between 7 and 11 PM

and analyzed using ELISA.

Results: Core body and skin temperature above the SCI gradually

decreased from 7 to 11 PM in all groups with no statistically inter-

action between the 3 groups. Skin temperature below the SCI in

tetraplegics significantly increased, whilst controls and paraplegics

demonstrated a gradual decline. A statistically significant and com-

parable increase in melatonin levels from 7 to 11 PM was observed in

controls (2.59 ± 1.04–10.62 ± 4.59 pg/ml) and paraplegics

(4.28 ± 3.28–13.10 ± 7.39 pg/ml), whilst tetraplegics demonstrated

a small decrease (5.25 ± 3.72–2.41 ± 1.25 pg/ml). In controls and

paraplegics, we found moderate correlations between melatonin lev-

els and core body temperature (r = 0.44 (P = 0.01) and r = 0.54

(P = 0.01), respectively), whilst no statistically significant correlation

was evident in tetraplegics.

Conclusion: We found a strong relation between the increase in mela-

tonin levels and decline in core body temperature during the evening

hours in controls and paraplegics, whilst such relation was not present in

tetraplegics. A potential explanation may relate to the skin temperature,

as the decline in lower limbs skin temperature during evening hours in

controls and paraplegics was not present in tetraplegics.

Poster #51

Post-exercise recovery period in patients

with idiopathic ventricular arrhythmias

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

Almazov Federal Heart, Blood and Endocrinology Centre, Saint

Petersburg, Russian Federation

A delayed decline of recovery heart rate (HRR) has been associated

with autonomic dysfunction. Appearance of ventricular arrhythmia

(VA) also often depends on autonomic nervous system modulation.

Objective: to examine HR and VA in the recovery period (RP) in

patients with idiopathic VA.

Materials and Methods: the study enrolled 30 patients (14 men; mean

age 38.2 ± 4.1 years old) with idiopathic VA, control group con-

sisted of 32 healthy persons (16 men, 36.2 ± 1.6 years old).

Structural cardiac pathology was excluded. Done Holter ECG.

Exercise training test (ETT) was performed according to standard

Bruce protocol, without any therapy, till to submaximal HR (85 % or

more). The HR and the quantity of VA at the 1, 2, 3 and 5 min of RP

were studied.

Results: Holter ECG showed mean 9722.5 single VE (sVE) daily, pre-

dominantly day-long type. In the control group there was no VA. During

the ETT there were no significant differences between patients and

control groups (p[ 0.05): the pre-test HR was 84.3 ± 15 and

86.7 ± 7.3 bpm, resp.; HRmax = 159.4 ± 13.1 and 177.9 ± 3.9 bpm

with 10.5 ± 2.5 and 12.5 ± 0.9 METS, resp. In RP the most decline

HRR was at 1 min (HRR1) = 22.4 ± 7.6 and 28.2 ± 8.2 bpm, resp.

(p\ 0.05). HRR2 min = 17.3 ± 2.1 and 23.6 ± 4.1 bpm,

resp.(P \ 0.05). HRR3 min = 11.2 ± 3.4 and 12.1 ± 5.2 bpm, resp.

(p[ 0.05). The pre-test number of sVE—mean 6.3 sVE/min, at peak

test—3.3, at 1 min—4.3, at 2 min—5.1, at 3 min—4.3, at 5 min—4.7

sVE/min. The HRR1 had negative correlation to amount VE of the third

minute of recovery (r = -0.52, p \ 0.05).

Conclusions: HRR index was normal (more then 12 bpm). Most likely,

there is an evidence of the deceleration of parasympathetic activation

and/or the increasing of sympathetic activity. It is accompanied by

decrease in HR speed restoration and increasing activity of ventricular

ectopic center to the 3rd minute of RP. Further investigation is needed.

250 Clin Auton Res (2012) 22:207–258

123

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

Department of Pediatric and Adolescent Medicine, Mayo Clinic,

Rochester, MN, USA

Introduction: We have shown that adolescents with the constellation

of symptoms comprising fatigue, nausea, pain (usually headache), and

dizziness, with or without syncope, have relative tachycardia during

exercise. While high heart rates (HR) are expected with decondi-

tioning, we observed unexpected changes in blood pressure and

cardiac output as well.

Methods: We reviewed records of adolescents presenting with long-

standing history of any mix of aforementioned symptoms, who

underwent both head-up tilt (HUT) and symptom-limited maximal

cardiopulmonary exercise (CPEX) testing from Jan 2010 to April

2012. Those with POTS had C40 bpm rise in HR with HUT. Cardiac

output (Q) was measured by inert gas rebreathing at rest and at 2–3

levels of light-moderate exercise.

Results: 277 patients between 9 and 19 years of age (78 % female)

underwent both HUT and CPEX. Cardiac output (Q) rose with

exercise on average 6 L/min per L/min rise in oxygen uptake (VO2)

for the group as a whole. 87 patients met definition of POTS. The

Q-VO2 relationships among patients with this group was bimodal,

with breakpoint at *7.5 L/min per L/min increase of VO2. The slope

of the Q-VO2 relationship averaged 5.2 ± 1.1 versus 9.0 ± 1.3 in the

normal (N = 65) and high output (N = 32) subgroups of POTS

patients, respectively. The change in mean arterial blood pressure

from rest to exercise was blunted in normal vs high output POTS

subgroups. HR change with HUT did not vary between these sub-

groups (48 ± 9.5 versus 50.5 ± 10 bpm, p = 0.167). None of these

patients was anemic.

Conclusions: A sub-group of adolescents with POTS who demon-

strate a hyperdynamic circulation during exercise also have a blunted

blood pressure response to exercise. We speculate this group of

patients has failure of normal regional vasoconstriction required

during dynamic exercise and must greatly increase flow through an

inappropriately dilated systemic circulation to maintain perfusion

pressure.

Poster #53

Neuropsychological profiles in adolescents with postural

tachycardia syndrome (POTS)

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

Department of Pediatrics, Baylor College of Medicine,

Houston, TX, USA

Objective: POTS is associated with complaints of cognitive symp-

toms, ‘‘brain fog’’, and anxiety that may contribute to severe

functional disability. To date, there are no published data on neuro-

psychological profiles of pediatric patients with POTS.

Methods: We reviewed the medical records and neuropsychological

data of 6 adolescents with frequent symptoms of orthostatic intoler-

ance for [3 months and increased HR of C40 or HR of C120 bpm

minutes within 10 min of active standing or head-up tilt test (HUT),

who were evaluated between 10/2008 and 8/2010 at a tertiary care

Pediatric Neurology Clinic. All underwent a 6 h neuropsychological

evaluation utilizing well-standardized measures of cognitive and

emotional functioning: WISC-IV/WAIS—IV, WRAML-2, Conners’

CPT-II, and Clinical Assessment of Depression.

Results: One patient had an antecedent H1N1 infection, and no eti-

ology was found in 5. Four patients were not in a formal school

setting secondary to their cognitive symptoms. All patients reported

significant difficulty concentrating. All but one endorsed significant

problems with processing speed or ‘‘brain fog’’. Two complained of

excessive fatigue and one reported anxiety. Clinically reported

symptoms of poor concentration and difficulty processing information

differed dramatically from the patients’ performance on standardized

measures of sustained attention, processing speed, and memory.

Despite the fact that many were not attending school due to clinically

reported symptoms of inattention and ‘‘brain fog’’, all patients’ scores

on measures of processing speed, attention, working memory, and

verbal memory were within the Average to Above Average range.

Conclusions: While adolescents with POTS often endorse debilitating

cognitive and psychiatric symptoms, formal testing reveals no neu-

ropsychological deficits. This preliminary finding indicates the

necessity of further study to elucidate the bases for this disparity.

Investigations looking at parental and adolescents’ reactions to the

diagnosis of POTS and assessment of the relationships between

medical symptoms, parenting style, and pre-morbid emotional func-

tioning seem warranted.

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

Department of Pediatrics, Baylor College of Medicine,

Houston, TX, USA

Objective: To evaluate whether children who meet adult but not

pediatric criteria (J Pediatr 2012; 60:222) for POTS represent a

similar clinical phenotype.

Background: Published reports of pediatric POTS have used adult

values of heart rate increment (HRinc) or absolute HR (HRabs).

However, normative pediatric data point to higher HR cut off values

than adults.

Methods: We reviewed the records of 64 patients evaluated between

April 2007 and March 2011 for probable POTS by standing or head-

up tilt test (HUT) or both at a Tertiary Pediatric Neurology Clinic.

POTS-pc (pediatric criteria) was defined as frequent, 2 or more

symptoms of OI for [3 months and HRinc of C40 or

HRabs C 120 bpm ages 14–19 and HRabs C 130 ages 8–13 years.

Diagnosis of POTS-ac-only (adult criteria) used HRinc of C30 bpm

or HRabs C 120 bpm regardless of age, within 10 min of active

standing or HUT, without arterial hypotension. Data are presented as

mean ± SD.

Results: 32 patients had POTS-pc (81 % female; age 15 ± 1.8 years),

with mean duration of symptoms of 1.8 years. Pre-existing conditions

included ADHD (19 %), anxiety (22 %), and depression (16 %).

Symptoms included chronic fatigue (81 %), sweating disorder

(59 %), sleep disorder (57 %), nausea (58 %), abdominal pain

(39 %), vomiting (26 %), weight loss (35 %), brain fog (32 %), and

migraine (31 %). Quantitative sudomotor axon testing was abnormal

in 14 of 25 patients (56 %), abnormal GI motility with gastroparesis

in 5/24 (21 %), and slow gastric emptying in 7/10 (70 %). There were

Clin Auton Res (2012) 22:207–258 251

123

30 patients with POTS-ac-only who had the same clinical phenotype

as the POTS-pc group without any significant differences in preva-

lence of age, sex, duration of symptoms, pre-existing conditions,

symptoms, test results, or outcome data.

Conclusions: Children and adolescents with POTS diagnosed using

newly proposed pediatric criteria have a similar phenotype to those

who only meet adult criteria. We propose a diagnosis of probable

POTS for the latter group.

Poster #55

Palpitations in postural tachycardia syndrome: what

do they tell?

R.K. Khurana

Department of Medicine, Medstar Union Memorial Hospital,

Baltimore, MD, USA

Introduction: In patients with postural tachycardia syndrome, multi-

plicity and severity of symptoms exceeds demonstrable organic

pathology, favoring the hypothesis of hypochondriasis. To test this

hypothesis, we used the somatosensory amplification scale (SSAS), a

validated 10-item questionnaire for the assessment of hypochondria-

sis, and palpitations (heart beat perception), a psychophysiological

variable that could be quantitatively manipulated.

Methods: Participants 21, 10 normals compared to 11 patients. All

participants rated each of the 10 items of the SSAS scale from 0 to 4.

All were asked to select the quality (pounding, thumping, heart

beating in the neck, racing, skipping, stopping, fluttering, heart

beating irregularly) of palpitations at supine rest and in response to

tachycardia produced by two sympathetic stimuli (Valsalva maneuver

[VM] and 10 min head-up tilt [HUT]) and one vagolytic stimulus

(atropine administration, 0.03 mg/kg body weight I.V.). Data were

compared using a t test.

Results: Total SSAS scores (mean ± SEM): normals 14.4 ± 2.3,

patients 17.45 ± 1.5, p = 0.27. Palpitations: There were no differ-

ences between palpitations at rest or following atropine

administration. However, patients had a higher response after VM

(81.8 % vs. 10 %, p = 0.001) and with HUT (63.6 % vs. 0 %,

p = 0.002). Quality of palpitations was better discriminated by

patients compared to normals despite identical stimuli. For example,

one patient felt fluttering at rest, pounding with VM, racing with

HUT, and heart beating in the neck with atropine.

Conclusions: Insignificant overall increase in SSAS scores militated

against somatosensory amplification and hypochondriasis. Palpita-

tions are mediated by sympathetic excitation and not vagal

withdrawal. The ability of patients to discriminate the quality of

palpitations in response to individual stimuli suggests visceral sen-

sitization, possibly of cortical origin. Psychophysiologic or

pharmacologic management of this phenomenon may be of symp-

tomatic benefit.

Poster #56

The spectrum of neuropathic orthostatic tachycardia

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


Objective: To assess autonomic function and epidermal nerve fiber

density in patients with postural tachycardia and evidence of a small

fiber neuropathy based on laboratory and/or clinical evaluation.

Background: The Postural Tachycardia Syndrome (POTS) comprises

a heterogeneous group of patients who have in common excessive

orthostatic tachycardia and symptoms of orthostatic intolerance.

Evidence of a limited autonomic neuropathy is not infrequently

encountered in these patients and has lead to the designation of a

‘‘neuropathic’’ subtype of POTS. On the other hand, definitions of

POTS typically exclude the presence of more widespread autonomic

failure and secondary causes of postural tachycardia, although these

cases may represent the continuation of a spectrum of limited auto-

nomic neuropathies with an orthostatic tachycardia phenotype, and

may provide helpful information towards a better understanding of

neuropathic POTS.

Design/Methods: 11 patients were recruited with evidence of (1)

orthostatic tachycardia (HR increment C30 bpm) and (2) the presence

of a small fiber neuropathy (abnormal QSART at the foot or at least

two other sites, or clinical symptoms consistent with small fiber

neuropathy). Secondary neuropathic causes of orthostatic tachycardia

were specifically not excluded. These patients were compared to 11

healthy control subjects. All participants underwent standardized

autonomic reflex testing and a CASS score was obtained. Punch skin

biopsies were performed at the distal and proximal leg. After staining

with PGP9.5, the number of intraepidermal fibers/mm (IENFD) was

quantified by one observer blinded to site and clinical status.

Results: 2 patients had orthostatic tachycardia in the setting of a more

widespread idiopathic autonomic neuropathy, 1 patient had auto-

nomic neuropathy in the setting of CIDP, 7 patients had POTS with

abnormalities on QSART, and 1 patient had POTS with normal

QSART but distal sensory symptoms. Both patients with idiopathic

autonomic neuropathy had markedly abnormal sudomotor function;

only one of them had abnormal IENFD, but significant morphologic

abnormalities (fiber tortuosity and swelling, patchy fiber distribution)

were noted in the other patient. The patient with CIDP had absent

sudomotor responses and absent IENFD at all tested sites. The seven

patients with POTS and abnormalities on QSART had all normal

IENFD but two (29 %) had significant morphologic abnormalities

(fiber segmentation and swelling). The patient with POTS and distal

sensory symptoms had normal QSART and normal IENFD.

Conclusions: Neuropathic POTS comprises a limited neuropathy with

almost exclusive involvement of autonomic fibers, while involvement

of somatic fibers is seen in a number of patients with secondary

causes of orthostatic tachycardia and more widespread autonomic

neuropathies. The findings support the hypothesis of neuropathic

POTS as part of a spectrum of autonomic disorders resulting in

orthostatic tachycardia with mild, selective autonomic neuropathy on

one side and widespread autonomic and somatic fiber loss on the

other side of the spectrum. Supported by NIH (NS32352,

U54NS065736, K23NS075141, UL1RR24150) and Mayo Funds.

Poster #57

Origins of cognitive dysfunction in postural tachycardia

syndrome

A.C. Arnold1, K. Haman2, E.M. Garland1, S.Y. Paranjape1,

C.A. Shibao1, I. Biaggioni1, D. Robertson1, S.R. Raj1

1Division of Clinical Pharmacology, Vanderbilt University School

of Medicine, Nashville, TN, USA; 2Department of Psychiatry,


252 Clin Auton Res (2012) 22:207–258

123

Background: Postural tachycardia syndrome [POTS] is a disabling

condition characterized by excessive tachycardia upon standing, in

the absence of blood pressure changes. Although the underlying

pathophysiology remains unclear, upright posture produces numerous

symptoms in POTS including profound impairments in cognitive

function. However, the nature of these cognitive impairments has not

been fully described. Thus, we tested the hypothesis that POTS

patients will exhibit greater abnormalities on neuropsychiatric testing

relative to controls.

Methods and Results: A series of validated neuropsychiatric tests

were administered to 23 POTS patients and 21 age-, gender- and

intelligence-matched healthy subjects [HS] in seated and standing

positions. Orthostatic heart rate increases were greater in POTS

(34 ± 11 vs. 17 ± 9 bpm; p \ 0.01), with no differences in pressure.

Attention and cognitive processing speed were reduced in seated

POTS patients (Ruff 2&7 t-scores: POTS 40 ± 9 vs. HS 49 ± 8;

p \ 0.01; Symbol Digit Modalities Test t-scores: POTS 45 ± 12 vs.

HS 51 ± 8; p \ 0.01), despite similar psychomotor speed between

groups. Measures of executive functioning were also lower in seated

POTS patients suggesting difficulties in tracking, mental flexibility

and set-shifting (Trails B: POTS 46 ± 8 vs. HS 52 ± 8; p \ 0.01;

Stroop Word-Color, POTS 45 ± 10 vs. HS 56 ± 8; p \ 0.001).

While groups did not differ in seated memory performance, logical

memory task scores were significantly decreased in POTS upon

standing (Randt short story immediate recall: POTS 10 ± 4 vs.

healthy 13 ± 3; delayed recall: POTS 8 ± 4 vs. healthy 11 ± 4;

p \ 0.01). There were no differences in measures of verbal fluency,

associative memory or working memory between groups in either

posture.

Conclusions: These findings suggest global deficits in attention and

executive processing, even when POTS patients are seated. Impair-

ments in standing semantic memory were also evident, which may

contribute to postural cognitive dysfunction. Further studies are

needed to localize specific brain regions of pathology in order to

develop treatments for cognitive dysfunction in POTS.

Poster #58

Pharmacological I(f) pacemaker current inhibition

in a human postural tachycardia syndrome (POTS)

model

C. Schroeder1, K. Heusser1, D. Rieck2, F.C. Luft3, J. Tank1, J. Jordan1

1Institute of Clinical Pharmacology, Hannover Medical School,

Hannover, Germany; 2Institute for Biometry, Hannover Medical

School, Hannover, Germany; 3Experimental Clinical Research

Center, Medical University Charite, Berlin, Germany

Background: POTS is characterized by excessive cardiac sympathetic

drive during orthostatic stress. The condition can be mimicked in

healthy subjects through pharmacological norepinephrine reuptake

transporter (NET) inhibition. The final pathway mediating the

tachycardia at the level of the sinus node is beta-adrenoceptor stim-

ulation and subsequent I(f) pacemaker current modulation.

Aim: To compare hemodynamic responses to placebo, I(f)-blockade,

and beta1-adrenergic blockade in a human POTS model.

Methods: We included 19 healthy men in a three-way double-blind,

randomized, and crossover trial. Subjects ingested ivabradine

(7.5 mg), metoprolol (95 mg), or matching placebo 13 and 1 h before

testing. Additionally, subjects ingested the selective NET inhibitor

reboxetine (4 mg) on all 3 occasions. We measured heart rate, blood

pressure, and cardiac stroke volume (impedance cardiography) in the

supine position and during graded head-up tilt.

Results: Compared with placebo, ivabradine had no effect on supine

heart rate, blood pressure, or cardiac stroke volume, while metoprolol

decreased supine heart rate (p \ 0.001) and blood pressure

(p \ 0.001). On reboxetine + placebo, upright heart rate was

113 bpm (95 % CI 104–123). Compared with placebo, ivabradine and

metoprolol reduced upright heart rate 12 (95 % CI 4–21, p \ 0.006)

and 21 (95 % CI 13–30, p \ 0.0001) bpm, respectively. The decrease

in stroke volume during head-up tilt was similar between treatment

groups. However, stroke volume and cardiac output at a given heart

rate were decreased with metoprolol, but not with ivabradine.

Orthostatic tolerance—measured as the time to (pre)syncope during

head-up tilt—was not affected by either treatment.

Conclusion: Short-term pharmacological I(f) inhibition with maximal

recommended ivabradine doses ameliorates hyperadrenergic ortho-

static tachycardia elicited by NET inhibition, albeit to a lesser extent

than beta1-adrenergic blockade. At a given heart rate, beta1-adren-

ergic blockade but not I(f) inhibition decreased cardiac stroke volume

and cardiac output. Funded by Deutsche Forschungsgemeinschaft.

Poster #59

Cardiovascular autonomic response to nitric oxide

inhibition in POTS patients

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



Background: Earlier reports associate alterations in nitric oxide (NO)

availability with POTS. Studies of cutaneous microcirculation suggest

decreased NO availability in non-neuropathic POTS, whereas NO

availability is increased or normal in neuropathic POTS patients.

Studies of NO synthase (NOS) polymorphisms also suggest that NO

may play a role in the development of POTS. Despite these reports, it

is not known whether NO abnormalities are merely a biological

marker or they also have clinical significance.

Objective: To investigate the role played by NO in cardiovascular

autonomic control in POTS.

Methods: In a double-blind, placebo-controlled study, NO inhibition

was performed in 24 POTS patients (20F, 4M, 32 ± 9 years) and 10

healthy control subjects (7F, 3M, 28 ± 7 years). Placebo and NO

inhibition were administered in randomized order on two consecutive

days. Nitric oxide inhibition was achieved by a 15-min loading dose

of 5 mg/kg NG-Monomethyl-L-Arginine (L-NMMA) infusion, fol-

lowed by a maintenance dose of 50 lg/kg/min L-NMMA infusion

throughout the study. The form of placebo administration was iden-

tical with that of L-NMMA. Deep breathing, random breathing,

modified Oxford baroreflex test and tilt-table test were performed

during the study. Changes in autonomic measures such as heart rate

variation with breathing, baroreflex sensitivity (BRS) and hemody-

namic response to tilt test during placebo and NO inhibition were

analyzed by repeated measures ANOVA and unpaired t-test within

and between subjects. Patients and controls were also classified as

neuropathic or non-neuropathic based on IENFD using skin biopsy,

quantitative sensory testing and QDIRT.

Results: Baseline blood pressure was not different between POTS

patients and controls (SBP: 113 ± 9 vs. 112 ± 15 mmHg; DBP:

69 ± 6 vs. 68 ± 5 mmHg), while baseline heart rate was higher in

POTS patients compared to controls (68 ± 12 vs. 59 ± 10 bpm,

P \ 0.01). Patients with neuropathic POTS had higher resting heart

Clin Auton Res (2012) 22:207–258 253

123

rates and blood pressures compared to non-neuropathic POTS and

healthy control subjects (P \ 0.05).

Conclusion: Baseline characteristics were similar between POTS sub-

jects and control subjects, with the exception of resting and tilted heart

rate. Additional baseline differences were noted between subtypes of

neuropathic and non-neuropathic POTS. The effects of NO inhibition on

POTS will be reported at the AAS meeting after study unblinding.

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

Autonomic Dysfunction Center, Division of Clinical Pharmacology,


Objectives: Postural tachycardia syndrome (POTS) is characterized

by a heart rate increase (dHR) C30 beats per min (bpm) within

10 min of upright posture with orthostatic symptoms. However, many

POTS patients show significant increases in heart rate with a 1 min

stand. If POTS diagnostic testing could be performed in \10 min,

clinical efficiency could be significantly increased. We hypothesized

POTS patients would meet the 30 bpm dHR criterion in \10 min.

Methods: Patients with POTS (n = 14, 12F, 37 ± 3 years) and

healthy subjects (n = 15, 13F, 34 ± 2 years) underwent both a 608tilt table test (TILT) and a stand test (STAND) for 10 min each. dHR

was assessed at 1 min intervals for TILT and at 1, 3, 5, and 10 min for

STAND. Data was used to generate the sensitivity (SN) and speci-

ficity (SP) at each time point for dHR C30 bpm.

Results: For TILT, SN increased and SP decreased from 1 min

(SN = 64 %, SP = 93 %) to 3 min (SN = 100 %, SP = 73 %),

when all POTS patients achieved the 30 bpm criterion. SP continued

to decrease over time, and SP = 40 % at 10 min. With STAND, SN

increased but SP decreased from 1 min (SN = 56 %, SP = 73 %) to

10 min (SN = 100 %, SP = 67 %). SN for STAND did not reach

100 % until 10 min.

Conclusions: All POTS patients achieved the 30 bpm criterion within

3 min of TILT, and TILT beyond 3 min decreased specificity. In

contrast, 100 % sensitivity was not achieved with STAND before

10 min. Diagnostic tilt table testing for POTS can be truncated to

3 min without a decrease in sensitivity. This shorter test could allow

for increased clinic efficiency and cost effectiveness, without sacri-

ficing patient care by missing the POTS diagnosis.

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, I. Biaggioni


Vanderbilt University, Nashville, TN, USA

Circulating plasma C-reactive protein (CRP) is elevated in obesity,

induced in part by increased secretion of interleukin-6 (IL-6) derived

from adipocytes. To test the hypothesis that sympathetic activation is

associated with the increase in IL-6 and CRP, we measured these

inflammatory markers in 44 lean (29 ± 2 years., BMI 22.6 ± 0.4)

and 16 overweight or obese (37 ± 2 years., BMI 29.6 ± 0.9) female

patients with postural tachycardia syndrome (POTS), a condition

characterized by increased sympathetic tone, and in 26 lean

(29 ± 3 years., BMI 22.6 ± 0.4) and 19 overweight or obese

(45 ± 2 years., BMI 35.3 ± 1.5) female healthy controls. Compared

to lean controls, lean POTS, overweight POTS and overweight con-

trols had greater sympathetic activity measured by low-frequency

variability of blood pressure (LFSBP, 3.1 ± 0.3 vs. 5.6 ± 0.6,

7.2 ± 1.3, and 7.9 ± 0.7 mmHg2, respectively, P \ 0.01), lower

parasympathetic tone measured by high-frequency heart rate vari-

ability (HFRRI, 1,441 ± 356 vs. 381 ± 65, 425 ± 120 and

440 ± 129 ms2, respectively, P \ 0.01 for lean POTS vs. lean con-

trols), and increased serum levels of IL-6 (2.3 ± 0.4 vs. 4.1 ± 0.5,

4.9 ± 0.9 and 3.9 ± 0.4 pg/mL, respectively, P \ 0.01). CRP, on the

other hand, was increased only in the overweight groups (4.9 ± 1.7

and 3.8 ± 1.0 for overweight POTS and overweight controls) but not

in the lean groups (0.8 ± 0.2 and 0.9 ± 0.2 mg/L for lean POTS and

lean controls, P \ 0.01 for the differences between groups). IL-6 was

very low in 3 patients with dopamine-b-hydroxylase deficiency and

congenital absence of norepinephrine (1.1 ± 0.3 pg/mL), consistent

with sympathetic modulation of this cytokine. We conclude that

sympathetic activation and parasympathetic withdrawal are associ-

ated with increased serum IL-6 levels in POTS patients and controls

with excess weight. The coupling between IL-6 and CRP, however,

requires increased adiposity. These results suggest a non-adipocyte

origin of IL-6 in POTS.

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

Center of Excellence for the Medical Consequences of SCI, James J

Peters VA Medical Center, Bronx, NY, USA

In 1992, Muneta and colleagues reported the clinical utility of

droxidopa to treat hypotension in a 72-year-old female with a T4

spinal cord injury (SCI). In combination with a high sodium diet,

droxidopa (600 mg) reduced the fall in blood pressure (BP) during

seated postures. To date, the BP effect of droxidopa has not been

reported in a sample of individuals with SCI. Therefore, we sought to

determine the BP effect of escalating dose of droxidopa (100, 200 and

400 mg) during 3 laboratory visits in hypotensive subjects with SCI.

Nine individuals with SCI participated. The level of SCI ranged from

cervical to low thoracic (C3 to T10) lesions; all were chronically

injured (2–14 years) and non-ambulatory; 8 were motor complete

(AIS A & B). Subjects were hypotensive at baseline (BL: systolic BP:

86 ± 15 mmHg; diastolic BP: 52 ± 9 mmHg); BL BP did not differ

among the 3 visits. Upon supine repositioning prior to drug admin-

istration, BP increased significantly (systolic BP: 101 ± 13 mmHg;

diastolic BP: 62 ± 7 mmHg; p \ 0.0001 vs. seated BL); droxidopa

did not augment this positional increase in BP (systolic BP:

100 ± 23 mmHg; diastolic BP: 62 ± 16 mmHg). Seated BP was

significantly increased from BL after droxidopa in a dose-dependent

manner (100 mg: 94 ± 15/61 ± 8 mmHg; 200 mg: 98 ± 14/

62 ± 8 mmHg; 400 mg: 108 ± 12/68 ± 9 mmHg; p \ 0.0001).

Although the average elevation in seated BP was relatively modest,

mean BP remained significantly increased above BL values for 4 h

after droxidopa administration (systolic BP: 94 ± 16 mmHg,

254 Clin Auton Res (2012) 22:207–258

123

p \ 0.01; diastolic BP: 61 ± 10 mmHg, p \ 0.0001). These pre-

liminary data suggest that low to moderate doses of droxidopa do not

worsen supine increases in BP in persons with SCI. Although drox-

idopa increased seated BP in a dose-dependent manner, subjects

remained relatively hypotensive. Question remains as to the effective

dose of droxidopa that normalizes BP in this population.

Poster #63

Prevalence of orthostatic hypotension in asymptomatic

veterans

J. Wecht, C. Yen, S. Pena, A. Ivan, W. Bauman

Center of Excellence for the Medical Consequences of SCI, James J

Peters VA Medical Center, Bronx, NY, USA

Orthostatic hypotension (OH), defined as a fall in systolic blood

pressure (SBP) C20 mmHg and/or a fall in diastolic blood pressure

(DBP) C10 mmHg within 3 min of assuming an upright position, is

associated with multiple adverse consequences in otherwise healthy

asymptomatic individuals. We aimed to determine the prevalence of

OH in an asymptomatic sample of veterans. Subject recruitment

included 100 veterans, 96 males, with a mean age of 56 ± 14 years,

height of 174 ± 9 cm and weight of 89 ± 18 kg. Individuals were

asked to lie on a clinic table for 10 min during which time BP was

recorded every minute, subjects were then asked to move to the

standing position and BP was recorded each minute for another

10 min. Mean SBP data did not differ between the supine and

standing positions (132 ± 15 vs. 132 ± 18 mmHg); however, DBP

was significantly higher while standing (74 ± 9 vs. 77 ± 11 mmHg;

p \ 0.001). Asymptomatic OH was evident in 27 individuals (27 %:

OH+); within the first 3 min of assuming the standing position SBP

fell an average 32 mmHg (range -20 to -90 mmHg); DBP fell an

average 16 mmHg (range -10 to -55 mmHg). Borderline OH (fall

in BP of 10–19/5–9 mmHg) was evident in an additional 26 subjects

(26 %); 47 % of the subjects studied had no orthostatic fall in BP

(OH-). The OH + group was statistically older than OH- group

(61 ± 12 vs.54 ± 15 years, respectively; p \ 0.05); albeit not old,

and was prescribed more anti-hypertension medications (2.6 ± 2.1

vs. 1.5 ± 1.6, respectively; p \ 0.05). These data suggest a relatively

high prevalence of OH in otherwise healthy, asymptomatic, middle-

aged veterans, which may be attributable to the aggressive treatment

of hypertension by clinicians in the Veterans Affairs healthcare

system.

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

Department of Medicine, Vanderbilt University, Nashville, TN, USA

Orthostatic hypotension is the most disabling symptom of autonomic

failure. Severely affected patients often require medication to coun-

teract the blood pressure fall and to improve pre-syncopal symptoms

on standing. Isolated clinical observations have suggested that the

combination ergotamine and caffeine can be useful in the treatment of

orthostatic hypotension. The aim of this study was to examine the

effect of the combination ergotamine and caffeine on blood pressure

and pre-syncopal symptoms on standing in a group of patients with

autonomic failure. A total of 12 patients participated in this study.

Eight were men and the average age was 64 ± 10 years. The com-

bination ergotamine and caffeine increased seated SBP by 19 mm Hg

compared with placebo (95 % CI: -2 to 40 mm Hg, P = 0.07) and

reduced the orthostatic symptom score by 9 points (95 % CI: 0.9–16,

P = 0.03), compared with baseline. In conclusion, the combination

ergotamine and caffeine could be an alternative therapy for orthostatic

hypotension in patients with autonomic failure.

Poster #65

Abnormal autonomic findings in chronic subjective

dizziness: sympathetic dysfunction or hyperactivity

H. Lee, H.A. Kim

Department of Neurology, Keimyung University School of Medicine,

Daegu, South Korea

Introduction: Dysautonomia is considered as a trigger factor of

chronic dizziness, but there have been few reports about autonomic

findings in patients with chronic dizziness.

Objectives: To investigate the frequency and the specific pattern of

abnormal autonomic finding in chronic subjective dizziness (CSD)

after strictly eliminating other trigger or cause of dizziness.

Methods: From May to October 2011, we prospectively investigated

the patients with CSD at the Dizziness Clinic of Keimyung University

Dongsan Medical Center. For sorting patients with CSD without other

causes or triggers, all patients took a routine medical check-up

including history taking, physical examination, routine blood sam-

pling, electrocardiography, chest X-ray and a detailed neurological

examination, a quantitative audiovestibular testing, brain MRI or CT,

and Symptom Checklist-90-Revised (SCL-90-R). Standardized auto-

nomic function tests were performed including tilt table, Valsalva and

heart rate deep breathing tests. The autonomic data were compared to

these of 38 age-and sex-matched controls.

Results: We identified 18 patients with CSD without other cause of

dizziness. In 12 (67 %) patients, two patterns of autonomic abnor-

mality were found: sympathetic dysfunction including orthostatic

hypotension during tilt table test, reduction of phase II late or sym-

pathetic index 3, or increase of phase II early or pressure recovery

time during Valsalva test (n = 6); sympathetic hyperactivity includ-

ing increased heart rate response during tilt table test or exaggerated

phase IV during Valsalva test (n = 9).

Discussion: Abnormal autonomic findings may in part be associated

with CSD. Sympathetic failure or hyperactivity may be postulated as

a possible mechanism in chronic dizziness.

Poster #66

Neurogenic mechanisms and venous physiology

in patients with orthostatic intolerance

L. Saju1, Z. Sun2, R. Shields3, F. Fouad-Tarazi1

1Department of Cardiovascular Medicine, Cleveland Clinic,

Cleveland, OH, USA; 2Department of Quantitative Health Sciences,

Cleveland Clinic, Cleveland, OH, USA; 3Department of Neurology,

Cleveland Clinic, Cleveland, OH, USA

Clin Auton Res (2012) 22:207–258 255

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Introduction: Accentuated venous pooling (Ac-VP) may be related to

neuro-autonomic or circulatory disturbances and often plays an

important role in orthostatic intolerance (OI). We assessed VP in

patients with OI using a hemodynamic test (HEMO) and correlated

the presence of accentuated VP (Ac-VP) with findings on quantitated

sudomotor axon reflex test (QSART) to determine if abnormal

QSART, as a measure of postganglionic sympathetic sudomotor

function, predicted Ac-VP.

Methods: The patient population (n = 181) included 55 males and

126 females (18–87 years old) with a history of OI. HEMO is a

nuclear test that measures an index of VP as the cardiopulmonary

volume fraction to total blood volume. All patients had HEMO and

QSART (01/2009 to 01/2010). Ac-VP and adequate VP (Ad-VP)

were defined according to lab standards. Patients were divided

between Ac-VP and Ad-VP and normal (NL) and abnormal (AB)

QSART. Association between VP and QSART was assessed using X2

test. A logistic regression model was used to assess the relationship

between HEMO response and QSART while controlling for age and

gender.

Results: 6 patients had Ad-VP + AB QSART, 74 patients had Ac-

VP + AB QSART, 23 patients had Ad-VP + Nl QSART, and 78

patients had Ac-VP + Nl QSART. Ad-VP patients were more likely

to have Nl QSART than Ac-VP patients (79.3 vs. 51.3 %, p = 0.005).

Ac-VP patients were more likely to have AB QSART than Ad-VP

patients (48.7 vs. 20.7 %, p = 0.005). After controlling for age and

gender, Ac-VP patients were more likely to have AB QSART than

Ad-VP patients (odds ratio: 3.401 [1.294, 8.943], p = 0.013).

Conclusion: Ac-VP in OI patients is often associated with sympa-

thetic hypofunction. Thus, assessing VP with QSART may help

define the pathophysiology of the VP and OI and provide information

helpful in guiding therapeutic interventions.

Poster #67

Mechanisms underlying the relationships

between cardiovascular dysfunction and fall

susceptibility in older adults

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

Department of Biomedical Physiology and Kinesiology, Simon Fraser

University, BC, Canada

Objectives: Cardiovascular impairments are a risk factor for falls.

However, we need an improved understanding of the precise rela-

tionships between cardiovascular disease and fall susceptibility. The

primary aim of this study is to evaluate the role of impairments in

blood pressure and cerebral hemodynamics in falling risk in a cohort

(n = 59) of long-term care residents.

Method: We used portable equipment installed in two long-term care

facilities to assess residents’ beat-to-beat blood pressure control in

response to orthostatic stress while simultaneously monitoring cere-

bral blood flow. Medical records were used to assess covariates such

as cognitive function, medication use, and mobility. These data will

be compared to their 1 year retrospective and prospective falling risk

as recorded through incident report forms.

Results: Evaluation of falls within the previous year indicates that

53 % of subjects are previous fallers (1 or more falls in the previous

year). Preliminary data from the cardiovascular risk assessment of 20

subjects indicates that previous fallers have lower resting cerebral

blood flow (difference of 15.9 ± 7.6 cm/s), and greater systolic blood

pressure drops in response to orthostatic stress (difference of

11.5 ± 9.7 mmHg) in comparison to non-fallers.

Conclusions: These preliminary data indicate that differences in blood

pressure and cerebral hemodynamics may influence falling risk in

these elderly individuals. This work has important implications for the

use of noninvasive blood pressure and cerebral blood flow assess-

ments as screening tools to assess risk for falls.

Poster #68

Arterial baroreflex asymmetry: an additional

mechanism of orthostatic insufficiency in patients

with non-cardiac syncope

O.V. Mamontov1, M.I. Bogachev2, E.V. Shlyakhto1

1Almazov Federal Heart, Blood and Endocrinology Centre, Saint-

Petersburg, Russian Federation; 2Radio Systems Department SPb

Electrotechnical University

Orthostatic syncope genesis in patients without obvious heart disease

is often unclear, even after becoming a specialized survey. We sug-

gested that in some patients the syncope is associated with the

asymmetry of arterial baroreflex (ABR) indicated by the discrepancy

between its activation (AF) and deactivation functions (DF).

Aim: assessing neurogenic regulation of the circulation in patients

with a positive tilt-test (TT), dependent their ABR activation and

deactivation functions discrepancy.

Patients and methods: The study included 74 patients without significant

cardiovascular disease, with syncope confirmed by TT (Italian protocol).

Mean age was 41.5 ± 18.8 years. During TT hemodynamics were

recorded using blood pressure monitor (Finometer-PRO) and ECG. Also

Valsalva maneuver and hand-grip test (HGT) were performed. ABR was

evaluated using the first differences time-domain method (AF and DF

separately), and the asymmetry coefficient (AC) defined as

[(DF - AF) 9 2/(DF + AF))] 9 100 % was calculated.

Results: The average AC value was about 25 %. We found that

patients with asymmetric reflex (AR) (with AC was above 25 %, n = 36)

were older than patients with AC below 25 % (n = 38): 52.7 ± 16.9 %

versus 30.8 ± 13 %, p \ 0.001. They also had lower AF: 7.2 ± 4.4

versus 13.6 ± 7.6 ms/mm Hg, p \ 0.001, whereas the DF didn’t differ:

12.1 ± 6.8 and 13.5 ± 8.4 ms/mm Hg, p [ 0.05. Heart rate reduction

(vagal activation indicator) in presyncope was lower in AR group: -

17.1 ± 23.8 versus -39.7 ± 25.7 beats/min, p \ 0.001. AC also varied

in different types of syncope: cardioinhibitory 16 ± 15 %, mixed

13 ± 5 %, vasodepressor 32 ± 8 %, and progressive orthostatic hypo-

tension 47 ± 8 %, F = 4.4, p \ 0.01. Diastolic blood pressure response

to HGT was lower in AR group: 13.4 ± 4.8 vs 18.3 ± 8.4 mm Hg,

p \ 0.001, while Valsalva index in these groups remained unchanged:

2.1 ± 1.0 and 2.4 ± 1.3, p [ 0.05.

Conclusion: In patients with noncardiac syncope ABR asymmetry

(due to reduced ABR activation) is common and associated with the

age and predisposition to orthostatic insufficiency. We attribute this

asymmetry to the central modulation of ABR, since Valsalva index

(which indicates the function of cardiac efferent) was similar in both

groups, while blood pressure to HGT response (which indicates

increased central sympathetic vascular tone) was reduced.

Poster #69

Myoclonic jerks in syncope are probably generated

in the cortex

J.G. van Dijk1, R.D. Thijs1, J. van Niekerk1, W. Wieling2,

D.G. Benditt3

256 Clin Auton Res (2012) 22:207–258

123

1Department of Neurology, Leiden University Medical Centre, The

Netherlands; 2Department of Internal Medicine, Academic Medical

Centre, University of Amsterdam, The Netherlands; 3Cardiac

Arrhythmia Center, Cardiovascular Division, University of Minnesota

Medical School, Minneapolis, MN, USA

Diagnosing syncope rests on identifying signs and symptoms. As

severity of cerebral hypoperfusion is reflected in either a slow (S) or a

slow-flat-slow (SFS) pattern, we studied signs of tilt-induced syncope

at a 1 s resolution, using videos, EEG, blood pressure (BP) and heart

rate (HR) to search for signs identifying S and SFS forms. Data were

selected from consecutive tilt table tests. Inclusion relied on uncon-

sciousness on video, BP and HR patterns and S or SFS EEG patterns.

Among clinical events were oral, facial, arm and eye movements, eye

closure, pupils, and sounds. EEG changes lasted longer in the SFS

group (n = 38, 26 ± 9 s.) than in the S group (n = 31, 17 ± 6 s.,

p \ 0.001). Flattening lasted 12 ± 8 s. Duration of the first slow

phase was inversely correlated to the flat phase (p \ 0.001). The most

common events were: eyes open, 93 %; dilated pupils, 77 %; sounds,

61 %; myoclonic jerks, 60 %. The following events occurred at sig-

nificantly different rates in the SFS vs. S groups: eyes open 100 vs.

83 %; sounds 82 vs. 38 %; eyes upwards: 83 vs. 23 %; roving eye

movements: 43 vs. 0 %. Myoclonic jerks occurred almost exclusively

during S phases (p \ 0.001); in fact, ongoing jerks were abolished by

flattening. These findings help differentiate more and less severe

cerebral hypoperfusion in syncope. The absence of myoclonic jerks

during EEG flattening argues against the common belief that they are

due to cortical disinhibition; a cortical origin is likely.

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

Department of Medicine/Diabetes & Endocrinology, Rosalind

Franklin University of Medicine and Science/Chicago Medical

School, and JAL Federal Health Care Center, North Chicago, IL,

USA

Objectives: Although glycemic control is important for prevention of

complications in Diabetes Mellitus (DM), ACCORD and ADVANCE

studies suggest that mortality is higher in patients with extremely tight

glucose control, especially in those with longer DM duration and

already established chronic complications. The increased hypogly-

cemia (HYPO) may be responsible for further autonomic failure

(AN), and sudden death. In addition, Obstructive Sleep Apnea (OSA),

a common condition in DM, and in patients with autonomic neu-

ropathy, is also associated with increased risk of sudden death.

Therefore, we evaluated whether glucoregulation is altered by AN in

older male DM with symptomatic OSA.

Methods: A retrospective chart review of 77 DM [(21 Type 1: 56

Type 2) (age = 63 ± 1.3 years) (BMI = 33.3 ± 0.85) (Duration

DM = 18.0 ± 11.3 years) (HbA1c = 7.95 ± 1.7 %) (BezettQTc =

439 ± 5.0 mm)] identified 29 patients with significant OSA, con-

firmed by polysomnography (AHI = 33.57 ± 6.7), who had unbiased

glucose measurements by 72 h continuous glucose monitoring system

(CGMS). Glucose values were then mathematically transformed

into % time above normal ([140 mg %), % normal (70–140 mg %),

and % below normal (\70 mg %) for 3 time intervals: (T1 =

0600–1800 h); (T2 = 1800–2400 h); (T3 = 2400–0600 h). Glucose

averages for the 72 h time period were also calculated.

Results: Despite similar Hgba1c, OSA patients with QTc \ 440 mm

had more HYPO than those with QTc C 440 mm for all time periods

(T1 = 6 ± 2 vs. 2 ± 1 %; p \ 0.06), (T2 = 7±3 vs. 2 ± 1 %;

p \ 0.05), and (T3 = 7±2 vs. 1 ± 1 %; p \ 0.05), as well as overall

72 h (6 ± 2 vs. 2 ± 1 %; p \ 0.05). Patients without OSA had no

significant differences for HYPO. DM with OSA had a higher BMI

than those without OSA (p \ 0.01).

Conclusions: Glucoregulation in OSA may depend upon the integrity

of the autonomic nervous system, since patients with QTC \ 440 mm

were more likely to be vulnerable to hypoglycemia. Therefore, it is

important to evaluate autonomic function when recommending a

regimen of tight glycemic control in older male DM with OSA.

Acknowledgements: Research sponsored by JAL FHCC

Poster #71

A case of paraneoplastic autonomic failure preceding

Hodgkin’s lymphoma

P. Muppa, C.E. Ramirez, B. Black, D. Robertson, A. Peltier, S.R. Raj,

C. Shibao, I. Biaggioni

Autonomic Dysfunction Center, Division of Clinical Pharmacology,

Department of Medicine, Vanderbilt University School of Medicine,

Nashville, TN, USA

We report a rare case of Hodgkin’s Lymphoma (HL) with initial

presentation of autonomic failure and generalized lymphadenopathy.

A 27-year-old previously healthy male was referred to our clinic with

recurrent syncopal episodes, panic attacks, and constipation. Clinical

examination revealed profound orthostatic hypotension (121/83 mm

of Hg supine and 81/65 mm of Hg after 1 min of standing) with

preserved heart rate response on standing (heart rate increase from 78

to 103 beats per minute). Autonomic function test showed a blunted

sinus arrhythmia ratio of 1.07 (normal [1.2). The patient’s Valsalva

maneuver showed blunted pressor response on phase II late and

phase IV, which is consistent with sympathetic vasoconstrictor fail-

ure and abnormal cardiovagal response. He also had left

supraclavicular lymphadenopathy. Considering initial presentation of

pandysautonomia, the patient underwent screening for autoimmune

autonomic failure. His paraneoplastic panel including antibodies

against autonomic ganglia (Anti-AChR) was negative. He was

diagnosed with sub-acute autonomic failure of unidentified etiology

and prescribed with midodrine. Initial biopsy of lymph nodes from

mediastinum showed reactive hyperplasia, but not lymphoma. The

patient received empirical treatment with plasma exchange, which

gave him a temporary symptom relief for 2 days. His symptoms

(syncopal episodes while sitting, increase in number of panic attacks,

constipation) worsened over the course of next few months, con-

fining him to a wheel chair. Repeat biopsy of lymph nodes from

mediastinum showed classical HL. A paraneoplastic antibody panel

still failed to detect any known autoantibodies. The patient, however,

showed significant clinical improvement after the first cycle of

chemotherapy. Autonomic function test performed 1 year after the

therapy showed normal cardiovagal response, however his sympa-

thetic vasoconstrictor response was still abnormal. We conclude that

this is a rare case of paraneoplastic autonomic failure associated with

Hodgkin’s Lymphoma. Treatment of underlying malignancy with

chemotherapy reversed cardiovagal dysfunction but not sympathetic

failure.

Clin Auton Res (2012) 22:207–258 257

123

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


Objective: To describe the natural disease course of a patient with

seronegative autoimmune autonomic ganglionopathy (AAG) over a

timeframe of 11 years with standardized assessment of autonomic

symptoms and function.

Background: AAG is an immune-mediated autonomic disorder usu-

ally presenting as acute pandysautonomia. The pathophysiology of

this disorder has been well characterized owing to the discovery of

nicotinic ganglionic acetylcholine receptor antibodies in patients with

AAG. Nevertheless, the majority of cases presents without detectable

autoantibodies. Little is known about the long-term course and

prognosis of AAG in general and seronegative AAG in particular.

Methods: We followed a case of seronegative AAG for 11 years, with

serial evaluations from 1 month to 11 years after disease onset. In

addition to routine clinical and laboratory assessments, standardized

autonomic testing (autonomic reflex screen, ARS; thermoregulatory

sweat test, TST; plasma catecholamines) and standardized assessment

of autonomic symptoms and function (composite autonomic symptom

score, COMPASS) were completed.

Results: The patient presented at age 17, 1 month after subacute onset

of abdominal pain, vomiting, bloating, constipation, orthostatic

hypotension, anhidrosis, urinary retention, and erectile dysfunction.

ARS showed generalized autonomic failure with widespread sudo-

motor impairment, severe cardiovascular adrenergic, and moderate to

severe cardiovagal failure (CASS score = 9 out of 10). Treatment

with IVIG resulted in negligible benefit and was discontinued. Upon

re-evaluation 1 year later, most symptoms had modestly improved.

COMPASS score was 61.3 out of 200. CASS score was 7 related to

improvement in cardiovagal function. TST showed global anhidrosis

except for small islands of preserved sweating. Plasma norepineph-

rine (NE) was 199 pg/ml and failed to increment in the upright

position. By 11 years after symptom onset, symptoms had improved

markedly and he had returned to a near normal level of functioning

without further immunomodulatory therapy. Remaining symptoms

included severe erectile dysfunction and lack of thermoregulatory

abilities. COMPASS was improved to 34. There was unchanged

severe sudomotor failure. Cardiovascular adrenergic function showed

only modest impairment, cardiovagal function had returned to nor-

mal. Plasma NE was 94 supine and 149 pg/ml upright.

Conclusions: 11-year follow-up in a young patient with seronegative

AAG revealed definite but incomplete improvement of autonomic

function and symptoms. Sudomotor and erectile function remained

markedly impaired. This report parallels prior short-term follow-up

reports of an overall favorable prognosis but often incomplete

recovery from both seronegative and seropositive AAG. The long

duration of selected deficits would suggest structural impairment

beyond functional blockade of ganglionic function. Supported by NIH

(NS32352, U54NS065736, K23NS075141, UL1RR24150), and Mayo

Funds.

Poster #73

Autonomic function test outcomes in diabetes mellitus

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

Department of Neurology, National Neuroscience Institute, TTSH

Campus, Singapore

We evaluate the autonomic function test outcomes of 123 diabetic

patients referred over a 5 year period from 2007 to 2011. There were

93 patients with abnormal autonomic function testing (75.6 %). In

comparison with the control group (n = 30), there was a significant

difference in resting heart rates (75 ± 13 vs. 70 ± 12, p = 0.05). In

addition, there was a significant difference in the degree of drop of

systolic blood pressures with postural change (36 ± 24 vs.

16 ± 19 mmHg, p \ 0.01), diastolic drop in blood pressure with

postural change (14 ± 12 vs. 3 ± 10 mmHg, p \ 0.01) and diastolic

blood pressure changes with isometric exercise (7.5 ± 7 vs.

15 ± 7 mmHg, p \ 0.01). The most sensitive tests were postural

drop in diastolic blood pressure (95.7 %, PPV 80.2 %) and postural

drop in systolic blood pressure (92.5 %, PPV 78.2 %). Diastolic

blood pressure change to isometric exercise was specific (83.3 %) but

not sensitive (58.1 %) in picking up autonomic dysfunction. None of

the tests had high negative predictive values. In summary, we found

that resting heart rates, postural blood pressure changes and diastolic

blood pressure changes to isometric exercise are useful in assessing

diabetic autonomic neuropathy.

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clinical autonomic research, issue 22, 2012

Health & Medicine

task force

clin auton

bilateral

tavares de

tavares de

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simplied scoring

pulse wave