Download - 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
7:00–7:30 AM Breakfast & ExhibitsImperial Ballroom B
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
7:30–8:00 AM Breakfast & ExhibitsImperial Ballroom B
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
Saint-Petersburg, Russian Federation
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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
Saint-Petersburg, Russian Federation
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
Clinical Neurocardiology Section, NINDS/NIH, Bethesda, MD, USA
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
Clinical Neurocardiology Section, NINDS/NIH, Bethesda, MD, USA
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
Clinical Neurocardiology Section, NINDS/NIH, Bethesda, MD, USA
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
Department of Neurology, Mayo Clinic, Rochester, MN, USA
Background and Objective: Orthostatic intolerance (OI) is increas-
ingly recognized among adolescents but pathophysiologic
mechanisms underlying this condition remain poorly understood.
These patients typically have normal autonomic function as assessed
using standardized autonomic testing. We frequently see high or very
high values for cardiovagal indices in these patients and made the
observation that those with unusually high HR responses to deep
breathing (HRDB) and Valsalva maneuver (VM, Valsalva
ratio = VR) also seem to have the most excessive HR responses to
tilt. Such 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
Department of Neurology, Beth Israel Deaconess Medical Center,
Harvard Medical School, Boston, MA, USA
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
New York University Dysautonomia Center, New York, NY, USA
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
123
Poster #12
The antiemetic efficacy of carbidopa: a randomized,
double-blind, placebo-controlled, crossover study
in patients with familial dysautonomia
L. Norcliffe-Kaufmann, J. Martinez, F. Axelrod, H. Kaufmann
New York University Dysautonomia Center, New York, NY, USA
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
Department of Neurology, Mayo Clinic, Rochester, MN, USA
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
Department of Medicine, Division of Clinical Pharmacology,
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
1Department of Biomedical Physiology and Kinesiology, Simon
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,
Saint-Petersburg, Russian Federation
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
1Department of Biomedical Physiology and Kinesiology, Simon
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
Department of Neurology, Mayo Clinic, Rochester, MN, USA
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,
Vanderbilt University School of Medicine, Nashville, TN, USA
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
Department of Neurology, Beth Israel Deaconess Medical Center,
Harvard Medical School, Boston, MA, USA
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,
Vanderbilt University School of Medicine, Nashville, TN, USA
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
Department of Medicine, Division of Clinical Pharmacology,
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
Department of Neurology, Mayo Clinic, Rochester, MN, USA
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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