Clin Auton Res (2002) 12 : 297–330 © Steinkopff Verlag 2002

ABSTRACTS

Abnormal parasympathetic activity in patients with gastro-esophageal reflux disease (GERD) D Gruosso1, D Cozzolino1, R Torella1,A Rimoldi2, F Perego2, F Pace3, G Bianchi-Porro3, L Montano2, A Malliani2, R Furlan2 1 Dip. Geriatria, Seconda Univ. di Napoli, Napoli, Italy; 2 Med Int. 2, Univ. Milano, Milano, Italy; 3 Gastroenterologia, Univ Milano, Milano, Italy Both sinus node cells and lower esophageal sphincter (LES) are innervated by efferent vagal fibers originating from dorsal motor nucleus and nucleus ambiguus. It is likely that changes in the vagal modulation of the sinus node activity are paralleled by analogous modifications in the parasympathetic control of the LES. Vagal activation increases the number of spontaneous relaxations of LES and keeps it patent for longer time. We tested the hypothesis that GERD is characterized by an abnormal autonomic modulation consisting in a vagal predominance. Twelve patients with GERD (Los Angeles, grade A) and 14 healthy controls were studied in recumbent position before and after a standardized meal (ham and cheese sandwich plus 250 ml of water). Power spectrum analysis of RR variability provided the markers of vagal (high frequency component, 0.25 Hz, HFRR) and sympathetic (low frequency component, 0.1 Hz, LFRR) modulation of the sinus node activity. Plasma pancreatic polypeptide (PP) assessed the vagal activation after meal. Before meal, heart rate, arterial blood pressure and respiratory activity were similar in both GERD and control subjects. PP was 31.7 ± 6 pmol/l in GERD and 40.2 ± 7 pmol/l in Controls. The spectral marker of cardiac vagal modulation HFRR was higher (50.7 ± 4 normalized units, n. u.) and LFRR lower (38.6 ± 5 n. u.) in patients with GERD than in controls (23.8 ± 3 and 71.3 ± 3 n. u., respectively). After meal, HFRR decreased in both groups but was still higher in GERD (30.6 ± 6 n. u.) than in control subjects (15.1 ± 2 n. u.). PP increased compared to pre-meal condition in the two groups and reached higher values in GERD (146.6 ± 25 pmol/l) than in controls (72.8 ± 13 pmol/l). Thus, GERD seems to be associated with predominant vagal activity. This abnormal autonomic profile by promoting LES relaxation and increasing the time available for gastro-esophageal passage might play a pathogenetic role in sustaining the mechanism of reflux.

The effect of intra-duodenal glucose on muscle sympathetic nerve activity (MSNA) is attenuated in older subjects NP van Orshoven1, LJ van Schelven1, PAF Jansen1, M Horowitz2, LMA Akkermans1, AC van Huffelen1, PL Oey1 1 University Medical Center Utrecht, Utrecht, The Netherlands; 2 Royal Adelaide Hospital, Adelaide, Australia

Recent studies indicate that in healthy older subjects the magnitude of the postprandial fall in blood pressure (BP) induced by intraduodenal glucose infusion (IDGI) is related to the rate of caloric delivery [1]. We have now evaluated the effect of IDGI on muscle sympathetic nerve activity (MSNA), BP (Finapres), and heart rate (HR) in young and older subjects. Methods: in 8 young healthy volunteers (4 men, 28.5 ± 2.8 year SEM) and 5 older healthy volunteers (4 men, 75.8 ± 2.1 year) the parameters were measured during a 30 min baseline period (intraduodenal infusion of 0.9 % saline) followed by 60 min IDGI (25 % glucose; 3 kCal/min) (see Table). Results are summarized in the table (mean ± SEM). In the young subjects IDGI was associated with increases in HR and MSNA, and a minor decrease in BP. The progressive increase in MSNA was evident at 30 min. In the older subjects HR also increased during IDGI, but systolic BP fell considerably more and there was no change in MSNA. Conclusion: (i) IDGI causes a blood pressure fall in older as well as young healthy subjects, (ii) in young subjects IDGI of as little as 60 kCal of glucose in 20 minutes stimulates MSNA and (iii) in the older subjects the MSNA response is attenuated and associated with a substantial fall in systolic BP. The latter mechanism is likely to be important in the etiology of postprandial hypotention. Reference 1. O’Donovan, Feinle, Tonkin, Horowitz, Jones (2002) Postprandial hypotension in response to duodenal glucose delivery in healthy older subjects. J Physiol 540 (Pt 2): 673–679

Water – A Thermogenic Drug? Jens Jordan1, Jochen Steiniger1, Uta Hille2, Jens Tank1, Friedrich C. Luft1, Michael Boschmann2 1 Franz Volhard Clinical Research Center, Humboldt University, Berlin, Germany; 2 German Institute for Human Nutrition (DIFE), Potsdam, Germany Water drinking elicits a profound pressor response in patients with autonomic failure. The response may be mediated through sympathetic activation. We tested the hypothesis that the water drinking induced sympathetic activation might increase metabolic rate. Protocol 1: In 10 healthy subjects (5 males, 28 ± 2.4 years, 171 ± 3.6 cm, 64 ± 4.7 kg) we measured metabolic rate in a whole-room indirect calorimeter (metabolic chamber). After a baseline period of 60 minutes, subjects drank 500 ml water (21°C) within one minute. Protocol 2: In 9 subjects, we inserted two microdialysis catheters in abdominal adipose tissue. Dialysate [ethanol], [glycerol], and [lactate] were measured before and after water drinking to assess changes in blood flow (ethanol dilution technique), lipolysis, and glycolysis, respectively.

Table to van Orshoven et al.

Young (n = 8) Old (n = 5)

∆° Syst BP [mmHg]

∆Mean BP [mmHg]

∆HR [BPM]

Minimum values

0–30 min

30–60 min

0–30 min

30–60 min

0–30 min

30–60 min

–5±2 –15±5*

–4±2 –2±1

–5±2* –5±1*

+3±2 +2±1

+6±2* +4±1*

+2±1 –0±2

+8±2* +1±2

∆ = differences between mean over baseline and mean over selected half hour of IDGI. ∆° = differences between minimum in baseline and minimum in IDGI. * = significant (p < 0.05) difference from zero.

∆MSNA [Burst/Min]

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Protocol 1: Before water drinking, resting metabolic rate was 4.49 ± 0.29 kJ/minute. Water drinking increased metabolic rate to a maximum of 1.19 ± 0.18 kJ/minute (27 ± 5.2 %) above the baseline level after 40–50 minutes (p < 0.001). The respiratory quotient increased 12 % with water drinking. Protocol 2: Ethanol ratio, [dialysate glycerol], and dialysate [glucose] did not change. However, dialysate [lactate] increased from 0.3 ± 0.04 mM at baseline to 0.42 ± 0.08 (p < 0.01) 60 minutes after water drinking. We conclude that water drinking elicits a rapid increase in energy expenditure fueled mainly by an increase in carbohydrate oxidation. The time course of the effect parallels the time course of plasma norepinephrine concentration and sympathetic nerve traffic. The effect of water on energy expenditure should be recognized as a confounding factor in metabolic studies.

Insight Into the Mechanism of Cerebral Blood Flow Regulation Giris Jacob1, Shachar Lavi2 Recanati Autonomic Dysfunction Center, Medical Center, IIT-Technion, Haifa, Israel

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2

Cardiology, Rambam

Introduction: From animal studies emerged that nitric oxide is necessary to maintain CO2 – mediated cerebral blood flow regulation (CBF, chemoregulation). However, it does not participate in the pressor autoregulation (mechanoregulation). We tested this hypothesis in seventeen healthy subjects. Methods: Peak velocity (PV), diastolic velocity (DV) and mean velocity (MV) were measured by Trans Cranial Doppler of the middle cerebral artery. Chemoregulation (CO2 vasoreactivity) was assessed during normocapnia, hypocapnia and after 6 min of inhaled mixture of O2 95 % + CO2 5 %. Mechanoregulation was evaluated with incremental doses of phenylephrine. The protocol was repeated during the infusion of nitroprusside (NP) after reaching a steady state of drop in systolic BP by 10 mmHg. Estimated regional cerebrovascular resistance was calculated as CVR = MAP/MV (MAP = mean arterial pressure). Results: During NP infusion MAP decreased by 7 mmHg. Concurrently there was a significant decrease in cerebrovascular resistance as estimated by CVR (1.38 ± 0.08 to 1.29 ± 0.09 ; p = 0.001) ensuing in unaffected cerebral velocity indices. Phenylephrine (25–250 µg) caused an increase in BP in a dose response fashion before and during NP infusion. Despite these change in BP with and without NP, PV, DV and MV remained unaffected. During hypoventilation (EtCO2 ~ 24 mmHg) CVR increased by 71 ± 6 % (p < 0.001), PV and DV decreased significantly (by –27 ± 2 % and –43 ± 2 % respectively; P < 0.001). NP infusion blunted the vasoconstrictive effect of hypocapnia (CVR went to 57 % ± 5, PV to –23 % ± 2, and DV to –35 % ± 3, P < 0.01 for all). Also, NP augmented the vasodilatory effect of hypercapnia (PV: 20 % ± 2 to 27 % ± 5; P = 0.07, DV: 24 % ± 3 to 29 % ± 5; P = 0.1). Conclusion: Exogenous nitric oxide donor selectively affects the chemoregulation but not the pressor autoregulation of cerebral blood flow in healthy humans.

Cross-Correlation Analysis of Cerebral Autoregulation During Sympathetic Stimulation Shoou-Jeng Yeh1, Chuang-Chien Chiu2 1 Department of Neurology, Cheng-Ching General Hospital, Taichung, Taiwan; 2 Institute of Automatic Control Engineering, Feng, Taichung, Taiwan Objectives and purposes: Time domain cross-correlation analysis of pre-filtered mean arterial blood pressure (MABP) and mean cerebral

blood flow velocity (MCBFV) was applied to assess the cerebral autoregulation (CA) by sympathetic stimulation. Materials and methods: Beat-to-beat time series of spontaneous arterial blood pressure, end-tidal CO2 (Et-CO2) and cerebral blood flow velocity were obtained from 8 young normal volunteers with the Finapres device and the transcranial Doppler for periods of approximately five minutes respectively during the supine position and cold pressor test (CPT). Cross-correlation functions (CCFs) were estimated using a 64 beat wide moving window. Mean CCF patterns were obtained for each subject and for the entire population. The MABP and MCBFV signals were bandpass filtered in the low-frequency range (LF, 0.07–0.15 Hz) and high-frequency range (HF, 0.15–0.40 Hz) before applying CCF for the purpose of studying the effect of different bandwidths on the resulting mean CCFs. Results: MABP increased significantly (85.2 + 11.8 vs 105.9 + 15.7 mmHg, p = 0.002) in CPT but MCBFV and Et-CO2 did not change significantly. The corresponding time lags of the peak values of the MABP-MCBFV CCFs decreased significantly from 2.51 + 1.71 sec in the supine position to 1.21 + 0.77 sec in the LF ranges but not in the HF range. Conclusions: Cerebral blood flow was kept stable despite much increase in MABP by sympathetic stimulation. The decreasing time lag of the CCF peak indicated evidence of the autoregulatory adjustment and a result of the phase-lead property. These data indicate an altered response to keep cerebral autoregulation in CPT and the CCF of prefiltered spontaneous MABP and MCBFV could be a useful tool to estimate the CA dynamic response.

Interictal Dysautonomic in Temporal Lobe Epilepsy Vera Novak1, Robert Cambridge2 Harvard Medical School, Division of Gerontology, Boston, Massachusetts, USA; 2 The Ohio State University, Columbus, Ohio, USA

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Background: Episodic behavior and unexplained loss of consciousness may suggest a wide range of neurological disorders that often require evaluation of autonomic functions. Differential diagnosis of syncope and seizures frequently imposes a major problem. It is not known, if interictal autonomic responses to orthostatic stress are affected in the temporal lobe epilepsy. Methods: We studied 11 patients with temporal lobe epilepsy and compared them to the patients with mild dysautonomia due to orthostatic tachycardia (N = 15), vasodepressor syncope (N = 17) and 13 healthy controls. The diagnosis of temporal lobe epilepsy was based on the clinical presentation of complex partial seizures (with or without secondary generalization) and confirmed by abnormal EEG. All epilepsy patients were seizure-free. Heart rate (HR) and beat-to-beat blood pressure (BP) were monitored during supine rest and head-up tilt at 80° up to 20 minutes. Initial five minutes of stable recordings during tilt were analyzed. Results: Mild dysautonomia was found in the epilepsy group. Heart rate during tilt was increased in the epilepsy group compared to controls (min –1 p < 0.02, min –2 p < 0.002, min –3 p < 0.002, min –4 p < 0.001 and min –5 p < 0.0003). As expected, in the orthostatic tachycardia group heart rate was elevated in supine rest (p < 0.01), and increased higher with the tilt-up compared to the control group (min –1 p < 0.02, min –2 p < 0.0002, min –3 p < 0.00001, min –4 p < 0.00 001 and min –5 p < 0.00001). No significant differences were found between the epilepsy and tachycardia groups. Similarly, no significant difference was found between the syncope and control groups. Orthostatic heart rate declined in the syncope group and was lower compared to the tachycardia group at min –4 (p < 0.05) and min –5 (p < 0.03) of the tilt-up. Slower HR and lower diastolic BP during tilt-up (p < 0.05) differentiated syncope patients from other groups. Conclusions: Interictal evaluation of autonomic functions in temporal lobe epilepsy have revealed the presence of mild dysautonomia with a orthostatic tachycardia.

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Individual Differences in Neural Control of the Heart Moderates the Effect of Stress on Neuropsychological Performance AL

Hansen1, B

Johnsen1, JJ

III2, JF

Thayer2

Helge Sollers Bergen, Bergen, Norway; 2 National Institute on Aging, Baltimore, Maryland, USA 1 University of

Heart rate variability (HRV) has been used to index neural control of the heart in a variety of settings. Recent work has also indicated that HRV is associated with activity of the prefrontal cortex as measured by neuroimaging, pharmacological blockade, and performance on neuropsychological tasks. The present experiment sought to extend this prior work by investigating the effects of stress, induced by threat of electric shock, on the relationship between HRV and neuropsychological performance. Sixty healthy males and females in the Norwegian Navy underwent a series of neuropsychological tasks designed to index delayed response and working memory performance as well as non-delayed responses and vigilance. The former tasks have been associated with activity in the prefrontal cortex. HRV was monitored continuously during a pre-task baseline, the task performance, and a post-task recovery. Participants were divided into two groups (Low HRV and High HRV) based on their resting HRV. Half of each of these groups performed the neuropsychological tasks under threat of electric shock and half without such threat. Results indicated that performance on the delayed response and working memory tasks were significantly reduced in the Low HRV group compared to the High HRV group under threat of shock (p’s < 0.05). Threat of shock did not differentially affect performance of the two groups on the non-delayed response and vigilance tasks. The present results replicate and extend the prior findings. Moreover, they suggest that individual differences in neural control of the heart as indexed by HRV can moderate the effect of stress on neuropsychological performance. Importantly, these effects were specific to tasks that involved the prefrontal cortex. The implication of these results for the neuropsychological deficits found in a number of diseases of the autonomic nervous system will be discussed.

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The effect of 18 days strict head-down tilt bed rest on leg venous properties and orthostatic tolerance M Bleeker1, J Pawelczyk1, P de Groot1, M Hopman1, B Levine2 Department of Physiology, University Medical Center, Nymegen, The Netherlands; 2 Institute for Exercise and Environmental Medicine, Dallas, Texas, USA

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Veins play an important role in cardiovascular homeostasis by both passively (conduit function) and actively (venomotor function) facilitating venous return which determines cardiac filling pressure. In humans, microgravity such as head down tilt bed rest, induces orthostatic intolerance. Purpose: To assess the effect of 18 days of strict head-down tilt bed rest on leg venous properties. In addition, we hypothesize that the magnitude of these leg venous changes is related to orthostatic intolerance. Methods: Eleven healthy subjects (10 men, 1 woman), mean age 24 ± 6 years participated in the study. Before and after 18 days of 6° head down tilt bed rest, mercury strain gauge venous occlusion plethysmography was used to assess leg venous vascular characteristics. Results: Leg venous compliance was significantly decreased after 18 days bed rest (pre: 0.048 ± 0.007 ml/100 ml/mmHg, post: 0.033 ± 0.007 ml/100 ml/mmHg, p < 0.01). Venous flow resistance in the leg increased significantly after bed rest (pre: 1.73 ± 1.08 mmHg/ ml/100 ml/min, post: 3.10 ± 1,00 mmHg/ml/100 ml/min, p < 0.05). Orthostatic tolerance, which was assessed by increasing LBNP levels until symptoms of pre-syncope occurred and expressed as cumulative stress index (negative pressure x time), decreased in all subjects after bed rest (pre: 932 mmHg·min, post: 747 mmHg·min). These changes in orthostatic tolerance were not related to changes in venous vascular compliance. Conclusion: this study demonstrates that after bed rest leg venous compliance is reduced and venous outflow resistance is enhanced.We were unable to relate any changes in leg venous vascular properties to measures of orthostatic tolerance, therefore alterations in venous compliance do not to play a major role in orthostatic intolerance after bed rest.

Vestibulosympathetic Reflex During Mental Stress J Carter1, W Cooke1, C Ray2 1 Michigan Technological University, Houghton, Michigan, USA; 2 Penn State College of Medicine, Hershey, Pennsylvania, USA

Comparison of muscle sympathetic outflow between patients with postural tachycardia syndrome (POTS) and healthy subjects

Increases in sympathetic neural activity occur independently with either vestibular or mental stimulation, but it is unknown whether sympathetic activation is additive or inhibitive when both stressors are combined. The purpose of the present study was to investigate the combined effects of vestibular and mental stimulation on sympathetic neural activation and arterial pressure in humans. Muscle sympathetic nerve activity (MSNA), arterial pressure, and ECG were recorded in 10 healthy volunteers in the prone position during 1) head-down rotation (HDR), 2) mental stress (MS; using arithmetic), and 3) combined HDR and MS. HDR significantly (P < 0.05) increased MSNA (9 ± 2 to 13 ± 2 bursts/min). MS significantly increased MSNA (8 ± 2 to 13 ± 2 bursts/min) and MAP (87 ± 2 to 101 ± 2 mmHg). Combined HDR and MS significantly increased MSNA (9 ± 1 to 16 ± 2 bursts/min) and MAP (89 ± 2 to 100 ± 3 mmHg). Increases in MSNA (7 ± 1 bursts/min) during the combination trial were not different from the algebraic sum of each trial performed alone (8 ± 2 bursts/min). We conclude that the interaction for MSNA and arterial pressure is additive during combined vestibular and mental stimulation. Therefore, vestibular- and stress-mediated increases of MSNA appear to occur independently in humans. Support by NIH, AHA, NASA, and NSBRI.

I Bonyhay1, JA Taylor2, W Farquhar2, R Freeman1 1 Center for Autonomic and Peripheral Nerve Disorders, Beth Israel Deaconess Medical Center, Department of Neurology, Harvard Medical School, Boston, Massachusetts, USA; 2 HRCA Research and Training Institute, Harvard Medical School, Boston, Massachusetts, USA Objective: To compare directly measured baseline sympathetic activity and baroreflex mediated sympathetic responses between POTS patients and healthy subjects. Background: The sympathetic nervous system plays an important role in the pathophysiology of POTS. Increased sympathetic activity and/or deficient neurotransmission mechanisms are among the alterations implicated in this disorder.Despite this,little is known about the sympathetic neural outflow in these patients. Methods: Baseline muscle sympathetic nerve activity and baroreflex mediated sympathetic responses were measured from the peroneal nerve using microneurography in 9 female POTS patients and 10 age-matched healthy female subjects. Nitroprusside (NTP) induced blood pressure fall was used to estimate of sympathetic baroreflex responses. Results: Baseline sympathetic burst frequency was similar in patients and controls (20 ± 8.2 vs. 24 ± 11.4 burst/min, P = ns). Since pa-

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tients had significantly higher resting heart rate (77 ± 13.7 vs. 61 ± 10.1 beat/min, P < 0.001) burst incidence for 100 heart beats was also calculated. This was significantly less in patients (27 ± 9.9 vs. 39 ± 14.3 burst/100 heart beat, P < 0.05).While NTP injection resulted in similar decrease in diastolic blood pressure in patients and controls (18 ± 3.9 vs. 18 ± 4.2 mmHg) the increase in sympathetic activity was higher in POTS patients. The relative increase in both burst frequency (1.9 ± 0.46 vs. 1.4 ± 0.37, P < 0.05) and burst incidence (1.7 ± 0.35 vs. 1.3 ± 0.51, P < 0.05, respectively) was significantly higher in POTS patients over the pressure fall. However, the relative increase in average burst area was not different between the groups (2.5 ± 1.07 vs. 2.3 ± 1.24, P = ns). Conclusion: POTS patients have lower baseline muscle sympathetic outflow but increase sympathetic activity more than healthy subjects in response to baroreceptor unloading. The higher increase in sympathetic activity in POTS patients compared to controls mainly manifests as a greater increase in burst incidence and not in burst area. The lower baseline sympathetic activity and increased baroreflex responsiveness in POTS patients, mostly ascribable to changes in sympathetic burst incidence, may be the result of impaired distal sympathetic neural function, abnormalities in sympathetic-neurovascular transmission or increased central sympathetic baroreflex gain.

Baroreflex Response of Muscle Sympathetic Activity to Diastolic BP in Patients with Vasovagal Syncope D Jardine, J Sutherland, S Bennett, C Frampton, I Crozier Department of Cardiology, Christchurch Hospital, Christchurch, New Zealand Baroreflex control of heart rate and blood pressure [BP] are transiently overridden during vasovagal syncope [VVS] and patients may be predisposed to recurrent episodes because of permanently abnormal baroreflex function. Vasoconstriction mediated by muscle sympathetic nerve activity [MSNA] is the most important mechanism for maintaining blood pressure [BP] during orthostasis. We therefore measured MSNA burst area and diastolic BP responses to one minute ramps of hypotension induced by rapid injections of nitroprusside [NP]. We compared 13 normal subjects [mean age 50.5 ± 5 yrs] to 20 patients with VVS [mean age 48.4 ± 5 yrs] and a positive tilt test [mean syncope time 24 ± 2 min]. In normals, diastolic BP decreased by 15.9 ± 2 mmHg following 112 ± 8 µg of NP and MSNA increased by 359 ± 40 %. In patients with VVS, diastolic BP decreased by 15.5 ± 2 mmHg following 109 ± 10 µg of NP and MSNA increased by 409 ± 35 %. Ratios of %MSNA increase to %diastolic BP decrease were similar between groups: 4.4 ± 0.6 in normals versus 4.9 ± 0.4 in patients [P = 0.4]. Regression slopes of MSNA versus diastolic BP were similar between groups: 17.5 ± 3 [burst area/mmHg] versus 28.8 ± 5, [P = 0.09, –0.7 > R > –1.0]. There was no evidence for a negative correlation between MSNA versus DP regression slopes and age [P = 0.5, R = 0.1, or absolute decrease in diastolic BP [P = 0.3, R = 0.4]. Patients with recurrent VVS do not have decreased MSNA responses to a rapid decrease in BP. VVS is a transient disorder of BP control which may override the normal baroreflex control mechanisms.

Arterial Compliance – Adrenergic Influence and Findings in Patients with Orthostatic Intolerance W Singer, P Low Mayo Clinic, Rochester, Minnesota, USA Objective: To evaluate alpha- and beta-adrenergic influence on arterial compliance using measurements of pulse wave velocity (PWV), and to apply the findings to patients with orthostatic intolerance (OI). Background: PWV is a classical physiologic tool to assess arterial compliance and Windkessel function. A decrease in arterial compliance results in an increase of PWV and vice versa.Although the Windkessel function is known as one of the main parameters affecting tissue blood flow, a systematic assessment of the influence of the sympathetic nervous system on arterial compliance is lacking. The sympathetic nervous system appears to play a significant role in the pathophysiology of OI. Hyperadrenergic symptoms, excessive phase IV of the Valsalva maneuver, abnormalities of norepinephrine spillover, betareceptor-hypersensitivity as well as the treatment effect of beta-blockers are findings supporting this theory. If the sympathetic nervous system has significant effects on arterial compliance, this parameter might be abnormal in OI with consequences for blood flow to various tissues in these patients. Design/methods: Using EKG and continuous blood pressure recordings, central pulse wave latency and PWV were derived from the time delay between R-wave peak of the EKG and the nadir of the subsequent pulse wave derived from finger or wrist. In part one of the protocol we assessed the influence of alpha- and beta-receptor blockade and stimulation in a total of 14 healthy controls (12 female, 30.8 ± 7.5 years). Following periods of supine rest, phentolamine (10 mg; n = 4), propranolol (10 mg; n = 4), phenylephrine (200mcg, n = 5) and isoproterenol (0.03 mcg/kg/min; n = 5) were given intravenously. In part two of the protocol we compared PWV in 8 healthy controls (7 female, 29.1 ± 9.4 years) and 9 patients with OI (8 female, 31.7 ± 9.4 years) in the supine and 70 degree head-up tilt position. Results: Alpha- and beta-adrenergic blockade resulted in mild, non-significant changes of PWV (phentolamine tended to increase, propranolol to decrease PWV). The effect of phenylephrine was a modest but significant increase of PWV (3.43 ± 0.12 vs. 3.65 ± 0.21, p = 0.03), while isoproterenol lead to a dramatic increase of PWV (4.15 ± 0.29 vs. 5.33 ± 0.31, p < 0.001). There was no difference in PWV between OI patients and controls, neither for the supine nor for the tilted position (supine: 4.12 ± 0.34 vs. 4.12 ± 0.21, tilt: 3.93 ± 0.35 vs. 3.91 ± 0.29, both p > 0.90). Conclusions: The sympathetic nervous system has significant influences on arterial compliance. In particular, beta-receptor stimulation leads to a dramatic increase of PWV and therefore decrease of arterial compliance. Even though the adrenergic system seems to play a significant role in OI, abnormalities of arterial compliance do not appear to be involved in the pathophysiology of OI. Supported by NIH (PO1 NS32352) and Mayo GCRC (M01 RR00585).

Continuous Monitoring of Cardiac Output and Muscle Sympathetic Activity During Tilt-Induced Syncope D Jardine1, J van Lieshout2, J Sutherland1, S Bennett1, I Crozier1 Department of Cardiology, Christchurch Hospital, Christchurch, New Zealand; 2 Academic Medical Center, Amsterdam, The Netherlands 1

Vasovagal syncope is thought to be mediated primarily by sympathetic withdrawal and vasodilation. In some patients, hypotension may also be mediated by decreased cardiac output [CO] but the relative importance of both mechanisms remains uncertain.We observed tilt-induced syncope in 14 patients with a history of recurrent vaso-

13th International Symposium on the Autonomic Nervous System

vagal syncope [mean age 49 ± 6 yrs, mean time to syncope 17 ± 3 min]. We measured brachial artery blood pressure [MBP] and derived CO from the BP waveform using Modelflow. Heart rate [HR] and muscle sympathetic nerve activity [MSNA] were continuously monitored. Baroreflex slopes were calculated by plotting change in MSNA against diastolic BP during Valsalva phase IIa. During the final 3 minutes before syncope, MBP decreased from 96 ± 4 mmHg to 70 ± 4 [P = 0.001]; MSNA from 41 ± 6 burst area/min to 21 ± 3 [P = 0.001] and HR from 78 ± 5 bpm to 68 ± 5 [P = 0.02]. CO decreased by 11.9 ± 5 % and total peripheral resistance [TPR] by 12.3 ± 5 %. Correlation analysis demonstrated that ∆MBP was more strongly related to ∆CO [R = 0.6, P = 0.04] than ∆MSNA [R = 0.08, P = 0.8]. In 50 % of patients, CO decreased severely [> 15 %] and this appeared to be mediated by decline in HR rather than stroke volume. ∆MSNA and baroreflex slopes were not related to ∆CO or ∆MBP. A rapid decline in CO may be the major determinant of blood pressure in some vasovagal reactions. The response of MSNA to hypotension mediated by decreased CO does not appear to be different to that in patients who maintain CO during VVS.

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that changes in resistance vessel diameter might play a role in these deficits. Methods: To investigate this possibility we used lower limb ischemia and reactive hyperemia to produce maximal arteriolar vasodilation in 12 patients aged 13–19 years compared to 9 healthy age matched controls. An occlusive blood pressure cuff was inflated to 20 mmHg above systolic blood pressure for 4 minutes. On release, blood flow was measured by venous occlusion strain gauge plethysmography. Flow measurements began 3 seconds following release of the ischemic cuff and were obtained every 25 seconds thereafter. Results: Are shown in the figure. There was no significant difference in peak flow between patients and controls. There was a slower decrease (p < 0.05) in flow back towards baseline in OI patients. Separate assessment of maximum skin flow at 42 °C was measured in a subgroup of 4 OI patients and 3 control subjects similarly showed no difference in cutaneous peak flow.

Hemodynamic and Sympathetic Responses to Buttock Clenching in Patients with Vasovagal Syncope I de Bruin1,D Jardine2,J Sutherland2,S Bennett2,W Wieling1,I Crozier2 1 Department of Internal Medicine, Academic Medical Center, Amsterdam, The Netherlands; 2 Department of Cardiology, Christchurch Hospital, Christchurch, New Zealand Muscle tensing in the lower limbs has been demonstrated to increase blood pressure in patients with autonomic failure and recurrent vasovagal syncope [VVS]. The mechanism for this is thought to involve an increase in cardiac output [CO] secondary to venoconstriction in the lower limbs. We measured digital artery blood pressure by Finapres [MBP], heart rate [HR] and muscle sympathetic nerve activity [MSNA] continuously during a 2 minute buttock clenching maneuver performed in the head-up 60 degree position. CO, stroke volume [SV] and total peripheral resistance [TPR] were derived from the BP waveform using Modelflow. Ten studies were undertaken in 9 patients [mean age 52 ± 7] with VVS. Baroreflex slopes [MSNA versus diastolic BP] were calculated from hypotensive responses to IV nitroprusside. MBP increased from 104 ± 3 mmHg to 114 ± 4 [P = 0.008] and CO increased from 4.2 ± 0.4 L/min to 4.6 ± 0.4 [P = 0.01]. HR and SV tended to increase from 87 ± 6 bpm to 92 ± 7 [P = 0.1] and from 49 ± 4 ml to 51 ± 5 [P = 0.4]. TPR and MSNA remained constant at 1630 ± 126 dyne. s.cm3 [P = 0.7] and between 238 ± 80 burst area/min and 241 ± 65 [P = 0.9] respectively. No correlation was observed between CO and MBP [R = 0.2, P = 0.6]. Increases in MSNA [% baseline] were correlated to the baroreflex slopes [R = 0.6, P = 0.07, slope = 0.3]. Transient increase in blood pressure during buttock clenching is secondary to increased CO and stable TPR. Increased CO is achieved by the maintenance of SV during a tachycardic response. The MSNA response to isometric activity is probably limited by baroreflex mechanisms.

Normal Reactive Hyperemic Response in Chronic Orthostatic Intolerance J Stewart, K Kyle New York Medical College, Valhalla, New York, USA Chronic orthostatic intolerance is characterized by exaggerated tachycardia and lightheadedness, associated with failure of appropriate arterial vasoconstriction in the lower extremities when upright. Vasoconstrictor deficits are also observed supine. We hypothesized

Conclusions: No difference in maximal lower limb flow occurs in OI patients compared to control. This suggests that maximal resistance vessel diameter is not different in patients and that vessel diameter changes alone cannot account for abnormalities in vasoconstriction.

Water drinking improves cerebral autoregulation in healthy subjects V Bush1, C Schröder2, L Norcliffe1, J Jordan2, J Tank2, R Hainsworth1 1 Institute for Cardiovascular Research, Leeds, W. Yorkshire, UK; 2 Franz-Volhard Clinical Research Center, Berlin, Germany Drinking 500 ml water improves orthostatic hypotension in patients with autonomic dysfunction. In this study we determined the effects of water in healthy volunteers and, in addition to assessing effects on orthostatic tolerance, we also assessed its effects upon cerebral blood flow autoregulation. Tests were carried out on 13 healthy volunteers (aged 31 ± 2 years) who drank 500 ml (test) or 50 ml of water (control) in a randomised crossover study on different days. We recorded finger arterial pressure (Finapres), brachial pressure (autoinflating sphygmomanometer), and heart rate (E. C. G.). End-tidal CO2 was recorded using a nasal catheter. Orthostatic tolerance was assessed using the “Leeds” test, which determines time to presyncope during head-up tilt with added lower body suction [1]. Middle cerebral artery blood flow velocity (MCV) was recorded using transcranial Doppler. The efficiency of cerebral autoregulation was quantified as the correlation coefficient (R) of the relationship between MCV and cerebral arterial pressure (CBP), both of which were determined as pressure changed during the orthostatic stress. The results showed that drinking water (500 ml compared to 50 ml) resulted in significantly greater orthostatic tolerance (36 ± 3

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compared to 31 ± 3 min, p < 0.001). The index of autoregulation (R for regression of MCV on CBP) was significantly less after water (0.52 ± 0.08 compared to 0.72 ± 0.06, p < 0.05). A low value of R indicates good autoregulation. The autoregulation index (R) was significantly inversely correlated with orthostatic tolerance (p < 0.05). Water had no effect on end-tidal CO2; this implies that changes in cerebral autoregulation are independent of CO2 levels. These experiments have demonstrated an improved orthostatic tolerance after drinking water. This was associated with an improvement in cerebral flow autoregulation. Reference 1. El-Bedawi KM, Hainsworth R (1994) Clinical Autonomic Research 4: 239–244

Water Drinking Acutely Improves Orthostatic Tolerance in Healthy Subjects C Schröder1, V Bush2, L Norcliffe2, F Luft2, J Tank2, J Jordan2, R Hainsworth1 1 Franz-Volhard Clinical Research Center; Medical Faculty of the Charité; Humboldt-University, Berlin, Germany; 2 Institute for Cardiovascular Research Background: Orthostatic symptoms and syncope are common, even in apparently healthy subjects. In patients with severe autonomic dysfunction, water drinking elicits an acute pressor response and improves orthostatic hypotension. In 13 healthy subjects (9 men, 4 women, 31 ± 2 yrs) we tested the hypothesis that water drinking also improves orthostatic tolerance. Methods: In a randomised, controlled, crossover fashion, subjects ingested 500 ml (test) and 50 ml of water (control) 15 min before head-up tilt on different days. Finger blood pressure, brachial blood pressure, heart rate, and thoracic impedance were measured. Orthostatic tolerance was determined as the time to presyncope during a combined protocol of 20 min of 60° head-up tilt alone, followed by additional increasing steps of lower body negative pressure (–20, –40, and –60 mmHg for 10 min each or until presyncope). Results: After drinking 50 ml water, orthostatic tolerance was 31 ± 3 min. Drinking 500 ml water improved orthostatic tolerance by 5 ± 1 min (range –1 to + 11 min, p < 0.001). After drinking 500 ml water,supine mean blood pressure increased slightly (p < 0.01) due to increased peripheral resistance (106 ± 1 % of baseline value compared to 100 ± 1 % after 50 ml water, p < 0.01). With head-up tilt, drinking 500 ml water blunted both the increase in heart rate (+ 10 ± 1 bpm, compared to + 16 ± 2 bpm after control, p < 0.01) and the decrease in stroke volume (–38 ± 3 %, compared to–45 ± 2 % with 50 ml water, p < 0.01). Conclusion: Water drinking elicits an acute hemodynamic response in healthy subjects. These effects are associated with a marked improvement in orthostatic tolerance.

Water Ingestion as Prophylaxis Against Syncope CC Lu1, A Diedrich1, CS Tung2, B Black1, S Paranjape1, V Watkins1, J Jordan3, D Robertson1 1 Vanderbilt University, Nashville, Tennessee, USA; 2 National Defense Medical Center, Taipei, Taiwan; 3 Franz Volhard Klinik, Berlin, Germany Syncope may occur in normal subjects in response to orthostatic or emotional stress, but determinants of such susceptibility are poorly understood. We postulated that water ingestion would enhance or-

thostatic tolerance and tested this using head-up tilt, which can often induce presyncope or syncope in normal subjects. Methods: Twenty two healthy subjects on a 150 mEq sodium diet, aged 18 to 42 years, with no history of syncope underwent head-up tilt testing at 60 degrees for 45 minutes or until hypotension/bradycardia supervened. Subjects were randomized to either tilt with water or tilt alone with the alternative in a second test on a different day.Water (16 oz) was given orally 5 minutes prior to head-up tilt. Subjects underwent continuous monitoring of heart rate, blood pressure (Finapres), cardiac output and total peripheral vascular resistance (impedance cardiography). Plasma catecholamines and their metabolites were monitored during the study. Results: The average time subjects tolerated head-up tilt was 24 % longer after water (mean (SD), 40.9 (8.0) vs 33.0 (14.2) minutes; p < 0.01). During the first 30 minutes of tilt, 10/22 subjects without water experienced bradycardia/hypotension, but only 1/22 who had ingested water. Water drinking attenuated the heart rate increase associated with tilt (p < 0.05), while accentuating the tilt-induced increase in total peripheral resistance (p < 0.001). Plasma epinephrine doubled prior to syncope and increased four-fold with syncope (p < 0.01). Water ingestion attenuated the decrease in plasma dopa at 10 and 15 min after head up tilt. Conclusions: We conclude that acute water ingestion strongly enhances tolerance of upright posture and attenuates the tachycardia associated with upright tilt. This effect is mediated by increases in peripheral vascular resistance, and possibly attenuation of posture-related plasma volume fall. Water ingestion may thus constitute a simple and effective means of prophylaxis against vasovagal reactions in healthy subjects, for example, after blood donation, bedrest, or in astronauts after return from microgravity.

Sodium lactate infusion in patients with orthostatic intolerance and orthostatic tachycardia. R Khurana Union Memorial Hospital, Baltimore, Maryland, USA Background: Patients with orthostatic intolerance and orthostatic tachycardia (OIOT) might be misdiagnosed due to panic symptoms and elevated Acute Panic Inventory (API) scores (Khurana et al. Neurology 2002; 58: A346). We hypothesized that sodium lactate infusion (SLI), known for inducing panic symptoms (PS) in patients with panic disorder (PD), will not precipitate PS in OIOT patients. Aim: To compare API responses between OIOT patients and control subjects to head-up tilt (HUT) and SLI. Methods: Nine OIOT patients and nine controls, without prior history of PD, participated in an IRB-approved, prospective, placebocontrolled study. Panic symptoms were assessed using API questionnaire: participants rated each of the 17 symptoms on a scale of 0 (none) to 3 (severe). An increase in API score > 13 or an absolute score > 20 separates panic subjects from controls (sensitivity 84 %, specificity 100 %). The participants answered the questionnaire after each 10 minute dextrose infusion (DI) and after each of the two provoking stimuli: a 10-minute 90° head-up tilt and a 20-minute infusion of 10 ml/kg body weight of 0.5 M sodium lactate (DL). Non-parametric Wilcoxon two sample exact test for median (rank sums) was used to compare API scores for patients and controls using SAS. Results: Controls: API median scores were 0.00 during pretilt DI and after HUT. Scores increased from 1.00 during the prelactate DI to 6.00 after SLI. Patients: API median scores increased from 3.00 during pretilt DI to 11.00 after HUT. Scores increased from 3.00 during prelactate DI to 13.00 after SLI. Three OIOT patients showed increased API scores > 13 and one developed a panic attack following SLI. Two controls had increases > 13. This was not significantly different from the OIOT patients (p < 0.05 %, Exact test). Conclusions: (i) Sodium lactate infusion may not distinguish

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OIOT patients from normal controls. (ii) Increase in API scores following SLI in four out of nine OIOT patients suggests that OIOT and PD share some common predisposition. Supported by: Medstar Research Institute

Yohimbine: Tachyphylaxis With Chronic Use S Kansal, S Paranjape, A Diedrich, V Watkins, RM Robertson Division of Cardiovascular Medicine, Vanderbilt University, Nashville, Tennessee, USA Yohimbine is an α2-adrenoreceptor antagonist that enhances blood pressure (BP) and heart rate (HR) responses to sympathetic stimuli. In studies of neurally mediated syncope, we studied the acute and chronic effects of yohimbine on tilt tolerance, catecholamine levels and hemodynamic responses. Methods: Patients were selected if they had neurally mediated syncope on at least two separate 75° head-up tilt table tests prior to enrollment. If tilt tolerance improved after yohimbine (5.4 mg) as compared with placebo, patients took yohimbine 5.4 mg tid for 5 days followed by a repeat tilt table test. Tilt tolerance in minutes, BP, HR and plasma catecholamine levels were assessed after 30 minutes supine and throughout tilt. Results: In 2 patients, acute treatment with yohimbine increased plasma NE levels supine by 64 % and 187 % and at tilt termination by 112 % and 59 %. The rise in HR with tilt increased by 45 % and 72 %, with a significant improvement in tilt tolerance (from 19 and 27 min to 43 and 45 min). However, after five days of yohimbine, tilt tolerance returned to baseline duration and neither patient completed the entire tilt. Plasma norepinephrine levels had returned nearly to baseline and HR and BP response to tilt were not significantly different from baseline. Although yohimbine enhances sympathetic outflow and tilt tolerance acutely, this effect may be attenuated in patients with neurocardiogenic syncope after continuous administration. As these are doses commonly used in autonomic failure, potential tachyphylaxis should be assessed in these latter disorders as well. The mechanism of tachyphylaxis has not yet been defined, but may be related to enhanced metabolism of yohimbine, to up-regulation of central α2 adrenergic receptors, or to down-regulation of peripheral (heart and blood vessel) α1 adrenergic receptors.

Norepinephrine Transporter Function and Autonomic Control of Metabolism M Boschmann1, C Schröder2, NJ Christensen3, J Tank2, FC Luft2, AM Sharma2, J Jordan2 1 Deutsches Institut für Ernährungsforschung, Bergholz-Rehbrucke, Brandenburg, Germany; 2 Franz Volhard Clinical Research Center, Humboldt University, Berlin, Germany; 3 University of Copenhagen, Denmark Genetic variability, numerous medications, and some illicit drugs influence norepinephrine transporter (NET) function; however, the metabolic consequences of NET inhibition are poorly understood.We performed a randomized, double-blind, cross-over trial in 15 healthy subjects who ingested 8 mg of the selective NET inhibitor reboxetine or placebo. Protocol 1: Energy expenditure and substrate oxidation rates were determined by indirect calorimetry before and during intravenous infusion of 0.25, 0.5, 1, and 2 µg isoproterenol/min. Protocol 2: Adipose tissue metabolism was studied by microdialysis before and during local isoproterenol perfusion. Protocol 1: At rest, energy expenditure and substrate oxidation rates did not differ between reboxetine and placebo treatment. At 1 µg/min isoproterenol, energy expenditure was significantly increased with both reboxetine and

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placebo treatment. However, carbohydrate oxidation rate was significantly increased with reboxetine compared to placebo. Reboxetine increased basal plasma concentrations of free fatty acids (0.71 ± 0.11 vs. 0.48 ± 0.10 mmol/l in men, p < 0.01, 1.07 ± 0.24 vs. 0.55 ± 0.03 mmol/l, p < 0.05 in women). This effect was maintained during isoproterenol infusion. Protocol 2: Baseline and isoproterenol-stimulated blood flow, glucose supply and metabolism, and lipid mobilization were significantly higher in adipose tissue with reboxetine treatment compared to placebo. Microdialysate norepinephrine concentrations were not increased with reboxetine. We conclude that acute NET inhibition increases adipose tissue glucose uptake and metabolism.While lipid mobilization is increased, overall lipid oxidation is decreased during beta-adrenergic stimulation. This effect cannot be explained by increased systemic or adipose tissue norepinephrine concentrations. Instead, NET inhibition may sensitize adipose tissue to beta-adrenergic stimulation.

Transnasal iontophoresis, a non-invasive brain drug delivery system that bypasses the blood-brain barrier EN Lerner1, GR Stewart2 1 Lerner Medical Technology Ltd., Amsterdam, Noord-Holland, The Netherlands; 2 Genzyme Corporation, Framingham, Massachusetts, USA Introduction: Pharmacological treatment of many central nervous system (CNS) diseases is limited due to the presence of the bloodbrain barrier. The olfactory pathway has been suggested as an alternative drug administration route to the CNS that circumvents the blood brain barrier. However, brain uptake of large, hydrophilic compounds such as peptides and proteins via this route is limited. The present study examined whether transnasal iontophoresis can be used to increase drug delivery to the CNS of a rabbit. Methods: The study included a total of 45 rabbits that were treated with the following test substances: Methylprednisolone hemisuccinate (n = 8 animals), Methotrexate disodium (n = 5 animals), Tacrine hydrochloride (n = 14) and Octreotide acetate (n = 18 animals). Drug formulations were delivered via electrodes placed deep within the nasal cavity with a current strength of 3.0 mA. No current was applied to the nasal electrodes of the control animals. The treatment was stopped after 60 minutes. Brain, spinal cord, plasma and spinal fluid samples were examined for their drug content. Tacrine hydrochloride and Octreotide acetate were also administered in exsanguinated rabbits, in order to exclude systemic drug transport to the brain. The nasal mucosa was collected for histopathological examination to assess the safety of transnasal iontophoresis. Results: Brain levels of all tested substances were significantly higher following transnasal iontophoresis compared to the controls. Plasma levels of all test drugs were not significantly different between the two treatment groups. Transnasal iontophoretic delivery of both Tacrine hydrochloride and Octreotide acetate in exsanguinated rabbits resulted in significant increased brain levels compared to the controls. Histopathological examination of the nasal mucosa revealed no current induced epithelial damage. Conclusion: The results indicate that transnasal iontophoresis is a potentially useful and safe drug delivery technique to the brain.

Vasomotor Mapping of the Ventro-Lateral Medulla S Patel, J Nicholas, E Sribnick, B Egan Medical University of South Carolina, Charleston, South Carolina, USA Vascular compression of the ventro-lateral medulla (VLM) has been postulated to produce neurogenic hypertension. In animals, both

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sympatho-excitatory and inhibitory neurons lie close to the VLM surface. In humans similar neurons have been histochemically located in the retro-olivary sulcus (ROS). To confirm their physiological role in vasomotor control, we electrically stimulated the ROS in subjects undergoing posterior fossa surgery for other reasons. IRB approved consent had been signed. Ipsilateral ROS was stimulated (bipolar electrode) with 30 second stimulation trains of constant current pulses (3.0 mA; 100 Hz; 0.1 msec pulse duration). Heart rate (HR) and blood pressure (BP) were recorded continuously starting at baseline (10 seconds before the stimulus) for a minute after the stimulus. 17 stimulation responses were recorded from 6 subjects. Subject A: 4 ‘sham’ (electrode placed/no stimulation) 4 stimulation responses recorded during the 30 second stimulation (Table). All stimulation responses were significantly different from sham recordings. Repeat stimulations (same parameters) produced similar responses. Stim #

max∆HR

max∆sBP

max∆mBP

1 2 3 4 Sham Sham Sham Sham p values (stim vs sham)

–6 –3 –6 –3 0 1 –1 0 0.008*

–10 –8 –7 –9 2 –1 –2 0 0.000*

–8 –6 –6 –7 1 –1 –1 0 0.000*

3 subjects had consistent responses with similar repeated stimulations in the ROS. 2 subjects had similar responses to singles stimulations in the ROS. One subject showed no response to olive stimulation. Hypotensive/bradycardic responses during stimulation were followed in each case by a reflex hypertensive response. This technique of mapping the vasomotor areas of the human VLM proved to be safe and reproducible. The human ROS may be important in cardiovascular regulation. Stimulations now being done with measures of sympathetic tone (microneurography) and cardiovascular responses should yield further data to understand the role of the human VLM in vasomotor control.

Cerebral Vasoregulation and MRI at 8 Tesla in Hypertension and Stroke V Novak1, A Abduljalil2, H Nagaraja3, A Chowdhary4, B Farrar4, J Braun4, P Novak5, A Slivka4, D Chakeres2, P Robittaile2 1 Harvard Medical School, Beth Israel Deaconess Medical Center, Division of Gerontology, Boston, Massachusetts, USA; 2 The Ohio State University, Dept. of Radiology, Columbus, Ohio, USA; 3 The Ohio State University, Dept. of Statistics, Columbus, Ohio, USA; 4 The Ohio State University, Dept. of Neurology, Columbus, Ohio, USA; 5 Boston University, Boston, Massachusetts, USA Background: To determine if impaired cerebral vasoregulation after stroke predisposes to silent hypoperfusion during orthostatic stress. Methods: We studied 30 control, 30 hypertensive and 20 minor stroke subjects (age 48.3 + 2.3 years) using transcranial Doppler. Bilateral blood flow velocities (BFV) from the middle cerebral arteries, heart rate, blood pressure (BP) and CO2 were obtained during hyperventilation and CO2 rebreathing during supine rest and tilt at 80°. Side-to-side BFV difference, vasomotor range (VMR) and cerebrovascular resistance (CVR) were calculated during normo-, hypoand hypercapnia. Results: Mean BFV were similar between groups in supine position. VMR was reduced in the hypertensive group (p < 0.05) and declined further during tilt (p < 0.01). In the stroke group, BFV dimin-

ished on the stroke side in upright position and BFV asymmetry differentiated stroke patients from the other groups (p < 0.0001). CVR increased (p < 0.0001) and VMR decreased (p < 0.01) on the stroke side during tilt with hyperventilation and CO2 rebreathing. Vasomotor responses were preserved on the normal side. During tilt, BFV difference between the normal vs. stroke side was the largest in strokenormotensive (N = 7) compared to stroke-hypertensive (N = 13) patients and the two other groups (p < 0.0001). Reduced autoregulatory index in the stroke-normotensive patients (p < 0.03), was associated with BFV decline and blunted BP response to tilt (p < 0.0001). 8 Tesla MRI: Axial and sagittal 2D gradient echo were obtained in 15 controls, 6 hypertensive, 4 TIA and 8 stroke subjects (slices 2–5mm, TR = 750–1000ms, TE = 4–15ms, matrix 512512; 10241024, FOV = 2020). Microvasculature and white/gray matter differentiation were visible with resolution 100 µm. Stroke imaging revealed: 1) infarcts in 2 TIA pts; 2) relationship of infarct site to microvasculature; 3) angiomas and small hemorrhages. Conclusion: Cerebral vasoregulation is impaired after stroke and perfusion declines on the affected side during orthostatic stress. High resolution MRI at 8 Tesla revealed silent abnormalities, not apparent on the lower magnetic filed at 1.5 Tesla.

Mechanisms of Sympathetic Activation by Adenosine H Timmers, G Karemaker, W Wieling, J Lenders Department of General Internal Medicine, University Medical Center Nijmegen, Academic Medical Center, Nijmegen, The Netherlands The direct vasodilatory and negative chronotropic effects of adenosine in humans are counterbalanced by a reflex increase in sympathetic nerve traffic. Suggested mechanisms for this reflex include peripheral chemo- and baroreceptor activation. Aim: To assess the relative contribution of peripheral chemoreceptor activation to the increase in muscle sympathetic nerve activity (MSNA) by adenosine. Methods: Finger arterial pressure (Finapres) and MSNA (microneurography) were recorded during steady state infusion of adenosine (140 microgram/kg/min, 5 min) in five patients that had lost carotid chemoreflex function due to bilateral carotid body tumor resection (BCBR, 1m:4 f, 51 ± 11 years) and in 6 healthy controls (2m:4 f, 50 ± 7 years). MSNA responses to sodium nitroprusside injections were assessed for the estimation of baroreceptor mediated sympathetic activation. Results: In response to adenosine, controls show no significant change in systolic/diastolic blood pressure (+ 1.1 ± 2.6/–2.1 ± 2 %), a + 48.2 ± 13.2 % increase in heart rate (p = 0.003) and a + 195 ± 103 % increase in MSNA total amplitude/minute (p = 0.022). In contrast, BCBR patients showed a decrease in systolic/diastolic blood pressure of –14.6 ± 4.9/–17.6 ± 6 % (p < 0.05) an increase in heart rate of + 25.3 ± 8.4 % (p = 0.032) and no significant increase in MSNA (+ 63.1 ± 30.8 %). Hypotension during adenosine infusion in the individual BCBR patients elicited a smaller increase in MSNA than did equihypotensive doses of sodium nitroprusside. Conclusions: Absence of carotid body chemoreflex function following BCBR results in abolishment of a significant MSNA response to continuous adenosine infusion. Carotid chemoreceptor activation is essential for the prevention of vasodilation by adenosine. Blunting of the baroreflex mediated MSNA response to adenosine-induced hypotension suggests a sympatho-inhibitory effect of adenosine on ganglionic neurotransmission.

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Baro- and Chemoreflex Control of Muscle Sympathetic Nerve Activity Following Bilateral Carotid Body Tumor Resection H Timmers, J Karemaker, W Wieling, H Marres, J Lenders Department of General Internal Medicine, University Medical Center Nijmegen, Academic Medical Center, Nijmegen, The Netherlands Efferent sympathetic nerve traffic in humans is under the reflex control of arterial baro- and chemoreceptors. Bilateral carotid body tumor resection causes a permanent attenuation of vagal baroreflex sensitivity and abolishment of carotid body chemoreflex function. It is unknown whether the modulation of sympathetic nerve traffic is affected by carotid body tumor resection as well. Aim: To examine the chronic effects of bilateral carotid body tumor resection on the baro- and chemoreflex control of sympathetic nerve activity. Methods: We investigated five patients that had undergone bilateral carotid body tumor resection (BCBR, 1m:4 f, 51 ± 11 years) and in 6 healthy controls (2m:4 f, 50 ± 7 years). Vagal and sympathetic baroreflex sensitivity were calculated from changes in heart rate and muscle sympathetic nerve activity in response to bolus injections of phenylephrine and nitroprusside. Sympathetic responses to Valsalva’s maneuver, 2 minutes of cold pressor test and end-expiratory apnea were assessed. Results: Both vagal and sympathetic baroreflex sensitivity were lower in patients than in controls. vagal (phenylephrine): 3.68 ± 0.93 versus 11.61 ± 4.72 ms/mmHg, p = 0.011; vagal (nitroprusside): 2.53 ± 1.36 versus 5.82 ± 1.94 ms/mmHg, p = 0.05; sympathetic (phenylephrine): 3.70 ± 2.90 versus 7.53 ± 4.12 total integrated sympathetic activity/100beats/mmHg, p = 0.10; sympathetic (nitroprusside): 3.93 ± 4.43 versus 15.27 ± 10.03 total integrated sympathetic activity/100beats/mmHg, p = 0.028; Valsalva’s maneuver elicited normal reflex changes in muscle sympathetic nerve activity, whereas heart rate responses were blunted in patients. Maximal sympathetic responses to cold pressor test did not differ between groups. Apnea elicited sympatho-excitation in both patients and controls. Conclusions: Denervation of carotid sinus baroreceptors due to bilateral carotid body tumor resection produces a chronic decrease in vagal as well as sympathetic baroreflex sensitivity. However, functional implication of decreased baroreflex sensitivity mainly involves control of vagal outflow. Activation of peripheral chemoreceptors is not essential for sympatho-excitation during voluntary apnea.

Differential Activity-dependent “Resetting” of Subtypes of Isolated Baroreceptor Neurons in Culture V Snitsarev1, C Whiteis1, F Abboud1, M Chapleau2 of Iowa, Iowa City, Iowa, USA; 2 University of Iowa and Veterans Affairs Medical Center, Iowa City, Iowa, USA 1 University

Action potential (AP) discharge of baroreceptor (BR) afferents is inhibited and the pressure-activity curve is shifted to higher pressures after periods of acute hypertension. This BR “resetting” preserves the ability of BR to buffer rapid fluctuations in pressure at the higher prevailing pressure level. The major goal of this study was to determine whether isolated BR neurons in culture “reset” after “conditioning” the neurons with a sustained train of APs. BR neurons were identified among neurons isolated from mouse nodose ganglia by fluorescent DiI applied previously to aortic arch adventitia in vivo.APs evoked by depolarizing current injection (0.5 nA for 1s) were measured with sharp microelectrodes before and after applying a conditioning stimulus (20 Hz current pulses for 1 min). Two types of BR neurons were identified: slowly-adapting neurons that fired repetitive APs during current injection (n = 8) and phasic neurons that fired only 1–3 spikes at the onset of sustained current injection (n = 7). The activity of

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slowly-adapting neurons was significantly inhibited (reset) after (5 ± 2 spikes/s) compared with before (28 ± 14 spikes/s) conditioning (P < 0.05). BR activity recovered within 15 minutes (30 ± 14 spikes/s). In contrast, the activity of phasic neurons was not inhibited after conditioning (1.7 ± 0.3 vs. 1.7 ± 0.6 spikes/s). Phasic neurons also failed to reset when activity was enhanced by applying repetitive brief current pulses (20 pulses of 0.5 nA within 1s) (12.6 ± 1.6 spikes/s after vs. 10.3 ± 2.5 spikes/s before conditioning, n = 5). Conditioning a nodose neuron also suppressed AP discharge in adjacent unconditioned slowly-adapting nodose neurons (n = 4). We conclude: 1) activity-dependent inhibition (resetting) of AP discharge occurs in slowlyadapting BR neurons in culture but does not occur in phasic BR neurons, and 2) the activity-dependent inhibition is mediated in part by an autocrine/paracrine mechanism. These results provide new insights into novel mechanisms of baroreceptor resetting.

Effects of simulated obstructive sleep apnoea on the carotid baroreceptor-vascular resistance reflex V Cooper1, C Bowker2, S Davis2, S Pearson3, M Elliott3, R Hainsworth1 Institute for Cardiovascular Research, 2 Department of Respiratory Medicine, Leeds, West Yorkshire, UK

1

Obstructive sleep apnoea may lead to hypertension. This study was designed to determine whether the changes in inspiratory resistance and asphyxia which occur in this condition can change the gain and/or setting of the carotid baroreflex to maintain arterial pressure at a higher level. In 8 healthy subjects (aged 21–62 years) we changed the stimulus to carotid baroreceptors, using a neck chamber and graded pressures of –40 to + 60 mmHg, and assessed vascular resistance responses in the forearm from changes in blood pressure (Finapres) divided by brachial flow velocity (Doppler ultrasound). Stimulus response curves were defined during (a) sham (no additional stimulus), (b) inspiratory resistance ~ 10 mmHg, (c) breathing asphyxic gas (12 % O2, 5 % CO2), (d) resistance and asphyxia. Sigmoid functions were applied to the curves and maximum differential (equivalent to peak gain) and the corresponding carotid pressure (equivalent to “set point”) were determined. The sham test had no effect on either gain or “set point”. Inspiratory resistance alone had no effect on blood pressure. However, it reduced gain from –3 ± 0.6 to –2.1 ± 0.4 units (P < 0.05) but the curve was not displaced. Asphyxia alone increased blood pressure (+ 7.0 ± 1.1 mmHg, P < 0.0005) and displaced the curve to higher pressures by + 16.8 ± 2.1 mmHg (P < 0.0005), but did not effect gain. The combination of resistance and asphyxia both reduced gain and displaced the curve to higher pressures. These results show that inspiratory resistance decreases the gain of the baroreceptor reflex and in combination with asphyxia also shifts the curve to hypertensive levels. If these changes are sustained they would provide a mechanism linking hypertension to obstructive sleep apnoea.

Selective sympathetic baroreflex impairment induced by norepinephrine transporter inhibition J Tank, A Diedrich, C Schröder, F Luft, J Jordan Franz Volhard Clinical Research Center, Helios Klinikum, Charitè, Humboldt University, Berlin, Germany Norepinephrine transporter (NET) blockade increases the sensitivity to vasoactive medications by an unknown mechanism. The change in sensitivity could be due to an increase in vascular sensitivity or impaired baroreflex blood pressure buffering. We studied the effect of

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the selective NET blocker reboxetine and placebo on blood pressure control in a randomized, double-blind, crossover fashion in healthy male controls (n = 10, age 31 ± 6 yrs). Subjects ingested 8 mg reboxetine or placebo 12 hrs and 1 hr before testing. EKG, brachial, and finger blood pressure, and muscle sympathetic nerve activity (MSNA) were measured. Sympathetic and parasympathetic baroreflex slopes were determined using incremental phenylephrine and nitroprusside infusions. HR and BP increased with NET inhibition (61 ± 2 placebo vs. 68 ± 3 bpm reboxetine,119 ± 4/67 ± 2 placebo vs. 133 ± 6/72 ± 3 mm Hg reboxetine, p < 0.05). The dose to reach BP changes of 12.5 mm Hg was significantly lower during NET inhibition (0.25 vs. 0.68 µg/kg/min phenylephrine and 0.41 vs. 1.13 µg/kg/min nitroprusside, p < 0.01). Baroreflex control of heart rate was similar (15 ms/mm Hg with placebo vs. 16 ms/mm Hg with reboxetine) but reset to higher blood pressure values. MSNA was profoundly reduced at baseline and failed to increase sufficiently during nitroprusside infusion. Reboxetine attenuated BP and MSNA responses to cold pressor testing. We conclude that NET inhibition selectively impairs sympathetic control of vascular tone. Baroreflex heart rate regulation remains intact. The selective loss of sympathetic baroreflex blood pressure buffering is associated with a profound increase in the sensitivity to vasoactive medications.

Baroreflex and Sympathetic Failure in Parkinson’s Disease with Orthostatic Hypotension

Increased Basal Sympathetic Activity with Human Aging is Related to Decreased Arterial Baroreflex Buffering P Parker Jones, D Christou, D Seals University of Colorado, Boulder, Colorado, USA The arterial baroreflex is responsible for short-term control of arterial blood pressure (BP) and exerts a tonic inhibitory influence on sympathetic outflow to the periphery. Physiological aging in humans is associated with a marked increase in basal muscle sympathetic nerve activity (MSNA).We hypothesized that tonic arterial baroreflex buffering (BRB) is reduced with age and is related to the age-associated increase in MSNA. We studied 23 young (25 ± 1 yr, BP = 126/65 ± 2/1) and 16 older (64 ± 2; 126/63 ± 4/1) healthy men before and during ganglionic blockade with trimethaphan. The potentiation of the BP response (i. e., after vs. before the baroreflex was removed with ganglionic blockade) to: a) a 25 µg bolus of phenylephrine (phe) (BRBBOLUS); and b) 6-min incremental doses of phe (slope of ∆ SBP/[phe]plasma; BRBSLOPE) was used to characterize BRB. MSNA was 63 % higher (37.4 ± 1.7 vs. 22.9 ± 2.9 bursts/min, p = 0.003) and BRB was 55–60 % lower (p < 0.001) (BRBBOLUS: 2.1 ± 0.4 vs. 5.1 ± 1.1; BRBSLOPE: 1.6 ± 0.2 vs. 3.5 ± 0.4) in the older men. MSNA was inversely related to BRB (BRBBOLUS: r = –0.57, p = 0.004; BRBSLOPE: r = –0.69, p < 0.001). Adjusting for BRBSLOPE (ANCOVA) reduced the age-related difference in MSNA to 36 %. These findings indicate: 1) tonic BRB decreases with physiological aging in healthy men; and 2) this may contribute to the age-associated elevation in MSNA. Supported by NIH: AG13038, AG06537, AG00828, RR-00051

D Goldstein, S Brentzel, C Holmes, Y Sharabi Clinical Neurocardiology Section, NINDS, NIH, Bethesda, Maryland, USA Background: Recent work has established that orthostatic hypotension occurs commonly Parkinson’s disease (PD), the orthostatic hypotension reflects sympathetic neurocirculatory failure, and the sympathetic neurocirculatory failure reflects loss of cardiovascular sympathetic innervation. PD also commonly involves symptoms suggesting parasympathetic nervous system failure, such as constipation and urinary retention, and patients with PD often have a constant pulse rate, suggesting decreased baroreflex-cardiovagal gain. This study assessed baroreflex cardiovagal and sympathetic function in PD with or without orthostatic hypotension. Methods: Blood pressure and pulse rate during the Valsalva maneuver were used to calculate baroreflex gain and plasma norepinephrine to indicate sympathetic innervation in patients with PD with or without orthostatic hypotension. Plasma DOPA, dopamine, and dihydroxyphenylacetic acid levels were used to indicate production of dopamine from DOPA outside the central nervous system. Results: Mean baroreflex-cardiovagal gain was markedly less in the group with orthostatic hypotension (0.77 ± 0.14 msec/mm Hg, N = 22) than in that without orthostatic hypotension (3.05 ± 0.76 msec/mm Hg, N = 19, t = 2.77, p = 0.009). Mean plasma norepinephrine was also less in the group with orthostatic hypotension (1.44 ± 0.14 nmol/L, N = 19, vs. 2.40 ± 0.26 nmol/L, N = 19, t = 3.28, p = 0.002). Seventeen of 18 patients with orthostatic hypotension had both baroreflex gain less than 1.8 msec/mm Hg and plasma norepinephrine less than 2.3 nmol/L; only 3 of 17 without orthostatic hypotension had this combination (p = 0.000004). For given plasma DOPA levels, the groups with and without orthostatic hypotension did not differ in plasma dopamine and dihydroxyphenylacetic acid levels Conclusions: PD with othostatic hypotension involves both baroreflex-cardiovagal failure and sympathetic denervation. This combination can help explain worsened orthostatic tolerance in PD, especially during levodopa treatment, when extracerebral dopamine could elicit unopposed systemic vasodilation.

Cardiovascular Consequences of the Chronic Increase in Sympathetic Nervous System Activity with Physiological Aging in Humans: Arterial Vascular Alpha-Adrenergic Desensitization D Seals, P Parker Jones University of Colorado, Boulder, Colorado, USA Basal peripheral sympathetic nervous system activity (SNA) increases with physiological aging in adult humans as indicated by greater total plasma norepinephrine spillover in healthy older compared with young men and women. This increase in net systemic SNS activity with age is mediated by increases in SNA to the heart, gut, and skeletal muscle (MSNA). However, little is known about the effects of this chronic elevation in SNS activity on peripheral cardiovascular function. We hypothesized that the tonic increase in SNA with physiological aging would be related to arterial vascular α-adrenergic desensitization. We studied 23 young (mean ± SE age 24 ± 1 years) and 16 older (65 ± 1) healthy men. Arterial vascular α-adrenergic responsiveness was determined by i. v. infusion of phenylephrine (phe) after eliminating baroreflex modulation of vascular tone with ganglionic blockade (trimethaphan). During supine rest, MSNA was ~60 % greater (38 ± 2 vs 24 ± 3 bursts/min, p < 0.001) and venous plasma norepinephrine concentrations were 45 % higher (2.31 ± 0.20 vs. 1.59 ± 0.12 nmol/L, p < 0.005) in the older men. The increase in mean arterial blood pressure per unit increase in plasma concentration of phe (∆MAP/phe) was 35 % smaller in the older men (2.1 ± 0.3 vs 3.2 ± 0.3 U, p < 0.01). Among individual subjects within the pooled study sample, ∆MAP/phe was positively related to basal MSNA (r = 0.62, p < 0.005). Our results are consistent with the hypotheses that: 1) vascular α-adrenergic responsiveness declines with physiological aging in adult humans; and 2) the chronic elevation in SNA with aging contributes to this desensitization of the peripheral vascular α-adrenergic vasoconstrictor system. Support: NIH awards AG06537, AG06537, AG00828, and RR00 051

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Selegiline Mediated Neuroprotection in Dopaminergic Neurons Are Mostly Unrelated to its Inhibition of Monoamine Oxidase B S Sharma1, E Carlson2, M Ebadi1 1 Departments of Pharmacology, Physiology, and Therapuetics, 2 Departments of Anatomy and Cell Biology, University of North Dakota School of Medicine & Health Science, Grand Forks, North Dakota, USA We have investigated the molecular mechanism of neuroprotection by Selegiline, a potent antioxidant and monoamine oxidase B inhibitor, in MPP+-induced model of neurodegeneration in human dopaminergic cell line (SK-N-SH), employing Digital fluorescence microscopy, electron microscopy, and reverse transcription-polymerase chain reaction in mitochondrial genome encoding complex1 activity. MPP+-induced a concentration-and time-dependent reduction in the mitchondrial membrane potential (∆ ψ), which was ameliorated with selegiline (10uM) pretreatment as estimated by JC1 and Decifer fluorochromes. Overnight exposure to very low doses of MPP+ (100 nM) induced significant changes in mitochondrial ultrastructural morphology, characterized by swelling, loss of cristae, and plasma membrane aggregation.At this concentration of MPP+ no significant change in the nuclear morphology as well as nuclear DNA was observed. Mitochondrial genome encoding complex-1 activity was however significantly suppressed in response to overnight MPP+ (100 nM) exposure, while pretreatment with Selegiline (10 µM) attenuated MPP+-induced alteration in the mitochondrial genome. These data suggest that mitchondrial DNA encoding complex-1 activity of the respiratory chain and the mitochondria are highly susceptible to the neurotoxic influence of MPP+, a neurotoxin causing Parkinsonism. Selegline inhibits MPP+ neurotoxicity hence protecting the mitochondrial genome, ∆ ψ, and the ultrastructural morphology by preserving the intramitochondrial redox balance. Supported in part by grants from NINDS No. 2R01NS3456608; and NIA 1R01-AG17-059-04.

Aerobic training and autonomic modulation in AfricanAmerican males A Zion, V Bond, M Bartels, R Sloan, R De Meersman, J Downey Departments of Rehabilitation Medicine and Psychiatry, Columbia University, New York, New York, USA; Department of Medicine, Howard University, Washington, DC

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We examined the efficacy of aerobic training on autonomic mechanisms and blood pressure during psychologic and physiologic stressors in young African-American males with positive and negative history of hypertension. Thirty-two healthy, normotensive AfricanAmerican males between 18–26 years of age met the criteria for positive (n = 16 PFH)) and or negative (n = 16 NFH) family history of hypertension and were randomly assigned to an 8 week exercise training (experimental) or sedentary (control) group. Analysis of variance revealed significant improvements in aerobic capacity (19.3 %), autonomic and blood pressure responses during some of the provocations following the aerobic training period in the experimental group, no such improvements were seen in the posttests of the control group (Table 1). These findings emphasize the prominent role of regular aerobic exercise as a component in the regulation of autonomic mechanisms and the control of blood pressure in young African-American males with positive and negative family-history of hypertension. Supported by VIDDA foundation.

Gender Differences in the Cardiovascular Effects of Norepinephrine Reuptake Inhibition C Schröder1, J Tank1, S Haertter2, F Luft1, J Jordan1 1 Franz-Volhard Clinical Research Center, Medical Faculty of the Charité, Humboldt-University, Berlin, Germany; 2 Neurochemical Laboratory, Department of Psychiatry, University of Mainz, Germany Background: Norepinephrine transporter (NET) dysfunction can contribute to the pathogenesis of orthostatic intolerance.The fact that orthostatic intolerance predominantly affects women might suggest a gender difference in NET function. Methods: In a randomised, double-blind, crossover fashion 24 healthy subjects (12 men, aged 29 ± 2 yrs and 12 women, aged 29 ± 2 yrs) ingested 8 mg of the selective NET inhibitor reboxetine or placebo 12 hrs and 1 hr before testing. Finger blood pressure, brachial blood pressure, and heart rate were measured. After reaching a stable baseline in the supine position, we conducted a graded head-up tilt test. Results: Reboxetine plasma concentration was 230±30 ng/ml in men and 255±28 ng/ml in women (ns). Compared with placebo, NET inhibition íncreased supine blood pressure + 14 ± 3 mmHg in men and + 5 ± 3 mmHg in women (p < 0.05). NET inhibition increased supine heart rate independently from gender (+ 6 ± 2 for men and + 6 ± 3 bpm for women). The increase in heart rate with tilt was identical in men and women with placebo. With NET inhibition, the tilt-induced increase in heart rate was more profound in men

Table 1 Means and SDs in normalized units (nu) for autonomic variables between pre- and post-treatment for controls and trained groups for rest, cold pressure test (CPFoot), color conflict test (CCT), breathing protocol (BRTH), and blood pressure (Table to “Aerobic training and autonomic modulation in African-American males”). HFRR (nu)

Trained REST CPFoot CCT BRTH Controls REST CPFoot CCT BRTH

α-index (LF)

LFSBP (nu)

Blood Pressure (mmHg)

pre

post

pre

post

pre

post

pre

post

29 (14) 28 (16) 22 (9) 11 (9)

31 (13) 27 (17) 25 (8)* 14 (10)*

70 (7) 57 (13) 54 (12) 88 (6)

67 (12)* 53 (17)* 54 (12) 84 (16)*

8 (3) 9 (7) 8 (4) 13 (7)

14 (3)* 16 (4)* 13 (7)* 18 (9)*

118 (17) 143 (21) 139 (20) 114 (14)

118 (16) 134 (20)* 133 (25) 113 (17)

31 (11) 28 (16) 24 (7) 10 (6)

29 (10) 29 (17) 23 (8) 11 (13)

69 (16) 54 (19) 50 (14) 86 (23)

70 (12) 53 (18) 52 (13) 88 (20)

9 (7) 7 (5) 9 (5) 14 (6)

10 (14) 8 (9) 7 (11) 12 (5)

122 (23) 150 (21) 143 (17) 110 (13)

123 (15) 153 (15) 145 (19) 111 (8)

* denotes significant differences from preceding value at a p < 0.05.

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(+ 56 ± 5 bpm, compared with + 42 ± 4 bpm in women, p < 0.001). With placebo, blood pressure was well maintained during head-up tilt in both sexes. With NET inhibition. systolic blood pressure decreased more profoundly with head-up tilt in men (–16 ± 5 mmHg, compared to –5 ± 4 mmHg in women, p < 0.01). Conclusion: Pharmacological NET inhibition resulted in more pronounced hemodynamic changes in men than in women, both, while supine and during head-up tilt. This observation suggests that the contribution of NET to cardiovascular regulation is attenuated in women.

Gene Expression in the Andes and Autonomics at Sea Level O Appenzeller1, T Minko2, V Posharov3, M Bonfichi4, L Malcovati4, L Bernardi4, LJ Gamboa5 1 NMHEMC Research Foundation, Albuquerque, NM, USA; 2 State Univ. of New Jersey, Piscataway, New Jersey, USA; 3 Orchid BioSciences, Inc., Princeton, New Jersey, USA; 4 Univ. of Pavia, Pavia, Italy; 5 Univ. Peruana Cayetano Heredia, Lima, Peru Chronic mountain sickness (CMS), a maladaptation syndrome to chronic hypoxia, occurs in the Andes. Gene expression in Andeans could explain adaptation and maladaptation of the nervous system to hypoxia both of which are relevant to the autonomic nervous system at sea level. Expression of genes responsive to cellular oxygen concentration, hypoxia inducible factor (HIF-1α), 3 splicing variants of vascular endothelial growth factor (VEGF) and von Hippel-Lindau protein (pVHL) was measured by reverse transcription polymerase chain reaction in 12 Cerro de Pasco (CP), Peru, (altitude 4338 m.) normal natives and 15 CMS patients in CP. Thirteen high altitude natives living in Lima and 5 Lima natives were sea level controls.A CMS score (CMSsc) was assigned clinically. Expression was related to the clinical assessment. High expression of HIF-1α and VEGF-121 was found in CMS (P < 0.001). All samples from CP had higher expression than those from Lima (P < 0.001). Expression of HIF-1α and VEGF-121 was related to age (P < 0.001); adjusting for age did not abolish the group effect. Higher CMS-sc was related to expression independent of age (P < 0.001). VEGF-165 and -189 were expressed only in CMS. Altitude birth had no effect on gene expression. pVHL was not quantifiable. HIF-1α and VEGF-121 participate in adaptation to hypoxia. The high levels may explain blood vessel proliferation in Andeans and hold lessons for patients at sea level. VEGF-165 expression, in CMS, shown to contribute to preservation of neuronal function in hypoxic animals, suggests that it may play a similar role in human chronic hypoxia. VHL mutations may mark those destined to develop neural crest tumors (carotid body tumors) which are common in the Andes. Support: NMHEMC Research Foundation & NIH grant IHSEP-02. Thanks to: Clifford Qualls, Ph. D. for statistical analysis, to Alfredo Gamboa, MD, Rosario Tapia & Manuel Vargas MD for help with patient selection and interviews.

Progressive Impairment of Cardiac Complexity in Chagas’ Disease C Morillo, H Leon, J Guzman, M Lindarte, T Kuusella, F Silva Autonomic Function Laboratory, Fundacion Cardiovascular de Oriente Colombiano-Research Institute, Bucaramanga, Santander, Columbia Heart rate complexity assessed by nonlinear dynamics of RR interval (NLDRR) in the different stages of Chagas’ disease (ChD) has not been systematically studied. Objective: To assess heart rate complexity in the different stages of ChD.

Design: Crossectional descriptive cohort study Methods: 60 ChD (59.7 % females) patients with and without clinical disease and 20 (CON) healthy subjects (50 % females) were studied. ChD patients were classified according to the clinical stage: Asymptomatic subjects with normal ECG (ChD1, n = 20), Asymptomatic subjects with abnormal ECG (ChD2 n = 20) and symptomatic subjects with heart failure and/or brady or tachyarrhythmias (ChD3, n = 17). ECG and non-invasive blood pressure (Finapres2300/Colin 9200) were monitored. A 5–10 minute baseline recording of RR interval was performed. Heart rate complexity was assessed by NLDRR indexes, approximate entropy (ApEn20 %) and detrended fluctuation analysis (Alpha1) using winCPRS software (Absolutly Aliens). A ttest or a Mann-Whitney test was used to establish difference between continuous variables, a p < 0,05 was taken as statistically significant. Results: Statistical differences were found in ApEn20 %: CON vs ChD1 (1.13 ± 0.07 vs 1.01 ± 0.17 p < 0.04); CON vs ChD2 (1.13 ± 0.07 vs 1.05 ± 011 p < 0.03); CON vs ChD3 (1.13 ± 0.07 vs 0.92 ± 0.24 p < 0.01) and Alpha1: CON vs ChD1 (1.21 ± 0.22 vs 1.04 ± 0.18 p < 0.02) CON vs ChD2 (1.21 ± 0.22 vs 0.83 ± 0.17 p < 0.01), CON vs ChD3 (1.21 ± 0.22 vs 0.53 ± 0.18 p < 0.01), ChD1 vs ChD2 (1.04 ± 0.18 vs 0.83 ± 0.17 p < 0.01) ChD1 vs ChD3 (1.04 ± 0.18 vs 0.53 ± 0.18 p < 0.01) and ChD2 vs ChD3 (0.83 ± 0.17 vs 0.53 ± 0.18 p < 0.01) Conclusion: Patients with subclinical and clinical ChD have a progressive decrease in heart rate complexity. This alteration can be related to a premature autonomic impairment that contributes to the simplification of cardiac reflex responses and subsequently the alteration of heart rate adaptability to the different physiologic stimulus. NLDRR indexes may be used in the future for clinical staging and risk stratification of ChD.

Cerebral and Cutaneous Blood Flow Fluctuations: A Common Etiology? R Schondorf, J Benoit, R Stein SMBD Jewish General Hospital, Montreal, QC, Canada Fluctuations in cerebral blood velocity (CBV) occur at frequencies similar to those of arterial blood pressure (BP) especially during orthostatic stress. The fact that these coherent signals have a positive phase relationship but an admittance gain below 1 at low frequencies suggest that these fluctuations in CBV are primarily due to cerebral autoregulation. Others have postulated, based on the observed positive phase relationship between CBV and BP, that CBV oscillations are the consequence of centrally generated sympathetic activity directed to cerebral vasculature. This rhythmic sympathetic activity may also imposed on other vascular beds. The current study (n = 19 subjects) compares fluctuations in forearm (FORE) and finger (FING) skin blood flow (non pressure autoregulating vascular beds) with those in CBV and examines their relation to BP. Periodograms of these variables were constructed from data obtained during head-up tilt and coherence, and phase relationships estimated from filtered (0.02–0.8 Hz) data segments (204.8 s). BP and CBV fluctuations had two peaks one at very low frequency (VLF) (0.02–0.04 Hz) and a second at the low frequency (LF) band of 0.06–0.1 Hz with the majority of power concentrated in the LF band. In contrast most of FORE and FING fluctuations occurred in the VLF band. As reported previously, fluctuations in BP and CBV cohered (> 0.5) at frequencies between 0.06 and 0.3 Hz. In contrast, there were no coherent regions between BP and FORE or BP and FING nor did we observe coherence between any combination of CBV, FORE and FING. There was however a high degree of coherence between right and left sided FING fluctuations with zero phase. These data demonstrate that while sympathetically mediated oscillations may be imposed on identical vascular beds this activity though similar in frequency is not ubiquitously imposed on other sympathetically innervated vasculature. The tight relationship between BP and CBV is a consequence of dynamic cerebral autoregulation.

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Orthostatic challenge shows impaired vascular resistance control but normal venous pooling and capillary filtration in Familial Dysautonomia C Brown1, M Hilz1, 2, G Gulli1, M Brys2, B Stemper1, G Welsch1, F Axelrod2 1 Dept of Neurology, University of Erlangen-Nuremberg, Erlangen, Germany; 2 Dept of Neurology, New York University School of Medicine, New York, New York, USA Patients with Familial Dysautonomia (FD) frequently have profound orthostatic hypotension (OH) without compensatory tachycardia.Although the etiology is presumed to be sympathetic impairment, peripheral vascular responses to orthostasis have not been assessed. The aim of this study was to evaluate the control of vascular responses to postural stress in FD patients. Nine FD patients and eleven control subjects had measurements of heart rate, blood pressure, cardiac stroke volume and cardiac output (CO) by impedance cardiography, and calf volume changes by impedance plethysmography while supine and during head-up tilt. During lowering of the legs, we also assessed the venoarteriolar reflex (VAR) by measuring skin blood flow. Head-up tilting for 10-min induced sustained falls in mean arterial pressure in the FD patients but not in the controls. Total peripheral resistance (TPR, mean arterial pressure/CO) increased significantly in the controls (+ 39.8 ± 6.8 %) but not in the FD patients. Calf volume changes during tilting, when normalized for the initial calf volume, did not differ significantly between the patients (4.62 ± 1.99 ml 100 ml–1) and the controls (3.18 ± 0.74 ml 100 ml–1). The venoarteriolar reflex was present in the patients (47.7 ± 9 % decrease in skin blood flow) but was impaired as compared with the controls (80.7 ± 3.4 %) (P < 0.05). The impaired VAR and absent increase of TPR confirm that orthostatic hypotension in FD is primarily due to a lack of sympathetically-mediated vasoconstriction without evidence of abnormally large shifts in blood volume towards the legs during orthostasis. This may be due to the partially preserved venoarteriolar reflex.

Impaired limb blood flow in Familial Dysautonomia B Stemper1, H Marthol2, G Welsch1, C Brown1, M Brys2 Department of Neurology, University of Erlangen-Nuremberg, Erlangen, Germany; 2 Department of Neurology, New York University School, New York, New York, USA

1

Familial Dysautonomia patients present with deficient sympathetic vasomotor control, orthostatic hypotension and recumbent hypertension. These blood pressure fluctuations might contribute to pathological changes in the structure of the vessel walls with increased rigidity and impairment of skin blood flow modulation. The purpose of this study was to evaluate blood flow and vessel reactivity of FD patients noninvasively using venous occlusion plethysmography and postischemic flow measurements in patients and healthy controls. Fifteen FD patients (mean age 29.4 ± 9.9 yrs.) and 15 healthy controls (mean age 30.2 ± 8.4 yrs.) underwent venous occlusion plethysmography (Hokanson Inc.) by inflation of the arm cuff to 50 mmHg. The blood flow was expressed as % volume change/minute during venous occlusion and was calculated as the average arterial influx of eight artifact-free measurements. Postischemic vascular reactivity was determined as the influx peak during the first venous occlusion following 3min of ischemia induced by inflating the arm cuff above systolic blood pressure. Skin blood flow (SBF) was monitored at the index finger pulp before, during and after ischemia (Perimed™). Baseline blood inflow during venous occlusion was lower in FD patients (4.6 ± 1.8 %/min) than in controls (6.1 ± 1.4 %/min; p < 0.05), as was postischemic hyperperfusion (12.8 ± 5 %/min vs. 16.9 ± 2.9 %/

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min; p < 0.05). Before ischemia, SBF did not differ between patients (250.74 ± 293.22 PU) and controls (217.5 ± 102.5 PU). During hyperemia, SBF was significantly higher in patients (964.35 ± 421.67 PU) than in controls (266.1 ± 65.1 PU; p < 0.05). Reduction of overall baseline as well as postischemic influx indicates impaired forearm blood flow that might be due to an increased rigidity of vessel walls resulting from chronic recumbent hypertension. The exaggerated skin perfusion after ischemia can be attributed to the impaired sympathetic innervation of FD patients with deficient vasoconstrictor tone and enhanced vasodilatation due to denervation hypersensitivity of peripheral blood vessels.

Spectral Analysis of Action Potential Trains of Muscle Sympathetic Nerve Activity during Cardiovascular Stimulation in Humans RJ Brychta1, W Charoensuk2, L Bernardi3, R Furlan4, R Shiavi1, AC Ertl5, I Biaggioni5, A Diedrich5 1 Vanderbilt University, Dept. of Biomedical Engineering, Nashville, Tennessee, USA; 2 Mahidol University, Thailand; 3 Università di Pavia, Italy; 4 Università Degli Studi Di Milano, Italy; 5 Vanderbilt University, Autonomic Dysfunction Center, Nashville, Tennessee, USA The application of conventional signal processing methods used to obtain an integrated signal from muscle sympathetic nerve activity (MSNA) reduces the amount of information and may confound the spectral characteristics.We present a novel alternative method of processing the raw MSNA signal using a wavelet transform denoising technique that enables detection of individual action potentials and facilitates spectral analysis. A spike density function is generated from the denoised signal by replacing the detected action potentials with delta functions and convolving with an optimized Gaussian filter. Low (LF; 0.04–0.15 Hz), high (HF; 0.15–0.4 Hz), and cardiogenic (CF; 0.5–3.5 Hz) frequency spectral components of peroneal nerve recordings were studied in seven healthy subjects (3m/4 f, 32 ± 3 years) during lower body negative pressure suction (LBNP) and sinusoidal neck suction (NS). Oscillations of sympathetic nerve firings closely followed the frequency of NS at 0.1 and 0.2 Hz. Resting conditions were characterized by dominant power in LF and limited power in CF. Under –15mmHg LBNP, LF, HF, and CF power respectively demonstrated increases of 100.5 ± 67.3, 448.2 ± 355.3, and 1.3 ± 1.3107 % from baseline levels. Additional increases of 410.4 ± 221.8, 1162.3 ± 710.2, and 2.8 ± 2.3107 % were observed during –30 mmHg.

In conclusion, the spike density function representation allows for a novel and insightful analysis of spectral components of action potential trains in raw MSNA.

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Influence of partial end-tidal carbon dioxide pressure on the postural reduction in cerebral blood velocity R Immink, J Gisolf, G Van Montfrans, J Van Lieshout Cardiovascular Research Institute Amsterdam, Department of Internal Medicine, Amsterdam, Noord Holland, The Netherlands Background and Purpose: Cerebral autoregulation implies that cerebral blood flow (CBF) remains relatively constant by changing vessel diameter over a range of blood pressure (BP). Changes in CO2 tension modify the cerebral vessel diameter. A reduction in CO2 lowers CBF in parallel with the transcranial Doppler-determined middle cerebral artery (MCA) mean blood velocity (Vmean) by cerebral vasoconstriction. In the upright body position the CBF is challenged by a reduction in BP at brain level and a reduction in end-tidal CO2 concentration (PetCO2). The contribution of the postural decrease in PetCO2 to the fall in CBF is, however, unknown. This study addressed the hypothesis that restriction of the postural fall in PetCO2 enhances the MCA Vmean in the upright position. Methods: In 10 healthy young adults, the contribution of PetCO2 and body position on MCA Vmean and systemic hemodynamic variables were evaluated during 5 minutes head-up tilt (HUT) at two levels of PetCO2. During free breathing (HUTFB), the postural fall in PetCO2 was unrestricted and during rebreathing the postural fall in PetCO2 was restricted by the use of an expiratory CO2 rebreathing device (HUTRB). Results: Systemic hemodynamic responses to both tilts did not differ. Upright, during HUTRB, PetCO2 was 4 mm Hg (p < 0.05) higher compared to HUTFB with a smaller postural decline in MCA Vmean during HUTRB when compared to HUTFB (3 ± 4 vs. 10 ± 4 cm·s–1; p < 0.05). After 55 s upright during HUTFB, a steady increase in MCA Vmean of 0.62 cm·s–1·min–1 (p < 0.05) was present in 8 out of 10 subjects. Conclusion: The postural fall in MCA Vmean is related to the PetCO2 in the first minute only. From then on the 4 mm Hg difference in PetCO2 does not affect the MCA Vmean. This questions the contribution of the fall in PetCO2 to the reduction in MCA Vmean during prolonged orthostatic stress.

Incidence and Prevalence of Complex Regional Pain Syndrome Type I (CRPS I) in Olmsted County: An Epidemiologic Study P Sandroni, R McClelland, L Benrud-Larson, P Low Mayo Clinic, Rochester, Minnesota, USA Introduction: CRPS I is a troublesome pain condition that can complicate post-trauma course. Due to many controversial issues about this syndrome, little information is available in regard to its epidemiology. Methods: We reviewed all charts from the period 1989–1999 (source: Olmsted County registry and Rochester Epidemiologic Project) with diagnostic codes compatible with the diagnosis of CRPS I. Inclusion criteria were the current IASP diagnostic criteria for CRPS I. We analyzed demographics and clinical characteristics. Results: Seventy-one cases of CRPS I were identified, resulting in an incidence rate of 5.3/100,000/yr. Eighteen of the seventy-one cases were still unresolved at the time prevalence was calculated, resulting in a value of 13.6/100,000. Women: men ratio was 4:1. Age at onset ranged from 15 to 86, with a mean of 47.8 ± 16.13 SD, median was 47. Upper limbs were affected twice as much as lower limbs. Fracture was the inciting event in 48 % of the cases. Vasomotor manifestations (swelling, color and temperature asymmetry) were the most common, while sweating and trophic changes were the least commonly seen. Concordance between symptom and sign frequency was excel-

lent. Nuclear and autonomic studies were done in half of the cases and were abnormal in 80 % of them. Most patients improved on physical therapy alone (85 %). Sympathetic blocks and prescription medications were required in less than 50 %. No prognostic factor was identified. Disability occurred only in 4 out of 18 still affected cases. Conclusions: CRPS I is a rare pain syndrome, with good prognosis in most cases.

Autoimmune Autonomic Neuropathy S Vernino, P Low, V Lennon Mayo Clinic, Department of Neurology, Rochester, Minnesota, USA Many case of acute or subacute peripheral autonomic failure are associated with antibodies specific for neuronal ganglionic nicotinic acetylcholine receptors. Seropositive patients have a characteristic clinical profile with prominent parasympathetic failure (including impaired pupillary responses), impaired bowel and bladder motility and orthostatic hypotension. The severity of dysautonomia ranges from isolated gastrointestinal dysmotility to complete panautonomic failure. Antibody levels correlate positively with severity of clinical symptoms. The serum of some patients inhibits binding of agonist to the ganglionic receptor in vitro, and clinical findings in several cases suggest impairment of transmission at autonomic ganglia. Our findings indicate that ganglionic AChR antibodies cause dysautonomia by interfering directly with ganglionic synaptic transmission.

Autonomic Function in Scleroderma P Sandroni1, MK Connolly2, P Low1 Mayo Clinic, Rochester, Minnesota, USA; 2 UCSF, San Francisco, California, USA

1

Introduction: Scleroderma is a connective tissue disorder with a presumed autoimmune pathogenesis. Characteristic features of this disorder are skin lesions, Raynaud’s phenomenon and visceral involvement. As scleroderma lesions have a distribution similar to the pseudosyringomyelic pattern seen in some small fiber neuropathies, a possible role of the nervous system in the pathogenesis of this disorder has been suggested. Skin biopsies studies have shown increased density of NPY pos.-fibers, myelin disintegration and occasionally axon fragmentation. Cardiac abnormalities, gastrointestinal dysmotility, abnormal SSR, altered vasomotor responses have been reported as proof of autonomic involvement in this disorder. Aims: To evaluate the severity and distribution of autonomic dysfunction and to compare the distribution of autonomic and skin involvement. Subjects and methods: Ten scleroderma patients (8 women,2 men) participated in the study. They underwent a complete neurologic examination, an autonomic reflex screen (including: tilt, deep-breathing, Valsalva maneuver and QSART), orthostatic catecholamines measurements and thermoregulatory sweat test. Results: Neurologic exam was normal in all except one subject who suffered from myopathy associated to scleroderma. Cardiovagal, adrenergic vasomotor, cardiosympathetic functions and catecholamine measurements were normal. Thermoregulatory sweat test was markedly abnormal in 6/10 subjects, with areas of anhidrosis involving proximal regions (forehead, chest, proximal limbs) and relative distal sparing, including the hands that were the most severely affected body segment in all of them. These 6 patients reported itching in the involved areas to be a major symptom, while the remaining 4 did not. Discussion: Hypo/anhidrosis in scleroderma has a different distribution to that of skin lesions, suggesting that is not simply due to

13th International Symposium on the Autonomic Nervous System

excess of collagen disrupting sweat glands nor nerve function. Itching, which often precedes the appearance of new lesions, indicates Cfiber irritation or dysfunction. This suggests either a pathogenetic role of C-fibers in scleroderma or it may indicate they are targeted by same process that triggers the excess of collagen deposition.

Sweat Output in QSART: Effect of Measurement Time and Waveform Configuration S Jaradeh, T Prieto Department of Neurology, Medical College of Wisconsin, Froedtert Hospital, Milwaukee, Wisconsin, USA The quantitative sudomotor axon reflex test (QSART) measures evoked sweat responses mediated by postganglionic sympathetic sudomotor axons. Acetylcholine is iontophoresed using a 2 mA current applied for 5 minutes. Traditionally, the sweat response is recorded during the stimulation and subsequent 5 minutes. The area under the curve (amplitude) is proportional to sweat volume.We have observed that the evoked response waveform seldom returns to baseline by 10 minutes, and many normal subjects continue to sweat for more than 5 minutes after the end of the stimulus. This may bear significant effects on determining normative data as well as reproducibility. We prospectively examined QSART responses from 234 sites in 65 subjects. We measured QSART latencies and amplitudes at 10 and 15 minutes after stimulus onset, and classified waveform configuration (full or normal, small, persistent). Absent responses were excluded. Thirty subjects had normal amplitudes at all sites. The mean sweat latency was 127 ± 62 seconds (range 35–373). Mean amplitudes after 10 and 15 minutes were 0.55 and 0.71 respectively. The mean 15/10 ratio was 1.28 ± 0.22 (range 1.0–2.4). Amplitude correlated negatively with latency in all groups, but the value was significant mainly when responses were small (r = –0.59). Amplitude ratio correlated positively with the latency when the responses were small (r = 0.47) or persistent (r = 0.53), or when the latency exceeded 3 minutes (r = 0.52). This was less robust when the response had a full waveform regardless of the amplitude (r = 0.22). Comparisons of all subgroup ratios were highly significant (p < 0.001). The 15-minute response was 77 % higher in the persistent and 38 % higher in the small group. Of particular interest, 16/31 responses with a ratio > 1.50 had a full waveform. Our findings suggest the 10-minute QSART measurement may significantly underestimate sweat output in many subjects. The 15minute measurement may be a more accurate measure of the total evoked sweat response.

RR interval Variability During Sleep and Awake periods in Women with Fibromyalgia M Risk1, R Freeman1, E Klerman2, D Goldenberg3, R Rackow2, G Adler2 1 Harvard Medical School – BIDMC, Boston, Massachusetts, USA; 2 Harvard Medical School – Brigham Women’s Hospital, Massachusetts, USA; 3 Newton-Wellesley Hospital, Massachusetts, USA Objective: To determine if heart rate variability during the night and day differs between patients with fibromyalgia and healthy controls and if differences in sleep architecture contribute to differences in RR interval variability. Material and methods: Six healthy controls (32.6 ± 9.3 years old, BMI 24.9 ± 3.9 kg/m2) and five patients with fibromyalgia (37.2 ± 11 years old, BMI 25.9 ± 2.5 kg/m2), all premenopausal women, were studied for 48 hours (8 hours during sleep at the habitual sleep time, followed by 40 hours of non-sleep and constant posture). ECG and polysomnographic recordings were obtained; RR interval variability

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was assessed by frequency domain analysis: LF over total power (LFt, from 0.04 to 0.15 Hz), and HF over total power (HFt, from 0.15 to 0.5 Hz) every 3 minutes, then the values were averaged for every one hour; sleep stage was calculated using the EEG recordings and annotated. Results: During the 8 hours sleep period LFt was 0.51 ± 0.03 for controls, and 0.67 ± 0.03 for patients (P < 0.05), HFt was 0.49 ± 0.03 for controls and 0.33 ± 0.03 for patients (P < 0.05); during the 40 hours non sleep period LFt was 0.71 ± 0.04 for controls, and 0.75 ± 0.02 for patients (P < 0.05), HFt was 0.29 ± 0.04 for controls and 0.25 ± 0.02 for patients (P < 0.05). These differences between subject groups in LFt and HFt were not due to differences in sleep architecture between the two subject groups based on standard sleep scoring. Conclusion: In patients with fibromyalgia LFt was higher and HFt was lower compared to the control group during the sleep period and to a lesser extent while awake. These data suggest decreased parasympathetic and possibly increased sympathetic nervous system modulation of the sinus node in patients with fibromyalgia that were not due to differences in sleep architecture.

Pure sympathetic dysfunction associated with severe delayed gastric emptying and antro-duodenal hypomotility: a pediatric case report. G Chelimsky1, T Chelimsky2 1 Division of Gastroenterology, Case Western Reserve University and Rainbow Babies and Children’s Hospital, Cleveland, Ohio, USA; 2 Department of Neurology, Case Western Reserve University, Cleveland, Ohio, USA A 10 year old girl diagnosed with Devic’s syndrome 2 years prior, was admitted to the hospital for intractable emesis of several weeks’ duration. MRI of the spine at diagnosis had shown increased T2 signal at the cervico-medullary junction. Repeat study 3 months prior to admission demonstrated a new lesion from T4 to T7, with improvement in the previous cervical findings. Brain MRI showed no new lesions or masses. Upper GI series demonstrated no malrotation. Antro-duodenal manometry showed no migrating motor complexes in the fasting phase, with quiescent motor activity and occasional irregular contractions. She was unable to eat for evaluation of the post-prandial phase. High dose solumedrol produced dramatic improvement in her gastrointestinal symptoms. Markedly delayed gastric emptying (T 1/2 clearance 390 minutes), normalize (50 minutes) after treatment. Motility studies were not repeated. Autonomic testing demonstrated normal responses to deep breathing and to Valsalva maneuver. Tilt table demonstrated a baseline BP of 109/51 mmHg with a HR of 69 bpm, compared to 142/60 and 90 after treatment. After 10 minutes at 90 degrees, her heart rate increased to 123 bpm with a gradual drop in BP to 64/43 mmHg, compared to a brief drop to 80/60 after treatment. Initially absent sudomotor axon reflex responses (2/2 sites) became present post-treatment. In conclusion, her new thoracic lesion was in an appropriate location to produce a virtual mesenteric sympathectomy. The preservation of cardiac responses on autonomic testing was compatible with this location. The resolution of both her symptoms and her findings after treatment suggests that this lesion was, in fact, the source of her chief complaint. To our knowledge, this is the first anatomic demonstration of the critical role the sympathetic nervous system may play in the foregut motility.

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Fatty acid reduces tolerance to a liquid meal independently of caloric content in man S Lal1, J Barlow2, DG Thompson 1 G. I. Sciences, 2 Dept Gastrointestinal Physiology, University of Manchester, Salford, Lancashire, UK Background & Aims: The mechanism by which cholecystokinin (CCK) regulates food intake is unclear, although the autonomic nervous system (vagus nerve) is believed to play a key role [1]. We have shown previously that dodecanoic acid (C12) releases CCK to limit tolerance to a liquid meal in man [2], but it is unclear whether it is the volume or the caloric content of the meal that determines the maximum amount tolerated.We therefore aimed to determine the effect of caloric content on fatty acid-induced tolerance to a liquid meal in man. Methods: Vehicle (250 ml PBS/Tween-80) alone or with 0.1M C12 (45 kCal) was infused into the stomach of 7 healthy subjects (2 females; mean age 37) in the morning after an overnight fast. 20 minutes later, water, 5 % glucose (200 kCal.l–1) or 25 % glucose (1000 kCal.l–1) was infused into the stomach in a blinded randomized manner at 200 ml.min–1 to maximum volume tolerated. Gastric contents were then aspirated. Data are mean ± SEM (ml) compared using 1way repeated measures ANOVA followed by Student-Newman-Keuls post hoc test. Results: C12 reduced the volume of water (1480 ± 260 following vehicle vs. 890 ± 190 following C12; p < 0.05), 5 % glucose (1340 ± 200 following vehicle vs. 880 + 230 following C12; p < 0.05), and 25 % glucose (1150 ± 170 following vehicle vs. 780 ± 180 following C12; p < 0.05), tolerated when compared to vehicle, but this effect was independent of the caloric load delivered. There was no difference in the volume of gastric contents aspirated at the end of the infusion period following any of the test meals (1050 ± 190, 1140 ± 190, 1180 ± 170, 1030 ± 170, 1050 ± 210, 960 ± 160 following vehicle/water, vehicle/5 % glucose, vehicle/25 % glucose, C12/water, C12/5 % glucose, C12/25 % glucose respectively), indicating that tolerance was limited by intragastric capacity, which in turn is determined by gastric emptying. Conclusions: CCK-releasing fatty acids reduce tolerance to a liquid meal by delaying gastric emptying. Maximum tolerance is determined by the volume and not the caloric content of the meal. References 1. Moran T (1997) Am J Physiol 272: R1245–1251 2. Lal S (2002) Gut 11 (50): A1

Nocturnal loss of consciousness of vasovagal origin CT Paul Krediet1, DL Jardine2, AGR Visman3, P Cortelli4, W Wieling1 Academic Medical Center, Amsterdam, The Netherlands; 2 Christchurch Hospital, Christchurch, New Zealand; 3 Beatrix Ziekenhuis, Gorinchem, The Netherlands; 4 Neurologic Section, University of Modena and Reggi Emilia, Italy 1

Vasovagal reaction starting while supine has been described triggered by serious pain or emotions but seems to be rare. Loss of consciousness at night after waking up is associated with epilepsy and Long QT Syndrome. In this report we describe 13 patients with nocturnal loss of consciousness after waking up at night. The clinical features point at a vasovagal reaction, starting during sleep. Characteristics: Thirteen patients (10 females) had a consistent history of waking up at night with nausea and urge to defecate. In some patients light headedness was followed by supine loss of consciousness, in others immediately after leaving bed. When regaining consciousness patients perspired profusely, felt extremely week, and

could not get upright but were well oriented. There was no tongue bite. Episodes had a frequency varying from once a week to several times a year. Most patients also suffered from transient loss of consciousness during day time, apparently of vasovagal origin. In one patient an overnight EEG telemetric recording during an episode did not show any epileptic activity. The parallel EKG showed a pronounced bradycardia. Tilt table testing was positive in 8/11, with recognition of prodromal symptoms and significant cardio-inhibitory reaction in 4/8. The possibility of organic cardiac pathology was excluded by additional examinations. EEG performed in 3 patients revealed epileptiform activity in 1. Discussion: The presented nocturnal loss of consciousness seems to be a form of vasovagal syncope, caused by a vasovagal reaction starting supine during sleep. Possible triggers are the GI-complaints, although they might also be caused by parasympathic vagal overdrive during REM sleep. Based on positive tilt table testing with recognition of symptoms and the absence of other than typical vasovagal prodromal symptoms, vasovagal origin should be considered in patients with nocturnal loss of consciousness after waking up with GI complaints.

Clonidine improves baroreflex sensitivity after gastrostomy feeding in Familial Dysautonomia M Hilz, M Brys, H Marthol, R Franta, M Tutaj, F Axelrod Department of Neurology, New York University School of Medicine, New York, New York, USA Familial Dysautonomia (FD) patients frequently experience hypertensive autonomic crises after gastrostomy feeding (GF). In our experience, the central alpha 2-agonist clonidine buffers GF induced crises, which might be due to a clonidine induced modification of baroreflex function, a reflex compromised in FD. To evaluate effects of clonidine on cardiovascular autonomic modulation and baroreflex sensitivity (BRS) of FD patients after standardized GF. In nine FD children (11.6 ± 3.1 years, four girls), we monitored RR interval (RRI), systolic blood pressure (BP) (Colin Pilot®) and respiration at supine before (baseline 1) and 20 minutes after GF of 7.5 ml/kg Isomil® (feeding 1). One day later, recordings were repeated 30 minutes after intake of 0.004 mg/kg clonidine via gastrostomy (baseline 2) and another 20 min after GF of 7.5 ml/kg Isomil® (feeding 2). We determined spectral powers of RRI and BP in the low- (LF: 0.04–0.15Hz) and high-frequency range (HF: 0.15–0.5Hz) using 90 sec autoregressive analysis. BRS was assessed from the LF-transfer function gain of BP and RRI for coherence > 0.5. RRI decreased significantly after feeding 1 (709.5 ± 52.8 vs. 622.3 ± 86.5 msec) and feeding 2 (851.6 ± 99.1 vs. 749 ± 92.9 msec), while BP decreased slightly after feeding 1 (146.1 ± 20.3 vs. 134.8 ± 27.1 mmHg) but was stable after feeding 2 (115.5 ± 19.0 vs. 113.4 ± 22.9 mmHg). Compared to baseline 1 and feeding 1, Clonidine induced significantly higher RRIs at baseline 2 (851.6 ± 99.1 vs. 709.5 ± 52.8 msec) and feeding 2 (749.0 ± 92.9 vs. 622.3 ± 86.5 msec) but lower BPs at baseline 2 (115.5 ± 19.0 vs. 146.1 ± 20.3 mmHg) and feeding 2 (113.4 ± 22.9 vs. 134.8 ± 27.1 mmHg) (p < 0.05). Respiration, LF- and HF-powers remained unchanged throughout. BRS at baselines 1 and 2 were similar. Feeding 1 did not change BRS, but BRS was slightly higher after feeding 2 than at baseline 2 (42.4 ± 26.4 vs. 33.1 ± 29.9msec/mmHg). BRS was significantly higher after feeding 2 (42.4 ± 26.4msec/mmHg) than after feeding 1 (21.1 ± 12.8msec/ mmHg). In the FD patients, clonidine improves BRS only after GF. The resulting cardiovascular stabilization might attenuate GF induced crises.

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Diffuse Lewy body disease (DLBD) presenting as pure autonomic failure. A neuropathological report and spectrum of the disease H Kaufmann, K Bhattacharya, D Wolfe, D Perl Mount Sinai School of Medicine, New York, New York, USA Background: DLBD is a recently described disorder characterized pathologically by Lewy bodies in the cortex and, clinically, by dementia, and parkinsonism. Autonomic failure has occasionally been described in DLBD but rarely as its sole presenting feature. We report a case of pathologically confirmed DLBD presenting with isolated autonomic failure for several years. Case report: A Caucasian male, age 73, developed symptomatic orthostatic hypotension with recurrent syncope and a provisional diagnosis of pure autonomic failure was made. Eighteen months later, he developed mild levodopa-responsive parkinsonism and the diagnosis was amended to multiple system atrophy (MSA-P). Autonomic dysfunction and parkinsonism progressed little over the ensuing two years but the patient developed progressive severe cognitive dysfunction, and at time of death, six years later, age 83, was unable to recognize family and friends. Pathology: Ubiquitin and alpha synuclein positive Lewy bodies were present in post-ganglionic adrenergic neurons and in the epicardial nerves of the heart. Lewy bodies were also observed in the substantia nigra and locus coeruleus where there was extensive neuronal loss. In addition, Lewy bodies were present in other subcortical structures including the nucleus gracilis, inferior olivary complex, brainstem tegmentum, habenular commissure and substantia innominata, as well as the cerebral cortex particularly in the frontal, temporal. Congulate and parahippocampal regions. There was marked hippocampal atrophy but no Alzheimer-type pathology, nor glial cytoplasmic inclusion (GCI) bodies characteristic of MSA. Discussion: Pathology mirrored clinical signs with Lewy body deposition in autonomic, brainstem and cortical areas. This case may represent the “full spectrum” of DLBD. Thus, it is tempting to speculate that pure autonomic failure, Parkinson disease and DLBD rather than distinct disease entities are a similar disorder whose clinical expression depends on the temporal formation of Lewy bodies with associated neurodegeneration within the central and peripheral nervous system both in somatic and autonomic neurons.

Depletion Of NK1 Receptor Containing Neurons Of The Ventrolateral Medulla And Preservation Of Neurons Of The Nucleus Ambiguus In MSA A Schmeichel, E Benarroch Mayo Clinic, Rochester, Minnesota, USA Disorders of respiration; including dysrrhythmic breathing, sleep apnea, and laryngeal stridor; are prominent manifestations in multiple system atrophy (MSA); but their anatomical substrate in unknown. Loss of the neurons in the nucleus ambiguus have been reported in some, but not all, cases. Neuro-kinine 1 receptor (NK1R) containing neurons in the pre-Bötzinger complex of ventrolateral medulla play a critical role in respiratory rythmogenesis. We sought to determine whether or not NK1R neurons are affected in MSA, and whether there is a consistent involvement of neurons of the nucleus ambiguus in this disorder. Brains were obtained at autopsy from five patients with MSA (3 MSA-P, 2 MSA-C; 4 male, 1 female) and five controls (3 male, 2 female) matched for age and postmortem delay. All patients with MSA had orthostatic hypotension and neurogenic bladder as well as clinical or polysomnographic evidence of sleep apnea or larygeal stridor. Diagnosis of MSA was confirmed neuropathologically. Frozen 50 micron sections were obtained throughout the medulla from –4 to + 6 mm from the orbex. Sections were stained for: choline acetyl-

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transferace (CAT) and NK1R. NK1R neurons, distinct from cholinergic and adrenergic neurons, were consistently found in the ventrolateral medulla, suggesting that they might correspond to the preBötzinger complex. There was a marked depletion of these NK1R neurons in all MSA cases (6 ± 1 vs. 50 ± 2 cells per section, respectively, p < 0.001). By contrast, the number of cholinergic neurons in the compact region of the nucleus ambiguus was similar in both groups. We conclude the depletion of NK1R neurons of the ventrolateral medulla, probably corresponding to the pre-Botzinger complex, might contribute to respiratory abnormalities in MSA. Our results argue against a prominent role of loss of branchimotor neurons of the nucleus ambiguus as a cause of laryngeal stidor or obstructive sleep apnea in these patients.

Cerebral oxygenation and cerebral blood flow in patients with multiple system atrophy M Asahina1, J Sato2, M Tachibana3, A Suzuki2, T Hattori1, 2 Department of Neurology, 2 Department of Anestheology, 3 Department of Otolaryngology, Chiba University School of Medicine, Chiba, Japan

1

Aim: To measure cerebral blood flow and cerebral oxygenation using transcranial Doppler ultrasound (TCD) and near-infrared spectroscopy (NIRS), and to investigate cerebral autoregulation in patients with multiple system atrophy (MSA). Methods: Mean blood flow velocity in the middle cerebral artery (MFVMCA) and cerebral oxygen saturation (SCO2) of the frontal cortex were measured with TCD (PCDop 842, SciMed) and NIRS (PSAIII, Biomedical Science), respectively. Mean arterial blood pressure was recorded via the radial artery and adjusted at the level of the middle cerebral artery (MABPMCA). Cerebrovascular resistance (CVR) was obtained by dividing MABPMCA by MFVMCA. Measurements were performed in 8 MSA patients with autonomic failure (59 ± 6 year old, 4 males and 4 females) before and during head-up tilt (10 min, 70°). Results: MABPMCA decreased from 94 ± 21 mmHg to 58 ± 23 mmHg (–38 %) during head-up tilt. MFVMCA fell from 36 ± 6 cm/sec to 30 ± 6 cm/sec (–18 %), and SCO2 was reduced from 71.0 ± 3.5 % to 69.4 ± 4.6 % (–2 %). Reductions of MFVMCA and SCO2 were not as prominent as that of MABPMCA. On the other hand, CVR decreased from 2.4 ± 0.6 to 1.7 ± 0.8 (–29 %). A patient with severe orthostatic hypotension complained of light-headedness during headup tilt, when MABPMCA was reduced from 95 mmHg to 37 mmHg (–61 %). In this patient, MFVMCA (–31 %) and SCO2 (–6 %) markedly decreased despite a decrease of CVR (–74 %). Conclusion: Blood flow is directly proportional to perfusion pressure, and inversely proportional to vascular resistance. The patients with MSA showed preserved cerebral autoregulation, where CVR decreased to maintain cerebral blood flow and oxygenation in response to a reduction in arterial pressure. In the patient with an extreme fall in arterial pressure, however, cerebral blood flow and cerebral oxygenation were severely reduced despite the decrease of CVR.

Transfer function analysis shows impaired cerebral autoregulation in normal-pressure and open-angle glaucoma M Tutaj1, C Brown2, M Brys1, H Marthol1, M Dutsch2, M Hecht2, G Michelson3, M Hilz1, 2 1 Dept. of Neurology, New York University School of Medicine, New York, New York, USA; 2 Dept. of Neurology, University of ErlangenNuremberg, Erlangen, Germany; 3 Dept. of Ophthalmology, University of Erlangen-Nuremberg, Erlangen, Germany

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Autonomic dysfunction is likely to contribute to the pathophysiology of normal pressure (NPG) and open-angle glaucoma (OAG). Although there is evidence of altered vasomotor function with decreased peripheral and optic nerve blood flow, cerebral autoregulation (CA) has not been evaluated, so far. To assess CA in NPG and OAG patients in response to blood pressure (BP) oscillations. In 10 NPG (57 ± 3.2 years), 10 OAG patients (55 ± 2.8 years) and 10 healthy controls (58 ± 2.3 years), we monitored electrocardiographic RR interval (RRI), mean blood pressure (BP), mean middle cerebral artery blood flow velocity (CBFV), respiration and end-expiratory carbon dioxide (CO2) concentration and induced BP fluctuations by 6/minute (0.1 Hz) metronomic breathing in supine position. The spectral powers at the 0.1 Hz peak frequency of RRI, BP and CBFV oscillation were determined by autoregressive analysis. Static cerebrovascular resistance (CVR) was estimated as BP to CBFV ratio. CA was determined from the transfer function phase and gain between BP and CBFV oscillations at 0.1 Hz for coherence > 0.5 and normalized by conductance (1/CVR). RRI, BP, CBFV, end-expiratory CO2 and 0.1Hz spectral powers of RRI, BP and CBFV did not differ between NPG, OAG patients and controls. CVR was slightly, but not significantly higher in NPG (3.3 ± 0.6 mmHg cm–1 s) than in OAG (2.4 ± 0.3) and controls (2.03 ± 0.2). Phase shift was slightly lower in NPG (46.9 ± 10.4°) than in OAG (58.4 ± 6.6°) and controls (54.1 ± 7.8°). In contrast, normalized transfer function gain was significantly higher in NPG (2.27 ± 0.3 cm s–1 mmHg–1) and OAG (2.15 ± 0.2) than in controls (1.29 ± 0.1). Increased transfer function gain in NPG and OAG patients indicates inadequate dampening of BP fluctuations onto CBFV fluctuations and shows impaired cerebral autoregulation. Compromised cerebral autoregulation may contribute to the pathogenesis of both types of glaucoma.

Changes in the Performance of Schedule-induced Polydipsia (SIP) in Rats after Arecoline and Amphetamine Treatments FJ Wan, CS Tung National Defense Medical Center, Taipei, Taiwan, R. O. C. This study investigated the performance of schedule-induced polydipsia (SIP) rats in the novel or the intermittent-reward SIP sessions after arecoline (AREC) and amphetamine sulfate (AMPH) treatments. The parameters observed included two parts, part one: locomotion and stereotyped behaviors in the novel sessions and part two: schedule-induced licks (SL), water intake (WI), schedule-dependent nose-pokes (SN), pellets earned and stereotyped behaviors of the facultative stage in the SIP sessions. It was shown that when the rats received AMPH (0.5–2.0 mg/kg) but not AREC (0.1–1.6 mg/kg) in the novel sessions, the locomotion was increased in a dose-dependent manner. However, when AREC (0.8 mg/kg) and AMPH (1.0 mg/kg) were both given, AMPH on locomotion was significantly attenuated. In the SIP sessions, a single injection of AMPH increased the SN at the dose of 1.0 mg/kg, whereas decreased the SL and WI at the dose of 2.0 mg/kg. On the other hand, a single injection of AREC caused no operant behavior changes at doses below 0.8 mg/kg. However, when the dose was increased to above 0.8 mg/kg (1.6 mg/kg), the SL and WI were increased but the SN was decreased. The significant effect of large-dose AREC effects on SIP was attenuated after co-administration of scopolamine (0.1 mg/kg). Furthermore, the effects of AMPH on SIP performance were not changed by the co-administration of AREC at a dose of 0.8 mg/kg. These results are discussed under the hypothesis that combined utilization of the main component in chewing betel quid, AREC, and AMPH may yield changes of AMPH-induced psychomotor responses in a special environmental context.

Is Depression a Characteristic or a Cause of Neurocardiogenic Syncope? JC Guzman, BE Vesga, FA Silva, MA Lindarte, C Morillo Autonomic Function Laboratory, Fundacion Cardiovascular del Oriente Colombiano-Research Institute, Bucaramanga, Santander, Columbia Objective: To assess the association between mood disorders and autonomic dysfunction in patients with neurocardiogenic syncope (NS) documented by a positive response to the head up tilt test (HUT). Methods: 58 subjects (female: 75,9 %) with history of NS were screened for depression (MD) with the Beck depression inventory. Subjects were evaluated by HUT response and SF-36 quality of Life Test. Autonomic profile was obtained by the analysis of heart rate variability (HRV). RMSSD, nuLF (low frequency), nuHF (high frequency), LF/HF ratio (sympathovagal balance) and Deep breathing test (DBT) were analyzed with winCPRS (Absolutely Aliens, Finland). A t-test or a Mann-Whitney test was used to establish difference between continuous variables, a p < 0,05 was taken as statistically significant. Results: 47 (81 %) subjects had a positive HUT. Syncope response was documented in 23 (39,7 %) and presyncope response in 24 (41,4 %) subjects. Mean age 34,4 ± 19 vs 33,9 ± 12, respectively p = 0,75). No statistical differences were found in the mean frequency of previous events in both groups (syncope = 3,3 ± 4,7 vs presyncope = 2,5 ± 1,4, p = 0,48). Variable

RMSSD nuLF nuHF LF/HF index DBD General Health

Presyncope (Mean Age: 33,9±12:)

Syncope (Mean Age: 34,4±19)

Means Beck (–)

P value Beck (+)

Means

p value Beck (–)

Beck (+)

63,9 39,6 35,8 2,1

74,6 46,2 45,9 1,4

0,18 0,14 0,15 0,25

60,6 38,6 34,5 1,5

31,6 41,1 24,4 2,9

0,03 0,90 0,14 0,02

17,9 71,8

22,5 65

0,29 0.68

19,2 73,3

14,3 35,8

0,37 0,01

Conclusion: Subjects with NS and MD have a decreased HRV with an increased in low frequency oscillations as well as a worst perception of general health. These associations suggest a severe cardiac autonomic impairment and mood alterations that could be related with a common pathway central serotoninergic dysfunction.

Is reduced pupillary modulation in diabetic patients due to brainstem dysfunction? M Dutsch, C Brown, B Stemper, B Neundörfer, M Hilz Department of Neurology, University of Erlangen-Nuremberg, Erlangen, Germany Reduced fluctuations of pupillary diameter (PD) are a characteristic of diabetic autonomic neuropathy. The factors contributing to PD fluctuations in diabetics have not been assessed yet. Animal studies suggest an influence of mechanical changes (induced by respiration and blood pressure) and of brainstem structures (e. g. baroreflex-mediating neurons) on PD changes. We evaluated whether respiration, systolic blood pressure or the baroreflex affect PD fluctuations dur-

13th International Symposium on the Autonomic Nervous System

ing metronomic breathing. In 11 diabetics without peripheral neuropathy (3 IDDM, 8 NIDDM, 6 female, mean age 52±11 years) and 19 controls (10 female, mean age 53±19 years), we continuously monitored heart rate (ms), systolic blood pressure (mmHg) [Pilot™, Colin], respiration [Respitrace™, Ambulatory Monitoring, Inc.] and PD [V-CIP1.0/1.1™, AMTech] for 125s after 30 minutes adaptation to an ambient light intensity of 120 lux. After removal of blink artifacts, we performed spectral analysis of the frequencies underlying PD modulation and calculated spectral power in the low frequency band (LF: 0.04–0.15 Hz). Additionally, we studied the influence of respiration and systolic blood pressure on PD as well as of systolic blood pressure on heart rate (i. e. baroreflex sensitivity) by calculating the LF transfer function gain for the corresponding signals (coherence > 0.5). In the diabetics, LF fluctuations of PD were significantly lower than in the controls (0.09 ± 0.10 mm2 vs. 0.22 ± 0.16 mm2; p < 0.05). Coherence values for the LF transfer function gain between respiration (systolic blood pressure) and PD were < 0.5. Baroreflex sensitivity was significantly lower in the diabetic patients (0.71 ± 0.56 bpm/mmHg) than in the controls (1.35 ± 0.94 bpm/mmHg; p < 0.05). Our data show reduced PD modulation in diabetics during metronomic breathing. Neither blood pressure nor respiration had a significant influence on PD modulation. In the absence of peripheral neuropathy, the reduced baroreflex sensitivity in our diabetics suggests that the decreased pupillary variability is primarily due to a brainstem dysfunction.

A Population-Based Study of Orthostatic Intolerance and its Association with Syncope D Mehta, R Rodeheffer, D Mahoney, P Low, W Shen Mayo Clinic, Rochester, Minnesota, USA Background and Objective: Orthostatic Intolerance (OI) is a symptom complex being recognized with an increasing frequency by physicians in the clinical setting. Our objective was to estimate the prevalence of OI and its association with syncope. Materials and methods: A random sample of men and women, aged ≥ 45 years, who were residents of Olmsted County, Minnesota was surveyed. Using a self-administered questionnaire subjects were asked the following questions: (1) If they had experienced lightheaded spells (2) If yes, did the symptoms occur in the upright posture (OI) (3) If they ever had syncope. 1597 responded to (1), 1557 to (2), and 1649 responded to (3). Results: Of 1597 subjects (mean age 62, 768 men), 42 % (672/1597) reported experiencing spells of lightheadedness. Of the 1557 subjects (mean age 62, 754 men) 30 % (468/1557) reported symptoms of OI. There was no association in the prevalence of OI and gender (p = 0.86), body mass index (p = 0.64), diabetes (p = 0.33), history of hypertension (p = 0.78), coronary artery disease (p = 0.75), or orthostatic hypotension (p = 0.12). OI was associated with lower mean systolic blood pressure (SBP), 129.8 vs. 132.1 (p = 0.04) and lower mean age, 60.6 vs. 62.4 (p < 0.001). Syncope was reported by 30 % of subjects with OI vs. 15 % of subjects with no OI (p < 0.001). Conclusions: Orthostatic intolerance is a common symptom complex with a prevalence of 30 % in community dwelling persons aged ≥ 45 years. OI is associated with lower SBP and lower mean age statistically but its clinical significance is unclear. There is an association between the prevalence of OI and patient reported syncope in this population group.

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Characteristics of cardiac vagal baroreflex response curve in patients with postural tachycardia syndrome (POTS) I Bonyhay1, J Taylor2, W Farquhar1, R Freeman1 Center for Autonomic and Peripheral Nerve Disorders, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA; 2 Research and Training Institute, Harvard Medical School, Boston, Massachusetts, USA 1

Objective: To characterize vagal baroreflex control of RR interval in patients with postural tachycardia syndrome. Background: Posture related excessive tachycardia is the cardinal feature of orthostatic intolerance. Since baroreceptor engagement plays a major role in the physiological response to orthostatic stress it is likely that baroreflex control of heart rate is involved in the pathogenesis of this disorder. The mechanisms whereby heart rate baroreflex control may contribute to the development of orthostatic tachycardia are not clearly defined. Methods: We characterized the baroreflex mediated RR interval responses in 18 POTS and 18 healthy subjects using the modified Oxford pharmacologic method. Blood pressure changes were induced by bolus injection of nitroprusside followed by subsequent injection of phenylephrine. RR intervals and blood pressure were continuously monitored during the response. Baroreflex function was assessed with logistic function analysis. The sigmoid relationship between the corresponding data point of RR interval and systolic blood pressure was calculated. Threshold, saturation values and operational point were determined. Results: Following the nitroprusside-induced fall in blood pressure, bolus injection of phenylephrine increased systolic blood pressure by 47 ± 18.0 and 52 ± 18.7 mmHg in patients and controls, respectively.While there was no significant group difference in baseline blood pressure POTS patients had significantly lower resting RR interval (787 ± 134.6 vs. 1027 ± 148.5 ms, P < 0.001) At both threshold and saturation, POTS patients had significantly lower RR intervals than healthy subjects, however the difference was larger at threshold than at saturation (164 vs. 330 ms, P < 0.001). Relative set-point location of RR interval was also significantly different, being closer to saturation in POTS patients than in healthy subjects (71 ± 17.8 % vs. 60 ± 13.8 %, P < 0.05). Conclusion: Baroreflex mediated RR interval-pressure response curve is significantly shifted to lower RR intervals in POTS patients compared to healthy subjects. This shift is disproportional implying reduced operational range and closer set-point location to saturation in POTS patients. These alterations in cardiac-vagal control may contribute to the excessive tachycardia in POTS patients.

Postural Tachycardia Syndrome Following Varicella Encephalitis R Jarrar1, W Cheshire2 1 Mayo Clinic, Rochester, Minnesota, USA; 2 Mayo Clinic, Jacksonville, FL, USA Background: Postural Tachycardia Syndrome (POTS) is defined by the combination of orthostatic tachycardia and symptoms of orthostatic intolerance. The etiopathogenesis and localization are diverse and remain unclear. A disturbance at the level of the brain stem has been suggested. In approximately half of patients a viral syndrome precedes POTS. Varicella zoster has a particular affinity for the nervous system, the classic example being postherpetic neuralgia. Dysautonomia is not a known complication. Methods: We report the case of a woman who contracted chicken pox at age 11 years. During the acute phase of chicken pox, she developed seizures and was told to have evidence of brain stem involvement. Shortly afterwards, she developed orthostatic tachycardia with

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heart rates 180–200, severe orthostatic lightheadedness, recurrent syncopal episodes, urinary retention and gastric dysmotility. Exam at age 24 was significant for hyperreflexia, absent gag reflex, purplish discoloration of the legs upon standing and orthostatic tachycardia (heart rate increased from 84 to144) without concomitant hypotension. Results: Serum electrolytes, markers of autoimmunity, head/cervical spine MRI, and needle EMG were normal. Gastric motility studies confirmed delayed emptying. On autonomic testing; heart responses to deep breathing, QSART latencies and sweat volumes, the Valsalva ratio, and beat-to-beat blood pressure responses to the Valsalva maneuver were normal. The patient was tilted for 3 minutes. Although orthostatic hypotension did not occur, heart rate increased from 94 b/min to a mean of 160 b/min. Syncope occurred at 3 minutes with a heart rate = 164. The patient recovered rapidly once returned to the supine position. Conclusion: In this patient, the historical time course clearly suggests a relationship between varicella infection and subsequent dysautonomia including chronic POTS. In addition, clinical evidence of central nervous system involvement suggests possible brain stem localization of postural tachycardia. This case expands the current understanding of the localization and pathogenesis of POTS.

Patients with Posturally Related Syncope have Increased Responsiveness of the Cerebral Circulation to Carbon Dioxide L Norcliffe, V Bush, R Hainsworth Institute for Cardiovascular Research, Leeds, West Yorkshire, UK A decrease in cerebral blood flow to below the critical level results in syncope. The two factors mainly responsible for determining cerebral flow are perfusion pressure and arterial PCO2. PaCO2 decreases during orthostatic stress and this raises the question of its contribution to the initiation of syncope. We wished to determine whether, in subjects who have a lower tolerance to orthostatic stress, this could be at least partly explained either by a greater reduction in PCO2 during this stress or a greater sensitivity of the cerebral circulation to the same change in CO2. Subjects for this study had been referred for orthostatic stress testing with suspected attacks of posturally-related syncope. We recorded arterial blood pressure (Finapres and automatic sphygmomanometer), heart rate (e. c. g), and end-tidal CO2 (nasal catheters and infrared analyser) and middle cerebral artery blood velocity (CBV transcranial doppler). Orthostatic tolerance was assessed as time to presyncope using the “Leeds” test of head-up tilt with added lower body suction [1]. Cerebral vascular responsiveness to CO2 was assessed by voluntary hypoventilation (using added deadspace) and hyperventilation, and calculating the regression of change in CBV on end-tidal CO2. Fifteen patients had lower than predicted times to presyncope (17.1 ± 2.4 mins) and 11 were normal (32.6 ± 0.8 mins). At presyncope end-tidal CO2 in the two groups were not different (3.9 ± 0.12 and 3.7 ± 0.19 % respectively, P = 0.25). The CO2 responsiveness, i. e. the gradients of the regression of CBV on end-tidal CO2, in low tolerance and normal patients respectively, were 23.5 ± 0.5 and 18.1 ± 0.9 units (P < 0.001). Overall, the gradients were significantly correlated with the time to presyncope. These results imply that, in some patients at least, an increased responsiveness of the cerebral circulation to the developing hypocapnia could contribute to the decrease in cerebral blood flow and predispose to early presyncope. Reference 1. El-Bedawi KM, Hainsworth R (1994) Clinical Autonomic Research 4: 239–244

Neurovascular Normalcy in Simple Faint Contrasts with POTS J Stewart New York Medical College, Valhalla, New York, USA Background: Simple faint (neurocardiogenic syncope) and postural tachycardia (POTS) characterize acute and chronic orthostatic intolerance respectively. We explored the hypothesis that they are pathophysiologically similar. Methods: To accomplish this we studied 20 patients with episodic simple faints who were otherwise well, comparing them to 29 patients with POTS and to 15 healthy control subjects. We measured continuous heart rate, respirations and blood pressure, and used venous occlusion strain gauge plethysmography to measure calf and forearm blood flow, peripheral arterial resistance, peripheral venous resistance, and venous pressure. Upright tilt was performed to 70° for 10 minutes during which calf blood flow and volume were measured. Results: Calf venous pressure was increased (Pv = 27.2 ± 1.1) in a subgroup of POTS who also had increased arterial resistance (57±6 mmHg/ml/min/100 ml tissue), increased venous resistance (2.4 ± 0.3 mmHg/ml/min/100 ml tissue), and decreased peripheral flow (1.0 ± 0.2 ml/min/100 ml tissue), while other POTS patients with normal venous pressure had decreased arterial resistance (18 ± 2) and increased blood flow (3.8 ± 0.3). Syncope patients were not different from control (Pv = 11.4 ± 0.5; calf flow = 3.1 ± 0.2; arterial resistance = 27 ± 2; venous resistance = 1.0 ± 0.1). When upright, syncope and control patients had similar increases in heart rate, stable blood pressure, decreasing blood flow, and increases in calf volume during compared to POTS patients who had marked increased heart rate, unstable BP, increased calf blood flow, and pooling in the lower extremities regardless of subgroup. Conclusions: Peripheral vascular physiology in neurocardiogenic syncope is similar to control and dissimilar to POTS pathophysiology.

Comparison of the Responses of Patients with Postural Tachycardia Syndrome (POTS) and Neurally-Mediated Syncope (NMS) to Heat Stress R Schondorf, J Benoit, R Stein SMBD Jewish General Hospital, Montreal, QC, Columbia Patients with POTS often have livedo reticularis during orthostatic stress. Abnormally high levels of sympathetic activity directed to cutaneous vasculature may help maintain orthostatic tolerance. In contrast many patients with NMS appear to have impaired vasoconstrictor responses both to orthostatic stress and to other stimuli that normally increase sympathetic outflow. The symptoms of patients with POTS and NMS are exacerbated by heat stress but the pathophysiology of these symptoms may not be the same. We postulated that patients with POTS would have less cutaneous vasodilatation than those with NMS during heat stress and consequently poorer heat dissipation. The responses of 10 women with POTS and 11 women with NMS were measured during heat stress achieved by perfusing a tube-lined suit with warm water. Heart rate (HR), blood pressure (BP), forearm skin blood flow and sweating, oral and skin temperatures were continuously recorded. Cutaneous vasodilatation was expressed as % maximal cutaneous vascular conductance (% CVCmax) observed during direct heating of forearm skin. All comparisons are expressed as POTS vs. NMS. Baseline HR (73.7 ± 5.1 vs 70.5 ± 4.4 bpm) systolic (115.5 ± 3.0 vs. 116.5 ± 4.6 mmHg) and diastolic (60.3 ± 2.6 vs 59.4 ± 3.4 mmHg) BP, oral temperature (36.2 ± 0.1 vs. 36.1 ± 0.1 °C) and %CVCmax (10.3 ± 2.3 vs 5.7 ± 0.8 %) were similar. Cutaneous vasodilatation was evident after an oral temperature increase of 0.26 ± 0.06 °C in POTS and 0.47 ± 0.07 °C in NMS (p = 0.04). However there was no difference in the temperature increase at which forearm

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sweating began (0.38 ± 0.13 vs. 0.47 ± 0.08 °C). By the end of the heat stress protocol the increases in oral temperature (0.59 ± 0.11 vs. 0.79 ± 0.08 °C), HR (30.7 ± 4.2 vs. 22.5 ± 2.2 bpm), %CVCmax (53.1 ± 8.6 % vs. 35.3 ± 5.5 %) and sweat output (0.95 ± 0.17 vs. 0.87 ± 0.20 ul/cm2/min) were not significantly different. The sensitivity of the cutaneous vasodilator response to heat stress (% CVCmax/°C; 96.4 ± 17.5 vs. 91 ± 22.2), rate of cutaneous vasodilatation (% CVCmax/min; 1.36 ± 0.17 vs. 1.80 ± 0.40), sensitivity of forearm sweating (3.12 ± 1.10 vs. 2.16 ± 0.45 ul/cm2/min/°C) and the rate of forearm sweating (0.06 ± 0.01 vs. 0.03 ± 0.01 ul/cm2/min2) were also similar. Contrary to our hypothesis there were no significant differences in the heat stress response in POTS and NMS.

Clinical and Psychosocial Correlates of Functional Disability in Patients with Postural Tachycardia Syndrome L Benrud-Larson1, P Sandroni1, J Haythornthwaite2, M Dewar1, T Rummans1, P Low1 1 Mayo Clinic, Rochester, Minnesota, USA; 2 Johns Hopkins University School of Medicine, Baltimore, Maryland, USA Although extensive research indicates that psychosocial factors play an important role in predicting outcome among patients with chronic medical conditions, few data have investigated this in patients with Postural Tachycardia Syndrome (POTS). The present study aimed to identify demographic, clinical, and psychological correlates of physical and psychosocial function in a cohort of 94 patients with POTS (89 % female; mean age = 34.2 ± 10.1). Participants completed a questionnaire including measures of physical function, psychosocial function, autonomic symptom severity, and several anxiety-related personality and cognitive variables. Results indicated that both disease-related and psychosocial variables were significant correlates of function. Path analyses supported a model in which autonomic symptom severity, treatment status, employment status (disabled vs. not), and somatic vigilance independently predicted physical function [χ2 [3]= 2.0, p = 0.57; RMSEA < 0.0001], together accounting for 49 % of the variance. Psychological variables played a stronger role in the model predicting psychosocial function. Autonomic symptom severity and employment status were directly associated with psychosocial function, while catastrophic cognitions mediated the relationship between anxiety-related personality characteristics and psychosocial function [total R2 = 67 %; χ2 [10]= 7.5, p = 0.67; RMSEA < 0.0001]. This suggests that anxiety-related personality characteristics may prompt a person with POTS to catastrophize (e. g., expect the worst, experience feelings of helplessness and lack of control) in response their symptoms, which then contributes to impaired psychosocial function. These findings are important because they point to modifiable correlates of function (somatic vigilance, catastrophic cognitions) that can be targeted with psychosocial interventions.

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Aim: To study the natural history of symptom recurrence in patients with a predominantly vasodepressor type of carotid sinus syndrome. Methods: We did a retrospective study of 52 patients referred to the EP lab at the Mayo Clinic with symptoms ranging from lightheadedness to presyncope and syncope who had a positive carotid sinus massage for the vasodepressor type of carotid sinus syndrome. These patients did not receive pacemakers and were followed up for a period ranging from 6 months to 4 years. The follow-up was assessed from the electronic records, and patients who did not have any documented follow-up were contacted by telephone about recurrence of symptoms. The risk of recurrence was analyzed using the Kaplan-Meier curve. Results: We were able to find 52 patients with the vasodepressor type of carotid sinus syndrome who did not receive pacemakers. 49 of these patients had follow-up. The average follow-up time was 3 years. The age ranged from 19–84 years, with a mean age of 69 and SD = 12. There were 19 females and 33 males. The cumulative probability of recurrence of syncope was 35 % at 4 years and the 4-year mortality was 10 % (95 % CI = 0–19 %). Conclusion: In patients with a vasodepressor form of carotid sinus syndrome, the risk of recurrence of symptoms without pacing is 35 % over 4 years.

Syncopal seizure semiology in children T Lobban1, S Mordekar2, G Bates3, W Whitehouse4 STARS, Warwickshire, Stratford upon Avon, UK; 2 Queen’s Medical Centre, Nottingham, Nottinghamshire, UK; 3 Birmingham Children’s Hospital, Birmingham, West Midlands, UK; 4 The University of Nottingham, Nottingham, Nottinghamshire, UK 1

Aim: To gain a better understanding of the semiology of syncopal seizures in children with reflex anoxic seizures (RAS). Method: A confidential survey of the national support group: Syncope Trust And Reflex anoxic Seizures (STARS), was undertaken using a self-report questionnaire. Results: 52 % of the questionnaires have been returned so far. Preliminary data on 105 affected children has been analysed, including 42 males. 80 % of children had a different diagnosis before RAS was diagnosed: breath holding (28 %), epilepsy (14 %), temper tantrums (6 %). Pain (82 %), surprise (70 %), fear (22 %) and tiredness (25 %) were the common trigger factors. Most seizures lasted between 0.5–2 minutes, but were usually followed (in 77 %) by at least an hour’s sleep. 60 % reported incontinence of urine during the seizure and 33 % sustained injury. 75 % reported tonic spasms and 37 % reported hypotonic seizures. 47 % had jerking during some seizures. Conclusions: RAS is still under diagnosed. Many seizures have features commonly presumed to suggest an epileptic basis. It should be recognised that both tonic, tonic clonic, clonic and hypotonic seizures may be due to syncope and are not necessarily epileptic. This will help avoid misdiagnosis.

Natural History of Vasodepressor Carotid Sinus Syndrome in Non-Paced Patients M Abraham, M Salazar, D Hodge, W Shen Mayo Clinic, Rochester, Minnesota, USA Background: Carotid sinus syndrome is characterized as recurrent falls or syncope due to exaggerated bradycardia (cardio-inhibitory) and/or hypotension(vasodepressor) in response to carotid sinus stimulation. SAFE PACE, a randomized controlled trial demonstrated the benefit of pacing in reducing the number of falls in patients with the cardio-inhibitory form of carotid sinus syndrome. There is little information about the natural history of patients with the vasodepressor form of carotid sinus syndrome who do not get paced.

Reflex Asystolic Syncope – results of a parent based questionnaire T Lobban1, S Hvidsten2, G Bates3, W Whitehouse4 STARS: Syncope Trust And Reflex Anoxic Seizures, Stratford upon Avon, Warwickshire, UK; 2 Child and Adolescent Mental Health Service, Coventry, UK; 3 Princess of Wales Children’s Hospital, Birmingham, UK; 4 Queen’s Medical Centre, Birmingham, UK 1

Objective: To delineate the range of clinical presentation, epidemiology and psychosocial aspects of children with reflex asystolic (hypoxic) syncope.

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Design and setting: This was a community-based study based on parental postal questionnaires. Participants: The questionnaires were sent to all parents joining the Charity for families of children with reflex asystolic syncope. Of the 298 reports sent back, 289 were useable. Results: There is a variety of data relating to the clinical presentation, natural history and impact on the family of the disorder. The median duration of an attack is 1.5 minutes. Drowsiness after an attack is typical and lasts on average one hour. The median age at onset of the attacks is 12 months. The frequency of attacks is variable, usually peaking in the second year. There is a 75 % spontaneous remission rate from around the age of 5 years. There are no associated medical problems but an increased incidence of behavioural problems. Sixtysix per cent of respondents described problems of family functioning resulting from the disorder. Fifty per cent gave a positive family history for fits and faints. Conclusion: Despite the fact that families joining support groups may not provide a fully representative sample this is the largest descriptive study of children with reflex asystolic syncope. Clinical experience and other smaller studies support the major findings relating to the natural history of the condition. The high incidence of behavioural and sleep problems has not been previously described.

Reflex Anoxic (syncopal) Seizures: associated features, impact and family history W Whitehouse1, T Lobban2, R Gayatri3, G Bates4 The University of Nottingham, Nottingham, Nottinghamshire, UK; 2 STARS, Stratford upon Avon, Warwickshire, UK; 3 Queen’s Medical Centre, Nottingham, Nottinghamshire, UK; 4 Birmingham Children’s Hospital, Birmingham, West Midlands, UK 1

Aims: To examine the associated features, parentally percieved impact and family history of children with reflex anoxic (syncopal) seizures (RAS), commonly refered to as reflex asystolic “breath-holding”. Method: A confidential survey of the national support group in the UK: Syncope Trust And Reflex anoxic Seizures (STARS) was undertaken using a self-report questionnaire. An age sex matched control, without RAS, was selected by the affected child’s family. Results: 52 % of the questionnaires have been returned so far. 84/105 returns concerned children with RAS currently < 17 years of age. 40 control questionnaires have been returned so far. Parental reports of leg (40 vs 20 %), or chest (65 vs 7 %) pains, night terrors (63 vs 13 %), hyperactivity (69 vs 7 %), behaviour problems (63 vs 2 %) and severe clumsiness (75 % vs 0) were more common than in controls. Parents reported that stress coping with RAS affected their relationship with well siblings (64 %), well sibling’s behaviour (74 %), parental discipline style (50 %), parents relationships with friends and family (54 %), RAS child’s relations with friends (74 %). A family history of syncope or probable syncope was reported more often for children with RAS than for controls (76 vs 10 %). A family history of epileptic seizures or febrile convulsions was also reported more often for children with RAS than for controls (40 vs 8 %). Conclusions: Although recall and reporting bias will tend to amplify associated complaints by parents of children with RAS, these observations provide insight into the impact on family life and suggest that RAS has a major genetic determinant. The association with other complaints requires further investigation.

What is the Minimum Duration of Head-Up Tilt Necessary to Detect Orthostatic Hypotension? J Gehrking, S Hines, L Benrud-Larson, T Opfer-Gehrking, P Low Mayo Clinic, Rochester, Minnesota, USA

Background & Objective: There is uncertainly as to the minimum duration of head-up tilt (HUT) needed to detect orthostatic hypotension (OH). The orthostatic duration has variably been suggested to be 1, 2, 3, and 5 minutes. The purpose of the current study was 1) to determine the minimum duration of HUT necessary to detect OH and 2) to identify different patterns of orthostatic blood pressure (BP) response in patients with OH. Design/methods: We reviewed the medical records of 66 patients (mean-age 69.9 ± 10.2 years; 64 % male) seen at Mayo Medical CenterRochester from 2000–2001 who were found to have OH (defined as systolic blood pressure [SBP] reduction ≥20 mm Hg within 3 minutes of HUT) during routine clinical autonomic studies. Diagnoses included: Neurogenic OH (N = 32), Autonomic Neuropathy (N = 16), Multiple System Atrophy (N = 9), Pure Autonomic Failure (N = 4), Parkinson’s Disease (N = 2), and Small Fiber Neuropathy (N = 3). All patients had completed an autonomic reflex screen with continuous monitoring of heart rate and blood pressure during supine rest and 5 minutes of 70 degree HUT. Severity of autonomic deficits was quantified with the Composite Autonomic Severity Score (CASS; range = 0–10; Low 1993), which corrects for the confounding effects of age and gender. Results: Eighty-eight percent of patients (N = 58) developed OH by 1 minute of HUT, with an additional 11 % (N = 7) developing OH by 2 minutes and the remaining 1 % (N = 1) developing OH by 3 minutes. Two primary patterns of SBP response to HUT were identified. Fortyeight percent (N = 32) of patients demonstrated an initial drop in SBP (≥ 20 mmHg),which remained stable until tilt-back.Thirty-six percent (N = 24) demonstrated an initial drop (≥ 20mmHg) followed by a progressive decline in SBP until tilt-back. Repeated measures analysis of variance examined whether SBP change in response to HUT significantly differed among patients with a stable vs. progressive pattern. Changes in SBP from baseline to 1, 2, 3, and 5 minutes served as the repeated measures. Results revealed a significant time X group interaction (F [3, 32]= 25.1, p < 0.001). Patients in the two groups had similar SBP responses at 1 and 2 minutes of HUT, but differed at 3 and 5 minutes,when patients in the progressive group showed a continuing drop in SBP that did not occur in patients in the stable group. Patients with these two patterns of SBP response to HUT also differed in severity of autonomic deficits. Patients with the progressive pattern had more severe adrenergic impairment than those with a stable pattern (mean CASS-adrenergic (range = 0–4) = 3.25 ± 0.74 vs. 2.75 ± 0.88., t[54]= –2.2; p < 0.05). Conclusions: One minute of HUT will detect OH in the great majority (88 %) of patients and three minutes will detect the balance. Orthostatic stress beyond 2 minutes is necessary to detect the pattern of progressive OH. Since this group has more severe adrenergic deficits than the group with stable OH, we suggest that the progressive pattern is due to greater impairment of compensatory reflexes. Recognition of the group with progressive fall in BP is important since this group would be at greater risk of orthostatic syncope.

Acute and Chronic Aspects of Dysautonomia Prompt Proposed Novel Pharmacological Treatment DM Lindsay University City, Montana, USA While autonomic nervous system disorders, or dysautonomias, have varied symptomatic presentation, two common symptoms are fatigue and orthostatic intolerance (OI) [1, 3]. Despite current treatments, these frequently disabling symptoms cannot be alleviated effectively in a significant number of the estimated 500,000 American OI sufferers [2]. While some dysautonomias have clear, orthostatically caused symptoms like tachycardia, syncope, and venous pooling [3, 4], other symptoms like fatigue, thermoregulatory problems, and impaired renin/angiotensin/aldosterone system (RAAS) function [3, 4], are not

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necessarily linked to orthostasis. These non-orthostatic symptoms may implicate a chronic sympathetic nervous system (SNS) insufficiency which causes the acute orthostatic symptoms of some dysautonomias. The β-adrenergic hypersensitivity [5] and/or regional alpha adrenergic hypersensitivity [3] found in some dysautonomia patients may indicate chronic SNS insufficiency because the former is reversed by isoproterenol [6], and the latter is linked to autonomic denervation [3]. Jacob and Biaggioni outlined the four primary goals in dysautonomia treatment:“(1) improve intravascular volume; (2) decrease the exaggerated sympathetic activation; (3) improve peripheral arterial or venous tone; and (4) counteract β receptor hypersensitivity.” [5 p. 96]. Concomitant Midodrine and isoproterenol administration may accomplish all four outlined goals, and also treat dysautonomia fatigue. Alpha-1 adrenergic vasoconstriction augmentation by Midodrine is already an accepted treatment for OI [5], addressing goal 3. Isoproterenol, a non-selective β-adrenergic agonist currently contraindicated, may accomplish other treatment goals because β-adrenergic agonists stimulate the RAAS [7] and erythropoietin secretion [8, 9]. RAAS stimulation and erythropoeietin secretion may accomplish goals 1, 2, and 3 because angiotensin II is a potent vasoconstrictor, assisting the less potent SNS neurotransmitter norepinephrine [10],and increased aldosterone and erythropoietin secretion would boost plasma volume. Isoproterenol also reverses β receptor hypersensitivity (goal 4) [6], and improves fatigued skeletal muscle function [11, 12, 13]. Therefore, concomitant administration of isoproterenol and Midodrine may be an effective treatment that may improve the quality of life of some dysautonomia sufferers. References 1. Grubb, Blair P, Kosinski Daniel (1997) Neurocardiogenic Syncope and Related Syndromes of Orthostatic Intolerance. Cardiology in Review 5: 182–190 2. Robertson David (1999) The Epidemic of Orthostatic Tachycardia and Othostatic Intolerance. The American journal of the Medical Sciences 317: 75–77 3. Streeten, David HP (1999) Orthostatic Intolerance. A Historical Introduction to the Pathophysiological Mechanisms. The American journal of the Medical Sciences 317: 78–87 4. Grubb, Blair P, Karas Barry (1999) Clinical Disorders of the Autonomic Nervous System Associated with Orthostatic Intolerance: An Overview of Classification, Clinical Evaluation and management. Pacing Clin Electrophysiol 22: 798–810 5. Giris Jacob, Biaggioni Italo (1999) Idiopathic Orthostatic and Postural Tachycardia Syndromes. The American journal of the Medical Sciences 317: 88–101 6. Davies, Albert O, Mares Adolph, James L, Pool, Addison A. Taylor (1987) Mitral Valve Prolapse with Symptoms of Beta Adrenergic Hypersensitivity. Beta 2 Adrenergic Receptor SuperCoupling with Desensitization on Isoproterenol Exposure. The American journal of Medicine 82: 193–201 7. Holmer, Stephan R, et al. (1997) Beta Adrenergic Stimulation of Renin Expression In Vivo. journal of Hypertension 15: 1471–1479 8. Freudenthaler SM, Schenck T, Lucht I, Gleiter CH (1999) Fenoterol Stimulates Human Erythropoietin Production Via Activation of the Renin Angiotensin System. Br J Clin Pharmaco 48: 631–634 9. Gleiter, Christoph H, et al. (1997) Fenoterol but Not Dobutamine Increases Erythropoietin Production in Humans. Clinical Pharmacology and Therapeutics 61: 669–676 10. Katzung, Bertram G (1998) Basic and Clinical Pharmacology. 7th Ed. Stamford CT. Appleton and Lange, p. 289 11. Jami L, Laporte Y, Scott JJA (1984) Some Effects of Sympathetic Stimulation and Isoprenaline on Fatigued Tetanic Contractions of Skeletal Muscle in the Cat. Brain Res 321: 386–389

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12. Howell S, Roussos C (1984) Isoproterenol and Aminophylline Improve Contractility of Fatigued Canine Diaphragm. Am Rev Respir Dis 129: 118–124 13. Fujimura, Naoyuki, et al. (2000) Effects of Isoproterenol on DiaphragmaticContractility in Septic Peritonitis. American journal of Respiratory and Critical Care Medicine 161: 440–446

Effect of ACE Inhibitor on Neurally Mediated Syncope M Suzuki1, S Hori2, S Miyatake2, N Aikawa2 Department of Emergency Medicine, Saiseikai Utsunomiya Hospital, Utsunomiya, Japan; 2 Department of Emergency Medicine, Keio University School of Medicine, Tokyo, Japan

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Background: Syncope is one of the most common clinical problems in medical practice. Neurally mediated syncope (NMS) has been reported to account for more than half of patients with syncope. ACE inhibitor (ACEI) has been reported to improve symptom of elderly patients with NMS. However, there is no report to study the effect of ACEI on orthostatic intolerance in healthy subjects without syncope. Objective: To study the effect of ACEI on orthostatic intolerance in healthy young male subjects. Methods: Eight healthy male (mean age: 22 y/o) who had no experience of syncope were enrolled and gave written informed consent to the study. All subjects underwent HUT (80 degrees) for 30 min without any provocative agent. Five days after the initiation of imidapril (ACEI) administration at an oral dose of 5 mg/day, they were reevaluated by HUT at the same time of day as in the initial HUT. The time interval form start to termination of HUT (HUT-time) and plasma concentrations of norepinephrine (NE), epinephrine (E), rennin (R), anigiotensin I (ATI) and angiotensin II (ATII) were studied at supine and 10 min of HUT. Results: Of the 8 subjects, presyncope was induced in 4 subjects during HUT (positive-subjects, HUT-time: 12.9 ± 9.6 min) while the others completed the 30 min session of HUT (negative-subjects, HUT-time: 30 min) before administration of ACEI. In 4 positive-subjects after the administration of ACEI, HUT-time prolonged (HUTtime: 21.1 ± 10.3 min) and the response to HUT became negative in 2 of them. In other 4 subjects whose initial HUT was negative (negativesubjects), HUT-time decreased and presyncope was induced in 2 of them after the administration of ACEI (HUT-time: 24.8 ± 6.9). Thus, HUT-time increased in the positive-subjects and decreased in the negative-subjects by administration of ACEI (repeated measures ANOVA: P = 0.04). Although the orthostatic changes of the plasma hormonal levels after the administration of ACEI were compared with those before the administration, those changes were similar between the positive-subjects and the negative subjects (repeated measures ANOVA, R: P = 0.87, ATI: P = 0.50, ATII: P = 0.72, NE: P = 0.94, E: P = 0.09). Conclusion: ACEI may prevent syncope in subjects who were vulnerable to orthostatic stress, while it may induce syncope in the subjects who had negative baseline. It was also suggested that plasma hormonal levels of rennin-angiotensin system and catecholmines might not contribute significantly to the effect of ACEI on orthostatic intolerance.

Chronic fatigue syndrome with impairments of neuromuscular junction and autonomic nervous system: three case reports M Kihara1, Y Kawamura2, M Takahashi1 Department of Neurology, Kinki University, Osaka, Japan; 2 Kawamura Hospital, Gifu, Japan 1

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Chronic fatigue syndrome (CFS) is characterized by persistent or relapsing physical and mental fatigue over a period of several years. It is a poorly understood condition with uncertain etiology, and there has been little development in an establishes treatment. We will discuss three cases of CFS who presented with impairment of the neuromuscular junction and autonomic nervous system. Case 1: 18 yearold female. She had a three years history of CFS. The response to repetitive nerve stimulation (RNS) detected by surface electrodes overlying the left abductor pollicis brevis showed a 42 % incremental response at the stimulation rate of 10 Hz. Composite autonomic scoring system (CASS) showed mild cholinergic impairment (cardiovagal score 1, sudomotor score 2). Serological tests for Epstein-Barr (EB) Virus revealed positive antiviral capsid antigen (anti-VCA) immunoglobulins G (IgG). Oral pyridostigmine therapy (30 mg) has resulted in a dramatic improvement of her symptoms. Case 2: 28 yearold female with a ten years history of CFS. The response to RNS, detected on the left abductor pollicis brevis, showed a 60 % incremental response at the stimulation rate of 10 Hz. CASS showed mild cholinergic impairment (cardiovagal score 1, sudomotor score 2). EB virus antibodies were positive in serum. Oral pyridostigmine therapy (10 mg) has resulted in dramatic improvement of her symptoms. Case 3: 29 year-old female with a history of more tha 15 years of CFS. The response to RNS, detected on the left abductor pollicis brevis, showed a 42 % incremental response at the stimulation rate of 10 Hz. CASS showed mildly cholinergic impairment (cardiovagal score 2, sudomotor score 1). Antibodies of EB virus were positive. Oral pyridostigmine therapy (30 mg) resulted in improvement of her symptoms. Our findings from these three cases introduce the hypothesis that CFS might be due, in part, to impairment of the neuromuscular junction and the autonomic nervous system. A small dose of oral pyridostigmine therapy may be expected to improve the symptoms of similar patients.

Peripheral Sudomotor Function in Familial Dysautonomia A Bickel1, F Axelrod2, H Marthol2, B Stemper1, B Neundörfer1, M Hilz1, 2 1 Department of Neurology, University of Erlangen-Nuremberg, Erlangen, Germany; 2 Department of Neurology, New York University School of Medicine, New York, New York, USA Background: Although suffering from a severe autonomic neuropathy, patients with Familial Dysautonomia (FD) commonly show episodic hyperhidrosis when stressed. Aim of this study was to examine function of peripheral sudomotors and sweat glands and to test for the hypothesis of peripheral denervation hypersensitivity. Methods: We performed a conventional quantitative sudo-motor axon-reflex test after installation of acetylcholine via a microdialysis membrane in 14 patients with FD and 15 healthy controls and additionally recorded direct and axon-reflex mediated sweat responses by measuring the transepidermal water loss (TEWA), a technique used for this purpose in neuropathy patients for the first time. Microdialysis samples were evaluated for acetylcholine induced plasmaextravasation. Results: Direct and axon-reflex mediated sweat responses measured by QSART and TEWA were highly correlated (p < 0,01), but no significant differences between patients and controls could be demonstrated. Conclusion: Despite sympathetic denervation, function of peripheral sweat glands and axon reflex sweating were undisturbed in FD patients. Therefore peripheral nerve damage seems not to be the relevant mechanism to explain impaired sweating reactions in FD patients.

Autonomic and Quantitative Sensory Testing in Diabetes A Wang1, K Bhattacharya1, Saadia2, H Kaufmann1 1 Mount Sinai Medical Center, New York, New York, USA; 2 Institute of Neurological Research, Buenos Aires, Argentina Objective: To evaluate the usefulness of cardiovascular autonomic testing and quantitative sensory testing (QST) in the detection of diabetic autonomic neuropathy. Background: Symptoms of autonomic neuropathy, the second most common type of diabetic neuropathy, are often non-specific. Non-invasive cardiovascular autonomic testing and QST are commonly used in the evaluation of autonomic neuropathies. Methods: A retrospective chart review of diabetic patients referred for neurological evaluation from 2000–2002 was undertaken. Results of non-invasive cardiovascular autonomic testing, including heart rate and blood pressure responses to deep breathing, Valsalva maneuver (VM) and postural change, and QST evaluation of cold and heat detection thresholds were analyzed. Results: Of 124 patients, 36 % were type 1 DM, 61 % type 2 DM and 3 % type 1.5 DM; age was 56 ± 14 years (range 23–93); and 53 % were female.Autonomic symptoms present in 109 patients (88 %) included: orthostatic hypotension (54 %); gastrointestinal motility disturbances (54 %); secretomotor dysfunction (53 %); erectile dysfunction (36 %); bladder dysfunction (26 %); vasomotor changes (11 %), blurred vision (9.1 %) and distal pain and burning (9.1 %). Forty-one of 109 symptomatic patients had autonomic testing. Parasympathetic function was abnormal in 8 (20 %), sympathetic function in 3 (7 %), and both in 9 (22 %). Twenty-seven of 29 (93 %) patients were found to have abnormal QST. Seventeen patients (17 %) with normal cardiovascular autonomic testing had abnormal QST. Conclusions: In patients with diabetes, the most common autonomic symptoms were orthostatic hypotension and gastrointestinal motility disturbances. Tests of cardiovascular function were abnormal in 49 % of patients tested. QST was abnormal in 93 % of patients tested. QST was abnormal in 17 % of patients with normal autonomic testing. A prospective study will be helpful to determine if cardiovascular autonomic testing and quantitative sensory testing are sensitive and specific enough to detect autonomic neuropathy in patients with diabetes.

Alterations in Autonomic and Cardiovascular Function among Individuals with Acute Neuromusculoskeletal Injury D Grimm1, R Kinnard1, J Weir2, J Burke1 New York Chiropractic College, Seneca Falls, New York, USA; 2 Des Moines University of Osteopathic Medicine, Des Moines, Iowa, USA

1

It is well established that consequences of peripheral tissue injury extend beyond the site of insult and include spinal and supraspinal changes in neuron excitability and activity. The purpose of this study was to noninvasively quantify alterations in autonomic and cardiovascular function among individuals with acute (< 1week) neuromusculoskeletal (NMS) injury. Autonomic cardiovascular modulation, baroreceptor sensitivity (BRS), skin conductance (SCR) and peripheral skin temperature (PStemp) were obtained in 6 subjects with acute NMS injury and 6 age- and gender-matched controls. The average level of pain as assessed using a Visual Analogue Scale was 4.6 ± 1.07 (range 0–10). Power spectral analysis was performed on both beat-to-beat R-R intervals (RRIHF) and continuous systolic blood pressure peaks (SBPLF). BRS was calculated using the Ω index: 1/2 [(RRILF/SBPLF)1/2 + (RRIHF/SBPHF)1/2]. SCR was determined as described by Lykken et al., (Psychophysiology 8: 656–675, 1971), and PStemp was assessed by applying a thermistor on the volar surface of the distal phalange of digit IV of the hand. The standard deviation of R-R intervals (SDNN), a time domain variable, were significantly different for the acute injury group relative to controls (49.8 ± 10.5

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vs. 76.8 ± 12.7 ms; p < 0.01); however, no differences were observed for the frequency domain variable RRIHF. In addition, SBPLF and SCR were significantly elevated (59.6 ± 6.7 vs. 23.8 ± 6.4 mmHg2/Hz; p < 0.01 and 3.87 ± 1.04 vs. 2.19 ± 0.29 1/Ω; p < 0.01, respectively) and BRS was reduced (0.97 ± 0.07 vs. 1.10±0.08 mmHg; p < 0.02) in the acute injury group compared to controls. Regression analysis revealed significant relationships between SCR and SBPLF (r = 0.75; p < 0.01) and SCR and BRS (r = 0.64; p < 0.02).These preliminary findings suggest that activity of and interaction between cutaneous and vasomotor sympathetic neurons in response to peripheral tissue injury, reflected as increased afferent input from sensitized nociceptors, can be depicted by alterations in autonomic and cardiovascular function.

Nonuniform Behavior of Baroreflex Control of Sinus Node During Sleep J Legramante1, F Placidi2, M Marciani2, A Romiti2, A Galante1, S Aquilani1, G Raimondi1, M Massaro1, M Pallante1, F Iellamo1 1 Dipartimento di Medicina Interna, Riabilitazione Cardiologica S. Raffaele Hospital, Universita “Tor Vergata”, Roma, Italy; 2 Clinica Neurologica, Universita “Tor Vergata”, Roma, Italy Recently we have shown that baroreflex control of sinus node is more active in buffering AP increases possibly occurring in REM stage in which a sympathoexcitation has been largely reported (Baroreflex control of sinus node during sleep. J. M. Legramante et al. XII Int. Symp. Auton. Nerv. System, 2001). Previous studies reported contrasting results showing no significant changes in BRS during the sleep stages. We hypothesized that these conflicting results might be due to a nonuniform behavior of the baroreflex control of sinus node during different phases of the night. We studied 10 healthy subjects. Polygraphic sleep recordings were performed. Arterial pressure (AP) and RR interval were recorded by Finapres and by an ECG lead. Baroreflex sensitivity (BRS) was calculated through the Sequence Method (Lag 1) both for hypertensive (up) and for hypotensive (down) sequences. The measurements were performed in the morning (Baseline) and during light, deep and REM sleep. * = p < 0.05 Vs Baseline UP Seq.

Baseline

Light

Deep

REM

Early Night msec/mmHg Late Night msec/mmHg

16.8±2.6

21.8±3.5

18.2±3.1

17.9±3.5

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Previously we have reported that distension of the main pulmonary artery by pressures in excess of 30 mm Hg leads to reflex increases in systemic vascular resistance (McMahon et al. 2000). These pressures are higher than those normally observed in the pulmonary circulation, indicating that physiological pressures may not elicit this response. However, this failure to observe reflex vasoconstriction at pressures below 30 mm Hg might also reflect the effects of general anaesthesia on autonomic reflex mechanisms. The aim of the present study, therefore, was to determine whether or not vagal afferent fibres respond to physiological changes in pressure distending the extrapulmonary pulmonary arteries. Experiments were undertaken in anaesthetised dogs (α-chloralose, 100 ml.kg–1) connected to a cardiopulmonary bypass. A pouch consisting of the entire extrapulmonary parts of the pulmonary arteries and the trunk was created and this was independently perfused with venous blood from a pressurized reservoir. Afferent activity was recorded from single unit or small multi-units in slips dissected from the left or right cervical vagi. In nine units, pulmonary baroreceptor activity was identified by an increase in mean discharge in response to an increase in pulsatile pouch pressure. An increase in mean pressure over the range from 4.5 ± 2.25 to 45.75 ± 3.75 mm Hg elicited an increase in activity from 11.5 ± 2.5 to 39.2 ± 7.0 impulses.s–1. At a mean pulmonary pressure of 21.0 ± 0.75 mm Hg, activity was significantly increased to 18.4 ± 4.8 impulses.s–1 (P < 0.05), representing 25 % of the overall response. We conclude that baroreceptors located in the extrapulmonary pulmonary arteries do show a significant increase in discharge in response to distension of this region over a physiological range of pressures. It is likely, therefore, that the vagal afferents attached to these receptors contribute to normal circulatory control. This work was supported by the British Heart Foundation. Reference McMahon, N. C. et al. (2000) Reflex responses from the main pulmonary artery and bifurcation in anaesthetized dogs. Experimental Physiology 85: 411–420

Baroreflex Sensitivity is Increased in AT2 Receptor Disrupted Mice J Tank1, J Jordan1, V Gross2, R Plehm2, A Diedrich3, M Obst2, F Luft1 Franz Volhard Clinical Research Center, Helios Klinikum, Charitè, Humboldt University, Berlin, Germany; 2 Max-Delbrück-Center for Molecular Medicine; 3 Vanderbilt University, Nashville, TN, USA 1

15.1±1.5*

20.3±2.4*

20.4±3.2*

26.4±3.0*

Down sequences did not demonstrate significant changes during the different sleep stages. Our results show that the baroreflex control of sinus node in response to hypertensive stimuli shows a significant increase in the gain along the different sleep stages recorded in the late night reaching the maximum value during REM sleep, whereas no significant changes were observed along the different sleep stages recorded during the first part of the night. Our data support our initial hypothesis of a non uniform behavior of BRS during sleep stages in different phases of the night.

An electrophysiological study of baroreceptors in the pulmonary artery of the anaesthetised dog J Moore, R Hainsworth, D Myers, M Drinkhill Institute for Cardiovascular Research, Leeds, West Yorkshire, UK

Acting through the AT1 receptor in the central nervous system, angiotensin II has effects on autonomic pathways regulating cardiovascular function. The role of the AT2 receptor is less well understood.We tested the hypothesis, that the AT2 receptor is involved in autonomic vascular regulation. Therefore, we investigated heart rate variability (HRV) and the spontaneous baroreflex sensitivity (BRS) in AT2 –/– (n = 8) and in AT2 +/+ , (n = 7) mice. We employed telemetry and adapted sequence analysis from humans to the mouse for this purpose. Data analysis was performed off-line for two hours segments (8 to 10 a. m.). HRV and BRS (cross spectra) were analyzed during 5 minutes of stationary data in the time and frequency domain (coefficient of variation, CV, standard deviation, SD, HF-power:1.0–3.0, LFpower:0.25–0.60, and VLF-power:0.015–0.250 Hz). Mean arterial pressure was 103 ± 3 mm Hg in AT2 –/– mice and 101 ± 2 mm Hg in AT2 +/+ mice. Mean pulse interval was 128 ± 5 ms in AT2 –/– mice and 123 ± 4 ms in AT2 +/+ mice. HRV tended to be higher in AT2 –/– mice (CV: 8.5 ± 1.3 vs. 6.1 ± 0.7; HF-power: 25 ± 10 vs. 9 ± 3 ms2). Systolic blood pressure variability in the LF band was markedly lower in AT2 –/– mice (LF-power: 0.6 ± 0.1 vs. 4 ± 1.3 mm Hg2). Baroreceptor-heart rate reflex sensitivity, calculated with the sequence technique, was

322

3.2 ± 0.3 in AT2 –/– and 2.1 ± 0.3 ms/mm Hg in AT2 +/+ mice (p < 0.05). Our data supports the hypothesis of an inhibitory central effect of the AT2-receptor with respect to baroreflex function.

Identification of Open-loop Transfer Function in Closedloop Baroreflex System using Random Breathing in Humans T Yingthawornsuk1, T Kawada2, T Sato2, M Inagaki2, K Sunagawa2, J Cox3, R Shiavi1, I Biaggioni4, A Diedrich4 1 Vanderbilt University, Dept. of Biomedical Engineering, Nashville, Tennessee, USA; 2 National Cardiovascular Center Research Institute; 3 Strayer University; 4 Vanderbilt University, Autonomic Dysfunction Center, Nashville, Tennessee, USA The existence of feedback loop in the baroreflex system makes it difficult to determine the open-loop transfer function characteristics of the central arc by which blood pressure (BP) modulates sympathetic nerve activity (SNA) and the peripheral arc by which SNA modulates BP. Random aortic pressure perturbation and electrical stimulation of aortic depressor nerve has been proposed to identify these openloop characteristics under closed-loop conditions in animals, but are limited for application in humans. We explored random breathing technique to identify open-loop characteristics under closed loop conditions in 14 healthy subjects (10m/4 f, 27 ± 2years, mean ± se). Random interval breathing perturbed BP with white noise characteristics in a frequency range of 0.01–0.3 Hz. We measured muscle SNA of the peroneal nerve and continuous BP. The peripheral arc transfer function (SNA→BP) could be approximated by a second-order lowpass filter. It’s fitted dynamic gain, natural frequency, and the damping ratio were 1.12 ± 0.35, 0.06 ± 0.01 Hz, and 0.49 ± 0.14 respectively. The central arc transfer function (BP→SNA) could be approximated with a first-order high-pass filter. Its fitted dynamic gain and corner frequency were 1.75 ± 0.28 and 0.17 ± 0.04 respectively. The low and high pass filter characteristics are similar to reported values in humans. In conclusion, the proposed random breathing technique is the useful tool for identification of the open-loop transfer functions of the central and peripheral arcs of the baroreflex system.

Prognostic Value of Baroreflex Gain in Post Acute Myocardial Infarction Patients Using the Modified Oxford C Morillo, MA Lindarte, JC Guzman, JP Casas, LA Cubillos, N Villamizar, F Silva, P Lopez-Jaramillo Research Institute, Fundacion Cardiovascular del Oriente, Bucaramanga, Santander, Columbia Background: Baroreflex sensitivity (BRS), using the Oxford method, has been useful as risk stratifier after myocardial infarction (MI). Administration of repeated sequential vasoactive agents (phenyleprine (PHE)- nitroprusside (NTP) and NTP-PHE) has been proposed as the most physiological method to evaluate baroreflex gain. The aim of this study was to evaluate the prognostic value of this sequential

method for the prediction of cardiovascular events after a first MI in a Colombian Population. Methods: 99 patients with a non-fatal MI were enrolled and followed. After clinical evaluation, the following variables were measured between 7 and 21 days after MI: BRS (sequential method [PHE1-NTP1 and NTP2-PHE2] and LVEF (by 2D-echo). Results: After mean follow up of 16.7 months (range 1 to 42), the cumulative rate of cardiovascular events was 25.2 % per year. LVEF (< 35) carried a univariated RR of cardiovascular events (2.5 [95 %CI 1.3–4.7). BRS Gain

PHE1 NTP1 PHE2 NTP1 < 8.0 ms per < 6.0 ms per < 8.0 ms per < 6.0 ms per mmHg mmHg mmHg mmHg

RR [95% CI]

3.5 [1.6–7.6] 65 76.4 50 85.7

Sensitivity % Specificity % PPV % NPV %

4.1 [1.7–10.1] 78.3 64.6 43.9 89.4

5.2 [1.31–20.7] 90.5 45.5 38.8 92.6

2.85 [1.1–7.3] 75 56.4 35.7 87.5

PPV Positive predictive value; NPV Negative predictive value Conclusion: As in previous trials our preliminary report, showed that reduced BRS was good predictor of an increased risk of cardiac events after an MI. However, the RR and diagnostic accuracy was higher after acute baroreflex resseting induced by either drops or increases in blood pressure. Thus, we recommend the use of repeated sequential vasoactive agents as a simple and efficient method to stratify patients at risk following an MI.

Cardiac Sympathetic Nerve Activity During Myocardial Infarction D Jardine, C Charles, R Brennan, C Frampton, G Nicholls Department of Medicine, Christchurch School of Medicine, Christchurch, New Zealand Cardiac sympathetic nerve activity [CSNA] affects infarct size, left ventricular remodelling and survival following myocardial infarction [MI] however direct measurement of CSNA has not been achieved in humans. We have recorded mean blood pressure [MBP], heart rate [HR] and CSNA continuously for 120 minutes during myocardial infarction [n = 8] in 6 conscious sheep. CSNA was recorded from stainless-steel electrodes placed in the left cardiothoracic nerves via thoracotomy 7 days before MI. Myocardial infarction was undertaken by applying sustained tension [for 24 hours] to a suture around the second diagonal branch of the anterior descending coronary artery 5 minutes after IV pethidine and diazepam. ECG changes consistent with acute MI were seen within one minute of occlusion. MBP remained constant between 83 ± 4 mmHg at baseline and 86 ± 5 at 120 minutes post occlusion [ANOVA P = 0.6]. HR increased from 114 ± 6 bpm at baseline to 125 ± 5 at 120 minutes [ANOVA P = 0.04]. HR increased 1 minute post occlusion to 130 ± 7 bpm [P = 0.05] and remained elevated after 15 minutes at 137 ± 6 [P = 0.03]. Thereafter HR gradually decreased to 125 ± 4 bpm at 120 minutes [P = 0.2]. CSNA increased from 63 ± 7 bursts/100 beats at baseline to 70 ± 7 at 120 minutes [ANOVA P = 0.06]. CSNA tended to decrease following analgesia to 56 ± 6 bursts per 100 beats [P = 0.3] and increased 1 minute post occlusion to 69 ± 5 [P = 0.5]. There was no correlation between CSNA and MBP [R = 0.3, P = 0.5] or HR [R = 0.4, P = 0.2]. Frequent ventricular ectopics [> 10 per minute] were seen between 10 and 20 minutes post occlusion in 75 % of MI’s. CSNA increases during myocardial infarction and appears to be sustained from approximately 60 minutes following arterial occlu-

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sion. IV analgesia may transiently inhibit CSNA and delay the CSNA response to MI. Increased CSNA was associated with an increase in HR. Ventricular ectopics following MI did not appear to be triggered by paroxysms of increased CSNA.

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Differential Effects of Aging on Baro- and Chemoreflex Regulation of Arterial Pressure: Selective Impairment of Baroreflex in Senescent Mice W Sun1, X Ma1, F Abboud1, M Chapleau2 of Iowa, Iowa City, Iowa, USA; 2 University of Iowa, Veterans Affairs Medical Center, Iowa City, Iowa, USA 1 University

No role for adrenaline in the pathogenesis of hypoglycaemia-induced counterregulatory failure BE de Galan, SJ Rietjens, CJ Tack, JWM Lenders, P Smits Department of Internal Medicine, University Medical Center Nijmegen, Nijmegen, The Netherlands Background and aims: The exact pathogenesis of hypoglycaemia-induced counterregulatory failure is not yet determined. Because adrenaline is one of the most important counterregulatory hormones and critical for acute glucose counterregulation in type 1 diabetes, we hypothesized that adrenaline would be involved in the development of hypoglycaemia-induced counterregulatory failure. Methods: Eleven healthy subjects (5M/6F, age 22 ± 2 y) participated in a randomized placebo-controlled single blind cross-over study, which consisted of two experimental days separated by 3–8 weeks. In the morning, participants received either adrenaline intravenously at three consecutive rates of 0.04, 0.06 and 0.08 µg·kg–1·min–1 that lasted 20 minutes each (aiming at plasma levels that match those caused by hypoglycaemia) or placebo (normal saline). After a 3-hour rest period, these infusions were followed by a hyperinsulinemic (60 mU·m–2·min–1) hypoglycaemic (5.0–3.5–2.5 mM) glucose clamp. Measurements included metabolic and cardiovascular responses, hypoglycaemic symptoms, sweat detection using a dew point electrode, and cognitive function. Results: Adrenaline infusion increased plasma glucose (+ 3.7 ± 3.5 mM), heart rate (+ 18 ± 2 bpm), systolic BP (+ 9 ± 2 mmHg), pulse pressure (16 ± 2 mmHg), and cardiac workload (+ 2.8 ± 0.3·103 bpm*mmHg, all P < 0.001), and decreased diastolic BP (–8 ± 2 mmHg, P < 0.001). Except for a slight fall in heart rate (–2 ± 1 bpm, P = 0.03), placebo infusion did not affect any of these parameters. Hypoglycaemia induced clear metabolic, symptomatic and cardiovascular responses on both occasions. Yet, these responses were similar after prior adrenaline or placebo infusion. In addition, no differences were found between prior adrenaline or placebo infusion in the fall of cognitive function and the glycaemic thresholds for the sweating response. Conclusions: Despite substantial increases in plasma adrenaline and consequent metabolic and cardiovascular responses, adrenaline infusion fails to affect counterregulatory responses to a subsequent hypoglycaemic event. These results do not support a role for adrenaline in the pathogenesis of hypoglycaemia-induced counterregulatory failure.

The effects of aging on baroreflex (BR) control of blood pressure (BP) and on afferent, central, and efferent components of the BR are controversial. The goal of this study was to contrast effects of aging on BR and chemoreflex (CR) control of BP in anesthetized, vagotomized mice (C57BL/6J). The BR and CR were assessed by measuring reflex increases in BP in response to bilateral carotid artery occlusion (BCO) during room air (21 % O2) ventilation (BR + CR) and after inhibition of CR activity by 100 % O2 ventilation (BR only). The CR component was calculated by subtracting responses during 100 % O2 from responses during 21 % O2. Baseline BP measured before BCO averaged 74 ± 4, 68 ± 7, and 63 ± 4 mmHg in young (10 ± 1 weeks), middle-aged (42 ± 3 weeks), and senescent (74 ± 7 weeks) mice, respectively. The initial increase in BP during BCO of 5 sec. was mediated entirely by the BR (see table). The CR contributed to the reflex as BCO was maintained for 30 sec. (table). The BR component of the reflex was robust and similar in young and middle-aged mice but was abolished in senescent mice (* P < 0.05, senescent vs. young and middle-aged). In contrast,the CR component of the reflex was enhanced in the old mice (**P < 0.05) (see Table). We conclude that aging selectively impairs BR mediated increases in BP. The effective CR mediated increase in BP in senescent mice suggests that efferent mechanisms are intact and that impaired afferent/central BR signaling is responsible for the loss of BR sensitivity.

Cardiovascular reactivity to perception of affect among older African-American adults M Merritt, D Abernathy, M Evans, J Sollers III,A Zonderman, J Thayer National Institute on Aging, Baltimore, Maryland, USA The present study used the Perception of Affect Test (PAT) to test autonomic and vascular responses to emotional stimuli. Participants were 69 African-Americans (37 males, 32 females; aged 18–85) who are part of the Healthy Aging In Nationally Diverse Longitudinal Samples Study. Participants evaluated emotional expressions in faces and sentences (PAT) and stood for five minutes (orthostasis, ORT). The PAT and ORT tasks were preceded by a five-minute baseline and followed by a five-minute recovery period. Heart rate (HR) and blood pressure (BP) were obtained continuously using a Portapres beat-tobeat BP monitor. Measures of log-transformed high frequency heart rate variability (HF-HRV) and alpha index (AI) were computed to assess vagal response and baroreceptor sensitivity (a combination of vagal and alpha-adrenergic factors). AI (p < 0.008) scores decreased during ORT but increased from ORT to PAT and from PAT to recovery. While HF-HRV (p < 0.0001) scores decreased during ORT and increased from ORT to PAT, HF-HRV scores leveled off during recovery.

Table to Sun et al. BCO Reflex Increase in BP (mmHg) Young (n = 8)

Middle-aged (n = 7)

Senescent (n = 6)

Duration of BCO

5 sec

30 sec

5 sec

30 sec

5 sec

30 sec

21% O2 (BR + CR) 100 % O2 (BR) Difference (CR)

+21±5 +17±4 +4±3

+47±6 +32±5 +15±4

+19±4 +21±4 –2±2

+56±3 +33±6 +23±6

+8±2* +2±3* +6±2

+41±8 +1±4 * +40±6**

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During recovery, low PAT scores were linked with higher vascular resistance (TPR), AI scores, and HF-HRV scores. We conclude that the recovery effect for TPR and diastolic BP is due to alpha-adrenergic influences. Thus, for African-Americans, poor emotion processing is linked with elevated vascular responses. These findings differ from those for Whites, for whom poor emotional processing has been associated with autonomic dysregulation.We consider possible cultural and social explanations for the different patterns found.

Stretching increases heart rate variability in athletes complaining about limited muscular flexibility M Mueck-Weymann, G Janshof, H Mueck Institute of Physiology and Cardiology, Univ. of Erlangen, Erlangen, Bavaria, Germany Introduction: Patients with coronary heart disease and signs of reduced heart rate variability (HRV) – indicating reduced vagal and/or increased sympathetic tone – have increased risk to suffer sudden cardiac death. Other cardiac risk factors (e. g. diabetic neuropathy, increased age) are also associated with reduced HRV, while normal or increased HRV seems to indicate good health. Statistical measures of HRV, e. g. by calculating the root mean square of successive differences (RMSSD) are thought to indicate cardiac risk. Subjects and methods: For further results of the role of stretching on HRV, we organized a pilot study with 15 male, healthy athletes (age: 22–44 years), initially complaining about “limited muscular flexibility”.All subjects practice “body building”for at least 2 hours a day and 5 times a week for more than one year. Starting at day 0, all volunteers practiced a standardized 15–20 min stretching program for 28 days. Measurements of i) HRV (using Polar Vantage & Advantage with Polar Performance 2.0 software), ii) flexibility in large joints (e. g. shoulder, hip), and iii) “well-being” were obtained at days 0 and 28. Results: Comparing individual data before and after the 28 days training period, we observed that HR decreased (e. g. whilst resting 79.1 ± 10.6 bpm vs. 65.1 ± 12.9 bpm, p < 0,001) while HRV increased significantly (25.2 ± 10.4 ms vs. 62.4 ± 26.9 ms, p < 0,001). In addition, there was a significant increase of flexibility and a tendency to better “well-being”. Conclusion: It is indicated, that putative mechanisms of HRV increase by: i) release of vasodilative agents (e. g. EDRF) due to “stretching of vessels endothelia”, ii) neuromuscular interferences reducing muscle tone, and iii) common psycho-physiological relaxation. With respect to the wide spread suggestion that HRV is an indicator of cardiac risk one could speculate on cardioprotective effects of stretching.

Symptoms of Autonomic Dysfunction in Patients with Neurogenic Orthostatic Hypotension Compared to Other Chronic Diseases J Gilden, M Saegh, D Ramirez, A Tartakover, G Wahidi, I Garcia Diabetes/Endocrinology Section, Finch University of Health Sciences/The Chicago Medical School, North Chicago, Illinois, USA Autonomic neuropathy can result in abnormal function of the gastrointestinal tract, urogenital system, pupillary responses, as well as sleep disturbances, sweating abnormalities, and orthostatic hypotension. In order to evaluate the prevalence of other abnormal autonomic symptoms in patients with neurogenic orthostatic hypotension (NOH), a 21-item questionnaire was administered to 35 NOH (due to Diabetes Mellitus (DM), Pure Autonomic Failure, Parkinson’s Disease, Multiple System Atrophy, Mitral Valve Prolapse, and other autoimmune etiologies) (mean age = 48 ± 3yrs) (12 = male:23 = female) (mean decrease in systolic blood pressure (SBP) following upright

posture = 25 ± 2 mm with lack of an adequate tacchycardic response) (expiratory:inspiratory RR EKG ratio = 1.00 ± 0.1)(QTC interval = 408 ± 6 mm) (resting HR on EKG = 73 ± 2).The responses were compared to 157 patients with other chronic Endocrine diseases without NOH (80 % = DM, 15 % = thyroid disorders, 5 % = other (mean age = 52 ± 3 yrs) (55 male:102 female). Patients with NOH were more likely to identify dizziness (p < 0.000), as well as, symptoms suggestive of other abnormalities of the autonomic nervous system (gastrointestinal, especially gastroparesis (p < 0.002), salivary (p < 0.012), sleep apnea (p < 0.04), tiredness (p < 0.000), venous pooling upon standing (p = 0.05), and sweating (p < 0.06). A composite autonomic neuropathy score was also abnormal (p < 0.000). Patients with other chronic diseases were less likely to note these abnormalities. Items suggestive of abnormal pupillary responses, sexual and bladder function were not significantly different between either group. Symptoms of peripheral neuropathy were more common in NOH (p < 0.05). Additionally, 2 questions not related to AN were added and did not elicit positive responses in NOH. Greater autonomic dysfunction correlated with symptoms of tiredness (R = 0.5; p < 0.04), and venous pooling (R = 0.5; p < 0.05). These patients had greater decreases in SBP after upright posture (R = 0.4; p < 0.01). In conclusion, patients with neurogenic orthostatic hypotension clearly identify other symptoms of autonomic dysfunction more frequently than patients with chronic Endocrinologic disease states. Therefore, this questionnaire can serve as a reliable assessment tool for identifying other features of autonomic dysfunction which may require further evaluation and treatment interventions in patients with Neurogenic Orthostatic Hypotension.

Cardiovascular and Autonomic Recovery from Maximal Exercise in Persons with Pareplegia J Wecht1, R Marsico2, A Spungen1, W Bauman1, R DeMeersman3 Bronx VAMC, Bronx, New York, USA; 2 University of Medicine and Dentistry of New Jersey, Stratford, New Jersey, USA; 3 Columbia University College of Physicians and Surgeons, New York, New York, USA

1

Recovery from a maximal exercise test has been used to identify cardiovascular conditioning and overall health. We observed the recovery rate in cardiovascular and autonomic function following a maximal arm ergometry exercise test in individuals with paraplegia. Subjects were male, 38 ± 9 years of age with a complete injury below T-6 who were either endurance trained (ET, n = 10) or sedentary (S, n = 9).An incremental arm exercise test was performed (ET: 24 and S: 12 watts/min) with cardiovascular/autonomic measurements collected during baseline and recovery at 10, 30, 60 and 90 minutes. Heart rate (HR) and the normalized low (LF-RRI) and high (HF-RRI) frequency spectral components of HR variability were assessed in the recovery phase and compared to baseline measures. Paired t-tests were used to determine the difference between recovery and baseline measures for the dependent variables. Exponential regression was used to determine the predicted rate of recovery in the ET and S groups separately. Simple regression was applied to predict the time to return to baseline. Maximal oxygen consumption and watts were significantly higher in the ET compared to the S group [2.22 ± 0.24 vs. 1.48 ± 0.42 (L/min) and 164 ± 19 vs. 105 ± 27 (watts); respectively, P < 0.0001]. For the entire group HR was significantly elevated above baseline at 10 & 30 minutes of recovery (P < 0.0001 & P < 0.01, respectively), but not at 60 & 90 minutes (P = 0.08 & P = 0.64). HF-RRI was significantly reduced compared to baseline at all time points during recovery (P < 0.01) for the entire group. LF-RRI was not statistically different from baseline at 10 minutes but was significantly elevated at 30,60 and 90 minutes of recovery (P < 0.01, P < 0.01 & P < 0.05, respectively). In the ET compared with the S group, the predicted time to return to baseline HR was 81 vs. 85 minutes (NS); HF-RRI was 105 vs. 121 minutes (P < 0.05); and LF-RRI was 36 vs. 42 minutes (P = 0.06). A significant inverse relationship between HF-RRI and HR was identified in

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the ET group (r2 = 0.40, P < 0.01) but not in the S group. These preliminary results suggest that cardiovascular fitness plays a role in exercise recovery and that specific “vagal reactivation” may be the key mechanism.

A biphasic model of limb venous compliance: a comparison with linear and exponential models M Risk1, V Lirofonis1, R Armentano2, R Freeman1 1 Harvard Medical School – BIDMC, Boston, Massachusetts, USA; 2 Favaloro University Objective: To model limb venous compliance in healthy subjects. Background: Venous compliance plays an important role in cardiovascular homeostasis. Recent studies have used linear techniques to characterize the pressure-volume relationship of the venous system. Compliance is not linear within the physiological range of pressures and linear modeling of the venous pressure-volume relationship may not adequately describe venous physiology. Material and methods: Forearm and calf venous compliance was assessed in 9 subjects. Changes in venous volume.Venous compliance was modeled with: 1) a biphasic model with high- and low-pressure linear phases separated by a break point; 2) a linear model and 3) a two coefficient exponential model. Results: The biphasic model showed superior modeling characteristics. The mean coefficient of determination for the biphasic model was greater than the linear and exponential models in the calf (biphasic 0.94 ± 0.03, linear 0.54 ± 0.05, and exponential 0.87 ± 0.05, P < 0.05) and forearm (biphasic 0.84 ± 0.16, exponential 0.80 ± 0.15, P = NS, and linear 0.51 ± 0.05 P < 0.05). The breakpoint pressure between the low- and high-pressure phases was significantly higher in the calf than the forearm (34.3 ± 4.6 mmHg vs. 27 ± 3.8 mmHg, P = 0.003). The venous compliance versus pressure slopes for the low-pressure phase were significantly steeper than the high-pressure phase in the calf (–0.0035 ± 0.0025 ml/dl/mmHg2 vs 0.0014 ± 0.0004 ml/dl/mmHg2, P = 0.04). There was a trend, which approached significance, toward differences between the high- and low-pressure phase slopes in the forearm. Conclusion: Limb venous compliance in the calf and forearm is best described with a biphasic model. This model accurately delineates differences in venous physiology at high and low pressures. Furthermore, this model yields insight into differences between the venous function in the calf and forearm. The steep low-pressure phase of the compliance curve (below the breakpoint) extends to higher pressures in the calf than the forearm. Thus, consistent with the homeostatic requirement of the upright posture, the range in which hemodynamic regulation by the calf venous circulation occurs is enlarged.

Cerebral autoregulation remains stable during physical challenge in healthy persons M Brys1, H Marthol1, B Stemper2, R Franta2, F Axelrod1, M Hilz1, 2 1 Department of Neurology, New York University, New York, New York, USA; 2 Department of Neurology, University of Erlangen-Nuremberg, Erlangen, Germany The effects of physical activity on cerebral blood flow and cerebral autoregulation (CA) have not been fully evaluated so far. There is controversy whether increasing heart rate (HR), blood pressure (BP), sympathetic and metabolic activity with altered levels of carbon dioxide (CO2) might compromise cerebral blood flow and CA. To evaluate these effects we studied middle cerebral artery blood flow velocity (CBFV) and CA in healthy volunteers at rest and during increasing levels of physical exercise.

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In 40 healthy young adults (24 male, 16 female; 27.9 ± 5.4 years) we continuously monitored HR, beat-to-beat BP, end-expiratory CO2 (Colin Pilot™) and CBFV using transcranial Doppler sonography at rest and during standardized,stepwise ergometric challenge at 50,100 and 150 Watt (3 min each). For each level of activity, sympathetic modulation of BP and CBFV was derived from the spectral powers of signal modulation in the 0.04–0.15 Hz range (LF-power) using autoregressive analysis of 60 sec epochs. CA was calculated as the transfer function phase between BP and CBFV in the LF range provided signal coherence was above 0.5. In addition, we calculated cerebrovascular resistance (CVR = BPmean adjusted to brain level/ CBFVmean). HR, BP, CO2 and CBFV increased significantly with exercise (p < 0.05). Transfer function phase (+ 41.2 ± 18.9° at rest, + 32.9 ± 23.3° at 50 Watt, + 44.5 ± 26.5° at 100 Watt, + 55.2 ± 51.3° at 150 Watt; p > 0.05) and CVR (1.24 ± 0.3, 1.20 ± 0.3, 1.19 ± 0.3, 1.22 ± 0.3) remained stable during exercise. Stable phase shift and CVR demonstrate that in healthy persons increasing levels of physical challenge do not alter cerebral autoregulation despite increasing HR, BP, sympathetic activity and CO2.

Cerebral autoregulation remains stable in atherosclerotic patients during enhanced external counterpulsation H Marthol1, D Werner2, C Brown3, B Neundörfer3, WG Daniel2, M Hilz1, 3 1 Department of Neurology, New York University, New York, New York, USA; 2 Department of Cardiology, University of Erlangen-Nuremberg, Erlangen, Germany; 3 Department of Neurology, University of Erlangen-Nuremberg, Erlangen, Germany Enhanced external counterpulsation (EECP) is a new method to improve coronary perfusion in atherosclerotic patients. EECP augments mean blood pressure (BP) by means of rhythmical lower-body compression during the diastole of the electrocardiogram (ECG). Effects of EECP on cerebral perfusion and particularly cerebral autoregulation have not yet been analyzed. In this study, we assessed whether EECP affects cerebral autoregulation in healthy controls and in atherosclerotic patients. In 23 healthy volunteers (27.9 ± 4.0 years) and 15 patients with atherosclerosis (64.7 ± 7.7 years), we monitored heart rate (HR), BP [Colin Pilot™, San Antonio, TX] and middle cerebral artery blood flow velocity (CBFV) by means of transcranial Doppler sonography [MultiDop X4™, DWL], before and during 5 min EECP. Respiration was paced at 12/min. During EECP, ECG triggered pressure of 300 mmHg was rhythmically applied [Vasomedical Inc., Westbury, USA]. Spectral powers of the time series of HR, BP and CBFV were analyzed in the low (LF: 0.04–0.15 Hz) and high (HF: 0.15–0.5 Hz) frequency range. Cerebral autoregulation was determined from the transfer function gain and phase shift of BP and CBFV in the low frequency range (0.04–0.15 Hz). HR and BP increased during EECP in controls (72.7 ± 9.0 vs. 75.6 ± 8.6 bpm, 83.4 ± 10.2 vs. 86.2 ± 9.8 mmHg) and in patients (69.7 ± 9.4 vs. 73.6 ± 9.1 bpm, 86.4 ± 20.0 vs. 92.4 ± 24.1 mmHg) (p < 0.05). CBFV decreased in controls (55.0 ± 18.5 vs. 50.1 ± 17.0 cm/s), but did not change in patients (46.7 ± 11.5 vs. 47 ± 11.8 cm/s). EECP had no influence on transfer function gain (controls: 0.8 ± 0.3 vs. 1 ± 0.5 cm/s/mmHg, patients: 0.8 ± 0.3 vs. 1.1 ± 0.8 cm/s/mmHg) or phase (controls: 0.8 ± 0.3 vs. 0.9 ± 0.4 rad, patients: 1.0 ± 0.4 vs. 0.9 ± 1.1 rad). Stable gain and phase values during EECP suggest that EECP does not compromise cerebral autoregulation. EECP, therefore, does not seem to bear any cerebrovascular risks such as inadequate increase of cerebral perfusion with secondary risk of cerebral hemorrhage.

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Head orientation in the coronal plane modulates sympathetic outflow during linear acceleration H Kaufmann1, I Biaggioni2, A Voustianiouk1, A Diedrich2, R Clarke3, M Gizzi3, T Raphan1, B Cohen1 1 Mount Sinai School of Medicine, Department of Neurology, New York, New York, USA; 2 Vanderbilt University, Department of Medicine, Nashville, Tennessee, USA; 3 New Jersey Neuroscience Institute, JFK Medical Center, Edison, New Jersey, USA We have recently shown that a short latency vestibulosympathetic reflex, likely originating in the otolith organs, is activated by linear acceleration along the head naso-occipital axis (Kaufmann et al., Exp Brain Res 2002). To determine the potential contribution of extravestibular afferents to this reflex, we dissociated the orientation of the head (otolith afferents) and body (extravestibular afferents) by having subjects turn their head and neck 65° during rotation at 60°/s about an axis tilted 15° (off-vertical axis rotation, OVAR). This produced 0.24 g of sinusoidal linear acceleration along all axes in the coronal plane. Rotation with the head turned about an earth vertical axis (EVAR), which does not stimulate the otoliths, and OVAR with the head straight provided controls. Muscle sympathetic nerve activity (MSNA) was continuously monitored in the peroneal nerve. During OVAR with the head straight and turned, MSNA entrained to the frequency of rotation in all (5) subjects with the peak occurring shortly after the nose-up position. When subjects turned their heads opposite to the direction of rotation, peak MSNA activity occurred about 30° later in the rotation cycle (p = 0.03) than when the head was straight. Thus, the peak in MSNA was driven by the maximal acceleration along the head naso-occipital axis. This finding confirms the presence of a vestibulosympathetic reflex in humans and indicates that otolith afferents play an important role in the genesis of this reflex. This vestibulosympathetic reflex could contribute to maintenance of blood pressure during the forward linear acceleration experienced upon standing. Supported by NIH grant NGA 5 R01 DC04212.

Case study: Reinnervation of cutaneous vasoconstrictor but not active vasodilator pathways in a split thickness skin graft C Crandall, J Cui, T Wilson, K Williams Institute for Exercise and Environmental Medicine, Dallas, Texas, USA The objective of this study was to identify whether reinnervation of cutaneous vasoconstrictor and active vasodilator pathways occur in a split thickness skin graft. The study was completed on a 31 year old female, 6 years following split thickness skin grafting on her thigh (area ~60 cm2). Reinnervation of the cutaneous vasoconstrictor pathway was assessed via indirect whole-body cooling, while reinnervation of the cutaneous active vasodilator pathway was assessed via indirect whole-body heating. Sweat gland function and endothelial dependent cutaneous vasodilation was assessed via intradermal microdialysis administration of acetylcholine. For all protocols skin blood flow (SkBF) and sweat rate (SR) were measured from grafted and adjacent ungrafted skin. SkBF was quantified via laser-Doppler imaging, while SR was quantified using a ventilated capsule. Indirect whole-body cooling reduced SkBF by 33 % at the grafted site (54 to 36 flux units) and reduced SkBF by 51 % at the ungrafted site (101 to 49 flux units). During the heat stress, at the grafted site the elevation in SkBF (54 to 84 flux units, increase 56 %) and SR (0.06 to 0.07 mg/cm2/min) was greatly attenuated relative to the elevation in SkBF (101 to 380 flux units, increase 277 %) and SR (0.05 to 0.49 mg/ cm2/min) at the ungrafted site. Intradermal administration of acetylcholine did not cause sweating from grafted skin, while nor-

mal sweating responses were observed from ungrafted skin. However, appropriate vasodilator responses were observed in both grafted and ungrafted skin during administration of acetylcholine, suggesting functional endothelial dependent vasodilation. For this patient the cutaneous vasoconstrictor pathway seems to be reinnervated, while innervation of the cutaneous active vasodilator pathway is less apparent. It is unclear whether the absence of sweating from grafted skin during the heat stress is due to a lack of innervation of sweat glands or an absence of functional sweat glands.

Deep breathing test is very important marker of cardiovascular dysfunction by patients with diabetes mellitus and vagal denervation B Milovanovic, M Krotin, L Vusovic, S Kulezic, V Bisenic, A Milovanovic* C. H. C. *B.Kosa, Department of Cardiology, University of Belgrade, Belgrade, Yugoslavia Introduction: Diabetic autonomic dysfunction is very often followed with cardiovascular dysfunction which can lead to appearance of sudden heart death depending of vagus damage and sympathicus activity. The aim: of the study was to establish significance of deep breathing test in diagnosis of vagal denervation and assessment of risk prediction significance using correlation of test results with signs of cardiovascular dysfunction including: left ventricle dysfunction, arrhythmias and ischaemia. Methodology: 83 (44\M,39\F) diabetics are being examined and divided into 3 groups in dependence of results of Deep breathing test: Diabetics with negative test (n = 32, 15\M, 17\F), Diabetics with borderline test (n = 19, 14M, 5F), Diabetics with positive test (n = 32, 15\M, 17\F). All diabetics were underwent to cardiovascular reflex tests (according to Ewing): Valsalva maneuver, deep breathing, 30\15 ratio test (for vagus), orthostatic hypotension test, hand grip test (for sympathicus). The most patients had 24h Holter ECG Monitoring (with parameters: ischemia-ST depression > 1mm, disorder of rhythm: Lown > II, Lown < II) and echocardiograhy examination (systolic dysfunction-EF < 40 %, diastolic dysfunction-A > E, MMODparameters). Results: Diabetics with complete autonomic sympathetic and vagal denervation had positive test in 22 (68,75 %) cases, borderline in 8 (42,10 %) and negative in 5 (15,62 %) patients. p < 0,01. Diabetics with vagal denervation had positive test in 32 (100 %) p., borderline in 12 (63,15 %) and negative in 6 (18,75 %) p. p < 0,01. Test of 30; 15 ratio was positive in 22 (68,75 %) p. IIIG, 13 (68,42 %) p. IIG, 12 (37,50 %) p. IG. P < 0,01 Valsalva maneuver was positive in 20 (68,96 %) p. IIIG, 3 (20 %) p. IIG, 3 (9,67 %) p. IG. p < 0,01. Disorder of systolic function had 10 (35,71 %) p. with positive test, 9 (47,36 %) borderline and 3 (11,53 %) p. with negative test. p < 0,05. Dilatation of left ventricle had 12 (42,85 %) p. IIIG, 6 (31,57 %) p. IIG and 3 (11,53 %) p. IG. p < 0,05. Disturbance of rhythm had 12 (54,54 %) p. IIIG, 9 (60 %) p. IIG, 5 (26,31 %) p. IG. p > 0,05 Ischaemia was present in 22 (36,36 %) p. with positive test, 6 (42,85 %) p. with borderline and by 6 (31,57 %) p. with negative test. p > 0.05 Ischaemia with arrhythmias was present in 8 (38,09 %) p. with positive test, 8 (66,66 %) with borderline and 3 (18,75 %) p. with negative test. p < 0,05. Conclusions: There is statistical significance in correlation of positive deep breathing test with disorder of systolic function, dilatation of left ventricle and appearance of ischaemia and arrhythmias together.

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Deep breathing test as a risk predictor in patients with myocardial infarction B Milovanovic, M Krotin, S Kulezic, L Vusovic, V Bisenic, A Milovanovic C. H. C. B. Kosa, Neurocardiological Laboratory, University of Belgrade, Belgrade, Yugoslavia The investigation of cardiac autonomic dysfunction using combination of cardiovascular reflex tests and analysis of heart rate variability can play very important role in risk stratification of patients with myocardial infarction. The aim was to examine the comparison between deep breathing test and other risk predictors especially nonlinear parameters (space plot) of HRV. Methodology: We have analyzed the data from 590 patients who are involved in our program for risk stratification after myocardial infarction.All patients were underwent to short (5 minute.) power spectral analysis of heart rate variability with late potentials and nonlinear analysis (Poincare plot) using commercial software (Schiller, Switzerland) (1st, 7th day, 3rd week). The results of nonlinear analysis were divided related to visual form (cigarette, cluster, comete). Long term power spectral and QT interval analysis was made with Holter ECG (3rd week). Cardiovascular reflex test according to Ewing. were performed by all patients. Some patients were underwent to mental stress test, hyperventilation test and cold pressure test. QTc. interval and dispersion was analyzed 1st–7th day and 3rd week. Echocardiography examination (Acuson,Sequoia) included: Mmod parameters,systolic disorder-EF < 40 %, diastolic disorder-A > E. Results: The deep breathing test was positive in 46 (79,30 %) patients with space plot as a cigarette, 28 (60,90 %) patients with comet and by 7 (43,80 %) with cluster form (p < 0,01). The deep breathing test was positive in 17 (94,40 %)patients with systolic dysfunction of left ventricle and 54 (64,30 %)without (p < 0,05). Valsalva maneuver was more positive in patients with space plot as a cigarette, but sex months after infarction. There was not a statistically difference comparing other cardiovascular reflex tests and nonlinear parameters of heart rate variability. Conclusions: Patients with positive deep breathing test had more often presence of space plot parameters as a cigarette and comet form related to the fact that damage of vagus is followed with higher sympathetic nonlinear parameters.

Influences of the Norepinephrine Transporter on Cardiac Electrical Activity M Behrend, A Gapelyuk, J Tank, FC Luft, A Schirdewan, J Jordan Franz Volhard Clinic, Humboldt University, Berlin, Germany The heart is particularly dependent on norepinephrine transporter (NET) function for the inactivation of released norepinephrine. NET expression and regional distribution of NET in the heart are influenced by age, diabetes, uremia, and heart failure. All these conditions are associated with the propensity to experience cardiac dysrhythmias. Therefore, we characterized the role of NET in cardiac depolarization in 9 healthy subjects (24–39 years) using magnetocardiography. Magnetocardiography records magnetic fields generated by the electrical activity of the heart. Testing was conducted after the subjects had ingested 8 mg of the selective NET blocker reboxetine or placebo 12 hrs and 1 h before testing. On a separate occasion, subjects were tested after ingestion of 200 mg metoprolol 1 h before testing. NET blockade increased supine heart rate and blood pressure moderately and induced orthostatic tachycardia (upright heart rate 81 ± 3 bpm with placebo, 111 ± 4 bpm with reboxetine p < 0.001). Metoprolol decreased supine as well as upright heart rate and blood pressure. QT interval length was reduced with NET inhibition (407 ± 9 msec

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with placebo, 390 ± 8 msec with reboxetine, 412 ± 8 msec with metoprolol, p < 0.001). However, QT dispersion (36 leads reconstruction), T-wave amplitude, and other markers related to homogeneity of cardiac depolarization and repolarization were not changed with NET inhibition. We conclude that NET function influences QT interval length in humans.This effect appears to be homogenously distributed in the healthy heart. We propose that in disease states associated with changes in cardiac NET distribution, NET might contribute to the inhomogeneity in cardiac electric activity.

Sweat response of the face to intraoral application of capsaicin Y Inukai, J Sugenoya, N Nishimura, T Umeyama, T Matsumoto, M Kato, A Ogata Department of Physiology, School of Medicine, Aichi Medical University, Aichi, Japan In a warm environment (30 °C,40 % relative humidity) sweating in the facial areas was examined by the ventilated capsule method in seventeen healthy young males. Local application of Tabasco® or red pepper (capsaicin as principal ingredient) to the tip of the tongue, the mucosal sites under the tongue or the sites of buccal mucosa produced a sweat response characterized by an early rapid and a subsequent slow rise during application, and a slow decline after removal. Such responses were almost always noted in the perioral regions, but less frequently in the cheek or the forehead. Similar, but rather weak, responses were often noted when vinegar, salt or sugar solution was applied to those intraoral sites. Sweating in the chest and the forearm was essentially unaffected, but was sometimes suppressed during the application of red pepper. When red pepper suppressed the sweating, the tympanic temperature fell rather rapidly. Skin pressure applied unilaterally to the axillary region suppressed the Tabasco®-induced sweating in the ipsilateral face. When unilateral stellate ganglion was blocked, Tabasco® did not elicit sweat responses in the face on the blocked side.The results suggest that the efferent pathway of the sweat response to capsaicin is the usual sudomotor nerve fibers that descend the spinal cord and ascend via the cervical sympathetic ganglions to the facial skin. It is most likely that the receptors of the sweat response are nociceptors located extensively in the oral mucosa involving the tongue. However, the afferent pathway and the center of the reflex mechanism were not identified by the present data.

Kidney length as a parameter of renal damage in children with spina bifida T de Jong-de Vos van Steenwijk1, E van Os1, P Dik1, T de Jong1, J van Gool2 1 University Medical Centre Utrecht/Wilhelmina Children’s Hospital, Utrecht, The Netherlands; 2 Dept. of Urology, University Hospital Antwerp, Belgium Introduction: there are no data in the literature on the incidence of kidney parenchymal damage in children with myelomeningocele (MMC), but we do know that in 30 % of adolescents with MMC endstage renal failure is the cause of death. Starting in the mid-seventies, in Utrecht, urological management of children with MMC consisted of regular screening for urinary tract infection and low-dose chemoprophylaxis, uroradiological imaging, and periodic urodynamic investigations in children with detrusorsphincter dyssynergia and obstructive uropathy or high-pressure reflux, the aim was to restore complete bladder emptying and combat detrusor overactivity. As of 1986, this was achieved mainly with clean intermittent catheterization (CIC) and treatment with antimus-

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carinics, and because of the promising results of this management we then introduced CIC and antimuscarinics in all infants with MMC and detrusor-sphincter dyssynergia. Material and methods: the aim of the present study is to evaluate renal growth in all subjects with MMC, followed in Utrecht, and born between 1965 and 1995. As renal damage in children with MMC occurs mostly at adolescence, kidney length was the only parameter available to measure loss of kidney parenchyma over such a long period of time. Results: Before age 2–3 years, all individual kidney lengths are within the normal centiles for age.After age 2–3 years, individual kidney lengths start to show deviation from the values for normal children: they can be above the 95th centile, indicating upper tract dilatation and obstructive uropathy, or below the 5th centile, as a consequence of retarded growth and/or scarring. The incidence of kidney parenchymal scars in the Utrecht population is 15 %, about half the 30 % reported in the literature.As yet, there are no cases of renal failure in this population. Abnormal kidney lenghts as well as scarred kidneys occur predominantly in the MMC-children with detrusor-sphincter dyssynergia. Conclusions: It seems clear that children with MMC are born with normal kidneys, and that even with up-to-date management scarring and upper tract dilatation do occur, predominantly in the presence of detrusor-sphincter dyssynergia. Progression of scarring to renal failure can and should be avoided, by introducing CIC with antimuscarinics as soon as possible in the management of the MMC-children at risk.

The next step towards non-invasive microneurography E Lerner1, J Peuscher2 1 Lerner Medical Technology Ltd., Amsterdam, Noord Holland, The Netherlands; 2 Twente Medical Systems International BV, Enschede, Twente, The Netherlands Previously, we described the presence of fast waves (FW) with frequencies of 3–15 Hz in the palmar and plantar skin potentials. Recent spectral analysis showed that the FW have the highest power between 2 and 6 Hz. In this frequency range the power is 10 to 20 times higher. The existence of a 2–6 Hz rhythm in sympathetic nerve discharge has been described in literature and is suggested to be generated by a brainstem network. We developed a new registration method that filters the muscle activity and movement artefacts from the skin recorded potentials. Studies were performed in healthy subjects (n = 12) that were administered atropine (1 mg i. m.) and in patients (n = 5) subjected to a right-sided stellate block. Registrations were made from the palmar and plantar sites as well as from the underarms and legs using a reference amplifier of which all channels are equipped with an AD convertor, so there was no sampling skew. The analogue bandwidth was DC to 30 Hz. Additionally, the signal was high pass filtered using a third order software filter with a cut-off frequency of 1.5 Hz. The results of these studies showed that the FW recorded from all investigated skin sites were affected by atropine and by a stellate block. Spectral analysis revealed a strongly reduced power of the FW in the 2–6 Hz range, which confirms that the FW are of autonomic origin and are at least partly under cholinergic control. Based on the obtained results in this and previous studies we think that: a) the 2–6 Hz FW are the same as the 2–6 Hz rhythm in the sympathetic nerve discharge and, b) the 2–6 Hz FW may be used as in a non-invasive method to test the activity of the autonomic nervous system.

Kinetics of Heart Period Variability During Head-up Tilt: A Preliminary Analysis Using the Discrete Wavelet Transform J Weir1, J Wecht2, R DeMeersman3, A Spungen2, W Bauman2 1 Des Moines University – Osteopathic Medical Center, Des Moines, Iowa, USA; 2 Spinal Cord Damage Research Center, Bronx VAMC, Bronx, New York, USA; 3 Dept of Rehabilitation Medicine, Columbia University, New York, New York, USA Frequency domain analysis of heart period variability using the Fourier transform assumes stationary data. In contrast, the discrete wavelet transform (DWT) does not assume stationarity and therefore allows for the study of changes in heart period frequency characteristics during provocations. The purpose of this study was to apply the DWT to heart period data during orthostatic provocation. Electrocardiogram data from 17 subjects with paraplegia (P) and 6 able-bodied (AB) controls matched for age, height and weight (39 ± 8 yrs, 177 ± 8 cm and 83 ± 19 kg, respectively) were analyzed during 120 seconds of 75-degree head-up tilt (HUT) compared to supine recordings. The transition from supine to HUT was accomplished within the first 10 seconds of the 120-second maneuver.After peak detection was performed the heart period data were interpolated, re-sampled and fed into a Daubechies 4 algorithm. The wavelet coefficients from the scales corresponding to the low-frequency (LF: 0.04–0.15 Hz) and high-frequency (HF: 0.15–0.4 Hz) regions of traditional Fourier analysis were isolated into six, 20-second epochs. From each epoch the sums of squares of the wavelet coefficients were calculated and the LF/HF ratio was determined. These data were statistically analyzed with a group by condition by time (2  2  6) mixed ANOVA with the Huynh-Feldt correction. There were no group effects, however the condition  time interaction approached significance (p = 0.051). The baseline condition was essentially flat while tilt resulted in an increase in the LF/HF ratio over the first three epochs that was attenuated over the final three epochs. These results indicate that an increase in LF/HF occurs in the first minute of HUT and declines thereafter. The similar kinetics between P and AB likely reflects the fact all P subjects had lesions below T6 and therefore had intact innervation to the heart.

Correlation of peak frequencies from power spectral analysis of slow modulation of EEG background amplitude, heart rate, blood pressure, and middle cerebral artery flow velocity during head-up tilt in subjects with Postural Tachycardia Syndrome (POTS) and controls T Lagerlund1, V Novak2, P Novak2, P Low1, S Hines1, N Busacker1 1 Mayo Clinic, Rochester, Minnesota, USA; 2 Ohio State University De-

partment of Neurology, Columbus, Ohio, USA It has been suggested that slow (< 0.5 Hz) modulation of EEG background amplitude may have a brainstem autonomic origin because similar slow frequencies were recorded from brainstem cardiovascular/respiratory centers in animals. We recorded EEG, blood flow velocity in middle cerebral artery (MCAFV) with transcranial Doppler, heart rate (RRI), respirations (RES), and blood pressure (BP) from POTS patients and age-matched controls during head-up tilt (HUT). Peak alpha amplitudes were found by time-frequency analysis of 0.512-s epochs of EEG. Spectra calculated by time-frequency analysis using 128-s epochs were divided into 3 bands (ultraslow, 0–0.045 Hz; middle, 0.045-–x Hz; respiratory, x–0.5 Hz) where x is peak frequency of respiratory spectrum minus 12 times half width at half maximum of respiratory spectral peak. Correlations were obtained between peak frequencies within each band for all signal pairs during pre-tilt and HUT. Highest correlations occurred between systolic and diastolic BP modulation frequencies (0.26 for POTS, 0.27 for controls in ultraslow band pre-tilt [NS]; 0.50 for POTS, 0.47 for controls in middle band during HUT [NS]; 0.67 for POTS, 0.54 for controls in respi-

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ratory band for entire recording [p < 0.01]). Moderate correlations occurred between diastolic and systolic MCAFV modulation frequencies in ultraslow band pre-tilt (0.22 for both POTS and controls); between diastolic MCAFV and (1) diastolic BP modulation frequencies (0.43 for POTS, 0.31 for controls [NS]) and (2) systolic MCAFV modulation frequencies (0.44 for POTS, 0.25 for controls [p < 0.02]) in middle band during HUT; and among multiple cardiovascular parameters (RRI, BP, MCAFV) in respiratory band (range 0.30–0.65). Correlations between EEG and cardiovascular parameter modulation frequencies were negligible in ultraslow band and low-moderate in other bands (0.01–0.32 in middle band, greatest correlations with RES; 0.11–0.55 in respiratory band, greatest correlations with diastolic BP and MCAFV). In conclusion, EEG modulation frequencies are not closely related to cardiovascular parameter modulation frequencies.

Questionnaire based survey of autonomic laboratories in Germany CA Haensch Department of Neurology, University of Witten/Herdecke, Klinikum Wuppertal GmbH, Wuppertal, NRW, Germany

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ver. In the other group we used along with a detailed history and clinical examination the results of the Schellong test for 3 minutes, electrocardiogram and electroencephalogram as well. Neurally mediated syncope was diagnosed in 5 (11 %) patients by autonomic testing and in 7 (15 %) patients on the basis of clinical features. Postural tachycardia syndrome (POTS) was find out in 16 (35 %) patients by headup tilt in the autonomic testing group but never by Schellong test or clinical examination. It seems that cardiological reasons for syncope are to frequently diagnosed without autonomic testing (30 % vs. 9 %). In 30 % syncope was of unknown cause in the autonomic testing group. Heart rate variability shows additional cardiac autonomic neuropathy in 3 patients. If a autonomic lab is not available Schellong test should be performed for 10 minutes at least not to fail to notice POTS. In recurrent syncope and presyncope autonomic investigation can aid management by making, confirming, or excluding various factors or diagnoses.

Accurate QRS Detection At Times of High Artifact During Tilt Table Testing Z Sahul1, J Black2, WK Shen1 Mayo Clinic, Rochester, Minnesota, USA; 2 Stanford University, Palo Alto, California, USA

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A survey in departments of neurology in university hospitals and among members of the German Autonomic Society shows 19 autonomic labs in Germany in the year of 2001. Most are in the field of neurocardiovascular and sudomotoric evaluation. The most important questions were the evaluation of syncope, orthostatic hypotension and polyneuropathies with autonomic dysfunction. On the other hand special tests like QSART, microdialysis, Laser-Doppler are used for scientific research. The equipment is not standardised and contains BP and ECG-monitoring, transcranial Doppler-monitoring, pupillography or MIBG-SPECT. For neurocardiovascular monitoring the non-invasive arterial blood pressure monitoring by the Portapress™ or Colin™ device is generally accepted as golden standard. Till now self-made devices for heart rate variability are being used, although autonomic device therefore are available from industrial commerce.As a rule autonomic tests are done by an doctor. The half of autonomic labs in Germany are equipped with a medical technician. Quality criteria will be essential. The applicability of normative values used in clinical routine testing depends on the reproducibility of the method, the equipment and environmental factors. This further calls for the definition of standards for the routinely used autonomic tests. Given such standards it will be possible to equip new labs, to evaluate existing labs and to evaluate new commercially available devices.

Diagnostic value of autonomic testing versus conventional evaluation in syncope of unexplained origin. CA Haensch, J Jörg Departement of Neurology, University of Witten/Herdecke, Klinikum Wuppertal GmbH, Wuppertal, NRW, Germany Syncope is a common disorder that is potentially disabling. The object was to find out whether autonomic investigation helped diagnosis. We therefore did a retrospective study on 91 consecutive patients (40 male, 51 female) referred to our autonomic laboratory in 2001 with recurrent syncope and presyncope in comparison to case notes from 1998 before our autonomic lab started. We did not include patients with syncope referred to our unit with a confirmed or provisional diagnosis of autonomic failure like Parkinson disease, multiple system atrophy or diabetes mellitus. The autonomic function tests contains 70°-head-up tilt for at least 10 to 45 minutes, heart rate variability in supine position and deep respiration and Valsalva maneu-

Objective: Due to high noise in the EKG, heart rate variability (HRV) analysis during tilt table testing and inducible syncope has required difficult manual editing. A robust and accurate QRS detection algorithm was developed to automate the process. Methods: Digitized single lead EKG recordings sampled at 100 Hz were made on patients undergoing tilt table testing. The EKG was filtered using a high-pass digital filter with a Hamming window. A single heart beat was marked on the EKG as a template and used as a matched filter. Matched filtering corresponded to computing the correlation between the template and the EKG at each signal point: C(i) = Σ T(j) * S(i + j) for j = 0 . . M – 1, where T is the template, S is the filtered EKG, and M is the template length. Correlation values were post-processed by a triggering circuit equivalent as follows: if C(i) < Cmin, then C(i) = 0. This results in groupings and the maximum within each grouping was then the QRS deflection. The matched filter template may be automatically updated periodically with nonectopic beats. A default template is also available for fully automated analysis. Results: Algorithm performance was compared with manual editing on 20 consecutive tilt induced syncopal patients. There were only 132 errors in the detection of 100 397 heartbeats (0.13 % error rate) in over 21 hours of recording. Approximately 40 % of errors were due to missed PVCs. Approximately 20 % of the errors were at the beginning and end of the recording. Only 33 errors (0.03 % of beats) were due to misinterpretation of noise as signal. Conclusion: A simple and accurate algorithm has been developed for automatically analyzing HRV for tilt table testing. The algorithm performed well even during syncope when there was significant artifact.

Breath-to-Breath Variability in Children with Idiopathic Congenital Central Hypoventilation Syndrome (CCHS) D Weese-Mayer, H Koch, J Ramirez, W Drongelen, A Kenny, M Hayes, J Silvestri Rush University & University of Chicago, Chicago, Illinois, USA To test the hypothesis that children with CCHS and associated ANS dysfunction (ANSD) have limited breath-to-breath variability, we developed a software program to measure individual breaths over time.

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Presented below are representative data from a child with CCHS (spontaneously breathing in non-REM sleep). TOP TRACING: exhaled (upward deflection) end tidal carbon dioxide over time. MIDDLE TRACING: instantaneous cycle length of individual breaths over time. BOTTOM TRACING: breath-to-breath variability of consecutive breaths. This quantitative approach allows comparison of instantaneous breath-to-breath variability among children with CCHS at different ages and in different states. Although our preliminary data suggest an attenuated breath-to-breath variability among these children with CCHS, it will be necessary to compare to age-appropriate controls and to a larger population of CCHS children to determine the relationship of respiratory frequency and state to breath-to-breath variability. Our approach will also allow us to assess the relative contribution of thorax and abdomen by state, an important step to quantitatively evaluate the regulation of breathing in these unique children with ANSD.

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