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Unlabelled: We evaluated whether droxidopa, a prodrug converted to norepinephrine, is beneficial in the treatment of symptomatic neurogenic orthostatic hypotension, which results from failure to generate an appropriate norepinephrine response to postural challenge. Patients with symptomatic neurogenic orthostatic hypotension and Parkinson disease, multiple system atrophy, pure autonomic failure, or nondiabetic autonomic neuropathy underwent open-label droxidopa titration (100-600 mg, 3× daily). Responders then received an additional 7-day open-label treatment at their individualized dose. Patients were subsequently randomized to continue with droxidopa or withdraw to placebo for 14 days. We then assessed patient-reported scores on the Orthostatic Hypotension Questionnaire and blood pressure measurements. Mean worsening of Orthostatic Hypotension Questionnaire dizziness/lightheadedness score from randomization to end of study (the primary outcome; N=101) was 1.9±3.2 with placebo and 1.3±2.8 units with droxidopa (P=0.509). Four of the other 5 Orthostatic Hypotension Questionnaire symptom scores and all 4 symptom-impact scores favored droxidopa, with statistical significance for the patient's self-reported ability to perform activities requiring standing a short time (P=0.033) and standing a long time (P=0.028). Furthermore, a post hoc analysis of a predefined composite score of all symptoms (Orthostatic Hypotension Questionnaire composite) demonstrated a significant benefit for droxidopa (P=0.013). There was no significant difference between groups for standing systolic blood pressure (P=0.680). Droxidopa was well tolerated. In summary, this randomized withdrawal droxidopa study failed to meet its primary efficacy end point. Additional clinical trials are needed to confirm that droxidopa is beneficial in symptomatic neurogenic orthostatic hypotension, as suggested by the positive secondary outcomes of this trial., Clinical Trial Registration Url: http://www.clinicaltrials.gov. Unique identifier: NCT00633880., (© 2014 The Authors. Published on behalf of the American Heart Association, Inc., by Wolters Kluwer.)

Background: Children with Congenital Central Hypoventilation Syndrome (CCHS) typically present as newborns with alveolar hypoventilation. With the advent of genetic testing, parents of affected children and other unrelated adults, all heterozygous for the disease-defining PHOX2B polyalanine expansion mutation with the 20/25 genotype, are being identified in adulthood. Though children with PHOX2B mutation-confirmed CCHS demonstrate ANS dysregulation, including altered heart rate and blood pressure control, it is unknown if adults with CCHS have similarly affected autonomic function in blood pressure control., Methods and Results: An autonomic profile of blood pressure control has been studied with recording of muscle sympathetic activity and spectral analysis of heart rate and blood pressure variability of one adult patient with alveolar hypoventilation and the 20/25 PHOX2B genotype. All parameters of heart rate variability were reduced. Cardiac baroreflex sensitivity was decreased. Sympathetic responses to Valsalva maneuver, hypoxemia, isometric exercise and cold pressor were blunted., Conclusion: In summary, we found a reduced cardiac baroreflex and a blunted sympathetic mediated response in the individual with adult-onset CCHS, possibly due to dysfunction in the afferent pathway. Our results confirm that PHOX2B affects the development of the autonomic nervous system, possibly causing absence of normal maturation of carotid body and visceral sensory ganglia and leading to autonomic dysfunction in adult-onset CCHS.

The cardiovascular and cerebrovascular responses to head-up postural change are compromised in pure autonomic failure (PAF) patients because of sympathetic denervation. The aim of this study was to characterize the rate of change of systemic mean blood pressure (MBP) and cerebral haemodynamics in response to passive posture changes. Nine PAF patients and 9 age-matched controls took part in this study. MBP and oxy- (O2Hb), deoxy-haemoglobin (HHb), and tissue oxygenation index (TOI) on the forehead were continuously monitored non-invasively using the Portapres and near-infrared spectroscopy (NIRS), respectively. From visual inspection of the haemoglobin difference signal (Hb(diff) = O2Hb-HHb), seven distinct phases were marked (1: supine, 2: start passive tilt, 3: head up to 60 degrees degrees, 4: end of tilt, 5: tilt reversal, 6: return to supine, 7: rest); the same time points were used for all of the other signals. For each phase, the slope was calculated using a linear regression algorithm. Significant differences were found between PAF patients and controls in the Hb(diff) slope magnitudes for phases 3 (P < .05) and 5 (P = .01), and the duration of phase 2 (P < .05). MBP slope magnitudes showed significant differences for phases 2 (P < .01) and 5 (P < .01). These differences in the rate of change suggest differences in blood vessel resistance related to sympathetic activation.

Background: There have been previous reports of enhanced sympathoexcitation in autism spectrum disorder (ASD). However, there has been no formal investigation of autonomic dysfunction in ASD. Also, the joint hypermobile form of Ehlers-Danlos syndrome (hE-DS) that maybe overrepresented in ASD and orthostatic related autonomic dysfunction. This study examined the comorbidity of ASD, autonomic dysfunction and hE-DS in two UK autonomic national referral centers. Proven, documented and globally accepted clinical autonomic investigations were used to assess neuro-cardiovascular autonomic function in a cohort of ASD subjects and in age-matched healthy controls. Methods: Clinical data from 28 referrals with a confirmed diagnosis of ASD over a 10-year period were compared with 19 age-matched healthy controls. Autonomic function was determined using methods established in the centers previously described in detail. Results: 20/28 ASD had a diagnosed autonomic condition; 9 had the postural tachycardia syndrome (PoTS), 4 PoTS and vasovagal syncope (VVS), 3 experienced presyncope, 1 essential hyperhidrosis, 1 orthostatic hypotension, 1 VVS alone and 1 a combination of PoTS, VVS and essential hyperhidrosis. 16/20 ASD with autonomic dysfunction had hE-DS. In ASD, basal heart rate and responses to orthostatic tests of autonomic function were elevated, supporting previous findings of increased sympathoexcitation. However, sympathetic vasoconstriction was impaired in ASD. Conclusion: Intermittent neuro-cardiovascular autonomic dysfunction affecting heart rate and blood pressure was over-represented in ASD. There is a strong association with hE-DS. Autonomic dysfunction may further impair quality of life in ASD, particularly in those unable to adequately express their experience of autonomic symptoms. [ABSTRACT FROM AUTHOR]

Non-motor symptoms are now commonly recognized in Parkinson's disease (PD) and can include dysautonomia. Impairment of cardiovascular autonomic function can occur at any stage of PD but is typically prevalent in advanced stages or related to (anti-Parkinsonian) drugs and can result in atypical blood pressure (BP) readings and related symptoms such as orthostatic hypotension (OH) and supine hypertension. OH is usually diagnosed with a head-up-tilt test (HUT) or an (active) standing test (also known as Schellong test) in the laboratory, but 24 h ambulatory blood pressure monitoring (ABPM) in a home setting may have several advantages, such as providing an overview of symptoms in daily life alongside pathophysiology as well as assessment of treatment interventions. This, however, is only possible if ABPM is administrated correctly and an autonomic protocol (including a diary) is followed which will be discussed in this review. A 24-h ABPM does not only allow the detection of OH, if it is present, but also the assessment of cardiovascular autonomic dysfunction during and after various daily stimuli, such as postprandial and alcohol dependent hypotension, as well as exercise and drug induced hypotension. Furthermore, information about the circadian rhythm of BP and heart rate (HR) can be obtained and establish whether or not a patient has a fall of BP at night (i.e., "dipper" vs. non-"dipper"). The information about nocturnal BP may also allow the investigation or detection of disorders such as sleep dysfunction, nocturnal movement disorders, and obstructive sleep apnea, which are common in PD. Additionally, a 24-h ABPM should be conducted to examine the effectiveness of OH therapy. This review will outline the methodology of 24 h ABPM in PD, summarize findings of such studies in PD, and briefly consider common daily stimuli that might affect 24 h ABPM. [ABSTRACT FROM AUTHOR]

On head down tilt to the supine horizontal position (tilt reversal) after head up tilt (HUT), patients with orthostatic hypotension may show an increase in blood pressure (BP) relative to baseline readings. We assessed this BP overshoot in 8 patients with pure autonomic failure (PAF, 64±13 years) and 8 patients with multiple system atrophy (MSA, 66±10 years). BP was intermittently measured during pre-tilt supine, HUT (60°, 10 min), and post-tilt supine periods. In addition, beat-to-beat BP was measured continuously using the Portapres model 2 device to calculate stroke volume (SV), cardiac output (CO) and total peripheral resistance (TPR). There was systolic BP overshoot of = 15mmHg after tilt reversal in 5 out of 8 PAF, but in only one of 8 MSA. A mean increase of systolic BP in PAF was significantly higher than that in MSA (p<0.01). TPR increased over baseline level after tilt reversal, although there was no significant difference. SV and CO levels during the post-tilt supine period were similar to baseline levels. In conclusion, BP overshoot was prominent in the PAF group but not in the MSA group. The phenomenon of BP overshoot while supine, especially in PAF, may have implications for long term cardiac and vascular damage in such patients. [ABSTRACT FROM AUTHOR]

Continuous haemodynamic responses to head-up tilt (HUT) and its reversal were studied in 21 subjects with sympathetic denervation due to primary chronic autonomic failure; 10 had pure autonomic failure (PAF; peripheral failure) and 11 had multiple system atrophy (MSA; central failure); 8 healthy subjects (controls) also were studied. Supine systolic, diastolic and mean arterial pressure (MAP) and total peripheral resistance (TPR) were highest in PAF. The MAP response to HUT and tilt reversal were different between groups. After HUT, MAP increased in controls (12±4 mmHg), but decreased in PAF and MSA (41±4 & 19±4 mmHg respectively); the fall in PAF was greater than in MSA. With tilt reversal, MAP returned promptly, but not entirely to pretilt levels in controls, with small (insignificant) overshoots in MSA and PAF. The TPR response to HUT and tilt reversal was different between groups. After HUT, TPR increased in controls (0.31±0.04 PRU), decreased in PAF (0.23±0.1 PRU) and was unchanged in MSA. With tilt reversal, TPR remained elevated (15 %) above baseline in the controls and rose in PAF (13 %) with no change in MSA. There were no differences in supine heart rate (HR), stroke volume (SV) or cardiac output (CO) between the three groups; HR, SV or CO responses to HUT or tilt reversal also did not differ between the groups. Thus, after HUT, MAP decreased, with greater hypotension induced in PAF than MSA. Since CO did not differ between groups, the decrease in TPR appears to account for the greater fall in BP in PAF than in MSA. The elevated TPR at rest pre-tilt and after tilt reversal probably contributed to supine hypertension in PAF. These haemodynamic observations may aid therapeutic strategies to reduce orthostatic hypotension and prevent supine hypertension. [ABSTRACT FROM AUTHOR]

n effective baroreflex and autonomic pathways normally ensure that blood pressure (BP) is satisfactorily maintained, despite various stimuli in daily life that include postural changes. We describe a 20-year-old man with a cerebellar hematoma and acute hydrocephalus, who had a vermian and partial right cerebellar hemisphere resection followed by orthostatic hypertension (OHT) and mutism. On standing his systolic BP rose over 60 mmHg with a fivefold increase in plasma noradrenaline. After a period of 8 weeks, postural BP regulation improved along with his ability to communicate. We conclude that transient impairment of cerebellar autonomic modulation or dysfunction of the baroreflex medullary circuit, may have resulted in OHT. [ABSTRACT FROM AUTHOR]

Background: The oral ingestion of water increases seated blood pressure in chronic autonomic failure although the mechanisms of this effect remain unclear. Recent studies in normal subjects suggest that oropharyngeal stimulation during swallowing may be of greater importance in causing a rise in blood pressure (BP) than the gastric effects of water. We therefore assessed the haemodynamic effects of water instilled directly into the stomach via a gastrostomy tube in pure autonomic failure (PAF). Methods: The subject had longstanding (>20 years) PAF. A gastrostomy tube had been previously placed because of dysphagia. Distilled water (480 ml) was instilled in the seated position with BP and heart rate (HR) measured over the following 40 min while the subject remained seated. Systolic and diastolic BP (SBP and DBP) and heart rate (HR) were recorded intermittently every 3 min with a Dinamap automated syphgmomanometer and continuously using a Portapres device. Subsequent model flow analysis of the Portapres data provided beat-to-beat estimates of cardiac output, stroke volume, and total peripheral resistance (TPR). Subjective orthostatic symptoms were recorded before and after water. Results: Seated SBP and DBP increased after water instillation with increases first noted between 5 and 8 min after the water had been instilled. The BP remained elevated until 35 min post water increase over baseline being +36.5 mm Hg SBP and +24.3 mm Hg DBP. HR, cardiac output, and stroke volume remained unchanged during the study. Total peripheral resistance (TPR) increased post water. These results are similar to those reported in a recent study involving oral ingestion of 480 ml of water in PAF subjects. Conclusions: Instilling water directly into the stomach in a patient with PAF resulted in similar haemodynamic responses to those seen when water is taken orally. Thus, oropharyngeal factors and swallowing do not appear to be essential in the generation of the water pressor effect in autonomic failure. [Copyright &y& Elsevier]

Nocturnal polyuria is a common symptom in autonomic failure. In patients with urinary bladder involvement nocturia can be troublesome and considerably add to their disabilities. Nocturnal diuresis and natriuresis account for overnight weight loss that appears to worsen the extent of, and symptoms resulting from, orthostatic hypotension in the morning. Some patients are considerably incapacitated and find it difficult to function until late morning; even a light breakfast and minimal exertion can substantially worsen symptoms. This partly may be helped by the use of head-up tilt at night. Nocturnal polyuria probably results in redistribution of body fluids, reducing central filling pressure, stroke volume, cardiac output and thus blood pressure. This is consistent with recent studies confirming that orthostatic hypotension is worse in the morning and indicating that there are greater changes in stroke volume and cardiac output on standing in the morning compared to the evening. The reduction in overnight fluid loss presumably reverses this cycle of events, thus reducing morning orthostatic hypotension.

Focuses on two studies by Jens Jordan and colleagues which report that oral water has substantial pressor effects. Effect that drinking water has on the blood pressures of healthy individuals, as well as those with orthostatic hypotension, Parkinson's disease and autonomic failure; Factors influencing blood pressure; Conclusion that the precise mechanisms causing the pressor response to oral water, especially in patients with sympathetic denervation, still remain to be determined.

Abstract: The autonomic nervous system closely integrates a range of vital processes, including, cardiovascular function. Physical activity, or exercise, requires a range of integrated autonomic and cardiovascular adjustments in order to maintain homeostasis. Pathological conditions that result in dysfunction of the autonomic nervous system, such as autonomic failure, can therefore jeopardize the control of blood pressure resulting in hypotension and have serious implications for health. Exercise induced hypotension, defined as a ≥10mmHg fall in systolic blood pressure during exercise, can be a significant symptom/event for autonomic failure, as well as other autonomic disorder, patients, including, Multiple System Atrophy and Spinal Cord Injury, and can reduce physical capacity, orthostatic tolerance, result in falls, complicate management and reduce quality of life. The likely mechanisms do not appear to be an altered cardiac output or active muscle vasodilation response to exercise, but rather, a lack of and/or a blunted increase in sympathetic nerve activity during exercise and/or excessive vasodilation in the splanchnic circulation. The severity of exercise induced hypotension seems to be higher during dynamic relative to static exercise. The possible management strategies for exercise induced hypotension include both non-pharmacological, e.g., reducing risk factors, and pharmacological measures, such as sympathomimetics, but studies on other pharmacological agents are limited. [Copyright &y& Elsevier]

Abstract: Neurocardiogenic syncope (NCS, simple fainting) is a common and typically benign familial condition, which rarely may result in traumatic injury or hypoxic convulsions. NCS is associated with emotional triggers, anxiety states and stress. However, the etiology of NCS, as a psychophysiological process, is poorly understood. We therefore investigated the relationship between NCS and brain anatomy. We studied a non-clinical sample of eighteen individuals with histories characteristic of NCS, and nineteen matched controls who had never fainted. We recorded fainting frequency, resting heart rate variability measures and anxiety levels. Structural T1-weighted magnetic resonance images (MRI) were acquired at 1.5 T. Associations between brain morphometry (regional gray and white matter volumes) and NCS, resting physiology and anxiety were tested using voxel-based morphometry (VBM). Compared to controls, NCS participants had lower regional brain volume within medulla and midbrain (a priori regions of interest). Moreover, across NCS individuals, lower gray matter volume in contiguous regions of left caudate nucleus predicted enhanced parasympathetic cardiac tone, fainting frequency and anxiety levels. Our findings provide preliminary evidence for a hierarchical anatomical basis to NCS. First, differences in the volume of brainstem centers supporting cardiovascular homeostasis may relate to constitutional predisposition to NCS. Second, differences in the structural organization of the caudate nucleus in NCS individuals may relate to fainting frequency via interactions between emotional state and parasympathetic control of the heart. These observations highlight the application of VBM to the identification of neurovisceral mechanisms relevant to psychosomatic medicine and the neuroscience of emotion. [Copyright &y& Elsevier]

Aim: To clarify the characteristics of hemodynamic responses to exercise and orthostasis in Parkinson's disease patients, especially those with autonomic failure. Methods: Clinical audit of supine cycling exercise test data (with active standing tests pre- and post-exercise) of Parkinson's patients with autonomic dysfunction. 23 patients (71 ± 7 yr, 7 females) with a confirmed diagnosis of Parkinson's were identified. Results: Group mean systolic blood pressure (SBP) fell during pre-exercise standing (−39 ± 29 mmHg, P < 0.001, 17 patients had orthostatic hypotension (OH)), while heart rate (HR) increased (+13 ± 7 beats min−1, P < 0.001). SBP (P < 0.001) increased during exercise with a wide variation in responses. SBP increased in 13 patients (INC; +30 ± 14 mmHg) and either did not change or decreased in 10 patients (DEC −12 ± 11 mmHg, P < 0.001 vs INC). The increase in HR was not different between sub-groups (30 ± 12 vs 25 ± 10 beats min−1, INC vs. DEC, P = 0.29). The size of the pre-exercise stand SBP reduction was greater in DEC vs INC (−64 ± 23 (10 out of 10 had OH) vs −19 ± 16 mmHg (7 out of 13 had OH), respectively, P < 0.001). The HR elevation was not different between sub-groups (13 ± 8 vs 13 ± 4 beats min−1, DEC vs INC, P = 0.94). Post-exercise SBP/DBP were lower for both sub-groups compared to pre-exercise and the standing SBP reduction post-exercise was not greater relative to pre-exercise in either sub-group. Conclusion: Exercise-induced hypotension can occur in Parkinson's disease patients with autonomic failure with the magnitude of the exercise response being related to the severity of autonomic dysfunction. Exercise does not appear to worsen OH in this sample of Parkinson's patients. [ABSTRACT FROM AUTHOR]

Abstract: In Parkinsons disease and multiple system atrophy (MSA), cardiovascular dysfunction may occur for a variety of reasons and may manifest itself through inappropriate changes and/or levels in blood pressure, heart rate and/or regional vascular perfusion in a range of situations. The early occurrence of orthostatic hypotension often leads to consideration of MSA, especially in the presence of other features of autonomic failure. Orthostatic hypotension, however, is increasingly recognised in PD, and especially with increasing age, severity of disease and as a result of drug therapy, sometimes for associated disorders. Investigation of cardiovascular autonomic dysfunction in Parkinsonism is therefore important for a variety of reasons, that include determining the precise diagnosis and in predicting prognosis. In Parkinsonian disorders, understanding the pathophysiological basis of the cardiovascular autonomic dysfunction aids targeting of therapy, improves management strategies and provides benefit for such patients. [Copyright &y& Elsevier]