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Background: Neurogenic orthostatic hypotension (nOH) is a chronic disabling condition associated with significant morbidity and mortality. Currently, the diagnosis of nOH relies on impaired autonomic reflexes as determined by testing available only in specialized centers. Our objective was to test the hypothesis that a blunted heart rate (HR) increase in response to a given systolic blood pressure (SBP) fall will correctly diagnose nOH. Methods: We performed a retrospective study of nOH patients (studied in an inpatient environment off medications that can interfere with autonomic function) and control subjects. nOH was diagnosed on the basis of SBP fall ≥20 mmHg on standing associated with a decrease in SBP≥ 20 mmHg during phase 2 of the Valsalva maneuver and absence of phase 4 SBP overshoot. Controls had any SBP fall on standing but intact autonomic reflexes. Receiver operator characteristic curve (ROC) analysis was performed on the ratio of the changes from supine to 3 min standing in HR and SBP (ΔHR/ΔSBP). Results: We studied 171 nOH patients (66±1 years, males 61%, multiple system atrophy 42%, Parkinson disease 14%, pure autonomic failure 32% and undetermined 12%) and 53 controls (51±3 years, males 28%). nOH patients had a greater drop in standing SBP (-63±2 vs. -16±4 mmHg in controls; p Conclusions: Our study suggests that a simple ratio of ΔSBP/ΔHR

Background: Postural tachycardia syndrome (POTS) is characterized by an increase in sympathetic activity, with an exaggerated rise in heart rate upon standing and symptoms of cerebral hypoperfusion. Endothelial/Nitric Oxide (NO) dysfunction might be involved in POTS pathophysiology. As part of the non-pharmacologic treatment of POTS, a high sodium diet is often recommended to increase plasma volume. We assessed endothelial/NO function in conduit vessels (using flow-mediated dilation, FMD) and resistance vessels (using finger pulse arterial tonometry, PAT) in POTS patients during high and low salt diets. Methods: In 14 female POTS patients (34±9 years, BMI 23±3 kg/m 2 ) and 13 matched healthy control subjects (29±4 years, BMI 24±3 kg/m 2 ), we evaluated the time course responses to FMD and PAT. Subjects were randomly assigned to either high salt diet (300mEq/day) or low salt diet (10mEq/day) for 6 days and crossed over to the other arm after 1 month. The areas under the curve for brachial artery diameter by FMD and finger artery dilation by PAT were compared between interventions and groups. Results: No differences in NO function in a conduit artery were seen. In contrast, in resistance vessels, high salt diet increased vasodilation in both POTS and healthy subjects (figure). In addition, POTS patients have greater vasodilation than healthy subjects during both low and high salt diets (p=0.036 and 0.033 for high and salt diets respectively). Conclusions: POTS patients may have an exaggerated NO response to reactive hyperemia in resistance vessels, but not in conductance vessels. This excessive vasodilation could contribute to POTS symptoms on standing.

Nebivolol, unlike other selective β 1 -receptor blockers, induces vasodilation attributable to increased NO bioavailability. The relative contribution of this mechanism to the blood pressure (BP)–lowering effects of nebivolol is unclear because it is normally masked by baroreflex buffering. Autonomic failure provides a unique model of hypertension devoid of autonomic modulation but sensitive to the hypotensive effects of NO potentiation. We tested the hypothesis that nebivolol would decrease BP in these patients through a mechanism independent of β-blockade. We randomized 20 autonomic failure patients with supine hypertension (14 men; 69±2 years) to receive a single oral dose of placebo, nebivolol 5 mg, metoprolol 50 mg (negative control), and sildenafil 25 mg (positive control) on separate nights in a double-blind, crossover study. Supine BP was monitored every 2 hours from 8:00 pm to 8:00 am . Compared with placebo, sildenafil and nebivolol decreased systolic BP during the night ( P P =0.036, by mixed-effects model, maximal systolic BP reduction 8-hour postdrug of −20±6 and −24±9 mm Hg, respectively), whereas metoprolol had no effect. In a subanalysis, we divided patients into sildenafil responders (BP fall >20 mm Hg at 4:00 am ) and nonresponders. Nebivolol significantly lowered systolic BP in sildenafil responders (−44±13 mm Hg) but not in nonresponders (1±11 mm Hg). Despite lowering nighttime BP, nebivolol did not worsen morning orthostatic tolerance compared with placebo. In conclusion, nebivolol effectively lowered supine hypertension in autonomic failure, independent of β 1 -blockade. These results are consistent with the hypothesis that NO potentiation contributes significantly to the antihypertensive effect of nebivolol.

Obesity is an important risk factor for the development of insulin resistance. Initial compensatory mechanisms include an increase in insulin levels, which are thought to induce sympathetic activation in an attempt to restore energy balance. We have previously shown, however, that sympathetic activity has no beneficial effect on resting energy expenditure in obesity. On the contrary, we hypothesize that sympathetic activation contributes to insulin resistance. To test this hypothesis, we determined insulin sensitivity using a standard hyperinsulinemic euglycemic clamp protocol in obese subjects randomly assigned in a crossover design 1 month apart to receive saline (intact day) or trimetaphan (4 mg/min IV, autonomic blocked day). Whole-body glucose uptake ( M BW in mg/kg per minute) was used as index of maximal muscle glucose use. During autonomic blockade, we clamped blood pressure with a concomitant titrated intravenous infusion of the nitric oxide synthase inhibitor N -monomethyl-L-arginine. Of the 21 obese subjects (43±2 years; 35±2 kg/m 2 body mass index) studied, 14 were insulin resistant; they were more obese, had higher plasma glucose and insulin, and had higher muscle sympathetic nerve activity (23.3±1.5 versus 17.2±2.1 burst/min; P =0.03) when compared with insulin-sensitive subjects. Glucose use improved during autonomic blockade in insulin-resistant subjects ( M BW 3.8±0.3 blocked versus 3.1±0.3 mg/kg per minute intact; P =0.025), with no effect in the insulin-sensitive group. These findings support the concept that sympathetic activation contributes to insulin resistance in obesity and may result in a feedback loop whereby the compensatory increase in insulin levels contributes to greater sympathetic activation.

Postural tachycardia syndrome (POTS) is associated with exercise intolerance, hypovolemia, and cardiac atrophy, which may contribute to reduced stroke volume and compensatory exaggerated heart rate (HR) increases. Acute volume loading with intravenous (iv) saline reduces HR and improves orthostatic tolerance and symptoms in POTS, but its effect on exercise capacity is unknown. In this study, we determined the effect of iv saline infusion on peak exercise capacity (V̇o2peak) in POTS. Nineteen patients with POTS participated in a sequential study. V̇o2peak was measured on two separate study days, following administration of placebo or 1 liter of iv saline (NaCl 0.9%). Patients exercised on a semirecumbent bicycle with resistance increased by 25 W every 2 min until maximal effort was achieved. Patients exhibited blood volume deficits (−13.4 ± 1.4% ideal volume), consistent with mild to moderate hypovolemia. At baseline, saline significantly increased stroke volume (saline 80 ± 8 ml vs. placebo 64 ± 4 ml; P = 0.010), increased cardiac output (saline 6.9 ± 0.5 liter/min vs. placebo 5.7 ± 0.2 liter/min; P = 0.021), and reduced systemic vascular resistance (saline 992.6 ± 70.0 dyn-s/cm5 vs. placebo 1,184.0 ± 50.8 dyn-s/cm5; P = 0.011), with no effect on HR or blood pressure. During exercise, saline did not produce differences in V̇o2peak (saline 26.3 ± 1.2 mg·kg−1·min−1 vs. placebo 27.7 ± 1.8 mg·kg−1·min−1; P = 0.615), peak HR [saline 174 ± 4 beats per minute (bpm) vs. placebo 175 ± 3 bpm; P = 0.672] or other cardiovascular parameters. These findings suggest that acute volume loading with saline does not improve V̇o2peak or cardiovascular responses to exercise in POTS, despite improvements in resting hemodynamic function.

OBJECTIVE This study aimed to identify optimal blood pressure cut-offs to diagnose orthostatic hypotension during a sit-to-stand manoeuvre. METHODS This was a cross-sectional study of patients and healthy controls from the Vanderbilt Autonomic Dysfunction Center. Blood pressure was measured while supine, seated and standing. Blood pressure changes were calculated from supine-to-standing and seated-to-standing. Orthostatic hypotension was diagnosed on the basis of a supine-to-standing SBP drop at least 20 mmHg or a DBP drop at least 10 mmHg. Receiver operator characteristic (ROC) curves identified optimal sit-to-stand cut-offs. RESULTS Amongst the 831 individuals, more had systolic orthostatic hypotension [n = 354 (43%)] than diastolic orthostatic hypotension [n = 305 (37%)] during lying-to-standing. The ROC curves had good characteristics [SBP area under curve = 0.916 (95% confidence interval: 0.896-0.936), P

At least half of primary autonomic failure patients exhibit supine hypertension, despite profound impairments in sympathetic activity. Although the mechanisms underlying this hypertension are unknown, plasma renin activity is often undetectable, suggesting renin–angiotensin (Ang) pathways are not involved. However, because aldosterone levels are preserved, we tested the hypothesis that Ang II is intact and contributes to the hypertension of autonomic failure. Indeed, circulating Ang II was paradoxically increased in hypertensive autonomic failure patients (52±5 pg/mL, n=11) compared with matched healthy controls (27±4 pg/mL, n=10; P =0.002), despite similarly low renin activity (0.19±0.06 versus 0.34±0.13 ng/mL per hour, respectively; P =0.449). To determine the contribution of Ang II to supine hypertension in these patients, we administered the AT 1 receptor blocker losartan (50 mg) at bedtime in a randomized, double-blind, placebo-controlled study (n=11). Losartan maximally reduced systolic blood pressure by 32±11 mm Hg at 6 hours after administration ( P P =0.0461), and did not worsen morning orthostatic tolerance. In contrast, there was no effect of captopril on supine blood pressure in a subset of these patients. These findings suggest that Ang II formation in autonomic failure is independent of plasma renin activity, and perhaps Ang-converting enzyme. Furthermore, these studies suggest that elevations in Ang II contribute to the hypertension of autonomic failure, and provide rationale for the use of AT 1 receptor blockers for treatment of these patients.

Primary autonomic failure (AF) is characterized by disabling orthostatic hypotension that is acutely worsened by environmental heat. Given that about half of AF patients have paradoxical supine hypertension, we hypothesized that controlled local passive heat would lower supine blood pressure (BP) in these patients. Fourteen AF patients with supine hypertension (age 71±2 years, 9 men, systolic BP 172±6 mmHg) were randomized to receive passive heat (40-42°C, commercial heating pad over abdomen and pelvis) and sham control for up to 2 hours in a 2-day crossover study. Hemodynamic parameters and core body and skin temperatures were measured in the supine position. The heating pad increased abdominal skin temperature to 40.8±0.4°C and 40.1±0.3°C after 1 and 2 hours of passive heat (vs 35.2±0.2°C and 35.1±0.4°C in sham controls). Core body temperature increased after 1 hour (by 0.2±0.1°C [to 36.9±0.8°C] vs 0.0°C [36.7±0.1°C] in sham controls; P=0.04) and 2 hours (by 0.4±0.1°C [to 37.2±0.1°C] vs 0.1±0.03°C [to 36.8±0.1°C] in sham controls; P=0.04). Systolic BP decreased during heat stress compared to sham control (P

Postural tachycardia syndrome (POTS) is a heterogeneous disorder characterized by an excessive rise in HR and symptoms consistent with cerebral hypoperfusion while upright. Increased sympathetic activity may contribute to this condition and may also impair nitric oxide (NO)-function. We evaluated NO function using flow-mediated dilation (FMD) and Peripheral Artery Tonometry (PAT) in POTS patients and age-matched controls. We studied 16 POTS patients (30±2 years, BMI 22.3±1 kg/m 2 ) and 7 healthy control subjects (HC; 31±2 years, BMI 22.1±1 kg/m 2 ). Medications affecting BP, blood volume, the immune system, and autonomic function, were withheld for ≥5 half-lives. All subjects followed the same low-monoamine, caffeine-free diet for ≥3 days before testing. Endothelial function was measured as the percentage change in FMD (%FMD) and using the reactive hyperemic index (RHI) for PAT. We also measured autonomic function, plasma levels of catecholamines, renin activity (PRA) and aldosterone. We found that POTS patients had a significantly blunted FMD (6.11±0.8 vs. 9.67±1.6 %, P=0.049, figure), compared to healthy controls. This blunted FMD response was similar as what our group has reported in obese hypertensive females (N=13, 5.7±0.9%, figure). Also, as expected they had higher upright HR (121±6 vs. 90±6 bpm, for POTS and HC, P=0.020). There were no differences in PAT (2.08±0.12, vs. 1.8±0.13 RHI, for POTS and HC, P=0.168). There were no differences in norepinephrine (765±150 vs. 545±39 pg/mL, P=0.955), renin activity (5.3±1.3 vs. 5.2±1.6 ng/mL/hr, P=0.735) or aldosterone (19.6±3.8 vs. 15.9±5.5 ng/dL, P=0.129).

African American (AA) women have the highest prevalence of hypertension and obesity in the United States. We tested the hypothesis that sympathetic activity contributes to hypertension in obese AA women, as we previously shown to be the case in Caucasians. We studied 42 obese women (16 whites, body mass index (BMI) 36± 4 kg/m 2 , 44% with diagnosis of hypertension (HTN) and 26 AA, BMI 35± 4 kg/m 2 , 46% HTN). Anti-HTN medications were discontinued for 2 weeks prior to the study day. All subjects underwent complete autonomic blockade with the ganglionic blockade trimethaphan at doses of 4 mg/min. Autonomic blockade was evaluated by the lack of heart rate changes in response to ~25 mm Hg increase in blood pressure produced by a bolus infusion of the alpha 1 adrenergic agonist, phenylephrine and the decrease in norepinephrine levels. Results: Plasma norepinephrine significantly decreased during trimethaphan infusion (from baseline 253±1107 to 61±29 pg/ml, trimethaphan). The decrease in mean arterial blood pressure (MAP) produced by trimethaphan was greater in obese HTN compared with normotensive (NTN) Caucasians (-27±10 vs. -15±8 mm Hg, P=0.016). In contrast, no difference in the decrease in MAP induced by trimethaphan was found between HTN and NTN obese AA women (-16±11 vs. -12±10, P=0.451, figure ). Heart rate increased similarly with trimethaphan between HTN and NTN caucasians (+9.1± 6 vs. 16± 9, P=0.109) and AA women (+22± 7 vs. 21±12 bpm, P=0.760). MAP remained elevated in HTN obese AA women during trimethaphan infusion (84±15 vs. 72±9.8 mm Hg in NTN AA, P=0.021). Conclusion: Sympathetic activity does not contribute to hypertension in AA women

Context: The scavenger receptor CD36 influences the endothelial nitric oxide-cGMP pathway in vitro. Genetic variants that alter CD36 level are common in African Americans (AAs), a population at high risk of endothelial dysfunction. Objective: To examine if the minor allele (G) of coding CD36 variant rs3211938 (G/T) which reduces CD36 level by approximately 50% influences endothelial function, insulin sensitivity (IS), and the response to treatment with the nitric oxide-cGMP potentiator sildenafil. Design: IS (frequently sampled iv glucose tolerance) and endothelial function (flow mediated dilation [FMD]) were determined in age- and body mass index-matched obese AA women with or without the G allele of rs3211938 (protocol 1). Effect of chronic sildenafil treatment on IS and FMD was tested in AA women with metabolic syndrome and with/without the CD36 variant, using a randomized, placebo-controlled trial (protocol 2). Setting: Two-center study. Participants: Obese AA women. Intervention: A total of 20-mg sildenafil citrate or placebo thrice daily for 4 weeks. Main outcome: IS, FMD. Results: G allele carriers have lower FMD (P = .03) and cGMP levels (P = .01) than noncarriers. Sildenafil did not improve IS, mean difference 0.12 (95% confidence interval [CI], −0.33 to 0.58; P = .550). However, there was a significant interaction between FMD response to sildenafil and rs3211938 (P = .018). FMD tended to improve in G carriers, 2.9 (95% CI, −0.9 to 6.8; P = .126), whereas it deteriorated in noncarriers, −2.6 (95% CI, −5.1 to −0.1; P = .04). Conclusions: The data document influence of a common genetic variant on susceptibility to endothelial dysfunction and its response to sildenafil treatment.

The clinical picture of autonomic failure is characterized by severe and disabling orthostatic hypotension. These disorders can develop as a result of damage of central neural pathways or peripheral autonomic nerves, caused either by a primary autonomic neurodegenerative disorder or secondary to systemic illness. Treatment should be focused on decreasing pre-syncopal symptoms instead of achieving blood pressure goals. Non-pharmacologic strategies such as physical counter-maneuvers, dietary changes (i.e. high salt diet, rapid water drinking or compression garments) are the first line therapy. Affected patients should be screened for co-morbid conditions such as post-prandial hypotension and supine hypertension that can worsen orthostatic hypotension if not treated. If symptoms are not controlled with these conservative measures the next step is to start pharmacological agents; these interventions should be aimed at increasing intravascular volume either by promoting water and salt retention (fludrocortisone) or by increasing red blood cell mass when anemia is present (recombinant erythropoietin). When pressor agents are needed, direct pressor agents (midodrine) or agents that potentiate sympathetic activity (atomoxetine, yohimbine, pyridostigmine) can be used. It is preferable to use short-acting pressor agents that can be taken on as needed basis in preparation for upright activities.

Supine hypertension is difficult to manage in patients with pure autonomic failure (PAF), because treatment can worsen orthostatic hypotension. Supine hypertension in PAF has been associated with left ventricular hypertrophy, but end organ damage in the kidney has not been assessed. We reviewed hemodynamic and laboratory data of 64 male patients with PAF who were 69±11 (mean±SD) years old. Systolic blood pressure fell by 67±40 mm Hg within 10 minutes of standing, with an inappropriately low 13±11-bpm increase in heart rate. Plasma norepinephrine levels were below normal (0.62±0.32 nmol/L supine and 1.28±1.25 nmol/L standing). A control data set of 75 men (67±12 years) was obtained from a deidentified version of the Vanderbilt University Medical Center electronic medical chart database. Compared with controls, PAF patients had lower hemoglobin (8.3±0.9 versus 9.3±0.8 mmol/L; P P 12 versus 5.0±0.5×10 12 cells/L; P P =0.021) and estimated glomerular filtration rate was lower (57±22 versus 70±20 mL/min per 1.73 m 2 ; P =0.022) compared with patients who did not have supine hypertension. These findings may indicate that renal function is diminished in PAF in association with supine hypertension.

Parkinson disease, an α-synucleinopathy, is associated with reduced insulin sensitivity, impaired glucose tolerance, and diabetes mellitus. Importantly, these metabolic alterations have been shown to contribute to disease progression. The purpose of this study was to determine if reduced insulin sensitivity is also present in other α-synucleinopathies associated with autonomic failure. We studied 19 patients with multiple system atrophy and 26 patients with pure autonomic failure. For comparison, we studied 8 healthy controls matched for body mass index. Insulin sensitivity and beta cell function were calculated using fasting glucose and insulin levels according to the homeostatic model assessment 2. A multiple linear regression model was performed to determine factors that predict insulin sensitivity in autonomic failure. There was a significant difference in insulin sensitivity among groups (P = 0.048). This difference was due to lower insulin sensitivity in multiple system atrophy patients: 64 % [interquartile range (IQR), 43 to 117] compared to healthy controls 139 % (IQR, 83 to 212), P = 0.032. The main factor that contributed to the reduced insulin sensitivity was the presence of supine hypertension and residual sympathetic tone. Multiple system atrophy patients have reduced insulin sensitivity that is associated with residual sympathetic activation and supine hypertension. These patients may therefore be at high risk for development of impaired glucose tolerance and diabetes mellitus.

Primary autonomic failure is characterized by disabling orthostatic hypotension; but at least half of these patients have paradoxical supine hypertension. Renin-angiotensin (Ang) mechanisms were not initially thought to contribute to this hypertension as autonomic failure patients often have undetectable plasma renin activity. Despite suppressed renin, plasma aldosterone levels are normal and we recently showed that plasma Ang II is elevated and acts at AT 1 receptors to contribute to supine hypertension in these patients. Since aldosterone and Ang II also bind mineralocorticoid receptors (MR) to elevate blood pressure, we tested the hypothesis that MR activation plays a role in the hypertension of autonomic failure. To test this, we determined the acute effects of the MR antagonist eplerenone (50 mg, PO) versus placebo on supine blood pressure in a randomized, double blind, crossover study. Medications were given at 8:00 PM and blood pressure was recorded q2 hours for 12 hours. Seven autonomic failure patients with supine hypertension completed this study (5 pure autonomic failure, 1 Parkinson’s, 1 multiple system atrophy; 5 male; 68±2 years of age). Eplerenone maximally reduced supine systolic blood pressure by 34±6 mmHg at 8 hours after administration (vs. 6±12 mmHg for placebo, p=0.047), with no effect on volume measures (12-hour urine volume: 927±205 placebo vs. 1247±151 ml eplerenone, p=0.438; nocturnal weight loss: -1.1±0.2 placebo vs. -1.2±0.2 kg eplerenone, p=0.813). These findings suggest that inappropriate MR activation may contribute to hypertension in autonomic failure, and provide rationale for use of eplerenone in treatment of these patients. While still under investigation, the lack of effect on volume measures combined with the rapid time course for blood pressure lowering following eplerenone may suggest extra-renal mechanisms are involved in MR antagonism in autonomic failure.

CD36, a scavenger receptor expressed on endothelial cells, interacts with thrombospodin-1, a matrix protein that modulates nitric oxide-soluble guanylate cyclase (NO-sGC) signaling. CD36 genetic variants associate with endothelial dysfunction, atherosclerosis, hypertension and insulin resistance. A coding variant of CD36 (rs3211938, G/T genotype) that causes partial CD36 deficiency (50% reduction) is common (~18%) in African Americans (AA); however, it is unknown, if this genotype influences NO-dependent endothelial function. This study examined whether potentiating NO-sGC pathways with the phosphodiesterase 5 inhibitor, sildenafil citrate, improves endothelial function and insulin sensitivity in AA women with or without the G/T genotype. Forty-six AA women with metabolic syndrome (MetS) participated in a 4-week, parallel-arm, double-blind, and placebo-controlled study. Carefully matched subjects were randomly assigned to sildenafil citrate 20 mg TID versus placebo; sildenafil (n= 23, 42±10 years old, BMI 39±5 kg/m2, fasting insulin 15±8 uU/ml) and placebo (n=23, age 43±10, BMI 39±6 kg/m2, fasting insulin 14±10 uU/ml). Primary endpoints were insulin sensitivity and endothelial function measured by intravenous glucose tolerance test and flow mediated dilation, respectively. Treatment compliance was documented with plasma sildenafil levels (mean 57±50 ng/ml). There was no difference in insulin sensitivity (p=0.676) or flow-mediated dilation (p=0.649) between intervention groups. However, subgroup analyses showed a significant interaction between sildenafil citrate treatment and G/T genotype (p=0.018). Sildenafil citrate improved endothelial function in G/T carriers (the mean difference: 2.9, the 95% CI: -0.90 to 6.8, p = 0.126) and decreased endothelial function in T/T carriers (the mean difference: -2.6, the 95% CI: -5.1 to -0.1, p = 0.040). We conclude that the rs3211938 common CD36 genetic variant influences NO-dependent endothelial function in response to chronic treatment with phosphodiesterase 5 inhibition. Further studies are needed to determine if rs3211938 and other common CD36 genotypes influence endothelial function and the inter-individual variability in response to the drug.

Sympathetic activation is thought to contribute to the inflammatory process associated with obesity, which is characterized by elevated circulating C-reactive protein (hsCRP) and interleukin-6 (IL-6). To evaluate whether sympathetic activation is associated with inflammation in the absence of obesity, we studied patients with postural tachycardia syndrome (POTS), a condition characterized by increased sympathetic tone in otherwise healthy individuals. Compared with 23 lean controls, 43 lean female POTS had greater vascular sympathetic modulation (low-frequency blood pressure variability, LFSBP, 3.2 ± 0.4 vs. 5.5 ± 0.6 mmHg2, respectively, P = 0.006), lower cardiac parasympathetic modulation (high-frequency heart rate variability, 1,414 ± 398 vs. 369 ± 66 ms2, P = 0.001), and increased serum IL-6 (2.33 ± 0.49 vs. 4.15 ± 0.54 pg/ml, P = 0.011), but this was not associated with increases in hsCRP, which was low in both groups (0.69 ± 0.15 vs. 0.82 ± 0.16 mg/l, P = 0.736). To explore the contribution of adiposity to inflammation, we then compared 13 obese female POTS patients and 17 obese female controls to matched lean counterparts (13 POTS and 11 controls). Compared with lean controls, obese controls had increased LFSBP(3.3 ± 0.5 vs. 7.0 ± 1.1 mmHg2; P = 0.016), IL-6 (2.15 ± 0.58 vs. 3.92 ± 0.43 pg/ml; P = 0.030) and hsCRP (0.69 ± 0.20 vs. 3.47 ± 0.72 mg/l; P = 0.001). Obese and lean POTS had similarly high IL-6 but only obese POTS had increased hsCRP (5.76 ± 1.99 mg/l vs. 0.65 ± 0.26; P < 0.001). In conclusion, sympathetic activation in POTS is associated with increased IL-6 even in the absence of obesity. The coupling between IL-6 and CRP, however, requires increased adiposity, likely through release of IL-6 by visceral fat.

Background— The objective of this study was to determine the effect of inspiratory resistance through an impedance threshold device (ITD) on orthostatic tolerance in patients with postural tachycardia syndrome. We hypothesized that the ITD would result in a greater negative intrathoracic pressure to enhance cardiac venous return, improve stroke volume, and reduce heart rate in these patients. Methods and Results— We compared the effect of a sham device (sham, no resistance) versus an ITD (increased inspiratory resistance) in 26 patients with postural tachycardia syndrome in a randomized, single-blind, crossover study. Hemodynamic assessments were performed at baseline while supine and during head-up tilt to 70° for 10 minutes. We did not find differences in baseline hemodynamic parameters between the ITD and the sham devices. After 10 minutes of head-up tilt, the heart rate was lower with the ITD versus sham device (102±4 versus 109±4 beat/min, respectively; P =0.003). The ITD also improved stroke volume compared with the sham device (35±2 versus 26±1 mL; P =0.006). Conclusions— These findings suggest that increasing negative intrathoracic pressure with ITD breathing improves heart rate control in patients with postural tachycardia syndrome during upright posture. Clinical Trial Registration— clinicaltrials.gov ; Unique Identifier: NCT00962728.

The clinical presentation of autonomic failure is orthostatic hypotension. Severely affected patients require pharmacological treatment to prevent presyncopal symptoms or frank syncope. We previously reported in a proof of concept study that pediatric doses of the norepinephrine transporter blockade, atomoxetine, increases blood pressure in autonomic failure patients with residual sympathetic activity compared with placebo. Given that the sympathetic nervous system is maximally activated in the upright position, we hypothesized that atomoxetine would be superior to midodrine, a direct vasoconstrictor, in improving upright blood pressure and orthostatic hypotension–related symptoms. To test this hypothesis, we compared the effect of acute atomoxetine versus midodrine on upright systolic blood pressure and orthostatic symptom scores in 65 patients with severe autonomic failure. There were no differences in seated systolic blood pressure (means difference=0.3 mm Hg; 95% confidence [CI], −7.3 to 7.9; P =0.94). In contrast, atomoxetine produced a greater pressor response in upright systolic blood pressure (means difference=7.5 mm Hg; 95% CI, 0.6 to 15; P =0.03) compared with midodrine. Furthermore, atomoxetine (means difference=0.4; 95% CI, 0.1 to 0.8; P =0.02), but not midodrine (means difference=0.5; 95% CI, −0.1 to 1.0; P =0.08), improved orthostatic hypotension–related symptoms as compared with placebo. The results of our study suggest that atomoxetine could be a superior therapeutic option than midodrine for the treatment of orthostatic hypotension in autonomic failure.

Sympathetic activation contributes to blood pressure (BP) elevation in obesity, but it is unknown whether this contribution differs between obese prehypertensives (PreHTN) and obese hypertensives (HTN). We, therefore, assessed hemodynamic parameters during autonomic withdrawal with the ganglionic blocker trimethaphan (TMT) in 15 lean normotensives (NTN; 34±3 yrs., BMI 23.4±0.4), 11 obese PreHTN (38±2 yrs., BMI 33.6±0.8) and 14 obese HTN (40±1 yrs., BMI 33.8±0.7). As expected, baseline supine systolic BP (SBP) was higher in PreHTN and HTN compared to NTN (P

Autonomic cardiovascular regulation involves sympathetic rhythms that contribute to blood pressure fluctuations in the low frequency range. It has been suggested that fluctuations in sympathetic vasomotor tone reflect a resonance phenomenon due to interplay between the vasculature and baroreflex. Alternatively, this could reflect an intrinsic rhythm of pacemaker neurons. To dissect the autonomic origin of this cardiovascular rhythm, we studied autonomic failure patients with loss of baroreflex buffering. We hypothesized that if this rhythm originates in pacemaker neurons, it would be present in multiple systems atrophy (MSA) patients in whom residual sympathetic tone is intact but not regulated by the baroreflex, and absent in pure autonomic failure (PAF) patients with postganglionic sympathetic denervation. We studied 28 MSA and 34 PAF patients with severe autonomic impairment and neurogenic orthostatic hypotension. Low-frequency systolic blood pressure variability (LFSBP), an index of sympathetic modulation of vasomotor tone, and baroreflex sensitivity (BRS) were assessed by spectral analysis of continuous blood pressure and heart rate recordings. MSA patients had higher LFSBP during supine rest compared with PAF patients (3.3±0.5 versus 1.5±0.2 mmHg2, respectively; p=0.003), despite similarly low BRS (3.6±0.6 PAF versus 4.3±0.7 msec/mmHg MSA; p=0.380). LFSBP was higher in MSA patients with supine hypertension compared with normotensive patients (4.1±0.6 versus 2.3±0.6 mmHg2; p=0.041), with no differences in PAF patients (1.5±0.2 hypertensive versus 1.6±0.3 mmHg2 normotensive, respectively; p=0.984). These findings suggest that LFSBP is driven by an intrinsic rhythm originating in central sympathetic pathways in MSA patients, independent of baroreflex-mediated blood pressure fluctuations. The precise origin of this rhythm is unclear but may include central pacemaker neurons, spinal cord neurons or loops, or hormonal mechanisms. In addition, LFSBP is higher in MSA patients with sympathetically-mediated hypertension, but low and fixed in PAF patients with sympathetic-independent hypertension. Overall, these findings provide new insight into neural regulatory mechanisms involved in blood pressure control.

African American women have the highest prevalence of hypertension (46%) in the world. African Americans (AA) have decreased vascular reactivity to pharmacologic (methacholine, nitroprusside, isoproterenol) and physiological (ischemia) stimuli. Such findings could be explained by racial differences in nitric oxide (NO) release, NO responsiveness, or by a differential suppression of NO by the sympathetic nervous system. The goal of this study was to evaluate tonic restraint of blood pressure by NO during complete autonomic blockade in obese AA vs. white women. We hypothesized that if AA women had a primary NO “deficiency” then they would have less increase in systolic blood pressure (SBP) during intravenous infusion of the NO synthase inhibitor N(ω)-monomethyl-l-arginine (L-NMMA, 250 ug/kg/min) during autonomic blockade. We studied 8 obese AA women and 9 obese white women matched by age (41±6.4 vs. 42±8.2 years, P=0.66), BMI (34±4.4 vs 35±4.1 kg/m2, P=0.83) and seated SBP (121±11 vs. 125±7 mm Hg, P=0.49). Antihypertensive medications were discontinued for 2 weeks and smokers were excluded. All subjects underwent complete autonomic blockade with the ganglionic blocker trimethaphan (TMT, 4 mg/min) followed by L-NMMA. The alpha-1 adrenergic agonist phenylephrine was titrated to clamp systolic blood pressure at 110 mm Hg prior to infusion of L-NMMA. SBP response to L-NMMA was greater in obese AA women (54±13.6 vs. 39±9.6 mm Hg in whites, P=0.02, Figure) suggesting that NO, in the absence of autonomic influences, is an important regulator of blood pressure in obese AA women. This suggests that sympathetic activation contributes to "NO deficiency" in AA.

Severely affected patients with autonomic failure require pressor agents to counteract the blood pressure fall and improve presyncopal symptoms upon standing. Previous studies suggest that combination ergotamine and caffeine may be effective in the treatment of autonomic failure, but the efficacy of this drug has not been evaluated in controlled trials. Therefore, we compared the effects of ergotamine/caffeine on seated blood pressure and orthostatic tolerance and symptoms in 12 primary autonomic failure patients without history of coronary artery disease. Patients were randomized to receive a single oral dose of placebo, midodrine (5-10 mg), or ergotamine and caffeine (1 mg and 100 mg, respectively) in a single-blind, crossover study. Blood pressure was measured while patients were seated and after standing for up to 10 minutes, at baseline and at 1 hour post-drug. Ergotamine/caffeine increased seated systolic blood pressure, the primary outcome, compared with placebo (131±19 and 95±12 mmHg, respectively, at 1 hour post-drug; p=0.003 for time effect). Midodrine also significantly increased seated systolic blood pressure (121±19 mmHg at 1 hour post-drug; p=0.015 for time effect versus placebo), but this effect was not different from ergotamine/caffeine (p=0.621). There was no significant effect of either medication on orthostatic tolerance; however, ergotamine/caffeine improved presyncopal symptoms (p=0.034). These findings suggest that combination ergotamine and caffeine elicits a seated pressor response that is similar in magnitude to midodrine, and improves symptoms in autonomic failure. Thus, ergotamine/caffeine could be used as an alternate treatment for autonomic failure, in carefully selected patients without comorbid coronary artery disease.

Angiotensin (Ang) II contributes to hypertension by direct vasoconstriction, and indirectly by promoting sympathetic activation. The importance of the latter to blood pressure regulation remains controversial, particularly in clinical populations. As a novel approach to test the hypothesis that Ang II promotes sympathetically-mediated hypertension, we compared depressor responses to the Ang II AT1 receptor antagonist losartan in central autonomic failure (AF) patients in whom supine hypertension is driven by residual sympathetic tone to peripheral AF patients with noradrenergic denervation and sympathetic-independent hypertension. Single dose losartan (50 mg, PO) was administered at bedtime to 10 peripheral and 7 central AF patients, with supine blood pressure measured q2 hours for 12 hours in a randomized, double-blind, placebo-controlled study. There were no differences in plasma Ang II levels between groups (42±3 central vs. 43±5 pg/ml peripheral AF; p=0.734); however, peak depressor responses to losar...

Background Patients with postural tachycardia syndrome ( POTS ) have exaggerated orthostatic tachycardia often following a viral illness, suggesting autoimmunity may play a pathophysiological role in POTS . We tested the hypothesis that they harbor functional autoantibodies to adrenergic receptors ( AR ). Methods and Results Fourteen POTS patients (7 each from 2 institutions) and 10 healthy subjects were examined for α1AR autoantibody‐mediated contractility using a perfused rat cremaster arteriole assay. A receptor‐transfected cell‐based assay was used to detect the presence of β1AR and β2AR autoantibodies. Data were normalized and expressed as a percentage of baseline. The sera of all 14 POTS patients demonstrated significant arteriolar contractile activity (69±3% compared to 91±1% of baseline for healthy controls, P P cAMP response curves to the left, consistent with enhanced β1AR and β2AR agonist activity. Autoantibody‐positive POTS sera demonstrated specific binding to β1AR, β2AR, and α1AR in transfected cells. Conclusions POTS patients have elevated α1 AR autoantibodies exerting a partial peripheral antagonist effect resulting in a compensatory sympathoneural activation of α1 AR for vasoconstriction and concurrent β AR ‐mediated tachycardia. Coexisting β1 AR and β2 AR agonistic autoantibodies facilitate this tachycardia. These findings may explain the increased standing plasma norepinephrine and excessive tachycardia observed in many POTS patients.

Obesity has a greater detrimental impact on the health of African American (AA) women than any other racial or gender group. Nearly 80% of AA women are overweight or obese and have higher incidence of insulin resistance compared to Caucasian women. The sympathetic nervous system (SNS) is increased in obesity and previous studies have reported that it may contribute to insulin resistance. However, most of these studies were performed in Caucasians. Thus, the contribution of the SNS to insulin resistance in African Americans remains unknown.The aim of this study was to determine if sympathetic activity is increased in obese AA women with insulin resistance. A total of 35 obese AA women with metabolic syndrome were studied (age 43±9 years, body mass index 38.7±5.5 Kg/m 2 , percentage body fat 48±4). Insulin sensitivity (SI) was evaluated by frequently sampled intravenous tolerance test and analyzed with Bergman's minimal model (MINMOD). Measurement of sympathetic regulation of vasomotor tone and baroreflex gain were determined with baroreflex-cross spectral analysis. Our results showed that SI was directly associated with baroreflex sensitivity, Figure. Subjects with insulin resistance (SISBP ; 5.9±3.4 vs 3.7±2.0 mm Hg 2 , P=0.057). In conclusion, insulin resistance is associated with decreased baroreflex gain and increased sympathetic activity in obese AA women.

Treatment of orthostatic hypotension (OH) with pressor agents can worsen supine hypertension, cause drug interactions, or may be contraindicated in patients with cardiovascular disease. Splanchnic venous compression can improve OH but compliance and efficacy are limited with available garments. We developed an automated inflatable abdominal binder that provides servo-controlled compression (40 mm Hg) only on standing. To compare this device to standard of care with the α-1 agonist midodrine we studied ten autonomic failure patients (5 men, 68±2 yrs) who received placebo, their regular midodrine dose (2.5-10 mg), placebo combined with binder and midodrine combined with binder on separate days, in a randomized, single-blind, crossover study. Systolic blood pressure (SBP) was measured with patients seated and standing before and 1 hr postdrug. Midodrine alone and midodrine with the binder deflated increased seated SBP compared to placebo (29±7 and 25±7 vs. 3±6 mmHg at 1 hr, respectively, Figure A, p

Objective: To determine the effect of low-dose propranolol on maximal exercise capacity in patients with postural tachycardia syndrome (POTS). Methods: We compared the effect of placebo vs a single low dose of propranolol (20 mg) on peak oxygen consumption (VO 2 max), an established measure of exercise capacity, in 11 patients with POTS and 7 healthy subjects in a randomized, double-blind study. Subjects exercised on a semirecumbent bicycle, with increasing intervals of resistance to maximal effort. Results: Maximal exercise capacity was similar between groups following placebo. Low-dose propranolol improved VO 2 max in patients with POTS (24.5 ± 0.7 placebo vs 27.6 ± 1.0 mL/min/kg propranolol; p = 0.024), but not healthy subjects. The increase in VO 2 max in POTS was associated with attenuated peak heart rate responses (142 ± 8 propranolol vs 165 ± 4 bpm placebo; p = 0.005) and improved stroke volume (81 ± 4 propranolol vs 67 ± 3 mL placebo; p = 0.013). In a separate cohort of POTS patients, neither high-dose propranolol (80 mg) nor metoprolol (100 mg) improved VO 2 max, despite similar lowering of heart rate. Conclusions: These findings suggest that nonselective β-blockade with propranolol, when used at the low doses frequently used for treatment of POTS, may provide a modest beneficial effect to improve heart rate control and exercise capacity. Classification of evidence: This study provides Class II evidence that a single low dose of propranolol (20 mg) as compared with placebo is useful in increasing maximum exercise capacity measured 1 hour after medication.

The objective is to study the role of nitric oxide (NO) on cardiovascular regulation in healthy subjects and postural tachycardia syndrome (POTS) patients. Reduced neuronal NO function, which could contribute to a hyperadrenergic state, and increased NO-induced vasodilation, which could contribute to orthostatic intolerance, have been reported in POTS. In protocol 1, 13 healthy volunteers (33±3 years) underwent autonomic blockade with trimethaphan and were administered equipressor doses of Nω-monomethyl-L-arginine (L-NMMA, a NO synthase inhibitor) and phenylephrine to determine the direct chronotropic effects of NO (independent of baroreflex modulation). In protocol 2, we compared the effects of L-NMMA in 9 POTS patients (31±3 years) and 14 healthy (32±2 years) volunteers, during autonomic blockade. During autonomic blockade, L-NMMA and phenylephrine produced similar increases in systolic blood pressure (27±2 versus 27±3 mm Hg). Phenylephrine produced only minimal heart rate changes, whereas L-NMMA produced a modest, but significant, bradycardia (–0.8±0.4 versus –4.8±1.2 bpm; P =0.011). There were no differences between POTS and healthy volunteers in the systolic blood pressure increase (22±2 and 28±5 mm Hg) or heart rate decrease (–6±2 and –4±1 bpm for POTS and controls, respectively) produced by L-NMMA. In the absence of baroreflex buffering, inhibition of endogenous NO synthesis results in a significant bradycardia, reflecting direct tonic modulation of heart rate by NO in healthy individuals. We found no evidence of a primary alteration in NO function in POTS. If NO dysfunction plays a role in POTS, it is through its interaction with the autonomic nervous system.

At least 50% of primary autonomic failure [AF] patients exhibit supine hypertension, despite profound impairments in sympathetic activity. Plasma renin activity is often undetectable in AF suggesting renin mechanisms are not involved in the hypertension. However, since aldosterone levels are preserved we examined the status and contribution of the renin-angiotensin [Ang] system in AF. Supine plasma Ang peptide levels were measured in hypertensive AF patients [AF-HT, n=18], normotensive patients [AF-NT, n=11] and matched healthy subjects [n=10]. Despite suppressed renin activity, total renin concentration was intact in AF [16 ± 5 AF-HT vs 11 ± 4 AF-NT vs 7 ± 1 pg/mL healthy; p=0.29] and plasma prorenin was selectively elevated in hypertensive patients [2.0 ± 0.5 AF-HT vs 0.7 ± 0.1 AF-NT vs 0.6 ± 0.1 ng/mL healthy; p < 0.05]. While levels of Ang I were similar among groups, Ang II was paradoxically elevated [39 ± 4 AF-HT vs 42 ± 6 AF-NT vs 27 ± 4 pg/mL healthy; p1 receptor antagonist losartan [50mg, PO] significantly reduced supine systolic blood pressure [25 ± 15 mmHg at 6 hrs after administration; p

Orthostatic hypotension is the most disabling symptom of autonomic failure. Severely affected patients often require medication to counteract the blood pressure fall and to improve pre-syncopal symptoms on standing. Isolated clinical observations have suggested that the combination ergotamine and caffeine can be useful in the treatment of orthostatic hypotension. The aim of this study was to examine the effect of the combination ergotamine and caffeine on blood pressure and pre-syncopal symptoms on standing in a group of patients with autonomic failure. A total of 12 patients participated in this study. Eight were men and the average age was 64±10 years. The combination ergotamine and caffeine increased seated SBP by 19 mm Hg compared with placebo (95% CI: -2 to 40 mm Hg, P=0.07) (Figure A) and reduced the orthostatic symptom score by 9 points (95% CI: 0.9 to 16, P=0.03), compared with baseline (Figure B). In conclusion, the combination ergotamine and caffeine could be an alternative therapy for orthostatic hypotension in patients with autonomic failure.

C-reactive protein (CRP) is a marker of inflammation in obesity, induced in part by interleukin-6 (IL-6) derived from adipocytes. To test the hypothesis that sympathetic overactivity contributes to the increase in IL-6 and CRP, we measured these inflammatory markers in female subjects: 16 obese (42±2 yrs., BMI 37.5±1.3), 30 healthy controls (32±3 yrs., BMI 23.2±0.4), and 54 with postural tachycardia syndrome (POTS, 31±1 yrs., BMI 22.2±0.4), a condition characterized by increased sympathetic tone. We also included 3 patients with congenital absence of norepinephrine (dopamine ß-hydroxylase deficiency, DBH) as a comparison group for isolated sympathetic failure. Sympathetic activation, measured by low-frequency variability of blood pressure (LFSBP), was greater in obese and POTS compared to healthy controls (8.5±0.8 and 6.1±0.6 vs. 3.4±0.4 mmHg^2, P

Patients with autonomic failure have disabling orthostatic hypotension because of impaired sympathetic activity. Norepinephrine transporter blockade with atomoxetine raises blood pressure in autonomic failure by increasing synaptic norepinephrine concentrations in postganglionic sympathetic neurons. This effect requires tonic release of norepinephrine, which is decreased in patients with low sympathetic tone. We hypothesized that increasing residual sympathetic outflow with the α-2 antagonist yohimbine would potentiate the pressor effect of norepinephrine transporter blockade with atomoxetine and improve orthostatic tolerance in peripheral autonomic failure. Seventeen patients received a single oral dose of either placebo, yohimbine 5.4 mg or atomoxetine 18.0 mg, and the combination yohimbine and atomoxetine in a single blind, crossover study. Blood pressure was assessed while patients were seated and standing for ≤10 minutes before and 1 hour postdrug. Neither yohimbine nor atomoxetine significantly increased seated systolic blood pressure or orthostatic tolerance compared with placebo. The combination, however, significantly increased seated systolic blood pressure and orthostatic tolerance ( P P =0.016, respectively) in a synergistic manner. The maximal increase in seated systolic blood pressure seen with the combination was 31±33 mm Hg at 60 minutes postdrug. Only the combination showed a significant improvement in orthostatic symptoms. In conclusion, the combination of yohimbine and atomoxetine had a synergistic effect on blood pressure and orthostatic tolerance in peripheral autonomic failure, which may be explained by an increased release of norepinephrine in peripheral sympathetic neurons by α-2 antagonism combined with a reduced norepinephrine clearance by norepinephrine transporter blockade. Safety studies are required to address the clinical usefulness of this pharmacological approach.

The purpose of this study was to determine if tonic restrain of blood pressure by nitric oxide (NO) is impaired early in the development of hypertension. Impaired NO function is thought to contribute to hypertension, but it is not clear if this is explained by direct effects of NO on vascular tone or indirect modulation of sympathetic activity. We determined the blood pressure effect of NO synthase inhibition with Nω-monomethyl-l-arginine (l-NMMA) during autonomic blockade with trimethaphan to eliminate baroreflex buffering and NO modulation of autonomic tone. In this setting, impaired NO modulation of vascular tone would be reflected as a blunted pressor response to l-NMMA. We enrolled a total of 66 subjects (39 ± 1.3 yr old, 30 females), 20 normotensives, 20 prehypertensives (blood pressure between 120/80 and 140/90 mmHg), 17 hypertensives, and 9 smokers (included as “positive” controls of impaired NO function). Trimethaphan normalized blood pressure in hypertensives, suggesting increased sympathetic tone contributing to hypertension. In contrast, l-NMMA produced similar increases in systolic blood pressure in normal, prehypertensive, and hypertensive subjects (31 ± 2, 32 ± 2, and 30 ± 3 mmHg, respectively), whereas the response of smokers was blunted (16 ± 5 mmHg, P = 0.012). Our results suggest that sympathetic activity plays a role in hypertension. NO tonically restrains blood pressure by ∼30 mmHg, but we found no evidence of impaired modulation by NO of vascular tone contributing to the early development of hypertension. If NO deficiency contributes to hypertension, it is likely to be through its modulation of the autonomic nervous system, which was excluded in this study.

Publisher Summary Chronic fatigue syndrome (CFS) is a complex disorder characterized by severe, disabling fatigue, associated with several nonspecific systemic symptoms. CFS is a fairly common, incompletely understood disorder, which overlaps clinically with autonomic dysfunction, frequently manifested as orthostatic intolerance. The onset of illness is often acute or subacute and, in many patients, is preceded by an infectious illness. The fatigue in CFS is characterized by persisting or relapsing chronic fatigue lasting at least 6 months in the absence of any definable medical diagnosis. In addition to the case-defining symptoms, many CFS patients experience a constellation of other debilitating symptoms and signs consistent with autonomic dysfunction, particularly those associated with orthostatic intolerance. These autonomic features include orthostatic symptoms and tachycardia, increased sweating, pallor, sluggish pupillary responses, gastrointestinal symptoms, and frequency micturition. Orthostatic intolerance (OI) is defined as the development of characteristic symptoms while standing, which are significantly improved by recumbency.

Publisher Summary The autonomic nervous system plays a crucial role in the regulation of acute blood pressure changes in response to upright posture. The mechanism underlying orthostatic hypotension in autonomic failure is an impairment of autonomic reflexes that affects the ability to release norepinephrine from the postganglionic sympathetic neurons. Among the different strategies to engage residual sympathetic activity, one can stimulate what is left of the patient's own sympathetic nervous system, preventing the uptake of norepinephrine, hence increasing its availability in the synapse or enhancing sympathetic transmission through the autonomic ganglia. Yohimbine is found in a variety of botanical sources and is the principal alkaloid extracted from the bark of the Pausinystalia yohimbe tree. It is rapidly absorbed after oral administration with a peak plasma concentration occurring at 30 minutes and a half-life of 5 hours. Atomoxetine is a selective norepinephrine transporter (NET) blocker commonly used for the treatment of attention deficit hyperactivity disorder in children and adults.

Several studies recognized an overlap between CFS (chronic fatigue syndrome) and POTS (postural tachycardia syndrome). We compared the autonomic and neurohormonal phenotype of POTS patients with CFS (CFS–POTS) to those without CFS (non-CFS–POTS), to determine whether CFS–POTS represents a unique clinical entity with a distinct pathophysiology. We recruited 58 patients with POTS, of which 47 were eligible to participate. A total of 93% of them reported severe fatigue [CIS (Checklist of Individual Strength), fatigue subscale >36], and 64% (n=30) fulfilled criteria for CFS (CFS–POTS). The prevalence of CFS symptoms (Centers for Disease Control and Prevention criteria) was greater in the CFS–POTS group, but the pattern of symptoms was similar in both groups. Physical functioning was low in both groups (RAND-36 Health Survey, 40±4 compared with 33±3; P=0.153), despite more severe fatigue in CFS–POTS patients (CIS fatigue subscale 51±1 compared with 43±3; P=0.016). CFS–POTS patients had greater orthostatic tachycardia than the non-CFS–POTS group (51±3 compared with 40±4 beats/min; P=0.030), greater low-frequency variability of BP (blood pressure; 6.3±0.7 compared with 4.8±1.0 mmHg2; P=0.019), greater BP recovery from early to late phase II of the Valsalva manoeuvre (18±3 compared with 11±2 mmHg; P=0.041) and a higher supine (1.5±0.2 compared with 1.0±0.3 ng/ml per·h; P=0.033) and upright (5.4±0.6 compared with 3.5±0.8 ng/ml per h; P=0.032) PRA (plasma renin activity). In conclusion, fatigue and CFS-defining symptoms are common in POTS patients. The majority of them met criteria for CFS. CFS–POTS patients have higher markers of sympathetic activation, but are part of the spectrum of POTS. Targeting this sympathetic activation should be considered in the treatment of these patients.

Orthostatic hypotension affects patients with autonomic failure producing considerable disability because of presyncopal symptoms. Severely affected patients may have residual sympathetic tone that can be engaged to increase blood pressure (BP) with the α-2 adrenergic antagonist yohimbine. This medication activates sympathetic outflow centrally and unrestrains norepinephrine release from noradrenergic neurons. Alternatively, the acetylcholinesterase inhibitor, pyridostigmine, can increase sympathetic tone by improving ganglionic cholinergic neurotransmission. Our purpose was to compare these complementary approaches and to explore whether the combination would lead to synergistic increases in BP. We compared the effects of 60 mg of pyridostigmine and 5.4 mg of yohimbine in a single-blind, randomized, placebo-controlled, crossover fashion. In a subset of patients we tested the combination of pyridostigmine and yohimbine. Our primary outcome was the change in standing diastolic BP 60 minutes after drug administration from baseline. We studied a total of 31 patients with severe autonomic failure. Yohimbine significantly improved standing diastolic BP as compared with placebo (11±3 mm Hg [95% CI: 6 to 16 mm Hg]; P P =0.823). Only yohimbine showed a significant improvement in presyncopal symptoms. Sixteen patients received the combination of pyridostigmine and yohimbine, but no evidence of synergistic pressor effect was found. Engaging residual sympathetic tone with yohimbine is a more effective approach to improve orthostatic hypotension as compared with pyridostigmine in patients with severe orthostatic hypotension.

decrement comparing brain to calf perfusion. Conclusion: In pediatric and adolescent dysautonomia patients, there was significant decrease in perfusion from baseline in cerebral hemispheres, shoulders, low back, and calves during HUTT. The degree of perfusion impairment in the brain was similar to the gastrocnemius, suggesting a defect in vascular reactivity [cerebral autoregulation] and muscle vasculature. The physiological mechanism requires further investigation.