Adrenal gland response to adrenocorticotropic hormone is intact in patients with postural orthostatic tachycardia syndrome.

BACKGROUND: Many patients with postural orthostatic tachycardia syndrome (POTS) are hypovolemic with plasma volume deficits of 10-30 %. Some also have low levels of aldosterone and diminished aldosterone-renin ratios despite elevations in angiotensin II, pointing to potential adrenal dysfunction. To assess adrenal gland responsiveness in POTS, we measured circulating levels of aldosterone and cortisol following adrenocorticotropin hormone (ACTH) stimulation. METHODS: While on a low Na+ diet (∼10 mEq/day), 8 female patients with POTS and 5 female healthy controls (HC) received a low dose (1 µg) ACTH bolus following a baseline blood sample. After 60 min, a high dose (249 µg) infusion of ACTH was administered to ensure maximal adrenal response. Venous aldosterone and cortisol levels were sampled every 30 min for 2 h. RESULTS: Aldosterone increased in both groups in response to ACTH but was not different between POTS vs. HC at 60 min (53.5 ng/dL [37.8-61.8 ng/dL] vs. 46.1 ng/dL [36.7-84.9 ng/dL]; P = 1.000) or maximally (56.4 ng/dL [49.2-67.1 ng/dL] vs. 49.5 ng/dL [39.1-82.8 ng/dL]; P = 0.524). Cortisol increased in both groups in response to ACTH but was not different in patients with POTS vs. HC at 60 min (39.9 µg/dL [36.1-47.7 µg/dL] vs. 39.3 µg/dL [35.4-46.6 µg/dL]; P = 0.724) or maximally (39.9 µg/dL [33.9-45.4 µg/dL] vs. 42.0 µg/dL [37.6-49.7 µg/dL]; P = 0.354). CONCLUSIONS: ACTH appropriately increased the aldosterone and cortisol levels in patients with POTS. These findings suggest that the response of the adrenal cortex to hormonal stimulation is intact in patients with POTS.

Continuous Positive Airway Pressure for the Treatment of Supine Hypertension and Orthostatic Hypotension in Autonomic Failure.

BACKGROUND: Supine hypertension affects most patients with orthostatic hypotension (OH) due to autonomic failure, but it is often untreated for fear of worsening OH. We hypothesized that increasing intrathoracic pressure with continuous positive airway pressure (CPAP) had a Valsalva-like blood-pressure-lowering effect that could be used to treat nocturnal supine hypertension in these patients, while reducing nocturnal pressure diuresis and improving daytime OH. METHODS: In Protocol 1, we determined the acute hemodynamic effects of increasing levels of CPAP (0, 4, 8, 12, and 16 cm H2O, 3 minutes each) in 26 patients with autonomic failure and supine hypertension studied while awake and supine. In Protocol 2 (n=11), we compared the effects of overnight therapy with CPAP (8-12 cm H2O for 8 hours) versus placebo on nocturnal supine hypertension, nocturnal diuresis and daytime OH in a 2-night crossover study. RESULTS: In Protocol 1, acute CPAP (4-16 cm H2O) decreased systolic blood pressure in a dose-dependent manner (maximal drop 22±4 mmHg with CPAP 16) due to reductions in stroke volume (-16+3%) and cardiac output (-14±3%). Systemic vascular resistance and heart rate remained unchanged. In Protocol 2, overnight CPAP lowered nighttime systolic blood pressure (maximal change -23±5 versus placebo -1±7 mmHg; P=0.023) and was associated with lower nighttime diuresis (609±84 versus placebo 1004±160 mL; P=0.004) and improved morning orthostatic tolerance (AUC upright SBP 642±121 versus placebo 410±109 mmHg*min; P=0.014). CONCLUSIONS: CPAP is a novel nonpharmacologic approach to treat the supine hypertension of autonomic failure while improving nocturia and daytime OH. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT03312556.

Ganglionic Acetylcholine Receptor Antibodies in Postural Tachycardia Syndrome.

OBJECTIVE: Postural tachycardia syndrome (POTS), the most common form of dysautonomia, may be associated with autoimmunity in some cases. Autoantibodies against the ganglionic acetylcholine receptor (gAChR) have been reported in a minority of patients with POTS, but the prevalence and clinical relevance is unclear. METHODS: Clinical information and serum samples were systematically collected from participants with POTS and healthy control volunteers (n = 294). The level of positive gAChR antibodies was classified as very low (0.02-0.05 nmol/L), low (0.05-0.2 nmol/L), and high (>0.2 nmol/L). RESULTS: Fifteen of 217 patients with POTS (7%) had gAChR antibodies (8 very low and 7 low). Six of the 77 healthy controls (8%) were positive (3 very low and 3 low). There were no clinical differences between seropositive and seronegative patients with POTS. CONCLUSIONS: Prevalence of gAChR antibody did not differ between POTS and healthy controls, and none had high antibody levels. Patients with POTS were not clinically different based on seropositivity. Low levels of gAChR antibodies are not clinically important in POTS.

Effect of High Dietary Sodium Intake in Patients With Postural Tachycardia Syndrome.

BACKGROUND: High sodium intake is recommended for the treatment of postural tachycardia syndrome (POTS) to counteract the hypovolemia and elevated plasma norepinephrine that contribute to excessive orthostatic tachycardia, but evidence of its efficacy is not available. OBJECTIVES: This study tested whether a high sodium (HS) diet reduces orthostatic tachycardia (Δ heart rate) and upright heart rate compared with a low sodium (LS) diet in POTS patients, and secondarily its effect on plasma volume (PV) and plasma norepinephrine. METHODS: A total of 14 POTS patients and 13 healthy control subjects (HC), age 23 to 49 years, were enrolled in a crossover study with 6 days of LS (10 mEq sodium/day) or HS (300 mEq sodium/day) diet. Supine and standing heart rate, blood pressure, serum aldosterone, plasma renin activity, blood volume, and plasma norepinephrine and epinephrine were measured. RESULTS: In POTS, the HS diet reduced upright heart rate and Δ heart rate compared with the LS diet. Total blood volume and PV increased, and standing norepinephrine decreased with the HS compared with the LS diet. However, upright heart rate, Δ heart rate, and upright norepinephrine remained higher in POTS than in HC on the HS diet (median 117 beats/min [interquartile range: 98 to 121 beats/min], 46 beats/min [interquartile range: 32 to 55 beats/min], and 753 pg/ml [interquartile range: 498 to 919 pg/ml] in POTS vs. 85 beats/min [interquartile range: 77 to 95 beats/min], 19 beats/min [interquartile range: 11 to 32 beats/min], and 387 pg/ml [interquartile range: 312 to 433 pg/ml] in HC, respectively), despite no difference in the measured PV. CONCLUSIONS: In POTS patients, high dietary sodium intake compared with low dietary sodium intake increases plasma volume, lowers standing plasma norepinephrine, and decreases Δ heart rate. (Dietary Salt in Postural Tachycardia Syndrome; NCT01547117).

Local Passive Heat for the Treatment of Hypertension in Autonomic Failure.

Background Supine hypertension affects a majority of patients with autonomic failure; it is associated with end-organ damage and can worsen daytime orthostatic hypotension by inducing pressure diuresis and volume loss during the night. Because sympathetic activation prevents blood pressure (BP) from falling in healthy subjects exposed to heat, we hypothesized that passive heat had a BP-lowering effect in patients with autonomic failure and could be used to treat their supine hypertension. Methods and Results In Protocol 1 (n=22), the acute effects of local heat (40-42°C applied with a heating pad placed over the abdomen for 2 hours) versus sham control were assessed in a randomized crossover fashion. Heat acutely decreased systolic BP by -19±4 mm Hg (versus 3±4 with sham, P<0.001) owing to decreases in stroke volume (-18±5% versus -4±4%, P=0.013 ) and cardiac output (-15±5% versus -2±4%, P=0.013). In Protocol 2 (proof-of-concept overnight study; n=12), we compared the effects of local heat (38°C applied with a water-perfused heating pad placed under the torso from 10 pm to 6 am) versus placebo pill. Heat decreased nighttime systolic BP (maximal change -28±6 versus -2±6 mm Hg, P<0.001). BP returned to baseline by 8 am. The nocturnal systolic BP decrease correlated with a decrease in urinary volume (r=0.57, P=0.072) and an improvement in the morning upright systolic BP (r=-0.76, P=0.007). Conclusions Local heat therapy effectively lowered overnight BP in patients with autonomic failure and supine hypertension and offers a novel approach to treat this condition. Future studies are needed to assess the long-term safety and efficacy in improving nighttime fluid loss and daytime orthostatic hypotension. Registration URL: https://www.clinicaltrials.gov; Unique identifiers: NCT02417415 and NCT03042988.

Impaired Endothelial Function in Patients With Postural Tachycardia Syndrome.

The purpose of this study is to evaluate endothelial function in postural tachycardia syndrome (PoTS), a poorly understood chronic condition characterized by a state of consistent orthostatic tachycardia (delta heart rate ≥30 beats per minute) upon standing without orthostatic hypotension. Nineteen patients with PoTS and 9 healthy controls were studied after 3 days of a fixed, caffeine-free, normal sodium (150 milliequivalents/day) diet. All participants underwent autonomic function testing, including sinus arrhythmia, valsalva maneuver, hyperventilation, cold pressor, handgrip, and a standing test with catecholamine measurements, followed by endothelial function testing. We analyzed 3 measures of endothelial function: percent brachial flow-mediated dilation, digital pulsatile arterial tonometry, and postischemic percent leg blood flow. Flow-mediated dilation was significantly lower in patients with PoTS (6.23±3.54% for PoTS) than in healthy controls (10.6±4.37% for controls versus, P=0.014). PoTS and controls had similar digital pulsatile arterial tonometry (1.93±0.40 arbitrary units for controls versus 2.13±0.63 arbitrary units for PoTS). PoTS had similar but suggestive percent leg blood flow to controls (313±158% for PoTS versus 468±236% for controls, P=0.098). Patients with PoTS have significantly reduced flow-mediated dilation compared with healthy controls, suggesting that PoTS is characterized by endothelial dysfunction in conduit arteries. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01308099.

Splanchnic Venous Compression Enhances the Effects of ß-Blockade in the Treatment of Postural Tachycardia Syndrome.

Background Splanchnic venous pooling induced by upright posture triggers a compensatory increase in heart rate (HR), a response that is exaggerated in patients with postural tachycardia syndrome. To assess whether abdominal compression attenuates orthostatic tachycardia and improves symptoms, 18 postural tachycardia syndrome patients (32±2 years) were randomized to receive either abdominal compression (40 mm Hg applied with an inflatable binder ≈2 minutes before standing) or propranolol (20 mg) in a placebo-controlled, crossover study. Methods and Results Systolic blood pressure, HR, and symptoms were assessed while seated and standing, before and 2 hours postdrug. As expected, propranolol decreased standing HR compared with placebo (81±2 versus 98±4 beats per minute; P<0.001) and was associated with lower standing systolic blood pressure (93±2 versus 100±2 mm Hg for placebo; P=0.002). Compression had no effect on standing HR (96±4 beats per minute) but increased standing systolic blood pressure compared with placebo and propranolol (106±2 mm Hg; P<0.01). Neither propranolol nor compression improved symptoms compared with placebo. In 16 patients we compared the combination of abdominal compression and propranolol with propranolol alone. The combination had no additional effect on standing HR (81±2 beats per minute for both interventions) but prevented the decrease in standing systolic blood pressure produced by propranolol (98±2 versus 93±2 mm Hg for propranolol; P=0.029), and significantly improved total symptom burden (-6±2 versus -1±2 for propranolol; P=0.041). Conclusions Splanchnic venous compression alone did not improve HR or symptoms but prevented the blood pressure decrease produced by propranolol. The combination was more effective in improving symptoms than either alone. Splanchnic venous compression can be a useful adjuvant therapy to propranolol in postural tachycardia syndrome. Registration URL: https://www.clini​caltr​ials.gov; Unique identifier: NCT00262470.

Congenital absence of norepinephrine due to CYB561 mutations.

OBJECTIVE: Cytochrome b561 (CYB561) generates ascorbic acid, a cofactor in the enzymatic conversion of dopamine to norepinephrine by dopamine ß-hydroxylase. We propose that the clinical relevance of this pathway can be revealed by characterizing the autonomic and biochemical characteristics of patients with CYB561 mutations. METHODS: We performed autonomic evaluations in 4 patients with lifelong orthostatic hypotension in whom CYB561 mutations were determined by genomic sequencing. RESULTS: Patients had disabling lifelong orthostatic hypotension (OH) and impaired blood pressure response to the Valsalva maneuver (VM), with exaggerated hypotension during phase 2 and lack of overshoot during phase 4. Heart rate ratios for sinus arrhythmia and the VM were normal. Plasma norepinephrine and metabolites were undetectable, and plasma dopamine and metabolites were normal. Droxidopa restored norepinephrine levels and improved OH. Patients 1 and 2 were sisters and homozygous for a nonsense mutation in exon 2, c.131G>A, p.Trp44 (Circ Res 2018). Their brother (patient 3) died at age 16 and his DNA was not available. Patient 4 was compound heterozygous; one allele had a missense mutation in exon 2, c157C>T, p.His.53Tyr, and the other had an exon 2 deletion. CONCLUSION: CYB561 deficiency is characterized by selective sympathetic noradrenergic failure with lifelong, disabling OH but with normal sympathetic cholinergic (sweating) and parasympathetic (heart rate regulation) functions. We report a novel case of CYB561 deficiency due to an exon 2 deletion in one allele and a missense mutation in the other. These patients highlight the critical role CYB561 plays in sympathetic function and cardiovascular regulation.

Synergistic Pressor Effect of Atomoxetine and Pyridostigmine in Patients With Neurogenic Orthostatic Hypotension.

Patients with autonomic failure are characterized by disabling orthostatic hypotension because of impaired sympathetic activity, but even severely affected patients have residual sympathetic tone which can be harnessed for their treatment. For example, norepinephrine transporter blockade with atomoxetine raises blood pressure (BP) in autonomic failure patients by increasing synaptic norepinephrine concentrations; acetylcholinesterase inhibition with pyridostigmine increases BP by facilitating ganglionic cholinergic neurotransmission to increase sympathetic outflow. We tested the hypothesis that pyridostigmine will potentiate the pressor effect of atomoxetine and improve orthostatic tolerance and symptoms in patients with severe autonomic failure. Twelve patients received a single oral dose of either placebo, pyridostigmine 60 mg, atomoxetine 18 mg or the combination on separate days in a single blind, crossover study. BP was assessed seated and standing before and 1-hour postdrug. In these severely affected patients, neither pyridostigmine nor atomoxetine improved BP or orthostatic tolerance compared with placebo. The combination, however, significantly increased seated BP in a synergistic manner (133±9/80±4 versus 107±6/66±4 mm Hg for placebo, 105±5/67±3 mm Hg for atomoxetine, and 99±6/64±4 mm Hg for pyridostigmine; P<0.001); the maximal increase in seated BP with the combination was 33±8/18±3 mm Hg at 60 minutes postdrug. Only the combination showed a significant improvement of orthostatic tolerance and symptoms. In conclusion, the combination pyridostigmine and atomoxetine had a synergistic effect on seated BP which was associated with improvement in orthostatic tolerance and symptoms. This pharmacological approach could be useful in patients with severe autonomic failure but further safety and long-term efficacy studies are needed.

A functional cell-based bioassay for assessing adrenergic autoantibody activity in postural tachycardia syndrome.

BACKGROUND: Activating autoantibodies (AAb) to adrenergic receptors (AR) have previously been reported in patients with postural tachycardia syndrome (POTS). These AAb may contribute to a final common pathway for overlapping disease processes, reflecting a possible autoimmune contribution to POTS pathophysiology. In prior studies, measurement of AAb activity was inferred from costly, low-throughput, and laborious physiological assays. In the present study, we developed and validated an alternative cell-based bioassay for measuring AAb activity in serum by means of pre-treatment with monoamine oxidase (MAO). METHODS: A total of 37 POTS patients and 61 sex-matched healthy control participants were included. Serum was pre-treated with MAO to remove endogenous catecholamines that could falsely inflate AR activation by AAb. A receptor-transfected cell-based bioassay was used to detect presence of α1AR-AAb and ß1AR-AAb in serum. RESULTS: MAO effectively degraded catecholamines as demonstrated by suppression of norepinephrine-induced α1AR activation in POTS (6.4 â€‹± â€‹0.7 vs. 5.5 â€‹± â€‹0.9; P â€‹= â€‹0.044) and in controls (4.1 â€‹± â€‹0.5 vs. 3.9 â€‹± â€‹0.6; P â€‹= â€‹0.001). Mean activity values were greater in the POTS vs. Controls for α1AR-AAb (6.2 â€‹± â€‹1.2 vs. 5.3 â€‹± â€‹1.0; P â€‹< â€‹0.001) and ß1AR-AAb (5.7 â€‹± â€‹1.8 vs. 4.1 â€‹± â€‹0.9; P â€‹< â€‹0.001). Compared to controls, more POTS patients were positive for α1AR-AAb activity (22% vs 4%; P â€‹= â€‹0.007) and ß1AR-AAb activity (52% vs. 2%; P â€‹< â€‹0.001). CONCLUSIONS: The co-presence of norepinephrine in serum samples can artifactually elevate α1AR and ß1AR activity, which can be avoided by serum pre-treatment with MAO. Using this novel bioassay, we show that POTS patients have increased α1AR-AAb and ß1AR-AAb activity compared to healthy controls in the largest POTS cohort reported to-date.

Optimal diagnostic thresholds for diagnosis of orthostatic hypotension with a 'sit-to-stand test'.

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 < 0.001; DBP area under curve = 0.930 (95% confidence interval: 0.909-0.950), P < 0.001]. A sit-to stand SBP drop at least 15 mmHg had optimal test characteristics (sensitivity = 80.2%; specificity = 88.9%; positive predictive value = 84.2%; negative predictive value = 85.8%), as did a DBP drop at least 7 mmHg (sensitivity = 87.2%; specificity = 87.2%; positive predictive value = 80.1%; negative predictive value = 92.0%). CONCLUSIONS: A sit-to-stand manoeuvre with lower diagnostic cut-offs for orthostatic hypotension provides a simple screening test for orthostatic hypotension in situations wherein a supine-to-standing manoeuvre cannot be easily performed. Our analysis suggests that a SBP drop at least 15 mmHg or a DBP drop at least 7 mmHg best optimizes sensitivity and specificity of this sit-to-stand test.

Overactive bladder and autonomic dysfunction: Lower urinary tract symptoms in females with postural tachycardia syndrome.

AIMS: Postural Tachycardia Syndrome (POTS) represents an autonomic disorder predominantly affecting females between 15 and 50 years of age. POTS is a chronic disorder (>6 months) characterized by an excessive heart rate increment on standing (>30 beats/min) in the presence of characteristic symptoms of cerebral hypoperfusion or sympathetic activation. Patients have clinically been noted to describe lower urinary tract symptoms (LUTS), although urologic symptoms have not been methodically assessed in the POTS population. Herein, we present data from a pilot study designed to identify and quantitate overactive bladder (OAB) in patients diagnosed with POTS. METHODS: Patients admitted to the Vanderbilt Autonomic Dysfunction Center between June 2009 and October 2010 for evaluation for the potential diagnosis of POTS completed a validated, standardized questionnaire for OAB (OAB-q) at presentation. Symptom score and subscale analyses were conducted. Subscale health related quality of life (HRQL) scores were transformed into a 0-100 scale, with higher scores reflecting superior HRQL. Data are presented as mean ± SD. RESULTS: Thirty-two females presented for evaluation of symptoms consistent with POTS. Twenty-nine women were subsequently diagnosed with POTS with 19 of these patients completing the OAB-q questionnaire (65.5% response rate). Average age was 33.5 ± 8.3 years. Symptom severity transformed score was 26.0 ± 16.4, with 13 of 19 patients (68.4%) meeting clinical criteria for diagnosis of probable clinically significant OAB. Nocturia was the most bothersome symptom, followed by increased daytime frequency and urgency. CONCLUSIONS: This pilot study describes bothersome lower urinary tract dysfunction in patients presenting with POTS as assessed by patient-reported questionnaire data. Nocturia demonstrated the greatest negative impact on health-related quality of life (HRQL), while social interaction was the least affected HRQL domain. In patients with dysautonomia, this data provides a critical baseline for mechanistic insight into both disease-specific and global pathophysiology of nocturia and OAB. Neurourol. Urodynam. 36:610-613, 2017. © 2016 Wiley Periodicals, Inc.

Efficacy of Servo-Controlled Splanchnic Venous Compression in the Treatment of Orthostatic Hypotension: A Randomized Comparison With Midodrine.

UNLABELLED: Splanchnic venous pooling is a major hemodynamic determinant of orthostatic hypotension, but is not specifically targeted by pressor agents, the mainstay of treatment. We developed an automated inflatable abdominal binder that provides sustained servo-controlled venous compression (40 mm Hg) and can be activated only on standing. We tested the efficacy of this device against placebo and compared it to midodrine in 19 autonomic failure patients randomized to receive either placebo, midodrine (2.5-10 mg), or placebo combined with binder on separate days in a single-blind, crossover study. Systolic blood pressure (SBP) was measured seated and standing before and 1-hour post medication; the binder was inflated immediately before standing. Only midodrine increased seated SBP (31±5 versus 9±4 placebo and 7±5 binder, P=0.003), whereas orthostatic tolerance (defined as area under the curve of upright SBP [AUCSBP]) improved similarly with binder and midodrine (AUCSBP, 195±35 and 197±41 versus 19±38 mm Hg×minute for placebo; P=0.003). Orthostatic symptom burden decreased with the binder (from 21.9±3.6 to 16.3±3.1, P=0.032) and midodrine (from 25.6±3.4 to 14.2±3.3, P<0.001), but not with placebo (from 19.6±3.5 to 20.1±3.3, P=0.756). We also compared the combination of midodrine and binder with midodrine alone. The combination produced a greater increase in orthostatic tolerance (AUCSBP, 326±65 versus 140±53 mm Hg×minute for midodrine alone; P=0.028, n=21) and decreased orthostatic symptoms (from 21.8±3.2 to 12.9±2.9, P<0.001). In conclusion, servo-controlled abdominal venous compression with an automated inflatable binder is as effective as midodrine, the standard of care, in the management of orthostatic hypotension. Combining both therapies produces greater improvement in orthostatic tolerance. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT00223691.

Objective Sleep Assessments in Patients with Postural Tachycardia Syndrome using Overnight Polysomnograms.

STUDY OBJECTIVES: Patients with postural tachycardia syndrome (POTS) commonly complain of fatigue, unrefreshing sleep, daytime sleepiness, and diminished quality of life. The study objective was to assess objective sleep quality in POTS patients using overnight polysomnography. METHODS: We studied 16 patients with POTS and 15 healthy control subjects performing daytime autonomic functions tests and overnight polysomnography at the Vanderbilt Clinical Research Center. RESULTS: There were no significant differences in the objective sleep parameters including sleep efficiency, sleep onset latency, wake time after sleep onset, REM latency, percentage of time spent in N1, N2, N3, and REM sleep, arousal index, apnea-hypopnea index, or periodic leg movement index in POTS patients as compared with healthy control subjects. There were significant negative correlations between sleep efficiency and the change in HR from supine to stand (rs = -0.527; p = 0.036). CONCLUSIONS: POTS patients do not have significant differences in objective sleep parameters as compared to control subjects based on overnight polysomnograms. Activation of the sympathetic nervous system may contribute significantly to the hyper arousal state and worsening of subjective estimates of sleep quality as previously reported in POTS patients.

Valsalva Maneuver in Pulmonary Arterial Hypertension: Susceptibility to Syncope and Autonomic Dysfunction.

BACKGROUND: Patients with pulmonary arterial hypertension (PAH) are routinely instructed to avoid performing the Valsalva maneuver for fear of syncope or sudden cardiac death. The mechanism of this action has not been elucidated. We conducted a case-control trial of nine patients with PAH and 15 healthy control subjects to determine if systemic hemodynamic changes during the Valsalva maneuver in these patients invoke greater susceptibility to syncope than healthy control subjects. Metrics commonly employed in autonomic testing were used to assess the degree of autonomic failure. METHODS: Common Valsalva parameters, including adrenergic baroreflex sensitivity, pressure recovery time, systolic BP (SBP) recovery, diastolic BP (DBP) recovery, mean arterial pressure recovery, and the Valsalva ratio, were calculated. Mann-Whitney U tests were used to compare continuous variables. The primary end point was adrenergic baroreflex sensitivity. RESULTS: Patients with PAH had lower adrenergic baroreflex sensitivity (9.7 ± 4.6 mm Hg/s vs 18.8 ± 9.2 mm Hg/s; P = .005), longer pressure recovery time (3.6 ± 2.5 s vs 1.7 ± 0.8 s; P = .008), similar SBP recovery (-13 ± 11 mm Hg vs -12 ± 23 mm Hg; P = .640), less DBP recovery (-1 ± 12 mm Hg vs 13 ± 14 mmHg; P = .025), less mean arterial pressure recovery (-5 ± 11 mm Hg vs 5 ± 17 mm Hg; P = .048), and a decreased Valsalva ratio (1.25 ± 0.11 vs 1.60 ± 0.22; P < .001) compared with healthy control subjects. CONCLUSIONS: Compared with healthy control subjects, patients with PAH are more susceptible to syncope during the Valsalva maneuver because of autonomic dysfunction causing cerebral hypoperfusion. These study patients with PAH exhibited a degree of susceptibility to syncope similar to a spectrum of patients with intermediate autonomic failure who typically experience a SBP drop of 10 to 30 mm Hg with standing.

Mineralocorticoid Receptor Activation Contributes to the Supine Hypertension of Autonomic Failure.

Primary autonomic failure is characterized by disabling orthostatic hypotension, but at least half of these patients have paradoxical supine hypertension. Renin-angiotensin mechanisms were not initially thought to contribute to this hypertension because plasma renin activity is often undetectable in autonomic failure. Plasma aldosterone levels are normal, however, and we recently showed that plasma angiotensin II is elevated and acts at AT1 (angiotensin type 1) receptors to contribute to hypertension in these patients. Because aldosterone and angiotensin II can also bind mineralocorticoid receptors to elevate blood pressure, we hypothesized that mineralocorticoid receptor activation plays a role in the hypertension of autonomic failure. To test this hypothesis, we determined the acute effects of the mineralocorticoid receptor antagonist eplerenone (50 mg, oral) versus placebo on supine blood pressure in a randomized, double-blind, crossover study. Medications were given at 8:00 pm with blood pressure recorded every 2 hours for 12 hours. Ten primary autonomic failure patients with supine hypertension completed this study (7 pure autonomic failure, 2 multiple system atrophy, 1 parkinson's disease; 7 male; 70±2 years of age). Eplerenone maximally reduced supine systolic blood pressure by 32±6 mm Hg at 8 hours after administration (versus 8±10 mm Hg placebo, P=0.016), with no effect on nocturia (12-hour urine volume: 985±134 mL placebo versus 931±94 mL eplerenone, P=0.492; nocturnal weight loss: -1.19±0.15 kg placebo versus -1.18±0.15 kg eplerenone, P=0.766). These findings suggest that inappropriate mineralocorticoid receptor activation contributes to the hypertension of autonomic failure, likely independent of canonical mineralocorticoid effects, and provides rationale for use of eplerenone in these patients.

Sympathetic activation is associated with increased IL-6, but not CRP in the absence of obesity: lessons from postural tachycardia syndrome and obesity.

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 mmHg(2), respectively, P = 0.006), lower cardiac parasympathetic modulation (high-frequency heart rate variability, 1,414 ± 398 vs. 369 ± 66 ms(2), 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 mmHg(2); 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.

Inspiratory resistance improves postural tachycardia: a randomized study.

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.

Neurogenic hyperadrenergic orthostatic hypotension: a newly recognized variant of orthostatic hypotension in older adults with elevated norepinephrine (noradrenaline).

Patients with neurogenic orthostatic hypotension (OH) typically have impaired sympathetic nervous system tone and therefore low levels of upright plasma norepinephrine (NE) (noradrenaline). We report a subset of patients who clinically have typical neurogenic OH but who paradoxically have elevated upright levels of plasma NE. We retrospectively studied 83 OH patients evaluated at the Vanderbilt Autonomic Dysfunction Center between August 2007 and May 2013. Based on standing NE, patients were dichotomized into a hyperadrenergic OH group [hyperOH: upright NE ≥ 3.55 nmol/l (600 pg/ml), n=19] or a non-hyperadrenergic OH group [nOH: upright NE < 3.55 nmol/l (600 pg/ml), n=64]. Medical history and data from autonomic testing, including the Valsalva manoeuvre (VM), were analysed. HyperOH patients had profound orthostatic falls in blood pressure (BP), but less severe than in nOH [change in SBP (systolic blood pressure): -53 ± 31 mmHg compared with -68 ± 33 mmHg, P=0.050; change in DBP (diastolic blood pressure): -18 ± 23 mmHg compared with -30 ± 17 mmHg, P=0.01]. The expected compensatory increase in standing heart rate (HR) was similarly blunted in both hyperOH and nOH groups [84 ± 15 beats per minute (bpm) compared with 82 ± 14 bpm; P=0.6]. HyperOH patients had less severe sympathetic failure as evidenced by smaller falls in DBP during phase 2 of VM and a shorter VM phase 4 BP recovery time (16.5 ± 8.9 s compared with 31.6 ± 16.6 s; P<0.001) than nOH patients. Neurogenic hyperOH patients have severe neurogenic OH, but have less severe adrenergic dysfunction than nOH patients. Further work is required to understand whether hyperOH patients will progress to nOH or whether this represents a different disorder.

Nebivolol, but not metoprolol, lowers blood pressure in nitric oxide-sensitive human hypertension.

Nebivolol, unlike other selective ß1-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 ß-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<0.001 and 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 ß1-blockade. These results are consistent with the hypothesis that NO potentiation contributes significantly to the antihypertensive effect of nebivolol.