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Overactive bladder and autonomic dysfunction: Lower urinary tract symptoms in females with postural tachycardia syndrome.
Kaufman MR, Chang-Kit L, Raj SR, Black BK, Milam DF, Reynolds WS, Biaggioni I, Robertson D, Dmochowski RR
(2017) Neurourol Urodyn 36: 610-613
MeSH Terms: Adult, Female, Humans, Lower Urinary Tract Symptoms, Pilot Projects, Postural Orthostatic Tachycardia Syndrome, Quality of Life, Surveys and Questionnaires, Urinary Bladder, Overactive
Show Abstract · Added September 16, 2019
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.
© 2016 Wiley Periodicals, Inc.
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Understanding the placebo effect in clinical trials for postural tachycardia syndrome.
Nwazue VC, Arnold AC, Raj V, Black BK, Biaggioni I, Paranjape SY, Orozco C, Dupont WD, Robertson D, Raj SR
(2014) Clin Exp Pharmacol Physiol 41: 325-30
MeSH Terms: Adult, Analysis of Variance, Blood Pressure, Cardiovascular Physiological Phenomena, Circadian Rhythm, Cross-Over Studies, Female, Heart Rate, Humans, Male, Placebo Effect, Placebos, Postural Orthostatic Tachycardia Syndrome, Posture, Prospective Studies, Time Factors
Show Abstract · Added March 21, 2014
Postural tachycardia syndrome (POTS) is characterized by excessive increases in heart rate (HR) upon standing. Previous studies have shown that standing HR decreases over time in POTS patients given placebo. We hypothesized that this reduction is due to cardiovascular physiological alteration, as opposed to psychological benefit from perceived therapy. To prospectively test this hypothesis, we examined the effects of an open-label 'no treatment' intervention (NoRx) compared with a patient-blinded placebo on standing HR in POTS patients. Twenty-one POTS patients participated in a randomized cross-over trial with oral placebo versus NoRx administered at 0900 h. Seated blood pressure (BP) and HR were measured at baseline and every hour for 4 h. Similarly, BP and HR were measured while patients stood for 10 min at these time points. Standing HR decreased significantly over time with both NoRx (112±13 and 103±16 b.p.m. at baseline and 4 h, respectively) and placebo (112±14 and 102±16 b.p.m. at baseline and 4 h, respectively; Ptime<0.001), but this effect was not different between interventions (Pdrug=0.771). Postural tachycardia syndrome patients have exaggerated orthostatic tachycardia in the morning that decreases over time with either placebo or NoRx interventions, suggesting this phenomenon is due to cardiovascular physiological variation. These data highlight the need for a placebo arm in haemodynamic clinical trials in POTS and may have important implications for the diagnosis of these patients.
© 2014 Wiley Publishing Asia Pty Ltd.
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16 MeSH Terms
Melatonin reduces tachycardia in postural tachycardia syndrome: a randomized, crossover trial.
Green EA, Black BK, Biaggioni I, Paranjape SY, Bagai K, Shibao C, Okoye MC, Dupont WD, Robertson D, Raj SR
(2014) Cardiovasc Ther 32: 105-12
MeSH Terms: Administration, Oral, Adult, Anti-Arrhythmia Agents, Blood Pressure, Cross-Over Studies, Drug Administration Schedule, Female, Heart Rate, Humans, Male, Melatonin, Norepinephrine, Postural Orthostatic Tachycardia Syndrome, Sympathetic Nervous System, Tennessee, Time Factors, Treatment Outcome, Young Adult
Show Abstract · Added March 21, 2014
BACKGROUND - Postural tachycardia syndrome (POTS) induces disabling chronic orthostatic intolerance with an excessive increase in heart rate (HR) upon standing, and many POTS patients have a hyperadrenergic state. Medications that restrain HR are a promising approach to this problem.
OBJECTIVE - We tested the hypothesis that melatonin will attenuate the tachycardia and improve symptom burden in patients with POTS.
METHODS - Patients with POTS (n = 78) underwent acute drug trials with melatonin 3 mg orally and placebo, on separate mornings, in a randomized crossover design. Blood pressure, HR, and symptoms were assessed while seated and after standing for up to 10 min prior to, and hourly for 4 h following study drug administration.
RESULTS - The reduction in standing HR was significantly greater 2 h after melatonin compared with placebo (P = 0.017). There was no significant difference in the reduction of systolic blood pressure between melatonin and placebo, either with standing or while seated. The symptom burden was not improved with melatonin compared with placebo.
CONCLUSION - Oral melatonin produced a modest decrease in standing tachycardia in POTS. Further research is needed to determine the effects of regular night-time use of this medication in POTS.
© 2014 John Wiley & Sons Ltd.
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Acute hemodynamic effects of a selective serotonin reuptake inhibitor in postural tachycardia syndrome: a randomized, crossover trial.
Mar PL, Raj V, Black BK, Biaggioni I, Shibao CA, Paranjape SY, Dupont WD, Robertson D, Raj SR
(2014) J Psychopharmacol 28: 155-61
MeSH Terms: Adult, Blood Pressure, Cross-Over Studies, Female, Heart Rate, Hemodynamics, Humans, Male, Norepinephrine Plasma Membrane Transport Proteins, Postural Orthostatic Tachycardia Syndrome, Serotonin Uptake Inhibitors, Sertraline
Show Abstract · Added March 7, 2014
BACKGROUND - Selective serotonin reuptake inhibitors (SSRIs) are often prescribed in patients with postural tachycardia syndrome (POTS), and act at synaptic terminals to increase monoamine neurotransmitters. We hypothesized that they act to increase blood pressure and attenuate reflex tachycardia, thereby improving symptoms. Acute hemodynamic profiles after SSRI administration in POTS patients have not previously been reported.
METHODS - Patients with POTS (n=39; F=37, 39 ±9 years) underwent a randomized crossover trial with sertraline 50mg and placebo. Heart rate, systolic, diastolic, and mean blood pressure were measured with the patient seated and standing for 10 min prior to drug or placebo administration, and then hourly for 4 h. The primary endpoint was standing heart rate at 4 h.
RESULTS - At 4 h, standing heart rate and systolic blood pressure were not significantly different between sertraline and placebo. Seated systolic (106±12 mmHg vs. 101±8 mmHg; p=0.041), diastolic (72±8 mmHg vs. 69±8 mmHg; p=0.022), and mean blood pressure (86±9 mmHg vs. 81±9 mmHg; p=0.007) were significantly higher after sertraline administration than placebo. At 4 h, symptoms were worse with sertraline than placebo.
CONCLUSIONS - Sertraline had a modest pressor effect in POTS patients, but this did not translate into a reduced heart rate or improved symptoms.
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Effects of norepinephrine reuptake inhibition on postural tachycardia syndrome.
Green EA, Raj V, Shibao CA, Biaggioni I, Black BK, Dupont WD, Robertson D, Raj SR
(2013) J Am Heart Assoc 2: e000395
MeSH Terms: Adrenergic Uptake Inhibitors, Adult, Atomoxetine Hydrochloride, Cross-Over Studies, Female, Heart Rate, Humans, Male, Norepinephrine Plasma Membrane Transport Proteins, Postural Orthostatic Tachycardia Syndrome, Propylamines, Severity of Illness Index
Show Abstract · Added March 7, 2014
BACKGROUND - Postural tachycardia syndrome (POTS) is a disorder of chronic orthostatic intolerance accompanied by excessive orthostatic tachycardia. Patients with POTS commonly have comorbid conditions such as attention deficit hyperactivity disorder, depression, or fibromyalgia that are treated with medications that inhibit the norepinephrine reuptake transporter (NRI). NRI medications can increase sympathetic nervous system tone, which may increase heart rate (HR) and worsen symptoms in POTS patients. We sought to determine whether NRI with atomoxetine increases standing tachycardia or worsens the symptom burden in POTS patients.
METHODS AND RESULTS - Patients with POTS (n = 27) underwent an acute drug trial of atomoxetine 40 mg and placebo on separate mornings in a randomized, crossover design. Blood pressure (BP), HR, and symptoms were assessed while seated and after standing prior to and hourly for 4 hours following study drug administration. Atomoxetine significantly increased standing HR compared with placebo (121 ± 17 beats per minute versus 105 ± 15 beats per minute; P = 0.001) in POTS patients, with a trend toward higher standing systolic BP (P = 0.072). Symptom scores worsened with atomoxetine compared to placebo (+4.2 au versus -3.5 au; P = 0.028) from baseline to 2 hours after study drug administration.
CONCLUSION - Norepinephrine reuptake inhibition with atomoxetine acutely increased standing HR and symptom burden in patients with POTS.
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Low-dose propranolol and exercise capacity in postural tachycardia syndrome: a randomized study.
Arnold AC, Okamoto LE, Diedrich A, Paranjape SY, Raj SR, Biaggioni I, Gamboa A
(2013) Neurology 80: 1927-33
MeSH Terms: Adult, Cross-Over Studies, Double-Blind Method, Exercise Test, Female, Humans, Oxygen Consumption, Postural Orthostatic Tachycardia Syndrome, Propranolol, Young Adult
Show Abstract · Added December 10, 2013
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 (VO2max), 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 VO2max 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 VO2max 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 VO2max, 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.
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Norepinephrine transporter variant A457P knock-in mice display key features of human postural orthostatic tachycardia syndrome.
Shirey-Rice JK, Klar R, Fentress HM, Redmon SN, Sabb TR, Krueger JJ, Wallace NM, Appalsamy M, Finney C, Lonce S, Diedrich A, Hahn MK
(2013) Dis Model Mech 6: 1001-11
MeSH Terms: Animals, Baroreflex, Behavior, Animal, Biological Transport, Catecholamines, Disease Models, Animal, Female, Gene Knock-In Techniques, Humans, Methoxyhydroxyphenylglycol, Mice, Mutant Proteins, Norepinephrine, Norepinephrine Plasma Membrane Transport Proteins, Postural Orthostatic Tachycardia Syndrome, Telemetry
Show Abstract · Added June 2, 2014
Postural orthostatic tachycardia syndrome (POTS) is a common autonomic disorder of largely unknown etiology that presents with sustained tachycardia on standing, syncope and elevated norepinephrine spillover. Some individuals with POTS experience anxiety, depression and cognitive dysfunction. Previously, we identified a mutation, A457P, in the norepinephrine (NE; also known as noradrenaline) transporter (NET; encoded by SLC6A2) in POTS patients. NET is expressed at presynaptic sites in NE neurons and plays a crucial role in regulating NE signaling and homeostasis through NE reuptake into noradrenergic nerve terminals. Our in vitro studies demonstrate that A457P reduces both NET surface trafficking and NE transport and exerts a dominant-negative impact on wild-type NET proteins. Here we report the generation and characterization of NET A457P mice, demonstrating the ability of A457P to drive the POTS phenotype and behaviors that are consistent with reported comorbidities. Mice carrying one A457P allele (NET(+/P)) exhibited reduced brain and sympathetic NE transport levels compared with wild-type (NET(+/+)) mice, whereas transport activity in mice carrying two A457P alleles (NET(P/P)) was nearly abolished. NET(+/P) and NET(P/P) mice exhibited elevations in plasma and urine NE levels, reduced 3,4-dihydroxyphenylglycol (DHPG), and reduced DHPG:NE ratios, consistent with a decrease in sympathetic nerve terminal NE reuptake. Radiotelemetry in unanesthetized mice revealed tachycardia in NET(+/P) mice without a change in blood pressure or baroreceptor sensitivity, consistent with studies of human NET A457P carriers. NET(+/P) mice also demonstrated behavioral changes consistent with CNS NET dysfunction. Our findings support that NET dysfunction is sufficient to produce a POTS phenotype and introduces the first genetic model suitable for more detailed mechanistic studies of the disorder and its comorbidities.
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Estimation of sleep disturbances using wrist actigraphy in patients with postural tachycardia syndrome.
Bagai K, Wakwe CI, Malow B, Black BK, Biaggioni I, Paranjape SY, Orozco C, Raj SR
(2013) Auton Neurosci 177: 260-5
MeSH Terms: Actigraphy, Adult, Cohort Studies, Female, Humans, Male, Middle Aged, Polysomnography, Postural Orthostatic Tachycardia Syndrome, Prospective Studies, Sleep Stages, Sleep Wake Disorders, Wrist, Young Adult
Show Abstract · Added March 7, 2014
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 sleep quality in POTS patients using wrist actigraphy.
DESIGN - Prospective study with control group.
METHODS - Patients with POTS (n = 36) and healthy subjects (n = 36) completed a detailed sleep log and actigraphy for 7 days.
RESULTS - Compared with healthy subjects, POTS patients have more self-reported problems including days with restless sleep (53 ± 30% vs. 21 ± 20%; P<0.001) and tiredness (75 ± 23% vs. 39 ± 27%; P<0.001). Using actigraphy, POTS patients have lower sleep efficiency (73 ± 13% vs. 79 ± 6%; P = 0.01). Actigraphy determined sleep onset latency (SOL) did not vary significantly in the two groups, but subjective SOL was higher in POTS patient (56 ± 66 min vs. 1 3 ± 9 min; P = 0.001). In POTS patients, there was a significant correlation between subjective complaints of tiredness and actigraphic sleep efficiency (Rs = -0.36; R(2) = 0.15; P = 0.01), significant correlations between actigraphic SOL and upright norepinephrine levels (P = 0.040), and between wake after sleep onset and standing heart rate (P = 0.02).
CONCLUSIONS - POTS patients have more sleep-related symptoms and poor sleep efficiency. The pattern of subjective vs. objective SOL mismatch is suggestive of sleep-state misperception. High norepinephrine correlated with actigraphic SOL, and this activation of the stress system may contribute significantly to a hyperarousal state with consequent insomnia, poor mental and physical health in POTS patients.
Copyright © 2013 Elsevier B.V. All rights reserved.
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Nitric oxide and regulation of heart rate in patients with postural tachycardia syndrome and healthy subjects.
Gamboa A, Okamoto LE, Raj SR, Diedrich A, Shibao CA, Robertson D, Biaggioni I
(2013) Hypertension 61: 376-81
MeSH Terms: Adult, Autonomic Nervous System, Baroreflex, Blood Pressure, Enzyme Inhibitors, Female, Heart Rate, Humans, Male, Nitric Oxide, Nitric Oxide Synthase, Phenylephrine, Postural Orthostatic Tachycardia Syndrome, omega-N-Methylarginine
Show Abstract · Added December 10, 2013
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.
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Diagnosing postural tachycardia syndrome: comparison of tilt testing compared with standing haemodynamics.
Plash WB, Diedrich A, Biaggioni I, Garland EM, Paranjape SY, Black BK, Dupont WD, Raj SR
(2013) Clin Sci (Lond) 124: 109-14
MeSH Terms: Adult, Female, Heart Rate, Humans, Male, Middle Aged, Postural Orthostatic Tachycardia Syndrome, Posture, ROC Curve, Retrospective Studies, Sensitivity and Specificity, Tennessee, Tilt-Table Test, Time Factors
Show Abstract · Added March 7, 2014
POTS (postural tachycardia syndrome) is characterized by an increased heart rate (ΔHR) of ≥30 bpm (beats/min) with symptoms related to upright posture. Active stand (STAND) and passive head-up tilt (TILT) produce different physiological responses. We hypothesized these different responses would affect the ability of individuals to achieve the POTS HR increase criterion. Patients with POTS (n=15) and healthy controls (n=15) underwent 30 min of tilt and stand testing. ΔHR values were analysed at 5 min intervals. ROC (receiver operating characteristic) analysis was performed to determine optimal cut point values of ΔHR for both tilt and stand. Tilt produced larger ΔHR than stand for all 5 min intervals from 5 min (38±3 bpm compared with 33±3 bpm; P=0.03) to 30 min (51±3 bpm compared with 38±3 bpm; P<0.001). Sn (sensitivity) of the 30 bpm criterion was similar for all tests (TILT10=93%, STAND10=87%, TILT30=100%, and STAND30=93%). Sp (specificity) of the 30 bpm criterion was less at both 10 and 30 min for tilt (TILT10=40%, TILT30=20%) than stand (STAND10=67%, STAND30=53%). The optimal ΔHR to discriminate POTS at 10 min were 38 bpm (TILT) and 29 bpm (STAND), and at 30 min were 47 bpm (TILT) and 34 bpm (STAND). Orthostatic tachycardia was greater for tilt (with lower Sp for POTS diagnosis) than stand at 10 and 30 min. The 30 bpm ΔHR criterion is not suitable for 30 min tilt. Diagnosis of POTS should consider orthostatic intolerance criteria and not be based solely on orthostatic tachycardia regardless of test used.
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14 MeSH Terms