Symptoms of postural orthostatic tachycardia syndrome in pregnancy: a cross-sectional, community-based survey.

OBJECTIVE: To evaluate the relationship between postural orthostatic tachycardia syndrome (POTS) and pregnancy. DESIGN: Cross-sectional survey. SETTING: International. SAMPLE: A total of 8941 female patients with a diagnosis of POTS. METHODS: Data from the survey were analysed using descriptive measures and stratified for comparisons. MAIN OUTCOME MEASURES: Symptom course of POTS during pregnancy. Secondary outcomes included pregnancy loss, POTS onset during pregnancy and the impacts of a comorbid diagnosis of Ehlers-Danlos syndrome or an autoimmune disorder on symptoms during pregnancy. RESULTS: Overall, 40.8% (n = 3652) of participants reported one or more pregnancies. Most participants experienced worsening of symptoms in the first (62.6%) and third (58.9%) trimesters and 3 months after pregnancy (58.7%), and 81.1% experienced worsening symptoms at any point in their pregnancy. Most participants with worsening symptoms in the first trimester also experienced worsening symptoms in the second (61.6%) and third (68.1%) trimesters, but if they improved in the first trimester then this improvement persisted in the second and third trimesters. Of participants who reported that POTS was triggered by a specific event (41.3%), 8.1% reported pregnancy as the trigger for the onset. CONCLUSIONS: Postural orthostatic tachycardia syndrome symptoms in the first trimester of pregnancy may help predict symptom course throughout the duration of pregnancy. Some individuals may experience an initial onset of POTS during pregnancy. This novel information may guide clinicians in counselling patients with POTS who are planning pregnancy.

Postural orthostatic tachycardia syndrome is associated with significant employment and economic loss.

BACKGROUND: Postural orthostatic tachycardia syndrome (POTS) is a debilitating form of chronic orthostatic intolerance that primarily affects women and causes substantial impairment in quality of life and function. Yet, there is minimal literature describing the employment and economic consequences of POTS. We explored these aspects of the POTS patient experience through a self-reported study designed using community-based participatory research principles. METHODS AND RESULTS: A comprehensive questionnaire, including employment and economic consequences, was developed in partnership with Dysautonomia International, a patient advocacy organization. The POTS community engaged in all stages of the research design and analysis. Participants were recruited through Dysautonomia International's website and social media channels. The analysis included 5,556 adult (age ≥18 years) participants with a physician-confirmed diagnosis of POTS. The majority of participants were female (95%). Forty-eight per cent of participants reported employment during the three months prior to the survey, and of these participants, 66.8% would work greater hours if not for illness limitations. Over two-thirds (70.5%) of participants have lost income due to POTS symptoms, with 36.0% of the total cohort losing more than $10,000 USD in the 12 months prior to the survey. Almost all (95%) participants reported POTS-related out-of-pocket medical expenses since diagnosis, with 51.1% of participants spending $10,000 USD or more. CONCLUSIONS: This is the largest study reporting the employment and economic challenges experienced by individuals with POTS. Exposure of these challenges emphasizes the need for earlier diagnosis and improved therapeutic strategies to reduce the negative individual and societal consequences of this disorder.

Elevated cerebral blood flow in patients with pure autonomic failure.

PURPOSE: Pure autonomic failure (PAF) results from an impaired peripheral autonomic nervous system, and clinical symptoms present with orthostatic hypotension. While the impact on cardiovascular indices of orthostatic intolerance are well-characterized, more limited information is available regarding cerebral hemodynamic dysfunction in PAF. The objective of this study was to test the hypothesis that cerebral blood flow (CBF) is reduced in PAF, and to quantify the relationship between CBF and clinical indicators of disease severity, including peripheral supine arterial blood pressure. METHODS: Participants with PAF (n = 17) and age- and sex-matched normotensive healthy controls (n = 17) were examined using established clinical rating scales, cardiovascular autonomic function tests, and 3T MRI measurements of CBF. CBF-weighted images were also used to determine the prevalence of venous hyperintensities from the major dural sinuses as evidence of abnormal capillary flow. Nonparametric tests and general linear models were used to evaluate differences and correlations between study variables. RESULTS: Gray matter CBF was higher in PAF (51.1 ± 13.4 mL/100 g/min) compared to controls (42.9 ± 6.5 mL/100 g/min, p = 0.007). Venous hyperintensities were more prevalent in PAF relative to controls, and the presence and degree of venous hyperintensities was associated with higher mean CBF (p = 0.027). In PAF participants, CBF and supine systolic blood pressure were inversely related (Spearman's rho = -0.545, p = 0.024). CONCLUSIONS: Findings suggest that PAF patients may exhibit elevated CBF and provide evidence that this condition exerts a hemodynamic impact in the central nervous system.

High-sodium diet does not worsen endothelial function in female patients with postural tachycardia syndrome.

PURPOSE: Postural tachycardia syndrome (POTS), a syndrome characterized by orthostatic symptoms and a heart rate increase of at least 30 beats per minute in the absence of hypotension upon standing, is often accompanied by increased sympathetic activity and low blood volume. A common non-pharmacologic recommendation for patients with POTS is a high-sodium (HS) diet with the goal of bolstering circulating blood volume. The objective of this study is to assess the effects of 6 days of a HS diet on endothelial function in POTS. METHODS: A total of 14 patients with POTS and 13 age-matched healthy controls, all females, were studied following 6 days on a low-sodium (LS) diet (10 mEq/day) and 6 days on a HS diet (300 mEq/day) in a crossover design. We measured endothelial function following reactive hyperemia in the brachial artery using flow-mediated dilation (FMD), leg blood flow (LBF) using strain gauge plethysmography in the calf, and reactive hyperemic index (RHI) in the microcirculation of the hand using pulsatile arterial tonometry. RESULTS: On the LS diet, FMD% did not differ between patients with POTS and the healthy controls although peak brachial artery diameter was lower for the patient group. RHI was higher for the patient group than for the controls, but there were no differences in post-ischemic LBF increase. On the HS diet, there were no between-group differences in FMD%, LBF increase, or RHI. CONCLUSION: In summary, a HS diet for 6 days did not induce endothelial dysfunction. This non-pharmacologic treatment used for patients with POTS does not negatively affect endothelial function when used for a sub-acute duration. TRIAL REGISTRATION: ClinicalTrials.gov NCT01550315; March 9, 2012.

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.

Cognitive dysfunction in postural tachycardia syndrome.

Mental clouding is an almost universal complaint among patients with postural tachycardia syndrome (POTS) but remains poorly understood. Thus, we have determined whether POTS patients exhibit deficits during neuropsychological testing relative to healthy subjects. A comprehensive battery of validated neuropsychological tests was administered to 28 female POTS patients and 24 healthy subjects in a semi-recumbent position. Healthy subjects were matched to POTS patients on age and gender. Selective attention, a primary outcome measure, and cognitive processing speed were reduced in POTS patients compared with healthy subjects (Ruff 2&7 Speed t-score: 40±9 compared with 49±8; P=0.009; Symbol Digit Modalities Test t-score: 45±12 compared with 51±8; P=0.011). Measures of executive function were also lower in POTS patients (Trails B t-score: 46±8 compared with 52±8; P=0.007; Stroop Word Color t-score: 45±10 compared with 56±8; P=0.001), suggesting difficulties in tracking and mental flexibility. Measures of sustained attention, psychomotor speed, memory function or verbal fluency were not significantly different between groups. The present study provides evidence for deficits in selective attention and cognitive processing in patients with POTS, in the seated position when orthostatic stress is minimized. In contrast, other measures of cognitive function, including memory assessments, were not impaired in these patients, suggesting selectivity in these deficits. These findings provide new insight into the profile of cognitive dysfunction in POTS and provide the basis for further studies to identify clinical strategies to better manage the mental clouding associated with this condition.

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.

Postural Tachycardia Syndrome: Beyond Orthostatic Intolerance.

Postural tachycardia syndrome (POTS) is a form of chronic orthostatic intolerance for which the hallmark physiological trait is an excessive increase in heart rate with assumption of upright posture. The orthostatic tachycardia occurs in the absence of orthostatic hypotension and is associated with a >6-month history of symptoms that are relieved by recumbence. The heart rate abnormality and orthostatic symptoms should not be caused by medications that impair autonomic regulation or by debilitating disorders that can cause tachycardia. POTS is a "final common pathway" for a number of overlapping pathophysiologies, including an autonomic neuropathy in the lower body, hypovolemia, elevated sympathetic tone, mast cell activation, deconditioning, and autoantibodies. Not only may patients be affected by more than one of these pathophysiologies but also the phenotype of POTS has similarities to a number of other disorders, e.g., chronic fatigue syndrome, Ehlers-Danlos syndrome, vasovagal syncope, and inappropriate sinus tachycardia. POTS can be treated with a combination of non-pharmacological approaches, a structured exercise training program, and often some pharmacological support.

SHC2 gene copy number in multiple system atrophy (MSA).

PURPOSE: Multiple system atrophy (MSA) is a sporadic, late onset, rapidly progressing neurodegenerative disorder, which is characterized by autonomic failure, together with Parkinsonian, cerebellar, and pyramidal motor symptoms. The pathologic hallmark is the glial cytoplasmic inclusion with α-synuclein aggregates. MSA is thus an α-synucleinopathy. Recently, Sasaki et al. reported that heterozygosity for copy number loss of Src homology 2 domain containing-transforming protein 2 (SHC2) genes (heterozygous SHC2 gene deletions) occurred in DNAs from many Japanese individuals with MSA. Because background copy number variation can be distinct in different human populations, we assessed SHC2 allele copy number in DNAs from a US cohort of individuals with MSA, to determine the contribution of SHC2 gene copy number variation in an American cohort followed at a US referral center for MSA. Our cohort included 105 carefully phenotyped individuals with MSA. METHODS: We studied 105 well-characterized patients with MSA and 5 control subjects with reduced SHC2 gene copy number. We used two TaqMan Gene Copy Number Assays, to determine the copy number of two segments of the SHC2 gene that are separated by 27 kb. RESULTS: Assay results of DNAs from all of our 105 subjects with MSA showed 2 copies of both segments of their SHC2 genes. CONCLUSION: Our results indicate that SHC2 gene deletions underlie few, if any, cases of well-characterized MSA in the US population. This is in contrast to the Japanese experience reported by Sasaki et al., likely reflecting heterogeneity of the disease in different genetic backgrounds.

Genome sequence analyses identify novel risk loci for multiple system atrophy.

Multiple system atrophy (MSA) is an adult-onset, sporadic synucleinopathy characterized by parkinsonism, cerebellar ataxia, and dysautonomia. The genetic architecture of MSA is poorly understood, and treatments are limited to supportive measures. Here, we performed a comprehensive analysis of whole genome sequence data from 888 European-ancestry MSA cases and 7,128 controls to systematically investigate the genetic underpinnings of this understudied neurodegenerative disease. We identified four significantly associated risk loci using a genome-wide association study approach. Transcriptome-wide association analyses prioritized USP38-DT, KCTD7, and lnc-KCTD7-2 as novel susceptibility genes for MSA within these loci, and single-nucleus RNA sequence analysis found that the associated variants acted as cis-expression quantitative trait loci for multiple genes across neuronal and glial cell types. In conclusion, this study highlights the role of genetic determinants in the pathogenesis of MSA, and the publicly available data from this study represent a valuable resource for investigating synucleinopathies.

Diagnosing postural tachycardia syndrome: comparison of tilt testing compared with standing haemodynamics.

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.

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.

Norepinephrine deficiency is caused by combined abnormal mRNA processing and defective protein trafficking of dopamine beta-hydroxylase.

Human norepinephrine (NE) deficiency (or dopamine ß-hydroxylase (DBH) deficiency) is a rare congenital disorder of primary autonomic failure, in which neurotransmitters NE and epinephrine are undetectable. Although potential pathogenic mutations, such as a common splice donor site mutation (IVS1+2T→C) and various missense mutations, in NE deficiency patients were identified, molecular mechanisms underlying this disease remain unknown. Here, we show that the IVS1+2T→C mutation results in a non-detectable level of DBH protein production and that all three missense mutations tested lead to the DBH protein being trapped in the endoplasmic reticulum (ER). Supporting the view that mutant DBH induces an ER stress response, exogenous expression of mutant DBH dramatically induced expression of BiP, a master ER chaperone. Furthermore, we found that a pharmacological chaperone, glycerol, significantly rescued defective trafficking of mutant DBH proteins. Taken together, we propose that NE deficiency is caused by the combined abnormal processing of DBH mRNA and defective protein trafficking and that this disease could be treated by a pharmacological chaperone(s).

Diurnal variability in orthostatic tachycardia: implications for the postural tachycardia syndrome.

Patients with POTS (postural tachycardia syndrome) have excessive orthostatic tachycardia (>30 beats/min) when standing from a supine position. HR (heart rate) and BP (blood pressure) are known to exhibit diurnal variability, but the role of diurnal variability in orthostatic changes of HR and BP is not known. In the present study, we tested the hypothesis that there is diurnal variation of orthostatic HR and BP in patients with POTS and healthy controls. Patients with POTS (n=54) and healthy volunteers (n=26) were admitted to the Clinical Research Center. Supine and standing (5 min) HR and BP were obtained in the evening on the day of admission and in the following morning. Overall, standing HR was significantly higher in the morning (102±3 beats/min) than in the evening (93±2 beats/min; P<0.001). Standing HR was higher in the morning in both POTS patients (108±4 beats/min in the morning compared with 100±3 beats/min in the evening; P=0.012) and controls (89±3 beats/min in the morning compared with 80±2 beats/min in the evening; P=0.005) when analysed separately. There was no diurnal variability in orthostatic BP in POTS. A greater number of subjects met the POTS HR criterion in the morning compared with the evening (P=0.008). There was significant diurnal variability in orthostatic tachycardia, with a great orthostatic tachycardia in the morning compared with the evening in both patients with POTS and healthy subjects. Given the importance of orthostatic tachycardia in diagnosing POTS, this diurnal variability should be considered in the clinic as it may affect the diagnosis of POTS.

Effect of mild hyperglycemia on autonomic function in obstructive sleep apnea.

INTRODUCTION: Obstructive sleep apnea (OSA) has been hypothesized to cause a hypersympathetic state, which may be the mechanism for the increased incidence of cardiovascular disease in OSA. However, there is a high prevalence of hyperglycemia in OSA patients, which may also contribute to autonomic dysfunction. METHODS: Thirty-five patients with OSA and 11 controls with average body mass index (BMI) of 32.0 ± 4.6 underwent polysomnography, glucose tolerance testing, autonomic function tests, lying and standing catecholamines, overnight urine collection, and baseline ECG and continuous blood pressure measurements for spectral analysis. A linear regression model adjusting for age and BMI was used to analyze spectral data, other outcome measures were analyzed with Kruskal-Wallis test. RESULTS: Twenty-three OSA patients and two control patients had hyperglycemia (based on 2001 American Diabetes Association criteria). Apnea-hypopnea index (AHI) correlated with total power and low frequency (LF) power (r = 0.138, 0.177, p = 0.031; and r = 0.013) but not with the LF/high frequency (HF) ratio (p = 0.589). Glucose negatively correlated with LF systolic power (r = -0.171, p = 0.038) but not AHI (p = 0.586) and was marginally associated with pnn50, total power, LF, and HF power (p ranged from 0.07 to 0.08). CONCLUSION: These data suggest that patients with OSA and mild hyperglycemia have a trend towards lower heart rate variability and sympathetic tone. Hyperglycemia is an important confounder and should be evaluated in studies of OSA and autonomic function.

Symptom Presentation and Access to Medical Care in Patients With Postural Orthostatic Tachycardia Syndrome: Role of Sex.

BACKGROUND: Postural orthostatic tachycardia syndrome (POTS) is a chronic form of orthostatic intolerance that primarily impacts female patients of childbearing age. The role of sex differences in POTS is not well understood. We sought to identify sex differences in diagnosis, symptoms, comorbidities, and treatments in female and male patients diagnosed with POTS. METHODS: A comprehensive survey was designed in partnership by Dysautonomia International (East Moriches, NY) and Vanderbilt University Medical Center (Nashville, TN). Patients were recruited through Dysautonomia International's website and social media channels. The survey was delivered online through a secure research data capture database. Responses were analyzed according to biological sex. Continuous variables are presented as median (25th percentile-75th percentile), and categorical variables are presented as number and proportion of participants. RESULTS: A total of 8919 patients reported a physician diagnosis of POTS and were included in this analysis. The majority of respondents were female (93.7%). Female and male patients experienced misdiagnosis at similar rates (76.2% vs 74.9%, P = 0.5) and saw a similar number of doctors before diagnosis (5 [3-8] vs 5 [3-8], P = 0.9). Despite these similarities, diagnostic delay was longer for female, compared with male, patients (1.50 [0.25-5.25] years vs 0.92 [0.08-2.91] years, P < 0.001). CONCLUSIONS: Despite the primarily female demographic of POTS patients, female patients experience more challenges with diagnosis than male patients. Increased awareness and recognition of POTS may help to reduce the diagnostic challenges in both female and male patients, and improve treatment and management for individuals living with this debilitating disorder.

CONTEXTE: Le syndrome de tachycardie orthostatique posturale (STOP) est une forme chronique d'intolérance orthostatique qui touche principalement les femmes en âge de procréer. L'incidence du sexe sur le STOP n'est pas bien comprise. Nous avons cherché à déterminer les différences entre les sexes en ce qui a trait au diagnostic, aux symptômes, aux comorbidités et aux traitements chez les patients féminins et masculins ayant reçu un diagnostic de STOP. MÉTHODOLOGIE: Une enquête exhaustive a été conçue en partenariat par Dysautonomia International (East Moriches, NY, États-Unis) et le Vanderbilt University Medical Center (Nashville, TN, États-Unis). Les patients ont été recrutés par l'entremise du site Web de Dysautonomia International et des médias sociaux. L'enquête a été réalisée en ligne au moyen d'une base de données sécurisée de saisie de données de recherche. Les réponses ont été analysées en fonction du sexe biologique. Les variables continues sont présentées sous forme de médiane (25e percentile-75e percentile), et les variables nominales sont présentées sous forme de nombre et de proportion de participants. RÉSULTATS: Au total, 8 919 patients ont signalé un diagnostic de STOP établi par un médecin et ont été inclus dans cette analyse. La majorité des répondants étaient des femmes (93,7 %). Les patients de sexe féminin et masculin ont été mal diagnostiqués dans des proportions similaires (76,2 % vs 74,9 %, p = 0,5) et ont vu un nombre similaire de médecins avant le diagnostic (5 [3-8] vs 5 [3-8], p = 0,9). Malgré ces similitudes, le retard de diagnostic était plus long chez les femmes que chez les hommes (1,50 [0,25-5,25] an contre 0,92 [0,08-2,91] an, p < 0,001). CONCLUSIONS: Même si les patients atteints de STOP sont principalement des femmes, ces dernières ont plus de difficultés à recevoir un diagnostic que les hommes. Une meilleure connaissance et reconnaissance du STOP peut contribuer à réduire les problèmes liés au diagnostic chez les patients féminins et masculins, et à améliorer le traitement et la prise en charge des personnes atteintes de ce trouble débilitant.

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.

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).

Distal sudomotor findings in postural tachycardia syndrome.

OBJECTIVES: Postural tachycardia syndrome (POTS) is a heterogeneous disorder characterized by excessive orthostatic tachycardia in the absence of orthostatic hypotension and by sympathetic nervous system activation. Postganglionic sudomotor deficits have been used to define a neurogenic postural tachycardia POTS subtype. Norepinephrine levels above 600 pg/ml have also been used to delineate patients with a hyperadrenergic state. This study aims to determine the relationship of sudomotor abnormalities to other aspects of dysautonomia in POTS. METHODS: Autonomic function was quantified in thirty women through tests of cardiovagal, adrenergic, and sudomotor function including quantitative sudomotor axon reflex testing (QSART) and spectral indices. Differences between patients with and without sudomotor dysfunction as defined by QSART and between patients with and without hyperadrenergic POTS were assessed with Mann-Whitney U test and Mantel-Haenszel Chi-Square test using a p value of 0.01 for significance. Spearman correlation coefficients were used to test raw sweat volume correlations with other variables. RESULTS: Of 30 women (ages 20-58), 17 patients (56%) had an abnormal QSART which was typically patchy and involved the lower extremity, while 13 patients had normal QSART results. Other autonomic tests, catecholamines or spectral indices did not correlate with QSART results. No differences in autonomic tests or spectral indices were observed between hyperadrenergic and non-hyperadrenergic POTS. INTERPRETATION: Our findings confirm that a large subset of POTS patients have sudomotor abnormalities which are typically patchy in distribution but do not correlate with other tests of autonomic function. Further studies are needed to determine the best method of endophenotyping patients with POTS.

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.