Detection of G Protein-Coupled Receptor Autoantibodies in Postural Orthostatic Tachycardia Syndrome Using Standard Methodology.

BACKGROUND: Postural orthostatic tachycardia syndrome (POTS) is a disorder of orthostatic intolerance that primarily affects women of childbearing age. The underlying pathophysiology of POTS is not fully understood, but it has been suggested that autoimmunity may play a role. The aim of this study was to compare concentrations of autoantibodies to cardiovascular G protein-coupled receptors between patients with POTS and healthy controls. METHODS: Sera were collected from 116 patients with POTS (91% female; medium age, 29 years) and 81 healthy controls (84% female; medium age, 27 years) from Calgary, Canada, and Malmö, Sweden. Samples were evaluated for autoantibodies to 11 receptors (adrenergic, muscarinic, angiotensin II, and endothelin) using a commercially available enzyme-linked immunosorbent assay. RESULTS: Autoantibody concentrations against all of the receptors tested were not significantly different between controls and patients with POTS. The majority of patients with POTS (98.3%) and all controls (100%) had α1 adrenergic receptor autoantibody concentrations above the seropositive threshold provided by the manufacturer (7 units/mL). The proportion of patients with POTS versus healthy controls who fell above the diagnostic thresholds was not different for any tested autoantibodies. Receiver operating characteristic curves showed a poor ability to discriminate between patients with POTS and controls. CONCLUSIONS: Patients with POTS and healthy controls do not differ in their enzyme-linked immunosorbent assay-derived autoantibody concentrations to cardiovascular G protein-coupled receptors. These findings suggest that these tests are not useful for establishing the role of autoimmunity in POTS.

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.

A comparison of health-related quality of life in autonomic disorders: postural tachycardia syndrome versus vasovagal syncope.

PURPOSE: Postural tachycardia syndrome (POTS) and vasovagal syncope (VVS) are two disorders of orthostatic intolerance which are often misdiagnosed as the other. In each case, patients experience a reduced health-related quality of life (HRQoL) compared to healthy populations. This study was conducted to test the hypothesis that HRQoL is worse in POTS. METHODS: POTS patients were recruited from the Dysautonomia International Annual Patient and Caregiver Conference. VVS patient data came from those enrolled in the Second Prevention of Syncope Trial. Participants aged ≥ 18 years (177 POTS and 72 VVS) completed the RAND 36-Item Health Survey, a generic and coherent health-related quality of life survey. RESULTS: POTS patients reported reduced HRQoL compared to VVS patients in physical functioning (42.5 ± 1.7 vs. 76.5 ± 2.9, p < 0.001), role limitations due to physical health (11.4 ± 1.9 vs. 33.0 ± 5.0, p < 0.001), energy and fatigue (27.2 ± 1.3 vs. 50.7 ± 2.6, p < 0.001), social functioning (45.2 ± 1.8 vs. 71.2 ± 2.9, p < 0.001), pain (48.8 ± 1.9 vs. 67.7 ± 2.9, p < 0.001), and general health (31.2 ± 1.5 vs. 60.5 ± 2.6, p < 0.001) domains. Scores did not differ significantly in the role limitations due to emotional health (p = 0.052) and emotional well-being (p = 0.271) domains. Physical and general health composite scores were lower in the POTS population, while mental health composite scores were not different. CONCLUSION: Differences in HRQoL exist between these patient populations. POTS patients report lower scores in physical and general health domains than VVS patients, but emotional health domains do not differ significantly. Targeting physical functioning in these patients may help improve quality of life.

Objective Hemodynamic Cardiovascular Autonomic Abnormalities in Post-Acute Sequelae of COVID-19.

BACKGROUND: Many COVID-19 patients are left with symptoms several months after resolution of the acute illness; this syndrome is known as post-acute sequalae of COVID-19 (PASC). We aimed to determine the prevalence of objective hemodynamic cardiovascular autonomic abnormalities (CAA), explore sex differences, and assess the prevalence of CAA among hospitalized vs nonhospitalized patients with PASC. METHODS: Patients with PASC (n = 70; female [F] = 56; 42 years of age; 95% confidence interval [CI], 40-48) completed standard autonomic tests, including an active stand test 399 days (338, 455) after their COVID-19 infection. Clinical autonomic abnormalities were evaluated. RESULTS: Most patients with PASC met the criteria for at least 1 CAA (51; 73%; F = 43). The postural orthostatic tachycardia syndrome hemodynamic (POTSHR) criterion of a heart rate increase of > 30 beats per minute within 5 to 10 minutes of standing was seen in 21 patients (30%; F = 20; P = 0.037 [by sex]). The initial orthostatic hypotension hemodynamic (IOH40) criterion of a transient systolic blood pressure change of > 40 mm Hg in the first 15 seconds of standing was seen in 43 (61%) patients and equally among female and male patients (63% vs 57%; P = 0.7). Only 9 (13%) patients were hospitalized; hospitalized vs nonhospitalized patients had similar frequencies of abnormalities (67% vs 74%; P = 0.7). CONCLUSIONS: Patients with PASC have evidence of CAA, most commonly IOH40, which will be missed unless an active stand test is used. Female patients have increased frequency of POTSHR, but IOH40 is equally prevalent between sexes. Finally, even nonhospitalized "mild" infections can result in long-term CAAs.

Mitigating Initial Orthostatic Hypotension: Mechanistic Roles of Muscle Contraction Versus Sympathetic Activation.

BACKGROUND: Initial orthostatic hypotension (IOH) is defined by a large drop in blood pressure (BP) within 15 s of standing. IOH often presents during an active stand, but not with a passive tilt, suggesting that a muscle activation reflex involving lower body muscles plays an important role. To our knowledge, there is no literature exploring how sympathetic activation affects IOH. We hypothesized involuntary muscle contractions before standing would significantly reduce the drop in BP seen in IOH while increasing sympathetic activity would not. METHODS: Study participants performed 4 sit-to-stand maneuvers including a mental stress test (serial 7 mental arithmetic stress test), cold pressor test, electrical stimulation, and no intervention. Continuous heart rate and beat-to-beat BP were measured. Cardiac output and systemic vascular resistance were estimated from these waveforms. Data are presented as mean±SD. RESULTS: A total of 23 female IOH participants (31±8 years) completed the study. The drops in systolic BP following the serial 7 mental arithmetic stress test (-26±12 mm Hg; P=0.004), cold pressor test (-20±15 mm Hg; P<0.001), and electrical stimulation (-28±12 mm Hg; P=0.01) were significantly reduced compared with no intervention (-34±11 mm Hg). The drops in systemic vascular resistance following the serial 7 mental arithmetic stress test (-391±206 dyne×s/cm5; P=0.006) and cold pressor test (-386±179 dyne×s/cm5; P=0.011) were significantly reduced compared with no intervention (-488±173 dyne×s/cm5). Cardiac output was significantly increased upon standing (7±2 L/min) compared with during the sit (6±1 L/min; P<0.001) for electrical stimulation. CONCLUSION: Sympathetic activation mitigates the BP response in IOH, while involuntary muscle contraction mitigates the BP response and reduces symptoms. Active muscle contractions may induce both of these mechanisms of action in their pretreatment of IOH. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03970551.

Lower body muscle preactivation and tensing mitigate symptoms of initial orthostatic hypotension in young females.

BACKGROUND: Initial orthostatic hypotension (IOH) is a form of orthostatic intolerance defined by a transient decrease in blood pressure upon standing. Current clinical recommendations for managing IOH includes standing up slowly or lower body muscle tensing (TENSE) after standing. Considering that IOH is likely due to a large muscle activation response resulting in excessive vasodilation with a refractory period (<2 minutes), we hypothesized that preactivating lower body muscles (PREACT) before standing would reduce the drop in mean arterial pressure (MAP) upon standing and improve presyncope symptoms. OBJECTIVE: The purpose of this study was to provide IOH patients with effective symptom management techniques. METHODS: Study participants completed 3 sit-to-stand maneuvers, including a stand with no intervention (Control), PREACT, and TENSE. Continuous heart rate and beat-to-beat blood pressure were measured. Stroke volume and cardiac output were then estimated from these waveforms. RESULTS: A total of 24 female IOH participants (mean ± SD: 32 ± 8 years) completed the study. The drops in MAP following PREACT (-21 ± 8 mm Hg; P <.001) and TENSE (-18 ± 10 mm Hg; P <.001) were significantly reduced compared to Control (-28 ± 10 mm Hg). The increase in cardiac output was significantly larger following PREACT (2.6 ± 1 L/min; P <.001) but not TENSE (1.9 ± 1 L/min; P = .2) compared to Control (1.4 ± 1 L/min). The Vanderbilt Orthostatic Symptom Score following PREACT (9 ± 8 au; P = .033) and TENSE (8 ± 8 au; P = .046) both were significantly reduced compared to Control (14 ± 9 au). CONCLUSION: Both the drop in MAP and symptoms upon standing improved with either PREACT or TENSE. These maneuvers provide novel symptom management techniques for patients with IOH.

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.

Compression Garment Reduces Orthostatic Tachycardia and Symptoms in Patients With Postural Orthostatic Tachycardia Syndrome.

BACKGROUND: Postural orthostatic tachycardia syndrome (POTS) is a chronic form of orthostatic intolerance associated with a significant symptom burden. Compression garments are a frequently prescribed treatment, but the effectiveness of waist-high compression has not been evaluated in adults with POTS. OBJECTIVES: This study evaluated compression garments as a treatment for POTS using a head-up tilt test (HUT), and a noninflatable core and lower body compression garment. METHODS: Thirty participants completed 10-min HUT with each of 4 compression conditions in a randomized crossover design. The conditions were no compression (NONE), lower leg compression (LEG), abdominal/thigh compression (ABDO), and full abdominal/leg compression (FULL). Heart rate, beat-to-beat blood pressure, and Vanderbilt Orthostatic Symptom Score ratings were measured during each HUT. RESULTS: The compression garment reduced heart rate (NONE: 109 ± 19 beats/min; LEG: 103 ± 16 beats/min; ABDO: 97 ± 15 beats/min; FULL: 92 ± 14 beats/min; p < 0.001) and improved symptoms (p < 0.001) during HUT in a dose-dependent manner. During HUT, stroke volume and systolic blood pressure were better maintained with FULL and ABDO compression compared with LEG and NONE compression. CONCLUSIONS: Abdominal and lower body compression reduced heart rate and improved symptoms during HUT in adult patients with POTS. These effects were driven by improved stroke volume with compression. Abdominal compression alone might also provide a clinical benefit if full lower body compression is not well tolerated. (Hemodynamic Effects of Compression in POTS; NCT03484273).

Postural orthostatic tachycardia syndrome (POTS): Priorities for POTS care and research from a 2019 National Institutes of Health Expert Consensus Meeting - Part 2.

The National Institutes of Health hosted a workshop in 2019 to build consensus around the current state of understanding of the pathophysiology of postural orthostatic tachycardia syndrome (POTS) and to identify knowledge gaps that must be addressed to enhance clinical care of POTS patients through research. This second (of two) articles summarizes current knowledge gaps, and outlines the clinical and research priorities for POTS. POTS is a complex, multi-system, chronic disorder of the autonomic nervous system characterized by orthostatic intolerance and orthostatic tachycardia without hypotension. Patients often experience a host of other related disabling symptoms. The functional and economic impacts of this disorder are significant. The pathophysiology remains incompletely understood. Beyond the significant gaps in understanding the disorder itself, there is a paucity of evidence to guide treatment which can contribute to suboptimal care for this patient population. The vast majority of physicians have minimal to no familiarity or training in the assessment and management of POTS. Funding for POTS research remains very low relative to the size of the patient population and impact of the syndrome. In addition to efforts to improve awareness and physician education, an investment in research infrastructure including the development of standardized disease-specific evaluation tools and outcome measures is needed to facilitate effective collaborative research. A national POTS research consortium could facilitate well-controlled multidisciplinary clinical research studies and therapeutic trials. These priorities will require a substantial increase in the number of research investigators and the amount of research funding in this area.

Postural orthostatic tachycardia syndrome (POTS): State of the science and clinical care from a 2019 National Institutes of Health Expert Consensus Meeting - Part 1.

Postural orthostatic tachycardia syndrome (POTS) is a chronic and often disabling disorder characterized by orthostatic intolerance with excessive heart rate increase without hypotension during upright posture. Patients often experience a constellation of other typical symptoms including fatigue, exercise intolerance and gastrointestinal distress. A typical patient with POTS is a female of child-bearing age, who often first displays symptoms in adolescence. The onset of POTS may be precipitated by immunological stressors such as a viral infection. A variety of pathophysiologies are involved in the abnormal postural tachycardia response; however, the pathophysiology of the syndrome is incompletely understood and undoubtedly multifaceted. Clinicians and researchers focused on POTS convened at the National Institutes of Health in July 2019 to discuss the current state of understanding of the pathophysiology of POTS and to identify priorities for POTS research. This article, the first of two articles summarizing the information discussed at this meeting, summarizes the current understanding of this disorder and best practices for clinical care. The evaluation of a patient with suspected POTS should seek to establish the diagnosis, identify co-morbid conditions, and exclude conditions that could cause or mimic the syndrome. Once diagnosed, management typically begins with patient education and non-pharmacologic treatment options. Various medications are often used to address specific symptoms, but there are currently no FDA-approved medications for the treatment of POTS, and evidence for many of the medications used to treat POTS is not robust.

Attention and executive function are impaired during active standing in postural tachycardia syndrome.

Postural tachycardia syndrome (POTS) is a chronic form of orthostatic intolerance associated with cognitive dysfunction. We hypothesized executive function and attention is impaired in POTS during active standing. Eighty-seven POTS participants and 39 healthy controls of similar age, sex, and education level completed executive function (Stroop word-color) and attention (CogState Identification) tests in supine and standing postures in a cross-sectional study. POTS participants had lower executive function (t-score: 48 ± 11 vs. 55 ± 10 control; p = 0.009) and worse attention (reaction speed: 2.78 ± 0.11 vs. 2.69 ± 0.06 control; p < 0.001) during standing. These data provide new evidence that active standing impairs attention and executive functioning in POTS.