: Patients with postural tachycardia syndrome (POTS) commonly experience gastrointestinal (GI) symptoms. We aim to assess the feasibility and preliminary efficacy data for DA-9701, a prokinetic agent targeting 5-hydroxytryptamine 1A, 5-hydroxytryptamine 4, and dopamine D receptors, in patients with POTS. : In a randomized, double-blind, placebo-controlled, single-center crossover trial, patients with POTS were given either 30 mg of DA-9701 or a placebo 3 times daily for eight weeks in a 1:1 ratio. After a 4-week washout, patients received the alternate treatment for another 8 weeks. The primary endpoint focused on assessing the change in GI symptoms (total Nepean Dyspepsia Index-Korean version [NDI-K] symptom score) from baseline over the 8 week-treatment period. Endpoints were assessed in all enrolled and randomized patients (intention-to-treat), and in those who completed the trial (per-protocol analysis). : Between January 2022 and August 2023, 24 patients were randomized (n = 12 per group), with 3 discontinuing after randomization. DA-9701 did not significantly improve primary endpoints for total NDI-K symptom scores in either the intention-to-treat (least-squares means, -13.9 vs. -9.5, = 0.326) or per-protocol analyses (-17.2 vs -12.0, = 0.242). Notably, a trend toward improvement in specific GI symptoms, such as upper abdominal pain, was observed in both intention- to-treat (-0.6 vs 0.7; = 0.066) and per-protocol analyses (-0.9 vs 0.6; = 0.045). No serious adverse events were observed. DA-9701 did not improve GI symptoms in this crossover trial; however, its potential effect on specific GI symptoms merits further investigation.

One of the most common complaints in ENT clinics is dizziness. Although most cases are caused by vestibular neuritis and benign paroxysmal positional vertigo (BPPV), a significant number of patients experience non-vestibular dizziness. One non-vestibular cause is postural orthostatic tachycardia syndrome (POTS), which presents with symptoms similar to vestibular migraine (VM) and persistent postural perceptual dizziness (PPPD). Dizziness from POTS is related to dysautonomia rather than the vestibular system. In otolaryngology, understanding the autonomic nature of non-vestibular dizziness is important for accurate diagnosis. This study aims to review the clinical characteristics and pathophysiology of POTS, vestibular migraine, and PPPD; examine historical, physical, and diagnostic findings that differentiate autonomic and vestibular causes of dizziness; and develop a more specific model for evaluating chronic dizziness in the ENT setting. Literature on dizziness, vestibular and autonomic pathophysiology, and the clinical presentation of POTS, VM, and PPPD is reviewed in this paper. The timing of symptoms, their triggers, and objective assessment are key differentiating factors for these disorders. Various diagnostic tools, including orthostatic vital signs, oculomotor assessment, gait and balance evaluation, vestibular function assessment, tilt table testing, and neuroimaging, are also reviewed. Clear distinctions among POTS, VM, and PPPD are made. The diagnostic criteria for POTS are orthostatic tachycardia and posture-dependent symptoms that improve when the patient is in a recumbent position, effectively ruling out vestibular involvement in these patients. Vestibular migraine presents with vertigo accompanied by migraine features such as photophobia, phonophobia, or headache, typically triggered by sensory or environmental factors rather than changes in posture. PPPD manifests as chronic non-spinning dizziness and imbalance lasting at least three months, exacerbated by motion, upright posture, and complex visual environments. Orthostatic vital signs and autonomic assessment should be included in the evaluation of patients presenting with dizziness to differentiate between these disorders. Both vestibular and autonomic dysfunction can lead to chronic dizziness. By incorporating autonomic assessments into vestibular evaluations, ENT physicians can apply a more precise diagnostic model for their patients. Identifying dysautonomia-related dizziness, including POTS, helps reduce the misdiagnosis of vestibular disorders. This approach enables physicians to provide more effective interventions for patients with complex dizziness.

Postural orthostatic tachycardia syndrome (POTS) is a chronic autonomic disorder associated with debilitating symptoms. No medications have been approved for treatment, and patients commonly use off-label medications to treat symptoms. The hemodynamic implications of certain medication use have been examined, but patient experiences with taking off-label medications are underreported. A qualitative descriptive study was conducted with 13 patients (all women; aged 38 ± 13 years) diagnosed with POTS who had taken off-label medications for their symptoms. Semistructured video interviews were conducted to explore how they experienced and perceived their medication use. Interviews were recorded, transcribed, and analyzed using conventional content analysis. Most patients described medications as being beneficial and life-altering, re-enabling basic activities, work, exercise, and social engagement. All patients intended to continue therapy. Side effects were common but generally manageable. Propranolol frequently was associated with fatigue and hypotension. Ivabradine often caused transient early headaches and visual symptoms that subsided. Dosing frequency was largely acceptable. Major barriers included the following: medication cost, especially for ivabradine when patients were not insured; limited clinician awareness of POTS; diagnostic delays; and uncertainty about long-term safety. Medications provide meaningful functional improvement for many patients, but treatment burden, financial barriers, and information gaps persist. Care should prioritize individualized, patient-centred prescribing, and shared decision-making. Additional research should compare common medications to increase exposure and evaluate long-term outcomes and access.

Mast cell activation syndrome (MCAS) is a challenging specialized condition that allergists-immunologists treat in the outpatient setting. Despite the wide prevalence of the disease, clinicians may feel overwhelmed to provide consistent compassionate care for these patients for a multitude of reasons. Patients uniformly describe feeling unheard during a clinical encounter and thereby often end up seeing multiple physicians and specialists which further complicates their medical care. As such, it is important to characterize patients with MCAS accurately, which includes the assessment of coexistent mimicking or confounding conditions to achieve best medical care outcomes.

What is the clinical question being addressed? What are the clinical and hemodynamic differences between postural orthostatic tachycardia syndrome and inappropriate sinus tachycardia? What is the main finding? Inappropriate sinus tachycardia exhibits higher rates of hypertension, whereas postural orthostatic tachycardia syndrome and dual pathology exhibit higher rates of presyncope, cognitive impairment, and nausea.

Bowel and skin biopsies from patients with gastrointestinal disorders have revealed neuropathic changes and altered connective tissue. Patients with postural orthostatic tachycardia syndrome (POTS) often suffer from gastrointestinal symptoms and concomitant hypermobility spectrum disorders, such as hypermobile Ehlers-Danlos syndrome (hEDS). Since the skin is more accessible than the bowel, the aim of the present study was to evaluate skin biopsies in a 3D manner using micro-CT in patients with POTS and controls and relate the findings to symptoms presented. Healthy controls (n=13) and patients with POTS with (n=11) or without hEDS/EDS (n=26) were evaluated. Skin biopsies were taken proximally to the lateral malleolus using a 3 mm needle, fixed in formaldehyde and embedded in paraffin. The samples were harvested using a 1.5 mm punch (length, 2-5 mm) and scanned using a laboratory X-ray phase-contrast micro-CT. Scans were evaluated in a blinded manner and the regularity, thickness and tightness of collagen fiber bundles were assessed. All dermal structures were visible without staining. Intraepidermal nerves were not visible and a number of cell types could not be separated. The percentage of disorganized collagen bundles differed between groups, due to the majority being disorganized in hEDS/EDS (P=0.030). The proportion of any disorganized and parallel bundles throughout the biopsy differed within both patient groups (P<0.001) but not within the control group (P=0.175). There were no differences in symptoms between participants with disorganized bundles and participants without disorganized bundles. In conclusion, X-ray phase-contrast micro-CT was suitable to visualize and characterize dermal skin components in 3D. Patients with POTS and hEDS/EDS exhibited more disorganized collagen bundles; however, the technique cannot currently be used for diagnostic purposes until more patients are examined.

Hypermobile Ehlers-Danlos Syndrome (hEDS) is a connective tissue disorder that is often diagnosed after diagnostic delays due to reliance on heightened clinical suspicion. Hypermobility spectrum disorders (HSD) bridge the gap between asymptomatic joint hypermobility and hEDS. Due to overlapping features and evolving diagnostic criteria, these entities are often discussed collectively as hEDS/HSD. Patients commonly present with gastrointestinal (GI) symptoms, prompting referral for specialized care. This review summarizes the diagnostic criteria, epidemiology, and GI manifestations of hEDS/HSD to aid gastroenterologists in recognizing common presentations and facilitating earlier diagnosis and appropriate management. We conducted a narrative review of the GI manifestations of hEDS/HSD, including associations with disorders of gut-brain interaction (DGBIs), organic GI disease, structural abnormalities, motility disorders, postural orthostatic tachycardia syndrome (POTS), and mast cell activation syndrome (MCAS). The strongest GI association in hEDS/HSD is with DGBIs. Evidence suggests possible associations with organic conditions, such as celiac disease and eosinophilic esophagitis, as well as structural GI abnormalities and dysmotility. In addition, hEDS/HSD is closely linked with POTS and MCAS, which may share pathophysiologic mechanisms and have synergistic effects on symptoms. Gastroenterologists should maintain a high index of suspicion for hEDS/HSD, which can be readily screened for using the Beighton score. Earlier diagnosis may be therapeutic by reducing uncertainty related to multisystem symptoms. A multidisciplinary approach incorporating mental health, nutrition, and pain management may be required to optimize patient outcomes.

Postural orthostatic tachycardia syndrome (POTS) is characterized by an excessive orthostatic heart rate increase and lacks approved pharmacologic therapies. The objective of the study was to compare hemodynamic effects of ivabradine and propranolol and assess medication preferences in patients with POTS. In a randomized, placebo-controlled, crossover trial, patients with POTS completed three 4-week treatment phases (ivabradine, propranolol, and placebo). Each phase concluded with a 10-minute head-up tilt test with continuous beat-to-beat hemodynamic monitoring. Analyses included 28 participants (mean age 33 ± 9 years, 100% female). The prespecified primary outcome was delta heart rate during tilt. Head-up tilt test hemodynamics were described as minute-by-minute averages, deltas from supine baseline, and peak heart rate (HR) in the last 5 to 10 minutes. Prespecified within-participant comparisons were performed between treatments. Treatment preference was recorded at each phase end. Compared to placebo, HR was lower for ivabradine (99 ± 3 vs 118 ± 3 beats/min; P < 0.001) and propranolol (100 ± 3 vs 118 ± 3 beats/min; P < 0.001). ΔHR (standing - supine) was lower for ivabradine (27 ± 2 vs 36 ± 2 beats/min; P = 0.001) and propranolol (28 ± 2 vs 36 ± 2 beats/min; P = 0.003) vs placebo. Ivabradine showed a greater increase in Δ systolic blood pressure compared to propranolol (4.9 mm Hg vs 1.9 mm Hg; P = 0.001) but no significant difference in either HR or ΔHR between them. Among 22 preferences, all participants preferred ivabradine (P < 0.001) or propranolol (P < 0.001) over placebo, without differences between active treatments (59% vs 41%; P = 0.52). Ivabradine and propranolol reduce orthostatic tachycardia vs placebo, lowering heart rate below POTS diagnostic criteria. Ivabradine elevates systolic blood pressuremore than propranolol, supporting personalized drug selection. Importantly, heart rate lowering was consistent whereas symptom and quality-of-life effects were more selective, supporting individualized treatment.

Cardiac arrhythmias remain a major cause of morbidity and mortality, and current therapies have notable limitations. Vagus nerve stimulation (VNS), which modulates autonomic tone, has emerged as a potential adjunctive treatment. This systematic review evaluated the efficacy of invasive and noninvasive VNS in patients with atrial fibrillation, heart failure, myocardial infarction, and other rhythm disorders. A search of PubMed, Scopus, and Web of Science identified 21 randomized controlled trials, including 11,368 patients. Overall, VNS was associated with reduced atrial fibrillation incidence and burden, improved autonomic function and left ventricular ejection fraction in heart failure, and reduced arrhythmic events and infarct biomarkers after myocardial infarction. Additional benefits were observed in conditions such as vagally mediated atrioventricular block and postural orthostatic tachycardia syndrome. Across studies, VNS demonstrated a favorable safety profile. These findings suggest that VNS may be a promising multimodal strategy for reducing arrhythmia burden and improving cardiac autonomic regulation, although larger confirmatory trials are needed.

Postural orthostatic tachycardia syndrome (POTS) is associated with multiple autonomic symptoms, including gastrointestinal (GI) complaints, and has been linked to insulin resistance. We aimed to explore HbA1c, circulating metabolic hormones (insulin, C-peptide, GIP, GLP-1, glucagon, leptin, and peptide YY) and cortisol, and their associations with hemodynamic parameters and GI symptoms in POTS. Two POTS cohorts were studied and compared with matched controls. In the fasting cohort, blood samples were drawn in 42 patients and 41 controls, followed by active standing tests with measurement of pulse and blood pressure (BP) in supine and standing positions. In the non-fasting cohort, questionnaires assessed GI symptoms and HbA1c was measured in 43 patients and 52 controls. Fasting C-peptide and insulin levels correlated with BP in POTS (q = 0.002) but not in controls. Fasting insulin tended to be higher in POTS but was not statistically significant after adjustment for BMI (β = 6.85; 95% CI: -1.04-14.74; p = 0.085). Morning cortisol was comparable between groups. In the non-fasting cohort, HbA1c and metabolic hormones were comparable between groups, with no associations with GI symptoms. Together, these findings suggest a potential link between insulin-related pathways and BP regulation in POTS. Future studies are warranted to further investigate insulin dynamics in POTS.

Postural orthostatic tachycardia syndrome (POTS) is a chronic form of orthostatic intolerance that primarily affects female patients. There are scarce data evaluating the long-term outcomes in POTS. This study sought to evaluate the long-term impacts of POTS over multiple decades in adult patients. Past research participants at the VUMC Autonomic Dysfunction Center Research Unit (symptomatic ≥10 years) were recruited to participate in the study. A custom survey was administered at one time point. Participants were grouped as IMPROVED or NOT IMPROVED based on symptom course over time. Continuous data are reported as median (25th, 75th). Patients with POTS (n = 44; 98% female) were included in the analysis (62% response rate). Patient age at the time of survey was 48 (38, 54) years, with 23 (15, 27) years from POTS symptom onset, and 17 (12, 24) years from POTS diagnosis. Since diagnosis, symptoms completely resolved in 2%, improved in 46%, worsened in 25%, were unchanged in 11%, and demonstrated a variable symptom course in 16%. Patients who were NOT IMPROVED were more likely than those IMPROVED to have neuropathy, gastroparesis, and overactive bladder symptoms. In a cohort of adult patients with POTS who received care at a national referral center for autonomic disorders, almost half reported their POTS symptoms as improved 10 or more years after symptom onset. Most patients with POTS experienced ongoing symptoms for many years after diagnosis.

Tilt table testing is commonly used to evaluate orthostatic intolerance and syncope and is typically performed with three-lead electrocardiography (ECG) monitoring, which limits P-wave interpretation. A 21-year-old woman with congenitally corrected transposition of the great arteries presented with recurrent tachy-palpitations and near syncope and was presumed to have postural tachycardia syndrome (POTS) after extensive noninvasive testing. During head-up tilt table testing incorporating intermittent 12-lead ECGs, she developed a sustained narrow-complex tachycardia that reproduced her symptoms. Careful P-wave analysis demonstrated P-wave morphologies that localized the rhythm to a left atrial focus, which was later confirmed on an electrophysiology study. This case highlights the diagnostic value of 12-lead ECGs during tilt table testing for the analysis of P-wave morphology and axis. Ectopic atrial tachycardia may mimic orthostatic syndromes and remain undetected with limited-lead testing. Incorporation of 12-lead ECGs during tilt table testing enables ECG-based localization of atrial arrhythmias, preventing misdiagnosis of orthostatic syndromes.

This report is an assessment of the characteristics associated with cardiovascular dysautonomia (CVD) in the context of long Coronavirus disease (COVID), which is currently inadequately characterized. A retrospective cross-sectional study was performed involving 106 patients with long COVID, including 34 individuals diagnosed with CVD, among whom eight met the criteria for Postural Tachycardia Syndrome (PoTS). The variables assessed encompassed individual characteristics (e.g., age, sex, comorbidities), immunization parameters (e.g., vaccination/viral status, timing, frequency), cellular and humoral anti-Spike and anti-Nucleocapsid (Nuc) immune responses, inflammatory and allergic biomarkers, as well as an extensive panel of common autoantibodies comprising anti-nuclear antibodies, anti-central nervous system antibodies (cerebellum, brain), and anti-peripheral nervous system antibodies (gangliosides). An age < 45 years, body mass index, hyperventilation syndrome as well as a higher cumulative number of antigenic contacts (vaccinations plus infections ≥ 3) and an elevated basophil count (≥0.06 G/L) were independently associated with CVD. There was no association between CVD and inflammatory markers or common autoantibodies. Patients with PoTS criteria had a strong anti-Spike cellular immune response and increased IgG anti-Nuc humoral immunity when compared with CVD and non-CVD long COVID counterparts. Compared to other long COVID patients, patients with long COVID-associated CVD have distinctive clinical and immunovirological features. Our results suggest the potential role of the immune response against Spike and of allergic pathways rather than humoral autoimmunity against common autoantibodies in long COVID CVD.

Long COVID Postural Orthostatic Tachycardia Syndrome (LCPOTS) is characterized by persistent orthostatic tachycardia and systemic symptoms following SARS-CoV-2 infection. Many features of LCPOTS suggest ongoing immune activation, but the mechanisms driving this response remain unclear. In this study, we show that patients with LCPOTS, compared with individuals who recovered from SARS-CoV-2 without POTS, exhibit increased monocyte mitochondrial content and superoxide production, along with downregulation of NRF2-dependent antioxidant enzymes. This is accompanied by a marked increase in the formation of isolevuglandins (IsoLGs) in monocytes, which modify self-proteins and act as neoantigens capable of activating T cells. Consistent with this, LCPOTS patients exhibit a 3-fold increase in circulating T cell-monocyte doublets with immunological synapse formation. T cells in these complexes display a proinflammatory effector-memory and TEMRA phenotype, producing IFN-γ and IL-17A, which correlated with symptom severity. Circulating cytokines, including IL-17A, IFN-γ, and TNF-α, are elevated in patients with LCPOTS by 1.5 to 3-fold. This immune response likely drives systemic inflammation and impaired cardiovagal regulation, hallmarks of LCPOTS. Our findings suggest that monocyte oxidative stress and IsoLG neoantigen formation sustain T cell activation, linking immune dysregulation to cardiovagal dysfunction. Targeting these pathways may offer novel therapeutic opportunities.

Postural orthostatic tachycardia syndrome (POTS) is a form of dysautonomia characterized by an excessive increase in heart rate upon standing, in the absence of orthostatic hypotension. Post-infectious forms, particularly following SARS-CoV-2 infection, have been increasingly reported. We report the case of a 34-year-old woman presenting with persistent palpitations, marked fatigue, and orthostatic intolerance that developed two weeks after a mild COVID-19 infection. Standard cardiological evaluation revealed no abnormalities. Comprehensive autonomic testing demonstrated an increase in heart rate from 72 to 109 beats per minute at the 11th minute of active standing (Δ +37 bpm), without significant blood pressure drop, confirming the diagnosis of POTS. Additional autonomic assessment identified a hyperadrenergic phenotype. After two months of treatment with ivabradine (5mg daily), heart rate in the standing position stabilized between 80 and 100 beats per minute, with partial clinical improvement. This case highlights the importance of comprehensive autonomic evaluation in post-COVID forms of POTS and supports the role of targeted therapy.

To support general neurologists, advanced practice providers, and general practitioners in the diagnosis and treatment of postural tachycardia syndrome (POTS) and related dysautonomias. This review and approach are based on the authors' clinical experience, nonsystematic literature review, and expert opinion, with experts drawn from the American Autonomic Society Education Committee. POTS is a common condition seen in general practice. The diagnosis can be easily made in a nonspecialist setting when patients meet the syndromic criteria for POTS: (1) chronic orthostatic intolerance (bothersome symptoms brought on by upright posture, and relieved by lying down), (2) excessive orthostatic tachycardia (heart rate augmentation with standing greater than 30 beats per minute in adults), (3) absence of orthostatic hypotension, and (4) reasonable exclusion of other causes (e.g., dehydration, anemia, hyperthyroidism). There are many causes, but the unifying perturbations are low effective circulating volume with decreased cerebral blood flow and a hypersympathetic state. Education and nonpharmacologic therapies such as salt, water, and exercise are first-line treatments. Several safe and effective medication options are also available, such as propranolol and midodrine. Several comorbidities are common, such as migraine and neurocardiogenic syncope, and should be screened for and treated rather than attributed out-of-hand to POTS. POTS and related conditions are common. Initial diagnostic and treatment steps can be undertaken in a general practice setting. Referral to specialists is appropriate for refractory cases or when the diagnosis is uncertain.

Postural orthostatic tachycardia syndrome (POTS) represents a growing clinical and public health challenge, particularly in the context of post-infectious and post-COVID-19 syndromes. Recent systematic synthesis highlights that, despite widespread clinical use of pharmacologic and non-pharmacologic interventions, high-certainty randomized evidence remains scarce and heterogeneous. In this correspondence, prompted by contemporary treatment reviews, we argue that the primary limitation is no longer the absence of therapies but the absence of decision-grade trial architecture. We propose an audit-ready, globally scalable framework that integrates phenotype-stratified pragmatic trials, platform-based comparative effectiveness designs, and a minimum core outcome set anchored to minimally clinically important differences. Emphasis is placed on patient-relevant functional recovery, interpretability across health systems, and equitable implementation beyond tertiary autonomic centers.

Disorders of gut-brain interaction (DGBI) affect about 40% of children and are often comorbid with hypermobility spectrum disorders (HSDs) and orthostatic intolerance (OI). However, how these comorbidities impact outcomes in pediatric DGBI is not well understood. This study aimed to compare outcomes in DGBI patients with HSD, OI, both, or neither. We reviewed records of patients aged 9-21 years from a multidisciplinary DGBI clinic. Patients met Rome IV criteria for DGBI and had documented HSD and/or OI diagnoses from specialists in gastroenterology, rheumatology, genetics, cardiology, adolescent medicine, and others. HSD terms included Ehlers-Danlos syndrome, hypermobile Ehlers-Danlos syndrome, and generalized hypermobility; OI terms included postural orthostatic tachycardia syndrome, dysautonomia, and orthostatic hypotension. Clinical data included the following validated questionnaires: abdominal pain index, nausea severity scale, functional disability inventory, patient health questionnaire-9 (Depression), children somatization inventory, pediatric insomnia severity index, pain catastrophizing scale for children, and screen for child anxiety related disorders (Anxiety). We compared DGBI patients with both HSD and OI, those with either disorder, and those without. Of 175 patients, 46% had HSD and 43% had OI. Patients with both HSD and OI had significantly worse nausea, depression, disability, and somatization scores than others (p < 0.01). HSD and OI groups individually also showed worse outcomes than non-HSD/non-OI groups. Moderate correlations were found between depression and anxiety in OI and nausea and disability in HSD. Comorbid HSD and OI worsen DGBI symptoms. Accurate diagnosis and treatment are critical to improving outcomes due to shared autonomic dysfunction.

Postural orthostatic tachycardia syndrome (POTS) is a common autonomic disorder characterized by orthostatic intolerance and excessive tachycardia upon standing. Despite its prevalence, POTS is often underdiagnosed or diagnosed late, largely due to limited access to autonomic specialists and testing. This study aimed to evaluate the performance of machine learning (ML) models in diagnosing POTS using validated symptom surveys and physiological measurements. We retrospectively analyzed data from patients evaluated at the Autonomic Laboratory at Brigham and Women's Faulkner Hospital (2017-2025), with POTS diagnoses confirmed by autonomic testing. ML models based on a multilayer perceptron were trained using patient-reported surveys (Survey of Autonomic Symptoms [SAS], COMPASS-31) and autonomic testing data. Importantly, no orthostatic heart rate criteria for the POTS diagnosis were provided to the models. A total of 3210 patients were included, of whom 810 had confirmed POTS. All patients completed SAS; 1337 also completed COMPASS-31 (334 with POTS). Models incorporating heart rate data achieved the highest diagnostic accuracy (PyTorch/LightGBM: AUC 0.98/0.99; precision 0.94/0.93; F1 score 0.88/0.93; sensitivity 83%/92%; specificity 98%/98%). In contrast, models trained solely on SAS (AUC 0.68/0.63) or COMPASS-31 (AUC 0.66/0.62) performed poorly. ML models accurately diagnosed POTS when incorporating heart rate data alongside survey responses, with heart rate data being the strongest predictor. These findings suggest ML could assist in POTS diagnosis. The study also highlights the importance of heart rate measures in POTS diagnosis.

Post‑acute sequelae of SARS‑CoV‑2 infection (Long COVID) affect a substantial proportion of individuals, and among the many reported symptom clusters, autonomic dysfunction, particularly postural orthostatic tachycardia syndrome (POTS), represents an important subset. The Researching COVID to Enhance Recovery Clinical Trials (RECOVER-CT) initiative developed by the National Institutes of Health included a platform trial (RECOVER-AUTONOMIC) designed to assess the safety, tolerability, and efficacy of 3 interventions-(1) coordinated nonpharmacologic care, (2) pharmacotherapy with intravenous immunoglobulin (IVIG), and (3) pharmacotherapy with ivabradine-in treating POTS in adults with Long COVID. RECOVER-AUTONOMIC is a multicenter, randomized, double-blinded, placebo-controlled, platform trial employing a flexible, adaptive design. Participants are randomized to IVIG or ivabradine with matching placebo, and (in a factorial design) to either coordinated nonpharmacologic care or usual care. The primary endpoint is the change in orthostatic intolerance symptoms measured by the Orthostatic Hypotension Questionnaire/Orthostatic Intolerance Questionnaire from baseline to the end of intervention. Secondary endpoints include quality of life, functional performance, symptom burden, and safety. Exploratory endpoints include autonomic function testing, wearable sensor data, and longitudinal biomarker profiling. RECOVER-AUTONOMIC seeks to determine the benefits and risks of IVIG and of ivabradine, as well as of coordinated nonpharmacologic care, for the treatment of POTS in Long COVID. Results from this trial will offer the largest source of evidence to help guide the medical care of this population. ClinicalTrials.gov-Platform: NCT06305780; Appendix A (intravenous immunoglobulin): NCT06305793; Appendix B (ivabradine): NCT06305806. Protocol available at https://trials.recovercovid.org/autonomic.

To compare Functional Disability Inventory (FDI) between adolescents with chronic orthostatic intolerance (COI) and postural orthostatic tachycardia syndrome (POTS). This cross-sectional study included adolescents ≤19 years with orthostatic symptoms >3 months referred to a tertiary pediatric autonomic clinic (August 2024-March 2025) and classified as POTS or COI based upon active stand testing. Self- and parent-reported FDI scores were collected. Group comparisons used chi-square and Wilcoxon-Mann-Whitney tests. Univariable and multivariable linear regression models compared FDI scores, adjusting for age, sex, and body mass index. Adjusted means were estimated using post-fit marginal estimation. Ninety-two adolescents were included (46 POTS, 46 COI). Groups were similar in age, sex, and body mass index, but differed in heart rate response by definition. Self-reported FDI scores did not differ between COI and POTS in unadjusted (22.9 vs 22.4; P = .81) or adjusted analyses (adjusted mean difference 1.0, 95% CI -3.0 to 4.9; P = .63). Parent-reported FDI scores were also comparable in unadjusted (23.1 vs 22.3; P = .70) and adjusted analyses (adjusted mean difference 0.4, 95% CI -3.4 to 4.2; P = .85). Differences were well below the prespecified threshold for clinical significance. There was no evidence for a difference in functional disability in adolescents with COI, regardless of tachycardia-based POTS classification. This suggests that heart rate response is not associated with functional differences in pediatric orthostatic intolerance.

Ivabradine is one of several off-label treatments for patients with postural orthostatic tachycardia syndrome (POTS). We conducted a systematic review of the literature to identify studies that evaluate ivabradine treatment in patients with POTS. The results were narratively synthesized given methodological heterogeneity among the identified studies. There were 11 studies included in the analysis with 305 participants between 2008 and 2020. The only randomized trial of 22 patients showed that ivabradine improved heart rate compared with placebo, and there were symptomatic benefits in terms of physical functioning and social functioning. All studies suggested a reduction in heart rate with ivabradine treatment; the proportion of patients with symptomatic benefit ranged from 67% to 100%. One study using the Malmo POTS score found that ivabradine improved the total score, including key components such as light-headedness with standing, feeling faint, feeling rapid heart rate, and chest pain. Although 2 studies did not report side effects and 2 studies described no side effects, others reported adverse effects including bradycardia, nausea, worsening syncope, palpitations, flushing, light sensitivity, headache, light-headedness, fatigue, scalded tongue, itching and burning, and visual disturbance. In conclusion, there is low-quality evidence derived from small observational studies and 1 small randomized trial that ivabradine is effective in reducing heart rate and improving symptoms in patients with POTS. The exact role of ivabradine in treatment of POTS needs to be clarified in further randomized trials and more robust evidence.

Compression garments are a relatively inexpensive and easy-to-implement treatment, but the longer term benefits of abdominal compression in a real-world setting are not known. In this study we sought to evaluate commercially available abdominal compression garments in a real-world setting in patients with postural orthostatic tachycardia syndrome (POTS). Participants completed four 10-minute active stand tests, with and without an abdominal compression garment, in the morning (Test #1: AM-OFF; Test #2: AM-ON) and afternoon (Test #3: PM-ON; Test #4: PM-OFF). Participants held medication that could augment heart rate (HR) and blood pressure during this 1-day study. A Holter monitor was used to record HR and participants recorded their symptoms using the Vanderbilt Orthostatic Symptom Score at the end of each standing test (range 0-90, where 0 = no symptoms). Continuous data are presented as median (25th-75th percentile). Standing HR (103 [91-114] vs 118 [99-134], P = 0.002) and change in HR with upright posture compared with supine (27 [19-42] vs 41 [26-48], P < 0.001) were reduced, and symptoms improved (29 [16-45] vs 35 [25-60], P = 0.005), during AM-ON compared with AM-OFF. When the garment was removed after several hours of use (PM-ON vs PM-OFF), standing HR (P = 0.04), ΔHR (P = 0.01), and symptoms (P = 0.02) increased. Commercially available abdominal compression garments reduced HR and improved symptoms both acutely and after several hours of use. Abdominal compression garments may provide a good alternative to full waist-high compression garments in patients with POTS. NCT04881318.