Postural orthostatic tachycardia syndrome (POTS) occurs in approximately 30% of people with highly symptomatic post-COVID-19 condition (PCC). It involves several symptoms that limit physical and psychological functions and cause reduced quality of life. Evidence for different treatments of POTS and PCC is limited, and this study aimed to evaluate the feasibility of individually tailored physical exercise. The secondary aim of the study was to evaluate the preliminary effectiveness of this intervention. Twenty-six participants (81% female, median age 41 years) were enrolled and performed individually tailored endurance and strength training, with progression, for twelve weeks. During the intervention period, the participants had weekly support from a physiotherapist. Feasibility was evaluated with good compliance, with 76% adherence to exercise prescription and 96% completing the study protocol. The treatment was safe, and the evaluation methods (questionnaires, physical assessments, and accelerometer monitoring) were judged to be feasible. After the intervention, improvements in symptom burden as well as in psychological and physical functions were observed. In conclusion, future randomized controlled trials can be performed with only minor adjustments and could include questionnaires, physical assessment and accelerometer monitoring, which were demonstrated as feasible by this study.

OBJECTIVE: Postural Tachycardia Syndrome (PoTS) is a poorly understood syndrome of multiple disabling symptoms. This study explored the process of seeking a diagnosis of PoTS. Analysis focused on changes before and after participants\' first appointment with a national PoTS clinic, and explored whether a diagnosis is beneficial in the context of multiple co-occurring conditions and an absence of licenced treatments.
METHODS: A longitudinal, qualitative study.
METHODS: Participants (n = 15) in this nested qualitative study were recruited from a larger study of people who had been newly referred to a National specialist NHS Cardiology PoTS service. Semi-structured interviews were conducted remotely before, and 6 months after their first appointment with the clinic. Data was analysed longitudinally and inductively using Reflexive Thematic Analysis.
RESULTS: Three overarching themes were identified: \"Slowly moving forward and finding positive gains\", \"Needing more pieces of the puzzle to see the bigger picture\", and \"The value and impact of investigations\". Findings suggested that not much had changed in the 6 months between interviews. Participants were moving forward in terms of diagnoses, treatment and adjustment following their appointment, but many were still seeking further clarity and possible diagnoses. Investigations, appointments, and new-found problems, continued to have a substantial impact over time.
CONCLUSIONS: The journey to diagnosis for patients with suspected PoTS appeared to promote acceptance of self, and of limitations posed by symptoms. However, many participants continued their search for an explanation for every symptom experience, and this may become increasingly complex, the more labels that have been acquired. Lack of clarity contributed to ongoing difficulties for this patient group alongside fraught relations with health care professionals (HCPs). A more coherent, integrated approach which is communicated clearly to patients is recommended.

OBJECTIVE: To determine in children, adolescent and young adult (CAYA) patients presenting with Orthostatic Intolerance (OI) or Postural Orthostatic Tachycardia Syndrome (POTS) associated with the additional symptoms of neuropathic discomfort (pain, paresthesia and/or allodynia): 1) the incidence of small fiber neuropathy, and 2) assess if there was serologic evidence for an underlying inflammatory or autoimmune state.
METHODS: A cohort of 109 CAYA patients with the above symptoms underwent epidermal skin biopsy for nerve fiber density. Blood biomarkers for inflammation were tested (CRP, ESR, ANA, complement (C3), thyroid function testing with antibodies (thyroid peroxidase antibody and thyroglobulin antibody), and cytokine panel 13). Patients completed a Quality of Health questionnaire. Statistical analysis was performed using Wilcoxon rank sum tests.
RESULTS: In CAYA patients with OI or POTS and neuropathic symptoms, skin biopsy for small fiber neuropathy was abnormal in 53 %. The sample population was predominantly female and Caucasian with moderately decreased perceived quality of health. OI /POTS patients with small fiber neuropathy had a 3-fold probability of having a positive ANA or anti-thyroid antibody, suggesting an underlying autoimmune or inflammatory process.
CONCLUSIONS: Our data suggest a link between OI and POTS and small fiber neuropathy. Small fiber neuropathy was found by skin biopsy in over half of the patients tested. OI and Postural orthostatic tachycardia patients with small fiber neuropathy expressed multiple markers suggesting an underlying autoimmune or inflammatory process. Future research will be done to evaluate the symptomatic implication of SFN and whether immune or pharmacologic manipulation can alter patient symptoms.

Orthostatic intolerance (OI), including postural orthostatic tachycardia syndrome (PoTS) and orthostatic hypotension (OH), are often reported in long covid, but published studies are small with inconsistent results. We sought to estimate the prevalence of objective OI in patients attending long covid clinics and healthy volunteers and associations with OI symptoms and comorbidities. Participants with a diagnosis of long covid were recruited from eight UK long covid clinics, and healthy volunteers from general population. All undertook standardized National Aeronautics and Space Administration Lean Test (NLT). Participants\' history of typical OI symptoms (e.g., dizziness, palpitations) before and during the NLT were recorded. Two hundred seventy-seven long covid patients and 50 frequency-matched healthy volunteers were tested. Healthy volunteers had no history of OI symptoms or symptoms during NLT or PoTS, 10% had asymptomatic OH. One hundred thirty (47%) long covid patients had previous history of OI symptoms and 144 (52%) developed symptoms during the NLT. Forty-one (15%) had an abnormal NLT, 20 (7%) met criteria for PoTS, and 21 (8%) had OH. Of patients with an abnormal NLT, 45% had no prior symptoms of OI. Relaxing the diagnostic thresholds for PoTS from two consecutive abnormal readings to one abnormal reading during the NLT, resulted in 11% of long covid participants (an additional 4%) meeting criteria for PoTS, but not in healthy volunteers. More than half of long covid patients experienced OI symptoms during NLT and more than one in 10 patients met the criteria for either PoTS or OH, half of whom did not report previous typical OI symptoms. We therefore recommend all patients attending long covid clinics are offered an NLT and appropriate management commenced.

Postural orthostatic tachycardia syndrome (POTS) and dysautonomia following a SARS-CoV-2 infection have been recently reported. The underlying mechanism of dysautonomia is not well understood. The impact of this viral illness on the underlying autonomic symptoms has not been studied in patients with a pre-existing POTS diagnosis. Our study aims to report the impact of a COVID-19 infection on patients with preexisting POTS, both during the acute phase of the disease and post-recovery.
Institutional Review Board (IRB) approval was obtained to access charts of the study subjects. All patients with known POTS disease who acquired COVID-19 infection between April 2020 and May 2021 were included. The end point of the study was worsening POTS related symptoms including orthostatic dizziness, palpitation, fatigue and syncope/ presyncope post COVID-19 infection that required escalation of therapy. Basic demographics, details of POTS diagnosis, medications, Additional information regarding COVID 19 infection, duration of illness, need for hospitalization, worsening of POTS symptoms, need for ED visits, the type of persisting symptoms and vaccination status were obtained from the retrospective chart review.
A total of 41 patients were studied. The alpha-variant was the most common causing SARS-CoV-2 infection. 27% (11 patients) of them had tested positive for COVID- 19 infection more than once. About 38 (92.7%) of them reported having worsening of their baseline POTS symptoms during the active infection phase. About 28 patients (68%) experienced worsening of their dysautonomia symptoms for at least 1-6 months post infection. Nearly 30 patients (73.2%) required additional therapy for their symptom control and improvement.
Patients with pre-existing POTS, most experienced a worsening of their baseline autonomic symptoms after suffering the COVID-19 infection which required additional pharmacotherapy for their symptom improvement.

This study assesses response to intravenous immunoglobulin (IVIG) in presumed autoimmune postural orthostatic tachycardia syndrome (POTS).
POTS may be associated with autoimmune disorders, serum autoantibodies, or recent infection. Uncontrolled case studies suggest that IVIG is beneficial for treating autoimmune POTS. No previous randomized controlled trials have been conducted.
This single-site randomized controlled trial compared IVIG with intravenous albumin infusions. Albumin comparator ensured blinding and control for effects of volume expansion. Eligible patients with POTS had COMPASS-31 total weighted score ≥ 40 and met predetermined criteria suggesting autoimmunity. Over 12 weeks, participants received eight infusions (0.4 gm/kg each). Four infusions were given weekly followed by four infusions every other week. Primary outcome measure was improvement in COMPASS-31 2 weeks after final infusion.
A total of 50 participants consented; 30 met inclusion criteria and received study drug (16 IVIG and 14 albumin; 29 female). Group baseline characteristics were well matched; 27 participants completed treatment protocol. Change in COMPASS-31 did not differ between groups (median change [IQR]; IVIG: -5.5 [-23.3, 2.5] versus albumin: -10.6 [-14.1, -4.7]; p-value = 0.629). The IVIG group had a higher response rate (46.7% versus 38.5%), but this was not statistically significant. Adverse events were common but usually mild and did not differ between treatment groups.
This small randomized controlled trial of IVIG in POTS found no statistical difference in response compared with albumin infusion. Both groups showed improvement possibly related to volume expansion or other effects obscuring group differences. These findings inform development of future immunomodulatory clinical trials in POTS.

Introduction: Abdominal and lower-extremity compression techniques can help reduce orthostatic heart rate increases. However, the effects of body compression on the cardiac autonomic systems, which control heart rate, remain unclear. The primary objective of this study was to compare heart rate variability, a reflection of cardiac autonomic regulation, during a head-up tilt test with and without abdominal and lower-extremity compression in healthy young individuals. The secondary objective was to conduct a subgroup analysis, considering participant sex, and compare heart rate and heart rate variability responses to head-up tilt with and without compression therapy. Methods: In a randomized crossover design, 39 healthy volunteers (20 females, aged 20.9 ± 1.2 years) underwent two head-up tilt tests with and without abdominal and lower-extremity compression. Heart rate and heart rate variability parameters were measured during the head-up tilt tests, including the Stress Index, root mean square of successive differences between adjacent R-R intervals, low- and high-frequency components, and low-to-high frequency ratio. Results: Abdominal and lower-extremity compression reduced the orthostatic increase in heart rate (p < 0.001). The tilt-induced changes in heart rate variability parameters, except for the low-frequency component, were smaller in the compression condition than in the no-compression condition (p < 0.001). These results were consistent regardless of sex. Additionally, multiple regression analysis with potentially confounding variables revealed that the compression-induced reduction in Stress Index during the head-up tilt position was a significant independent variable for the compression-induced reduction in heart rate in the head-up tilt position (coefficient = 0.411, p = 0.025). Conclusion: Comparative analyses revealed that abdominal and lower-extremity compression has a notable impact on the compensatory sympathetic activation and vagal withdrawal typically observed during orthostasis, resulting in a reduction of the increase in heart rate. Furthermore, this decrease in heart rate was primarily attributed to the attenuation of cardiac sympathetic activity associated with compression. Our findings could contribute to the appropriate application of compression therapy for preventing orthostatic tachycardia. This study is registered with UMIN000045179.

BACKGROUND: Low-level transcutaneous stimulation of the auricular branch of the vagus nerve at the tragus is antiarrhythmic and anti-inflammatory in animals and humans. Preliminary studies show that transcutaneous vagus nerve stimulation (tVNS) is beneficial in animal models of postural tachycardia syndrome (POTS).
OBJECTIVE: In this study the authors conducted a sham-controlled, double-blind, randomized clinical trial to examine the effect of tVNS on POTS over a 2-month period relative to sham stimulation.
METHODS: tVNS (20 Hz, 1 mA below discomfort threshold) was delivered using an ear clip attached to either the tragus (active; n = 12) or the ear lobe (sham; n = 14) for 1 hour daily over a 2-month period. Postural tachycardia was assessed during the baseline and 2-month visit. Heart rate variability based on 5-minute electrocardiogram, serum cytokines, and antiautonomic autoantibodies were measured at the respective time points.
RESULTS: Mean age was 34 ± 11 years (100% female; 81% Caucasian). Adherence to daily stimulation was 83% in the active arm and 86% in the sham arm (P > 0.05). Postural tachycardia was significantly less in the active arm compared with the sham arm at 2 months (mean postural increase in heart rate 17.6 ± 9.9 beats/min vs 31.7 ± 14.4 beats/min; P = 0.01). Antiadrenergic autoantibodies and inflammatory cytokines were lower in the active arm compared with the sham arm at 2 months (P < 0.05). Heart rate variability was better in the active arm. No device-related side effects were observed.
CONCLUSIONS: Our results support the emerging paradigm of noninvasive neuromodulation to treat POTS. Mechanistically, this effect appears to be related to reduction of antiautonomic autoantibodies and inflammatory cytokines, and improvement in autonomic tone. Further studies are warranted. (Autoimmune Basis for Postural Tachycardia Syndrome; NCT05043051).

Post-acute COVID-19 (PACS) are associated with cardiovascular dysfunction, especially postural orthostatic tachycardia syndrome (POTS). Patients with PACS, both in the absence or presence of POTS, exhibit a wide range of persisting symptoms long after the acute infection. Some of these symptoms may stem from alterations in cardiovascular homeostasis, but the exact mechanisms are poorly understood. The aim of this study was to provide a broad molecular characterization of patients with PACS with (PACS + POTS) and without (PACS-POTS) POTS compared to healthy subjects, including a broad proteomic characterization with a focus on plasma cardiometabolic proteins, quantification of cytokines/chemokines and determination of plasma sphingolipid levels. Twenty-one healthy subjects without a prior COVID-19 infection (mean age 43 years, 95% females), 20 non-hospitalized patients with PACS + POTS (mean age 39 years, 95% females) and 22 non-hospitalized patients with PACS-POTS (mean age 44 years, 100% females) were studied. PACS patients were non-hospitalized and recruited ≈18 months after the acute infection. Cardiometabolic proteomic analyses revealed a dysregulation of ≈200 out of 700 analyzed proteins in both PACS groups vs. healthy subjects with the majority (> 90%) being upregulated. There was a large overlap (> 90%) with no major differences between the PACS groups. Gene ontology enrichment analysis revealed alterations in hemostasis/coagulation, metabolism, immune responses, and angiogenesis in PACS vs. healthy controls. Furthermore, 11 out of 33 cytokines/chemokines were significantly upregulated both in PACS + POTS and PACS-POTS vs. healthy controls and none of the cytokines were downregulated. There were no differences in between the PACS groups in the cytokine levels. Lastly, 16 and 19 out of 88 sphingolipids were significantly dysregulated in PACS + POTS and PACS-POTS, respectively, compared to controls with no differences between the groups. Collectively, these observations suggest a clear and distinct dysregulation in the proteome, cytokines/chemokines, and sphingolipid levels in PACS patients compared to healthy subjects without any clear signature associated with POTS. This enhances our understanding and might pave the way for future experimental and clinical investigations to elucidate and/or target resolution of inflammation and micro-clots and restore the hemostasis and immunity in PACS.

BACKGROUND: Reduced preload and thoracic blood volume accompany postural tachycardia syndrome (POTS). Head-down tilt (HDT) increases both preload and intrathoracic blood volume. The objective of this study was to assess the safety and efficacy of HDT in POTS in acute settings.
METHODS: This retrospective study evaluated POTS patients. Analyzed data included heart rate, blood pressure, cerebral blood flow velocity (CBFv) in the middle cerebral artery, and capnography. The baseline supine hemodynamic data were compared with the data obtained at the second minute of the -10° HDT. A linear mixed-effects model was used to assess the effect of HDT on hemodynamic variables.
RESULTS: The HDT was explored in seven POTS patients and an additional seven POTS patients without HDT served as controls. In the HDT arm, four POTS patients had overlapping diagnoses of myalgic encephalopathy/chronic fatigue syndrome (ME/CFS) and one patient had comorbidity of post-acute sequelae of SARS-CoV-2 infection (PASC). HDT lowered heart rate by 10% and increased end-tidal CO2 by 8%. There was no change in other cardiovascular variables.
CONCLUSIONS: In the acute setting, HDT is safe. HDT reduces the heart rate presumably by modulating baroreflex by enhancing preload and stroke volume, which in turn increases thoracic blood volume with a net effect of parasympathetic cardiovagal activation and/or sympathetic withdrawal. This pilot study provides a foundation to proceed with longitudinal studies exploring the long-term effect of repetitive HDT in conditions associated with preload failure such as POTS, ME/CSF, and PASC.