Long-COVID describes a variety of COVID-19 side effects lasting longer than three months. Among these side effects are cardiovascular alterations, such as Postural Orthostatic Tachycardia Syndrome (POTS), caused by an autonomic nervous system dysfunction. A higher incidence of POTS and decreased baroreceptor sensitivity (BRS) has been reported in Long-COVID patients. Many of these patients present orthostatic intolerance similar to that observed in POTS, which does not strictly coincide with the criteria that have previously been established for POTS subtypes. Therefore, we aim to determine if the decrease of the baroreceptor sensitivity is enough to diagnose different degrees of the autonomic dysfunction spectrum. A cross-sectional study was conducted in a cohort of individuals who presented with various long-term symptoms for at least four weeks after a moderate acute COVID-19 infection. To further evaluate orthostatic intolerance (OI), we developed a new method that enables a more detailed characterization of cardiovascular dynamics using beat-to-beat physiological time series. Since these dynamics can be assessed through the measurement of baroreceptor sensitivity, this new method employs a geometric analysis that reveals varying degrees of baroreceptor sensitivity impairment. The proposed method generated a graph of baroreflex sensitivity that consistently showed a decrease in this index. Patients exhibited significantly lower BRS compared with healthy controls during orthostatism. Furthermore, we noticed that patients with lower BRS had a significantly higher arterial blood pressure and heart rate, as well as an overall lower heart rate variability. The proposed method also correlated with previously recognized canonical variables of HRV, as well as being validated with the sequence method. Additionally, this allows us to understand and reclassify patients' diagnoses within the spectrum of symptoms similar to postural orthostatic tachycardia syndrome (POTS). The proposed method allowed us to consider this decrease in baroreflex sensitivity measurement as a diagnostic tool through a spectrum-based approach to reclassify patients. This analysis can be incorporated into the set of variables considered to improve the diagnosis of patients with Long-COVID.

Hypermobile Ehlers-Danlos syndrome (hEDS) affects multiple systems, but comprehensive evaluations of a larger sample of hEDS patients are lacking. The objective of this study was to describe cerebrovascular, autonomic, and neuropathic features of hEDS. This retrospective case-control study was conducted at Brigham and Women's Faulkner Hospital between 2016-2023. Data from hEDS patients who completed autonomic testing and skin biopsies were analyzed. Outcome measures include validated surveys (Survey of Autonomic Functions, Neuropathy Total Symptom Score-6 (SAS)) and autonomic function testing (Valsalva maneuver, deep breathing, head-up tilt and sudomotor), cerebrovascular (cerebral blood flow velocity (CBFv) in the middle cerebral artery), respiratory (capnography), and neuropathic (skin biopsies for assessment of small fiber neuropathy) testing and inflammatory/ autoimmune markers. Total 270 hEDS patients were analyzed and compared to 29 healthy controls. Common hEDS complaints (prevalence > 90% ) were orthostatic sudomotor, vasomotor, gastrointestinal, and pain. Orthostatic cerebral blood flow velocity was reduced in 79% of hEDS and correlated with orthostatic dizziness. The head-up tilt test revealed postural tachycardia syndrome (prevalence 33%), hypocapnic cerebral hypoperfusion (22%), orthostatic cerebral hypoperfusion syndrome (18%), and neurogenic orthostatic hypotension (9%). Widespread but mild autonomic failure was present in 90% of hEDS patients on autonomic testing. Small fiber neuropathy using structural criteria was detected in 64%, and using combined structural and functional criteria in 82%. This study provided evidence of cerebrovascular dysregulation with reduced orthostatic cerebral blood flow velocity associated with symptoms of cerebral hypoperfusion, frequent small fiber neuropathy, and widespread but mild autonomic failure in hEDS.

Postural orthostatic tachycardia syndrome (POTS) is characterized by an excessive heart rate increase upon standing, often associated with dizziness, gastrointestinal symptoms, and decreased functional capacity. Acute hepatic porphyrias (AHP) are rare metabolic disorders with nonspecific neurovisceral and autonomic symptoms, some of which overlap with POTS. The purpose of this study was to evaluate AHP by molecular and biochemical testing in patients with POTS. We studied 50 patients diagnosed with POTS and gastrointestinal symptoms at the Vanderbilt Autonomic Dysfunction Center. They underwent neuro-hormonal evaluation for POTS and genetic and biochemical screening for AHP. Genetic testing was aimed mainly at the four genes relevant to AHPs. Porphobilinogen (PBG), delta-aminolevulinic acid (ALA), and total porphyrins were measured in urine with normalization to creatinine. The average age of the patients was 33 ± 8.6 years, 96% were female, and the average BMI was 28 ± 7.2 kg/m, average systolic blood pressure was 120 ± 15.5 mmHg, average heart rate was 77 ± 13.6 bpm at baseline, and average SBP was 126 ± 19.1 mmHg. A heart rate of 111 ± 15.8 bpm at 10 min upright, showed normal cardiovascular reflexes. The COMPASS-31 total score was 32 ± 8.4, with a normal autonomic function test. Urine PBG averaged 1 ± 0.7 mg/g creatinine, ALA 2 ± 0.9 mg/g creatinine, and total porphyrins 172 ± 74.2 mmol/g creatinine, which were all normal. None had variants in the four genes associated with AHPs. Three patients were heterozygous for a common low expression ferrochelatase gene variant (FECH). We found no evidence of AHP in patients with POTS with uncontrolled gastrointestinal symptoms, suggesting that screening for AHP, a rare genetic disorder, may not be warranted.

Hyperadrenergic POTS (Hyper-POTS) is characterized by excessive central sympathetic activity and impaired cardiovagal modulation. A single transcutaneous vagus nerve stimulation (tVNS) rebalanced cardiovascular autonomic control in previous studies. Repetitive tVNS may similarly restore autonomic balance and improve symptoms in Hyper-POTS. Twenty-two Hyper-POTS were studied at baseline (Pre-tVNS), after 14 days of tVNS (tVNS), and within 24 months post-discontinuation (Post-tVNS). The modified Vanderbilt Orthostatic Symptoms Score (mVOSS) quantified symptoms. ECG, arterial pressure, respiratory activity, and muscle sympathetic nerve activity (MSNA) were continuously recorded while supine and during 75° head-up tilt (HUT). Cardiac vagal modulation (high frequency power,HF), sinoatrial node sympatho-vagal interaction (low-to high-frequency ratio,LF/HF), sympathetic vasomotor control (LF) and arterial baroreflex sensitivity (α) were assessed by spectral analysis. Baroreflex sensitivity was also evaluated by spontaneous sequences (BRS) technique. At tVNS, MSNA decreased in both positions. tVNS increased HF and decreased LF/HF in supine. During HUT, αLF increased, HF increased and HR decreased compared to Pre-tVNS. Total symptom score declined in both positions, with improvements in multiple mVOSS domains during tilt. At Post-tVNS, HF and BRS increased in both positions. During HUT, αLF increased, HR and LF decreased. MSNA returned to Pre-tVNS in both positions. Total symptom score showed sustained improvement. Fourteen-day tVNS enhanced cardiovagal modulation, reduced sympathetic activity, and improved orthostatic symptoms in Hyper-POTS patients. Additionally, some benefits persisted beyond the stimulation period. Thus, tVNS could potentially be used as an additional therapeutic tool in Hyper-POTS.

This systematic review aimed to identify components of supportive self-management for postural orthostatic tachycardia syndrome and critically appraise the evidence base. Systematic review. EMBASE, MEDLINE, CINHAL and charity databases, trial registries and grey literature were searched until December 14th, 2023. The PRISMA guidelines were followed for the search strategy. Data were mapped to the Practical Reviews in Self-management Support taxonomy components and the Middle Range Theory of Self-Care in Chronic Illness. Synthesis and analysis followed guidance on reporting without meta-analysis with summary tables, a logic model, harvest plot, and narrative synthesis. 36 studies were included. Components of supportive self-management were found in 1) lifestyle advice, 2) provision of equipment, and 3) support with adherence. No studies were found on 1) education, 2) psychological well-being, 3) communication needs with health professionals and social support networks, 4) reliable sources of information, 5) training for practical self-management, or clinical action plans, and 5) social support. Studies efficacy' was hampered by poor research designs, short studies of one day duration, and appropriateness of outcome measures. Significant gaps were identified requiring further research 1) self-care monitoring activities 2) self-care management activities, 3) provision of education, information and resources 4) addressing psychological well-being and 5) addressing social support. A specific gap exists in the POTS evidence base in nurse led interventions. This review evaluates supportive self-management components and identifies key issues with the current evidence base that require addressing to improve and inform the support needs and services of this often disabling, and predominantly female condition. This review is a novel integration of the taxonomy and theory. Findings were discussed with a postural tachycardia syndrome advisory group, providing important insights into key issues with the studies validity, reliability and generalisability from their perspectives.

Postural Orthostatic Tachycardia Syndrome (POTS) is an autonomic dysfunction characterized by symptoms of orthostatic intolerance, associated with an increase in heart rate within 10 minutes of assuming an upright position or head-up tilt, in the absence of hypotension. There are three phenotypes of POTS - neuropathic, hypovolemic, and hyperadrenergic - and all result in tachycardia and altered cerebral perfusion. Pharmacological therapy is indicated in certain cases; however, no specific medication has yet been approved for this condition. Some studies have shown that ivabradine may be beneficial, as it reduces heart rate without affecting blood pressure. To evaluate the efficacy and safety of ivabradine in the treatment of POTS. Systematic review using the descriptors "Ivabradine" and "Postural Orthostatic Tachycardia Syndrome" in the PubMed, Scielo, LILACS, and Google Scholar databases. Articles were grouped and assessed using the PICO strategy. A total of 52 articles were identified, of which seven were included in the review - three prospective and four retrospective studies. In total, 203 patients were evaluated, the majority of whom were female. All studies reported a significant reduction in heart rate and improvement in symptoms of orthostatic intolerance, with most patients not reporting adverse effects, regardless of their POTS phenotype. Ivabradine proved to be effective and safe in the treatment of patients with POTS.

SARS-CoV-2 vaccination (SC2V) can be complicated by post-acute COVID-19 vaccination syndrome (PACVS). One manifestation of PACVS is small fibre neuropathy (SFN). A positive effect of intravenous immunoglobulins (IVIGs) even 3 years after the onset of PACVS is not known. The patient is a 52-year-old woman who developed PACVS after the second BNT162b2 vaccination in June 2021, which manifested clinically with SFN, myopericarditis, coagulopathy, and ocular, dermatologic, immunologic, and central nervous system (CNS) abnormalities. The SFN itself manifested as sensory disturbances, arterial hypotension and postural tachycardia syndrome (POTS). After the patient received three cycles of IVIGs, starting in June 2024, three years after the onset of PACVS, there was a significant positive effect on her SFN and other symptoms, as evidenced by various specific investigations. This case demonstrates that symptoms and signs of SFN as a manifestation of PACVS may benefit from the administration of IVIGs even years after onset.

Limited data exist on long-term outcomes associated with postural orthostatic tachycardia syndrome (POTS). We designed an online questionnaire to assess outcomes for patients formerly managed in a single-center pediatric POTS program. Here, we report the educational, economic, and social long-term impacts of pediatric POTS. In part, the Long-Term POTS Outcomes Survey (LT-POTS) sought to evaluate education, employment, and social impact of POTS. Patients aged ≤18 years at the time of POTS diagnosis were included. The survey was emailed to patients diagnosed or managed in the Children's Hospital of Philadelphia POTS Program. Of 862 patients surveyed, 227 returned questionnaires with enough data for interpretation. Respondents were predominantly women (85%) and White individuals (97%). Half of patients missed >100 days of school, and 20% temporarily dropped out of school. More than 90% of patients graduated high school, and <50% graduated college. Only 26% of patients were able to work >40 hours/week, with 35% having reduced hours due to POTS symptoms. Significant loss of income and financial expenditures were associated with POTS. Loss of social relationships and inability to live independently were additional associated social impacts. POTS is a long-term disorder associated with significant physical disability as well as adverse educational, economic, and social impacts. Although certain accommodations may mitigate the impact of the disease on education and employment, POTS poses significant educational, economic, and socioemotional risks, requiring further understanding of its pathophysiology and optimization of its management to reduce individual and societal impact.

Cardioneuroablation (CNA) is increasingly used worldwide in the treatment of functional bradyarrhythmia mediated by excessive vagal tone. However, a potential early or long-term complication is the development of postprocedural inappropriate sinus tachycardia (IST), which remains difficult to manage. Recent data suggest that sinus node (SN)-sparing hybrid ablation may offer promising long-term outcomes in patients with IST and postural orthostatic tachycardia syndrome (POTS). We present what is, to our knowledge, the first documented case of such a procedure performed for IST/POTS following an uncomplicated CNA for symptomatic vagally mediated sinus bradycardia (SB). The comprehensive treatment strategy included on-site cardiac rehabilitation, a home-based telerehabilitation program, and evaluation using cardiovascular autonomic functional testing (CAFT) and the Malmö POTS scoring system. We present a 33-year-old woman with a 6-month history of dizziness, palpitations, exercise and orthostatic intolerance, dyspnea, presyncope, and one syncope episode. Symptoms of IST (130-170 bpm) appeared within 1 week after CNA for symptomatic SB. Despite the diagnosis of IST, CAFT have confirmed POTS. Other causes of sinus tachycardia (ST) were excluded according to guidelines. Nonpharmacological and pharmacological treatment proved ineffective. Following shared decision-making, the patient was referred for SN-sparing hybrid ablation with right-sided video-assisted thoracoscopic surgery (VATS). The patient subsequently participated in hybrid cardiac rehabilitation. At the 3-month follow-up, she was drug free and maintained a normal sinus rhythm. No evidence of bradycardia, IST/POTS, or vasovagal syncope (VVS), including CAFT, was documented during the follow-up. The serial MALMO POTS scoring system before and 3, 6, 9, 12 and 18 months after SN-sparing hybrid ablation demonstrated consistent and significant improvement, with scores decreasing from 46 to 13, 10, 6 and 12 points, respectively, values comparable to those observed in the healthy population. This is the first reported case of SN-sparing hybrid ablation for IST/POTS that developed after primary, uncomplicated CNA. Although not yet included in guidelines, the implementation of both procedures for cardiovascular autonomic dysfunction (CVAD) requires comprehensive and multidisciplinary heart team management. The MALMO POTS scoring system might be a useful tool for assessing CVAD before and after cardioneuromodulation procedures and further comprehensive evaluation.

Forms of dysautonomia, including Postural Orthostatic Tachycardia Syndrome (POTS), significantly impacts youth, yet psychosocial aspects remain under-researched, particularly outside of patients diagnosed with POTS. This study examines the clinical and psychosocial profiles of youth with autonomic dysfunction and compares findings between groups with different heart rate (HR) responses to orthostatic testing. This retrospective review analyzed demographics, symptoms, quality of life (QoL), and mental health variables (e.g., anxiety, depression, ADHD) in youth with autonomic dysfunction. Differences between higher and lower HR response groups were compared. QoL was assessed using the PedsQL™ and symptom severity was measured with the Malmö POTS Symptom Score (MAPS). Medical history and psychosocial concerns were extracted from electronic medical records. Symptom severity scores exceeded clinical cutoffs for the full sample (65.8) and across HR groups. Independent t-tests showed no differences between groups for any variable. Pain (92.5 %) and impaired eating (42.5 %) were prevalent across the sample. QoL was clinically impaired in all domains, and mental health concerns, such as anxiety (83.3 %) and depression (54.3 %), were common. Findings describe the pervasive symptom and psychosocial burden in youth with autonomic dysfunction, which was consistent across higher and lower HR response groups. The study emphasizes the importance of addressing medical, mental health, and daily life challenges in all patients seen for autonomic dysfunction. Additionally, it highlights the importance of expanding research and clinical focus to include all youth with autonomic dysfunction, regardless of HR response to ensure youth who are experiencing impairment obtain the comprehensive care they need.

Cardiovascular autonomic disorders (CAD) were described following COVID-19 infection and vaccination, but previous reports were limited in size and follow-up. Here, we aimed to investigate the type and frequency of newly diagnosed and exacerbated CAD following COVID-19 infection or vaccination, and assessed their associated autonomic and non-autonomic complaints, applied treatment, and clinical outcome at last follow-up. Medical records of individuals referred to the Innsbruck Dysautonomia Center between March 2020 and March 2023 were reviewed for new onset of orthostatic intolerance, recurrent syncope, OR exacerbation of previously diagnosed CAD within 6 weeks from a passed COVID-19 infection or vaccination. Following COVID-19 infection (n = 75), 22 (29%) individuals were diagnosed with postural orthostatic tachycardia syndrome (POTS), 12 (16%) with vasovagal syncope (VVS), 1 with delayed and 1 with transient orthostatic hypotension (OH). Following COVID-19 vaccination (n = 26), 11 (42%) POTS, 2 (8%) VVS, and 3 (12%) transient OH cases were newly diagnosed. In half of newly referred individuals (n = 49/101, 49%), the diagnostic workup excluded any CAD. VVS was the most frequently exacerbated CAD (n = 8/19, 42%). Non-pharmacological measures were recommended to all newly diagnosed CAD, with one-third additionally receiving pharmacotherapy. Follow-up was available in 42 (81%) individuals with newly diagnosed CAD, with a symptomatic improvement observed in 26 (62%) cases. A specialized diagnostic workup is pivotal to diagnose or exclude CAD in individuals with new-onset orthostatic intolerance or recurrent syncope following COVID-19 infection or vaccination. A multimodal treatment approach can achieve a symptomatic improvement in a substantial proportion of affected individuals.

Postural orthostatic tachycardia syndrome (POTS) is defined as the presence of chronic symptoms of orthostatic intolerance accompanied by an increase in heart rate greater than 30 beats per minute within 10 min of assuming an upright posture in the absences of orthostatic hypotension. It is a condition which lacks a definitive treatment strategy, with weak evidence and clinical expertise to support the available guidelines from the Heart Rhythm Society in 2015 and the Canadian Cardiovascular Society in 2020. The limited systematic reviews evaluating the treatment for POTS only reported three or fewer trials when many more trials have been published. In this systematic review, we evaluate the evidence for different treatments for POTS from 21 randomized clinical trials with 750 patients that took place between 2000 and 2023. This review summarizes the available evidence from trials on propranolol, midodrine, pyridostigmine and ivabradine as well as less commonly used medications such as desmopressin, melatonin, atomoxetine, modafinil, sertraline and intravenous immunoglobulins. Moreover, the trial evidence for non-pharmacological treatments is described including increase intake of dietary sodium, exercise training, compression and devices. We conclude that many small trials have evaluated different treatments for POTS. Large randomized trials are needed to determine if mainstay treatments beta-blockers, midodrine, and pyridostigmine should be used as first line treatment(s).

Background Ehlers-Danlos syndrome (EDS) encompasses a group of connective tissue disorders often extending beyond musculoskeletal involvement. Emerging evidence indicates a high prevalence of cardiovascular autonomic dysfunction in this population, yet systematic physiologic evaluations remain limited. Objective To characterize cardiovascular autonomic function in EDS using standardized autonomic testing and heart rate variability (HRV) indices, and to explore intrinsic autonomic coupling by correlating resting heart rate with HRV parameters. Methods This cross-sectional study included 30 clinically diagnosed patients with EDS and 30 age- and sex-matched healthy controls. Short-term HRV analysis (five-minute supine ECG) and standard autonomic testing, including head-up tilt, were performed under controlled laboratory conditions. HRV indices were derived using Fast Fourier Transform (FFT) algorithms. Group differences were evaluated with independent t-tests, and correlations between resting heart rate and HRV measures were analyzed using Pearson's correlation. Results Compared with controls, patients with EDS exhibited higher resting heart rate (87.3±11.6 vs 75.2±9.8 bpm), lower parasympathetic time-domain indices (standard deviation of normal-to-normal intervals or SDNN 35.4±9.7 vs 49.1±11.4 ms; root mean square of successive differences (RMSSD; 20.7±6.9 vs 31.6±8.8 ms), and altered frequency-domain markers (low frequency (LF) power 671±205 vs 542±176 ms²; high frequency (HF) power 174±81 vs 272±106 ms²; LF/HF ratio 3.7±1.3 vs 1.8±0.7). Orthostatic intolerance was observed in 16 (53.3%) of the patients with EDS versus three (10%) of the controls. Correlation analysis revealed that in EDS, resting HR correlated negatively with SDNN (r=-0.45, p=0.01), RMSSD (r=-0.52, p<0.01), and HF power (r=-0.39, p=0.03), while showing a positive correlation with LF/HF ratio (r=0.58, p<0.001). Conclusion Patients with EDS had autonomic dysregulation, with sympathetic predominance and diminished vagal modulation. The intrinsic coupling between resting heart rate and HRV indices suggests impaired cardiovascular autonomic integration. HRV profiling is a valuable noninvasive biomarker for early identification and longitudinal monitoring of autonomic dysfunction in EDS, potentially enhancing disease characterization and guiding individualized therapeutic strategies.

Postural tachycardia syndrome (POTS) is a common, often disabling disorder of autonomic nervous system regulation without a unifying etiological account. Converging evidence suggests infectious, physical, and emotional threats frequently precede onset. We propose a hypothesis-generating model in which POTS may, in some individuals, involve threat-induced, centrally maintained disruption of brain-body communication that may be responsive to neuroplasticity-based behavioral medicine. In this paper, we synthesized multidisciplinary literature and our team's data spanning (a) autonomic and central nervous system responses to threat and trauma, (b) neurological alterations associated with early life stress, (c) links between adverse childhood experiences and posttraumatic stress disorder with autonomic symptom burden, and (d) clinical developments targeting the threat system and autonomic regulation. These data suggest that chronic or overwhelming threat exposure is associated with sympathetic activation, reduced vagal tone, and neuroplastic alterations within cortico-limbic and brainstem networks that parallel POTS features (exaggerated tachycardia, autonomic rigidity, multisystem dysregulation). Preliminary data indicate individuals with higher trauma exposure and PTSD symptoms report greater autonomic symptom severity and poorer global health. Emerging imaging suggests a potentially important role for the periaqueductal gray (PAG), a midbrain hub for autonomic, cardiovascular, motor, and pain responses to threat, which may fail to reset after trauma, leaving the ANS in a sustained escape-mode (fight/flight/freeze) that increases POTS risk. Overall, these findings provide preliminary conceptual support for a unified hypothesis linking trauma, PAG-mediated threat responses, and sustained autonomic dysregulation in POTS, underscoring the importance of trauma-informed care. Behavioral interventions that target threat reduction and autonomic regulation such as rate variability biofeedback and neuroplasticity-oriented psychotherapies, may complement standard medical care. Prospective, longitudinal studies are needed to clarify causal pathways and identify responsive subgroups, and randomized clinical trials are required to establish the efficacy of nervous system-focused behavioral interventions.

The combination of neurological, cardiac, and pulmonary disease in patients with systemic sclerosis (SS) is rare. The aim of the study was to report a patient with SS who manifested with migraine without aura, Raynaud's phenomenon, pulmonary hypertension, and postural tachycardia syndrome (POTS), a combination which has not been previously reported. The patient is a 53-year-old Caucasian woman with diffuse cutaneous SS who was treated with methotrexate and developed migraine without aura since the age of 6 years. Since age 31 years, she developed Raynaud's phenomenon with several attacks daily, which could be triggered by cold and also occurred in summer. At the age of 52 years, pulmonary fibrosis with secondary pulmonary hypertension was diagnosed and bosentan was administered. At the age of 53 years, POTS was diagnosed. The frequency of migraine was one per week at the age of 53 years. This case shows that migraine can be the initial manifestation of diffuse cutaneous SS, followed by Raynaud's syndrome, pulmonary hypertension and POTS.

hypermobile spectrum disorders (HSD) and Ehlers-Danlos syndromes (EDS) are connective tissue disorders often associated with systemic manifestations such as mast cell activation syndrome (MCAS), postural orthostatic tachycardia syndrome (POTS), irritable bowel syndrome (IBS), and autoimmune conditions, including spondyloarthritis (SpA). The overlap of these conditions complicates diagnosis and treatment. This study investigates the prevalence of MCAS and other comorbidities, as well as patterns of medication use, in individuals with HSD/EDS. this cross-sectional study included 37 participants diagnosed with HSD or EDS based on the 2017 Diagnostic Consensus Criteria. Participants were divided into two groups: 23 with SpA + EDS and 14 with EDS-only. Demographic variables, comorbidities, and medication use (biologics, disease-modifying antirheumatic drugs [DMARDs], and nonsteroidal anti-inflammatory drugs [NSAIDs]) were analyzed using comparative statistical methods. MCAS was significantly less prevalent in SpA + EDS participants (13%) compared to the EDS-only group (85.7%, p < 0.0001). POTS (60.9% vs 78.6%) and IBS (60.9% vs 85.7%) occurred at similar frequencies in both groups. The use of immunomodulators was higher in SpA + EDS (73.9%) than EDS-only (42.8%, p = 0.003). Biologic use was more common in SpA + EDS (34.8% vs 7.1%, p = 0.050), whereas NSAID use was higher in EDS-only participants (47.4% vs 30.4%, p > 0.05). the lower MCAS prevalence in SpA + EDS may reflect symptom overlap or suppression due to immunomodulatory treatments. Differences in medication use highlight variations in diagnostic and therapeutic strategies. Comprehensive evaluations are essential to ensure accurate diagnoses and optimal treatment approaches.

The aim of the study was to clarify the cause of orthostatic dysregulation in Japanese children by analyzing fluctuations in adenylate cyclase activity. Four types of orthostatic dysregulation in Japan include postural orthostatic tachycardia syndrome, delayed orthostatic hypotension, immediate orthostatic hypotension, and vasovagal syncope. However, the exact cause of these disorders remains unknown. To identify the cause of these conditions, we examined the resting blood adenylate cyclase activity and basic clinical data (blood pressure, pulse rate) of 30 patients diagnosed with orthostatic dysregulation (21 postural orthostatic tachycardia syndrome, eight delayed orthostatic hypotension, one immediate orthostatic hypotension, zero vasovagal syncope) and 20 previously reported healthy adults. The results of this study showed that adenylate cyclase activity (isoproterenol and adrenaline) in patients with postural orthostatic tachycardia syndrome was significantly higher than that in patients with delayed orthostatic hypotension and healthy adults. Moreover, patients with postural orthostatic tachycardia syndrome had significantly higher values than healthy adult controls at all five concentration points. Adenylate cyclase activity in patients with delayed orthostatic hypotension showed a trend toward higher values at 10 μM of adrenaline. Furthermore, owing to the higher adenylate cyclase activity in patients with postural orthostatic tachycardia syndrome, their systolic blood pressure was higher than that in patients with delayed orthostatic hypotension. These results suggest that increased adenylate cyclase activity may be related to the onset of orthostatic dysregulation (postural orthostatic tachycardia syndrome and delayed orthostatic hypotension). In conclusion, adenylate cyclase activity levels may be related to the onset of orthostatic dysregulation, and this can be used as a new strategy for diagnosing orthostatic dysregulation.

Abdominopelvic Vascular Compression Syndrome(s) (VCS) are rare disorders with diverse symptoms that appear to occur more frequently in patients with Ehlers-Danlos Syndrome (EDS) and Hypermobility Spectrum Disorder (HSD). The reported associations between EDS/HSD, Postural Orthostatic Tachycardia Syndrome (POTS), and Mast Cell Activation Syndrome (MCAS) further complicate the diagnosis and management of the VCS in this specific patient population. This review summarises the established literature on this complex topic, highlighting these relationships, with the aim to propose a framework for recognising and managing VCS among patients with EDS/HSD. Given the limited body of literature on this topic, we also aim to underscore the need for further research within this specific patient population. A PRISMA-guided systematic review was conducted using PubMed and Ovid/Medline databases. VCS included Median Arcuate Ligament Syndrome (MALS), Superior Mesenteric Artery Syndrome (SMAS), Nutcracker Syndrome (NCS), and May-Thurner Syndrome (MTS). Given the limited number of studies, small cohort studies and case reports/series were also reviewed. Of 183 screened studies, 62 met the inclusion criteria. Only six studies directly addressed the VCS in EDS/HSD. Five discussed an EDS-POTS association, two described links between MCAS, POTS, and EDS, and five associated POTS with VCS. Only one study explored all four conditions. Evidence suggests an association between EDS/HSD, VCS, POTS, and MCAS but remains limited. Underdiagnosis and delayed treatment are common and underscore the need for multi-disciplinary care. Invasive imaging and interventions appear generally safe in EDS/HSD, excluding vascular EDS, yet robust safety and outcome data and tailored diagnostic or treatment algorithms are lacking and require further investigation.

Postural Orthostatic Tachycardia Syndrome (POTS) is a chronic autonomic disorder characterized by chronic (> 3 months) orthostatic intolerance and an increase in heart rate (HR) of ≥ 30 beats per minute (bpm) without orthostatic hypotension. Traditional diagnostic approaches, such as the active standing or tilt-table test, are typically conducted under controlled clinical conditions, limiting their ability to capture the natural variability of symptoms and the intricate physiological responses occurring in daily life. These tests may cause patient discomfort, dizziness, nausea, or syncope. Furthermore, they are timeconsuming and cannot be used as a screening tool for POTS. To address these limitations, this study explored wearable devices that continuously collect physiological data-specifically, electrocardiogram (ECG) and accelerometer (ACC)-derived metrics-from POTS patients and healthy controls during routine daily activities. Physiological features around posturechange events identified in the data were processed and used to train and test a baseline deep learning model. The model demonstrated promising performance in accurately differentiating POTS patients from healthy controls in a relatively small cohort (66 from POTS patients and 20 from controls), indicating its potential as a feasibility study for clinical decision support. Future studies involving larger and more diverse samples under varying clinical conditions would be necessary to enhance the robustness and viability of our diagnostic model.

Long COVID and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) are relatively common and disabling multisystem disorders that share overlapping features, including post-infectious onset and similar clinical manifestations such as brain fog, fatigue, muscle pain, and dysautonomia with orthostatic intolerance. These similarities suggest that Long COVID and ME/CFS may share common pathophysiological mechanisms, though the underlying mechanisms remain poorly understood, partly due to the difficulty in quantifying many of the symptoms. This retrospective study evaluated Long COVID and pre-COVID ME/CFS patients who completed autonomic testing between 2018 and 2023 at the Brigham and Women's Faulkner Hospital Autonomic Laboratory. The evaluations included autonomic tests (Valsalva maneuver, deep breathing, tilt-table test, and sudomotor function) with capnography and transcranial Doppler monitoring of cerebral blood flow velocity (CBFv) in the middle cerebral artery, neuropathic assessment through skin biopsies for small fiber neuropathy (SFN), invasive cardiopulmonary exercise testing (ICPET), and laboratory analyses covering metabolic, inflammatory, autoimmune, and hormonal profiles. A total of 143 Long COVID and 170 ME/CFS patients were analyzed and compared to 73 healthy controls and 290 patients with hypermobile Ehlers-Danlos syndrome (hEDS). Tests revealed extensive similarities between Long COVID and ME/CFS, including reduced orthostatic CBFv (92%/88% in Long COVID/ME/CFS), mild-to-moderate widespread autonomic failure (95%/89%), presence of SFN (67%/53%), postural tachycardia syndrome (POTS) (22%/19%), neurogenic orthostatic hypotension (15%/15%) and preload failure (96%/92%, assessed in 25/66 Long COVID/ME/CFS). Patients with hEDS exhibited more severe peripheral neurodegeneration compared to the other groups. Laboratory tests did not distinguish between the conditions. Both Long COVID and ME/CFS demonstrate dysregulation in cerebrovascular blood flow, autonomic reflexes, and small fiber neuropathy, suggesting that these conditions may share a common underlying pathophysiology. However, differing distributions of findings in patients with hEDS raise the question of whether these conditions represent distinct but overlapping syndromes or reflect a shared underlying pathway. Further research is required to clarify the relationship between these conditions and the potential underlying pathophysiological mechanisms.

Autoimmune autonomic disorders are common, though often under-recognized, and suboptimally understood. Autonomic nervous system impairment may result from immune-mediated damage to central or peripheral autonomic pathways, and typically involve both sympathetic and parasympathetic systems, as well as the enteric nervous system. Various autoimmune conditions may primarily involve the autonomic nervous system, as in autoimmune autonomic ganglionopathy associated with ganglionic nicotinic acetylcholine receptor antibodies or may involve autonomic systems as part of a multisystem neurologic process with or without underlying malignancy, or autonomic nerves may be targeted in systemic autoimmunity as is seen with Sjögren's syndrome. A careful history and diagnostic evaluation is necessary to determine the type, distribution, and severity of dysautonomia; which may be generalized or more restricted in nature. An understanding of potential autonomic features in the various autoimmune autonomic disorders can help to provide diagnostic clarity, and recognition of autonomic signs and symptoms is necessary to direct symptomatic and immunotherapeutic decisions in these patients.

Postural orthostatic tachycardia syndrome (POTS) is a debilitating disorder characterized by excessive increases in heart rate upon standing and poor orthostatic tolerance. Impairments in large artery, endothelial, and venous function may collectively, or individually, result in excessive blood pooling and impaired venous return, or other inadequate vascular response to standing, thus contributing to POTS. Herein, we tested the hypothesis that patients with POTS would exhibit reduced large artery stiffness, enhanced endothelial function, and greater lower limb venous pooling while standing, compared with healthy controls. Fourteen participants with a clinical diagnosis of POTS and 15 age-matched controls (all females; median age [interquartile range]; 21 [19-37] yr, = 0.769) were recruited. Central arterial stiffness was determined using carotid-femoral pulse wave velocity (cfPWV; SphygmoCor). Endothelial function was assessed using brachial artery flow-mediated dilation (FMD) following a 5-min forearm occlusion at 200 mmHg. Functional measures of calf venous volume and filling time (90% maximal venous filling) were acquired (air plethysmography) while standing. cfPWV was increased in people with POTS [(means ± SD) 5.5 ± 0.9 vs. 4.8 ± 0.4, = 0.031], whereas FMD was not different between groups ( = 0.854). During standing, calf venous volume was 29% greater in people with POTS ( = 0.048), and venous filling time was almost twice as long (404 ± 199 vs. 207 ± 99 s; = 0.003). These findings indicate that people with POTS exhibit increased central arterial stiffness, preserved endothelial function, and increased calf venous filling during standing. Such differences in lower limb venous filling dynamics on standing likely contribute to the orthostatic intolerance that characterizes POTS. Females with POTS and age-matched healthy controls underwent assessments of central arterial stiffness, endothelial function, and calf distensibility. Pulse wave velocity was higher in people with POTS, but brachial artery flow-mediated dilatation was not different between groups. Standing calf volume was greater in people with POTS, and maximal filling times were twice as long, suggesting altered venous and/or microvascular function. Augmented venous pooling in patients with POTS may impair venous return and orthostatic tolerance.

A significant number of physicians are unclear of the vast clinical manifestations of dysautonomia and imbalance of the autonomic nervous system, specifically the parasympathetic and sympathetic nervous systems. The major obstacle has been an inability to determine the mechanism of action as well as multisystem dysfunction and a lack of clear-cut testing. Dysautonomia, a pathophysiological malfunction of the sympathetic and parasympathetic nerves in our bodies, can present as altered clinical functions of heart rate (tachycardia/bradycardia), altered breathing patterns, blood pressure (hypertension/hypotension), sweating, digestion, syncope, etc. These symptoms have caused specialists to miss this diagnosis because of relative nonspecificity. Our current analysis of patients demonstrates significant delays in diagnosis, misdiagnosis, and the development of chronic syndromes because of the above. We demonstrate that monitoring of heart rate and blood pressure with changes in position and respiration can be easily and quickly performed without orthostatic stress and can demonstrate the entities of sympathetic withdrawal, cholinergic excessive aspects as well as tachycardia, blood pressure dips with posture, etc. This analysis takes less than an hour without the need for injections or medication, thus more quickly informing the cardiologist/neurologist of the correct diagnosis. We will attempt to demystify these issues so that clinicians and the scientific community will have a better understanding of this entity and consider a diagnosis of dysautonomia earlier in the differential diagnostic process and start treatment approaches sooner.

A previous study showed a high prevalence of central sensitization syndrome (CSS) in patients with autonomic symptoms. The prevalence of CSS in postural tachycardia syndrome (POTS), a form of dysautonomia, is unknown. To analyze the prevalence of CSS in POTS. This case-control study included patients with a POTS diagnosis confirmed by autonomic testing at Brigham and Women's Faulkner Hospital between 2022 and 2025. Data were analyzed from April to August 2025. POTS with and without CSS. Central Sensitization Inventory (to assess central sensitization syndrome [CSS]), COMPASS-31 (autonomic symptoms), Neuropathy Total Symptom Score-6 (NTSS-6, sensory symptoms), PROMIS (global health), and autonomic testing (Valsalva maneuver, deep breathing, sudomotor function, and head-up tilt) with skin biopsies. Primary outcome was the central sensitization inventory score with secondary outcomes individual test performances. This study included 305 patients with POTS, of whom 264 (86.6%) met criteria for CSS (mean [SD] age, 33.21 [10.75] years; 30 males [11.4%]; 234 females [88.6%]). Patients with CSS compared with those without CSS had longer duration of symptoms, were more frequently female, exhibited higher rates of anxiety (195 [73.9%] vs 20 [48.8%]; P = .002), depression (168 [63.6% vs 14 [34.1%]; P = .001), fibromyalgia (46 [17.4%] vs 0 [0%]; P = .008), irritable bowel syndrome (IBS, 90 [34.1%] vs 7 [17.1%]; P = .046), headaches (176 [66.7%] vs 12 [29.3 %]; P < .001), treatment with antihistamine medication (136 [51.5%] vs 13 [31.7%]; P = .03), psychiatric medication (163 [61.7%] vs 17 [41.5 %]; P = .02), pain medication (127 [48.1%] vs 8 [19.5%]; P = .001), and gastrointestinal medication (82 [31.1%] vs 5 [12.2 %]; P = .02), and had higher COMPASS-31 scores (51.93 [13.23] vs 31.18 [10.49]; P < .001), NTSS-6 scores (11.32 [4.86] vs 4.44 [3.32]; P < .001), NRS scores (3.26 [2.73] vs 0.54 [1.21]; P < .001), and worse PROMIS scores (20.36 [5.45] vs 27.96 [4.73]; P < .001). Autonomic tests showed lower orthostatic end-tidal carbon dioxide (27.59 [6.39] mm HG vs 29.46 [4.68] mm HG; P = .002) and a greater orthostatic decline in cerebral blood flow velocity (17.08 [8.72] cm/sec vs 13.68 [5.04] cm/sec; P < .001) in the CSS group. Both groups had similar prevalence of autonomic failure (223 [84.5%] vs. 33 [80.5%]; P = .67, mostly mild intensity), and abnormal skin biopsy (43% in both groups). These findings suggest that CSS was common in patients with POTS and may represent a higher-order sequela of cerebrovascular, respiratory, and autonomic dysregulation. This heightened central processing may amplify symptom perception through altered interoceptive signaling. Central sensitization and autonomic impairment may coexist, and management should focus on both conditions.

Postural orthostatic tachycardia syndrome (POTS) is a complex disorder mainly of orthostatic intolerance, often accompanied by a spectrum of symptoms related to autonomic nervous system dysfunction. Although the diagnostic criteria require an orthostatic challenge test, the associated symptom burden can be broad and is often missed by treating healthcare professionals, resulting in significant diagnostic delay. Treatment of this highly heterogenous condition is nuanced and consists of non-pharmacologic and pharmacologic approaches. Availability of POTS care is limited, with a dearth of medical specialists or general practitioners specialising in autonomic medicine. The complexity of care for those with POTS necessitates a multidisciplinary approach due to the need for extended appointment times and frequent follow-ups to monitor therapeutic response and progress. This should include a primary team consisting of a general practitioner and trained autonomic physicians with specialist nurses, allied health professionals, and any other specialists required to manage the affected systems. This state-of-the-art review aims to cover the key aspects of diagnosing and managing POTS, including special neurological, gastroenterological, psychological, and paediatric considerations. There is an urgent need to provide services that meet the needs of the growing POTS population.