Clin Auton Res
· 2026 Jun · PMID 41910866
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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 highligh...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.
You Y, Han X, Qi G
… +5 more, Liu J, Tian L, An Y, Wang S, Zheng M
Clin Auton Res
· 2026 Jun · PMID 41888507
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PURPOSE: This study investigated the relationship between short-term blood pressure variability (BPV), autonomic function measured by heart rate variability (HRV), and the prevalence of complex arrhythmias in hypertensiv...PURPOSE: This study investigated the relationship between short-term blood pressure variability (BPV), autonomic function measured by heart rate variability (HRV), and the prevalence of complex arrhythmias in hypertensive patients. METHODS: We retrospectively analyzed 198 middle-aged and elderly patients with primary hypertension, stratified by tertiles of 24-h systolic BPV. Simultaneous 24-h ambulatory blood pressure and Holter monitoring were performed. Echocardiography was performed within 72 h of monitoring. HRV was analyzed in time and frequency domains, and a composite autonomic score was derived via principal component analysis. Complex arrhythmia was defined as Lown grade ≥ 3 or Kleiger grade ≥ 3. RESULTS: The high-BPV group showed significantly reduced HRV across all indices and a higher incidence of complex arrhythmias (71.2% versus 40.9% in low-BPV group). BPV was inversely correlated with all HRV parameters, most strongly with SDNN. Multivariate analysis confirmed BPV as an independent negative predictor of the composite autonomic score. Logistic regression adjusted for medication use identified higher BPV, older age, and larger left atrial diameter as independent predictors of complex arrhythmias. CONCLUSIONS: Increased short-term BPV is independently associated with impaired cardiac autonomic function and is a significant predictor of complex arrhythmias in hypertension. Assessment of BPV may improve autonomic and arrhythmic risk stratification in this population.
Bačkorová BP, Lazúrová Z, Lukáčová M
… +3 more, Valová K, Mitro P, Lazúrová I
Clin Auton Res
· 2026 Mar · PMID 41848980
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PURPOSE: This prospective observational study was carried out to evaluate the response of adrenocortical hormones (cortisol and aldosterone) to head-up tilt (HUT)-induced vasovagal syncope in relation to hemodynamic chan...PURPOSE: This prospective observational study was carried out to evaluate the response of adrenocortical hormones (cortisol and aldosterone) to head-up tilt (HUT)-induced vasovagal syncope in relation to hemodynamic changes. SUBJECTS AND METHODS: Blood samples from 79 patients (48 women and 31 men, age 19-73 years) who underwent the HUT test were analyzed for serum aldosterone and cortisol. On the basis of their response, patients were categorized into two groups: 50 HUT-positive (HUT+) and 29 HUT-negative (HUT-) patients. RESULTS: HUT+ patients exhibited significantly lower baseline aldosterone levels compared with HUT- patients (203.1 ± 78.8 versus 266.2 ± 76.3 pg/ml, p = 0.0009). Similarly, aldosterone levels after the HUT test were lower in the HUT+ as compared with the HUT- group (249.5 ± 101.3 versus 351.4 ± 98.11 pg/ml, p < 0.0001). However, serum cortisol showed no significant differences between groups. Aldosterone increased in response to HUT in both groups. Aldosterone positively correlated with systolic and diastolic blood pressure, as well as heart rate. Integration of aldosterone with clinical assessment and additional laboratory tests may improve diagnostic accuracy and risk stratification. CONCLUSIONS: The results demonstrate significantly lower serum aldosterone concentrations in HUT+ patients at baseline and after HUT test in comparison with HUT- patients. Moreover, aldosterone levels positively correlated with systolic and diastolic blood pressure (BP). However, serum cortisol levels did not discriminate HUT+ from HUT- patients.
Müller K, Thiel JC, Schopen L
… +3 more, Fimm B, Schulz JB, Maier A
Clin Auton Res
· 2026 Apr · PMID 41801611
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PURPOSE: Patients with hypermobile Ehlers-Danlos syndrome (hEDS) frequently present with circulatory dysfunction, including postural orthostatic tachycardia syndrome (POTS), and cognitive impairments, leading to substant...PURPOSE: Patients with hypermobile Ehlers-Danlos syndrome (hEDS) frequently present with circulatory dysfunction, including postural orthostatic tachycardia syndrome (POTS), and cognitive impairments, leading to substantial disability and limitations in daily functioning. Few studies have examined attention, and concentration and associated conditions in hEDS. In this case-control study, we used a comprehensive cognitive test battery to assess whether cognitive performance is impaired in individuals with hEDS and depends on different body positions. METHODS: Twenty-nine patients and 29 healthy controls (HC) were enrolled. Baseline cognitive assessments included the Performance Scale of an intelligence test (LPS), Montreal Cognitive Assessment (cognitive deficit screening), and Test of Attentional Performance (TAP). The main cognitive tests for assessing the effects of body position were conducted in randomized conditions (supine, standing, and standing legs-crossed) and included the Stroop test, Corsi block-tapping test, Trail Making Test Part B, and Wechsler Memory Scale-revised. RESULTS: Compared to HC, patients with hEDS had higher intellectual performance (p < .050), but besides relevant comorbid conditions, also significantly impaired attention in the TAP (p < .010) and an impairment of executive function assessed by the Stroop test (p < .010) in the legs-crossed compared to the supine position. CONCLUSION: Attention in the hEDS group was impaired compared to HC, and executive performance was dependent on body position. Individuals performed worse when standing legs-crossed. Hence, impaired proprioception as present in hEDS may, along with comorbid conditions such as pain, be a contributing factor affecting executive function.
Clin Auton Res
· 2026 Jun · PMID 41772339
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PURPOSE: 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 underdiagno...PURPOSE: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.
Kaufmann H, Palma JA, Millar Vernetti P
… +22 more, Kuijpers M, Nkrumah G, Kang UJ, Ma T, Betensky RA, Claassen DO, Vemuri P, Trujillo P, Siderowf A, Soto C, Feigin AS, Stebbins GT, Lindahl J, Qureshi I, Berger AK, Husnik M, Fanciulli A, Poewe W, Krismer F, Biaggioni I, Singer W, MuSyCA Working Group
Clin Auton Res
· 2026 Apr · PMID 41762390
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PURPOSE: The Unified Multiple System Atrophy Rating Scale (UMSARS) is widely used as an outcome measure in MSA trials, but it has limitations for clinical trial use. To address these, we developed the Multiple System Atr...PURPOSE: The Unified Multiple System Atrophy Rating Scale (UMSARS) is widely used as an outcome measure in MSA trials, but it has limitations for clinical trial use. To address these, we developed the Multiple System Atrophy Combined Outcome Assessment (MuSyCA), a comprehensive multimodal tool for disease-modifying MSA trials. The purpose of this manuscript is to describe the development and validation plan for MuSyCA, with emphasis on its structure, intended use, and assessment of reliability, validity, and sensitivity in tracking disease progression. METHODS: The development of MuSyCA followed a multistep process. Candidate outcome assessments were identified through systematic literature review and analysis of longitudinal data from large MSA cohorts. Content was refined through multiple Delphi-like consensus rounds involving MSA experts, patient advocacy groups representatives, and industry stakeholders. Cognitive interviews conducted in 20 patients with MSA evaluated the clarity and clinical relevance of patient- and clinician-reported outcomes; feedback was incorporated into a subsequent version of the MuSyCA. Validation is ongoing and includes assessment of construct validity, internal consistency, test-retest reliability, and responsiveness. Longitudinal analyses to determine sensitivity to change over time are ongoing. RESULTS: MuSyCA combines patient- and clinician-reported outcomes, biomarkers (neurofilament light chain, neuroimaging), and performance-based measures to capture subjective and objective aspects of MSA progression, enhancing its utility to detect treatment effects in clinical trials. MuSyCa is not intended to be used in clinical practice. CONCLUSIONS: MuSyCA offers a multidimensional approach to MSA assessment, supporting precise, disease-relevant evaluations in trials of putative disease-modifying therapies. Its validation will provide a standardized multimodal outcome measure, advancing MSA therapeutic development.
Crouch TB, Nguyen M, Wells M
… +8 more, Redman T, Ashar Y, Schubiner H, Westcott G, Kinser P, Maxwell M, Chelimsky G, Chelimsky T
Clin Auton Res
· 2026 Jun · PMID 41758479
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PURPOSE: Postural tachycardia syndrome (POTS) is a chronic disorder marked by excessive orthostatic tachycardia, without clear structural/organic (e.g., cardiovascular) etiology. Recent evidence suggests that persistent...PURPOSE: Postural tachycardia syndrome (POTS) is a chronic disorder marked by excessive orthostatic tachycardia, without clear structural/organic (e.g., cardiovascular) etiology. Recent evidence suggests that persistent autonomic symptoms may be driven by threat-induced and central nervous system-maintained dysregulation, similar to centralized chronic pain disorders. This study describes the rationale and development process of a brain-body intervention-POts Reprocessing Therapy (PORT)-aimed at reducing orthostatic symptomatology by taking advantage of the brain's plasticity. METHODS: PORT was adapted from pain reprocessing therapy (PRT), an evidence-based mind-body approach for treating centralized chronic pain. The initial protocol was developed through consultations with multidisciplinary experts, including the developers of PRT. To refine the protocol, a focus group was conducted with five women participants with POTS who underwent an early version of PORT. Rapid qualitative analysis was conducted to identify themes and inform intervention improvements. RESULTS: The intervention consists of a medical evaluation followed by eight weekly treatment sessions. Intervention components include psychoeducation, safety learning-based exposure to symptoms, somatic inquiry, and emotional processing. Focus group participants identified reduced fear about symptoms, greater understanding of their condition, and improved functioning. Participants provided suggestions around language and content, and some shared emotional challenges of the treatment, underscoring the need for sensitive provider communication and implementation. CONCLUSION: This study introduces a novel therapeutic treatment for POTS that targets centrally mediated processes hypothesized to underlie persistent autonomic dysregulation. Trials are underway to formally assess feasibility, acceptability, and efficacy.
Bastos P, Kermorgant M, Fabbri M
… +10 more, Roche F, Pichot V, Ory-Magne F, Leung C, Rascol O, Meissner WG, Foubert-Samier A, Bendetowicz D, Proust Lima C, Pavy-le-Traon A
Clin Auton Res
· 2026 Jun · PMID 41731258
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PURPOSE: Multiple system atrophy (MSA) is a progressive neurodegenerative disorder characterized by autonomic dysfunction, parkinsonism, and cerebellar impairment. Understanding the physiological correlates of disease se...PURPOSE: Multiple system atrophy (MSA) is a progressive neurodegenerative disorder characterized by autonomic dysfunction, parkinsonism, and cerebellar impairment. Understanding the physiological correlates of disease severity and survival remains challenging due to heterogeneity in disease progression. Heart rate variability (HRV) is a noninvasive measure of autonomic nervous system function. However, the role of nonlinear HRV in MSA remains incompletely understood. METHODS: This study investigated the association between HRV features, clinical severity, and survival in MSA (n = 214). Regression models were used to examine relationships between HRV and disease severity assessed by the Unified MSA Rating Scale (UMSARS), as well as time to death. Survival analyses evaluated the contribution of HRV features to risk stratification, and mediation analysis explored the relationships among HRV, UMSARS, and survival. RESULTS: HRV features were negatively associated with disease severity, consistent with progressive autonomic dysfunction. While individual HRV features showed limited associations with UMSARS, their combination demonstrated a stronger relationship. Models incorporating HRV features showed associations with time to death comparable to those based on UMSARS, and the combined inclusion of HRV and UMSARS was associated with improved accuracy. Mediation analyses suggested that HRV captures physiological information related to survival that is not fully reflected by clinical severity scores. CONCLUSIONS: HRV features are associated with disease severity and survival in MSA and provide complementary physiological information beyond established clinical scales. These findings support the relevance of HRV as an exploratory modeling tool for autonomic dysfunction in MSA and highlight candidate features for future longitudinal and validation studies, rather than establishing a validated prognostic model.
Dos Santos Machado LR, Guedes Jesus IC, Eliezeck M
… +9 more, de Godoy ACV, da Silva Cruz MH, Pinho V, de Miranda AS, Peruchetti DB, Campagnole-Santos MJ, Dos Santos RAS, Guatimosim S, Fontes MAP
Clin Auton Res
· 2026 Apr · PMID 41701299
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Habek M, Fanciulli A, Pavy-Le Traon A
… +25 more, Struhal W, Krbot Skorić M, Crnošija L, Adamec I, Bozzali M, Falup-Pecurariu C, Jordan J, Kaal E, Wenning GK, Calandra Buonaura G, Chiaro G, Cortelli P, Guaraldi P, Hilz MJ, Iodice V, Terkelsen AJ, Kamondi A, Milner MSD, Carneiro DR, Rocchi C, Rocha I, Rzepiński Ł, Stanković I, Tijero B, Thijs RD
Clin Auton Res
· 2026 Jun · PMID 41665778
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PURPOSE: The growing recognition of autonomic nervous system (ANS) dysfunction across a broad spectrum of neurological and systemic diseases calls for structured, multidisciplinary care. This position statement by the Eu...PURPOSE: The growing recognition of autonomic nervous system (ANS) dysfunction across a broad spectrum of neurological and systemic diseases calls for structured, multidisciplinary care. This position statement by the European Federation of Autonomic Societies aims to provide guidance on establishing an autonomic unit within a neurology department. METHODS: A Task Force appointed by the European Federation of Autonomic Societies board in October 2022 proposed staffing and equipment requirements for autonomic units, based on a literature review, survey data from ANS laboratories, and existing diagnostic guidelines. These propositions were integrated into the initial 25 questions and refined using a modified Delphi method to achieve expert consensus. Consensus was predefined as ≥ 80% agreement. Statements that did not reach consensus were revised and reassessed in subsequent rounds. RESULTS: After three rounds of Delphi surveys, expert consensus was achieved on the minimal and optimal requirements for autonomic unit personnel, technical equipment, and the availability of multidisciplinary care. CONCLUSION: This European Federation of Autonomic Societies position statement presents practical, expert-based recommendations to promote the development of autonomic units across various healthcare systems. By establishing minimum and optimal standards for staffing, equipment, and interdisciplinary collaboration, the document offers a clear framework for standardizing clinical care and supporting collaborative research. This statement serves as a foundational resource for clinicians, administrators, and policymakers committed to strengthening the ANS care infrastructure.
Chelimsky G, Thayer JF, Williams DP
… +2 more, Kang L, Chelimsky T
Clin Auton Res
· 2026 Jun · PMID 41642542
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BACKGROUND: Disorders of gut-brain interaction (DGBI) are common in pediatrics. Though the name clearly implies a neural contribution, the role of the autonomic nervous system remains unclear. Heart rate in healthy subje...BACKGROUND: Disorders of gut-brain interaction (DGBI) are common in pediatrics. Though the name clearly implies a neural contribution, the role of the autonomic nervous system remains unclear. Heart rate in healthy subjects (HC) follows a circadian pattern with dipping during the night with increased high frequency (hf) heart rate variability (HRV) and root mean square of successive differences (RMSSD). Our hypothesis was that reduced vagal modulation in adolescents with DGBI is associated with blunted rise in nocturnal vagal modulation. METHODS: An institutional review board (IRB) approved this study, which included children aged 12-18 years with a DGBI and carefully screened HC. All subjects underwent 24 h HRV recording. The following questionnaires/tools were included: Pain Catastrophizing Scale for Children (PCS-C), Pain Catastrophizing Scale for Parents (PCS-P), Revised Child Anxiety and Depression Scale (RCADS), Trauma Symptom Checklist for Children (TSCC), and Functional Disability Inventory (FDI). RESULTS: In total, 12 HC and 15 participants with DGBI participated (female individuals with DGBI versus HC: 93% versus 58%, p = 0.08). There was no age difference (median [range] HC 16.6 years [13.4, 18.2]; DGBI 16.8 years [13.8, 18.7], p = 0.92). The 24 h, daytime and nighttime HRV demonstrated that RMSSD, low-frequency (lf) HRV, and high-frequency (hf) HRV were lower in the DGBI group (p < 0.001). A nocturnal rise in RMSSD was present in the DGBI group, but less so in the HC group (p = 0.021). Higher catastrophizing correlated with lower nocturnal RMSSD (PCS-C correlation coefficient [CC]: -0.46), depression (RCADS depression CC: -0.51), and post-traumatic stress disorder (PTSD; TSCC PTSD CC: -0.58). CONCLUSIONS: HRV is reduced in patients with DGBI with a blunted rise in nocturnal RMSSD at night. As expected, vagal modulation is inversely correlated with catastrophizing, depression, PTDS, and FDI, with nocturnal HRV showing generally better correlations than daytime HRV.
Barkoula TR, Ioannou C, Rekatsina M
… +2 more, Theodoraki K, Zis P
Clin Auton Res
· 2026 Apr · PMID 41557119
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PURPOSE: Many methods have been developed for the assessment of dysautonomia, but they are often unreliable and not readily applicable to daily practice. Among the available investigation methods, the Ewing battery, whic...PURPOSE: Many methods have been developed for the assessment of dysautonomia, but they are often unreliable and not readily applicable to daily practice. Among the available investigation methods, the Ewing battery, which includes five non-invasive cardiovascular reflex tests, have become the reference standard in assessing dysautonomia and have been utilized for more than four decades. This systematic review evaluates the diagnostic thresholds and diagnostic performance of Ewing tests across studies in identifying autonomic nervous system (ANS) disorders. METHODS: We conducted a comprehensive multi-database literature search, including PubMed, EMBASE, Web of Science, Scopus, and the Cochrane Library, using a pre-defined search strategy, for studies that applied the Ewing tests to assess autonomic dysfunction. We focused on studies that used continuous recordings and those reporting extractable numerical data, including either normative values or diagnostic cutoff thresholds for the Ewing tests. The Ewing parameters that were tested were Valsalva manoeuvre, heart rate variability during deep breathing (E/I ratio), the isometric handgrip, heart rate response to standing (30:15 ratio) and blood pressure response to standing. RESULTS: Our analysis demonstrates good diagnostic performance of the Ewing tests, with sensitivity for individual components reaching up to 91% for Valsalva ratio (VR) in some cohorts. The normative data and respective cutoff points are influenced by age and sex. Optimal diagnostic performance was achieved when the Ewing battery was interpreted using the conventional criterion of ≥ 2/5 abnormal tests particularly when age-adjusted cutoffs were applied. CONCLUSION: The Ewing battery remains a highly effective tool for diagnosing ANS disorders, especially when age-adjusted normative thresholds are used. To further enhance its diagnostic performance, each laboratory should establish its own normative data reflective of the specific population it serves.