Interventions aimed to increase average 24-h systolic blood pressure reduce blood pressure drops in patients with reflex syncope and orthostatic intolerance.

AIMS: Systolic blood pressure (SBP) drops recorded by 24-h ambulatory blood pressure (BP) monitoring (ABPM) identify patients with susceptibility to reflex syncope and orthostatic intolerance. We tested the hypothesis that treatments aimed to increase BP (reassurance, education, and lifestyle measures plus pharmacological strategies) can reduce SBP drops. METHODS AND RESULTS: This was a multicentre, observational proof-of-concept study performed in patients with reflex syncope and/or orthostatic intolerance and with SBP drops on a screening ABPM. Among 144 eligible patients, 111 underwent a second ABPM on average 2.5 months after start of treatment. Overall, mean 24-h SBP increased from 114.1 ± 12.1 to 121.4 ± 14.5 mmHg (P < 0.0001). The number of SBP drops <90 and <100 mmHg decreased by 61%, 46% during daytime, and by 48% and 37% during 24-h period, respectively (P < 0.0001 for all). The dose-response relationship between difference in 24-h average SBP increase and reduction in number of SBP drops reached a plateau around ∼15 mmHg increase of 24-h SBP. The reduction in SBP drop rate was consistent and significant in patients who underwent deprescription of hypotensive medications (n = 44) and in patients who received BP-rising drugs (n = 67). CONCLUSION: In patients with reflex syncope and/or orthostatic intolerance, an increase in average 24-h SBP, regardless of the implemented strategy, significantly reduced the number of SBP drops and symptom burden. A 13 mmHg increase in 24-h SBP appears to represent the optimal goal for aborting the maximal number of SBP drops, representing a possible target for future interventions. ClincalTrials.gov identifier: NCT05729724.

Pyridostigmine for the Management of Neurogenic Orthostatic Hypotension: A Systemic Review.

BACKGROUND: Pyridostigmine is hypothesized to improve neurogenic orthostatic hypotension (nOH) symptoms without causing or exacerbating supine hypertension. The objective of this review was to evaluate the safety and efficacy of pyridostigmine for management of nOH. METHODS: A literature search of PubMed, Embase, and CENTRAL was performed in December 2023 for prospective trials with a placebo or active comparator. RESULTS: Four randomized and two non-randomized studies were reviewed. Three studies utilizing a single dose, crossover design found significant differences of orthostatics using adjunctive pyridostigmine. Two studies assessing longer-term endpoints demonstrated conflicting efficacy of pyridostigmine with one trial finding significant improvement in orthostatics and symptoms after three months of therapy. Use of pyridostigmine did not lead to supine hypertension with most adverse effects being cholinergic. CONCLUSION: Pyridostigmine may be considered as an adjunctive medication in individuals with nOH refractory to standard treatment options as it carries a favorable safety profile with low risk for supine hypertension.

Bridging the gap in BASCULE syndrome: A retrospective case series of a recently described clinical entity.

BACKGROUND: Bier anemic spots, cyanosis with urticaria-like eruption (BASCULE) syndrome is a recently described entity with episodic urticarial lesions and white anemic halos on a background of erythrocyanosis, commonly affecting the lower extremities. Possible association with autonomic dysfunction remains poorly understood. Existing publications are limited, but the condition is suggested as highly underrecognized. OBJECTIVE: To further characterize clinical and epidemiologic data for BASCULE syndrome. METHODS: We performed an IRB-approved retrospective chart review on patients with BASCULE syndrome evaluated at Mayo Clinic from April 2021 to November 2022. RESULTS: A total of 17 patients were identified (13 female, 4 male). Median age of onset was 12 years (range 9-17). Lower extremities were involved in all patients (17). Most patients were symptomatic with pruritus (8) or burning pain (8); three were asymptomatic. Triggers were standing (11), hot showers or hot environments (7), or no clear trigger (4). Autonomic dysfunction was present in 10 patients. Treatment responses were observed from propranolol (3) and high-dose cetirizine (1). CONCLUSION: Novel epidemiologic data from 17 pediatric and young adult patients with BASCULE syndrome further supports an association with autonomic dysfunction and suggests a higher prevalence than previously acknowledged.

Time-course of heart rate variability after total hip arthroplasty.

Heart rate variability (HRV) is a measure of the autonomic nervous system function and possibly related to postoperative outcome. Despite several HRV studies in different surgical settings, optimal indices and timepoints for measuring have not been adequately determined. Consequently, there is a need for detailed descriptive procedure-specific studies on the time-course of perioperative HRV within a modern fast-track surgical setting. We measured HRV continuously in 24 patients from 4 days before until 9 days after total hip arthroplasty (THA). Statistical methods included mainly ANOVA and t-tests or Kruskal-Wallis and pairwise Wilcoxon test. Patients completed the Orthostatic Discriminant and Severity Scale five times during the study describing autonomic nervous system dysfunction. Standard deviation between normal-to-normal beats and the total power of HRV were reduced for at least 9 days following THA, with a trend towards increased HRV leading up to the day of surgery. The balance between low- and high-frequency power of HRV was reduced in the postoperative evenings. There was increased orthostatic intolerance symptoms on the first postoperative day, with symptoms of pain, fatigue and weakness decreasing after the first postoperative day. Median hospital stay was 1 day. We provide the first detailed description of perioperative time-course of HRV and orthostatic symptoms in fast-track THA, showing reduced HRV after surgery for at least a week, and that HRV changes are sensitive to time of day and timing before and after surgery. These results are helpful in designing future HRV studies in perioperative risk assessment and outcome.

Differences in Heart Rate Variability in the Frequency Domain between Different Groups of Patients.

Background and Objectives: Heart rate variability (HRV) is defined as a physiological variation in duration between sinus beats. The aim of this study was to research and analyze the HRV between various groups of patients. Materials and Methods: A retrospective study was conducted in an outpatient setting. Patients who had undergone a tilt-table test were selected for this study and were divided into three groups based on their self-reported health anamnesis: group 1 (n = 84, mean age 45.8 ± 17.8) consisted of patients with no known orthostatic intolerance or neurodegenerative disease, group 2 consisted of patients with a known or suspected orthostatic intolerance (n = 50, mean age 46.5 ± 18.6), and group 3 consisted of patients with a known or suspected neurodegenerative disorder (n = 29, mean age 55.6 ± 20.4). During the tilt-table test, HRV frequency-domain parameters-normalized low frequency (LFnu) and high frequency (HFnu), absolute powers-absolute low frequency (LF-RRI), absolute high frequency (HF-RRI), and LF/HF ratio-were recorded during 5 min rest in the supine position. Results: Group 1 had a reduced LFnu at 52.93% (SD: 18.00) compared to group 2 at 58.57% (18.06) and group 3 at 61.80% (SD: 17.74), and group 1 had increased HFnu: group 1-47.08% (SD: 17.97), group 2-41.41% (SD: 18.03), and group 3-38.16% (SD: 14.7). LFnu and HFnu differences were statistically significant (p < 0.05). LF-RRI was reported as follows: group 1-531.32 ms2 (SD: 578.57), group 2-346.2 ms2 (SD: 447.96), and group 3-143.21 ms2 (SD: 166.96). HF-RRI was reported as follows: group 1-835.87 ms2 (SD: 1625.42), group 2-297.46 ms2 (SD: 507.15), and group 3-70.83 ms2 (SD: 75.67). LF-RRI and HF-RRI comparisons between groups were statistically significant (p < 0.001). LF/HF ratios were reported as follows: group 1-1.91 (SD: 2.29), group 2-2.43 (SD: 2.33), and group 3-2.54 (SD: 2.17). LF/HF ratio comparisons between groups were statistically significant at p < 0.05. Conclusions: This study shows that patients with known or suspected orthostatic intolerance and neurodegenerative disorders have reduced HRV, possibly caused by reduced parasympathetic modulation. HRV in patients with known or suspected neurodegenerative disorders is reduced more severely than in patients with orthostatic disorders. Other studies in HRV have indicated a possible increase of risk in cardiovascular disorders in patients with reduced HRV, and therefore, HRV analysis could be a potential clinical diagnostic tool. However, the lack of universally agreed upon methodology, reference values, and possible external and internal factor influence hinders the introduction of HRV examinations into wider clinical practice.

Fear conditioning as a pathogenic mechanism in the postural tachycardia syndrome.

Despite its increasing recognition and extensive research, there is no unifying hypothesis on the pathophysiology of the postural tachycardia syndrome. In this cross-sectional study, we examined the role of fear conditioning and its association with tachycardia and cerebral hypoperfusion on standing in 28 patients with postural tachycardia syndrome (31 ± 12 years old, 25 females) and 21 matched controls. We found that patients had higher somatic vigilance (P = 0.0167) and more anxiety (P < 0.0001). They also had a more pronounced anticipatory tachycardia right before assuming the upright position in a tilt-table test (P = 0.015), a physiological indicator of fear conditioning to orthostasis. While standing, patients had faster heart rate (P < 0.001), higher plasma catecholamine levels (P = 0.020), lower end-tidal CO2 (P = 0.005) and reduced middle cerebral artery blood flow velocity (P = 0.002). Multi-linear logistic regression modelling showed that both epinephrine secretion and excessive somatic vigilance predicted the magnitude of the tachycardia and the hyperventilation. These findings suggest that the postural tachycardia syndrome is a functional disorder in which standing may acquire a frightful quality, so that even when experienced alone it may elicit a fearful conditioned response. Heightened somatic anxiety is associated with and may predispose to a fear-conditioned hyperadrenergic state when standing. Our results have therapeutic implications.

Assessment of comorbid symptoms in pediatric autonomic dysfunction.

PURPOSE: Pediatric patients with autonomic dysfunction and orthostatic intolerance (OI) often present with co-existing symptoms and signs that might or might not directly relate to the autonomic nervous system. Our objective was to identify validated screening instruments to characterize these comorbidities and their impact on youth functioning. METHODS: The Pediatric Assembly of the American Autonomic Society reviewed the current state of practice for identifying symptom comorbidities in youth with OI. The assembly includes physicians, physician-scientists, scientists, advanced practice providers, psychologists, and a statistician with expertise in pediatric disorders of OI. A total of 26 representatives from the various specialties engaged in iterative meetings to: (1) identify and then develop consensus on the symptoms to be assessed, (2) establish committees to review the literature for screening measures by member expertise, and (3) delineate the specific criteria for systematically evaluating the measures and for making measure recommendations by symptom domains. RESULTS: We review the measures evaluated and recommend one measure per system/concern so that assessment results from unrelated clinical centers are comparable. We have created a repository to apprise investigators of validated, vetted assessment tools to enhance comparisons across cohorts of youth with autonomic dysfunction and OI. CONCLUSION: This effort can facilitate collaboration among clinical settings to advance the science and clinical treatment of these youth. This effort is essential to improving management of these vulnerable patients as well as to comparing research findings from different centers.

Poor health-related quality of life in postural orthostatic tachycardia syndrome in comparison with a sex- and age-matched normative population.

PURPOSE: The effect of postural orthostatic tachycardia syndrome (POTS) on health-related quality of life (HrQoL) remains poorly studied. Here, we sought to compare the HrQoL in individuals with POTS to a normative age-/sex-matched population. METHODS: Participants enrolled in the Australian POTS registry between 5 August 2021 and 30 June 2022 were compared with propensity-matched local normative population data from the South Australian Health Omnibus Survey. The EQ-5D-5L instrument was used to assess HrQoL across the five domains (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression) with global health rating assessed with a visual analog scale (EQ-VAS). A population-based scoring algorithm was applied to the EQ-5D-5L data to calculate utility scores. Hierarchical multiple regression analyses were undertaken to explore predictors of low utility scores. RESULTS: A total of 404 participants (n = 202 POTS; n = 202 normative population; median age 28 years, 90.6% females) were included. Compared with the normative population, the POTS cohort demonstrated significantly higher burden of impairment across all EQ-5D-5L domains (all P < 0.001), lower median EQ-VAS (p < 0.001), and lower utility scores (p < .001). The lower EQ-VAS and utility scores in the POTS cohort were universal in all age groups. Severity of orthostatic intolerance symptoms, female sex, fatigue scores, and comorbid diagnosis of myalgic encephalomyelitis/chronic fatigue syndrome were independent predictors of reduced HrQoL in POTS. The disutility in those with POTS was lower than many chronic health conditions. CONCLUSIONS: This is the first study to demonstrate significant impairment across all subdomains of EQ-5D-5L HrQoL in the POTS cohort as compared with a normative population. TRIAL REGISTRATION: ACTRN12621001034820.

Cognitive functioning in postural orthostatic tachycardia syndrome among different body positions: a prospective pilot study (POTSKog study).

PURPOSE: Approximately 96% of patients with postural orthostatic tachycardia syndrome (PoTS) report cognitive complaints. We investigated whether cognitive function is impaired during sitting and active standing in 30 patients with PoTS compared with 30 healthy controls (HCs) and whether it will improve with the counter manoeuvre of leg crossing. METHODS: In this prospective pilot study, patients with PoTS were compared to HCs matched for age, sex, and educational level. Baseline data included norepinephrine plasma levels, autonomic testing and baseline cognitive function in a seated position [the Montreal Cognitive Assessment, the Leistungsprüfsystem (LPS) subtests 1 and 2, and the Test of Attentional Performance (TAP)]. Cognitive functioning was examined in a randomized order in supine, upright and upright legs crossed position. The primary outcomes were the cognitive test scores between HCs and patients with PoTS at baseline testing, and among the different body positions. RESULTS: Patients with PoTS had impaired attention (TAP median reaction time) in the seated position and impaired executive functioning (Stroop) while standing compared with HC. Stroop was influenced by position (supine versus upright versus upright legs crossed) only in the PoTS group. Leg crossing did not result in an improvement in executive function. In patients with PoTS, there was a negative correlation of Stroop with norepinephrine plasma levels while standing. CONCLUSION: Compared with HCs, PoTS participants showed impaired cognitive attention and executive function in the upright position that did not improve in the legs crossed position. Data provide further evidence for orthostatic cognitive deterioration in patients with PoTS. TRIAL REGISTRATION INFORMATION: The study was registered at ClinicalTrials.gov (NCT03681080).

Alterations in short-term blood pressure variability related to disease severity and autonomic symptoms in myasthenia gravis patients.

OBJECTIVES: We aimed to evaluate beat-to-beat blood pressure variability (BPV) during head-up tilt test (HUTT) in patients with mild and moderate myasthenia gravis (MG) compared to healthy controls (HCs), and its association with the severity of autonomic symptoms. METHODS: A total of 50 MG patients and 30 HCs were evaluated. Patients were stratified into 2 groups regarding Myasthenia Gravis Foundation of America (MGFA) classification: mild (I,II MGFA), moderate form (III MGFA). Autonomic symptoms were assessed by COMPASS-31 questionnaire. Cardiovascular parameters, indices of very short-term systolic (SBPV), and diastolic blood pressure (BP) variability (DBPV) were assessed at rest, and during HUTT. RESULTS: Moderate MG patients were characterized by an overall shift of sympathovagal balance toward sympathetic predominance, either at rest and during HUTT, as well as lower values of high frequency (HFnu) of DBPV during HUTT, compared to HCs and mild MG. Similarly, moderate MG showed higher resting low frequency (LFnu) of DBPV (p=0.035), higher COMPASS-31 score (p=0.031), and orthostatic intolerance sub-score (p=0.019) than mild MG patients. Compared to HCs, mild MG patients showed lower Δmean BP (p=0.029), Δdiastolic BP (p=0.016). Autonomic symptoms were associated with lower BP values, at rest and during HUTT, and lower LF BPV parameters during HUTT. CONCLUSION: MG patients present significant alterations in BPV, both at rest and in response to orthostatic stress, which are related to autonomic symptoms and disease severity. This study confirms the importance of monitoring BPV when evaluating cardiovascular autonomic function and its evolution over the course of MG disease.

Orthostatic intolerance after acute mild hypovolemia: incidence, pathophysiologic hemodynamics, and heart-rate variability analysis-a prospective observational cohort study.

PURPOSE: Early postoperative mobilization can be hindered by orthostatic intolerance (OI). Postoperative OI has multifactorial pathogenesis, possibly involving both postoperative hypovolemia and autonomic dysfunction. We aimed to investigate the effect of mild acute blood loss from blood donation simulating postoperative hypovolemia, on both autonomic function and OI, thus eliminating confounding perioperative factors such as inflammation, residual anesthesia, pain, and opioids. METHODS: This prospective observational cohort study included 26 blood donors. Continuous electrocardiogram data were collected during mobilization and night sleep, both before and after blood donation. A Valsalva maneuver and a standardized mobilization procedure were performed immediately before and after blood donation, during which cardiovascular and tissue oxygenation variables were continuously measured by LiDCOrapid™ and Massimo Root™, respectively. The incidence of OI, hemodynamic responses during mobilization and Valsalva maneuver, as well as heart rate variability (HRV) responses during mobilization and sleep were compared before and 15 min after blood donation. RESULTS: Prior to blood donation, no donors experienced OI during mobilization. After blood donation, 6/26 (23%; 95% CI, 9 to 44) donors experienced at least one OI symptom. Three out of 26 donors (12%; 95% CI, 2 to 30) terminated the mobilization procedure prematurely because of severe OI symptoms. Cardiovascular and cerebral tissue oxygenation responses were reduced in patients with severe OI. After blood loss, HRV indices of total autonomic power remained unchanged but increased sympathetic and decreased parasympathetic outflow was observed during mobilization, but also during sleep, indicating a prolonged autonomic effect of hypovolemia. CONCLUSION: We describe a specific hypovolemic component of postoperative OI, independent of postoperative autonomic dysfunction, inflammation, opioids, and pain. STUDY REGISTRATION: ClinicalTrials.gov (NCT04499664); registered 5 August 2020.

RéSUMé: OBJECTIF: La mobilisation postopératoire précoce peut être entravée par une intolérance orthostatique (IO). L'IO postopératoire a une pathogenèse multifactorielle, impliquant peut-être à la fois une hypovolémie postopératoire et un dysfonctionnement autonome. Notre objectif était d'étudier l'effet d'une légère perte de sang aiguë due au don de sang simulant une hypovolémie postopératoire, à la fois sur la fonction autonome et sur l'IO, éliminant ainsi les facteurs périopératoires confondants tels que l'inflammation, l'anesthésie résiduelle, la douleur et les opioïdes. MéTHODE: Cette étude de cohorte observationnelle prospective comprenait 26 personnes ayant donné leur sang. Des données d'électrocardiogramme continu ont été recueillies pendant la mobilisation et le sommeil nocturne, avant et après le don de sang. Une manœuvre de Valsalva et une procédure de mobilisation standardisée ont été réalisées immédiatement avant et après le don de sang, au cours desquelles les variables d'oxygénation cardiovasculaire et tissulaire ont été mesurées en continu avec les moniteurs LiDCOrapid™ et Massimo Root™, respectivement. L'incidence d'IO, les réponses hémodynamiques pendant la mobilisation et la manœuvre de Valsalva, ainsi que les réponses de variabilité de la fréquence cardiaque (VFC) pendant la mobilisation et le sommeil ont été comparées avant et 15 minutes après le don de sang. RéSULTATS: Avant le don de sang, aucune personne ayant fait un don de sang n'a ressenti d'IO pendant la mobilisation. Après le don de sang, 6/26 (23 %; IC 95 %, 9 à 44) des donneurs et donneuses ont manifesté au moins un symptôme d'IO. Trois personnes sur 26 (12 %; IC 95 %, 2 à 30) ont interrompu prématurément la procédure de mobilisation en raison de symptômes graves d'IO. Les réponses d'oxygénation des tissus cardiovasculaires et cérébraux ont été réduites chez les personnes atteintes d'IO sévère. Après la perte de sang, les indices de VFC de la puissance totale autonome sont demeurés inchangés, mais une augmentation du flux sympathique et une diminution du flux parasympathique ont été observées pendant la mobilisation, mais également pendant le sommeil, indiquant un effet autonome prolongé de l'hypovolémie. CONCLUSION: Nous décrivons une composante spécifique hypovolémique de l'IO postopératoire, indépendante du dysfonctionnement autonome postopératoire, de l'inflammation, des opioïdes et de la douleur. ENREGISTREMENT DE L'éTUDE: www.ClinicalTrials.gov (NCT04499664); enregistrée le 5 août 2020.

Prevalence and associated factors of postoperative orthostatic intolerance at University of Gondar Comprehensive Specialized Hospital, Northwest Ethiopia, 2022: cross sectional study.

BACKGROUND: Postoperative orthostatic intolerance is an inability to maintain an upright position because of symptoms of cerebral hypoperfusion. It is a common problem in the early postoperative period and hinders early mobilization, however, there is limited information about factors associated with it. Thus, the main aim of this study was to determine the prevalence and identify factors associated with postoperative orthostatic intolerance. METHOD: Hospital based cross-sectional study was conducted from April 08 to July 20, 2022, at University of Gondar comprehensive Specialized Hospital. A semi-structured questionnaire containing sociodemographic variables and perioperative factors related to anesthesia and surgery was used for data collection. The presence of postoperative orthostatic intolerance during the first ambulation was evaluated with a standardized symptom checklist which contains symptoms of orthostatic intolerance. Binary logistic regression analysis was performed to assess factors associated with postoperative orthostatic intolerance. In multivariable regression, variables with P-value < 0.05 were considered statistically significant. RESULT: A total of 420 patients were included in this study with a response rate of 99.06%. Postoperative orthostatic intolerance was experienced in 254 (60.5%) participants. Being female (AOR = 2.27; 95% CI = 1.06-4.86), low BMI (AOR = 0.79; 95% CI = 0.71-0.95), ASA II and above (AOR = 3.34; 95% CI = 1.34-8.28), low diastolic blood pressure (AOR = 0.82; 95% CI = 0.88-0.99), general anesthesia (AOR = 3.26, 95% CI = 1.31-8.12), high intraoperative blood lose (AOR = 0.93, 95% CI = 0.88-0.99), high postoperative fluid intake (AOR = 2.09, 95% CI = 1.23-3.55), pain before ambulation (AOR = 1.99, 95% CI = 1.28-3.11) and pain during ambulation (AOR = 1.82, 95% CI = 1.23-2.69) were the significant factors associated with orthostatic intolerance. CONCLUSION: Our study revealed that postoperative orthostatic intolerance was experienced in nearly two-thirds of participants. During the time of ambulation, assessing patients for the presence of orthostatic intolerance is necessary to reduce the adverse effects of postoperative OI. In addition, maintaining preoperative normotension, reducing intraoperative blood loss and optimizing postoperative pain control is recommended to reduce the risk of postoperative orthostatic intolerance.

Continuous perioperative heart rate variability monitoring in video-assisted thoracoscopic surgery lobectomy-a pilot study.

Heart rate variability (HRV) is a measure of cardiac autonomic modulation and is potentially related to hypotension, postoperative atrial fibrillation, and orthostatic intolerance. However, there is a lack of knowledge on which specific time points and indices to measure. To improve future study design, there is a need for procedure-specific studies in an enhanced recovery after surgery (ERAS) video-assisted thoracic surgery (VATS) lobectomy setting, and for continuous measurement of perioperative HRV. HRV was measured continuously from 2 days before until 9 days after VATS lobectomy in 28 patients. After VATS lobectomy, with median length of stay = 4 days, the standard deviation between normal-to-normal beats and the total power of HRV were reduced for 8 days during the night and day times, while low-to-high frequency variation and detrended fluctuation analysis were stable. This is the first detailed study to show that HRV measures of total variability were reduced following ERAS VATS lobectomy, while other measures were more stable. Further, preoperative HRV measures showed circadian variation. The patch was well tolerated among participants, but actions should be taken to ensure proper mounting of the measuring device. These results demonstrate a valid design platform for future HRV studies in relation to postoperative outcomes.

Detection of Elevated Level of Tetrahydrobiopterin in Serum Samples of ME/CFS Patients with Orthostatic Intolerance: A Pilot Study.

Myalgic encephalomyelitis or chronic fatigue syndrome (ME/CFS) is a multisystem chronic illness characterized by severe muscle fatigue, pain, dizziness, and brain fog. Many patients with ME/CFS experience orthostatic intolerance (OI), which is characterized by frequent dizziness, light-headedness, and feeling faint while maintaining an upright posture. Despite intense investigation, the molecular mechanism of this debilitating condition is still unknown. OI is often manifested by cardiovascular alterations, such as reduced cerebral blood flow, reduced blood pressure, and diminished heart rate. The bioavailability of tetrahydrobiopterin (BH4), an essential cofactor of endothelial nitric oxide synthase (eNOS) enzyme, is tightly coupled with cardiovascular health and circulation. To explore the role of BH4 in ME/CFS, serum samples of CFS patients (n = 32), CFS patients with OI only (n = 10; CFS + OI), and CFS patients with both OI and small fiber polyneuropathy (n = 12; CFS + OI + SFN) were subjected to BH4 ELISA. Interestingly, our results revealed that the BH4 expression is significantly high in CFS, CFS + OI, and CFS + OI + SFN patients compared to age-/gender-matched controls. Finally, a ROS production assay in cultured microglial cells followed by Pearson correlation statistics indicated that the elevated BH4 in serum samples of CFS + OI patients might be associated with the oxidative stress response. These findings suggest that the regulation of BH4 metabolism could be a promising target for understanding the molecular mechanism of CFS and CFS with OI.

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and Comorbidities: Linked by Vascular Pathomechanisms and Vasoactive Mediators?

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is often associated with various other syndromes or conditions including mast cell activation (MCA), dysmenorrhea and endometriosis, postural tachycardia (POTS) and small fiber neuropathy (SFN). The causes of these syndromes and the reason for their frequent association are not yet fully understood. We previously published a comprehensive hypothesis of the ME/CFS pathophysiology that explains the majority of symptoms, findings and chronicity of the disease. We wondered whether some of the identified key pathomechanisms in ME/CFS are also operative in MCA, endometriosis and dysmenorrhea, POTS, decreased cerebral blood flow and SFN, and possibly may provide clues on their causes and frequent co-occurrence. Our analysis indeed provides strong arguments in favor of this assumption, and we conclude that the main pathomechanisms responsible for this association are excessive generation and spillover into the systemic circulation of inflammatory and vasoactive tissue mediators, dysfunctional ß2AdR, and the mutual triggering of symptomatology and disease initiation. Overall, vascular dysfunction appears to be a strong common denominator in these linkages.

Worsening Symptoms Is Associated with Larger Cerebral Blood Flow Abnormalities during Tilt-Testing in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS).

Background and Objectives: During tilt testing, myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) patients experience an abnormal reduction in cerebral blood flow (CBF). The relationship between this CBF reduction and symptom severity has not been examined in detail. Our hypothesis was that ME/CFS severity is related to the degree of the CBF reduction during tilt testing. Materials and Methods: First, from our database, we selected ME/CFS patients who had undergone assessments of ME/CFS symptomatology and tilt tests on the same day, one at the first visit and the second during a follow-up. The change in symptomatology was related to the change in CBF during the tilt test. Second, we combined the data of two previously published studies (n = 219), where disease severity as defined by the 2011 international consensus criteria (ICC) was available but not published. Results: 71 patients were retested because of worsening symptoms. The ICC disease severity distribution (mild-moderate-severe) changed from 51/45/4% at visit-1 to 1/72/27% at follow-up (p < 0.0001). The %CBF reduction changed from initially 19% to 31% at follow-up (p < 0.0001). Of 39 patients with stable disease, the severity distribution was similar at visit-1 (36/51/13%) and at follow-up (33/49/18%), p = ns. The %CBF reduction remained unchanged: both 24%, p = ns. The combined data of the two previously published studies showed that patients with mild, moderate, and severe disease had %CBF reductions of 25, 29, and 33%, respectively (p < 0.0001). Conclusions: Disease severity and %CBF reduction during tilt testing are highly associated in ME/CFS: a more severe disease is related to a larger %CBF reduction. The data suggest a causal relationship where a larger CBF reduction leads to worsening symptoms.

Selected biomarkers of orthostatic intolerance.

Orthostatic intolerance (OI) is defined as a group of diseases which symptoms are typically manifested in a standing position. These symptoms result from cerebral hypoperfusion and disappear in the supine position. We include postural orthostatic intolerance syndrome (POTS), orthostatic hypotension (OH) and vasovagal orthostatic syncope in this group of diseases. Each of them have similar clinical presentation (blurred vision, weakness, dizziness, nausea, headaches, fatigue). However, they vary from each other in biochemical, autonomic and hemodynamic characteristics. The aim of the work is to provide an overview of humoral and non-human markers that are involved in the etiopathogenesis of orthostatic intolerance.

Postural Orthostatic Tachycardia Syndrome: Mechanisms and New Therapies.

Postural orthostatic tachycardia syndrome (POTS) is a clinically heterogeneous disorder with multiple contributing pathophysiologic mechanisms manifesting as symptoms of orthostatic intolerance in the setting of orthostatic tachycardia (increase in heart rate by at least 30 beats per minute upon assuming an upright position) without orthostatic hypotension. The three major pathophysiologic mechanisms include partial autonomic neuropathy, hypovolemia, and hyperadrenergic state. Patients often will exhibit overlapping characteristics from more than one of these mechanisms. The approach to the treatment of POTS centers on treating the underlying pathophysiologic mechanism. Stockings, abdominal binders, and vasoconstrictors are used to enhance venous return in partial neuropathic POTS. Exercise and volume expansion are the main treatment strategies for hypo-volemic POTS. For hyperadrenergic POTS, beta-blockers and avoidance of norepinephrine reuptake inhibitors is important. Attempts should be made to discern which pathophysiologic mechanism(s) may be afflicting patients so that treatment regimens can be individualized.

Autonomic neuropathy as post-acute sequela of SARS-CoV-2 infection: a case report.

Symptoms of autonomic dysfunction, particularly those of orthostatic intolerance, continue to represent a major component of the currently recognized post-acute sequelae of SARS-CoV-2 infections. Different pathophysiologic mechanisms can be involved in the development of orthostatic intolerance including hypovolemia due to gastrointestinal dysfunction, fatigue-associated deconditioning, and hyperadrenergic state due to pandemic-related anxiety. Additionally, there has been a well-established association of a common primary autonomic disorder like postural orthostatic tachycardia syndrome, a subtype of orthostatic intolerance, with antecedent viral infections. Here we report a case of neuropathic type postural orthostatic tachycardia syndrome as a form of autonomic neuropathy that developed following COVID-19 infection.

Autonomic nervous system function in women with anorexia nervosa.

PURPOSE: Abnormalities in autonomic function have been observed in people with anorexia nervosa. However, the majority of investigations have utilised heart rate variability as the sole assessment of autonomic activity. The current study utilised a variety of methodologies to assess autonomic nervous system function in women with a current diagnosis of anorexia, a past diagnosis of anorexia who were weight-restored, and healthy controls. METHODS: The sample included 37 participants: 10 participants with anorexia, 17 weight-restored participants (minimum body mass index > 18.5 for minimum of 12 months) and 10 controls. Assessments of autonomic function included muscle sympathetic nerve activity (MSNA) using microneurography, heart rate variability, baroreflex sensitivity, blood pressure variability, head-up tilt table test, sudomotor function and assessment of plasma catecholamines. RESULTS: MSNA (bursts/min) was significantly decreased in both anorexia (10.22 ± 6.24) and weight-restored (17.58 ± 1.68) groups, as compared to controls (23.62 ± 1.01, p < 0.001 and p = 0.033, respectively). Participants with anorexia had a significantly lower standard deviation in heart rate, lower blood pressure variability and decreased sudomotor function as compared to controls. Weight-restored participants demonstrated decreased baroreflex sensitivity in response to head-up tilt as compared to controls. CONCLUSION: Women with a current or previous diagnosis of anorexia have significantly decreased sympathetic activity, which may reflect a physiological response to decreased energy intake. During the state of starvation, women with anorexia also displayed decreased sudomotor function. The consequences of a sustained decrease in MSNA are unknown, and future studies should investigate autonomic function in long-term weight-restored participants to determine whether activity returns to normal.