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Corresponding author at: Health Psychology Section, Psychology Dept, Institute of Psychiatry, Psychology & Neuroscience, King's College London, 5th floor Bermondsey Wing, Guy's Campus, London Bridge, London, SE1 9RT, United Kingdom.
5159 entries were screened; 29 eligible studies identified and narratively synthesized.
•
Serum activity against ADRA1 and a range of psychosocial factors were associated with symptom burden in POTS.
•
Orthostatic heart rate increase had no significant association with symptom burden.
•
No fully powered intervention studies to reduce symptom burden conducted to date.
•
Symptom burden measurement in POTS is inconsistent and a validated standardized instrument is needed.
Abstract
Background and objective
Postural Orthostatic Tachycardia Syndrome (POTS) is a chronic health condition affecting mostly women of childbearing age, and significantly impacting their health and quality of life. It is currently poorly understood with no approved licensed treatments. The aim of this systematic review was to contextualize the symptom burden of POTS, and review factors associated with this burden that may guide future treatments. The specific questions were (1) How does symptom burden in POTS compare to the burden in other long term conditions (LTCs), (2) Which factors are associated with POTS symptom burden, and (3) Which interventions show promise in reducing symptom burden in POTS.
Databases and data treatment
Electronic databases (CENTRAL, MEDLINE, EMBASE, CINAHL, PsycINFO, Web of Science, APA PsycArticles, OpenGrey) were searched from inception to January 2022 for observational studies reporting on the association between any biological, psychological or social factors and symptom burden, and randomized controlled trials reporting on interventions for symptom burden in adults with POTS. Two reviewers independently conducted eligibility screening, data extraction and quality assessment. A narrative synthesis was undertaken.
Results/Conclusion
5159 entries were screened for eligibility. Twenty-nine studies were included (1372 participants with POTS of a total sample size of 2314, 17 High-, 12 Medium-quality), seventeen were observational and twelve were randomized controlled experimental and intervention trials. Overall methodological quality of the evidence was medium-high but heterogeneity was high and sample sizes modest, allowing moderately robust conclusions. Orthostatic symptom burden was higher in POTS than other LTCs. Serum activity against adrenergic α1 receptors, physical functioning, depression, catastrophizing, prolonged cognitive stress testing and anxiety were significantly associated with symptom burden in medium-high quality studies. Preliminary medium-high quality evidence from predominantly proof-of-concept (n = 11) studies and one 3-month 2 × 2 factorial design trial suggest that compression garments, propranolol, pyridostigmine, desmopressin, and bisoprolol may hold promise in reducing symptom burden. Directions for future research include investigating associated factors over time, the development of complex interventions which address both biological and psychosocial factors associated with symptom burden, and effectiveness trials of these interventions.
Significance
POTS symptom burden is high, particularly in relation to orthostatic intolerance when compared to other long-term conditions (LTCs). Despite this burden, there are no effectiveness randomized controlled trials of treatment to reduce symptoms in POTS. This review provides a starting point to understanding researched biological and psychosocial factors associated with this burden. There was however inconsistency in the measurement of symptom burden, lowering the confidence of cross-study inferences. A coherent definition of POTS symptom range, severity and impact along with a validated and reliable POTS-specific instrument is currently lacking. A standardized questionnaire to assess POTS symptom burden as a core outcome measure will help clarify future research and clinical practice.
Postural orthostatic tachycardia syndrome (POTS) is an autonomic nervous system disorder, characterized by an excessive increase in heart rate of >30 bpm upon standing without a drop in blood pressure, accompanied by symptoms (
). The etiology is considered multifactorial but is poorly understood. Hypothesized putative pathophysiological mechanisms include the presence of an autoimmune disorder and auto-inflammation (
Cognitive function, health-related quality of life, and symptoms of depression and anxiety sensitivity are impaired in patients with the postural orthostatic tachycardia syndrome (POTS).
2015 heart rhythm society expert consensus statement on the diagnosis and treatment of postural tachycardia syndrome, inappropriate sinus tachycardia, and vasovagal syncope.
), POTS is primarily characterized by orthostatic intolerance (OI) or symptoms from being upright. What is considered symptoms of OI varies, but tends to include light-headedness, palpitations, tremulousness, generalized weakness, blurred vision, exercise intolerance, and fatigue (
2015 heart rhythm society expert consensus statement on the diagnosis and treatment of postural tachycardia syndrome, inappropriate sinus tachycardia, and vasovagal syncope.
)), secretomotor symptoms (such as dry eyes and mouth), sleep dysfunction, and vasomotor symptoms (e.g. skin color changes). Finally, patients report miscellaneous symptoms, in upright or other positions, such as respiratory (
Postural hyperventilation as a cause of postural tachycardia syndrome: increased systemic vascular resistance and decreased cardiac output when upright in all postural tachycardia syndrome variants.
Cognitive function, health-related quality of life, and symptoms of depression and anxiety sensitivity are impaired in patients with the postural orthostatic tachycardia syndrome (POTS).
), it is less clear which are the distinguishing symptoms of POTS when compared to other long term conditions. The high incidence of multimorbidity in POTS, may further complicate the severity and range of symptoms reported (
Postural orthostatic tachycardia syndrome (POTS): state of the science and clinical care from a 2019 National Institutes of Health Expert Consensus Meeting - Part 1.
), it did not include symptom burden as a defined outcome measure. As the etiology of POTS is poorly understood, managing symptoms is the focus of current treatments. However, none of these treatments are currently approved or licensed for POTS (
). A systematic review of factors associated with symptom burden in POTS and efficacy of interventions to reduce symptom burden, may lead to clearer treatment recommendations and future research into existing and novel treatments. As the literature on symptom burden in POTS is relatively sparse, the aims of this review are broadly focused to (1) review studies which compare proposed POTS measures of symptom burden in patients with POTS and other long term conditions to ascertain if POTS symptoms are distinguishing features of the condition, (2) synthesize evidence on factors associated with symptom burden in POTS, (3) synthesize evidence on the efficacy of interventions for symptom burden in POTS, (4) evaluate the methodological quality of evidence reviewed, and (5) to propose specific areas for future research in this area.
2. Literature search methods
The protocol for this review was registered on Prospero (ID CRD42021251780). Reporting was done in line with the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidance (
Eligibility criteria are summarized in Table 1. Studies were eligible if they included patients clinically diagnosed with POTS of any severity using published criteria from the 2015 heart rhythm society expert consensus statement on the diagnosis and treatment of POTS, which are as follows (
2015 heart rhythm society expert consensus statement on the diagnosis and treatment of postural tachycardia syndrome, inappropriate sinus tachycardia, and vasovagal syncope.
): (1) frequent symptoms that occur with standing such as lightheadedness, palpitations, tremulousness, generalized weakness, blurred vision, exercise intolerance, and fatigue; (2) an increase in heart rate of ≥30 bpm when moving from a recumbent to a standing position held for >30 s (or ≥ 40 bpm in individuals 12 to 19 years of age); and (3) the absence of orthostatic hypotension (>20 mmHg drop in systolic blood pressure) (
2015 heart rhythm society expert consensus statement on the diagnosis and treatment of postural tachycardia syndrome, inappropriate sinus tachycardia, and vasovagal syncope.
Table 1Inclusion and exclusion criteria for studies in the review.
Inclusion criteria
Exclusion criteria
Included patients with a clinical diagnosis of POTS Included a minimum of 70 % adults (16+) study population Measured symptom burden Measured any biomedical, psychological or social factors Observational studies investigating the association between symptom burden and at least one biomedical, psychological, or social factor by assessing bivariate relationships, multivariate relationships, or group/time comparisons Randomized controlled experimental and intervention trials of any intervention type where POTS symptom burden was a primary or secondary outcome measure.
Non-empirical, general discussion, or theoretical papers, case reports, case series and systematic reviews, qualitative studies. Studies not published in English Studies using mixed samples (i.e. POTS in combination with Orthostatic intolerance) where specific POTS data could not be extracted.
Studies with 70 % or more adult participants (over 16 years of age) were eligible if they examined the association between POTS symptom burden and at least one biomedical, psychological, or social factor by assessing bivariate relationships, multivariate relationships or group comparisons.
Study designs including cross-sectional (including baseline analysis of RCT data), prospective cohort, retrospective cohort, and case-control studies were included. Randomized controlled experimental and intervention trials of any intervention type where self-reported POTS symptom burden was a primary or secondary outcome measure were eligible and no restrictions were imposed on the type of control/comparator. Any type of control condition was deemed eligible.
Non-empirical, general discussion, or theoretical papers, case reports, case series, systematic reviews and qualitative studies were excluded. Studies not published in English, and studies using mixed samples where specific POTS data could not be extracted were also excluded.
2.1.1 Specific requirements regarding POTS symptom burden measures
POTS symptom burden was defined as symptoms reported directly by the patient (
) as a sum of scores from a standardized instrument which may measure the severity, range or impact of POTS-specific symptoms that limit normal activities or cause physical and psychological suffering (
). Questionnaires commonly used for quantifying self-reported symptom burden in POTS could be broadly divided into two types; those that measure autonomic symptoms, and those that measure orthostatic symptoms. Although POTS is characterized by orthostatic symptoms, as a syndrome, symptoms often extend beyond orthostatic intolerance and may include a range of non-orthostatic contributions to symptom burden (
). Therefore, both orthostatic and autonomic measures were included for the purpose of systematically reviewing characteristic features, associated factors and interventions related to symptom burden in POTS. Non-standardized lists of symptom questions or ratings were excluded. More generic questionnaires that measured impact or health-related quality of life (QoL) (such as SF-36) as opposed to POTS specific symptoms were also excluded (except as correlates of symptom burden). A table summarizing the symptom burden measures included can be found below (Table 2).
2.2 Search strategy and study selection
A comprehensive literature search was initially run on 30 November 2020 and then rerun on 18 January 2022. Studies were identified by conducting systematic online searches of APA PsycINFO (Ovid); MEDLINE(R) (Ovid) and Epub Ahead of Print, In-Process & Other Non-Indexed Citations and Daily (Ovid); Embase (Ovid); CINAHL; CENTRAL; Web of Science Core Collection; and APA PsycArticles for quantitative studies using relevant keywords, including Postural Orthostatic Tachycardia Syndrome, Postural Tachycardia Syndrome and POTS as search terms in titles, abstracts or keywords, contacting key authors to request unpublished or in-press literature, and hand-searching reference lists of included studies and a POTS medical text book. Grey literature was searched from conferences, registered databases (World Cat, OpenGrey, Greylit), and expert network consultation. Due to the relatively low volume of POTS literature, the search strategy did not contain terms directly related to intervention type or study type. All POTS-related titles of articles and abstracts were screened by I.K. and E.J. Non-English articles were excluded provided an English version could not be retrieved. If an English abstract was available, authors of the study were contacted to request access to data relevant to the research questions. References from each database search were collated in EndNote. Duplicates were removed, and titles and abstracts and full-text screening were carried out by I.K. and E.J. independently using pre-determined criteria. Disagreements on inclusion/exclusion criteria were discussed to reach consensus. If a consensus could not be reached, a third reviewer was consulted. The interrater reliability score for in/exclusion was 96.4 %, Cohen's kappa: 0.93.
2.3 Data extraction and synthesis
Two reviewers (I.K. and E.J.) independently extracted data using predefined data extraction criteria, based on the PICOS- PRISMA guidelines (
The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration.
). Extracted information included (1) study design; (2) study aim; (3) the number of participants; (4) characteristics of patient sample (age, sex, ethnicity, co-morbidities, treatments, duration of symptoms); (5) how presence of POTS was defined by the authors; (6) comparator/control group (if applicable); (7) recruitment source and response rate; (8) predictor factors; (9) measure of symptom burden used; (10) key findings; (11) analysis conducted; (12) key quantitative data; and in addition for intervention studies (13) type of intervention and rationale, and (14) how participants were randomized.
Due to the wide variety of symptom measures used, and limited amount of data, meta-analyses were not possible and so a narrative review was conducted (
). For comparisons of symptom burden in POTS and other chronic health conditions, a description of the synthesized findings and the certainty of the findings was provided (
). For instrument domain and composite baseline scores, weighted pooled means and standard deviations were calculated based on sample size for POTS. Where possible, bivariate correlations between psychosocial factors and outcomes were reported and interpreted as small (0.10), medium (0.30) and large (0.50), using conventional psychology criteria to interpret correlation coefficients as a benchmark (
The feasibility of creating a checklist for the assessment of the methodological quality both of randomised and non-randomised studies of health care interventions.
) (Table 3). The Downs & Black checklist assesses the quality of reporting, external validity, internal validity – bias, internal validity - confounding (selection bias), power, and a diagnostic validity question was added. For observational studies, the checklist was modified by removal of questions relevant to RCTs and scoring was adapted pro rata according to number of questions (15 was the maximum score; high- (12–15); medium- (9–11); and low-quality (8 or less)). Assessment of all studies yielded a low-, medium- or high-quality rating.
Studies were independently assessed by two reviewers (I.K. and E.J.). Any disagreement between reviewers was resolved through consensus and discussion. In cases where consensus could not be reached, the opinion of a third reviewer was sought.
3. Results
3.1 Overview of studies
The search yielded 5159 entries, detailed in the PRISMA diagram (Fig. 1). The 29 studies (17 observational; 12 interventional) eligible for inclusion were published between 2002 (
This questionnaire contains 169 items concerning different aspects of autonomic symptoms. ASP is a questionnaire designed to comprehensively evaluate the severity and distribution of symptoms and the autonomic functional capacity of patients with autonomic disorders.
169
11 domains:
1.
orthostatic intolerance
2.
secretomotor
3.
male sexual dysfunction
4.
urinary
5.
gastroparesis
6.
constipation
7.
diarrhoea
8.
pupillomotor
9.
vasomotor
10.
reflex syncope
11.
sleep
Severity, distribution of symptoms and autonomic functional capacity of patients
nr
Higher scores indicate worse symptoms. Selected questions from the ASP questionnaire were used to create COMPASS as a scoring instrument.
The Composite Autonomic Symptom Scale (COMPASS) with item-weighting was established from the ASP; higher scores indicate more or worse symptoms.
Autonomic function tests were performed to generate the Composite Autonomic Scoring Scale (CASS) and to quantify autonomic deficits. Results of the COMPASS were compared with the CASS derived from the Autonomic Reflex Screen to evaluate validity. For the overall total CASS score and COMPASS score, the rank correlation was 0.67. Scores of symptoms of orthostatic intolerance and secretomotor dysfunction best predicted the CASS on multiple stepwise regression analysis.
The abbreviated 31-item COMPASS-31 was developed through expert review and exploratory factor analysis, as a self-assessment instrument of autonomic symptoms and function. It provides clinically relevant scores of autonomic symptom severity based on the well-established 169-item Autonomic Symptom Profile (ASP) and its validated 84-question scoring instrument, the Composite Autonomic Symptom Score (COMPASS). It was designed to provide a global autonomic severity score and domain scores that are both clinically and scientifically meaningful.
31
It is grouped into 6 domains (no. items):
1.
Orthostatic intolerance (4)
2.
Vasomotor (3)
3.
Secretomotor (4)
4.
Gastrointestinal (12)
5.
Bladder (3)
6.
Pupillomotor (5)
Global autonomic symptom severity, and domain scores
Score out of a total of 100. Following appropriate weighting, COMPASS 31 is a refined, internally consistent, and markedly abbreviated quantitative measure of autonomic symptoms based on the original ASP and COMPASS
A symptom score that measures the frequency of nausea, tremor in hands, dizziness, palpitation, headache, profuse perspiration, blurred vision, chest discomfort, light-headedness, and concentration difficulties.
8
Symptoms when the individual stands up from a sitting or supine position or remains prolonged standing;
1.
nausea
2.
tremor in hands
3.
dizziness
4.
palpitation
5.
headache
6.
profuse perspiration
7.
blurred vision
8.
chest discomfort
9.
light-headedness
10.
concentration difficulties
The frequency of such symptoms is also taken into account: 0: never 1: once per month 2: 2–4 times per month 3: 2–7 times per week 4: more than once per day
Frequency of a range of symptoms
α = 0.888
Score between 0 and 4 for each symptom. The total symptom score is the sum of the single item scores (sometimes averaged for all 10 symptoms to aggregate the global symptom strain) The symptom score has some predictive value in head-up tilt test results, which can be used as a preliminary assessment instrument. The median score in POTS was highest among 272 5–18 year-olds with OI symptoms (including POTS and vasovagal syncope according to HUT).
A validated 10-item scale to assess the comprehensive symptom burden and severity of neurogenic orthostatic hypotension (NOH).
10
Two components: the six-item OH symptoms assessment scale 0–10 severity (OHSAS):
1.
dizziness
2.
vision problems
3.
weakness
4.
fatigue
5.
trouble concentrating
6.
head/neck discomfort
And a four-item OH daily activity scale to assess the burden of symptoms, 0–10 interference (OHDAS):
1.
activities that require standing for short time
2.
activities that require standing for long time
3.
activities that require walking for short time
4.
activities that require walking for long time
Severity of symptoms, functional impact
α≥0.8 Cronbach’s alpha values were above 0.8 for the OHQ composite scale and subscales
The composite OHQ score is calculated by averaging the OHSAS and the OHDAS, with higher being more severe symptoms. Validation analyses were performed on the two scales and a composite score of the OHQ. The OHQ can evaluate the severity of symptoms and the functional impact of NOH as well as assess the efficacy of treatment.
A reliable and valid measure of the severity of symptoms of orthostatic hypotension.
5
The 5-item self-report Orthostatic Grading Scale assesses symptoms of orthostatic intolerance due to orthostatic hypotension (e.g. severity, frequency, and interference with daily activities).
1.
Orthostatic intolerance
Severity, frequency, and interference with daily activities
α = 0.91
Each item is rated on a scale of 0 to 4. Adding the scores for the individual items creates a total score. Strong internal consistency. The scale items correlated significantly with each of the CASS sub-scores (total: r = 0.41), mostly with the CASS adrenergic sub-score (r = 0.40).
Self-rate of the severity of 9 symptoms on a 0 to 10 scale (with 0 reflecting an absence of symptoms). The sum of the scores at each time point is used as a measure of symptom burden. The symptoms were chosen because they reflect common complaints of patients with POTS.
9
Rating 0–10 for these symptoms: 1. mental clouding 2. blurred vision 3. shortness of breath 4. rapid heartbeat 5. tremulousness 6. chest discomfort 7. headache 8. light-headedness 9. nausea
Severity of symptoms
nr
Sum of scores indicates severity, with higher being more severe.
VOSS had different naming conventions over time (Vanderbilt POTS symptom score).
nr = not reported.
a Sletten DM, Suarez GA, Low PA, Mandrekar J, Singer W. COMPASS 31: A Refined and Abbreviated Composite Autonomic Symptom Score. Mayo Clinic Proceedings. 2012;87 (12):1196–201.
Performance of the COMPASS-31 questionnaire with regard to autonomic nervous system testing results and medication use: a prospective study in a real-life setting.
1. To evaluate the work ability of working POTS patients compared to a group of healthy controls. 2. To evaluate the roles of the autonomic impairment of POTS patients and their individual cardiovascular autonomic responses to the orthostatic stimulus in work ability.
40: 22 POTS/18 Healthy Control
COMPASS-31
WAI scores in POTS patients were inversely correlated to the intensity of autonomic symptoms and to the excessive cardiac sympathetic activation induced by gravitational stimulus.
Spearman correlation analysis
Individual WAI and COMPASS31 scores r = 0.46 (p = 0.03)
To compare clinical characteristics and sensory thresholds between disease groups and controls, as well as in a subgroup analysis within the PoTS group, based on headache phenotype.
80 PoTS 30, chronic migraine 30, and non-headache controls 20
COMPASS-31
COMPASS-31 scores were significantly higher in both PoTS and CM compared to controls as well as in PoTS-ALL compared to CM, the only domain where CM and PoTS significantly differed was that of orthostatic symptoms.
To quantitatively and semi-quantitatively assess the burden of autonomic symptoms in a cohort of POTS patients followed over a period of 2 years.
42, 25 had a 1-year follow-up and 12 had a 2-year follow-up
COMPASS-31
Overall COMPASS 31 was significantly reduced compared to baseline at both 1-year and 2-year follow-up. A significant improvement in pupillomotor function at the 2-year follow-up was also observed.
Cross-sectional (Baseline data for a larger intervention study)
USA
To describe baseline psychological symptoms in patients with POTS, and examine associations between psychological and self- report autonomic symptoms.
58
COMPASS-31
Depressive symptoms and pain catastrophizing were significantly associated with autonomic symptoms.
Spearman correlation analysis
Correlation coefficients between psychosocial measures, COMPASS-31 for each Measure: ASI total 0.16 GAD-7 total 0.26 PCS total 0.31a PHQ-8 total 0.48a PROMIS mental health T-score−0.45a PROMIS physical health T-score−0.60a a = statistically significant.
To investigate circulating GH levels in POTS versus age- and sex-matched healthy control group from the same geographical location by high-sensitivity chemiluminescence sandwich immunoassay for plasma GH detection.
88; 46 with POTS, 42 healthy controls
Orthostatic Hypotension Questionnaire (OHQ)
Impairment of daily life activities subscale of the OHQ was inversely correlated with GH in POTS.
To study serum antibody activity against G protein– coupled receptors in relation to symptoms in patients with POTS and controls using a commercial cell-based assay
73. 48 patients with POTS and 25 healthy controls
Orthostatic Hypotension Questionnaire (OHQ)
ADRA1 activation was associated with the OHQ composite score and OI symptoms during prolonged standing and walking for short or long periods. All 4 receptors were associated with a higher score for vision problems. OPRL1 activity was associated with symptoms during prolonged walking.
Linear regression. A logistic model with all 4 GPCRs as POTS predictors
Activation association with the OHQ composite score β (per SD), p-value: ADRA1: β=0.768, p=0.009 ADRB2: β=0.176, p=0.599 CHRM2: β=0.290, p=0.364 OPRL1: β=0.472, p=0.118
To prospectively evaluate patients who met standard criteria for postural tachycardia syndrome (POTS), at baseline and 1-year follow-up, using standard clinical and laboratory methods to assess autonomic function.
58
COMPASS (/ASP)
Orthostatic symptoms, the major autonomic symptom reported by patients, improved in most patients.
To compare the clinical presentation, autonomic dysfunction, and pregnancy outcomes in parous and nulliparous women with postural tachycardia syndrome (POTS) and in women with POTS before and after pregnancy.
112 Parous (n = 51) Nulliparous (n = 61)
Orthostatic grading scale (OGS)
OI did not differ significantly between parous and nulliparous groups. OI symptoms did not differ statistically during any of the 3 trimesters. However, the general trend observed was worsening of OI in the first trimester and improvement in the second and third trimesters.
Mann-Whitney test. Data (parametric) paired t test. Repeated measures of analysis of variance
To investigate the frequency and pattern of orthostatic symptoms during head-up tilt (HUT) in patients with orthostatic intolerance, and to assess the relationship between orthostatic symptoms during HUT and autonomic parameters.
464. 19 % (87/464) POTS. 28 % (132/464) OH, and the rest had normal HUT.
Korean Orthostatic Grading Scale (KOGS)
Patients with POTS had orthostatic symptoms more frequently during HUT compared to patients with OH.
To characterise patients with CFS and POTS and differentiate them from CFS patients without POTS in terms of clinical and autonomic features.
179 patients with CFS, CFS patients with POTS (13 %, n = 24)
Orthostatic grading scale (OGS)
CFS patients with POTS exhibited greater orthostatic intolerance, were younger, less fatigued, less depressed and had reduced day-time hypersomnolence compared with patients without POTS.
Fisher’s exact test and independent two-tailed Student’s t-test between continuous variables. Pearson R correlation for correlation between variables.
To verify if POTS patients' limitations are similar to patients with chronic fatigue syndrome (CFS)
136
Orthostatic Grading Scale (OGS)
The POTS group had statistically significantly higher autonomic symptom burden (OGS) despite comparable levels of fatigue and sleepiness compared with a matched CFS cohort.
To evaluate if the maximal heart rate (HR) increment after standing is associated with the clinical symptoms in patients with excessive orthostatic tachycardia (OT). Investigate the correlations among the symptoms of orthostatic intolerance (OI), depression, and health-related QOL, assess if patients with minimal OI symptoms suffer from depression or diminished QOL
107
Orthostatic Intolerance Questionnaire (OIQ)
The amount of the orthostatic HR increment was not associated with symptom burden. OI symptoms were significantly associated with depression and QOL. The total OIQ score revealed a positive linear relationship with the BDI-II score and an inverse linear correlation with both PCS and MCS of the SF-36 scale.
To quantitatively assess autonomic symptom burden in PoTS patients using the COMPASS-31, compared to that of autonomic failure/neuropathy and asymptomatic, healthy controls.
111 PoTS (n = 32); autonomic failure/neuropathy (AF/N; n = 47) and asymptomatic, healthy controls (n = 32)
COMPASS-31
Patients with PoTS diagnosis report greater symptom burden across all functional domains of autonomic function compared to controls, and with similar severity to AF/N.
Performance of the COMPASS-31 questionnaire with regard to autonomic nervous system testing results and medication use: a prospective study in a real-life setting.
To investigate the performance of the COMPASS-31 questionnaire in a real-life setting in consecutive patients referred for objective testing of the autonomic nervous system (ANS), with the hypothesis that COMPASS-31 results differ depending on medications and findings of the tilt table test results.
171. POTS: 6 patients (3.51 %)
Croatian version of the COMPASS-31
Patients with postural orthostatic tachycardia had significantly higher orthostatic intolerance and vasomotor domains of COMPASS-31 (p = 0.048 and p = 0.022, respectively).
To investigate the physiology underlying “brain fog” in the absence of orthostatic stress in POTS by assessing cognitive and haemodynamic responses in the middle cerebral artery at baseline, after initial cognitive testing, and after prolonged (30-min) cognitive stress test
40; 22 with POTS, 18 healthy controls.
OHQ, COMPASS-31
Prolonged cognitive stress test (PCST) resulted in greater symptom burden in POTS.
Performance of the COMPASS-31 questionnaire with regard to autonomic nervous system testing results and medication use: a prospective study in a real-life setting.
Performance of the COMPASS-31 questionnaire with regard to autonomic nervous system testing results and medication use: a prospective study in a real-life setting.
Performance of the COMPASS-31 questionnaire with regard to autonomic nervous system testing results and medication use: a prospective study in a real-life setting.
Performance of the COMPASS-31 questionnaire with regard to autonomic nervous system testing results and medication use: a prospective study in a real-life setting.
Note: For POTS, the weighted pooled average COMPASS-31 total score out of 100 is 48.69 (48.7%, range 35.15-52), range of SD ± 10.02-14.54 (n = 136), compared to VVS 20.98, OH 22.57, OI 27.57, CM 30 and AF/N 50.82, with orthostatic scores being the largest contributor (range 20-28).
Note: Total mean pooled weighted OGS (Orthostatic Grading Scale) score out of 20 is 10.54 ± 3.83 (52.7 % of total score, n = 247) compared to 6 ± 4 in CFS and 5.46 ± 2.6 in OH.
Total mean pooled weighted OHQ (Orthostatic Hypotension Questionnaire) score out of 10 is 6.1584 ± 1.7808 (61.6 % of total score, n = 75).
Total mean pooled weighted OIQ (Orthostatic Intolerance Questionnaire) baseline score is 16.4 ± 3.2 (41 % of total score, n = 184).
Reduce the hyperadrenergic state, reduce tachycardia
USA
78
Melatonin
Randomized, crossover design on two separate mornings
Placebo
VOSS
Symptom burden was not improved with melatonin compared with placebo, there was a modest decrease in standing tachycardia. Placebo improved VOSS more than melatonin at 2 h (P = 0.031), the two interventions had comparable scores at 4 h.
The symptom burden improvement from baseline to 2 h was greater with propranolol than placebo, the improvement in symptoms at 2 h was greater with low-dose propranolol than high-dose although HR was decreased more
Reducing splanchnic venous pooling induced by upright posture
USA
18
Abdominal compression or propranolol
A placebo-controlled, randomized crossover study on separate days
Placebo
VOSS
Neither propranolol nor compression improved symptoms compared with placebo. Splanchnic venous compression alone did not improve HR or symptoms but prevented the blood pressure decrease produced by propranolol. The combination was more effective in improving symptoms than either alone.
The use of the collar reduced the orthostatic symptom score of participants during upright tilt, increased the HR response to deep breathing, and decreased resting ventilation.
The studies included a total of 1372 participants with POTS of a total sample size (including healthy controls and other conditions) of 2314 (range 10–464). The overall mean age of participants with POTS was 32 years (range of SD ± 1.3–12.7). On average 81.4 % of participants were female. For those studies that reported it (n = 5), the average duration of symptoms was 4.98 years (range of SD ± 2.6–10).
Across the 29 studies, the 7 symptom burden instruments used summarized in Table 2 included autonomic symptom questionnaires COMPASS31 (
) n = 2). Symptom questionnaires varied widely from between 5 and 169 items assessing the range, severity and impact of symptoms. Domains and symptoms included orthostatic intolerance (OI) (although OI domain symptoms varied somewhat between questionnaires), vasomotor, secretomotor, gastrointestinal, bladder, pupillomotor/vision, fatigue/sleep, mental clouding, head/neck/chest discomfort, perspiration, shortness of breath, tremulousness, nausea, palpitations, syncope and more (Table 2).
Overall, the methodological quality score, using the Downs and Black quality assessment tool (
The feasibility of creating a checklist for the assessment of the methodological quality both of randomised and non-randomised studies of health care interventions.
Performance of the COMPASS-31 questionnaire with regard to autonomic nervous system testing results and medication use: a prospective study in a real-life setting.
The next part of the results is divided into two major sections. The first reviews the observational studies and the second the interventional ones.
3.2 Observational studies summary
Observational studies were conducted in the USA (n = 6), South Korea (n = 2), Italy (n = 2), UK (n = 2), Sweden (n = 2), Canada (n = 1), Australia, (n = 1) and Croatia (n = 1). The mean age of POTS participants was 31.1 (range of SD ± 1.3–12.5) in these observational studies. Observational studies included a total of n = 924 people with POTS and a total sample of n = 1853 (including healthy controls and other conditions). 6 observational studies were case-control, 8 were cross-sectional and 3 were longitudinal (including 2 prospective, 1 retrospective cohorts). Seven of the 17 observational studies used COMPASS31 to measure symptom burden, two used the Autonomic Symptom Profile (of which one only used the 9-item OI subscale of the ASP), one used COMPASS, four used the Orthostatic Grading Scale (OGS), one used the Orthostatic Intolerance Questionnaire (OIQ) and three used the Orthostatic Hypotension Questionnaire (OHQ) (Table 4). For observational studies, key weaknesses across studies were in adjustment for confounding, power and external validity.
3.2.1 Time course and comparisons of symptom burden in POTS and other groups
Medium-high quality longitudinal evaluation of POTS found a reduction of symptom burden over time (
). The range of percentages of total symptom burden scale scores for POTS was 34.5 % (ASP) - 61.6 % (OHQ) (Table 5a, Table 5b, Table 5c, Fig. 2). Medium-high quality studies found that people with POTS reported more orthostatic symptoms (mean ± SD OGS score 10.54 ± 3.83 out of 20 = 52.7 %; OHQ 6.16 ± 1.78 out of 10 = 61.6 %; OIQ 16.4 ± 3.2 out of 40 = 41 %) than healthy controls (
Performance of the COMPASS-31 questionnaire with regard to autonomic nervous system testing results and medication use: a prospective study in a real-life setting.
Performance of the COMPASS-31 questionnaire with regard to autonomic nervous system testing results and medication use: a prospective study in a real-life setting.
) and fatigue. Wider autonomic symptom burden was greater in people with POTS (mean ± SD COMPASS31 score 48.69 ± 10.02–14.54 out of 100 = 48.7 %; ASP 55.21 ± 18.19 out of 160 = 34.5 %) when compared to those with vasovagal syncope (
Performance of the COMPASS-31 questionnaire with regard to autonomic nervous system testing results and medication use: a prospective study in a real-life setting.
3.2.2 Factors associated with symptom burden in POTS
3.2.2.1 Heart rate increase
Orthostatic heart rate increase is the primary diagnostic feature of POTS. One medium quality study observed no significant correlation between the degree of orthostatic heart rate increment and symptom burden (
3.2.2.2 Serum activity against G protein–coupled receptors (GPCRs)
G protein-coupled receptors (GPCRs) comprise a large class of proteins that regulate many physiological functions such as vision, smell, taste, neurotransmission, cardiac output, and pain perception (
), and one high quality study investigated serum activity against specific GPCRs (ADRA1, ADRB2, CHRM2, OPRL1) in POTS using a commercial cell-based assay (
). Serum-mediated adrenergic α1 receptor activity had a strong association with orthostatic symptoms independent of the hemodynamic response. Activation of ADRB2, CHRM2, OPRL1 was not significantly associated with overall OHQ symptom scores. Results from this study indicated the presence of circulating proteins activating cardiovascular ADRA1 (adrenergic α1 receptor), ADRB2 (adrenergic β2 receptor), CHRM2 (cholinergic muscarinic type 2 receptor), and nociception-related OPRL1 (opioid receptor-like 1) in patients with POTS to a higher degree compared with controls. Confounders in terms of prevalent POTS co-morbidities (such as IBS or depression) which may have elicited their own bi-directional effects on immune responses (
Growth hormone plays a role in the maintenance of the cardiovascular system, with cardiovascular morbidity being linked to both up- and down-regulation of plasma levels of growth hormone (
). This study found that people with POTS had lower growth hormone levels than healthy controls, although levels were still within the normal range. The daily life activities subscale (OHDAS) of the OHQ symptom burden score had a medium inverse correlation with growth hormone in POTS, where higher impairment was associated with lower levels of growth hormone. The total overall OHQ symptom burden score was not significantly associated with growth hormone levels in POTS.
3.2.2.4 Anxiety
The association between anxiety and symptom burden was explored in two medium-high quality studies (
), where higher symptom burden scores were associated with higher depression scores. One medium quality study reported that some OI symptoms were more strongly associated with depression including chest discomfort and concentration difficulties (
Two medium-high quality studies explored catastrophizing (viewing or presenting a situation or future situation as considerably worse than it is) in relation to symptom burden and found small-medium correlations (
), where higher catastrophizing scores (from the pain catastrophizing scale and catastrophizing subscale of the coping strategies questionnaire) were associated with higher symptom burden. One medium quality study reported that the pain catastrophizing scale (helplessness, active rumination and excessive magnification of the experience of pain) had a medium significant association with greater autonomic symptoms (
), whereas one high quality study found that a modified version of the catastrophizing subscale of the coping strategies questionnaire (assessing catastrophic thinking in response to autonomic symptoms) had a small significant correlation with greater symptom burden (
Neuroticism (experiencing the world as distressing, unsafe or threatening) showed a small non-significant positive correlation with symptom burden in one high quality study (
), but no significant relationship with symptom burden was observed.
3.2.2.9 Functional ability
Functioning and health-related quality of life (SF-36 and PROMIS Global Health questionnaires which measure functional health and well-being, comprising domains such as physical, mental, and social aspects of health, physical functioning, and bodily pain) was measured in relation to symptom burden in four medium-high quality studies (
). All of these demonstrated significant medium-large correlations with self-reported symptom burden, where more severe symptoms were associated with increased impairment (
) in working POTS patients and controls, and found that a significant medium correlation was present between total autonomic symptom scores (COMPASS31) and Work Ability Index (WAI, an instrument which assesses the perceived ability to work) scores. The higher the total COMPASS31 score the lower the WAI score, and WAI scores were significantly lower in people with POTS compared to healthy controls (
). One medium quality study examined pain disability index scores and found that higher pain disability scores had a significant medium correlation with higher symptom burden (
). A significant increase in the OH symptoms assessment (OHSA) OHQ subscale was reported after the entire protocol, with a greater increase in people with POTS compared to the control group, although exact post-test symptom scores were not provided.
3.3 Randomized experimental and intervention studies summary
Randomized experimental and intervention studies were conducted in the USA (n = 9), Canada (n = 2), and South Korea (n = 1). The mean age of POTS participants was 34.1 (range of SD ± 2–12.7) in these studies. The 12 eligible studies had a total of n = 448 participants with POTS in a total sample of n = 461 (including healthy controls). Eleven of these studies measured symptom burden using the VOSS (Vanderbilt Orthostatic Symptoms Score, previously Vanderbilt POTS symptom score). One study measured symptom burden through the Orthostatic Intolerance Questionnaire (OIQ). 12 intervention studies assessed symptom burden as a primary or secondary outcome in randomized experimental trials (n = 11) and one 2 × 2 factorial design trial, of predominantly high quality using the Downs and Black rating (Table 6). For intervention studies, key weaknesses were the lack of reporting on distributions of principal confounders and adverse events, representativeness of participant samples and response rates among source populations, adjustment for confounding, and recruitment period according to the Downs & Black rating (Table 3). However, all 12 studies had limitations in terms of being experimental rather than treatment trials with endpoints in hours (n = 10) or not having a placebo control group (n = 2) (Table 3), and compression conditions were not able to be blinded from participants, staff or assessors.
3.3.1 Pharmacological RCT and experimental studies
Eight medium-high quality trials investigated pharmacological treatments (Table 6). Medications were selected for reducing tachycardia (Propranolol, Bisoprolol) (
In one high quality study, the only trial with longer term follow-up, 77 participants were randomized in a 2 × 2 factorial design clinical trial of a 3-month medical treatment regimen, and symptom burden was assessed over 3 months (
) (Table 6). Group one trialed propranolol, group two bisoprolol, group three propranolol + pyridostigmine and group four bisoprolol + pyridostigmine. OIQ score improvements were consistent across treatment groups compared to baseline, although this study did not include a placebo group.
Seven medications were trialed in laboratory/tilt-based single dose crossover trials with endpoints measured in hours trials without further follow-up. Three of these experimental proof-of-concept trials, of Desmopressin, Pyridostigmine, and Propranolol (low dose more than high dose and high dose more than placebo) were effective in reducing symptom burden compared to placebo or high dose controls after 4 h tilt test. Two medications showed no impact on symptom burden at the tilt test: Melatonin reduced tachycardia but did not improve symptom burden compared to placebo (
). Two pharmacological laboratory based randomized trials showed negative impacts of medications on symptom burden compared to placebo. POTS patients are often prescribed NRI medication for co-morbid conditions. Patients given Norepinephrine Reuptake Inhibition (NRI) atomoxetine reported increased symptom burden scores compared to placebo from baseline to 2 h after study drug administration. Sertraline, a selective serotonin reuptake inhibitor, also resulted in worse symptoms than placebo at 4 h, despite being hypothesized to target low blood pressure and reduce reflex tachycardia (
) assessed the effect of high dietary sodium intake in POTS to counteract the hypovolemia and elevated plasma norepinephrine that can contribute to excessive orthostatic tachycardia. 14 patients with POTS and 13 healthy controls trialed 6 days of a low salt (10 mEq sodium/day) or high salt (300 mEq sodium/day) diet. There was a non-significant trend for lower symptom burden scores after upright posture in POTS on the high salt diet compared to the low salt diet, particularly for mental confusion, palpitations, light-headedness and headache (
Compression garments are used to target blood flow, and reduce blood pooling and the associated exaggerated compensatory increase in heart rate. Neck compression, leg/abdominal compression, and splanchnic compression combined with propranolol were trialed in 3 randomized experimental crossover studies of short duration (5 min‑2 h per condition) (Table 6). All three trials were associated with a significant treatment effect on symptom burden relative to the comparison conditions. The trials of a neck compression collar (
) both improved symptom burden during head-up-tilt. In the trial (2 h) combining splanchnic venous compression and propranolol, splanchnic venous compression alone did not improve symptom burden, but it did prevent the blood pressure decrease produced by propranolol, therefore the combination was more effective in improving symptoms than either alone (
Synthesis of the evidence suggests a pattern of high burden of symptoms in POTS, particularly those of an orthostatic nature when compared to healthy controls and comparable conditions. Studies using the COMPASS31, showed people with POTS also report a wide range of autonomic symptoms of moderate to severe intensity (
). The reported overall burden of autonomic symptoms was higher in people with POTS than a number of other LTCs, and comparable to patients with autonomic failure. Although COMPASS31 and OGS were the most commonly used measures, 6 different symptoms scales were used across the 17 observational studies reviewed, highlighting a lack of standardization or agreement regarding symptom assessment for POTS. The recent development of a POTS-specific symptom burden score (
JM Spahic V Hamrefors M Johansson F Ricci O Melander R Sutton et al Malmö POTS symptom score: Assessing symptom burden in postural orthostatic tachycardia syndrome. Journal of Internal Medicine.n/a(n/a). n.d.
), which reportedly strongly correlates with orthostatic heart rate increase in POTS, is therefore welcomed, although the instrument requires further external validation and replication in larger multi-center settings (
JM Spahic V Hamrefors M Johansson F Ricci O Melander R Sutton et al Malmö POTS symptom score: Assessing symptom burden in postural orthostatic tachycardia syndrome. Journal of Internal Medicine.n/a(n/a). n.d.
In terms of correlates of symptom burden, there was high quality evidence from one study of a strong relationship between symptom burden and ADRA-1 activation. There was a larger volume of medium-high quality evidence of moderate to large associations between depression and physical functioning with symptom burden in POTS. Prolonged cognitive stress testing, anxiety and catastrophizing were also significantly associated with symptom burden, but there were fewer studies and sizes of the relationships were smaller. Heart rate increase, growth hormone, somatic vigilance and neuroticism showed no significant relationships to overall POTS symptom burden. Interestingly, despite the heterogeneity of measures, making it difficult to compare across studies, orthostatic symptom burden measures and autonomic symptom burden measures had fairly similar size correlation coefficients with factors in people with POTS.
Orthostatic intolerance (OI) is considered the hallmark feature of POTS (
), but this review confirms people with POTS also report high levels of autonomic symptoms. However, a study which used an objective measurement of autonomic dysfunction in people with POTS (the Composite Autonomic Severity Score, CASS) reported only mild autonomic dysfunction (a score of 3 or less in 95 % of patients at baseline and 92 % at 1 year) (
), reiterating the difficulty in POTS in identifying biomedical measurements that corroborate symptoms as reported by the patient.
The current review also found little robust evidence of biomedical measurements that correlated with symptom burden. For example, the orthostatic heart rate increase, the main clinical and diagnostic feature of POTS (
), was in one study found to have no significant association with symptom burden. People with POTS had a higher heart rate increment on head-up tilt (HUT) than healthy controls, people with CFS (
), but there was no significant relationship between the severity of symptom burden and HR increase. Whilst physical measurements such as orthostatic heart rate increases appear unrelated to symptom reports, orthostatic intolerance symptoms in children with POTS have shown significant positive associations with diastolic blood pressure variability (
). These associations warrant further investigation in adult POTS populations.
The only biomedical factor associated with symptom burden in this review was serum activity against G protein–coupled receptor ADRA1. However, there is uncertainty around the usefulness of antibodies against GPCRs (
Association of autoantibodies to muscarinic acetylcholine receptors with gastrointestinal symptoms and disease severity in patients with postural orthostatic tachycardia syndrome.
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