Abstract
Introduction
Exercise training is recommended as a complementary treatment in postural orthostatic tachycardia syndrome (POTS) according to international guidelines. However, less is known regarding how exercise training could successfully be implemented in clinical practice in patients with POTS. Thus, in the current study, we aim to assess the effect of a 16-week tailored exercise training programme in POTS.
Methods and analysis
A total of 200 patients diagnosed with POTS will be recruited. The study will be conducted as a randomised cross-over study. POTS symptoms will be evaluated using the Malmö POTS Symptom Score, Orthostatic Hypotension Questionnaire and 36-item Short Form Health Survey. Haemodynamic parameters will be evaluated by orthostatic tests and maximum working capacity evaluated by bicycle exercise test. Symptoms, haemodynamic parameters and exercise capacity will be assessed before and after a 16-week training programme.
Ethics and dissemination
The study was approved by the Swedish ethical review authority (2022-03186-01) and all procedures will be performed in accordance with the Helsinki Declaration. Results will be made available to patients with POTS, healthcare professionals, the funders and other researchers in publicly available (open access) medical journals.
Trial registration details
NCT05554107, registered on 26 September 2022.
Keywords: Cardiovascular Disease, Surveys and Questionnaires, Exercise
STRENGTHS AND LIMITATIONS OF THIS STUDY.
The randomised cross-over design allows both within-group and between-group comparisons and helps reduce confounding by measuring both interventions in the same participants.
Exercise and non-pharmacological interventions, when tolerated, are cost-effective and have minimal side effects if performed under careful supervision, but only a few studies have investigated exercise training in postural orthostatic tachycardia syndrome (POTS).
This study, including a relatively large sample of patients, addresses a gap in current knowledge by evaluating a supervised, structured exercise programme for POTS in a real-world clinical setting.
Although dropout and loss to follow-up may affect validity and statistical power, strategies to minimise this risk, such as respecting patients’ time commitments, using strong interpersonal skills among study personnel, and offering flexible testing hours, will be implemented.
No washout period is included, which may introduce carry-over effects, but this aligns with our hypothesis that the benefits of exercise will persist beyond the intervention period.
Background
Context
Postural orthostatic tachycardia syndrome (POTS) is a common, but incompletely understood condition, characterised by autonomic dysfunction, orthostatic intolerance and an excessive heart rate (HR) increase on standing.1 2 Diagnostic criteria for POTS include symptoms of orthostatic intolerance for at least 3 months together with an increased HR of ≥30 beats/min (bpm) (HR increase >40 bpm in patients <19 years) or HR exceeding 120 bpm during orthostatic provocation without orthostatic hypotension.3 4 In addition to the orthostatic intolerance and tachycardia, patients with POTS experience debilitating symptoms such as nausea, blurred vision, light-headedness, fatigue, generalised weakness, chest pain and gastrointestinal problems.2 4 Several potential underlying mechanisms have been suggested for POTS including autonomic denervation, hypovolemia, hyperadrenergic stimulation and autoantibodies against adrenergic and muscarinic receptors.2 However, none of these proposed mechanisms have led to a causative therapy.2 Investigators have found that 25% of patients with POTS are unable to work because of the disease.5 Some researchers have suggested that clues behind the pathophysiology of POTS may be found in studies on spaceflight and head-down bedrest and its effect on the cardiovascular autonomic system.6 Many studies have demonstrated that real and/or simulated microgravity exposure, such as spaceflight and head-down bed rest, induces a ‘POTS-like’ syndrome even in healthy, physically fit individuals.6 Furthermore, exercise training in combination with volume loading has been found to prevent cardiovascular deconditioning (ie, cardiac atrophy and hypovolemia) and orthostatic intolerance after simulated microgravity exposure.7,9 Cardiovascular deconditioning and reduced standing stroke volume play an important role in the pathophysiology of POTS.610,12 This idea is supported by studies showing that physical reconditioning with short-term exercise training significantly increased peak oxygen uptake (an indicator of physical fitness), increased heart size, expanded blood and plasma volume, as well as improved POTS symptoms and quality of life.10,14 Moreover, 50–70% of patients with POTS who completed 3 months of endurance training no longer met the haemodynamic criteria for POTS.10 15 16 In addition, short-term exercise training for 3 months increased baroreflex sensitivity and was associated with a decrease in upright HR.15 Finally, the semi-supervised training programme compared with standard care demonstrated superiority in reducing POTS symptoms.17
Thus, previous findings emphasise that tailored and supervised exercise training should be considered for most patients with POTS,4 because it is easy to implement, cost-effective and if performed under supervision with careful evaluation, is considered unlikely to have significant side effects. However, the data regarding how exercise training could be successfully implemented in clinical practice are sparse. While prior trials have shown exercise can improve symptoms, they have varied in design—some on-site, some home-based and others requiring general practitioner involvement.10 12 16 18 Our study combines elements from these protocols into a practical model conducted in routine clinical practice. With a relatively large sample size, it aims to detect clinically meaningful effects and improve generalisability, allowing for direct implementation if effective. Thus, in this study, we aim to assess the effect of a 16-week clinical training programme for POTS.
Study aims
The main aim of this study is to compare patients with POTS symptoms according to Malmö POTS symptom score (MAPS; primary outcome), Orthostatic Hypotension Questionnaire (OHQ) and the 36-Item Short Form Health Survey (SF-36) before and after a 16-week specialised training programme. Secondary aims are to compare haemodynamic parameters (HR and blood pressure) during orthostatic tests and maximal workload during maximal biking tests before and after the training programme.
Methods and analysis
Study protocol
A total of 200 patients diagnosed or treated for POTS at the Department of Cardiology, Skåne University Hospital, Malmö, will be asked to participate in the study. The study will be conducted as a crossover study. Study participants will be randomised into two groups (Group A and B). Randomisation will be performed through Research Randomizer, Urbaniak, G C, and Plous, S (2013). Research Randomizer (V.4.0) (computer software). Retrieved on 22 June 2013, from http://www.randomizer.org/. Group A will first start the training programme and when group A finishes the training programme, group B will start the training programme (see figure 1 for a schematic overview of study design). While the ‘non-active’ group is not performing the training programme, patients belonging to this group will be encouraged to engage in physical activity according to their own abilities (‘at home training’).
Figure 1. Schematic overview on study design. The study will be conducted as a crossover study. Patients with POTS (n=200) will continuously be randomised into two groups (Group A and B). Group A will first start the 16-week training programme and when group A finishes the training programme, group B will start the training programme. While each group is not performing the training programme, the patients will be encouraged to physical activity according to their own abilities (‘at home exercise training’). Symptom questionnaires, orthostatic tests and maximum biking tests will be performed before and after both the 16-week training programme and the ‘at home exercise training’ as shown above. POTS, postural orthostatic tachycardia syndrome.
This is a two-period crossover study. In the first phase, outcomes will be compared both between Group A and Group B, and within each group (before and after the training programme or at-home training). In the second phase, after the groups switch interventions, only within-group comparisons will be performed. Between-group comparisons will not be conducted in the second phase due to the expected lasting effects of the training programme and the absence of a washout period.
Inclusion criteria are patients ≥18 years old, diagnosed with POTS who have given written informed consent for participation in the study. Patients with myalgic encephalomyelitis and physical disabilities, that is, those who are unable to perform the physical exercises, are excluded from the study. Recruitment for the study will take place between November 2022 and November 2027.
The primary outcome is the MAPS, which measures symptom burden in patients with POTS. Secondary outcomes include the OHQ, the SF-36 health survey, orthostatic test results and maximum workload from the maximum biking tests. Prior to the start of the training programme MAPS, OHQ and SF-36 will be completed by the participants (questionnaires described in more detail below). Orthostatic tests will be performed for 10 min, measuring HR and blood pressure after 0, 1, 3 and 10 min of standing, following 5 min of rest in supine position. On a separate occasion, patients will perform a maximum biking test, while noting symptoms, degree of exertion, achieved effect, pulse and blood pressure reaction. Following this initial evaluation, the training programme will be performed during a total time of 16 weeks, which may be non-consecutive but within 6 months in total. Previous studies on training programmes for POTS had a duration of 3 or 6 months.1012 14,16 The time period of 16 weeks in the current study was primarily based on previous experience of exercise training in POTS at the clinic. After the final training session, MAPS, OHQ and SF-36 will be completed once again. In addition, orthostatic tests and maximum biking tests will be performed on a separate occasion soon after the last training session. MAPS, OHQ, SF-36, orthostatic tests and maximum workload will be compared before and after the 16-week training programme, and before and after the 16-week ‘at home exercise training’. Criteria for discontinuing the training programme are non-temporary worsening symptoms following the exercise and by participant request. Suspected adverse events will be immediately reported to the primary investigator for judgement, recorded and individual actions will be performed. All standard of care interventions are permitted during the trial. This study adheres to the CONSORT (Consolidated Standards of Reporting Trials) 2019 extension for randomised crossover trials to ensure transparent reporting.19
The 16-week training programme
The training programme consists of two visits per week, with each session lasting up to 60 min. There are 6–8 patients per occasion. The first training sessions will begin with a duration of about 10 min, gradually increasing each week, depending on the patient’s tolerance. Patients are also encouraged to perform specific exercises at home once per week, in addition to the two in-clinic visits. The training programme follows the well-acknowledged Children’s Hospital of Philadelphia (CHOPS) protocol for POTS.20 Part of the training may be performed on exercise bicycles, either in supine or upright position, depending on the severity of POTS symptoms. The training sessions at the clinic are supervised by physiotherapists specialised in POTS and are adapted to each participant’s ability. If significant side effects occur during or after training, such as postexercise malaise, the physiotherapists will adjust the programme guided by previous experience with patients with POTS.18 The ‘at-home training’ also follows the CHOPS protocol. However, unlike the in-clinic sessions, the ‘at-home training’ is performed without direct supervision or real-time modifications from physiotherapists. Both in-clinic and at-home training sessions will be recorded for each patient, allowing for the review of the exact exercises performed.
Variables studied
The following variables: age, sex, medications, duration of POTS and season when entering the training programme will be included to baseline characteristics.
Measurement of outcomes
Malmö POTS symptom score
MAPS is a questionnaire-based, symptom scoring system, for self-assessment of symptom burden using a visual analogue scale graded from 0 (no symptoms) to 10 (very pronounced symptoms).21 The questionnaire is based on patients’ own perception of 12 commonly reported symptoms: five cardiac symptoms (palpitations, dizziness, presyncope, dyspnoea and chest pain) and seven non-cardiac symptoms (gastrointestinal symptoms, insomnia, concentration difficulties, headache, myalgia, nausea and fatigue) during the last 7 days. The score ranges from 0 to a maximum score of 120 points. MAPS has been described in detail elsewhere.21
Orthostatic Hypotension Questionnaire
The OHQ is a questionnaire that has been previously validated and used for orthostatic hypotension,22 but is often used to evaluate POTS-related symptoms.2 23 The OHQ is divided into two parts: Orthostatic Hypotension Symptom Assessment (OHSA), consisting of six questions about specific symptoms ((1) Dizziness, light-headedness, feeling faint or feeling like you might black-out; (2) Problems with vision (blurring, seeing spots, tunnel vision, etc); (3) Generalised weakness; (4) Fatigue; (5) Trouble concentrating; (6) Head/neck discomfort) and Orthostatic Hypotension Daily Activity Scale (OHDAS) consisting of four questions that assess the impact of symptoms on daily activities (standing for long and short duration, walking for short or long duration). The recall period is over the last week. Items are scored from 0 to 10, where 0 indicates no symptoms and 10 indicates worst possible symptoms. The total OHQ score is calculated by averaging the OHDAS and OHSA. Activities that are marked with zero or ‘cannot be done for other reasons’ are not included in the symptom score. In the current study, a previously translated Swedish version of the OHQ will be used.
SF-36 Health questionnaire
The SF-36 is a 36-item patient-reported questionnaire covering eight health domains: physical functioning, bodily pain, role limitations due to physical health problems, role limitations due to personal or emotional problems, emotional well-being, social functioning, energy/fatigue and general health perceptions. Scores for each domain range from 0 to 100, with a higher score defining a more favourable health state.24 All three questionnaires used in this study have been validated in the Swedish language. The MAPS Swedish version is the original version,21 the OHQ has been translated into Swedish and validated by an expert in health status assessment,23 and the SF-36/RAND-36 is widely used and well-validated in the Swedish language.25
Orthostatic tests
After a supine rest of 5 min, blood pressure is measured in supine position with an automated blood pressure monitor. Pulse in supine position is derived from the automated blood pressure monitor, simultaneously to blood pressure measurement. Orthostatic tests are performed for 10 min, measuring HR and blood pressure after 0, 1, 3 and 10 min of standing. If the patient experiences symptoms such as dizziness, palpitations, etc, or if the patient’s HR increases by more than 30 bpm from baseline, the test will be ended, and the outcome will be noted.
Maximum biking exercise test
The test is performed on a bicycle ergometer according to clinical routine, at the Department of Clinical Physiology or the Department of Cardiology at Skåne University Hospital, as appropriate, with identical protocols and test procedures. Patients with POTS are instructed to take their medications as usual. Initial starting load may vary between 30 W and 100 W and is decided based on the patient’s exertion history, age and sex. The test is performed with an increased workload of 10–20 W every minute. The exercise test will be terminated when the patient reports symptoms of dyspnoea, chest pain or other characteristic effort-related POTS symptoms, that is, when exercise reproduces intolerable symptoms previously reported by the patient. The maximal level of physical exertion reached (or tolerated) by the patient will be documented. ECG and HR will continuously be monitored, and blood pressure will be measured before, during and after the biking test.
Statistical analysis plan
The data analysis will be performed after the data for the entire sample has been collected, using the IBM SPSS Statistics for Windows, V.29 (IBM, Armonk, New York, USA). A p value of <0.05 will be considered significant for all tests. A descriptive analysis of the baseline characteristics of the sample will be performed. All the quantitative variables will be assessed as normally distributed after visual inspection of distribution plots. According to the results of the homogeneity and normality analysis, parametric or non-parametric statistics will be used for the within and between-group analysis. Within-group results will be analysed with paired samples t-test (or Wilcoxon test for non-parametric data), whereas between-group results will be analysed using independent samples t-test (or Mann-Whitney U test for non-parametric data). The study will be done as a complete case analysis, and no imputations for missing values will be done. Analyses of the clinical characteristics of subjects not completing the trial compared with those who completed the trial will be done.
Sample size calculation
Drop-out rates should be taken into consideration when estimating the sample size. In previous exercise programme studies for patients with POTS, the drop-out rate varied between 10%, 24% and 59%, respectively.10 12 16 The latter study,16 with a drop-out rate of 59 %, hypothesised that the reason for such a high drop-out rate could partly be due to the training programme being delivered to the primary physicians with no input from the research team. The authors suggested that if physicians and healthcare providers developed healthcare systems to take further responsibility to monitor patients more frequently, a lower drop-out rate may have been expected. We calculated our sample size based on three previous studies.10 12 16 Two10 16 of these studies, there were 3-month training programmes for patients with POTS. Quality of life was assessed with SF-36 in both studies. Orthostatic test was performed in one study and head-up tilt test was performed in the other to measure haemodynamic parameters. The third study12 was a 6-month outpatient cardiovascular exercise programme. Autonomic testing included head-up tilt test and active standing test. Symptoms were assessed with the Krupp Fatigue Severity Scale, EuroQol Visual Analogue Scale and the Boston Autonomic Symptom Questionnaire.12 In the current study, the sample size was calculated using a web application, Kane S P. Sample Size Calculator. ClinCalc: https://clincalc.com/stats/samplesize.aspx. Updated 24 July 2019. Accessed 2 August 2021. The sample size calculation was based on the primary outcome measure, the MAPS questionnaire. In our own study population of stable patients with POTS from which MAPS was developed, the MAPS was 78 with an SD of 20.21 As most participants are expected to be newly diagnosed and therefore likely to be highly symptomatic, we conservatively assumed a somewhat higher baseline MAPS score of 90 for the current study. We considered a 10% improvement (ie, a 9-point reduction) to be clinically meaningful. Assuming an SD of 20, this yielded a required sample size of 156 to achieve 80% power at a two-sided alpha level of 0.05. Allowing for an estimated dropout rate of 25%, we planned to recruit approximately 200 participants. The patients will be consecutively asked for participation in the study until the target sample size has been achieved.
Methodological issues
This randomised crossover study design will allow us to look at changes over time and make comparisons between study groups as well as within study groups.26 Crossover studies may also minimise the risk of confounding since both interventions are measured on the same participants. Nevertheless, there is always a risk of drop-out and loss to follow-up, which may impact the validity of the results and affect the statistical power. However, efforts to minimise loss to follow-up will include respecting the time commitment of patients, strong interpersonal skills of study personnel and flexible hours for testing. Other factors that should be taken into consideration are possible carry-over effects. In the study design, we do not include a washout period since our hypothesis is that the effect of exercise will persist even after the training programme is ended. Challenges with exercise training for POTS include the heterogeneity of the condition, variations in symptom severity (necessitating personalised training), patient motivation and adherence, and, in some cases, symptom exacerbation (postexertional malaise).2 12 27 28 Although exercise training has significant potential to enhance the quality of life and improve symptoms in patients with POTS, it demands tailored approaches and robust support systems to address these challenges. A potential limitation of this study is the flexibility in the 16-week in-clinic training programme, which allows it to extend over a period of up to 6 months. This flexibility was introduced to increase the probability of subject retention. However, the at-home exercise programme follows a fixed timeline without extension. While this approach may not be optimal, it was necessary for practical purposes, and we have acknowledged this as a limitation in the study.
Another potential limitation is that medication changes will be allowed during the study period. However, this pragmatic approach aligns with real-world clinical care and enhances the generalisability of our findings. Given the randomised design, any such changes should be balanced across groups, reducing the likelihood of systematic confounding. Nonetheless, any potential confounding due to medication adjustments will be considered in the interpretation of the trial results. A strength with our exercise programme is that the training programmes will be individualised and supervised by physiotherapists with a special interest in POTS. Potential side effects are continuously recorded, and the exercise programme is continuously adapted by the physiotherapists. Additionally, patients will have the option to train in supine position when necessary. Lastly, the training sessions will be held in groups, which will make it more cost-effective.
To summarise, this cross-over study of an exercise training programme, aiming to include a relatively large group of patients with POTS, may offer valuable insights into its potential benefits and how it can be implemented in clinical practice.
Patient and public involvement
Patients were involved early in the research, providing feedback on study design and methodology. Their input led to minor adjustments of the study protocol to better align with patient preferences. Although they were not involved in developing the research questions or patient recruitment, their perspectives on potential risks and side effects of the intervention were considered. While the specific plans for patient involvement in dissemination are not finalised, we aim to collaborate with patients to create accessible summaries of the findings and ensure the results are shared in a meaningful way with relevant patient communities.
Protocol registration
This study is registered with ClinicalTrials.gov (NCT05554107).
Data monitoring
We believe that a data monitoring committee is not needed in the current study since this trial is an open label, single centre study and the intervention is well characterised and, if performed under supervision with careful evaluation, is considered unlikely to have significant side effects.
Data storage and security
Data will be stored on institutional network drives with firewalls and security measures in place. Access to records and data will be limited to study personnel. Study data will be pseudoanonymised and a subject identification code will be kept and stored separately from the data in a locked cabinet in a secure location.
Data availability statement
Anonymised data on a group level may be available on reasonable request to the corresponding author.
Acknowledgements
The authors would like to thank the staff at the Department of Cardiology, Skåne University Hospital, for all the support when planning the exercise programme. The authors used ChatGPT (OpenAI, 2025) to assist with clear and concise formulation and phrasing during the revision process. The authors carefully reviewed and edited the AI-generated suggestions to ensure accuracy and clarity. No AI tools were used during the original research or initial manuscript preparation.
Footnotes
Funding: This work was supported by grants from The Swedish Heart–Lung Foundation, The Swedish Heart and Lung Association, Petrus and Augusta Hedlund’s Foundation, The Governmental funding within the Swedish National Health Services (ALF), Skåne University Hospital Funds and Region Skåne.
Prepub: Prepublication history for this paper is available online. To view these files, please visit the journal online (https://doi.org/10.1136/bmjopen-2024-097057).
Patient consent for publication: Not applicable.
Provenance and peer review: Not commissioned; externally peer reviewed.
Patient and public involvement: Patients and/or the public were involved in the design, or conduct, or reporting, or dissemination plans of this research. Refer to the Methods section for further details.
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