Multimorbidity, functional impairment and health-related quality of life in postural orthostatic tachycardia syndrome: findings from an Australian observational cohort study

Postural orthostatic tachycardia syndrome (POTS) is an autonomic nervous system disorder characterised by orthostatic intolerance and a diverse array of multisystemic and extracardiac symptoms. 1 2 Predominantly affecting women (>80%), POTS primarily manifests in individuals of childbearing age. 3 The condition’s aetiology is complex and heterogeneous, including diverse mechanisms such as excessive sympathetic nervous system activity, hypovolaemia, venous pooling, peripheral autonomic neuropathy and autoimmunity. 3 Frequently occurring in temporal association with viral infection, POTS has been identified as the predominate phenotype of postacute sequelae of COVID-19 or long-COVID, affecting 3.4% of those infected. 4 – 6 Despite its prevalence, POTS is often under-recognised by healthcare professionals, leading to prolonged diagnostic delays and poor quality of life. 1 2 7 Symptom manifestation in POTS varies diurnally and in severity, significantly impacting daily activities, including self-care, education and employment. 1 8 Indeed, our prior research elucidated significant reductions in health-related quality of life (HrQoL) in POTS compared with a normative age-matched and sex-matched population. 1 Comparatively, despite their young age, those with POTS faced more severe disutility than older populations with other chronic conditions including cardiovascular and kidney disease, diabetes, chronic obstructive pulmonary disease and neoplasms. These findings highlighted the need for improved epidemiological and aetiological understanding of the condition. 1 9 Epidemiological understanding of POTS worldwide is limited, with existing data primarily derived from self-reported surveys conducted in the UK and the USA. 8 10 Similarly, clinician-confirmed longitudinal research on POTS has been largely confined to studies from highly specialised autonomic tertiary hospitals in North America, leaving a critical gap in characterisation of patients outside these settings. 11 – 14 To address a lack of contextual understanding of POTS in the Australian setting, we conducted a comprehensive analysis of an Australian POTS patient registry to investigate the symptom burden and quality of life parameters, diagnostic journey and comorbidities of participants. To our knowledge, this is the largest population study of older adolescents and adults with a physician-confirmed POTS diagnosis.

Consecutive participants aged 16 years and older enrolled in the Australian POTS patient registry between 1 May 2021 and 30 April 2024 were included (see online supplemental file for Study Protocol). The sample size was determined by the number of consecutive eligible participants enrolled during the study period rather than by a formal a priori power calculation. To be eligible, participants required a physician diagnosis of POTS confirmed by an experienced multidisciplinary team at a specialist cardiology clinic in the Australian state of South Australia. South Australia has a resident population of 1 898 600 (March 2025) with all residents of this and other states in Australia eligible to attend this clinic. Accepted international criteria were used to diagnose POTS including: a sustained heart rate increase of ≥30 beats per minute (≥40 bpm in 16–19 years old) or an absolute heart rate ≥120 bpm during a 10-minute active standing or head-up tilt table test; absence of orthostatic hypotension (defined as a drop of ≥20 mmHg systolic or ≥10 mm Hg diastolic blood pressure within the first 3 min of standing); and chronic presence of accompanying unexplained symptoms of orthostatic intolerance, lasting at least 3 months. 15 16 Patient-reported outcome measures were used to assess symptoms via electronic link to a Research Electronic Data Capture (REDCap) database. The Composite Autonomic Symptom Score (COMPASS-31) was used to evaluate autonomic symptoms across six domains: orthostatic intolerance, secretomotor, vasomotor, gastrointestinal, bladder and pupillary motor function. 17 Higher COMPASS-31 scores correlate with an increased burden of autonomic symptoms. 18 Clinically, a cut-off score of ≥40, as identified by our expert clinicians, was used to distinguish severe autonomic symptom burden in POTS patients and was applied to compare outcomes within our cohort. The Fatigue Severity Scale-9 (FSS) measures self-reported fatigue across 9-items. The total ‘N’ for this tool is lower due to its later inclusion as a tool in the registry, reflecting the recognition of ubiquitous fatigue in the cohort. Scores were reported as the mean of all scores (1 to 7) or a total score (maximum 63), with scores ≥36 indicating severe fatigue as per previous validation. 19 HrQoL was assessed using the EuroQol 5-Dimensional-5 Level instrument (EQ-5D-5L), which evaluates health status across five dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression, using a 5-response Likert scale, with responses ranging from no problems to extreme problems. 20 A Visual Analogue Scale (EQ-VAS) was employed to measure global health on a scale from 0 to 100, where 100 represents full health. 1 The Devlin et al UK value set was used to generate a single index utility score on a scale (EQ-utility) from 0 to 1, with ‘1’ representing full health. 21 Scores less than zero, while uncommon, indicate a perceived quality of life worse than death. 21 Due to its known association with POTS, hypermobility was also clinically assessed according to the 2017 hypermobile Ehlers-Danlos syndrome (hEDS) assessment criteria. 22 Historical generalised joint hypermobility (hGJH) was also evaluated using the Hakim 5-point hypermobility questionnaire. 23 This scale includes questions about current or past ability to perform hypermobility tasks. A score of ≥2 was considered indicative of generalised joint hypermobility, consistent with previous validation. 23 The REDCap database was populated with information extracted from medical records, including clinically verified comorbidities, demographic data and diagnostic experiences. For the purposes of this analysis, sex was defined as the gender recorded at birth, as reported by the participant. Diagnostic delay was defined as the time interval between the onset of orthostatic intolerance symptoms and the clinical diagnosis of POTS. SARS-CoV-2 infection as a precipitating trigger was determined by the treating clinician based on laboratory confirmation where available, including PCR or rapid antigen testing or on clinical diagnosis based on presenting symptoms and likely exposure. Normality of continuous variables was assessed using the Shapiro-Wilk test. Continuous data were expressed as mean and SD and categorical variables as frequencies and percentages. For continuous data, comparisons between two groups were assessed using an independent samples t-test or the Mann-Whitney U test for non-normally distributed data, while comparisons across more than two groups were performed using one-way analysis of variance or Kruskal-Wallis H test as appropriate. For categorical data, χ 2 tests or Fisher’s exact tests (when expected cell counts were low) were used to evaluate differences in proportions between groups. A direct logistic regression analysis was conducted to assess the association of five predictor variables: sex, race, age of POTS symptom onset, emergency department (ED) attendance prior to diagnosis and hGJH on the likelihood of experiencing diagnostic delays of ≥10 years. These variables were selected a priori based on clinical relevance and existing literature. Body mass index (BMI) and comorbidities were not included as primary predictors given the exploratory nature of the model and the clinical focus on modifiable diagnostic pathway factors. Spearman’s rank correlation was used to determine correlation between autonomic symptom burden, as determined by the COMPASS-31, and HrQoL (EQ-5D-5L utility score) and gastrointestinal symptom burden (Gastroparesis Cardinal Symptom Index, GCSI). For subgroup analyses, participants were categorised by COMPASS-31 score into lower autonomic symptom burden (score <40) and higher autonomic symptom burden (score ≥40). This threshold was selected based on clinical experience in this population and is consistent with our previously published work. 24 A cut-off of 38.28 has been validated to distinguish fibromyalgia patients from healthy controls, 25 supporting the clinical relevance of a similar threshold in conditions characterised by high autonomic symptom burden. All data were analysed in SPSS V.28.0.1.0.

From a total of 526 participants enrolled in the Australian POTS patient registry during the study period, 26 were excluded due to incomplete surveys (n=23) or withdrawal from the registry (n=3) ( online supplemental file 1 ). Complete data were available for all variables included in the primary analyses across the 500 included participants. A total of 500 consecutive participants were included in the study, with a mean age of 31.3±11.7 years. The cohort consisted predominantly of females (86.8%) and individuals of White ethnicity (92.7%). The baseline characteristics of our cohort have been previously published. 24 A summary of the following results is visually represented in the online supplemental graphical abstract . In total, 64.5% of participants experienced onset of symptoms that were clinically identifiable as being temporally associated with a precipitating environmental trigger. COVID-19 disease emerged as a predominant precipitant for POTS manifestation. Between May 2021 and May 2022, 1.8% of registrants developed POTS post SARS-CoV-2 infection at a time when South Australia experienced very low infection rates. However, between May 2022 and April 2023, SARS-CoV-2 infection accounted for 32.6% of all registrants. Overall, infection was the most common clinically identified precipitant, with 38.1% and 34.5% of participants developing POTS postinfection in years 2 and 3 of the registry, respectively. The most common triggers overall were infection (39.4%), trauma or concussion (6.8%), vaccination (5.8%) and surgery (3.4%). The median delay from symptom onset to diagnosis for the cohort was 3.0 years (IQR 9.0; mean 6.7 years), with 25.5% experiencing a prolonged diagnostic delay of ≥10 years ( table 1 ). Women experienced significantly longer diagnostic delays than men (median 3.0 years, IQR 9.0; mean 7.0±8.6 vs median 1.75 years, IQR 3.4; mean 3.8±5.4; p=0.008) and more than a quarter of women (28.1%) experienced ≥10 years of diagnostic delay compared with 12.5% of men (p=0.012). There were no differences in diagnostic delays according to race (p=0.720). Over half of the participants (54.5%) reported presenting to the ED for symptoms prior to diagnosis, with a median of 4 visits (IQR 4; mean 5.1±4.5) across the entire cohort prior to diagnosis. A significant proportion of participants (66.4%) reported having physical symptoms initially attributed to anxiety. Participants reported consulting more than 5 doctors and 13% reported consulting more than 10 doctors prior to their POTS diagnosis ( table 1 ). P values in bold represent statistical significance. COMPASS-31, Composite Autonomic Symptom Scale; ED, emergency department. Those with higher autonomic symptom burden (COMPASS-31 ≥40) were more likely to attend EDs for symptom management prior to diagnosis (59.1% vs 50.0%; p=0.045). They also experienced longer diagnostic delays, consulted more physicians and were more likely to have their symptoms misattributed to anxiety prior to diagnosis (69.4% vs 57.8%; p=0.012) ( table 1 ). Those who experienced a longer diagnostic delay (≥10 years) to their POTS diagnosis were more likely to: be younger when symptoms commenced (median 14.0 years, IQR 8.0 vs median 23.0 years, IQR 18.0; p<0.001), consult more doctors before receiving a diagnosis (median 5.0, IQR 5.0 vs median 4.0, IQR 3.0; p<0.001) and see more specialists on an ongoing basis (median 8.0, IQR 6.0 vs median 7.0, IQR 6.0; p=0.003). The direct logistic regression model, including all predictors of a diagnostic delay of ≥10 years, demonstrated a statistically significant fit, χ 2 (5, n=500)=108.8, p<0.001. Among the predictors, three variables contributed significantly to the model: female sex, age at POTS symptom onset and hGJH. In an exploratory analysis, BMI was added to the model and remained non-significant (OR 1.031, 95% CI 0.993 to 1.070; p=0.107), supporting its exclusion from the primary model. Of these, hGJH emerged as the predictor with the strongest association, with these individuals being 1.9 times more likely to experience a diagnostic delay of ≥10 years compared with those without hGJH (OR 1.9, 95% CI 1.2 to 3.1, p=0.011). Multimorbidity was ubiquitous in this patient cohort with 91.8% having at least one other comorbidity. Approximately half of participants in this patient registry had been diagnosed with anxiety, migraine and iron deficiency requiring treatment ( table 2 ). Diagnosed neurodivergent disorders such as attention deficit disorder and autism spectrum disorder were present in 15.4% and 11.4%, respectively. Allergy and atopy were also common with frequent diagnosis of hay fever (40.8%), asthma (35.6%) and eczema (23%) ( table 2 ). Gynaecological disorders were also prevalent with 37.4%, 31.6% and 21.9% of women having physician diagnosed menorrhagia, dysmenorrhoea and endometriosis, respectively. Disorders frequently associated with POTS such as hEDS, hypermobile spectrum disorder (HSD) and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) were similarly prevalent in this cohort (29.0%, 35.3% and 26.8%, respectively) ( table 2 ). In total, 13.2% of the population had a clinical diagnosis of autoimmune disease ( table 2 ). POTS, postural orthostatic tachycardia syndrome. HrQoL was attenuated in the cohort, with a mean utility score of 0.59±0.24 (where 1=full health) and a global health rating of 45.9±20.8 out of 100 ( online supplemental file 2 ). Across the EQ-5D-5L quality of life subdomains, usual activities and pain and discomfort showed the greatest overall burden, with moderate to severe problems reported by 69.4% and 63.6% of participants, respectively ( figure 1 ). There were no significant age-related differences in the mobility, self-care or pain and discomfort domains. However, younger participants (16–34 years) reported more severe self-reported anxiety and depression compared with older groups (p<0.001), while older participants demonstrated more problems with usual activities (p=0.016). In self-care, moderate to severe problems were most prevalent among the youngest (16–19 years, 19.7%) and oldest (55+, 22.7%) age groups. For usual activities, the highest proportion of severe or extreme issues occurred in middle-aged cohorts, peaking in the 35–44 age group (43.7%). Although mobility did not differ significantly by age, moderate problems were consistently reported across all groups. Similarly, problems with pain and discomfort were common across all ages, with moderate to severe issues most pronounced in participants aged 35–54 years (65.9%) ( figure 1 ). Upper gastrointestinal symptoms were marked with 23.0% of the population having a GCSI score ≥2, suggestive of severe bloating, nausea and early satiety symptoms. Likewise, fatigue was also a universally predominant feature with 87.2% of those who had completed the survey (n=477) registering severe fatigue with a FSS score ≥36. The majority (60.8%) of the cohort reported historical hypermobility on the Hakim 5-point hypermobility scale which approximately correlated with the 64.2% of the cohort with a clinically confirmed diagnosis of either HSD or hEDS. High autonomic symptom burden, defined as a COMPASS-31 score of ≥40, was observed in 74.4% of the cohort. Demographically, women were overrepresented in this group (92.5% vs 84.4%; p=0.008) ( table 1 ). Joint hypermobility was also more common for those with high autonomic symptom burden, with 68.3% scoring ≥2 on the Hakim 5-point questionnaire compared with 49.2% of those with lower symptom burden (p<0.001). Likewise, hEDS was more frequent in this group (46.2% vs 29.9%; p=0.007) ( online supplemental file 2 ). Participants with high autonomic symptom burden were less likely to work full-time (15.9% vs 25.0%; p=0.016) and more likely to be unemployed (23.9% vs 16.4%; p=0.047). Social engagement was also reduced, with 28.5% engaging in outings less than monthly compared with 18.8% of those with lower symptom burden (p=0.018) ( table 1 ). Quality of life and symptom burden were also markedly worse in the high autonomic symptom group. These participants reported significantly lower global health ratings on the EQ-VAS (43.1±19.0 vs 54.1±23.3; p<0.001) and lower EQ-utility index scores (0.55±0.24 vs 0.72±0.20; p<0.001) ( figure 2 a). They also experienced significantly more problems across all five EQ-subdomains compared with those with lower autonomic symptoms burden (p<0.001; online supplemental file 3 ). Gastrointestinal symptoms were also more burdensome in this group (GCSI: 1.60±0.77 vs 0.89±0.63; p<0.001) and fatigue was more severe (FSS: 56.0±8.8 vs 48.0±14.5; p<0.001) ( figure 2 b,c, online supplemental file 2 ). Worse autonomic symptoms were moderately correlated with increased gastrointestinal symptomatology (rs=0.610, p<0.001) and inversely correlated with quality of life (rs=−0.478, p<0.001) ( figure 3 a,b).

This is the first study to comprehensively characterise a large cohort of physician diagnosed POTS patients. Several new findings are of significance, most notably higher autonomic symptom burden was associated with greater disability, fatigue, gastrointestinal burden and poorer quality of life. We provide new insights into the diagnostic delay for individuals living with POTS, highlighting female sex, younger age and joint hypermobility as significant factors associated with prolonged delay. Finally, we affirm prior findings of patient demographics of this population, broadly affecting females of childbearing age, the increasing contribution of SARS-CoV-2 infection as a trigger for symptom onset and ubiquitous multimorbidity across this population including conditions such as migraine, autoimmunity, neurodivergence, allergy burden and joint hypermobility. Worldwide registry data on POTS remains limited, with much of the current understanding derived from two large self-reported cohort studies: Shaw et al ’s survey of 3835 international respondents and a UK-based survey of 779 participants. 8 10 However, these studies rely on self-reported data, underscoring the need for clinician-verified registries to better capture the complexities of the condition. In terms of clinician-confirmed POTS, the available evidence comes from a single retrospective review conducted at the Children’s Hospital of Philadelphia, which evaluated clinical data from 708 paediatric patients during their initial outpatient assessment. 12 While this study provides valuable clinician-confirmed insights into paediatric populations, it underscores the lack of equivalent data for adults living with POTS. Our study addresses this gap, presenting the first large adult patient registry with physician-confirmed POTS. It substantiates earlier self-reported findings, shedding light on the severe socioeconomic and health impacts of POTS on young individuals during their formative and otherwise most productive years. The demographics of our study closely align with previous international cohorts. Shaw et al ’s study reported 93% White and 94% female participants, while Kavi et al found 92% female representation but did not report on race. Similarly, the Philadelphia paediatric cohort showed a female-to-male ratio of 3.45:1 (77.5% female) and 94.1% White. Consistent with these findings, participants in our study were predominantly White women of childbearing age. Further research is needed to elucidate whether these demographic patterns reflect true epidemiological trends or the ethno-geographical recruitment patterns of predominantly White English-speaking countries. Notwithstanding this, our findings closely reflect that found in international surveys from countries with socialised health services. Despite the significant functional impact of POTS, extended diagnostic delays are frequently reported. Notably, the mean diagnostic delay in our cohort was 1.4 and 1.8 times longer than that reported in the US and UK cohorts, respectively. 8 10 Consistent with international data, young women in our cohort were disproportionately affected by prolonged diagnostic delays, placing them at the highest risk of delayed care. 8 To the best of our knowledge, our findings are the first to identify the association between hypermobility disorders and diagnostic delay in POTS. As heritable connective tissue disorders are associated with higher burden of pain and gastrointestinal syndromes it is possible that the heterogenic nature of autonomic symptom manifestation heightens the risk for misdiagnosis of psychogenic disorders in young females delaying appropriate treatment. 26 We theorise that intercontinental differences in diagnostic delays may reflect sociocultural variations in healthcare systems, clinical awareness and referral pathways. In the USA a unique and distinct autonomic specialty training pathway exists, facilitating the development of autonomic clinics and specialised care. In contrast, Australia and other countries around the world, lack such a pathway, leading to greater reliance on primary care and fragmented referral to alternative specialties under which systemic autonomic disorders do not fully align. This is reflected in our cohort, who saw a median of 4 (mean 5.1) specialists before diagnosis. Furthermore, it is important to note our cohort represents individuals who were ultimately diagnosed with POTS after seeking specialist care, and thus diagnostic delays in the broader community are likely to be significantly longer. Likewise, the long diagnostic delays in our cohort may have resulted in a filtering of less severe presentations, resulting in an under-representation of more mild POTS presentations. Our data suggest limited clinical awareness of POTS. We previously demonstrated that 67% of Australian long-COVID patients with POTS faced challenges in accessing diagnosis and care, while 69% had to actively suggest POTS as a potential diagnosis to their healthcare provider. 7 The siloed management across specialties, limited clinical recognition of POTS, and high healthcare interaction likely lead to repetitive, low-yield diagnostics and the reported delays in effective treatment. These findings highlight the urgent need for improved clinical pathways and education to augment ubiquitous clinical recognition and treatment of POTS. In the absence of formal clinical guidelines for POTS, a recently published state-of-the-art review provides expert consensus-based practical guidance on the diagnosis and management of POTS for clinicians including general practitioners, recommending the COMPASS-31 as a patient reported outcome measure to assist in identifying and monitoring individuals with significant autonomic symptom burden. 27 Proximity of infection to POTS symptom manifestation has frequently been reported. 1 5 10 28 Indeed, this finding led to an initial hypothesis that POTS represents a milder form of an acute pandysautonomia. 28 More recently, an increase in POTS has been associated with SARS-CoV-2 infection, with prior work indicating a high prevalence of autonomic disorders, finding 79% of those with long-COVID meet the diagnostic criteria for POTS. 4 – 6 29 The 10.5% rise in viral precipitated POTS over 3 years reported in our registry, further supports these findings. Despite being younger in age, a high prevalence and diverse range of comorbidities are frequently reported in POTS populations. 8 10 15 30 This is reflected in this Australian population where the vast majority of participants in this study had at least one other clinically confirmed comorbidity. Migraine in POTS is particularly common with formerly reported prevalence rates ranging from 40% to 49%, reflecting our current findings. 8 10 Joint hypermobility syndromes are also associated with autonomic dysregulation. 31 Using the 2017 hEDS checklist, a previous study found that 31% of POTS patients met the criteria for hEDS and 24% for generalised joint hypermobility. 31 This is similar to our study, where 29.0% were diagnosed with hEDS and 35.2% with HSD. The lower prevalences in the previous UK (49% combined hypermobile disorders) and USA (25% EDS) studies likely reflect the self-reported nature of those surveys and the subsequent increase in clinical awareness of hypermobility syndromes since those findings were published. 8 10 ME/CFS is characterised by postexertional malaise and neuroimmune and autonomic symptoms. 32 In our study, 26.8% of participants had ME/CFS, similar to the 21% reported by Shaw et al and the 29% reported by Kavi et al. 8 10 Given the general population prevalence of ME/CFS (0.4% to 1.4%), the high concurrence with POTS across all these studies warrants further investigation of shared aetiology. Importantly, assessing for POTS in ME/CFS patients may facilitate targeted therapeutic interventions known to be effective in orthostatic disorders, potentially providing better symptom control where autonomic dysregulation is present. 15 Prior studies demonstrate depression and anxiety rates in POTS patients are similar to the general population. 33 Given both have similar somatic manifestations, distinguishing between the two can be challenging for clinicians. 34 In our study, 52.2% of participants had a clinical diagnosis of anxiety, higher than the 42.2% self-reported rate of moderate to severe anxiety on EQ-5D-5L. This baseline discrepancy may result from clinical under-recognition of POTS and the commonly reported misattribution of symptoms to psychogenic influences. 8 10 35 Clinical discrimination of these influences can be aided with collection of a thorough patient health history. Where symptom manifestation originates or worsens with orthostasis and resolves, or lessens, with recumbence there should be a high clinical suspicion of POTS. Moreover, use of adjunctive patient reported outcome surveys, such as the recently developed and validated Malmo POTS symptom score, may be used to confirm clinical suspicion and aid in ongoing monitoring of symptom management. 36 Neurodivergent disorders also appeared more commonly in this POTS cohort than in the general population with 15.4% having a confirmed diagnosis of attention deficit disorder (compared with 2%–6% of the Australian population) and 11.4% a diagnosis of autism spectrum disorder (vs 1.3% of the general Australian population). 37 38 Previous studies have suggested that neurodivergent individuals are at heightened risk of autonomic disorders, including POTS. 39 There is also an established crossover between hypermobility disorders and neurodivergence. 39 Emerging evidence suggests an association between POTS and autoimmune disorders, particularly those with a marked female predominance, such as Sjögren’s syndrome (89% female) and Hashimoto’s thyroiditis (87% female). 40 – 42 Our findings further substantiate this association, revealing that autoimmune conditions were nearly three times more prevalent in our cohort compared with the general population (13.2% vs 4.6%), and that coeliac disease was 3.8 times more common than that found in the Australian general public (5.32% vs 1.4%). 43 44 Notably, a prior European study also identified an elevated risk of joint hypermobility syndromes among individuals with coeliac disease, raising questions about whether this association arises from an inherent genetic predisposition or surveillance bias. 45 Collectively, these findings, alongside the known pronounced female predominance in autoimmune conditions and the well-established role of viral precipitants, such as SARS-CoV-2, in the development of POTS, lend compelling support to the hypothesis of an autoimmune-mediated pathophysiology in POTS. 44 This growing body of evidence underscores the urgency of advancing clinical recognition and promoting targeted research into possible autoimmune mechanisms underlying POTS to enhance diagnostic precision and therapeutic strategies. Our study is the first to elucidate the impact of broad autonomic symptom burden severity on a suite of patient reported outcome measures. Notably, current consensus-based treatment pathways for POTS predominantly focus on cardiac autonomic regulation through vasopressor enhancement, plasma volume expansion and heart rate control, while largely neglecting other domains of autonomic regulation. 15 These treatments are known to be of modest efficacy, likely because they target only a subset of the systemic autonomic dysregulation present in POTS. 46 Other, often overlooked autonomic symptoms, particularly gastrointestinal dysfunction, significantly impact quality of life and demand greater clinical and research attention. 1 Additionally, the autonomic nervous system plays a critical role in endocrine function, including the regulation of insulin and glucose metabolism. Evidence of dysregulation of this function in POTS has already been demonstrated, raising concerns about the potential long-term effects of insulin imbalance, though research in this area remains limited. 47 Addressing these gaps requires urgent interdisciplinary collaboration in research and clinical translation to develop comprehensive, holistic management strategies and drive meaningful improvements in outcomes for a new generation of individuals living with POTS. Prior work has demonstrated that both orthostatic intolerance and other autonomic symptom domains, including gastrointestinal, secretomotor and pupillomotor functions, are strong predictors of worse HrQoL in POTS. 1 48 Our findings add new understanding and demonstrate that higher autonomic symptom burden is also associated with increased healthcare utilisation and work, educational and social withdrawal. These findings are particularly sobering given the rising prevalence of POTS due to COVID-19 and the substantial socioeconomic burden it imposes on both individuals and society. 6 With the condition disproportionately affecting a young population, the implications are far-reaching, with potential to disrupt education, career trajectories and economic productivity for decades to come. Fortunately, international consensus statements and state of the art reviews do provide best-practice pathways for diagnosis and cardiac autonomic treatment of POTS and stand as readily transferable resources to inform the management of autonomic dysregulation in associated conditions such as long-COVID and ME/CFS. 15 49 – 51 Implementation of such pathways would be optimally supported by training and professional development of primary care physicians with multidisciplinary supports to address the increasing burden of chronic autonomic disorders worldwide. Additionally, upskilling and involvement of physicians outside of cardiologists who frequently manage this population is an important consideration given the extensive symptom burden and comorbidity profile of this complex and heterogenous population. Importantly, our findings add weight to international calls for investment in research that prioritises appropriately powered, longitudinal studies to ascertain the efficacy of therapeutic treatments in attaining sustained improvement in autonomic symptoms, as well as functional and quality of life outcomes in POTS. 9 11 46 There are several limitations to this study. First, these data are cross-sectional and single centre in nature. To redress these inadequacies additional longitudinal data from multiple centres are needed. Second, the study may have unintentionally excluded the more severely affected or symptomatic individuals with POTS, as they are often impeded by severe fatigue and brain fog, limiting ability to complete online surveys and attend in person medical appointments. Due to the lack of specific public health clinics for POTS in Australia, the participants in this study were also seen in a private clinic, likely impacting on demographic and socioeconomic data. Finally, our cohort consisted predominantly of White female participants, which may limit generalisability to more diverse populations. However, this demographic profile is consistent with internationally published POTS cohorts and highlights an important evidence gap regarding the presentation and outcomes of POTS in racially and ethnically diverse populations.

This study is the first to comprehensively characterise a large cohort of physician-confirmed POTS patients in Australia and is the first large adult population studied globally. It highlights the significant clinical, socioeconomic and quality-of-life burdens associated with POTS, particularly for young women of childbearing age. Key findings include diagnostic delays, high symptom burden, poor HrQoL, substantial multimorbidity and a strong link with SARS-CoV-2 infection as a precipitant. These results align with earlier self-reported data while providing a robust, clinician-confirmed foundation for future research. However, as recruitment was limited to a single private specialist clinic and the majority of participants were White and female, findings may not fully generalise to all individuals living with POTS, particularly those in public health settings or from more diverse socioeconomic and cultural backgrounds. Multicentre studies across varied healthcare settings are needed to confirm and extend these findings. The study underscores the association between autonomic symptom burden and reduced education, employment and social participation, emphasising the need for targeted therapeutic strategies and tailored rehabilitation pathways for this predominantly young population. It highlights the urgent need for investment in longitudinal research, innovative therapies and policy reform to address the growing needs of this population.