Postural orthostatic tachycardia syndrome (POTS) is a cardiovascular autonomic disorder, characterized by a heart rate (HR) increase >30 beats per minute (bpm) or a HR of >120 bpm within 10 min upon standing, and no significant reduction in blood pressure (BP) (Brignole et al., 2018; Vernino et al., 2021). To fulfill the diagnostic criteria, the patient must have chronic symptoms (>3 months) of orthostatic intolerance, i.e., palpitations, blurred vision, fatigue, and lightheadedness upon standing that improve when the patient returns to supine position. Other causes of tachycardia and orthostatic intolerance, such as anemia, should be ruled out (Vernino et al., 2021; Raj et al., 2022). As diagnostic tool, the head up tilt test can be performed to measure HR and BP responses from supine to standing (Brignole et al., 2018). The more easily performed active standing test can be used as well, with the same diagnostic criteria (Brignole et al., 2018; Fedorowski, 2019). The epidemiology of POTS is not fully explored, but previous studies estimate a prevalence ranging from 0.2% to 1.0% in the U.S. population, with females over-represented with a 4:1 ratio, especially in younger ages (Fedorowski, 2019). POTS frequently presents with chronic comorbidities or conditions that are unrelated to orthostatic intolerance, such as migraine, fibromyalgia, chronic fatigue, and allergic disorders (Liao et al., 2017; Chelimsky and Chelimsky, 2018). Hypermobile spectrum disorders (HSD) including hypermobile Ehlers-Danlos syndrome (hEDS) are also more common in POTS (Miller et al., 2020; Tai et al., 2020). Autoimmunity has been proposed as a possible etiological mechanism in POTS, with high prevalence of diverse antibodies in previous reports (Fedorowski, 2019). Moreover, increased prevalence of co-morbid systemic autoimmune rheumatic disorders have been reported in POTS (Mannan and Pain, 2023), but causative autoantibodies have not been found so far (Vernino and Stiles, 2018). Mast cell activation disorder has been proposed to be associated with POTS with atypical symptom presentation, such as predominant gastrointestinal (GI) symptomatology (Kohno et al., 2021).

GI symptoms are very frequent in POTS, well described in several studies (Chelimsky and Chelimsky, 2018; DiBaise et al., 2018; Mehr et al., 2018; Tu et al., 2020). Some GI symptoms may be triggered by orthostatic challenge, and are thereby relieved in recumbent position, whereas most other GI complaints are non-orthostatic (Chelimsky and Chelimsky, 2018; Tu et al., 2020). The enteric nervous system is a part of the autonomous nervous system (Gibbons, 2019), receiving input from parasympathetic and sympathetic nerves, as well as input from the central nervous system (Koloski et al., 2012; Mehr et al., 2018). Disturbances of the enteric nervous system can cause GI disorders such as gastroparesis, and symptoms like pain and altered bowel habits (Camilleri, 2021). Since POTS is associated with disturbances of the cardiovascular autonomic nervous system (Vernino et al., 2021), our hypothesis was that more exaggerated pulse increase on tilt testing is associated with more severe GI symptoms, as a surrogate marker of autonomic and enteric nervous dysfunction.

Consequently, the first aim of this study was to explore GI symptoms in a POTS cohort compared with healthy controls using validated GI symptom questionnaires, and to investigate whether GI symptoms correlated with pulse increase during tilt test as a surrogate of disease severity. The second aim was to explore the prevalence of common autoantibodies found in systemic autoimmune rheumatic disorders, as well as markers of allergy and mast cell activation in POTS, compared with controls, and to investigate whether these immunological factors are associated with GI symptoms.

The main finding of the present study was that patients with POTS have a high burden of GI- and extraintestinal symptoms, compared with healthy controls. The most prevalent symptoms were nausea, abdominal fullness, and bloating. The most severe GI symptoms were bloating and flatulence, and constipation. GI symptoms were associated with low psychological wellbeing. Importantly, the magnitude of HR acceleration on the initial tilt test was inversely correlated with GI symptoms, i.e., a pronounced HR acceleration at diagnosis was associated with less severe chronic GI symptoms. Finally, there was no overexpression of circulating autoantibodies commonly seen in systemic autoimmune rheumatic diseases, or elevated baseline tryptase levels among POTS patients, and there was no association between autoantibodies and GI symptoms.

To our knowledge, this is the first study where specific GI symptoms have been studied in a POTS cohort in terms of prevalence and the degree of severity on validated GI symptom scales. Additionally, this is the first study that has investigated how the hemodynamic response, as well as signs of autoimmunity, correlated with specific GI- and extraintestinal symptoms.

The results are in line with previous studies examining GI symptoms in POTS (Huang et al., 2013; Wang et al., 2015; Mehr et al., 2018; Tai et al., 2020). In a review by Mehr et al. (2018), pooled data from six original articles showed that the most common, non-cardiovascular symptoms in POTS were nausea and abdominal pain. Conceptually, there is an important difference between orthostatic and non-orthostatic GI symptoms in POTS (Chelimsky and Chelimsky, 2018). Orthostatic GI symptoms, such as nausea and vomiting, can be relieved by recumbent position and cardiovascular treatment strategies (Sullivan et al., 2005; Fortunato et al., 2014), whereas non-orthostatic GI symptoms require other management strategies (Chelimsky and Chelimsky, 2018). Multisystem comorbid conditions are common in POTS, including functional GI disorders (FGID) (DiBaise et al., 2018). However, there is no evidence that POTS itself contribute mechanistically to these conditions, according to a previous study in children (Chelimsky et al., 2015). In the present study, the most severe GI symptoms were bloating and flatulence and constipation. These items are probably non-orthostatic, rather representing comorbidities. Twenty-eight percent of the POTS group reported a diagnosis of IBS, and the median total IBS-SSS score in POTS was 213, corresponding to moderate IBS (Francis et al., 1997). Moreover, 28% reported HSD/EDS and previous research has shown that HSD/EDS is associated with FGIDs, with and without POTS (Beckers et al., 2017; Fikree et al., 2017; Tai et al., 2020). In addition, seven patients reported a concomitant organic GI disorder. Hence, comorbid functional and organic GI disorders may explain the magnitude of GI symptoms in POTS in this study.

Almost all GI symptoms correlated with low psychological wellbeing in the present study. It is well known that low psychological wellbeing is associated with IBS and other FGIDs, where bilateral communication between the brain and the gut results in visceral hypersensitivity (Koloski et al., 2012; Ford et al., 2020). In POTS, previous studies have shown mild to moderate depression and anxiety levels, as well as positive associations between the degree of depression and self-rated orthostatic symptom burden (Raj et al., 2018). Somatic hypervigilance has been described in POTS (Khurana, 2006; DiBaise et al., 2018), suggesting central visceral sensitization (DiBaise et al., 2018). Previous studies regarding FGIDs have shown that lower psychological wellbeing is associated with less effective central pain modulation (Marcuzzi et al., 2019), including an increased membrane excitability, a facilitated synaptic strength, and decreased inhibitory influence on the dorsal horn neurons, all contributing to an abnormal responsiveness to noxious and non-noxious stimuli (Latremoliere and Woolf, 2009; Ossipov et al., 2014). According to a previous study, IBS patients with lowered pain thresholds upon testing also have higher circulating levels of cortisol and corticotrophin, as well as higher blood pressure, indicating a disturbed hypothalamic-pituitary-adrenal axis, possibly due to higher stress levels (Chang et al., 2009; Zhou et al., 2010). It is tempting to believe that these mechanisms contribute to central sensitization and hypervigilance in POTS as well. However, in the setting of the present study, we cannot draw any conclusions whether GI symptoms in POTS are caused by lowered psychological wellbeing with increased hypersensitivity, or vice versa.

To further explore the nature of GI symptoms in POTS, correlation tests were performed between symptoms and hemodynamic parameters. Surprisingly, there was a significant inverse correlation between maximum orthostatic HR acceleration at diagnostic tilt test and abdominal pain. The inverse correlation between HR acceleration and various chronic GI symptoms became even more distinct when the patients with organic GI disorders were excluded from the analyses. The same tendency between hemodynamic data and GI symptoms was seen when analyzing the active standing test performed a few years after the tilt test, closer to the recruitment period of the present study.

There are some possible theoretical explanations to the findings regarding the inverse correlation between orthostatic HR acceleration and GI symptoms among POTS patients. First, there may be a possible treatment bias. Patients who present with a pronounced HR acceleration may receive more aggressive treatment or more active follow-up. Active advice on higher salt- and fluid intake, as well as prescription of some cardiovascular drugs, often result in improvement of the typical orthostatic GI symptoms (Sullivan et al., 2005; Fortunato et al., 2014). A second explanation to the finding is that POTS represents a heterogenous syndrome rather than a disease, where multiple mechanisms can affect the phenotypic outcome (Mehr et al., 2018; Fedorowski, 2019). Some of the most important pathophysiological mechanisms behind POTS are (I) a hyperadrenergic state, (II) partial autonomic neuropathy, (III) a persistent predilection for hypovolemia leading to reflex orthostatic tachycardia, and (IV) physical deconditioning (Benarroch, 2012; Tu et al., 2020; Raj et al., 2022). These mechanisms interact; thus, one patient can exhibit characteristics from two or more of these pathophysiological mechanisms (Tu et al., 2020). Signs of autonomic neuropathy and distal peripheral neuropathy are seen in approximately 50% of the POTS population (Low et al., 2009). GI motility disorders are well described in POTS (Huang et al., 2013; Park et al., 2013; Loavenbruck et al., 2015), where up to 18% have delayed gastric emptying, and up to 48% have rapid gastric emptying (Loavenbruck et al., 2015). These disturbances may be considered manifestations of neuropathy. In a study by Gibbons et al. (2013), the HR increasement at tilt test was less pronounced in POTS patients with signs of neuropathy, compared with non-neuropathic POTS. More exaggerated GI symptoms have been reported in neuropathic POTS (Al-Shekhlee et al., 2005). Thus, neuropathic POTS may explain why a subset of patients in the present study exhibit more GI symptoms, but less pronounced HR acceleration. Lastly, more pronounced GI symptoms and less exaggerated orthostatic pulse acceleration were measured in the 28% with self-reported HSD/EDS in the present study. The mechanistic association between POTS and HSD/EDS is not entirely clear (Tai et al., 2020), but common mechanisms behind HSD/EDS and POTS may partly explain the inverse correlations between GI symptoms and HR acceleration in the present study.

Autoantibody microarray assay did not show any difference in expression of autoantibodies commonly found in systemic autoimmune rheumatic disorders, when comparing POTS with controls. Previous studies have shown that comorbid autoimmune disorders in POTS are prevalent (Vernino and Stiles, 2018; Vernino et al., 2021), as in our study, where approximately one-third of participants self-reported such disorders. However, contrasting our study, Blitshteyn (2015) observed in a retrospective study that the prevalence of antinuclear antibodies (ANA) and anti-phospholipid antibodies (aPL) were higher in POTS compared with the normal population. The results were compared with known cut-off values for normal population, and not with comparable controls (Blitshteyn, 2015). Further, others reported ganglionic acetylcholine receptor (AChR) autoantibodies and G-protein coupled receptor autoantibodies being more expressed in POTS, but the pathological significance remains uncertain (Vernino and Stiles, 2018). In the present study, no association was seen between expression of autoantibodies and any GI symptoms, suggesting that systemic autoimmunity is not a major driver of GI symptoms in POTS.

Allergic comorbidity and medications were common in the present study, and total IgE was elevated in a subset of patients. However, baseline total serum tryptase was only slightly elevated in one patient. GI symptoms were not more pronounced in patients with self-reported allergic disorders or on anti-allergic medications. Thus, the present study could not confirm the results by Kohno et al. (2021), who were suggesting that mast cell activation is a major driver of atypical POTS symptoms such as GI complaints.

The strength of this study is use of different validated scoring systems for assessment of GI symptom burden. The patients were thoroughly examined at a tertiary cardiovascular center with a syncope unit. The tilt data was present in all patients, and active standing test was performed in 88% of the patients at a later time point, which had the same correlation tendency to GI symptoms as the tilt test did, reflecting robustness of the findings. In addition, all patients were examined clinically at inclusion.

One limitation to the study may be a selection bias since POTS patients were recruited from a highly specialized center, and thus, might have more exaggerated symptoms than the POTS population in general. Furthermore, 82 patients with POTS were invited to the study, but only 43 ended up at inclusion. This is a limitation that has some explanations. Firstly, we wanted to examine the patients physically, and many patients declined to participate in the study due to long distance to the study center. In addition, some of the patients were hindered by severe orthostatic symptoms. Lastly, the study was conducted during the covid pandemic, and some patients were excluded due to covid symptoms. Another limitation was that a control group recruited from hospital staff might be healthier with less symptoms than controls recruited more randomly. All data on comorbidities were self-reported, which is especially problematic when it comes to HSD/EDS, as these diagnostic terms are used inconsistently among patients according to previous studies (Tai et al., 2020). Both HSD and EDS present with musculoskeletal symptoms and joint hypermobility, but whereas EDS is a rare disorder of the connective tissue with various systemic manifestations, HSD is more common, affecting approximately 3% of the population, but without systemic manifestations (Miller et al., 2020). However, the prevalence rates regarding self-reported HSD/EDS were fairly in line with previous studies (Miller et al., 2020; Tai et al., 2020). The patients were not asked whether GI symptoms worsened upon standing, which would have been interesting, to discriminate between orthostatic and non-orthostatic GI symptoms. Another limitation was that the tilt tests were performed some years ago in several patients, although the diagnosis was confirmed by active standing test during enrolment. Regarding measurement of baseline tryptase, the study was not designed to diagnose mast cell activation syndrome, where tryptase must be measured both at baseline, and upon acute symptoms. The patients were not fasting at blood sampling, and two patients were on oral mast cell stabilizing therapy. Finally, pharmacological treatment was abundant among POTS patients. Several of the reported agents, including opioids and cholinesterase inhibitors, are known to cause adverse GI symptoms (Kanjwal et al., 2011; Drewes et al., 2016).

A recent Indian study (Inbaraj et al., 2023) has investigated heart rate variability (HRV) in POTS, based on the assumption that HRV is the most reliable marker of cardiovascular autonomic dysfunction, showing affected HRV parameters in POTS compared with controls (Inbaraj et al., 2023). Based on the results from that study, future studies would be to further investigate the relationship between GI symptoms and parameters of HRV in POTS.

Gastrointestinal symptoms are common in POTS and are associated with low psychological wellbeing. More pronounced tachycardia during tilt testing or active standing test is associated with less severe GI complaints in POTS. This finding may reflect different contributing pathophysiological mechanisms and comorbidities in POTS. Finally, this study did not find any evidence supporting that POTS is associated with conventional biomarkers of autoimmunity.