Authors: Austin C. Hogwood (1Berne Cardiovascular Research Center, University of Virginia, Charlottesville, VA, USA), Gerardina Abbate (1Berne Cardiovascular Research Center, University of Virginia, Charlottesville, VA, USA), Georgia Thomas (2VCU Pauley Heart Center, Department of Internal Medicine, Virginia Commonwealth University, Richmond, VA, USA), Roshanak Markley (2VCU Pauley Heart Center, Department of Internal Medicine, Virginia Commonwealth University, Richmond, VA, USA), Anna G. Priday (1Berne Cardiovascular Research Center, University of Virginia, Charlottesville, VA, USA), Ross Arena (3Department of Physical Therapy, College of Applied Health Sciences, University of Illinois Chicago, Chicago, IL, USA), Antonio Abbate (1Berne Cardiovascular Research Center, University of Virginia, Charlottesville, VA, USA), Justin M. Canada (2VCU Pauley Heart Center, Department of Internal Medicine, Virginia Commonwealth University, Richmond, VA, USA)
Categories: Article, cardiac output, cardiopulmonary exercise test, heart rate, POTS, stroke volume
Source: Exercise, sport & movement
Authors: Austin C. Hogwood, Gerardina Abbate, Georgia Thomas, Roshanak Markley, Anna G. Priday, Ross Arena, Antonio Abbate, Justin M. Canada
Postural orthostatic tachycardia syndrome (POTS) is characterized by increased heart rate (HR) with standing and is associated with dizziness, palpitations, and exercise intolerance, with poorly understood mechanisms.
To review the literature on cardiorespiratory fitness in POTS, and explore possible determinants of exercise intolerance.
Systematic review of studies assessing exercise capacity in POTS.
Eligible studies were original prospective and retrospective cohort studies and randomized controlled trials investigating formal exercise assessments (maximal exercise duration with or without gas exchange oxygen consumption (VO2) measures) in patients with established POTS using standard criteria.
A literature search revealed 199 unique studies, of which we identified 17 cohorts with 1321 subjects with POTS and 502 age- and sex-matched controls. Peak VO2 was measured in 15 studies and exercise hemodynamics (stroke volume (SV), cardiac output) was measured in 10 studies.
Outcome measures were peak VO2, gas exchange parameters, and hemodynamics (i.e., HR, SV, cardiac output).
All studies described higher HR at standing and submaximal exercise, with earlier peak HR in POTS. Peak VO2 was reduced in 80% of studies, but only in 30% when matched for deconditioning. Seven of 10 studies (70%) reported reduced SV with standing/exercise versus controls, but only 10% showed reduced cardiac output. Intravenous fluids did not affect hemodynamics or peak VO2. Exercise training, as well as propranolol, improved peak VO2.
Patients with POTS reach peak HR faster. Increased HR accompanies reduced SV, but cardiac output is generally maintained or increased, making it unlikely to cause symptoms. Reducing HR may improve exercise capacity in POTS by delaying peak HR and reducing symptoms.
Postural orthostatic tachycardia syndrome (POTS)—characterized by an increase in heart rate (HR) of ≥30 bpm with standing without a decrease in systolic blood pressure of >20 mmHg—is associated with symptoms such as dizziness, palpitations, and/or chest pain (1). POTS disproportionately affects young women, often athletes, and is associated with exercise intolerance. Although the etiology of POTS is unclear, the prevailing hypothesis is that a reducted blood volume and a small left ventricle (LV) result in a reduced preload and stroke volume (SV) with standing, triggering a compensatory increase in HR to maintain cardiac output. Under this classic paradigm, the increase in HR with standing and exercise is insufficient to compensate for the reduced SV and, therefore, cardiac output is insufficient and exertional symptoms occur. It is also possible that the excessive increase in HR causes a decrease in SV, whereby the symptoms and exercise intolerance experienced by patients are a reflection of the adrenergic activation associated with the HR and respiratory rate (RR) increases, with associated changes in carbon dioxide (CO2) levels and cerebral perfusion, while cardiac output remains mostly unchanged. Accordingly, patients with POTS often experience notable symptom relief with exertion and HR lowering agents such as propranolol or ivabradine (2–4).
Several studies have attempted to address how the HR response in POTS affects exercise capacity or exertional symptoms (2–4). Cardiopulmonary exercise testing (CPET) with or without hemodynamic assessment is used to assess aerobic exercise capacity and to elucidate mechanisms of exercise intolerance. The burden of symptoms in POTS may lead patients to abstain from exercise and, thus, also cause deconditioning, aggravating aerobic exercise capacity and, more broadly, cardiorespiratory fitness (CRF), impairing quality of life (5).
The purpose of this study was to systematically review the literature for studies measuring cardiorespiratory fitness in patients with POTS, identify possible determinants of exercise intolerance, and assess the efficacy of interventions in patients with POTS.
We included original prospective and retrospective cohort studies, and randomized control trials that investigated formal exercise assessments (maximal exercise duration with or without gas exchange oxygen consumption (VO2)) in patients with established POTS using standard criteria.
Electronic databases (PubMed and Cochrane library) were searched for articles written in English and published through March 2025. The search terms were “exercise” and “postural orthostatic tachycardia syndrome.” The reference lists of all studies were also examined to identify further studies for inclusion. The study selection process is depicted in Fig. 1. This systematic review was registered in PROSPERO (CRD420250655716).
Titles and abstracts of articles were screened for eligibility manually using Covidence systematic review software (Veritas Health Innovation, Melbourne, Australia). The following criteria were determined a priori for 1) a diagnosis of POTS by standard criteria (1) and 2) a formal assessment of exercise capacity (maximal exercise duration with or without gas exchange VO2). The diagnosis of POTS requires an increase in HR of ≥30 bpm when standing (or ≥40 bpm in individuals 12–19 yr old) with an absence of orthostatic hypotension (>20 mmHg drop in systolic blood pressure) (1). The interventions under consideration were maximal or submaximal exercise tests. Patients with POTS were compared to either age- and sex-matched controls or percent predicted data. The outcomes of interest were gas exchange parameters such as peak VO2, predicted peak VO2, oxygen (O2) pulse, minute ventilation/CO2 production (VE/VCO2), and partial pressure of end-tidal CO2 (PETCO2), and exercise hemodynamics such as HR, blood pressure, SV, and cardiac output.
Full texts of the studies identified were reviewed to determine eligibility. Two investigators (A.C.H. and G.A.) independently completed study selection, and a senior investigator (A.A.) reviewed all screened studies for accuracy. The following data was extracted from articles meeting inclusion authors, year, age, male ratio, peak VO2, percent predicted peak VO2, hemodynamics (i.e., HR, SV, cardiac output, blood pressure), any relevant measures from CPET (i.e., O2 pulse, VE/VCO2, and PETCO2), and any interventions performed. The abstracted data is reported as either n and % or median and interquartile range.
Study quality was assessed using the study quality assessment tools developed by the National Heart, Lung, and Blood Institute (6). The tools are designed to assist reviewers in the critical appraisal of each study, focusing on key areas of internal validity. Areas such as flaws in methods, implementation, confounding, study power, blinding, and/or bias are considered. The appropriate quality assessment tool was chosen based on the design of each study. For each response, reviewers can select “yes,” “no,” “not reported,” “not applicable,” or “cannot determine.”
The literature search revealed 199 unique studies, of which 17 cohorts were identified across 19 studies meeting eligibility criteria (Fig. 1) (5,7–24). A total of 1321 subjects were studied (1194 females, 127 males; male ratio, 1), with 11 of the studies including a total of 502 age- and sex-matched controls (Table 1). Cycle ergometers were used in 13 studies (791 subjects, 60%) and treadmills in 4 studies (530 subjects, 40%). Peak VO2 was measured in 15 studies (1053 subjects, 80%). Exercise hemodynamics (e.g., SV and cardiac output) were reported in 10 studies (609 subjects, 46%).
Of the 17 studies included, three were case-control studies (7,21,23) (Supplemental Content 1, table), 10 were observational cohorts and cross-sectional studies (5,9,11,15–20,24) (Supplemental Content 2, table), two were controlled intervention studies (12,22) (Supplemental Content 3, table), and two were pre-post studies with no control groups (10,14) (Supplemental Content 4, table). All studies were deemed to be either “good” or “fair” quality. Studies were generally downgraded in quality based on study design, sample size, outcome measures, and clarity of data presentation.
All 17 (100%) studies described higher HR at rest, and 13 of the 17 (76%) studies reported a higher peak HR during exercise. Of the 13 studies that reported peak HR, eight studies (62%) compared peak HR between patients with POTS and a control; peak HR was similar in five of the eight (63%) studies (10,12,16,19,24), and higher in patients with POTS in the remaining three (37%) studies (11,18,21). In the one study comparing maximal HR to percent predicted HR, maximal HR was lower than predicted (20). In eight studies that assessed submaximal HR responses or slopes, seven (88%) studies described greater submaximal HR in patients with POTS (7,9–11,18,21,23), whereas one (13%) study showed no difference (16). Only one (13%) study assessed submaximal HR responses to exercise as a function of a relative workload, showing higher HR in POTS versus controls at both 50% and 70% of HR reserve (18).
Peak VO2 was reduced in 12 of 15 (80%) studies when compared with predicted values, but only in 3 of 10 (30%) studies with a comparator group matched for deconditioning (10,12,21). Three studies (18%) used treadmill exercise, all of which assessed and reported decreased peak VO2 compared to predicted (10,11,18). The remaining 14 studies (82%) used cycle ergometry, two of which tested with recumbent cycling (12,14). Submaximal exercise was assessed in isolation in four (24%) studies (7,17,21,23), with seven (41%) studies reporting both submaximal and maximal responses (9,10,12,14,16,18,20).
Six (35%) studies (11,16,17,20,22,24) reported other CRF metrics in addition to peak VO2. Four (24%) studies reported O2 pulse (16,17,20,22), of which only two studies compared patients with POTS to a subset of patients with chronic fatigue or predicted values (16,20), reporting no differences in peak O2 pulse. Respiratory rate was reported in two (12%) studies (13,20), with similar values in POTS versus orthostatic intolerance syndrome without tachycardia (13). Both VE/VCO2 and PETCO2 were each only reported in two (12%) studies (16,20), with worse ventilatory efficiency (elevated VE/VCO2) noted in both. Hyperventilation (low PETCO2) was also seen in adult patients with POTS compared to predicted values (20), with the lowest PETCO2 values corresponding to symptoms of dizziness as the cause of stopping exercise in one study (16). Minute ventilation was reported in two (12%) studies but not compared to a control or predicted values (17,20).
SV and cardiac output were assessed in 10 out of the 17 studies (59%). The methods included inert gas rebreathing in eight (80%) studies (7,9,10,12,14,16,17,22), Doppler echocardiography in one (10%) study (21), and right heart catheterization in one (10%) study (24). Seven of 10 (70%) studies that assessed hemodynamics reported reduced SV with standing and exercise compared with controls (7,9,10,12,21,22,24), whereas only one study (10%) documented reduced cardiac output with exercise versus controls (10). In two studies (12%) that enrolled teenagers, SV and cardiac output were variably increased (17,21). Four studies (24%) assessed the increase in cardiac output relative to increases in VO2, with two (50%) showing similar cardiac output/VO2 relationships (9,10). The two other (50%) studies stratified adolescents with POTS by the cardiac output/VO2 ratio and found that most patients (60–70%) had normal cardiac output/VO2 relationships, but 15% had either a higher or lower cardiac output/VO2~ relationship (16,17).
Only three studies (18%) reported hemoglobin concentrations (7,13,18), with none comparing hemoglobin between patients with POTS and controls. Hemoglobin concentrations were normal in all studies (7,13,18). Two studies (12%) measured blood volume (10,14). One study used a carbon monoxide rebreathing technique, reporting reduced blood volume versus controls, increased blood volume with exercise training, and a relationship between blood volume and peak VO2 (10); the other study used labeled serum albumin, reporting that patients with POTS had blood volume deficits suggestive of hypovolemia (14).
Interventions were completed in fives studies (29%) (7,10,12,14,22). In one study, 1 L of intravenous saline was administered prior to recumbent cycling (14). Hemodynamics measured with inert gas rebreathing showed that fluid administration increased SV and cardiac output only at rest, with no differences in SV, cardiac output, or VO2 during exercise at 75 watts (14). In another study (7), both patients with POTS and controls were administered overnight intravenous saline (125 mL/h for 8 h) prior to performing either supine or seated submaximal cycling exercise. Patients with POTS had higher HR at all timepoints in both supine and upright cycling compared with controls, but only a reduced SV in the upright position (7). Cardiac output was similar between patients with POTS and controls regardless of exercise workload or position (7).
Exercise training was performed in two studies, with both assessing hemodynamics via acetylene rebreathing (10,22). In one study, 19 patients with POTS completed a maximal CPET with submaximal and maximal cardiac output before and after a three-month combined aerobic and resistance training plan (10). The training included aerobic exercise at a goal of 75% of peak HR for 30–45 min 2–4 times per week and resistance training for 15–20 min once per week, with both duration and intensity increasing in each modality over time (10). After training, HR was lower at all submaximal workloads, SV increased at each workload including maximal, with cardiac output unchanged at submaximal workloads but increased at maximal exercise (10). Blood volume also increased with exercise (10). Values were compared to 10 healthy controls, with those with POTS having lower peak VO2 and SV, which remained lower after exercise training despite a similar cardiac output to VO2 relationship between those with POTS and controls (10).
In another study, 49 patients with POTS completed a maximal CPET with submaximal cardiac output before and after three months of either a semi-supervised aerobic exercise training program (n=26) or a standard-of-care intervention (n=23) (22). Training included eight supervised in-person/virtual exercise sessions (weekly and then biweekly) with a goal of 75–85% of peak HR for 20–30 min per session in three sessions per week. Exercise improved peak VO2, reduced HR at anaerobic threshold (AT), reduced rating of perceived exertion and dyspnea at AT, and improved peak O2 pulse without changing SV, total peripheral resistance, or cardiac output at either 25 watts or AT (22).
Beta-adrenergic blockade was tested in one study (12). Eleven patients with POTS and seven healthy controls completed a CPET, with cardiac output assessed via an inert gas rebreathing technique at rest and 75 watts, after either 20 mg of propranolol or placebo (12). Propranolol reduced peak HR in both groups (12). In patients with POTS, propranolol reduced HR, increased SV, and increased peak VO2 (12).
To our knowledge, this is the first systematic review to synthesize findings on exercise testing in patients with POTS. Patients with POTS show an excessive increase in HR with standing and submaximal exercise, which leads to an earlier achievement of peak HR and earlier exercise interruption versus healthy controls, as well as when compared with individuals matched for deconditioning.
Aerobic exercise capacity, while influenced by multiple factors, is primarily driven by differences in the increase in cardiac output during exercise. Given the centrality of the HR response in POTS, we sought to understand the relationship between HR and aerobic exercise capacity, a central component of CRF, and how the HR response affected SV and cardiac output (Fig. 2).
In 2010, Fu et al. (25) described a reduced cardiac size leading to reduced SV in patients with POTS versus controls, and proposed that chronic impairment in preload leads to remodeling of the heart to a smaller size, rendering it unable to maintain an adequate SV and cerebral perfusion when standing. Since then, the prevailing or classic paradigm of the pathophysiology of POTS has rested on tachycardia being a compensatory mechanism and exercise intolerance deriving from insufficient compensation and reduced cardiac output with exercise compared with controls. The results of this review challenge and expand the paradigm. We showed HR was consistently higher and SV lower in patients with POTS, but there were largely no significant differences in cardiac output between groups. Further, we found that, although the increase in HR with exercise is associated with a reduction in SV versus controls, cardiac output with exercise is generally comparable to healthy controls. This raises the question of whether the increase in HR is compensatory to the reduced SV or the reduced SV simply parallels the excessive increase in HR in those with POTS. Indeed, most studies have demonstrated preserved cardiac output in patients with POTS compared to controls (7,9,12,14,16,17,21,22,24). Although only one study showed a decrease in cardiac output with exercise (10), two studies in adolescents showed that different subgroups of patients with POTS exist where cardiac output variably changes with exercise, increasing in one subgroup but not another (16,17). Collectively, currently research suggests that lower cardiac output with exercise in those with POTS versus controls is unlikely to be the sole mechanism responsible for impaired exercise capacity in those with POTS (Fig. 3).
Reduced blood volume and venous return are additional proposed pathophysiologic mechanisms in POTS (26). The increase in HR would represent a compensatory mechanism due to reduced preload and SV. Along these lines, Figueroa et al. (14) attempted to reverse the impairment in exercise capacity in those with POTS by increasing preload with intravenous fluids. Although the infusion of fluids increased resting SV, it did not change resting HR and did not alter exercise SV or HR (14). This supports that the increase in HR in patients with POTS is not compensatory to decreased SV and increased preload does not result in improved exercise capacity.
The finding of a higher HR in supine and standing positions, and reaching peak HR earlier in the exercise phase with a maintained HR/workload slope is of interest. Although the increase in HR is considered the result of enhanced adrenergic signaling (i.e., higher norepinephrine and/or adrenergic receptor signaling), it is of note that tachycardia may itself be part of an expanded pathophysiological paradigm by which the tachycardia and ensuing tachypneic response may amplify the loop of central autonomic nervous system activation (Fig. 2). The mechanical pathway of the brain-heart axis links blood pressure and pulsatility changes in arteries to changes in central autonomic nervous system functions (27). Jammal Salameh et al. (27) noted that blood pressure pulsations modulate central neuronal activity via mechanosensitive ion channels. They propose that a brain-wide network of “heartbeat sentinel neurons” mediate interoceptive modulation of cognition, mood, and autonomic status, a way by which central neurons can feel the pulse within the brain via neuronal piezo channels and modulate autonomic responses in response to arousal (27). Accordingly, the tachycardia associated with changes in pulsatility may itself trigger more sympathetic symptoms and lead to early interruption of exercise. This is supported by Arnold et al. (12), who showed that low dose propranolol decreases HR and proportionately increases SV during submaximal exercise, which did not change in placebo conditions. Accordingly, Taub et al. (3), showed that resting HR reduction with ivabradine, an inhibitor of the funny current, resulted not only in an improvement in the symptoms of POTS but also in reduced norepinephrine levels. Similarly, de Asmundis et al. (28) performed a novel sinus node-sparing hybrid ablation in patients with POTS, normalizing resting HR and reducing patient symptoms. These data suggest that the exaggerated HR response in those with POTS utilizes a greater proportion of HR reserve at lower workloads and peak HR is reached sooner in exercise, and that, when associated with changes in VE, VCO2, and cerebral perfusion, it may be causal in contributing to exercise intolerance in patients with POTS (Fig. 4). As such, interventions aimed at reducing HR may improve exercise tolerance.
Abnormal ventilation and/or ventilatory inefficiency may cause early termination of exercise. The use of gas exchange measurements during CPET allows for the assessment of ventilatory limitations. Loughnan et al. (20) report that patients with POTS have an increase in VE/VCO2 slope relative to predicted values. This reflects ventilatory-perfusion mismatching which could be caused by exaggerated metabolic lactate production from skeletal muscle, abnormal afferent feedback inducing excessive respiration, or increased dead space ventilation (29). In the same study, Loughnan et al. (20) report a high VE value and low PETCO2 at rest, AT, and peak exercise compared to predicted values. These data, although limited, are consistent with dysregulation of breathing pattern in those with POTS (i.e., involuntary hyperventilation), likely due to sympathetic activation, in which the ventilatory drive is excessive and disproportional to CO2 production. This causes excessive CO2 elimination, reduces cerebral blood flow, and causes symptoms of dizziness and brain fog. In an elegant translational research study, Baker et al. (30) showed that the head-up tilt table test in patients with POTS was associated with increased HR and a reduction in SV compared to controls, with reduced pulse pressure and pulsatility despite maintained mean arterial pressure and cardiac output. The pulsatility changes resulted in sympathetic activation, reduced cerebral blood flow, a hyperventilatory response, and excessive CO2 production (30). These effects were most likely mediated by central nervous system sensors of abnormal pulse pressure, and independent of peripheral chemoreceptors (30). The authors reproduced these findings using a working heart-brainstem rat preparation whereby perfusion of the brain was entirely dependent upon a pump which is, at least in part, independent of peripheral chemoreceptors and baroreceptors (30). Abnormal functions of peripheral chemoreceptors and baroceptors in those with POTS have also been reported (31). These data are consistent with polypnea and the concept of “dysfunctional breathing” in POTS, defined as enhanced variability in VE, tidal volume, and respiratory rate (32,33). Therefore, abnormal control of ventilation with reduced CO2 may contribute to exercise intolerance in those with POTS. It is, however, important to note that hypocapnic cerebral hypoperfusion syndrome has similar symptoms as POTS but without the tachycardia, suggesting reduced orthostatic cerebral blood flow is a unifying feature of the two syndromes (24).
Oxygen carrying capacity, namely hemoglobin concentrations, can also determine exercise capacity. The available evidence argues against reductions in hemoglobin concentrations that would justify exercise intolerance in patients with POTS.
Low blood volume has been reported in patients with POTS (25). Figueroa et al. (14) showed that intravenous fluid loading increased blood volume and, therefore, preload and resting SV. This did not increase submaximal exercise hemodynamics nor peak VO2, suggesting reduced plasma volume is an unlikely cause of exercise intolerance (14). Exercise training was associated with an increase in blood volume, a parallel reduction in HR, and an increase in peak VO2 (25,34). It remains unclear, however, whether the improvements with exercise are due to an increase in vagal tone or improved blood volume, cardiac reserve, and/or oxygen extraction.
Deconditioning is a common cause of impaired CRF, affecting individuals with and without cardiac or pulmonary illnesses. Given the burden of the symptoms, it is expected that patients with POTS limit their standing time and physical activity, thus contributing to deconditioning. Evidence for deconditioning was indeed present in all studies in this systematic review, and in some degree explained the reductions in peak VO2. Studies in adolescents and younger adults with POTS often show less evident exercise limitations (9,16,20), whereas studies in adults with POTS show greater disparities versus controls (11,12,14,22). This could suggest longer durations of POTS symptoms may be associated with more prolonged periods of inactivity and, therefore, more significant physical deconditioning and/or greater reserve in younger patients. When correcting for deconditioning, however, a residual impairment in exercise capacity persisted, suggesting that additional mechanisms other than deconditioning contributed. Volitional failure secondary to exercise-induced symptoms, possibly related to abnormal HR and ventilatory response, can be easily confused with deconditioning. However, physical deconditioning alone is not likely to be responsible for the unusual symptoms experienced by patients with POTS like lightheadedness/dizziness, palpitations, and chest pain.
Exercise training effectively improves exercise capacity and symptom burden in patients with POTS (10,22,25,34). As mentioned above, exercise training increases SV through possible mechanisms such as vagal modulation, cardiac remodeling, and increased blood volume (10,25). By improving parasympathetic tone, exercise training may directly counter the sympathetic activation that is central to POTS. In a study by Shibata et al. (10), exercise training lowered HR and increased SV at rest and during exercise, and extended exercise time, thus leading to increased peak VO2. A more recent study by Wheatley-Guy et al. (22) confirmed these findings by randomizing patients with POTS to either endurance training or standard of care, showing similar changes in hemodynamics and exercise capacity while also showing notable improvements in symptom burden, confirming the role of exercise training as a tool in the management of POTS.
There are a several limitations to this study. Despite the prevalence of POTS, there are few studies and a relatively small number of patients studied. POTS is a heterogeneous disease and the phenotype of patients is often only partially characterized. Risk of bias was not assessed due to the variety of study designs included, and thus other quality assessment tools were used to accommodate the different study designs to assess each article. There is also likely a bias in each cohort because studies will exclude those with very mild symptoms of POTS, as well as those with more severe symptoms of POTS who are unable to complete exercise testing, which would not necessarily be captured by the quality assessment tools. Also, this systematic review is limited by the lack of a meta-analysis. The choice to not perform a meta-analysis was due to the substantial heterogeneity among a limited number of studies, including different exercise protocols (submaximal vs maximal vs both, different modalities, different postures), various assessment methods for hemodynamics (invasive catheter, Doppler echocardiography, gas rebreathing), and a substantial variety of control groups (healthy, deconditioned, other dysautonomia, matched vs unmatched controls, no controls). Finally, there is a dearth of interventional clinical trials in POTS and, therefore, an incomplete understanding of the effects of clinical interventions.
Patients with POTS suffer from exercise intolerance, but the mechanisms are incompletely understood. The classic paradigm is one of reduced SV and compensatory tachycardia compared with healthy controls. Patients with POTS, however, have elevated HR while at rest, supine, and standing, as well as during submaximal exercise. POTS is also associated with exaggerated ventilation and reduced CO2 values. Despite reduction in SV compared with controls, cardiac output is generally preserved with a maintained cardiac output/VO2 relationship, suggesting that exercise intolerance in patients with POTS is not likely to be secondary to reduced augmentation of cardiac output alone. Intravenous fluids augmenting venous return and SV had no impact on exercise capacity, whereas propranolol or exercise training reduced HR and increased exercise capacity. Patients with POTS often show signs of deconditioning, but deconditioning does not explain the hemodynamic and cardiorespiratory data, nor the exertional nature of symptoms. These data suggest that exaggerated HR and ventilatory responses to standing and exercise may be responsible for exercise intolerance, causing premature cessation of exertion due to symptoms of sympathetic activation and/or cerebral hypoperfusion (Fig. 2). Future studies are needed to determine whether other strategies to reduce HR may improve exercise capacity and tolerance in patients with POTS.