Gulf War Illness affects 25-32% of veterans from the 1990-91 Persian Gulf War. Post-exertional malaise with cognitive dysfunction, pain and fatigue following physical and/or mental effort is a defining feature of Gulf War Illness. We modelled post-exertional malaise by assessing changes in functional magnetic resonance imaging at 3T during an N-Back working memory task performed prior to a submaximal bicycle stress test and after an identical stress test 24 h later. Serial trends in postural changes in heart rate between supine and standing defined three subgroups of veterans with Gulf War Illness: Postural Orthostatic Tachycardia Syndrome (GWI-POTS, 15%,  = 11), Stress Test Associated Reversible Tachycardia (GWI-START, 31%,  = 23) and Stress Test Originated Phantom Perception (GWI-STOPP, no postural tachycardia, 54%,  = 46). Before exercise, there were no differences in blood oxygenation level-dependent activity during the N-Back task between control ( = 31), GWI-START, GWI-STOPP and GWI-POTS subgroups. Exercise had no effects on blood oxygenation level-dependent activation in controls. GWI-START had post-exertional deactivation of cerebellar dentate nucleus and vermis regions associated with working memory. GWI-STOPP had significant activation of the anterior supplementary motor area that may be a component of the anterior salience network. There was a trend for deactivation of the vermis in GWI-POTS after exercise. These patterns of cognitive dysfunction were apparent in Gulf War Illness only after the exercise stressor. Mechanisms linking the autonomic dysfunction of Stress Test Associated Reversible Tachycardia and Postural Orthostatic Tachycardia Syndrome to cerebellar activation, and Stress Test Originated Phantom Perception to cortical sensorimotor alterations, remain unclear but may open new opportunities for understanding, diagnosing and treating Gulf War Illness.

Postural orthostatic tachycardia syndrome (POTS) is a clinically heterogeneous disorder with multiple contributing pathophysiologic mechanisms manifesting as symptoms of orthostatic intolerance in the setting of orthostatic tachycardia (increase in heart rate by at least 30 beats per minute upon assuming an upright position) without orthostatic hypotension. The three major pathophysiologic mechanisms include partial autonomic neuropathy, hypovolemia, and hyperadrenergic state. Patients often will exhibit overlapping characteristics from more than one of these mechanisms. The approach to the treatment of POTS centers on treating the underlying pathophysiologic mechanism. Stockings, abdominal binders, and vasoconstrictors are used to enhance venous return in partial neuropathic POTS. Exercise and volume expansion are the main treatment strategies for hypo-volemic POTS. For hyperadrenergic POTS, beta-blockers and avoidance of norepinephrine reuptake inhibitors is important. Attempts should be made to discern which pathophysiologic mechanism(s) may be afflicting patients so that treatment regimens can be individualized.

This article reviews the diagnosis and management of the most common disorders of orthostatic intolerance: postural tachycardia syndrome (POTS) and neurally mediated syncope. POTS is a heterogeneous syndrome caused by several pathophysiologic mechanisms that may coexist (limited autonomic neuropathy, hyperadrenergic state, hypovolemia, venous pooling, joint hypermobility, deconditioning). Neurally mediated syncope occurs despite intact autonomic reflexes. Management of orthostatic intolerance aims to increase functional capacity, including standing time, performance of daily activities, and exercise tolerance. Nonpharmacologic strategies (fluid and salt loading, physical countermaneuvers, compression garments, exercise training) are fundamental for patients with POTS, occasionally complemented by medications to raise blood pressure or slow heart rate. Neurally mediated syncope is best managed by recognition and avoidance of triggers. Significant negative effects on quality of life occur in patients with POTS and in patients with recurrent neurally mediated syncope, which can be mitigated through targeted evaluation and thoughtful management.

Upright posture reduces venous return, stroke volume, and cardiac output (CO) while causing reflex sinus rate (heart rate [HR]) increase. Yet, in inappropriate sinus tachycardia (IST), postural tachycardia syndrome (POTS), and vasovagal syncope (VVS), symptomatic excessive HR occurs. We hypothesized that CO reaches maximum as function of HR in all. We recruited 12 healthy controls, 9 IST, 30 VVS, and 30 POTS patients (13-23years) selected randomly by disorder not by HR, each fulfilled appropriate diagnostic criteria. Subjects were instrumented for electrocardiography, beat-to-beat blood pressure, respiratory rate, CO-Modelflow algorithm, and central blood volume from impedance cardiography; 10-minute data were collected supine; subjects were tilted head-up for ≤10 minutes. We computed phase differences, ΔΦ, between fluctuations of HR (ΔHR) and CO (ΔCO) tabulating data when phases were synchronized, determined by a squared nonlinear phase synchronization index >0.5, describing extent/validity of CO/HR coupling. We graphed results supine, 1-minute post-tilt-up, mid-tilt, and pre-tilt-down using polar coordinates (HR-radius, ΔΦ-angle) plotting cos(ΔΦ) versus HR to determine if transition HR exists at which in-phase shifts to antiphase above which CO decreases when HR further increases. At baseline HR, diastolic and mean arterial pressures in IST and POTS were higher versus controls. Upright HR increased most in POTS then IST and VVS, with diverse changes in CO, SVR, and central blood volume. Each patient grouping was separately and collectively analyzed for HR change showing transition from in-phase to anti-phase (ΔΦ) as HR increased: HR=115±6 (IST), 123±8 (POTS), 124±7 (VVS), =ns. Controls never reached transitional HR. Excessive HR independently and equivalently reduces upright CO, in IST, POTS, and VVS.

Unfortunately, the 3rd author name was incorrectly published in the original publication. The complete correct name is given below.

Human papillomavirus (HPV) vaccination has been anecdotally connected to the development of dysautonomia, chronic fatigue, complex regional pain syndrome and postural tachycardia syndrome. To critically evaluate a potential connection between HPV vaccination and the above-noted conditions. We reviewed the literature containing the biology of the virus, pathophysiology of infection, epidemiology of associated cancers, indications of HPV vaccination, safety surveillance data and published reports linking HPV vaccination to autonomic disorders. At this time, the American Autonomic Society finds that there are no data to support a causal relationship between HPV vaccination and CRPS, chronic fatigue, and postural tachycardia syndrome to other forms of dysautonomia. Certain conditions are prevalent in the same populations that are vaccinated with the HPV vaccine (peri-pubertal males and females). This association, however, is an insufficient proof of causality.

Prior studies have reported ECG (Electrocardiogram) changes during tilt table testing (TTT), specifically during repolarization with ST-segment and T-wave changes. The correlation with ischemic evaluation remains unclear. The purpose of this study was to analyze the prevalence of ST-segment changes during TTT in a young, otherwise healthy population of patients with postural tachycardia syndrome (POTS), and correlate them with exercise stress test results. Two hundred and fifty-five patients with POTS who underwent TTT and an exercise treadmill test (ETT) were analyzed. Forty-five had ST-segment changes/depressions during TTT (91% female, average age 36 years). Of the 45, three had ST-segment depression during ETT; all three had negative exercise stress echocardiograms (ESEs). Two others had ST-segment depressions on ETT (but not TTT), with negative ESEs. In a cohort of young, female, otherwise healthy patients with POTS, ST-segment changes occurred in a significant portion (18%) of patients during TTT. When evaluated with exercise stress testing, these patients had no evidence of underlying ischemia on ETT or ESE.

Postural orthostatic tachycardia syndrome (POTS) in adults is defined as symptoms of chronic orthostatic intolerance (COI) and autonomic dysfunction (AD) with heart rate (HR) increase of 30 beats per minute (bpm), or HR > 120 bpm, during prolonged upright position. However, in adolescents, POTS is defined as symptoms of OI and AD with HR increase of ≥ 40 bpm, based on tilt table data. We assessed frequency of COI symptoms in pediatric patients versus HR criteria on prolonged standing to evaluate using criteria of increased HR of 30-39 bpm versus ≥ 40 bpm in our POTS Program. Patients with COI with symptoms for > 3 months plus HR increase of ≥ 30 bpm on 10 min stand aged ≤ 18 years at diagnosis were included. Patients were divided into two groups: those with HR increase of 30-39 bpm, and those with HR increase of ≥ 40 bpm or upright HR of > 120 bpm. A total of 28 symptoms described prior to diagnosis were evaluated using chi-square testing to assess for significant differences. Only insomnia was found to be significantly different between the two groups. The other 27 symptoms showed no significant difference as a function of HR. There are minimal statistically significant differences and no clinical differences between patients as a function of HR increase during standing. Thus, a 40-bpm threshold for adolescents on standing test may be too high, or a specific HR criteria threshold is neither predictive nor definitive in diagnosing POTS.

Postural orthostatic tachycardia syndrome (POTS) is a chronic, debilitating condition characterized by heterogeneous symptoms, such as lightheadedness, palpitations, pre-syncope, syncope, and weakness or heaviness, especially of the legs. It is frequently associated with hypermobile joints or conditions such as chronic fatigue syndrome, chronic abdominal pain, migraine headache, and diabetes mellitus. Described is a case of POTS, which though it is not rare, is rarely diagnosed. It can be diagnosed quickly with simple methods.

The current definition of postural orthostatic tachycardia syndrome (POTS) dates back to a small case series of patients with a subacute illness who presented with excessive orthostatic tachycardia and orthostatic intolerance, in the absence of another recognized disease. Conventional POTS criteria require an excessive orthostatic tachycardia in the absence of substantial orthostatic hypotension, and predominant symptoms of orthostatic intolerance, worse with upright posture and better with recumbence. POTS is a heterogeneous syndrome with likely several underlying pathophysiological processes, and not a specific disease. The primary panel for this Canadian Cardiovascular Society position statement sought to provide a contemporary update of the best evidence for the evaluation and treatment of POTS. We performed a systemic review of evidence for the evaluation of treatment of POTS using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) methodology, and developed recommendations on the basis of the Canadian Cardiovascular Society approach to position statements. One identified problem was that numerous patients who did not meet criteria for POTS would still be given that diagnoses by providers to validate the illness even though this diagnosis is incorrect. This includes patients with postural symptoms without tachycardia, orthostatic tachycardia without symptoms, and those with orthostatic tachycardia but another overt cause for excessive tachycardia. We developed a novel nomenclature ecosystem for orthostatic intolerance syndromes to increase clarity. We also provide more clarity on how to interpret the orthostatic vital signs. These concepts will need to be prospectively assessed.

Postural tachycardia syndrome is more frequently being recognised in adolescents and adults. However, its pathophysiology remains undefined. We evaluated our database for patterns in family history of clinical symptoms and associated disorders in these patients. Patients with postural tachycardia syndrome diagnosed in our clinic between 2014 and 2018 and who were less than 19 years at diagnosis were included. The history was reviewed for family members with postural tachycardia syndrome, dizziness and/or syncope, joint hypermobility with or without hypermobile Ehlers-Danlos syndrome, and autoimmune disorders. Statistical analysis assessed the entire cohort plus differences in gender, presence or absence of joint hypermobility, and presence or absence of familial autoimmune disease. A total of 579 patients met inclusion criteria. We found that 14.2% of patients had a family member with postural tachycardia syndrome, with male patients more likely to have an affected family member (20% versus 12.7%, p = 0.04). If the patient also had joint hypermobility, male patients were more likely to have a family member with postural tachycardia syndrome (25% versus 12.6%, p = 0.017), more than one affected family member (7.1% versus 0.74%, p = 0.001), and a family member with joint hypermobility (37.5% versus 23.7%, p = 0.032). Autoimmune disease was seen in 45.1% of family members, but more likely in female patients with concurrent hypermobility (21.1% versus 8.9%, p = 0.035). This in-depth analysis of associated familial disorders in patients with postural tachycardia syndrome offers further insight into the pathophysiology of the disorder, and informs further screening of family members in these patients.

To evaluate the prevalence of orthostatic intolerance and joint hypermobility in schoolchildren with and without functional gastrointestinal disorders (FGIDs) and to assess autonomic nervous system dysfunction in children with FGIDs and joint hypermobility. Schoolchildren (10-18 years) attending public schools from 3 Colombian cities (Cali, Palmira, and Bucaramanga) completed validated questionnaires for FGIDs and underwent testing for hypermobility and autonomic nervous system dysfunction. Heart rate and blood pressure were assessed in recumbency and upright position at regular intervals. The differences in characteristics between schoolchildren with and without FGIDs were compared with a t-test for continuous variables and with a Fisher exact test (2 × 2 contingency tables) for categorical variables. In total, 155 children with FGIDs were matched with 151 healthy controls. Children with FGIDs had historically significant greater frequency of 10 of 12 symptoms of orthostatic intolerance, no significant difference in any symptoms of orthostatic intolerance during recumbency, significantly greater frequency in 6 of 12 symptoms of orthostatic intolerance during orthostasis, trend toward statistical significance for orthostatic intolerance (P = .0509), and no significant difference in prevalence of orthostatic hypotension (OH) and postural orthostatic tachycardia syndrome (POTS). There was no significant difference in prevalence of orthostatic intolerance, OH, and POTS between those with joint hypermobility and those without. Children with FGIDs have a greater prevalence of symptoms of orthostatic intolerance but were not more likely to have OH and POTS as compared with children without FGIDs. Children with joint hypermobility did not have a greater prevalence of orthostatic intolerance, OH, and POTS.

Despite well-established clinical associations between Hypermobile Ehlers-Danlos syndrome (hEDS) and postural orthostatic tachycardia syndrome (POTS), the precise prevalence is unknown. We therefore evaluated for hEDS in 91 POTS participants using the 2017 hEDS diagnostic checklist, which has three major criteria: 1) generalized joint hypermobility (Beighton score), 2) systemic features, family history, and 3) absence of exclusion criteria. Overall, 28 out of 91 POTS participants (31%) met clinical criteria for hEDS. An additional 24% of participants had generalized joint hypermobility without meeting hEDS criteria. Identifying the prevalence of hEDS in POTS is important for understanding possible mechanisms connecting these two syndromes.

Postural orthostatic tachycardia syndrome (POTS) is accompanied by reduced brain blood flow, autonomic dysfunction, and orthostatic intolerance. We hypothesized that wearing a neck compression collar would attenuate orthostatic symptoms, increase brain blood flow, and influence autonomic reflexes. Ten participants with POTS (9 women, age: 36 ± 10) underwent two trials of supine rest, paced deep breathing (6 breaths/min), Valsalva maneuver (40 mmHg for 15 s), and 70° upright tilt. For one trial, participants wore a neck compression device (Q30 Innovations). Blood pressure, heart rate (HR), brain blood flow velocity, stroke volume, respiratory rate, and end-tidal gases were continuously measured. The Vanderbilt Orthostatic Symptom Score was compiled at the end of tilt. The use of the collar reduced the orthostatic symptom score of participants with POTS during upright tilt (26.9 ± 12.5 to 18.7 ± 13.1, = 0.04). Collar compression in the supine condition reduced the low-frequency domain of HR variability (60 ± 18 to 51 ± 23 normalized units, = 0.04) and increased the change in HR (15 ± 5 to 17 ± 6 bpm, = 0.02) and E:I ratio (1.2 ± 0.1 to 1.3 ± 0.1, = 0.01) during paced deep breathing. Throughout tilt, wearing the collar reduced respiratory rate (baseline: 13 ± 3 to 12 ± 4 breath/min; tilt: 18 ± 5 to 15 ± 5 breath/min; main effect of collar = 0.048), end-tidal oxygen (baseline: 115 ± 5 to 112 ± 5 mmHg; tilt: 122 ± 10 to 118 ± 11 mmHg; main effect of collar = 0.026). In participants with POTS, wearing the Q-collar reduced orthostatic symptoms, increased the HR response to deep breathing, and decreased resting ventilation. We found that using a neck compression collar alleviated orthostatic symptoms in upright posture in participants with postural orthostatic tachycardia syndrome (POTS). This could be due to compression of the baroreceptors and subsequent changes in autonomic function. Indeed, we observed increased heart rate responsiveness to paced deep breathing and reductions of respiratory rate and end-tidal O (suggesting reduced ventilation). Further, wearing the collar reduced mean blood velocity in the brain during Valsalva perhaps due to higher brain blood volume.

Human papillomavirus (HPV) vaccination has been associated with subsequent diffuse symptoms in girls, reducing public confidence in the vaccine. We examined whether girls have nonspecific outcomes of HPV vaccination, using triangulation from cohort, self-controlled case series (SCCS), and population time trend analyses carried out in Denmark between 2000 and 2014. The study population consisted of 314,017 HPV-vaccinated girls and 314,017 age-matched HPV-unvaccinated girls (cohort analyses); 11,817 girls with hospital records (SCCS analyses); and 1,465,049 girls and boys (population time trend analyses). The main outcome measures were hospital records of pain, fatigue, or circulatory symptoms. The cohort study revealed no increased risk among HPV vaccine-exposed girls, with incidence rate ratios close to 1.0 for abdominal pain, nonspecific pain, headache, hypotension/syncope, tachycardia (including postural orthostatic tachycardia syndrome), and malaise/fatigue (including chronic fatigue syndrome). In the SCCS analyses, we observed no association between HPV vaccination and subsequent symptoms. In time trend analyses, we observed a steady increase in these hospital records in both girls and (HPV-unvaccinated) boys, with no relationship to the 2009 introduction of HPV vaccine to Denmark's vaccination program. This study, which had nationwide coverage, showed no evidence of a causal link between HPV vaccination and diffuse autonomic symptoms leading to hospital contact.

Postural orthostatic tachycardia syndrome (POTS) is a variant of cardiovascular (CV) autonomic disorder of unknown etiology characterized by an excessive heart rate increase on standing and orthostatic intolerance. In this study we sought to identify novel CV biomarkers potentially implicated in POTS pathophysiology. We conducted a nested case-control study within the Syncope Study of Unselected Population in Malmö (SYSTEMA) cohort including 396 patients (age range, 15-50 years) with either POTS (n = 113) or normal hemodynamic response during passive head-up-tilt test (n = 283). We used a targeted approach to explore changes in cardiovascular proteomics associated with POTS through a sequential two-stage process including supervised principal component analysis and univariate ANOVA with Bonferroni correction. POTS patients were younger (26 vs. 31 years; p < 0.001) and had lower BMI than controls. The discovery algorithm identified growth hormone (GH) and myoglobin (MB) as the most specific biomarker fingerprint for POTS. Plasma level of GH was higher (9.37 vs 8.37 of normalised protein expression units (NPX); p = 0.002), whereas MB was lower (4.86 vs 5.14 NPX; p = 0.002) in POTS compared with controls. In multivariate regression analysis, adjusted for age and BMI, and stratified by sex, lower MB level in men and higher GH level in women remained independently associated with POTS. Cardiovascular proteomics analysis revealed sex-specific biomarker signature in POTS featured by higher plasma level of GH in women and lower plasma level of MB in men. These findings point to sex-specific immune-neuroendocrine dysregulation and deconditioning as potentially key pathophysiological traits underlying POTS.

Postural orthostatic tachycardia syndrome (POTS) is an autonomic disorder characterized by symptoms such as palpitations, dyspnea, chest discomfort, and lightheadedness affecting various systems. The pathophysiology of POTS is not completely understood due to a variety of symptoms showing that the disease is multifactorial. There is no approved uniform management strategy for POTS and hence, no drug has been approved by the United States (US) Food and Drug Administration (FDA) for it. Ivabradine is an FDA-approved drug for stable symptomatic heart failure (HF) and patients with an ejection fraction (EF) of ≤35%. Previous studies have depicted improvement in symptoms of POTS with the use of ivabradine. It is a selective inhibitor of funny sodium channels (I) in the sinoatrial (SA) node cells resulting in the prolongation of the slow diastolic depolarization (phase IV) and reduction in the heart rate (HR). Although beta-adrenoceptor blockers are commonly used to lower HR in patients with POTS, they are less ideal due to numerous adverse effects. This review aims to provide a comprehensive and up-to-date picture of all the studies and case reports that utilized ivabradine for the treatment of POTS along with a precise overview of epidemiology, pathophysiology, and types of POTS. To conclude, we recommend further research on the effectiveness of ivabradine in patients who experience symptoms of POTS. Other than stable chronic angina pectoris, its application in this setting has been proven to be effective and safe. Further evaluation by means of randomized control trials is required to encourage use of this HR-lowering agent in common disorders other than HF and stable angina, i.e. POTS.

Introduction Ehlers-Danlos syndrome (EDS), specifically the hypermobility type (hEDS), is associated with a variety of gastrointestinal (GI) conditions. This study aims to evaluate the prevalence of and factors associated with gut dysmotility in patients with hEDS. Methods This is a retrospective study of hEDS patients conducted at the Cleveland Clinic's Center for Personalized Genetic Healthcare between January 2007 and December 2017. Demographics, GI motility testing, endoscopic, and imaging data were extracted from the patients' charts. Results A total of 218 patients with hEDS were identified. Among them, 136 (62.3%) patients had at least one GI symptom at the time of EDS diagnosis. Motility testing was performed and reported in 42 (19.2%) patients. Out of them, five (11.9%) had esophageal dysmotility, 18 (42.8%) had gastroparesis, five (11.9%) had small bowel/colon altered transit time, and four (9.5%) had global dysmotility. In univariable analysis, patients with postural orthostatic tachycardia syndrome (POTS) [odds ratio (OR): 8.88, 95% CI: 3.69-24.9, p<0.0001], fibromyalgia (OR: 4.43, 95% CI: 2.04-10.1, p=0.0002), history of irritable bowel syndrome (OR: 5.01, 95% CI: 2.31-11.2, p<0.0001), and gastroesophageal reflux disease (OR: 3.33, 95% CI: 1.55-7.44, p=0.002) were more likely to be diagnosed with GI dysmotility. On multivariable analysis, only POTS (OR: 5.74, 95% CI: 2.25-16.7, p=0.0005) was significantly associated with an increased likelihood of GI dysmotility. Conclusions This study suggests that GI symptoms are relatively common among patients with hEDS. Of the patients tested for dysmotility, 76.2% were found to have some form of dysmotility. POTS was found to be an independent predictive factor for GI dysmotility.

Chronic fatigue syndrome, postural orthostatic tachycardia syndrome, complex regional pain syndrome and silicone implant incompatibility syndrome are a subject of debate among clinicians and researchers. Both the pathogenesis and treatment of these disorders require further study. In this paper we summarize the evidence regarding the role of autoimmunity in these four syndromes with respect to immunogenetics, autoimmune co-morbidities, alteration in immune cell subsets, production of autoantibodies and presentation in animal models. These syndromes could be incorporated in a new concept of autoimmune neurosensory dysautonomia with the common denominators of autoantibodies against G-protein coupled receptors and small fiber neuropathy. Sjogren's syndrome, which is a classical autoimmune disease, could serve as a disease model, illustrating the concept. Development of this concept aims to identify an apparently autoimmune subgroup of the disputable disorders, addressed in the review, which may most benefit from the immunotherapy.

Human papillomavirus vaccination (HPVV) was included in the national immunization program in 2013 in Japan. However, the Japanese government suspended proactive recommendations 2 months after this decision because various adverse events following the vaccination were reported by the media. More than 6 years have already passed since the suspension of proactive recommendations of all available vaccines in Japan. Although no causal relationship between the adverse effects and HPVV has been confirmed, the Japanese government has not withdrawn the suspension. Thus, it is important to show various possible causes of the adverse events other than HPVV. It is attempted to describe the possible contribution of the misunderstanding regarding the symptoms of postural tachycardia syndrome, deconditioning, and exercise-induced hyperalgesia as the adverse effects of HPVV in this review article.

Exercise intolerance is a hallmark of the postural orthostatic tachycardia syndrome (POTS). However, no data are available on the implications of an exaggerated submaximal heart rate (HR) on exercise intolerance in patients. We investigated whether exaggerated HR responses occurring early on during incremental stress testing relate with increased odds of POTS and exercise intolerance. Clinical characteristics and stress test HRs were compared between adults with POTS achieving ≥85% predicted metabolic equivalents (METs) (EX-TL, n = 101; body mass index [BMI] 24 ± 5 kg·m; 95% women) or <85% (EX-INTL, n = 71; BMI 28 ± 7 kg·m; 79% women) and sedentary controls (n = 30; BMI 36 ± 3 kg·m; 87% women). Multivariate logistic regressions were performed to estimate ORs and the probability of POTS and exercise intolerance associated with exercise HRs. Exercise tolerance was increased in EX-TL, but not in EX-INTL (10.0 ± 1.3 and 8.3 ± 1.5 METs vs 8.0 ± 1.6 METs, respectively) versus controls. Absolute peak HR was increased in EX-TL and EX-INTL versus controls (P < .01), whereas percent predicted did not differ. Exercise within the first-to-second stress stages was performed at exaggerated HRs (122 ± 17 bpm vs 103 ± 15 and 113 ± 15 bpm, P < .001) and percent HR reserve in EX-INTL versus controls and EX-TL (49% ± 12% vs 34% ± 11% and 41% ± 11%, P < .001), respectively. In multivariate analyses, peak HR was not significant, whereas increased submaximal HR (either variable) was associated with increased odds of EX-TL or EX-INTL. Lastly, odds of EX-INTL increased as METs decreased, whereas METs was not a predictor of EX-TL. An exaggerated submaximal exercise HR is predictive of POTS and exercise intolerance, and this chronotropic phenotype is exacerbated in patients achieving <85% predicted METs.

There is an association between joint hypermobility, hypermobile Ehlers-Danlos syndrome (hEDS) and different forms of orthostatic intolerance. Objective: to explore autonomic profile in a large cohort of adults with hEDS and hypermobility spectrum disorder (hEDS/HSD) with a multimodal approach. In this observational retrospective study, heart rate, blood pressure and baroreflex sensitivity were estimated in 102 hEDS/HSD subjects during deep breathing, Valsalva maneuver, standing up: 30-15 ratio, Head-Up Tilt and sustained handgrip. Abnormal results and head-up tilt test were common and included postural orthostatic tachycardia syndrome (POTS; 48%), orthostatic intolerance (25.5%) and hypotension (3.9%). Baroreflex sensitivity was significantly different in individuals with POTS compared to the others. This study confirms the high rate and heterogeneity of abnormal autonomic regulation in hEDS/HSD, and suggests the baroreflex sensitivity might distinguish comorbid POTS from other profiles in this subgroup of patients. Abnormal autonomic regulation is common in adults with hEDS/HSD and should be regularly assessed for tailoring the management approach.

The current surge of interest in postural orthostatic tachycardia syndrome commonly known as POTS requires good knowledge of the very complex physiology involved, but this is currently lacking. The often overlooked normal physiology of orthostasis is reviewed including the definition of normal postural orthostatic tachycardia. An illustrated functional anatomy that embeds orthostatic tachycardia within the learned and skilful motor functions in the human population is presented. The four physiological phases of orthostasis and the role of tachycardia are described in a laboratory-controlled and progressive orthostatic stress in normal human volunteers. Standardized surrogate measures of autonomic control were used to quantify the trigger level for excessive tachycardia and the minimum autonomic control required to sustain viable arterial blood pressure during severe orthostatic stress in normal human volunteers. Tachycardia during orthostasis is part of a "democratic" contribution by four cardiovascular parameters of which the chronotropic function of the heart is just one of the parameters contributing toward cardiovascular compensation. It is adjusted during orthostasis in proportion to contributions from the other three parameters, namely inotropic function of the heart, windkessel vascular resistance and venous vascular capacitance. The physiological effects of the two stressors during orthostasis, gravity and isometric contraction of skeletal muscles are reviewed. A model of how the four cardiovascular parameters are regulated during orthostasis to achieve proportionate contributions is proposed emphasizing the necessity to quantify individual contributions from all these four parameters. Any one or more of these parameters may be compromised due to disease requiring disproportionate contribution of the prevailing magnitude of orthostatic tachycardia in an individual. It therefore requires neurophysiological assessment of the autonomic regulation of all the four cardiovascular parameters to assess the condition fully. We recommend here some current and novel neurophysiological methods that use modern medical technology to quantify laboratory standardized surrogate measures of some of these cardiovascular parameters including central parasympathetic regulation in postural orthostatic tachycardia syndrome.

It remains unclear whether brain fog is related to impaired cerebral blood flow (CBF) in postural tachycardia syndrome (POTS) patients. We assessed CBF in the posterior cerebral artery (PCA) using transcranial Doppler with visual stimuli in 11 POTS and 8 healthy subjects in the seated position, followed by neurocognitive testing. CBF parameters were similar between the two groups. POTS patients demonstrated significantly longer latency in delayed match to sample response time and greater errors in attention switching task. Impaired short-term memory and alertness may underlie the symptom of brain fog in POTS patients, despite normal CBF.

Vasovagal syncope (VVS) and postural tachycardia syndrome (POTS) are the main forms of orthostatic intolerance in pediatrics and both are underlying causes of neurally-mediated syncope. In recent years, increasing attention has been paid to the management of VVS and POTS in children and adolescents. A number of potential mechanisms are involved in their pathophysiology, but the leading cause of symptoms varies among patients. A few studies thus have focused on the individualized treatment of VVS or POTS based on selected hemodynamic parameters or biomarkers that can predict the therapeutic effect of certain therapies and improve their effectiveness. This review summarizes the latest developments in individualized treatment of VVS and POTS in children and indicates directions for further research in this field.