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Background: Standard autonomic testing includes a 10-minute head-up tilt table test to detect orthostatic hypotension. Although this test can detect delayed orthostatic hypotension (dOH) between 3 and 10 minutes of standing, it cannot detect late-onset dOH after 10 minutes of standing. Methods: To determine whether Valsalva maneuver responses can identify patients who would require prolonged head-up tilt table test to diagnose late-onset dOH; patients with immediate orthostatic hypotension (onset 10 minutes; n=32) were retrospectively compared with controls (n=114) with normal head-up tilt table test and composite autonomic scoring scale score of 0. Results: Changes in baseline systolic blood pressure at late phase 2 (∆SBP VM2 ), heart rate difference between baseline and phase 3 (∆HR VM3 ), and Valsalva ratio were lower and pressure recovery time (PRT) at phase 4 was longer in late-onset dOH patients than in controls. Differences in PRT and ∆HR VM3 remained significant after correcting for age. A PRT ≥2.14 s and ∆HR VM3 ≤15 bpm distinguished late-onset dOH from age- and sex-matched controls. Patients with longer PRT (relative risk ratio, 2.189 [1.579–3.036]) and lower ∆HR VM3 (relative risk ratio, 0.897 [0.847–0.951]) were more likely to have late-onset dOH. Patients with longer PRT (relative risk ratio, 1.075 [1.012–1.133]) were more likely to have early-onset than late-onset dOH. Conclusions: Long PRT and short ∆HR VM3 can help to identify patients who require prolonged head-up tilt table test to diagnose late-onset dOH.

PURPOSE OF REVIEW: Patients with neurogenic orthostatic hypotension (OH) frequently have hypertension in the supine position (sHTN). We review the controversies surrounding the need and safety of treating sHTN in patients with OH. RECENT FINDINGS: The presence of sHTN complicates the management of OH because treatment of one can worsen the other. New approaches have been developed to treat OH without worsening sHTN by preferentially improve standing blood pressure, such as medications that harness the patient’s residual sympathetic tone like pyridostigmine and atomoxetine, and devices such as an automated abdominal binder that targets the inappropriate splanchnic venous pooling causing OH. There is a reluctance to treat sHTN for fear of increasing the risks of falls and syncope associated with OH, thought to be more immediate and dangerous than the late complications of organ damage associated with sHTN. This, however, does not take into account that nighttime sHTN induces natriuresis, volume loss, and begets daytime orthostatic hypotension. It is possible to treat sHTN in ways that reduce the risk of worsening OH. Furthermore, novel approaches, such as the use of local heat can control nighttime sHTN, reduce nocturia and improve OH. SUMMARY: Although continued progress is needed, recent findings offer hope that we can treat nocturnal sHTN with the goal of improving daytime OH, strongly suggesting the controversy whether to treat or not sHTN.

Background: Supine hypertension affects most patients with orthostatic hypotension (OH) due to autonomic failure, but it is often untreated for fear of worsening OH. We hypothesized that increasing intrathoracic pressure with continuous positive airway pressure (CPAP) had a Valsalva-like blood-pressure-lowering effect that could be used to treat nocturnal supine hypertension in these patients, while reducing nocturnal pressure diuresis and improving daytime OH. Methods: In Protocol 1, we determined the acute hemodynamic effects of increasing levels of CPAP (0, 4, 8, 12, and 16 cm H 2 O, 3 minutes each) in 26 patients with autonomic failure and supine hypertension studied while awake and supine. In Protocol 2 (n=11), we compared the effects of overnight therapy with CPAP (8–12 cm H 2 O for 8 hours) versus placebo on nocturnal supine hypertension, nocturnal diuresis and daytime OH in a 2-night crossover study. Results: In Protocol 1, acute CPAP (4–16 cm H 2 O) decreased systolic blood pressure in a dose-dependent manner (maximal drop 22±4 mmHg with CPAP 16) due to reductions in stroke volume (−16+3%) and cardiac output (−14±3%). Systemic vascular resistance and heart rate remained unchanged. In Protocol 2, overnight CPAP lowered nighttime systolic blood pressure (maximal change −23±5 versus placebo −1±7 mmHg; P =0.023) and was associated with lower nighttime diuresis (609±84 versus placebo 1004±160 mL; P =0.004) and improved morning orthostatic tolerance (AUC upright SBP 642±121 versus placebo 410±109 mmHg*min; P =0.014). Conclusions: CPAP is a novel nonpharmacologic approach to treat the supine hypertension of autonomic failure while improving nocturia and daytime OH. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03312556.

Sublingual nitroglycerin (SL NTG) is useful for treating acute decompensated heart failure, possibly by increasing splanchnic capacitance and reducing left ventricular (LV) preload. We evaluated a radionuclide method to study these effects, initially in subjects without heart failure.Red blood cells were labelled by an in vitro method. Abdominal and chest images were obtained at rest, showing relative regional blood volumes. The abdomen was then re-imaged during progressive escalation of intrathoracic pressure using continuous positive airway pressure to assess baseline splanchnic capacitance (pressure-volume relationship, PVR) and compliance (slope of PVR). The procedure was repeated after 0.6 mg SL NTG, followed by chest images. Relative splanchnic blood volume increased at rest after SL NTG (P.002), signifying an increase in splanchnic capacitance. The slope of the splanchnic PVR decreased in proportion to the baseline PVR (P = .0014), signifying increased compliance. The relative pulmonary blood volume decreased in proportion to the increase in splanchnic blood volume (P = .01).A semi-quantitative radionuclide method demonstrated the effect of SL NTG for increasing splanchnic capacitance and compliance, with a proportional decrease in pulmonary blood volume. These data may be applied to quantitatively evaluate the importance of splanchnic vasodilation as a mechanism of LV preload reduction in the treatment of heart failure.NCT02425566.

Supine hypertension affects most patients with autonomic failure (AF), complicates the treatment of orthostatic hypotension (OH) and induces nocturnal pressure diuresis, resulting in nocturnal volume depletion and worsening of daytime OH. However, it is often untreated for fear of worsening OH. We previously showed that continuous positive airway pressure (CPAP 4, 8, 12 and 16 cm H 2 O, each for 3 min) had an acute, dose-dependent, blood-pressure (BP)-lowering effect in these patients (maximal systolic BP [SBP] drop 22±4 mmHg with CPAP 16) driven by reductions in stroke volume (-16+3%) and cardiac output (-14±3%), suggesting a Valsalva-like effect. In this study, we hypothesized that overnight CPAP therapy can improve nocturnal supine hypertension, nocturia and daytime OH. Eleven AF patients with supine hypertension (age 74±2 years, 8 men, supine SBP 179±7 mmHg) had placebo or CPAP (8-12 cm H 2 O) applied for 8 hours (10pm-6am) in 2 separate nights. Supine BP was measured every 2 hr from 8pm-8am. Morning orthostatic tolerance was assessed at 8am. SBP significantly decreased during overnight CPAP therapy compared to placebo (Figure; P=0.044 by mixed-effects model) with a maximal reduction of 25±5 mmHg at 4 hours of CPAP. This BP effect was associated with lower nighttime diuresis (609±84 versus placebo 1004±160 mL; P=0.004) and improved morning orthostatic tolerance (AUC upright SBP 642±121 versus placebo 410±109 mmHg*min; P=0.014). In conclusion, CPAP is potentially a novel non-pharmacologic approach to treat the supine hypertension of AF that can improve nocturia and daytime OH.

Delayed orthostatic hypotension (dOH) is defined as OH occurring ≥3 minutes of standing. Standard autonomic testing now includes a 10 min head-up tilt (HUT) and detects “early” dOH, but “late” onset dOH (occurring ≥10 min of standing) remains a diagnostic challenge. To determine if the Valsalva maneuver (VM) can identify patients that would require a prolonged HUT (>10 min) to diagnose late dOH, we analyzed a database of 2,498 patients who underwent autonomic function tests (AFTs) in Korea University Anam Hospital between 2016-2022. Patients with diagnosis of OH (onset of OH VM2 ) and in heart rate at phase 3 (ΔHR VM3 ), pressure recovery time at phase 4 (PRT), Valsalva ratio (VR) and baroreflex sensitivity (BRSa and BRSv), were compared among groups. We found that ΔSBP VM2 , ΔHR VM3 and VR were lower in late dOH patients compared to controls (PVM3 remained significant. A receiver operating characteristic analysis revealed that cut-offs values of PRT ≥2.14 sec and ΔHR VM3 ≤15 bpm distinguished late dOH from an age and gender matched controls (PVM3 (OR=0.149 [0.056-0.398]) were more likely to have late dOH. In conclusion, our results in late dOH patients showed that PRT and ΔHR VM3 differ from those of controls, early dOH and OH, suggesting a milder form of autonomic dysfunction. These VM parameters could be used to identify patients who need prolonged >10min HUT to diagnose late-onset OH.

Postural Orthostatic Tachycardia Syndrome (POTS) might have altered endothelial function, causing abnormal vasomotion in the body and in cerebral vessels. Non-cardiac symptoms experienced by these patients suggest that they may be especially sensitive to acute reduction of arterial CO 2 concentration during hyperventilation (HV). We hypothesized HV induces more significant blood pressure (BP) fall with compensatory higher HR increase in POTS. Subjects previously diagnosed with POTS and gender-matched controls were enrolled. ECG, finger BP, and EtCO 2 were continuously recorded during hyperventilation (1breaths/sec) over 30 seconds. Hemodynamic parameters were computed in absolute and change. We studied 14 POTS and 15 controls matched for age (29 ± 2 vs 30 ± 3; p=0.63) and BMI (24.1±0.8 vs 23.0±0.7; p=0.34). At baseline mean HR (79±4 vs 70±3 bpm, p=0.12) was comparable and SBP was higher (113±3 vs 105±2 mmHg, p2 values were comparable at baseline (35±1 vs 38±1 mmHg, p=0.14) and at the end of the maneuver (20±1 vs 21±1 mmHg, p=0.58). POTS had greater SBP drop (-27±2 vs -19±2 mmHg, p

White noise perturbations using neck suction (NS) can be applied to identify open loop transfer function in a closed loop baroreflex system. It allows an estimation of central arc transfer function (H1) which represents how afferent baroreceptor information is translated into sympathetic outflow and peripheral arc transfer function (H2) which describes how muscle sympathetic nerve activity (MSNA) affects blood pressure (BP). We hypothesize that patients with postural tachycardia syndrome (POTS) have elevated central gain compared to healthy controls (CONT). We recorded raw MSNA and continuous finger BP during randomized NS (0 to -50 mmHg, 0.03-0.3 Hz) and controlled breathing at 0.25 Hz for 6 minutes in 10 female POTS and 9 female CONT. Both groups were matched for age (28.4±2.1 vs. 31.9±3.0 p=0.80) and BMI (23.0±0.7 vs 24.5±1.0, p=0.25). We derived the continuous spike rate using wavelet-based denoising. We estimated median central gain in H1 and peripheral gain in H2 for low (LF: 0.04-0.15 Hz) and high (HF: 0.15-0.4 Hz) frequency ranges (Figure). We found that POTS have significantly higher central gain in LF range (2.44±0.38 vs 1.53±0.24 spikes/s/mmHg, p=0.028, MN±SE) but not in HF range (9.02±3.02 vs. 5.06±0.52 spikes/s/mmHg, p=0.604). Median peripheral gains were comparable in LF (0.68±0.15 vs 0.58±0.09 mmHg/spikes/s, p>0.99) and HF ranges (0.18±0.02 vs 0.21±0.03 mmHg/spikes/s, p=0.497). Our results indicate that POTS have higher recruitment of neural sympathetic spike activity during BP oscillations in the LF range. This could explain why higher sympathetic activation/modulation and greater BP fluctuations in the LF range are found during upright in POTS.

About 1 out of 10 patients infected with Sars-CoV2 have persistent symptoms beyond 4 weeks and some of them meet diagnostic criteria for postural tachycardia syndrome (Long-COVID POTS). The pathophysiology of Long-COVID POTS is unknown, but autonomic dysfunction may play a role. We hypothesize Long-COVID POTS patients have impaired cardiovascular autonomic reflexes and cardiac sympathovagal balance. We conducted a case-control study with patients recruited from the Vanderbilt Autonomic Dysfunction Center and an historical population of healthy controls. Hemodynamic parameters were measured before and during 75° head up tilt. Supine ECG and finger blood pressure were continuously measured for spontaneous heart rate variability analysis. The Low Frequency (0.04-0.15Hz, LF RR ) and High Frequency (0.15-0.4 Hz, HF RR ) oscillatory modulations of sino-atrial node discharge were computed. We included 14 Long-COVID POTS patients and 15 controls matched by age (34 ± 11 vs 28 ± 7; p=0.09) and BMI (26.1 ± 5.3 vs 23.0 ± 2.6; p=0.06). As expected, the orthostatic HR increase was higher in Long-COVID POTS compared to controls (40 ± 18 vs 21 ± 1, pRR (363 ± 420 vs 933 ± 1000 ms 2 ; pRR (798 ± 596 vs 962 ± 1075 ms 2 ; p=0.68), resulting in a greater LF/HF ratio (3.7 ± 2.9 vs 1.4 ± 1.3; p

Postural Tachycardia Syndrome (POTS) is often associated to subtle cardiovascular autonomic alterations. Valsalva maneuver (VM) is commonly used in clinical settings to assess autonomic functions. Specific hemodynamic responses during VM phases can support POTS diagnosis and can provide pathophysiological characterization.We hypothesize that POTS patients present differences in VM morphology with respect to healthy controls. We conducted a case-control study enrolling subjects with prior clinical diagnosis of POTS and controls. ECG and finger blood pressure were continuously recorded during an against-resistance expiratory effort, producing a 30-mmHg straining pressure for 15 seconds in supine. Hemodynamic parameters were computed in absolute terms at baseline, early (VM2e) and late (VM2l) phase 2, phase 3 (VM3) and phase 4 (VM4) and in inter-phase changes. We studied 13 POTS and 12 controls matched for age (28 ±2 vs 31 ±3 ; p=0.98) and BMI (24.2 ± 1.0 vs 23.2 ± 0.8; p=0.46). Mean HR was increased at baseline (80 ±4 vs 69 ±3 bpm; p±4 vs 76 ±4 mmHg; p±5 vs 112 ±3 mmHg; p± 2 vs 12 ±4 bpm; p± 4 vs 10 ±3 mmHg; p± 3 vs 14 ± 3 mmHg; p=0.36). POTS have higher SBP rise during VM2l and higher VM2e HR increase. These results suggest that VM analysis can aid clinical diagnosis and that maximal baroreceptor unloading creates higher tachycardic response and vasoconstriction in POTS.

ObjectivePostural tachycardia syndrome (POTS), the most common form of dysautonomia, may be associated with autoimmunity in some cases. Autoantibodies against the ganglionic acetylcholine receptor (gAChR) have been reported in a minority of patients with POTS, but the prevalence and clinical relevance is unclear.MethodsClinical information and serum samples were systematically collected from participants with POTS and healthy control volunteers (n = 294). The level of positive gAChR antibodies was classified as very low (0.02–0.05 nmol/L), low (0.05–0.2 nmol/L), and high (>0.2 nmol/L).ResultsFifteen of 217 patients with POTS (7%) had gAChR antibodies (8 very low and 7 low). Six of the 77 healthy controls (8%) were positive (3 very low and 3 low). There were no clinical differences between seropositive and seronegative patients with POTS.ConclusionsPrevalence of gAChR antibody did not differ between POTS and healthy controls, and none had high antibody levels. Patients with POTS were not clinically different based on seropositivity. Low levels of gAChR antibodies are not clinically important in POTS.

Background: Postural tachycardia syndrome (POTS) is characterized by excessive upright tachycardia and disabling presyncopal symptoms, which are exacerbated after consuming a high-carbohydrate meal; it is unknown, however, what is the precise underlying mechanism. We seek to investigate the effect of glucose intake on orthostatic hemodynamic changes and gastrointestinal hormone secretion in POTS. Methods: Prospective, case-control study, 12 women with POTS who reported a postprandial worsening of their POTS symptoms and 13 age-matched female controls received 75-g oral glucose and 20 mg/kg acetaminophen to assess nutrient absorption. Hemodynamic, gastrointestinal hormone and acetaminophen levels were measured for up to 120 minutes postingestion while supine and standing. Results: Patients with POTS had significant orthostatic tachycardia, 48.7±11.2 versus 23.3±8.1 bpm, P =0.012 and elevated upright norepinephrine levels, 835.2±368.4 versus 356.9±156.7 pg/mL, P =0.004. After oral glucose, upright heart rate significantly increased in POTS, 21.2±11.9% versus 6.0±19.9%, P =0.033 with a concomitant decline in upright stroke volume, −10.3±11.90% versus 3.3±13.7%, P =0.027; total peripheral resistance, blood pressure and cardiac output remained unaltered. Acetaminophen rate of appearance was similar between groups ( P =0.707), indicating comparable nutrient absorption rates. POTS had increased plasma levels of C-peptide ( P =0.001), GIP (glucose-dependent insulinotropic polypeptide; P =0.001), peptide YY ( P =0.016), and pancreatic polypeptide ( P =0.04) following glucose consumption, but only GIP had a time-dependent association with the worsening upright tachycardia and stroke volume fall. Conclusions: The glucose-induced worsening orthostatic tachycardia in POTS was associated with a decline in SV; these changes occurred while GIP, a splanchnic vasodilator, was maximally elevated.

Background Patients with postural tachycardia syndrome (POTS) experience chronic symptoms of orthostatic intolerance. There are minimal data detailing the demographics, clinical features and clinical course of this condition. This online, community‐based survey highlights patients’ experience with POTS. It consists of the largest sample of POTS patients reported to date. Objectives To describe the demographics, past medical history, medications, treatments and diagnostic journey for patients living with POTS. Methods Postural tachycardia syndrome patients completed an online, community‐based, cross‐sectional survey. Participants were excluded if they had not received a diagnosis of POTS from a physician. The questions focused on the patient experience and journey, rather than physiological responses. Results The final analysis included 4835 participants. POTS predominantly affects white (93%) females (94%) of childbearing age, with approximately half developing symptoms in adolescence (mode 14 years). POTS is a chronic multisystem disorder involving a broad array of symptoms, with many patients diagnosed with comorbidities in addition to POTS. POTS patients often experience lengthy delays [median (interquartile range) 24 (6–72) months] and misdiagnosis, but the diagnostic delay is improving. POTS patients can present with a myriad of symptoms most commonly including lightheadedness (99%), tachycardia (97%), presyncope (94%), headache (94%) and difficulty concentrating (94%). Conclusions These data provide important insights into the background, clinical features and diagnostic journey of patients suffering from POTS. These data should serve as an essential step for moving forward with future studies aimed at early and accurate diagnoses of these patients leading to appropriate treatments for their symptoms.

The splanchnic vasculature is the largest blood volume reservoir in the human body. Reduced capacitance of this vascular bed, in part due to sympathetic venoconstriction, is proposed to play a role in hypertension and heart failure. Thus, interventions that increase splanchnic capacitance or decrease sympathetic activity may be beneficial in these conditions. In a proof-of-concept study in healthy and hypertensive subjects, we evaluated whether venodilation with nitroglycerin (NTG; Study 1) or sympathetic withdrawal with trimethaphan (Study 2) increase splanchnic capacitance and reduce cardiac and stroke volumes. In Study 1 (n=10, 36±4 yrs, BMI 26.1±1.7, 4 men), abdominal and chest scintigrams, to measure regional blood volumes, were obtained before and after 0.6 mg sublingual NTG. Splanchnic capacitance (volume-pressure relationships, VPR) and compliance (VPR slope) were estimated by recording abdominal scintigrams during progressive escalation of intrathoracic pressure using continuous positive airway pressure (CPAP) at 0, 4, 8, 12, and 16 cm H 2 O, each for ≤2 min. We found that NTG increased splanchnic blood volume at rest (4%, IQR 1.81-9.95; Pslope =0.46 and P intercept =0.01), indicating an increase in splanchnic capacitance. This was associated with a decrease in cardiac blood volume (-9%, IQR 2.2-10.3; Pslope =0.12 and P intercept

Inpatient acute rehabilitation is crucial in the management of patients after injuries, surgery, or those with debilitating or neurological conditions. Orthostatic hypotension (OH) is commonly associated with these conditions and can negatively impact their recovery. We found an incidence of OH of 4% in a cohort of 8350 patients at Vanderbilt Stallworth Rehabilitation Hospital (60±17yr, 72% men vs. non-OH 60±18 yr, 57% men). On admission, OH patients had a longer predicted length of rehabilitation hospitalization stay (LOS; 18±6 vs. non-OH 16±5 days; P

Postural Tachycardia Syndrome (POTS) is characterized by excessive upright tachycardia and disabling pre-syncopal symptoms, which are exacerbated after consuming a high-carbohydrate meal. The purpose of this study is to investigate the effect of oral glucose on orthostatic hemodynamic changes and gastrointestinal hormone secretion in POTS. We studied 12 women with POTS and 13 age-matched controls, all subjects received 75-gr oral glucose and 20 mg/kg acetaminophen for nutrient absorption measurement. Hemodynamic, GI hormone secretion and acetaminophen levels were measured at different time-points up to 120-min post-ingestion and while supine and standing. POTS patients had significant upright tachycardia ( delta HR: 48.7 ± 11.2 vs. 23.3 ± 8.1 bpm, P=0.012) and norepinephrine levels (835.2 ± 368.4 vs. 356.9 ± 156.7 pg/mL, P= 0.004). After oral glucose, upright HR significantly increased in POTS (92±15.5 vs. 112± 26 bpm, P=0.002) with a concomitant decline in upright stroke volume (P=0.027); total peripheral resistance, blood pressure and cardiac output remained unaltered. Acetaminophen rate of appearance was similar between groups (P=0.707). POTS patients had increased secretion of C-peptide (P=0.001), Glucose Dependent Insulinotropic Peptide (GIP) (P=0.001), peptide YY (P=0.016) and pancreatic polypeptide (P=0.04), but not GLP-1 (p=0.658) or Glucagon (P=0.836). Only GIP had a time-dependent association with the worsening upright tachycardia and SV fall, figure. Conclusions: Oral glucose exacerbated upright tachycardia in POTS, which was associated with a decline in SV; these changes occurred while GIP, a splanchnic vasodilator, is being maximally secreted.

Functional autoantibodies directed to the M2 muscarinic acetylcholine receptor (M2R) could affect the heart rate directly by altering cardiac M2R activity and/or indirectly by changing vagal-mediated cardiac M2R activity. We measured M2R autoantibody activity in sera from 10 subjects with postural tachycardia syndrome (POTS) and 5 healthy control subjects using a cell-based bioassay. Half of the POTS subjects demonstrated presence of elevated M2R autoantibody activity, while no significant M2R autoantibody activity was found in the healthy subjects. Serum-derived immunoglobulin G (IgG) from antibody-positive POTS patients induced a dose-dependent activation of M2R, which was blocked by the muscarinic antagonist atropine. Moreover, antibody-positive POTS IgG decreased the responsiveness to oxotremorine, an orthosteric muscarinic agonist, indicating an indirect inhibitory effect. These data suggest that M2R autoantibodies may contribute to the pathophysiology of POTS by increasing the normal vagal withdrawal during upright posture through its negative allosteric modulation of M2R activity. M2 muscarinic receptor-activating autoantibodies are present in a subgroup of patients with POTS and act as a negative allosteric modulator of the orthosteric ligand response.

Postural tachycardia syndrome (POTS), a syndrome characterized by orthostatic symptoms and a heart rate increase of at least 30 beats per minute in the absence of hypotension upon standing, is often accompanied by increased sympathetic activity and low blood volume. A common non-pharmacologic recommendation for patients with POTS is a high-sodium (HS) diet with the goal of bolstering circulating blood volume. The objective of this study is to assess the effects of 6 days of a HS diet on endothelial function in POTS. A total of 14 patients with POTS and 13 age-matched healthy controls, all females, were studied following 6 days on a low-sodium (LS) diet (10 mEq/day) and 6 days on a HS diet (300 mEq/day) in a crossover design. We measured endothelial function following reactive hyperemia in the brachial artery using flow-mediated dilation (FMD), leg blood flow (LBF) using strain gauge plethysmography in the calf, and reactive hyperemic index (RHI) in the microcirculation of the hand using pulsatile arterial tonometry. On the LS diet, FMD% did not differ between patients with POTS and the healthy controls although peak brachial artery diameter was lower for the patient group. RHI was higher for the patient group than for the controls, but there were no differences in post-ischemic LBF increase. On the HS diet, there were no between-group differences in FMD%, LBF increase, or RHI. In summary, a HS diet for 6 days did not induce endothelial dysfunction. This non-pharmacologic treatment used for patients with POTS does not negatively affect endothelial function when used for a sub-acute duration. ClinicalTrials.gov NCT01550315; March 9, 2012.

Background Postural orthostatic tachycardia syndrome (POTS) is a debilitating form of chronic orthostatic intolerance that primarily affects women and causes substantial impairment in quality of life and function. Yet, there is minimal literature describing the employment and economic consequences of POTS. We explored these aspects of the POTS patient experience through a self-reported study designed using community-based participatory research principles. Methods and results A comprehensive questionnaire, including employment and economic consequences, was developed in partnership with Dysautonomia International, a patient advocacy organization. The POTS community engaged in all stages of the research design and analysis. Participants were recruited through Dysautonomia International's website and social media channels. The analysis included 5,556 adult (age ≥18 years) participants with a physician-confirmed diagnosis of POTS. The majority of participants were female (95%). Forty-eight per cent of participants reported employment during the three months prior to the survey, and of these participants, 66.8% would work greater hours if not for illness limitations. Over two-thirds (70.5%) of participants have lost income due to POTS symptoms, with 36.0% of the total cohort losing more than $10,000 USD in the 12 months prior to the survey. Almost all (95%) participants reported POTS-related out-of-pocket medical expenses since diagnosis, with 51.1% of participants spending $10,000 USD or more. Conclusions This is the largest study reporting the employment and economic challenges experienced by individuals with POTS. Exposure of these challenges emphasizes the need for earlier diagnosis and improved therapeutic strategies to reduce the negative individual and societal consequences of this disorder.

Postural tachycardia syndrome (POTS) and vasovagal syncope (VVS) are two disorders of orthostatic intolerance which are often misdiagnosed as the other. In each case, patients experience a reduced health-related quality of life (HRQoL) compared to healthy populations. This study was conducted to test the hypothesis that HRQoL is worse in POTS. POTS patients were recruited from the Dysautonomia International Annual Patient and Caregiver Conference. VVS patient data came from those enrolled in the Second Prevention of Syncope Trial. Participants aged ≥ 18 years (177 POTS and 72 VVS) completed the RAND 36-Item Health Survey, a generic and coherent health-related quality of life survey. POTS patients reported reduced HRQoL compared to VVS patients in physical functioning (42.5 ± 1.7 vs. 76.5 ± 2.9, p

The purpose of this study is to evaluate endothelial function in postural tachycardia syndrome (PoTS), a poorly understood chronic condition characterized by a state of consistent orthostatic tachycardia (delta heart rate ≥30 beats per minute) upon standing without orthostatic hypotension. Nineteen patients with PoTS and 9 healthy controls were studied after 3 days of a fixed, caffeine-free, normal sodium (150 milliequivalents/day) diet. All participants underwent autonomic function testing, including sinus arrhythmia, valsalva maneuver, hyperventilation, cold pressor, handgrip, and a standing test with catecholamine measurements, followed by endothelial function testing. We analyzed 3 measures of endothelial function: percent brachial flow-mediated dilation, digital pulsatile arterial tonometry, and postischemic percent leg blood flow. Flow-mediated dilation was significantly lower in patients with PoTS (6.23±3.54% for PoTS) than in healthy controls (10.6±4.37% for controls versus, P =0.014). PoTS and controls had similar digital pulsatile arterial tonometry (1.93±0.40 arbitrary units for controls versus 2.13±0.63 arbitrary units for PoTS). PoTS had similar but suggestive percent leg blood flow to controls (313±158% for PoTS versus 468±236% for controls, P =0.098). Patients with PoTS have significantly reduced flow-mediated dilation compared with healthy controls, suggesting that PoTS is characterized by endothelial dysfunction in conduit arteries. Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT01308099.

BACKGROUND: High sodium intake is recommended for the treatment of postural tachycardia syndrome (POTS) to counteract the hypovolemia and elevated plasma norepinephrine that contribute to excessive orthostatic tachycardia, but evidence of its efficacy is not available. OBJECTIVES: We tested whether a high sodium (HS) diet reduces orthostatic tachycardia (ΔHR) and upright heart rate (HR) compared with low sodium (LS) diet in POTS patients, and secondarily its effect on plasma volume (PV) and plasma norepinephrine. METHODS: We enrolled 14 POTS patients and 13 healthy controls (HC), 23–49 years old, in a crossover study with six days of LS (10 mEq sodium/day) or HS (300 mEq sodium/day) diet. We measured supine and standing HR, blood pressure, serum aldosterone, plasma renin activity, blood volume, and plasma norepinephrine and epinephrine. RESULTS: In POTS, HS diet reduced upright HR and ΔHR compared with LS diet. Total blood volume and PV increased, and standing norepinephrine decreased with HS compared with LS diet However, upright HR, ΔHR and upright norepinephrine remained higher in POTS than in HC on HS diet [117 (98–121) beats per minute (bpm), 46 (32–55) bpm, and 753 (498–919) pg/mL in POTS vs. 85 (77–95) bpm, 19 (11–32) bpm, and 387 (312–433) pg/mL in HC], despite no difference in the measured PV. CONCLUSIONS: In POTS patients, high dietary sodium intake compared with low dietary sodium intake increases plasma volume, lowers standing plasma norepinephrine, and decreases ΔHR. CONDENSED ABSTRACT: Postural Tachycardia Syndrome (POTS) is a chronic form of orthostatic intolerance. Augmented oral sodium intake is a frequently prescribed treatment and recommended in professional society scientific statements on POTS, but evidence supporting the effectiveness was lacking. We evaluated one week of a very high sodium diet compared to a very low sodium diet in POTS patients. The high sodium diet expanded the plasma volume and total blood volume, reduced standing plasma norepinephrine levels (a marker of sympathetic nervous system tone), and reduced the orthostatic tachycardia. These data provide supporting evidence for the use of high sodium diets in POTS patients. ClinicalTrials.gov Identifier: NCT01547117

STUDY OBJECTIVES: Postural orthostatic tachycardia syndrome (POTS) and restless legs syndrome (RLS) are both characterized by sleep disturbance along with autoimmune/inflammatory features and autonomic dysfunction. However, to our knowledge, there has been no direct study looking at the prevalence of RLS in patients with POTS patients compared with healthy participants (controls). METHODS: Ninety-six physician-diagnosed patients with POTS (89 female and 7 male) and 130 controls (99 female and 31 male) were administered the Cambridge Hopkins questionnaire. Participants who were diagnosed with probable or definite RLS on the Cambridge Hopkins questionnaire were then contacted to determine the severity of RLS with the International Restless Legs Scale. RESULTS: More patients with POTS (15 of 96; 15.6%) than controls (6 of 130; 4.6%) were diagnosed with probable or definite RLS on the Cambridge Hopkins questionnaire (P = .0048). A sensitivity analysis with only female respondents yielded similar results. RLS severity was in the moderate range (12.23 ± 9.22). CONCLUSIONS: There is a higher prevalence of RLS in patients with POTS patients compared with controls. This association may have to do with shared increased inflammatory/autoimmune load and autonomic dysfunction. CITATION: Dodson C, Bagai K, Weinstock LB, et al. Restless legs syndrome is increased in postural orthostatic tachycardia syndrome. J Clin Sleep Med. 2021;17(4):791–795.

Inpatient rehabilitation is crucial in the management of patients after injuries, surgery, or those with debilitating or neurological conditions. Orthostatic hypotension (OH) is commonly associated with these conditions, and therefore, the inability to stand and participate in rehabilitation therapy can negatively impact their recovery. To test this hypothesis, we study a cohort of 8352 patients who underwent rehabilitation at Vanderbilt Stallworth Rehabilitation Hospital between 2014-2019 to assess the prevalence of OH and its impact on the length of stay (LOS), functional independence measure (FIM) change (discharge FIM-admission FIM), and FIM efficiency (FIM change/LOS), compared to patients without OH admitted during the same period. We found that the prevalence of OH was 3.8% (n = 314; 60±18 yrs; 227 men). OH was commonly associated with patients admitted for neurological conditions (29%, n = 91), spinal cord dysfunction (22%, n = 71), orthopedic disorders (13%, n = 13), and stroke (10%, n = 33). On admission, patients with OH had a longer predicted LOS compared to those without OH (18±6 vs. 16±5 days, respectively, p = 0.001), reflecting greater medical complexity. Moreover, the actual LOS at discharge was significantly longer in OH patients compared to those without OH (19±12 vs. 13±9 days; p = 0.001) as was the difference between actual-predicted LOC (1±11 vs. 2±8; p = 0.001). The change in FIM was similar in both patients with and without OH (30±26 vs. 33±20, respectively; p = 0.52) but FIM efficiency was lower in OH patients (2±2.2 vs. 3±2.2 without OH; p = 0.001). OH prolonged LOS regardless of the admission diagnosis (stroke, other neurological conditions, spinal cord dysfunction and orthopedic disorders). In conclusion, OH is present in a significant proportion of patients undergoing acute rehabilitation and adversely impacts the recovery of these patients as measured by lower FIM efficacy and a prolonged rehabilitation period to achieve the same functional gain as patients without OH.

Background Splanchnic venous pooling induced by upright posture triggers a compensatory increase in heart rate ( HR ), a response that is exaggerated in patients with postural tachycardia syndrome. To assess whether abdominal compression attenuates orthostatic tachycardia and improves symptoms, 18 postural tachycardia syndrome patients (32±2 years) were randomized to receive either abdominal compression (40 mm Hg applied with an inflatable binder ≈2 minutes before standing) or propranolol (20 mg) in a placebo‐controlled, crossover study. Methods and Results Systolic blood pressure, HR , and symptoms were assessed while seated and standing, before and 2 hours postdrug. As expected, propranolol decreased standing HR compared with placebo (81±2 versus 98±4 beats per minute; P P =0.002). Compression had no effect on standing HR (96±4 beats per minute) but increased standing systolic blood pressure compared with placebo and propranolol (106±2 mm Hg; P HR (81±2 beats per minute for both interventions) but prevented the decrease in standing systolic blood pressure produced by propranolol (98±2 versus 93±2 mm Hg for propranolol; P =0.029), and significantly improved total symptom burden (−6±2 versus −1±2 for propranolol; P =0.041). Conclusions Splanchnic venous compression alone did not improve HR or symptoms but prevented the blood pressure decrease produced by propranolol. The combination was more effective in improving symptoms than either alone. Splanchnic venous compression can be a useful adjuvant therapy to propranolol in postural tachycardia syndrome. Registration URL : https://www.clini​caltr​ials.gov ; Unique identifier: NCT 00262470.

Postural Tachycardia Syndrome (POTS) is a chronic disorder characterized by symptoms of orthostatic intolerance such as fatigue, lightheadedness, dizziness, palpitations, dyspnea, chest discomfort and remarkable tachycardia upon standing. Non-invasive transdermal vagal stimulators have been applied for the treatment of epilepsy, anxiety, depression, headache, and chronic pain syndromes. Anti-inflammatory and immunomodulating effects after transdermal vagal stimulation raised interest for applications in other diseases. Patients with sympathetic overactivity, reduced cardiac vagal drive and presence of systemic inflammation like POTS may benefit from tVNS. This article will address crucial methodological aspects of tVNS and provide preliminary results of its acute and chronic use in POTS, with regards to its potential effectiveness on autonomic symptoms reduction and heart rate modulation.

Neurogenic orthostatic hypotension (OH) is a disabling disorder caused by impairment of the normal autonomic compensatory mechanisms that maintain upright blood pressure. Nonpharmacologic treatment is always the first step in the management of this condition, but a considerable number of patients will require pharmacologic therapies. Denervation hypersensitivity and impairment of baroreflex buffering makes these patients sensitive to small doses of pressor agents. Understanding the underlying pathophysiology can help in selecting between treatment options. In general, patients with low "sympathetic reserve", i.e., those with peripheral noradrenergic degeneration (pure autonomic failure, Parkinson's disease) and low plasma norepinephrine, tend to respond better to "norepinephrine replacers" (midodrine and droxidopa). On the other hand, patients with relatively preserved "sympathetic reserve", i.e., those with impaired central autonomic pathways but spared peripheral noradrenergic fibers (multiple system atrophy) and normal or slightly reduced plasma norepinephrine, tend to respond better to "norepinephrine enhancers" (pyridostigmine, atomoxetine, and yohimbine). There is, however, a spectrum of responses within these extremes, and treatment should be individualized. Other nonspecific treatments include fludrocortisone and octreotide. The presence of associated clinical conditions, such as supine hypertension, heart failure, postprandial hypotension, PD, MSA, and diabetes need to be considered in the pharmacologic management of these patients.

Background: Obesity is associated with sympathetic activation which results in insulin resistance and a blunted insulin-mediated microvascular recruitment. We propose that removal of sympathetic vasoconstriction can result in improvement of insulin-mediated vasodilation and subsequently in sensitivity to insulin-mediated glucose uptake. Methods: We blocked sympathetic vasoconstriction in an isolated forearm model during a hyperinsulinemic euglycemic clamp to determine the effect of insulin recruitment on microvascular circulation using contrast-enhanced ultrasonography (CEU). We studied 9 obese human subjects (age 41±6 years, BMI 37±3 kg*m -2 , SBP 125±6 mm Hg). We assessed the effects of insulin on microvascular recruitment and glucose uptake on two separate occasions, randomly assigned and at least one month apart, during an intrabrachial infusion of the alpha-adrenergic blocker phentolamine (PHE, 25 micrograms/min, blocked day) or saline (SAL, Control day). Subjects were studied at baseline (BSL) and at the end of the clamp (CLAMP). Results: As expected forearm blood flow increased after insulin alone (67±27%, p=0.016) and with alpha blockade and insulin (140± 22%, p=0.0011). Microvascular blood volume (MBV, index of microvascular recruitment), showed a significant increased during PHE compared to SAL (figure). Muscle glucose uptake trended towards increase with PHE but did not reach statistical significance (p=0.0558). There were no systemic effects due to sympathetic blockade. Conclusions: This data shows that sympathetic vasoconstriction contributes to the blunted insulin-mediated microvascular recruitment seen in obesity.

Supine hypertension affects about half of patients with primary autonomic failure (AF), complicates the treatment of orthostatic hypotension (OH) and induces nocturnal polyuria, resulting in worsening of morning OH. We previously showed that short exposure to local passive heat (40-42°C applied for ≤2 hours over abdomen and pelvis with a heating pad) acutely decreased systolic blood pressure (BP) by -25±5 mmHg in AF patients with supine hypertension due to decreases in stroke volume (-29±5%) and cardiac output (-30±5%). In this study, we hypothesized that local passive heat therapy applied overnight would lower nocturnal BP and polyuria, and improve early morning OH in these patients. Ten AF patients with supine hypertension (age 76±2 years, 6 men, supine systolic BP 168±3 mmHg) received passive heat (38°C with a water-perfused heating pad placed under the torso) or placebo, in a 2-night crossover study. Supine BP was monitored every 2 hr from 8pm-8am. Heat therapy was applied from 10pm-6am. Morning orthostatic tolerance was assessed at 8 am. Systolic BP significantly decreased during overnight heat therapy compared to placebo (Figure; P

Objective: Non-syncopal fainting (psychogenic pseudo-syncope) is a diagnostic challenge, leading to unnecessary diagnostic procedures and inappropriate treatments. We explored the utility of elective electroencephalography (EEG) monitoring during head-up tilt table test (TTT) for diagnosis of NSF. Methods: We reviewed medical records of 131 patients presenting with transient loss of consciousness (TLOC) in whom TTT and EEG were done simultaneously for suspected NSF (>20 lifetime syncopal episodes, >2 episodes in a day, prolonged LOC, and atypical movements. Tilt responses were grouped into three categories: non-diagnostic (nDg, no TLOC during TTT), vasovagal syncope (VVS, TLOC with a slow wave pattern on EEG), and non-syncopal fainting (NSF, apparent TLOC with normal EEG). Results: 107 patients were included in the analysis; 57 were nDg (53%), 11 had VVS (10%), and 39 had documented NSF (37%). There was no difference in age (42±16, 42±20, and 40±15 yrs; respectively) or proportion of female gender (68, 81, 78%; respectively), but NSF patients were more likely to be taking psychotropic medications. Baseline blood pressure and heart rate were similar among groups. NSF patients had a shorter time to event (9 vs. 19 min in VVS) and had significantly higher BP during event than those in the nDg group (systolic 131±16 vs . 120±18; p=0.01 and diastolic BP 86±10 vs. 80±12 mmHg; p=0.05). Conclusions: In patients with suspected NSF, elective EEG monitoring during TTT yields a much higher incidence of NSF (37%) than unmonitored TTT (0-19%), or routine EEG monitoring (8-19%). We suggest that elective EEG monitoring provides a cost-efficient diagnostic approach, excludes cases of cerebral syncope, and helps in the management of patients with NSF. Prospective studies are needed to determine the clinical characteristics that warrant adding EEG monitoring to TTT.

Patients with autonomic failure are characterized by disabling orthostatic hypotension because of impaired sympathetic activity, but even severely affected patients have residual sympathetic tone which can be harnessed for their treatment. For example, norepinephrine transporter blockade with atomoxetine raises blood pressure (BP) in autonomic failure patients by increasing synaptic norepinephrine concentrations; acetylcholinesterase inhibition with pyridostigmine increases BP by facilitating ganglionic cholinergic neurotransmission to increase sympathetic outflow. We tested the hypothesis that pyridostigmine will potentiate the pressor effect of atomoxetine and improve orthostatic tolerance and symptoms in patients with severe autonomic failure. Twelve patients received a single oral dose of either placebo, pyridostigmine 60 mg, atomoxetine 18 mg or the combination on separate days in a single blind, crossover study. BP was assessed seated and standing before and 1-hour postdrug. In these severely affected patients, neither pyridostigmine nor atomoxetine improved BP or orthostatic tolerance compared with placebo. The combination, however, significantly increased seated BP in a synergistic manner (133±9/80±4 versus 107±6/66±4 mm Hg for placebo, 105±5/67±3 mm Hg for atomoxetine, and 99±6/64±4 mm Hg for pyridostigmine; P

Postural Tachycardia Syndrome (POTS) is a clinical syndrome characterized by an excessive increase in heart rate (>= 30 bpm) on standing in the absence of orthostatic hypotension, and frequent orthostatic symptoms for more than 6 months. While most researchers focus on the hyperadrenergic features of POTS, these patients also have significant cardio-vagal (parasympathetic) impairment. We tested the hypothesis that transdermal electrical stimulation of the auricular branch of the vagus nerve will enhance cardio-vagal modulation, reduce heart rate, upright symptoms, and improve orthostatic tolerance. We studied 14 patients with POTS (31.5+/-11.7 years, BMI 22.6+/-3.9 kg/m 2 ). Sham or sub-perception threshold transdermal electrical vagal stimulation was applied in random order to the auricular branch in the right ear in supine and during graded tilt maneuver. Patients with low vagal modulation (low high frequency HF < 200 ms 2 ) responded to vagal stimulation (Kruskal Wallis p=0.01, n=7, Fig left) with significant increase in HF power (eg @50Hz: +51+/-10 ms 2 , p=0.0032). Vagal stimulation during upright tilt tended to reduce orthostatic tachycardia and overall orthostatic symptom score. It improved significantly tilt time (+5.3+/-2.6 min, p=0.0156, Fig right). Patients with higher baseline vagal modulation (HF >= 200 ms 2 ) did not respond to vagal stimulation (interaction p=0.41). This proof of concept study indicates that auricular transdermal vagal stimulation improves supine cardio-vagal function in POTS patients with low vagal modulation. Further research will determine if this approach can be used therapeutically, alone or in combination with other therapies.

Primary autonomic failure is characterized by disabling orthostatic hypotension, but at least half of these patients have paradoxical supine hypertension. Renin–angiotensin mechanisms were not initially thought to contribute to this hypertension because plasma renin activity is often undetectable in autonomic failure. Plasma aldosterone levels are normal, however, and we recently showed that plasma angiotensin II is elevated and acts at AT 1 (angiotensin type 1) receptors to contribute to hypertension in these patients. Because aldosterone and angiotensin II can also bind mineralocorticoid receptors to elevate blood pressure, we hypothesized that mineralocorticoid receptor activation plays a role in the hypertension of autonomic failure. To test this hypothesis, we determined the acute effects of the mineralocorticoid receptor antagonist eplerenone (50 mg, oral) versus placebo on supine blood pressure in a randomized, double-blind, crossover study. Medications were given at 8:00 pm with blood pressure recorded every 2 hours for 12 hours. Ten primary autonomic failure patients with supine hypertension completed this study (7 pure autonomic failure, 2 multiple system atrophy, 1 parkinson’s disease; 7 male; 70±2 years of age). Eplerenone maximally reduced supine systolic blood pressure by 32±6 mm Hg at 8 hours after administration (versus 8±10 mm Hg placebo, P =0.016), with no effect on nocturia (12-hour urine volume: 985±134 mL placebo versus 931±94 mL eplerenone, P =0.492; nocturnal weight loss: −1.19±0.15 kg placebo versus −1.18±0.15 kg eplerenone, P =0.766). These findings suggest that inappropriate mineralocorticoid receptor activation contributes to the hypertension of autonomic failure, likely independent of canonical mineralocorticoid effects, and provides rationale for use of eplerenone in these patients.

Continuous positive airway pressure (CPAP) improves cardiac function and blood pressure (BP) in patients with sleep-breathing disorders by reducing increased sympathetic tone. The direct hemodynamic effects of increased intrathoracic pressure with CPAP, however, are not known and are likely masked by baroreflex buffering. To determine the acute hemodynamic effects of CPAP in the absence of autonomic modulation, we applied 5 levels of CPAP (0, 4, 8, 12 and 16 cm H 2 O, each for 2 min) to 7 healthy normotensive (NTN, 33±3 years, BMI 29±3, 4 females) and 12 hypertensive subjects (HTN, 50±2 years, BMI 30±2, 8 females) before and during autonomic withdrawal with the ganglionic blocker trimethaphan. Hemodynamic parameters were measured at the end of each CPAP level. At baseline, CPAP had no effect on systolic BP (SBP), heart rate (HR), cardiac output (CO), stroke volume (SV) or systemic vascular resistance (SVR) in either group. During the autonomic blockade, CPAP significantly decreased SBP in both groups (Figure). The maximal BP drop was twice as much in HTN than NTN (-17±2 vs. -8±2 mmHg at 16 cm H 2 O; P2 O, respectively; whereas in NTN, the decreases were -20±5% and -24±4%. Neither SVR nor HR changed significantly with CPAP in either group. We conclude that, in the absence of autonomic modulation, CPAP acutely decreases SBP significantly, due to decreases in CO and SV likely reflecting a decrease in venous return and increase in venous capacitance. The effect on BP was greater in HTN suggesting that a sympathetically mediated reduction in capacitance may contribute to the hypertension.

Postural tachycardia syndrome (POTS) is a chronic disabling condition with excessive upright tachycardia and symptoms due to enhanced sympathetic activity in otherwise healthy young individuals. Because it is not clear if sympathetic activation is a primary phenomenon, or an appropriate compensatory response to hypovolemia, deconditioning or partial neuropathy, we analyzed resting supine muscle sympathetic nerve activity (MSNA) in 38 female POTS patients (mean±SD, age 32.1±9.1, BMI 22.7±5.4). MSNA showed a wide range of burst rate (19.7±12.1 bursts/min, range 1.2 to 54, 95% CI: 15.7 to 23.6). We compared the 1 st and 4 th Quartiles of 28 MSNA records (MSNA_Q1: < 7.3; MSNA_Q4: > 23.4 bursts/min) to determine if resting MSNA is related to heart rate (HR) or blood pressure (BP) responses to orthostatic challenge and the Valsalva maneuver (2-way ANOVA with post-hoc tests). Upright HR was inappropriately high in both groups (MSNA_Q1: 120±19 vs. MSNA_Q4: 110±20 bpm, NS), but the MSNA_Q4 group had higher upright diastolic BP than MSNA_Q1 (81±12 vs. 62±8 mmHg, P The greater BP responses, but comparable HR responses, to posture and Valsalva challenges provide evidence that the subset of POTS patients with higher resting MSNA have a primary sympathetic activation. These patients might benefit from sympatholytic therapy in contrast to other POTS patients with low or absent resting MSNA.