Cutaneous alpha-synuclein deposition in postural tachycardia patients.

OBJECTIVE: To report a case series of patients with neuropathic POTS and cutaneous phosphorylated alpha-synuclein (P-SYN) deposition on skin biopsy and compare these to neuropathic POTS patients without P-SYN deposition. METHODS: The medical history, physical examination findings, autonomic function testing, and skin biopsy neuropathology of patients under the age of 50 with a postural tachycardia and a diagnosis of POTS were retrospectively reviewed. Included patients completed the composite autonomic severity score (COMPASS 31), the Wood Mental Fatigue Inventory, the Epworth Sleepiness scale, the REM Behavior Disorder Questionnaire, the Patient-Reported Outcomes Measurement Information System (PROMIS-10), and the Gastroparesis Cardinal Symptom Index. RESULTS: Of 296 patients seen with POTS, 22 patients with suspected neuropathic POTS had skin biopsies performed during their evaluation. Seven of 22 patients had P-SYN present on skin biopsy, while 15 individuals did not. Those with P-SYN on biopsy: (1) were more likely to be male; (2) had features of REM sleep behavioral disorder; (3) reported less sleepiness and cognitive impairment; and (4) noted greater symptoms of gastroparesis. On autonomic testing, the group with P-SYN deposition was more likely to have a hypertensive response to tilt-table testing and abnormal QSART responses. INTERPRETATION: Phosphorylated alpha-synuclein deposition is present in some postural tachycardia patients with neuropathic features. Individuals with a postural tachycardia and cutaneous phosphorylated alpha-synuclein deposition may be distinguished from other patients with neuropathic POTS.

Salivary Cortisol Levels Predict Therapeutic Response to a Sleep-Promoting Method in Children with Postural Tachycardia Syndrome.

OBJECTIVE: To determine the value of salivary cortisol concentrations in predicting the efficacy of sleep-promoting treatment in children with postural tachycardia syndrome (POTS). STUDY DESIGN: This prospective study involved 40 children with POTS and 20 healthy children (controls). POTS was diagnosed using the head-up or head-up tilt test. Patients with POTS received a sleep-promoting treatment: >8 hours of sleep every night and a midday nap in an appropriate environment; no drinking water or exercising before bedtime; and urination before bedtime. The Pittsburgh Sleep Quality Index was used to evaluate sleep quality, and symptom scores were used to assess POTS severity. Salivary samples were collected upon awakening, 30 minutes after awakening, at 12:00 p.m., 4:00 p.m., and 8:00 p.m., and at bedtime before treatment. Enzyme-linked immunosorbent assay was used to measure salivary cortisol concentrations. RESULTS: Cortisol concentrations were significantly higher in patients with POTS than in the controls at all time points (P < .05 for all). PSQI scores were significantly higher in patients with POTS (7.2 ± 3.0) than in the controls (1.35 ± 1.39; t = -10.370, P <.001). Salivary cortisol concentrations at awakening were significantly higher in responders than in nonresponders (4.83 ± 0.73 vs 4.05 ± 0.79 ng/mL, t = -3.197, P = .003). The area under the receiver operating characteristic curve was 75.8%, (95% CI 59.3%-92%). Cut-off at-awakening salivary cortisol concentrations of >4.1 ng/mL yielded 83.3% sensitivity and 68.7% specificity in predicting therapeutic efficacy. CONCLUSIONS: At-awakening salivary cortisol concentrations may predict the efficacy of sleep-promoting treatment in patients with POTS.

Decreasing cerebral oxygen consumption during upright tilt in vasovagal syncope.

We measured changes in transcranial Doppler ultrasound (TCD) and near infrared spectroscopy (NIRS) during 70° upright tilt in patients with recurrent vasovagal syncope (VVS, N = 20), postural tachycardia syndrome (POTS, N = 20), and healthy controls (N = 12) aged 15-27 years old. VVS was included if they fainted during testing within 5-15 min of upright tilt. We combined TCD and NIRS to obtain estimates of percent change in the cerebral metabolic rate of oxygen consumption (CMRO2), cerebral blood flow velocity (CBFv), and oxygen extraction fraction (OEF). Over the course of 10 min of upright tilt, CBFv decreased from a baseline of 70 ± 5 to 63 ± 5 cm/sec in controls and 74 ± 3 to 64 ± 3 cm/sec in POTS while decreasing from 74 ± 4 to 44 ± 3 cm/sec in VVS CMRO2 was unchanged in POTS and controls during tilt while OEF increased by 19 ± 3% and 15 ± 3%, respectively. CMRO2 decreased by 31 ± 3% in VVS during tilt while OEF only increased by 7 ± 3%. Oxyhemoglobin decreased by 1.1 ± 1.3 µmol/kg brain tissue in controls, by 1.1 ± 1.3 µmol/kg in POTS, and 11.1 ± 1.3 µmol/kg in VVS CBFv and CMRO2 fell steadily in VVS during upright tilt. The deficit in CMRO2 in VVS results from inadequate OEF in the face of greatly reduced CBF.

Pathogenesis and Individualized Treatment for Postural Tachycardia Syndrome in Children.

OBJECTIVE: Postural tachycardia syndrome (POTS) is one of the major causes of orthostatic intolerance in children. We systematically reviewed the pathogenesis and the progress of individualized treatment for POTS in children. DATA SOURCES: The data analyzed in this review are mainly from articles included in PubMed and EMBASE. STUDY SELECTION: The original articles and critical reviews about POTS were selected for this review. RESULTS: Studies have shown that POTS might be related to several factors including hypovolemia, high catecholamine status, abnormal local vascular tension, and decreased skeletal muscle pump activity. In addition to exercise training, the first-line treatments mainly include oral rehydration salts, beta-adrenoreceptor blockers, and alpha-adrenoreceptor agonists. However, reports about the effectiveness of various treatments are diverse. By analyzing the patient's physiological indexes and biomarkers before the treatment, the efficacy of medication could be well predicted. CONCLUSIONS: The pathogenesis of POTS is multifactorial, including hypovolemia, abnormal catecholamine state, and vascular dysfunction. Biomarker-directed individualized treatment is an important strategy for the management of POTS children.

Sympathetic activation is associated with increased IL-6, but not CRP in the absence of obesity: lessons from postural tachycardia syndrome and obesity.

Sympathetic activation is thought to contribute to the inflammatory process associated with obesity, which is characterized by elevated circulating C-reactive protein (hsCRP) and interleukin-6 (IL-6). To evaluate whether sympathetic activation is associated with inflammation in the absence of obesity, we studied patients with postural tachycardia syndrome (POTS), a condition characterized by increased sympathetic tone in otherwise healthy individuals. Compared with 23 lean controls, 43 lean female POTS had greater vascular sympathetic modulation (low-frequency blood pressure variability, LFSBP, 3.2 ± 0.4 vs. 5.5 ± 0.6 mmHg(2), respectively, P = 0.006), lower cardiac parasympathetic modulation (high-frequency heart rate variability, 1,414 ± 398 vs. 369 ± 66 ms(2), P = 0.001), and increased serum IL-6 (2.33 ± 0.49 vs. 4.15 ± 0.54 pg/ml, P = 0.011), but this was not associated with increases in hsCRP, which was low in both groups (0.69 ± 0.15 vs. 0.82 ± 0.16 mg/l, P = 0.736). To explore the contribution of adiposity to inflammation, we then compared 13 obese female POTS patients and 17 obese female controls to matched lean counterparts (13 POTS and 11 controls). Compared with lean controls, obese controls had increased LFSBP (3.3 ± 0.5 vs. 7.0 ± 1.1 mmHg(2); P = 0.016), IL-6 (2.15 ± 0.58 vs. 3.92 ± 0.43 pg/ml; P = 0.030) and hsCRP (0.69 ± 0.20 vs. 3.47 ± 0.72 mg/l; P = 0.001). Obese and lean POTS had similarly high IL-6 but only obese POTS had increased hsCRP (5.76 ± 1.99 mg/l vs. 0.65 ± 0.26; P < 0.001). In conclusion, sympathetic activation in POTS is associated with increased IL-6 even in the absence of obesity. The coupling between IL-6 and CRP, however, requires increased adiposity, likely through release of IL-6 by visceral fat.

Assessment of therapeutic biomarkers in the treatment of children with postural tachycardia syndrome and vasovagal syncope.

BACKGROUND: Postural tachycardia syndrome and vasovagal syncope are common causes of orthostatic intolerance in children. The supplementation with water, or salt, or midodrine, or ß-blocker was applied to children with postural tachycardia syndrome or vasovagal syncope. However, the efficacy of such medication varied and was not satisfied. This review aimed to summarise the current biomarkers in the treatment of the diseases. DATA SOURCES: Studies were collected from online electronic databases, including OVID Medline, PubMed, ISI Web of Science, and associated references. The main areas assessed in the included studies were clinical improvement, the cure rate, and the individualised treatment for postural tachycardia syndrome and vasovagal syncope in children. RESULTS: Haemodynamic change during head-up tilt test, and detection of 24-hour urinary sodium excretion, flow-mediated vasodilation, erythrocytic H2S, and plasma pro-adrenomedullin as biological markers were the new ways that were inexpensive, non-invasive, and easy to test for finding those who would be suitable for a specific drug and treatment. CONCLUSION: With the help of biomarkers, the therapeutic efficacy was greatly increased for children with postural tachycardia syndrome and vasovagal syncope.

Melatonin reduces tachycardia in postural tachycardia syndrome: a randomized, crossover trial.

BACKGROUND: Postural tachycardia syndrome (POTS) induces disabling chronic orthostatic intolerance with an excessive increase in heart rate (HR) upon standing, and many POTS patients have a hyperadrenergic state. Medications that restrain HR are a promising approach to this problem. OBJECTIVE: We tested the hypothesis that melatonin will attenuate the tachycardia and improve symptom burden in patients with POTS. METHODS: Patients with POTS (n = 78) underwent acute drug trials with melatonin 3 mg orally and placebo, on separate mornings, in a randomized crossover design. Blood pressure, HR, and symptoms were assessed while seated and after standing for up to 10 min prior to, and hourly for 4 h following study drug administration. RESULTS: The reduction in standing HR was significantly greater 2 h after melatonin compared with placebo (P = 0.017). There was no significant difference in the reduction of systolic blood pressure between melatonin and placebo, either with standing or while seated. The symptom burden was not improved with melatonin compared with placebo. CONCLUSION: Oral melatonin produced a modest decrease in standing tachycardia in POTS. Further research is needed to determine the effects of regular night-time use of this medication in POTS.

Low iron storage and mild anemia in postural tachycardia syndrome in adolescents.

OBJECTIVE: We reported low iron storage in neurally mediated syncope (NMS). While reduced red cell mass indicative of anemia has been reported in POTS, iron indices and hemoglobin (Hb) data were not reported. We investigated whether POTS, like NMS, is associated with low iron storage and anemia. METHODS: Thirty two children evaluated in 2007 and 2008 for probable POTS by a standing or tilt test or both at Texas Children's Hospital were included in a retrospective study. We measured serum ferritin (SF) and Hb values. We defined iron deficiency as SF < 12 µg/L, low iron storage as SF ≤ 25 µg/L, anemia as low Hb values for age and sex, and POTS as ≥2 symptoms of orthostatic intolerance >3 months and increased HR of >30 BPM or HR of >120 BPM within 10 min of standing or 70° tilt. RESULTS: Twenty four children had POTS, ages 12-18 years, 17 (71 %) were females. Value range (median) of SF 2-289 µg/L (25), Hb 11.5-14.6 (12.5) in females and 12-15.9 g/L (13.6) in males. Patients with POTS, when compared with normal US pediatric population had higher prevalence of low iron storage (50 vs. 14 %), iron deficiency (25 % of teenage girls vs. 9 %, and 16 % of teenage boys vs. 1 %), and anemia (18 % of teenage girls vs. 1.5 %, and 43 % of teenage boys vs. 0.1 %). INTERPRETATION: Low iron storage and mild anemia are associated with POTS suggesting that low iron storage is a potentially pathophysiologic factor in both POTS and NMS.

Norepinephrine transporter variant A457P knock-in mice display key features of human postural orthostatic tachycardia syndrome.

Postural orthostatic tachycardia syndrome (POTS) is a common autonomic disorder of largely unknown etiology that presents with sustained tachycardia on standing, syncope and elevated norepinephrine spillover. Some individuals with POTS experience anxiety, depression and cognitive dysfunction. Previously, we identified a mutation, A457P, in the norepinephrine (NE; also known as noradrenaline) transporter (NET; encoded by SLC6A2) in POTS patients. NET is expressed at presynaptic sites in NE neurons and plays a crucial role in regulating NE signaling and homeostasis through NE reuptake into noradrenergic nerve terminals. Our in vitro studies demonstrate that A457P reduces both NET surface trafficking and NE transport and exerts a dominant-negative impact on wild-type NET proteins. Here we report the generation and characterization of NET A457P mice, demonstrating the ability of A457P to drive the POTS phenotype and behaviors that are consistent with reported comorbidities. Mice carrying one A457P allele (NET(+/P)) exhibited reduced brain and sympathetic NE transport levels compared with wild-type (NET(+/+)) mice, whereas transport activity in mice carrying two A457P alleles (NET(P/P)) was nearly abolished. NET(+/P) and NET(P/P) mice exhibited elevations in plasma and urine NE levels, reduced 3,4-dihydroxyphenylglycol (DHPG), and reduced DHPG:NE ratios, consistent with a decrease in sympathetic nerve terminal NE reuptake. Radiotelemetry in unanesthetized mice revealed tachycardia in NET(+/P) mice without a change in blood pressure or baroreceptor sensitivity, consistent with studies of human NET A457P carriers. NET(+/P) mice also demonstrated behavioral changes consistent with CNS NET dysfunction. Our findings support that NET dysfunction is sufficient to produce a POTS phenotype and introduces the first genetic model suitable for more detailed mechanistic studies of the disorder and its comorbidities.

GNB3 C825T polymorphism is associated with postural tachycardia syndrome in children.

AIM: Postural tachycardia syndrome (POTS) is one of the most frequent forms of chronic orthostatic intolerance in children and adolescents. The aim of the present study was to examine the influence of a genetic background on POTS. METHODS: A total of 96 children and adolescents with orthostatic dysregulation were studied. The polymorphism of the G protein ß3 subunit (GNB3) C825T and G protein α subunit (GNAS1) T131C of genes encoding components of the autonomic nervous system were determined and compared with circulatory responses to active standing. RESULTS: In the GNB3 gene C825T polymorphism, the CT and TT genotype had a significant lower supine heart rate and a larger increase of heart rate by standing than the CC, associated with evaluated power of the high-frequency component of heart rate variability. According to the criteria of the Japanese clinical guidelines, 48 children were diagnosed as POTS and 30 were as normal responder with somatoform disorder (SD). In GNB3 C825T polymorphism, the TT genotype was more frequently found in the POTS group (45.8%) than in the SD group (20.0%; P = 0.036) [corrected]. In the GNAS1 T393C, the genotype frequencies for the T393C polymorphisms of GNA1 did not differ significantly between the groups. CONCLUSION: The gene polymorphisms GNB3 C825T might be a risk factor for POTS through the enhanced vagal withdrawal of the heart in children and adolescents.

Ascorbate improves circulation in postural tachycardia syndrome.

Low flow postural tachycardia syndrome (LFP) is associated with vasoconstriction, reduced cardiac output, increased plasma angiotensin II, reduced bioavailable nitric oxide (NO), and oxidative stress. We tested whether ascorbate would improve cutaneous NO and reduce vasoconstriction when delivered systemically. We used local cutaneous heating to 42°C and laser Doppler flowmetry to assess NO-dependent conductance (%CVC(max)) to sodium ascorbate and the systemic hemodynamic response to ascorbic acid in 11 LFP patients and in 8 control subjects (aged 23 ± 2 yr). We perfused intradermal microdialysis catheters with sodium ascorbate (10 mM) or Ringer solution. Predrug heat response was reduced in LFP, particularly the NO-dependent plateau phase (56 ± 6 vs. 88 ± 7%CVC(max)). Ascorbate increased baseline skin flow in LFP and control subjects and increased the LFP plateau response (82 ± 6 vs. 92 ± 6 control). Systemic infusion experiments used Finometer and ModelFlow to estimate relative cardiac index (CI) and forearm and calf venous occlusion plethysmography to estimate blood flows, peripheral arterial and venous resistances, and capacitance before and after infusing ascorbic acid. CI increased 40% after ascorbate as did peripheral flows. Peripheral resistances were increased (nearly double control) and decreased by nearly 50% after ascorbate. Calf capacitance and venous resistance were decreased compared with control but normalized with ascorbate. These data provide experimental support for the concept that oxidative stress and reduced NO possibly contribute to vasoconstriction and venoconstriction of LFP.

Altered sympathetic nervous reactivity and norepinephrine transporter expression in patients with postural tachycardia syndrome.

BACKGROUND: Clinical observations in patients with postural tachycardia syndrome (POTS) suggest abnormal sympathetic nervous system activity and a dysfunction of the norepinephrine (NE) transporter (NET). METHODS AND RESULTS: We examined sympathetic nervous system responses to head-up tilt by combining NE plasma kinetics measurements and muscle sympathetic nerve activity recordings and by quantifying NET protein content in peripheral sympathetic nerves in patients with POTS compared with that in controls. POTS patients had an elevated heart rate during supine rest (81+/-2 bpm versus 66+/-2 bpm in healthy subjects [HS], P<0.01). Head-up tilt to 40 degrees induced a greater rise in heart rate in patients with POTS (+24+/-4 bpm versus +13+/-2 bpm in HS, P<0.001). During rest in the supine position, muscle sympathetic nerve activity, arterial NE concentration, and whole-body NE spillover to plasma were similar in both groups. Muscle sympathetic nerve activity response to head-up tilt was greater in the POTS group (+29+/-3 bursts/min in patients with POTS and +13+/-2 bursts/min in HS, P<0.001), but the NE spillover rise was similar in both groups (51% in the POTS subjects and 50% in the HS). Western blot analysis of NET protein extracted from forearm vein biopsies in patients with POTS and HS demonstrated a decrease in the expression of NET protein in patients with POTS. CONCLUSIONS: Patients with POTS exhibit a decrease in NET protein in their peripheral sympathetic nerves. Paradoxically, whole-body NE spillover to plasma during rest in the supine position and in response to head-up tilt is not altered despite excessive nerve firing rate in response to the head-up tilt.