Hostname: page-component-74656f9884-8r8nv Total loading time: 0 Render date: 2026-11-07T04:11:08.798Z Has data issue: false hasContentIssue false
  • English
  • Français

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

Published online by Cambridge University Press:  28 April 2014

Jing Lin ,
Hongfang Jin  and
Junbao Du
Jing Lin
Affiliation:
Department of Pediatrics Peking University First Hospital, Beijing, China
Hongfang Jin
Affiliation:
Department of Pediatrics Peking University First Hospital, Beijing, China
Junbao Du*
Affiliation:
Department of Pediatrics Peking University First Hospital, Beijing, China
*
Correspondence to: J. Du, Department of Pediatrics Peking University First Hospital, Xi'an Street No.1, Xicheng District, Beijing 100034, China. Tel:+86-10-83573238; Fax:+86-10-65530532; E-mail: junbaodui@126.com
Rights & Permissions [Opens in a new window]

Abstract

Background: Postural tachycardia syndrome and vasovagal syncope are common causes of orthostatic intolerance in children. The supplementation with water, or salt, or midodrine, or β-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.

Keywords

Postural tachycardia syndromevasovagal syncopetherapeutic biomarkers

Information

Type
Review Articles
Information
Cardiology in the Young , Volume 24 , Issue 5 , October 2014 , pp. 792 - 796
Copyright
© Cambridge University Press 2014 

Orthostatic intolerance is a constellation of signs and symptoms that are elicited by standing upright and relieved by recumbency.Reference Low, Sandroni, Joyner and Shen 1 Postural tachycardia syndrome and vasovagal syncope are main entities of orthostatic intolerance in children. Postural tachycardia syndrome is defined by symptoms of orthostatic intolerance in association with excessive tachycardia.Reference Jarjour 2 Its symptoms include palpitations, light headedness, chest discomfort, shortness of breath, blurred vision, and exercise intolerance.Reference Jarjour 2 , Reference Stewart 3 Postural tachycardia syndrome is more frequent in female patients and most cases occur from the age 15 to 25 years old. Chronic fatigue, chronic headache, fibromyalgia, and sleep disturbances have been frequently associated with postural tachycardia syndrome. Physical deconditioning and psychological factors play an important role in these patients. Some individuals with serious symptoms were unable to participate in the school studies or the social activities. One-third of medical students report at least one syncopal episode in their life-time.Reference Kenny, Bhangu and King-Kallimanis 4

Treatment status of postural tachycardia syndrome and vasovagal syncope

The mechanisms for those diseases have been unclear yet. Absolute hypovolemia, hyper-adrenergic responses, imbalance in the autonomic nervous system, and impaired regulation of peripheral vascular resistance were thought to be involved in the pathogenesis.Reference Medow and Stewart 5 Therefore, the supplementation with water, or salt, or midodrine, or β-blockers was applied to children with postural tachycardia syndrome or vasovagal syncope; even the pyridostigmine or octreotide was sometimes used partly for postural tachycardia syndrome patients (Fig 1).

Figure 1

Schematic graph: Individualised therapy for orthostatic intolerance; DBP=diastolic blood pressure; FMD=flow-mediated dilation; H2S=hydrogen sulfide; MR-proAD=midregianl-proadenomedullin; ORS=oral rehydration saline; POTS=postural tachycardia syndrome; SBP=systolic blood pressure; VVS=vasovagal syncope.

For postural tachycardia syndrome, regardless of the basic pathophysiological mechanism, most patients require volume expansion with adequate daily water (1.5–2 L) and sodium intake.Reference Benarroch 6 β-blockers, such as metoprolol (25 mg/day), was used to control the excessive sinus tachycardiaReference Kanjwal, Karabin and Sheikh 7 and α1-adrenergic agonist midodrine (2.5 mg, twice a day) to elicit peripheral vasoconstriction and reduce venous pooling.Reference Chen, Wang and Sun 8 The efficacy of the medicine, however, varied. Zhang et al showed that oral rehydration salts plus midodrine hydrochloride or plus metoprolol improved the efficacy of drugs in children with postural tachycardia syndrome, and the efficacy of midodrine hydrochloride was superior to that of metoprolol.Reference Zhang, Liao, Li, Chen, Jin and DU 9 Another study revealed that midodrine hydrochloride was effective in the treatment of children with postural tachycardia syndrome, with the cure rate of 68.2%.Reference Chen, Wang and Sun 8 However, Lai et al said that adolescents taking β-blockers and midodrine both improved the conditions (63.6% versus 36.4%).Reference Lai, Fischer and Brands 10 Fu et al considered that for patients with postural tachycardia syndrome, exercise training is superior to propranolol at restoring upright haemodynamics, normalising renal–adrenal responsiveness, and improving the quality of life.Reference Fu, Vangundy, Shibata, Auchus, Williams and Levine 11 In contrast, a study by Arnold found that a single low dose of propranolol (20 mg) as compared with placebo was useful in increasing maximum exercise capacity measured 1 hour after medication.Reference Arnold, Okamoto and Diedrich 12

On the basis of cases of 20 children, Ross AJ et al conducted a double-blind placebo-controlled cross-over study. Postural tachycardia syndrome subjects received 2 weeks of treatment with midodrine or placebo. In neuropathic postural tachycardia syndrome, midodrine decreased supine heart rate, calf blood flow, and calf venous capacitance, while increasing mean arterial pressure and calf vascular resistance compared with placebo. In hyperadrenergic postural tachycardia syndrome, both placebo and midodrine decreased upright heart rate and increased supine calf vascular resistance. This suggests that midodrine is probably an effective treatment for neuropathic postural tachycardia syndrome, but not for hyperadrenergic postural tachycardia syndrome.Reference Ross, Ocon, Medow and Stewart 13 Arnold AC et alReference Arnold, Okamoto and Diedrich 14 provided Class II evidence that a single low dose of propranolol (20 mg daily) as compared with placebo was useful in increasing maximum exercise capacity measured 1 hour after medication. For patients with postural tachycardia syndrome, exercise training is superior to propranolol at restoring upright haemodynamics, normalising renal–adrenal responsiveness, and improving the quality of life.Reference Fu, Vangundy, Shibata, Auchus, Williams and Levine 15

As for the vasovagal syncope, a meta analysis showed that α-adrenergic agonists were found effective in preventing vasovagal syncopal recurrence. β-blockers were not found to be effective when only randomised studies comparing β-blockers with non-pharmacologic agents were assessed.Reference Vyas, Swaminathan, Zimmerman and Olshansky 16 A study by Chen et al showed that the cure rate of children who suffered from vasovagal syncope by taking oral metoprolol was 60.61%.Reference Chen, DU and Zhang 17 However, a study by Russia revealed that overall efficacy of atenolol and midodrine was 44% and 70%, respectively.Reference Kuchinskaia, Pevzner and Vershuta 18

Considering the different mechanisms of the diseases and currently unfavourable results of the treatment, great improvement was achieved in terms of an individualised therapy, and before the application of any treatment biological markers or predictors could provide useful information for doctors to choose the specific treatment regimen.Reference Liao, Yang and Zhang 19 – Reference Zhang, Li and Ochs 21

Predictors for oral rehydration salt therapy for postural tachycardia syndrome in children

The mechanisms for postural tachycardia syndrome have not been fully determined. Previous studies showed that it might be associated with relative hypovolemia.Reference Jacob, Robertson, Mosqueda-Garcia, Ertl, Robertson and Biaggioni 22 Increasing blood volume by increasing fluid and salt intake was proven to be partially beneficial for some children and adolescents.Reference Lu, Diedrich and Tung 23 , Reference Mathias and Young 24 Salt supplementation is sometimes effective in certain patients with postural tachycardia syndrome, but how to recognise those who will respond to this treatment is an issue worthy of investigation. El-Sayed and HainsworthReference El-Sayed and Hainsworth 25 validated 24-hour urinary sodium excretion as a marker for hypovolemic status. This marker, 24-hour urinary sodium excretion, correlated with plasma volume. A study by Zhang et al showed that lower 24-hour urinary sodium excretion was associated with more serious symptoms in children and adolescents with postural tachycardia syndrome, and 24-hour sodium excretion of <124 mmol/24 hours was an indicator of the effectiveness of salt supplementation in children and adolescents with postural tachycardia syndrome.Reference Zhang, Liao, Tang, Du and Jin 26

Predictors for therapeutic response to midodrine hydrochloride in children with postural tachycardia syndrome

Flow-mediated vasodilation

Symptom scores and changes in heart rate during head-up tilt test are usually used as markers for evaluating the therapeutic effects against postural tachycardia syndrome. As an α-adrenoceptor agonist, midodrine can treat the inappropriate control of peripheral vascular resistance that is supposed to be a cause of postural tachycardia syndrome.Reference Carew, Connor and Cooke 27 , Reference Grubb 28 Midodrine has been reported to improve symptoms and decrease standing heart rate for some postural tachycardia syndrome patients.Reference Paling, Vilches-Moraga, Akram, Atkinson, Staniland and Paredes-Galán 29 , Reference Chen, Du and Jin 30 To increase the effective rate, finding predictors for the therapeutic response of midodrine in cases of postural tachycardia syndrome is needed. Flow-mediated vasodilation by colour Doppler vascular ultrasound is a non-invasive method of evaluating endothelial function.Reference Liao, Yang and Zhang 19 Previous study revealed that children with postural tachycardia syndrome had greater flow-mediated vasodilation than healthy children and suggested that augmented flow-mediated vasodilation and abnormal endothelial function might play important roles in the development of adolescent postural tachycardia syndrome.Reference Liao, Chen and Liu 31 A study by Liao et al showed that flow-mediated vasodilation of 9.85% yielded a high sensitivity and specificity. Results demonstrated that flow-mediated vasodilation could be a predictor of the efficacy of midodrine for treating children with postural tachycardia syndrome.Reference Liao, Yang and Zhang 19

Erythrocytic hydrogen sulfide

Hydrogen sulfide (H2S) is a new vasodilating gasotransmitter.Reference Zhang, Li and Stella 32 , Reference Tang, Li and Du 33 Excessive vasodilation was thought to be involved in the mechanisms for postural tachycardia syndrome. Therefore, a possible link between H2S and postural tachycardia syndrome might exist. Zhang et al reported that the plasma content of H2S was increased in children with postural tachycardia syndrome.Reference Zhang, Li and Stella 32 Geng et al reported that endogenous H2S was primarily released from erythrocytes and that erythrocytic H2S production and serum H2S contents were positively correlated in hypotensive patients.Reference Geng, Yan and Zhong 34 A study by Jinyan et al indicated that H2S production from erythrocytes was significantly higher in the postural tachycardia syndrome patients than in the controls.Reference Yang, Zhao and Du 20 H2S production was also significantly higher in responders to midodrine hydrochloride than in non-responders. A cut-off value of erythrocytic H2S production of 27.1 nmol/minute/108 erythrocytes yielded the sensitivity of 78.9%, and the specificity 77.8% for predicting the effect of midodrine hydrochloride on children with postural tachycardia syndrome.Reference Yang, Zhao and Du 20

Midregional pro-adrenomedullin

Adrenomedullin is a circulating 52-amino-acid vasopeptide that has immune-modulating, metabolic, and vascular actions.Reference Nishida, Horio and Suzuki 35 It is a potent vasodilator with antimitogenic, natriuretic, and diuretic effects. Compared with its short half-life, pro-adrenomedullin was a much stable fragment. Pro-adrenomedullin is produced in equimolar amounts to adrenomedullin and reflects the level of adrenomedullin.Reference Al-Omari, Khaleghi and Mosley 36 , Reference Struck, Tao, Morgenthaler and Bergmann 37 A study by Zhang et al showed that plasma levels of pro-adrenomedullin were significantly higher in children with postural tachycardia syndrome than controls. In addition, plasma levels of pro-adrenomedullin in responders to midodrine hydrochloride were significantly higher than those of non-responders. Using a cut-off value for pro-adrenomedullin of 61.5 pg/ml produced both high sensitivity (100%) and specificity (71.6%) in predicting the efficacy of midodrine hydrochloride therapy for treating postural tachycardia syndrome.Reference Zhang, Li and Ochs 21

Upright blood pressure change during the standing

Owing to the fact that an α1-adrenoreceptor agonist increased vasculartension, it was used to successfully treat some postural tachycardia syndrome patients who had reduced contractility of peripheral blood vessels and low peripheral vascular resistance. Therefore, in clinical practice, it is important to recognise postural tachycardia syndrome children with a low vascular contractility and resistance, who might get a favourable response to midodrine hydrochloride. In 2013, Deng et al found that midodrine hydrochloride for children with postural tachycardia syndrome would be predicted to be effective when the pre-treatment increase in systolic blood pressure was ⩽0 mmHg, or when the pre-treatment increase in diastolic blood pressure was ⩽6.5 mmHg – from the supine position to standing – yielding a sensitivity of 72% and specificity of 88%.Reference Deng, Liu and Liu 38

Haemodynamic change during head-up tilt test as a predictor for the therapeutic response to β-adrenoceptor blocker in children with vasovagal syncope

In syncopal patients without cardiac pathological lesion, syncope is most commonly vasovagal syncope, and is due to an inappropriate reflex vasodilation and/or bradycardia that can often be elicited with head-up tilt testing.Reference Zhang, Du, Zhen, Li and Wang 39 The value of haemodynamic change during head-up tilt test is usually used as standards for evaluating the therapeutic effects against vasovagal syncope. A study by Zhang et al found that a marked increase in heart rate in head-up tilt test was a better predictor of metoprolol efficacy in the treatment of children with vasovagal syncope. If an increase of 30 beats/minute was taken as a borderline in heart rate during positive response in head-up tilt test compared with that of baseline value, with respect to predicting the metoprolol efficacy in the treatment of vasovagal syncope, the sensitivity was 81%, the specificity was 80%, and the diagnostic value was 81%.Reference Zhang, Du, Zhen, Li and Wang 39

Conclusion and prospect

The 24-hour urinary sodium excretion was a useful indicator for postural tachycardia syndrome patients. It can identify individuals with salt deficiency and also predict those who will benefit most from the increased salt intake. The flow-mediated vasodilation is inexpensive, non-invasive, and easy to carry out. As a biological marker, erythrocytic H2S and plasma pro-adrenomedullin are relatively stable and is simple and inexpensive. Hence, before the application of the different treatment, evaluating the possible biomarkers or predictors could increase the cure rate, and importantly would avoid unnecessary drugs and treatments. However, for the best treatment, we still need large-sized, randomised, double-blind, and controlled studies in the future.

Acknowledgements

Jing Lin and Hongfang Jin wrote the review and modified it. Junbao Du designed the review and revised it.

Financial Support

The work was supported by grants from the National Twelfth Five-Year Plan for Science & Technology Support [2012BAI03B03].

Conflicts of Interest

None.

References

1. Low, PA, Sandroni, P, Joyner, M, Shen, WK. Postural tachycardia syndrome (POTS). J Cardiovasc Electrophysiol 2009; 20: 352–358.Google Scholar
2. Jarjour, IT. Postural tachycardia syndrome in children and adolescents. Semin Pediatr Neurol 2013; 20: 18–26.Google Scholar
3. Stewart, JM. Common syndromes of orthostatic intolerance. Pediatrics 2013; 131: 968–980.Google Scholar
4. Kenny, RA, Bhangu, J, King-Kallimanis, BL. Epidemiology of syncope/collapse in younger and older Western patient populations. Prog Cardiovasc Dis 2013; 55: 357–363.Google Scholar
5. Medow, MS, Stewart, JM. The postural tachycardia syndrome. Cardiol Rev 2007; 15: 67–75.CrossRefGoogle ScholarPubMed
6. Benarroch, EE. Postural tachycardia syndrome: a heterogeneous and multifactorial disorder. Mayo Clin Proc 2012; 87: 1214–1225.Google Scholar
7. Kanjwal, K, Karabin, B, Sheikh, M, et al. Pyridostigmine in the treatment of postural orthostatic tachycardia: a single-center experience. Pacing Clin Electrophysiol 2011; 34: 750–755.CrossRefGoogle ScholarPubMed
8. Chen, L, Wang, L, Sun, J, et al. Midodrine hydrochloride is effective in the treatment of children with postural orthostatic tachycardia syndrome. Circ J 2011; 75: 927–931.Google Scholar
9. Zhang, FW, Liao, Y, Li, XY, Chen, L, Jin, HF, DU, JB. Therapies for postural tachycardia syndrome in children. Zhonghua Er Ke Za Zhi 2011; 49: 428–432.Google ScholarPubMed
10. Lai, CC, Fischer, PR, Brands, CK, et al. Outcomes in adolescents with postural orthostatic tachycardia syndrome treated with midodrine and beta-blockers. Pacing Clin Electrophysiol 2009; 32: 234–238.Google Scholar
11. Fu, Q, Vangundy, TB, Shibata, S, Auchus, RJ, Williams, GH, Levine, BD. Exercise training versus propranolol in the treatment of the postural orthostatic tachycardia syndrome. Hypertension 2011; 58: 167–175.CrossRefGoogle ScholarPubMed
12. Arnold, AC, Okamoto, LE, Diedrich, A, et al. Low-dose propranolol and exercise capacity in postural tachycardia syndrome: a randomized study. Neurology 2013; 80: 1927–1933.Google Scholar
13. Ross, AJ, Ocon, AJ, Medow, MS, Stewart, JM. A double-blind placebo-controlled cross-over study of the vascular effects of midodrine in neuropathic compared with hyperadrenergic postural tachycardia syndrome. Clin Sci (Lond) 2014; 126: 289–296.CrossRefGoogle ScholarPubMed
14. Arnold, AC, Okamoto, LE, Diedrich, A, et al. Low-dose propranolol and exercise capacity in postural tachycardia syndrome: a randomized study. Neurology 2013; 80: 1927–1933.CrossRefGoogle ScholarPubMed
15. Fu, Q, Vangundy, TB, Shibata, S, Auchus, RJ, Williams, GH, Levine, BD. Exercise training versus propranolol in the treatment of the postural orthostatic tachycardia syndrome. Hypertension 2011; 58: 167–175.Google Scholar
16. Vyas, A, Swaminathan, PD, Zimmerman, MB, Olshansky, B. Are treatments for vasovagal syncope effective? A meta-analysis. Int J Cardiol 2013; 167: 1906–1911.Google Scholar
17. Chen, L, DU, JB, Zhang, QY, et al. A multicenter study on treatment of autonomous nerve-mediated syncope in children with beta-receptor blocker. Zhonghua Er Ke Za Zhi 2007; 45: 885–888.Google ScholarPubMed
18. Kuchinskaia, EA, Pevzner, AV, Vershuta, EV, et al. Comparative efficacy and tolerance of atenolol and midodrine in patients with vasovagal syncopes. Ter Arkh 2006; 78: 64–68.Google ScholarPubMed
19. Liao, Y, Yang, J, Zhang, F, et al. Flow-mediated vasodilation as a predictor of therapeutic response to midodrine hydrochloride in children with postural orthostatic tachycardia syndrome. Am J Cardiol 2013; 112: 816–820.CrossRefGoogle ScholarPubMed
20. Yang, J, Zhao, J, Du, S, et al. Postural orthostatic tachycardia syndrome with increased erythrocytic hydrogen sulfide and response to midodrine hydrochloride. J Pediatr 2013; 163: 1169–1173.CrossRefGoogle ScholarPubMed
21. Zhang, F, Li, X, Ochs, T, et al. Midregional pro-adrenomedullin as a predictor for therapeutic response to midodrine hydrochloride in children with postural orthostatic tachycardia syndrome. J Am Coll Cardiol 2012; 60: 315–320.CrossRefGoogle ScholarPubMed
22. Jacob, G, Robertson, D, Mosqueda-Garcia, R, Ertl, AC, Robertson, RM, Biaggioni, I. Hypovolemia in syncope and orthostatic intolerance role of the renin-angiotensin system. Am J Med 1997; 103: 128–133.Google Scholar
23. Lu, CC, Diedrich, A, Tung, CS, et al. Water ingestion as prophylaxis against syncope. Circulation 2003; 108: 2660–2665.Google Scholar
24. Mathias, CJ, Young, TM. Water drinking in the management of orthostatic intolerance due to orthostatic hypotension, vasovagal syncope and the postural tachycardia syndrome. Eur J Neurol 2004; 11: 613–619.Google Scholar
25. El-Sayed, H, Hainsworth, R. Salt supplement increases plasma volume and orthostatic tolerance in patients with unexplained syncope. Heart 1996; 75: 134–140.Google Scholar
26. Zhang, Q, Liao, Y, Tang, C, Du, J, Jin, H. Twenty-four-hour urinary sodium excretion and postural orthostatic tachycardia syndrome. J Pediatr 2012; 161: 281–284.Google Scholar
27. Carew, S, Connor, MO, Cooke, J, et al. A review of postural orthostatic tachycardia syndrome. Europace 2009; 11: 18–25.CrossRefGoogle ScholarPubMed
28. Grubb, BP. Postural tachycardia syndrome. Circulation 2008; 117: 2814–2817.CrossRefGoogle ScholarPubMed
29. Paling, D, Vilches-Moraga, A, Akram, Q, Atkinson, O, Staniland, JR, Paredes-Galán, E. Midodrine hydrochloride is safe and effective in older people with neurocardiogenic syncope. J Am Geriatr Soc 2010; 58: 2026–2027.Google Scholar
30. Chen, L, Du, JB, Jin, HF, et al. Effect of selective alpha1 receptor agonist in the treatment of children with postural orthostatic tachycardia syndrome. Zhonghua Er Ke Za Zhi 2008; 46: 688–691.Google Scholar
31. Liao, Y, Chen, S, Liu, X, et al. Flow-mediated vasodilation and endothelium function in children with postural orthostatic tachycardia syndrome. Am J Cardiol 2010; 106: 378–382.Google Scholar
32. Zhang, F, Li, X, Stella, C, et al. Plasma hydrogen sulfide in differential diagnosis between vasovagal syncope and postural orthostatic tachycardia syndrome in children. J Pediatr 2012; 160: 227–231.Google Scholar
33. Tang, C, Li, X, Du, J. Hydrogen sulfide as a new endogenous gaseous transmitter in the cardiovascular system. Curr Vasc Pharmacol 2006; 4: 17–22.Google Scholar
34. Geng, B, Yan, H, Zhong, GZ, et al. Hydrogen sulfide: a novel cardiovascular functional regulatory gas factor. Beijing Da Xue Xue Bao 2004; 36: 106.Google Scholar
35. Nishida, H, Horio, T, Suzuki, Y, et al. Plasma adrenomedullin as an independent predictor of future cardiovascular events in high-risk patients: comparison with C-reactive protein and adiponectin. Peptides 2008; 29: 599–605.Google Scholar
36. Al-Omari, MA, Khaleghi, M, Mosley, TH Jr, et al. Mid-regional pro-adrenomedullin is associated with pulse pressure, left ventricular mass, and albuminuria in African Americans with hypertension. Am J Hypertens 2009; 22: 860–866.Google Scholar
37. Struck, J, Tao, C, Morgenthaler, NG, Bergmann, A. Identification of an adrenomedullin precursor fragment in plasma of sepsis patients. Peptides 2004; 25: 1369–1372.CrossRefGoogle ScholarPubMed
38. Deng, W, Liu, Y, Liu, AD, et al. Difference between supine and upright blood pressure associates to the efficacy of midodrine on postural or thostatic tachycardia syndrome (POTS) in children. Pediatr Cardiol 2013; Epub ahead of print.Google Scholar
39. Zhang, QY, Du, JB, Zhen, JL, Li, WZ, Wang, YL. Hemodynamic changes during head-up tilt test and predictive value thereof in predicting the efficacy of metoprolol therapy in children with vasovagal syncope. Zhonghua Yi Xue Za Zhi 2007; 87: 1260–1262.Google ScholarPubMed
Figure 0

Figure 1 Schematic graph: Individualised therapy for orthostatic intolerance; DBP=diastolic blood pressure; FMD=flow-mediated dilation; H2S=hydrogen sulfide; MR-proAD=midregianl-proadenomedullin; ORS=oral rehydration saline; POTS=postural tachycardia syndrome; SBP=systolic blood pressure; VVS=vasovagal syncope.