Association of adolescent postural tachycardia syndrome classifications with anxiety: a case control study

doi:10.21203/rs.3.rs-2914203/v1

Download PDF

Research Article

Association of adolescent postural tachycardia syndrome classifications with anxiety: a case control study

https://doi.org/10.21203/rs.3.rs-2914203/v1

This work is licensed under a CC BY 4.0 License

Journal Publication

published 29 Jan, 2024

Read the published version in BioPsychoSocial Medicine →

You are reading this latest preprint version

Background

Postural tachycardia syndrome (POTS), a subset of orthostatic dysregulation, has been reported to be associated with anxiety. POTS can be classified into two forms based on the degree of tachycardia during orthostasis. Reportedly, POTS with decreased orthostatic heart rate increase is associated with suppressed cardiac parasympathetic activity and increased sympathetic activity in the supine position. In this study, the relationship between the two types of POTS and anxiety was evaluated in terms of autonomic function.

Methods

Fifty-two patients (23 males, aged 10–15 years) who were diagnosed with POTS at the Department of Pediatrics, Osaka Medical and Pharmaceutical University from 2019 to 2021, provided completed the State-Trait Anxiety Scale for Children (STAIC) questionnaire. They then completed a standing test and were accordingly classified into the two groups of POTS, the Su group, with tachycardia from the supine position and a low heart rate increase on standing, and the SI group, with a high heart rate increase during standing. Autonomic function was assessed by frequency analysis (MemCalc method) based on heart rate, blood pressure changes, heart rate, and blood pressure variability during the orthostatic test.

Results

Patients in the Su group had higher characteristic anxiety, lower cardiac parasympathetic activity (RR-HF) in the supine position, and greater variability in cardiac parasympathetic activity during orthostasis than those of patients in the SI group. The Su group had a greater decrease in cardiac index on standing than that of the SI group.

Conclusions

The Su group results may be partly attributed to chronically low venous return. We also found that patients in the Su group had low parasympathetic activity in the supine position, which may interact with the anxiety-prone characteristics of these patients. Therefore, it seems necessary to consider both physical and psychosomatic treatment approaches for patients with POTS.

Trial registration

The clinical trial registry of Osaka Medical and Pharmaceutical University, Clinical Trial Registration No. 2662-2. Registered 5 March 2019.

https://ompu.bvits.com/rinri/Common/print_approve.aspx?ID=3479

POTS

Anxiety

Autonomic Function

Adolescent

frequency analysis

Postural tachycardia syndrome (POTS) is one of the most frequent forms of orthostatic dysregulation (OD) in children. OD is a condition in which a person presents with symptoms of orthostatic ataxia—such as dizziness, headache and palpitations, when standing up from a supine or seated position—that is mainly caused by a malfunction of the autonomic regulatory function. Previous Japanese studies reported that the prevalence of OD increases before adolescence and peaks at 15% in adolescents aged 14–15 years.¹

POTS is defined by the Japanese Society of Psychosomatic Pediatrics (JSPP) as an increase in heart rate ≥ 35 beats/min or heart rate during standing ≥ 115 beats/min without orthostatic hypotension.² The false-positive rate of the standing test using these criteria was 4.3% in healthy Japanese children (6/140 subjects aged 6–18 years).³ These criteria are very close to those proposed by the American Autonomic Society (increase in heart rate ≥ 30 beats/ min or heart rate during standing ≥ 120 beats/min).⁴

POTS has long been diagnosed as a psychological problem, such as chronic anxiety, due to symptoms such as fainting, fatigue, palpitations, and anxiety.⁵ Even after POTS became more widely recognized in recent years, there have been several reports of POTS being associated with anxiety. ^6,7 Therefore, we aimed to clarify the association between POTS and anxiety in greater detail.

Reports have classified POTS into two groups: standing-induced tachycardia (SI group; increase in HR ≥ 35 beats/min) and supine tachycardia (Su group; standing HR ≥ 115 beats/min with standing-induced HR increase < 35 beats/min).⁸ Reportedly, the Su group with tachycardia in the supine position had decreased parasympathetic function and increased sympathetic function in the supine position. We hypothesized that the Su group might be characterized by a tendency toward anxiety since anxiety and tachycardia are likely to be associated. Therefore, in this study, we evaluated autonomic function and trait anxiety in the Su and SI groups and assessed their relationships with anxiety.

Participants

We investigated children with orthostatic symptoms referred to Osaka Medical and Pharmaceutical University Hospital for further examination during 2019–2021. According to the JSPP clinical guideline criteria for POTS, 52 children (23 males and 29 females), aged 10–15 years (mean age, 13.0 ± 1.0 years and 13.4 ± 1.2 years, respectively), met the criteria. All patients underwent general physical examination, including neurological examination, chest radiography, 12-lead electrocardiogram (ECG), and blood tests including hematologic analysis, serum electrolytes, and serum thyroxine. No abnormalities, including anemia or febrile illness, were found in any of the patients.

Study design

All participants provided completed the State-Trait Anxiety Scale for Children (STAIC) questionnaire. They then completed a standing test and were accordingly classified into the two groups of POTS. Autonomic function was assessed by frequency analysis (MemCalc method) based on heart rate, blood pressure changes, heart rate, and blood pressure variability during the orthostatic test. This study is registered as a clinical trial at Osaka Medical and Pharmaceutical University (Clinical Trials ID: 2662-2). Data were collected in the period November 2019 until November 2021.

Informed consent was obtained from all participants and parents. The study was approved by the Ethics Committee of Osaka Medical and Pharmaceutical University.

Autonomic assessment

All patients performed the active standing test as previously reported.⁹ Briefly, patients were quietly seated for 15 min in a waiting room before the actual measurement started. The test was performed in the morning in a soundproof room at temperatures between 23°C and 25°C. A Finometer cuff (model 1; FMS, Amsterdam, Netherlands) was placed on the middle phalanx of the third finger of the right hand. To ensure optimal Finometer blood pressure (BP) measurement, we used appropriate cuff sizes (S or M), according to the manufacturer’s instructions.

Before the test, patients were instructed to stand up quickly and independently, without using their right hand, such as not to affect the Finometer recording. After 10 min in the supine position, the patients were asked to stand up actively by themselves and remain standing for 7 min. All patients stood within 3–4 s. During the active standing test, patients were monitored using continuous non-invasive finger arterial pressure measurements (Finometer).

Finger arterial BP and ECG signals were digitally stored on a personal computer system (Dynabook; Toshiba, Japan) during the entire test period. The default signal analysis program (Beat Scope; FMS, Amsterdam, Netherlands) provided data on sequential R-R intervals of the ECG (ms), beat-to-beat systolic and diastolic blood pressure (SBP and DBP; mmHg), and cardiac output (CO). Sequential RR intervals, SBP, and DBP were obtained in the supine position (4 min) and late period of standing (4–7 min after standing).

We evaluated the variability of the RR interval and BP of high frequency (HF; 0.15–0.4 Hz) and low frequency (LF; 0.04–0.15 Hz) components as an index of cardiovascular autonomic function. Generally, it is accepted that the HF component of RR interval variability (RR-HF) is mediated by cardiac parasympathetic tone generated by respiration, whereas the LF component is mediated by both cardiac sympathetic and parasympathetic tones. The ratio of the LF to HF components of RR interval variability (RR-LF/HF) is considered an index of cardiac sympathetic tone.^10–13 Contrastingly, the HF component of BP variability has been regarded as a mechanical consequence of respiration¹⁰ and the LF component of BP variability has been reported to parallel sympathetic vasomotor activity.^10,14 Regarding the influence of stroke volume, DBP variability can be evaluated more accurately using sympathetic vasomotor activity than SBP variability. Therefore, we used the LF component of DBP variability (DBP-LF) to evaluate sympathetic vasomotor activity. Spectral analysis using the maximum entropy method ¹⁵ (MemCalc for Windows version 1.2, Suwa Trust, Tokyo, Japan) was applied to the time-series data for each variable.

The Finometer includes the Modelflow method to derive continuous CO from finger pressure.¹⁶

We calculated the cardiac index (CI) in each subject by the following equation:

CI (L/min/m²) = CO (L/min)/ body surface area (m²)

Body surface area (m²) = (bodyweight (kg)× height (cm)/3600)^0.5) ¹⁷

Questionnaire

The State-Trait Anxiety Inventory for Children (STAIC) is a self-administered questionnaire (Spielberger et al, 1973) ¹⁸ which was developed based on the STAI (State-Trait Anxiety Inventory) for adults. The STAIC was standardized in Japanese by Soga (1983). It can measure both state (temporary anxiety in the moment) and trait (anxiety as a personality trait, that is, a relatively stable individual's tendency to react) anxiety. We administered the STAIC test to the participants after the active standing test. In this study, we used data on trait anxiety to investigate trends in autonomic function in children with POTS and anxiety-prone personality traits.

Data analysis

We divided the patients into two groups: a standing-induced tachycardia (SI) group, defined as an increase in heart rate during standing of ≥ 35 beats/min, and a supine tachycardia (Su) group, defined as an increase in heart rate during standing of < 35 beats/min with a standing heart rate of ≥ 115 beats/min.

We statistically evaluated the differences in the SI and Su groups using autonomic function and trait anxiety data.

Statistical analysis was performed using JMP pro14 (SAS Institute Inc., NC, USA). Data are presented as mean ± SE unless otherwise noted. Comparisons were made between the two POTS groups using the Student’s t-test. Statistical significance was set at p < 0.05.

This study included 52 children (23 males and 29 females), aged 10–15 years (mean age, 13.0 ± 1.0 years and 13.4 ± 1.2 years, respectively). Ten patients were classified in the Su group and 12 in the SI group. In terms of sex, there were significantly more females in the Su than the SI group. In the supine position, heart rate was significantly higher in the Su than in the SI group. on the other hand, the increase in heart rate during standing was higher in the SI than in the Su group. In the supine position, the DBP was significantly higher in the Su than in the SI group (Table 1).

Table 1

Subject characteristics
		SI group (mean ± SE)	Su group (mean ± SE)	P
M/F		21/16	2/13	0.004 *
Age (years)		13.3 ± 0.3	13.2 ± 0.2	0.840
HR (beats/min)	Supine	72.2 ± 1.5	91.7 ± 1.6	< 0.001 *
HR (beats/min)	Standing	114.2 ± 1.4	119.9 ± 1.8	0.164
ΔHR(beats/min)		42.1 ± 0.9	28.1 ± 1.0	< 0.001 *
SBP (mmHg)	Supine	109.4 ± 1.6	114.5 ± 1.8	0.073
SBP (mmHg)	Standing	112.0 ± 1.8	114.1 ± 2.5	0.500
DBP (mmHg)	Supine	63.7 ± 1.0	67.7 ± 1.0	0.023 *
DBP (mmHg)	Standing	76.2 ± 1.8	75.9 ± 1.7	0.837
RR-HF (mSec²)	Supine	669.6 ± 71.4	356.7 ± 84.9	0.010 *
RR-HF (mSec²)	Standing	95.9 ± 13.0	96.5 ± 24.4	0.785
RR-LF/HF (mSec²)	Supine	1.3 ± 0.1	1.5 ± 0.2	0.391
RR-LF/HF (mSec²)	Standing	4.6 ± 0.6	3.4 ± 0.5	0.369
DBP-LF (mmHg²)	Supine	6.8 ± 0.6	6.6 ± 1.1	0.832
DBP-LF (mmHg²)	Standing	11.9 ± 0.9	15.8 ± 2.2	0.143
Pulse pressure(mmHg)	Supine	45.7 ± 1.3	46.9 ± 1.5	0.792
Pulse pressure(mmHg)	Standing	35.8 ± 1.9	38.3 ± 2.1	0.935
Values are expressed as mean ± SE. *, p < 0.05 between SI and Su groups.
M, male; F, female; HR, heart rate; ΔHR, change in HR from supine to standing; SBP, systolic blood pressure; DBP, diastolic blood pressure; RR-HF, high-frequency component of RR interval variability; RR-LF/HF, ratio of the LF to HF components of RR interval variability; DBP-LF, low-frequency component of DBP variability; SI, standing-induced tachycardia; Su, supine tachycardia.

When upright, the reduction in the CI was significantly greater in the Su than the SI group (0.82 ± 0.05 vs 0.97 ± 0.03, respectively, p < 0.05) (Fig. 1).

For heart rate variability, in the supine position, the RR-HF was significantly lower in the Su than in the SI group (Table 1). The change in RR-HF during standing was also greater in the Su than in the SI group (0.33 ± 0.07 vs 0.19 ± 0.04, respectively, p < 0.05) (Fig. 2).

For BP variability, DBP-LF in the supine and standing positions did not differ between the two groups. The pulse pressures in the supine and standing positions did not differ between the two groups.

Trait anxiety was higher in the Su than the SI group (46.93 ± 1.93 vs 40.45 ± 1.49, respectively, p < 0.05) (Fig. 3).

POTS is characterized by a marked increase in heart rate during standing without apparent hypotension. POTS was first reported as a sympathetic tonic response.¹⁹ Subsequently, this response to orthostasis has been increasingly reported and studied in many countries in recent years. The excessive increase in heart rate in POTS is attributed to the low baroreflex system, which is activated by reduced venous return to the heart.²⁰

Yoshida classified POTS into SI and Su groups and referred to their hemodynamics.⁸ Both the SI and Su groups had lower RR-HF in the supine position, reflecting the parasympathetic function of the heart, compared to that of controls, indicating the presence of reduced vagal tone via the low-pressure baroreflex. However, they also reported different hemodynamic characteristics in both groups.

This means that the Su group, which tended to be more tachycardic in the supine position, had a lower RR-HF in the supine position than that of the SI group and tended to have a greater change in RR-HF when standing. Similar results were observed in this study, indicating that children in the Su group had more suppressed vagal activity and responded more significantly to the stress load of standing. Yoshida reported reduced central blood volume as a factor in the inactivation of the supine low baroreflex system in the Su group.⁸ The “low-flow” POTS proposed by Stewart²¹ is also characterized by a decrease in central blood volume, similar to the hemodynamic characteristics of the Su group. In this study, the Su group also showed a lower rate of change in CI than that of the SI group. This likely reflects a lower venous return to the heart when standing. Therefore, we considered it necessary to increase central blood volume in the Su group.

In this study, we considered two hypotheses regarding the pathogenesis in the Su group. One hypothesis is that higher anxiety may lead to lower resting parasympathetic function, resulting in the pattern of tachycardia tendency in the supine position in the Su group. The results of this study showed that the Su group had higher anxiety characteristics and lower cardiac parasympathetic activity in the supine position than the SI group. A report on the relationship between high-anxiety personality and autonomic function, evaluating autonomic function from heart rate variability, found that parasympathetic function was reduced in patients with anxiety disorders.²² This finding is consistent with the results of study.

Another hypothesis is that physical state may influence psychological anxiety. There are several reports of anxiety among POTS patients, indicating that anxiety in patients with POTS is caused by biological rather than psychological factors.²³ Patients with POTS have increased vigilance and anxiety related to their perception of cardiac symptoms.²⁴ The results of this study show that the Su group had a greater reduction in CI on standing than that of the SI group, indicating that there was less venous return to the heart while standing. The Su group had a lower central blood volume than that of the SI group and continued resting tachycardia that may have influenced anxiety in the Su group.

In both hypotheses, it seems anxiety is higher in POTS patients, and studies focusing on psychological anxiety symptoms suggest that patients with POTS are more anxious than normal patients.²⁵ Although the anxiety symptoms themselves may be a strong physical alertness unique to POTS patients, it is clinically important to consider the reported comorbidity of anxiety disorders in patients with POTS.⁷

Therefore, our results indicate that, clinically, patients in the Su group must be aware of high levels of anxiety and decreased central blood volume.

The study had several limitations. Regarding the assessment of autonomic function, adrenergic receptor sensitivity may be an important factor that is reportedly influenced by age.²⁶ As the age of the participants in this study was similar between the two groups, we considered adrenoceptor sensitivity differences to be negligibly small.

Another factor, the evaluation of the central blood volume, which we argue is important for supporting this hypothesis. However, accurate measurements require invasive methods, such as dye dilution. In this study, central blood volume was not measured in pediatric patients with POTS. Instead, CI, potential indicator of central blood volume, was used in this study. The CI data were automatically detected by Finometer's built-in software (Beat Port™), but its reliability with respect to absolute values in children is unknown. Therefore, only the CI ratio between standing and supine positions was calculated and evaluated.

In this study, two groups of POTS were examined in terms of autonomic nervous system function and psychological aspects. The results showed that the Su group, which had higher tachycardia from the supine position, had lower resting cardiac parasympathetic function and higher levels of anxiety. These results indicate that anxiety in the Su group may have a biological basis, and treatment should address the psychological as well as the physical aspects.

The association between anxiety and the autonomic nervous system in patients with POTS remains controversial. In this study, we were able to provide evidence for this association, which may provide clinical implications for treatment strategies for POTS.

POTS

Postural tachycardia syndrome

Orthostatic dysregulation

Heart rate

SBP

Systolic blood pressure

DBP

Diastolic blood pressure

Low frequency

High frequency

Cardiac output

Cardiac index

Ethics approval and consent to participate

This research protocol was approved by the Ethics Committee of Osaka Medical and Pharmaceutical University (approval No.2662-2). Informed consent was obtained from all children and their parents.

Consent for publication

Not applicable.

Availability of data and material

The anonymized data underlying this article will be shared upon reasonable request by the corresponding author.

Competing interests

The authors declare that they have no competing interests.

Funding

This research did not receive any specific grants from funding agencies in the public, commercial, or not-for-profit sectors.

Authors' contributions

MM and SY collected clinical data, participated in data analyses, contributed to study design and data interpretation. HT contributed to study design and supervised data analyses. GY, AK, YK and YO collected clinical data and contributed to study design. AA contributed to study design. All authors contributed to drafting of the manuscript. All authors read and approved the final manuscript.

Acknowledgements

We would like to thank Editage (www.editage.com) for English language editing.

Honda K, Nose T, Yoshida N, Tanimura M, Tanaka K. Responses to the postural change and orthostatic dysregulation symptoms: a population study on Japanese junior and senior high school students. Jpn Circ J 1997;41:629–41.
Tanaka H, Fujita Y, Takenaka Y, Kajiwara S, Masutani S, Ishizaki Y, et al. Japanese clinical guidelines for juvenile orthostatic dysregulation version 1. Pediatr Int 2009;51:169–179.
Yamaguchi H, Tanaka H, Adachi K, Mino M. Beat-to-beat blood pressure and heart rate responses to active standing in Japanese children. Acta Paediatr 1996;85:577–583.
Freeman R, Wieling W, Axelrod FB, Benditt DG, Benarroch E, Biaggioni I, et al. Consensus statement on the definition of orthostatic hypotension, neurally mediated syncope and the postural tachycardia syndrome. Clin Auton Res 2011;21:69–72; doi: 10.1007/s10286-011-0119-5.
Schondorf R, Low P. Idiopathic postural orthostatic tachycardia syndrome: An attenuated form of acute pandysautonomia. Neurology 1993;43:132-137.
Owens AP, Low DA, Iodice V, Critchley HD, Mathias CJ. The genesis and presentation of anxiety in disorders of autonomic overexcitation. Auton Neurosci 2017;203:81–87; doi:10.1016/j.autneu.2016.10.004.
Raj V, Opie M, Arnold AC. Cognitive and psychological issues in postural tachycardia syndrome. Auton Neurosci 2018;215:46-55; doi:10.1016/j.autneu.2018.03.004.
Yoshida S, Tanaka H, Nakao R, Okamoto N, Kajiura M, Kanbara Y, et al. Variant cardiovascular regulation in children with postural tachycardia syndrome. Pediatr Int 2014;56:328–335.
Tanaka H, Yamaguchi H, Matushima R, Tamai H. Instantaneous orthostatic hypotension in children and adolescents: a new entity of orthostatic intolerance. Pediatr Res 1999;46:691–696; doi:10.1203/00006450-199912000-00022.
Akselrod S, Gordon D, Madwed JB, Snidman NC, Shannon DC, Cohen RJ. Hemodynamic regulation: Investigation by spectral analysis. Am. J. Physiol 1985;249:H867–75; doi:10.1152/ajpheart.1985.249.4.H867.
Pagani M, Lombardi F, Guzzetti S, Rimoldi O, Furlan R, Pizzinelli P, et al. Power spectral analysis of heart rate and arterial pressure variabilities as a marker of sympatho-vagal interaction in man and conscious dog. Circ Res 1986;59: 178–193; doi:10.1161/01.res.59.2.178.
Pagani M, Mazzuero G, Ferrari A, Liberati D, Cerutti S, Vaitl D, Tavazzi L, Malliani A. Sympathovagal interaction during mental stress. A study using spectral analysis of heart rate variability in healthy control subjects and patients with a priormyocardial infarction. Circulation 1991;83 (4 Suppl.):II43–51.
Pomeranz B, Macaulay RJB, Caudill MA, Kutz I, Adam D, Gordon D, et al. Assessment of autonomic function in humans by heart rate spectral analysis. Am. J. Physiol 1985;248:H151–3; doi:10.1152/ajpheart.1985.248.1.H151.
Barnett SR, Morin RJ, Kiely DK, Gagnon M, Azhar G, Knight EL, et al. Effects of age and gender on autonomic control of blood pressure dynamics. Hypertension 1999;33:1195–200; doi:10.1161/01.hyp.33.5.1195.
Ohtomo N, Terauchi S, Tanaka Y, Tokiwano K, Kaneko N. New method of time series analysis and its application to Wolf’s sunspot number data. Jpn. J. Appl. Physiol 1994;33:2821–31
Wesseling KH, Jansen JR, Settls JJ, Schreuder JJ. Computation of aortic flow from pressure in humans using a nonlinear, three-element model. J Appl Physiol 1993;74:2566–2573.
Mosteller RD. Simplified calculation of body-surface area. N Engl J Med 1987;317:1098; doi:10.1056/NEJM198710223171717.
Spielberger CD, Gorsuch RL, Lushene RE. Manual for the State-Trait Anxiety Inventory (Self Evaluation Questionnaire). Palo Alto, CA: Consulting Psychologists Press 1970.
Thulesius O, Ferner U. Diagnose der orthostatischen Hyotonie. Z. Kreislaufforsch 1972;61:742–754.
Blomqvist CG, Stone HL. Cardiovascular adjustments to gravitational stress, in: Shepherd JT, Abboud FM (Eds.), Handbook of Physiology, Section 2, The Cardiovascular System. Vol Ⅲ: Peripheral Circulation and Organ Blood Flow, Part 2. American Physiological Society, Bethesda, 1983:1025-1063
Stewart JM, Montgomery LD. Regional blood volume and peripheral blood flow in postural tachycardia syndrome. Am. J. Physiol. Heart Circ. Physiol 2004;287:H1319–327.
Chang HA, Chang CC, Tzeng NS, Kuo TB, Lu RB, Huang SY. Generalized anxiety disorder, comorbid major depression, and heart rate variability: a case-control study in Taiwan. Psychiatry Investig 2013;10(4):326–335; doi:10.4306/pi.2013.10.4.326.
Raj V, Haman KL, Raj SR, Byrne D, Blakely RD, Biaggioni I, et al. Psychiatric profile and attention deficits in postural tachycardia syndrome. J Neurol Neurosurg Psychiatry 2009;80:339–344; doi:10.1136/jnnp.2008.144360.
Anderson JW, Lambert EA, Sari CI, Dawood T, Esler MD, Vaddadi G, et al. Cognitive function, health-related quality of life, and symptoms of depression and anxiety sensitivity are imp, aired in patients with the postural orthostatic tachycardia syndrome (POTS). Front Physiol 2014;25,5,230; doi:10.3389/fphys.2014.00230.
Masuki S, Eisenach JH, Johnson CP, Dietz NM, Benrud-Larson LM, Schrage WG, et al. Excessive heart rate response to orthostatic stress in postural tachycardia syndrome is not caused by anxiety. J Appl Physiol (1985) 2007;102:896–903; doi:10.1152/japplphysiol.00927.2006.
Tanaka H, Takenaka Y, Yamaguchi H, Mino M, Tamai H. Evidence of alpha-adrenoceptor-mediated chronotropic action in children. Pediatr Cardiol 2001;22:40–43; doi:10.1007/s002460010149.

Download PDF

Journal Publication

published 29 Jan, 2024

Read the published version in BioPsychoSocial Medicine →

Editorial decision: Major revision
20 Oct, 2023
Reviewers agreed at journal
11 Jun, 2023
Reviewers invited by journal
16 May, 2023
Editor assigned by journal
15 May, 2023
Submission checks completed at journal
14 May, 2023
Editor invited by journal
14 May, 2023
First submitted to journal
09 May, 2023

You are reading this latest preprint version

Association of adolescent postural tachycardia syndrome classifications with anxiety: a case control study

Status:

Journal Publication

Version 1

Abstract

Figures

Background

Methods

Participants

Study design

Autonomic assessment

Questionnaire

Data analysis

Results

Discussion

Conclusion

List Of Abbreviations

Declarations

References

Status:

Journal Publication

Version 1