Skin sympathetic nerve activity in patients with chronic orthostatic intolerance

doi:10.1016/j.hrthm.2022.03.015

Heart Rhythm

Volume 19, Issue 7, July 2022, Pages 1141-1148

https://doi.org/10.1016/j.hrthm.2022.03.015 Get rights and content

Background

Chronic orthostatic intolerance (OI) is characterized by the development of tachycardia and other symptoms when assuming an upright body position.

Objective

The purpose of this study was to test the hypothesis that skin sympathetic nerve activity (SKNA) bursts are specific symptomatic biomarkers in patients with chronic OI.

Methods

We used an electrocardiogram monitor with a built-in triaxial accelerometer to simultaneously record SKNA and posture in ambulatory participants. Study 1 compared chronic OI (14 women and 2 men; mean age 35 ± 10 years) with reference control participants (14 women; mean age 31 ± 6 years). Study 2 included 17 participants with chronic OI (15 women and 2 men; mean age 39 ± 12 years) not yet treated with ivabradine, pyridostigmine, or β-blockers.

Results

In study 1, there were 124 episodes (8 ± 4 per participant) of postural changes, with 11 episodes (8.9%) associated with symptoms. In comparison, 0 of 104 postural changes (7 ± 3 per participant) in controls were symptomatic (P = .0011). In participants with chronic OI, the SKNA bursts associated with symptoms had higher burst frequencies, longer burst durations, and larger mean burst areas than did bursts during asymptomatic periods. However, SKNA bursts and tachycardia were asymptomatic in controls. We analyzed 110 symptomatic episodes in study 2 (6 ± 5 per participant). Among them, 98 (89.1%) followed at least 1 SKNA burst. In comparison, only 41 (37.3%) had heart rate exceed 100 beats/min 1 minute before symptom onset (P < .0001).

Conclusion

SKNA bursts are a highly specific, albeit insensitive, symptomatic biomarker for chronic OI.

Introduction

The term “postural orthostatic tachycardia syndrome” (POTS) was coined by Schondorf and Low¹ to describe a clinical syndrome of tachycardia at rest or during a head-up tilt test. The commonly accepted diagnostic criteria include chronic (>3 months) orthostatic intolerance (OI) and an increase in heart rate (HR) of ≥30 beats/min without orthostatic hypotension when moving from a recumbent to a standing position.2, 3, 4 The symptoms of POTS include persistent lightheadedness and fatigue, but gastrointestinal dysmotility has also been frequently observed in patients with POTS since the original report.¹ Subsequent studies have confirmed that POTS is not a disease limited to the cardiovascular system. Rather, it is often associated with other systemic illnesses, especially mast cell activation syndrome and hypermobile Ehlers-Danlos syndrome.⁵^,⁶ While tachycardia is in the name, patients with POTS may not consistently demonstrate ≥30 beats/min HR increases during orthostatic tests.⁷^,⁸ For that reason, Raj et al⁸ noted that some patients with chronic OI have POTS while others have postural symptoms without tachycardia (PSWT). That statement downplays tachycardia as a diagnostic biomarker for this disease, but the term PSWT was not mentioned in the most recent National Institutes of Health expert panel.³

Patients with chronic OI have enhanced noradrenergic tone,⁹ while POTS is associated with increased cardiac norepinephrine release.¹⁰ It is possible that sympathetic nerve activity (SNA) patterns may serve as a better biomarker than tachycardia in identifying and defining chronic OI. We have developed and validated a method (neuECG) to simultaneously record electrocardiogram (ECG) and skin sympathetic nerve activity (SKNA) using conventional ECG patch electrodes.¹¹^,¹² Recently, we discovered that a commercially available Faros 180 ECG monitor (Bittium Corp, Oulu, Finland) can be used for neuECG recording.¹³ This ECG monitor also has a built-in accelerometer that can be used to determine body posture as well as a symptom marker. It is therefore an ideal instrument to study the relationship between HR, SKNA, and postural changes in ambulatory patients with chronic OI. The purpose of the present study was to perform simultaneous ambulatory neuECG and accelerometer recordings in chronic OI and normal healthy participants to test the hypothesis that SKNA bursts are specific biomarkers for chronic OI symptoms.

Section snippets

Methods

The detailed Methods are described in the Online Supplement. The protocol for this study was approved by the Cedars-Sinai Medical Center Institutional Review Board. Study 1 included 16 consecutive participants with a diagnosis of chronic OI who came for in-person clinical visits (Table 1). We also recruited 14 asymptomatic women of childbearing age as reference controls. After the results were analyzed, we performed study 2 in 17 participants with chronic OI not treated with sinus

Study 1: Postural changes, tachycardia, and SKNA in participants with chronic OI and control participants

The analyzed recording duration per participant was 1360 ± 210 and 1387 ± 131 minutes for participants with chronic OI and control participants, respectively (P = 0.67). Participant characteristics are listed in Table 1.

Discussion

We found that the symptoms of chronic OI are more often associated with SKNA bursts than tachycardia. While the symptoms of chronic OI primarily occur during postural changes or standing, a notable number of symptoms occurred while lying flat. In comparison, control participants also had significant increases in SKNA and HR during postural changes. However, they remained asymptomatic.

Conclusion

Postural changes increase aSKNA and HR in both control participants and participants with chronic OI, but only patients with chronic OI have symptoms during postural changes. In patients with chronic OI, symptoms are strongly associated with SKNA bursts but only weakly associated with tachycardia. These findings suggest that SKNA bursts may be a highly specific, albeit insensitive, biomarker for chronic OI.

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Idiopathic postural orthostatic tachycardia syndrome: an attenuated form of acute pandysautonomia?

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Mast cell activation disorder and postural orthostatic tachycardia syndrome: a clinical association

J Am Heart Assoc

(2021)

Cited by (3)

Postural orthostatic tachycardia syndrome after COVID-19 vaccination
2024, Heart Rhythm
There is an association between coronavirus disease 2019 (COVID-19) mRNA vaccination and the incidence or exacerbation of postural orthostatic tachycardia syndrome (POTS).
The purpose of this study was to characterize patients reporting new or exacerbated POTS after receiving the mRNA COVID-19 vaccine.
We prospectively collected data from sequential patients in a POTS clinic between July 2021 and June 2022 reporting new or exacerbated POTS symptoms after COVID-19 vaccination. Heart rate variability (HRV) and skin sympathetic nerve activity (SKNA) were compared against those of 24 healthy controls.
Ten patients (6 women and 4 men; age 41.5 ± 7.9 years) met inclusion criteria. Four patients had standing norepinephrine levels > 600 pg/mL. All patients had conditions that could raise POTS risk, including previous COVID-19 infection (N = 4), hypermobile Ehlers-Danlos syndrome (N = 6), mast cell activation syndrome (N = 6), and autoimmune (N = 7), cardiac (N = 7), neurological (N = 6), or gastrointestinal conditions (N = 4). HRV analysis indicated a lower ambulatory root mean square of successive differences (46.19 ±24 ms; P = .042) vs control (72.49 ± 40.8 ms). SKNA showed a reduced mean amplitude (0.97 ± 0.052 μV; P = .011) vs control (1.2 ± 0.31 μV) and burst amplitude (1.67 ± 0.16 μV; P = .018) vs control (4. 3 ± 4.3 μV). After 417.2 ± 131.4 days of follow-up, all patients reported improvement with the usual POTS care, although 2 with COVID-19 reinfection and 1 with small fiber neuropathy did have relapses of POTS symptoms.
All patients with postvaccination POTS had pre-existing conditions. There was no evidence of myocardial injuries or echocardiographic abnormalities. The decreased HRV suggests a sympathetic dominant state. Although all patients improved with guideline-directed care, there is a risk of relapse.
Sympathetic toggled sinus rate acceleration as a mechanism of sustained sinus tachycardia in chronic orthostatic intolerance syndrome
2022, Heart Rhythm
Citation Excerpt :
Data were analyzed to further confirm the findings of study 1. The control and the 17 patients not treated with sinus node–suppressing drugs were the same as those included in a previous study,13 but there were no overlaps in data analyses. The vast majority of patients with chronic OI (17 of 18 [94%] in study 1 and 12 of 17 [71%] in study 2) had an established diagnosis of postural orthostatic tachycardia syndrome (POTS) and the remaining had a suspicious diagnosis of POTS.
The role of sympathetic nerve activity to maintain sinus rate acceleration remains unclear.
The purpose of this study was to test the hypothesis that sustained (>30 seconds) sinus rate acceleration can be associated with either a sympathetic driven or a sympathetic toggled mechanism.
We used a patch monitor to record skin sympathetic nerve activity (SKNA) and electrocardiogram over 24 hours. Study 1 included chronic orthostatic intolerance (OI) (n = 18), atrial fibrillation (n = 7), and asymptomatic normal control (n = 19) groups. Study 2 included 17 participants with chronic OI not treated with ivabradine, pyridostigmine, or β-blockers.
While a majority of sinus rate acceleration was driven by persistent SKNA in study 1, some episodes were toggled on and off by SKNA bursts without persistent SKNA elevation. The sympathetic toggled sinus rate acceleration episodes were found in 7 of 18 participants with chronic OI (39%), 2 of 7 participants with atrial fibrillation (29%), and 6 of 19 normal control participants (32%) (P = .847) and were faster and longer in the chronic OI group than in other groups. In study 2, there were a total of 11 episodes of sinus rate acceleration that persisted for >200 seconds. Among these episodes, 6 (35%) were toggled on and off by SKNA bursts.
Sustained sinus rate acceleration (may be toggled on or off) is associated with SKNA bursts in participants with chronic OI, participants with atrial fibrillation, and normal controls. Patients with OI had more frequent and longer episodes than did other groups.
Alterations of sympathetic dynamics after atrial fibrillation ablation by analysis sympathetic nerve activity provide prognostic value for recurrence and mechanistic insights into ablation
2022, Frontiers in Cardiovascular Medicine

: Funding Sources: This study was supported in part by NIH Grants R01HL139829, OT2 OD028190, R01HL146158, U54AG065141, the Burns & Allen Chair in Cardiology Research, the Barbra Streisand Women’s Cardiovascular Research and Education Program, the Linda Joy Pollin Women’s Heart Health Program, the Erika Glazer Women’s Heart Health Project, and the Adelson Family Foundation, Cedars-Sinai Medical Center, Los Angeles, California.

: Disclosures: Indiana University was awarded U.S. patent no. 10,448,852 for inventing neuECG recording and Peng-Sheng Chen is a co-inventor. The other authors have no conflicts of interest to disclose.

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ClinicalGeneralSkin sympathetic nerve activity in patients with chronic orthostatic intolerance

Background

Objective

Methods

Results

Conclusion

Introduction

Section snippets

Methods

Study 1: Postural changes, tachycardia, and SKNA in participants with chronic OI and control participants

Discussion

Conclusion

Heart Rhythm

Auton Neurosci

Auton Neurosci

Prog Cardiovasc Dis

Can J Cardiol

Heart Rhythm

Heart Rhythm

Med Eng Phys

J Am Coll Cardiol

Auton Neurosci

Idiopathic postural orthostatic tachycardia syndrome: an attenuated form of acute pandysautonomia?

Neurology

Mast cell activation disorder and postural orthostatic tachycardia syndrome: a clinical association

J Am Heart Assoc

Clinical
General
Skin sympathetic nerve activity in patients with chronic orthostatic intolerance