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Volume 12 No. 05
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Scientific Investigations

Objective Sleep Assessments in Patients with Postural Tachycardia Syndrome using Overnight Polysomnograms

Kanika Bagai, MD, MSCI1,2; Amanda C. Peltier, MD, MSCI1,2; Beth A. Malow, MD, MS2; André Diedrich, MD, PhD1,3,4,6; Cyndya A. Shibao, MD, MSCI1,3; Bonnie K. Black, RN, CNP1,3; Sachin Y. Paranjape, BS1,3; Carlos Orozco, BS1; Italo Biaggioni, MD1,3,5; David Robertson, MD1,2,3,5; Satish R. Raj, MD, MSCI1,3,5,7
1Autonomic Dysfunction Center, Vanderbilt University School of Medicine, Nashville, TN; 2Department of Neurology, Vanderbilt University School of Medicine, Nashville, TN; 3Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN; 4Department of Clinical Pharmacology, Vanderbilt University School of Medicine, Nashville, TN; 5Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN; 6Biomedical Engineering, Vanderbilt University School of Medicine, Nashville, TN; 7Department of Cardiac Sciences, Libin Cardiovascular Institute of Alberta, University of Calgary, AB, Canada

ABSTRACT

Study Objectives:

Patients with postural tachycardia syndrome (POTS) commonly complain of fatigue, unrefreshing sleep, daytime sleepiness, and diminished quality of life. The study objective was to assess objective sleep quality in POTS patients using overnight polysomnography.

Methods:

We studied 16 patients with POTS and 15 healthy control subjects performing daytime autonomic functions tests and overnight polysomnography at the Vanderbilt Clinical Research Center.

Results:

There were no significant differences in the objective sleep parameters including sleep efficiency, sleep onset latency, wake time after sleep onset, REM latency, percentage of time spent in N1, N2, N3, and REM sleep, arousal index, apnea-hypopnea index, or periodic leg movement index in POTS patients as compared with healthy control subjects. There were significant negative correlations between sleep efficiency and the change in HR from supine to stand (rs = −0.527; p = 0.036)

Conclusions:

POTS patients do not have significant differences in objective sleep parameters as compared to control subjects based on overnight polysomnograms. Activation of the sympathetic nervous system may contribute significantly to the hyper arousal state and worsening of subjective estimates of sleep quality as previously reported in POTS patients.

Citation:

Bagai K, Peltier AC, Malow BA, Diedrich A, Shibao CA, Black BK, Paranjape SY, Orozco C, Biaggioni I, Robertson D, Raj SR. Objective sleep assessments in patients with postural tachycardia syndrome using overnight polysomnograms. J Clin Sleep Med 2016;12(5):727–733.


INTRODUCTION

Postural tachycardia syndrome (POTS) is a disabling chronic disorder for more than 6 months1 characterized by upright symptoms and orthostatic tachycardia of ≥ 30 bpm in the absence of orthostatic hypotension.2 POTS primarily affect women (∼80% to 85%) of child-bearing age (13–50 years). Symptoms of sympathoexcitation during orthostasis include palpitation, lightheadedness, and tremulousness. POTS may be associated with difficulties with concentration, fatigue, and sleep complaints.24

Our previous questionnaire based study demonstrated that patients with POTS have higher subjective daytime sleepiness, fatigue, and worse sleep and health-related quality of life (HRQL).1 Sleep problems contributed significantly to the diminished HRQL, accounting for about 50% of the variability in the HRQL. In this questionnaire-based study, Epworth Sleepiness Scale (ESS) scores > 10 were considered significant for excessive daytime sleepiness. Fatigue was assessed using the Fatigue Visual Analogue Scale, with a higher score indicating more fatigue. Compared with healthy control subjects, patients with POTS had higher scores on ESS indicating excessive daytime sleepiness (10.2 ± 5.7 vs. 6.2 ± 3.2; p < 0.0001) and higher fatigue levels (7.5 ± 2.0 vs. 2.8 ± 2.5; p < 0.0001).

Another recent survey based analysis has shown that patients with POTS commonly have sleep complaints including fatigue reported by 90% of the patients, early morning awakenings (51% patients), nighttime awakenings (46% patients), and insomnia in 39% of the patients.5

BRIEF SUMMARY

Current Knowledge/Study Rationale: This study was conducted to enhance our understanding of the sleep disturbances reported by patients with POTS.

Study Impact: Better understanding of the sleep quality of POTS patients with objective measures could lead to better management of sleep disturbances for these patients, with a resultant improvement in quality of life.

Recent studies have also shown that subjective complaints of poor sleep are associated with reduced physical performance6 and increased risk for cardiovascular diseases, and may predict mortality.7

Our recent study using wrist actigraphy and sleep logs in patients with POTS showed that there is a mismatch in the subjective vs. objective sleep onset latency, with greater latencies experienced subjectively.8 In addition, there were significant correlations between actigraphic sleep onset latencies and upright norepinephrine (NE) levels, and wake time after sleep onset and standing heart rate (HR), suggesting that POTS may have increased stress levels which might contribute to insomnia, with reduction of daytime concentration and fatigue.

The aim of this study was to evaluate sleep quality using “gold standard” overnight polysomnograms in patients with POTS and healthy control subjects, and confirm our previous findings with actigraphy. We hypothesized that objective measures of sleep disturbance would be worse in patients with POTS.

METHODS

Study Subjects

We enrolled 16 patients with POTS and 15 control subjects for overnight sleep polysomnography at the Vanderbilt Autonomic Dysfunction Center. Patients qualified if they developed symptoms of orthostatic intolerance accompanied by a HR rise ≥ 30 bpm within the first 10 minutes of upright posture, without any evidence of orthostatic hypotension (a fall in blood pressure [BP] ≥ 20/10 mm Hg).9,10 Patients must have had ≥ 6-month history of symptoms, in the absence of another chronic debilitating disorder or prolonged bed rest, and were at least 18 years of age. POTS patients were off all medications that could alter sleep including sedatives and stimulants, as well as off of medications that alter HR, BP, and blood volume regulation. Selective serotonin reuptake inhibitors (but not serotonin-norepinephrine reuptake inhibitors) were allowed to be continued if the patient had been on a stable dose for > 2 months. Patients with POTS underwent a posture study to assess their orthostatic tolerance (details below) and an assessment of cardiovagal function (sinus arrhythmia) at the Clinical Research Center (CRC) at Vanderbilt University. Healthy control subjects with no known history of sleep complaints were recruited from healthy volunteers known to the Vanderbilt Autonomic Dysfunction Center, through the Vanderbilt Research Volunteer Database, and through advertisements in the Vanderbilt community. These subjects (who did not meet criteria for POTS) were similar in age and gender to the POTS patients. The Vanderbilt Institutional Review Board approved the research protocol, and written informed consent was obtained from each subject before the study began. This study is registered with ClinicalTrials.gov (NCT00581022).

Supine and Upright Posture Study

HR, BP, and plasma NE and epinephrine were assessed after overnight rest in the supine position and again after standing up to 30 minutes (as tolerated) in the patients with POTS and control subjects. The standing test was performed in order to assess the hemodynamic and biochemical responses to gravity-induced relative hypovolemia. For catecholamine measurements, blood was collected in plastic syringes and immediately transferred to chilled vacuum tubes with EGTA and reduced glutathione (Amersham International PLC, Amersham, UK) and immediately put on ice. The plasma was separated by refrigerated centrifugation at −4°C and stored at −70°C until the assay. Concentrations of NE and epinephrine were measured by batch alumina extraction followed by high performance liquid chromatography for separation with electrochemical detection and quantification.11

Overnight Polysomnograms (PSGs)

Overnight polysomnography (PSG) with video was recorded digitally with PSG diagnostic system (Neurofax EEG-1100, Polysmith 6.0, Nihon-Kohden Corporation, Tokyo) at the Vanderbilt University Sleep Research Core. The PSG consists of 6 electroencephalogram (EEG) channels (F3, F4, C3, C4, O1, O2 by the International 10-20 system), 3 chin electromyogram (EMG) leads, 2 electrooculogram leads, 2 electrocardiogram leads, snoring sound, respiratory effort over the chest and abdomen, airflow at the nose and mouth using thermocouples and nasal pressure cannulas, and bilateral surface EMG recording from the legs (with electrodes placed over the anterior tibialis muscles). Oxyhemoglobin saturation (SpO2) was monitored by pulse oximetry. All studied were staged according to standard guidelines by a trained sleep technologist and sleep clinician.12,13 Sleep data was staged in 30-s time frames (epochs) using the American Academy of Sleep Medicine (AASM) staging criteria. PSG parameters measured included sleep efficiency (total sleep time / time in bed), sleep onset latency (SOL; in min), rapid eye movement (REM) latency (in min, calculated from sleep onset), quantity of time spent in N1, N2, N3, and REM sleep (percentage), apnea-hypopnea index (AHI), periodic leg movement index (PLMI), and arousal index (AI). Apneas were scored if there was a > 90% decrement in the thermistor ≥ 10 s. and hypopneas were scored if there was a 50% to 90% decrement in the nasal pressure transducer ≥ 10 s, with concurrent oxyhemoglobin desaturation ≥ 3% or an EEG arousal.13 Arousals were defined as abrupt changes in EEG pattern with return to alpha or theta frequency, lasting between 3 and 10 seconds and were also analyzed according to the criteria of the AASM.14

Statistical Analysis

This study was an exploratory objective study to evaluate sleep in patients with POTS; hence we analyzed multiple objective measures of sleep. The sleep onset latency (SOL), REM sleep latency, sleep efficiency (SE), wake after sleep onset (WASO), arousal index, duration of sleep stages, apnea-hypopnea index, and periodic leg movement index were compared in POTS patients and healthy control subjects. Comparisons between groups were made with Student t-tests. Comparisons within a group (e.g., supine vs. upright posture study values) were made with paired t-tests. Spearman correlations were performed to assess the relationships between sleep variable and autonomic measures. Descriptive statistics are reported as mean ± standard deviation. Statistical significance was defined as p < 0.05. All statistical analyses were performed using SPSS for Windows version 20 (SPSS Inc., Chicago, IL, USA). Figures were made using GraphPad Prism 6.0 (GraphPad Software, San Diego, CA, USA).

Post Hoc Power and Sample Size Calculations

There was no preliminary data available on PSG measures in patients with POTS at the start of this study. In our recent study using sleep actigraphy,8 POTS patients had a SE of 73% ± 13%, while it was 79% ± 6% in healthy control subjects, for a difference between groups of 6%. Assuming a pooled standard deviation of 6%, a sample size of 17 subjects in each group would provide 80% power to detect this difference with a 2-sided alpha error of 0.05. The true difference in SE was 1% with a standard deviation of 8.3% in the healthy control subjects. Assuming an alpha error rate of 0.05 and 80% power, we would have required study of 1,082 patients and 1,082 control subjects for this difference to be statistically (but not clinically) significant.15

RESULTS

Baseline demographic characteristics of POTS patients (n = 16; 15 female; 32 ± 8 years) and healthy control subjects (n = 15; 13 female; 35 ± 11 years) are detailed in Table 1. The baseline supine and standing hemodynamics and catecholamine characteristics of the POTS patients are listed in Table 2. As expected, upright HR and catecholamines in patients with POTS are significantly higher than previously reported normative values in healthy subjects.4

Subject characteristics and objective PSG parameters of the subjects with Postural Tachycardia Syndrome and healthy control subjects.

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Table 1

Subject characteristics and objective PSG parameters of the subjects with Postural Tachycardia Syndrome and healthy control subjects.

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Supine and standing hemodynamic parameters and catecholamine levels in patients with Postural Tachycardia Syndrome (n = 16).

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Table 2

Supine and standing hemodynamic parameters and catecholamine levels in patients with Postural Tachycardia Syndrome (n = 16).

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Sleep Assessments by Overnight Polysomnograms

The mean HR during sleep was significantly higher in patients with POTS than control subjects (Table 1). There were no significant differences in the SE, WASO, SOL, REM latency, percentage of time spent in N1, N2, N3 and REM sleep, AI, AHI, or PLMI in POTS patients as compared with healthy control subjects.

Correlation between Polysomnogram Data and Autonomic Data

In POTS patients, there were significant negative correlations between SE and both the maximal standing HR (rs = −0.528; p = 0.036; Figure 1A, Table 3), and the change in HR from supine to stand (rs = −0.527; p = 0.036; Figure 1B). There were no significant correlations between any of the sleep quality parameters and mean nocturnal HR.

Spearman correlations.

Spearman correlations (rs) are presented for polysomnogram based sleep efficiency versus Max Standing HR (A) and Delta HR (B), REM duration versus Max Standing HR (C) and Delta HR (D), and REM latency versus Max Standing HR (E), and Delta HR (F).

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Figure 1

Spearman correlations.

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Spearman correlation coefficients between PSG sleep measures and autonomic parameters in POTS patients.

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Table 3

Spearman correlation coefficients between PSG sleep measures and autonomic parameters in POTS patients.

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There was also a significant negative correlation between REM sleep duration (% REM sleep) and the maximal standing HR (rs = −0.580; p = 0.018; Figure 1C). The relationship between REM sleep and the change in HR from supine to stand was not significant (Figure 1D).

There were significant positive correlations between REM sleep latency and the maximal standing HR (rs = 0.637; p = 0.008, Figure 1E), and the change in HR from supine to stand (rs = 0.581; p = 0.018; Figure 1F).

There were no significant correlations between any of the sleep parameters and mean nocturnal HR, and supine or upright plasma norepinephrine levels. However, there was a significant negative correlation between change in epinephrine level from supine to standing and N2 sleep percentage (p = 0.002).

In healthy control subjects, there were no significant correlations between any of the sleep study measures and autonomic and physiological parameters.

DISCUSSION

In this study, we characterized the sleep pattern in subjects with POTS compared to a healthy control group using objective overnight PSG. Our results demonstrated that patients with POTS have no significant differences in sleep parameters as compared with healthy control subjects. This study confirms our previous results with actigraphy in POTS patients. We previously showed that although POTS patients reported longer subjective SOL with sleep diaries, no difference on actigraphy based SOL were noted in patients compared with control subjects. In this current study, although there was no significant difference in WASO between POTS and controls, there was a trend towards greater WASO in controls.

Mallien and colleagues recently reported PSG findings in POTS patients.16 Similar to our previously reported questionnaire based study in POTS patients,1 their study confirmed that POTS patients have significantly higher scores in Pittsburgh Sleep Quality Index (PSQI) questionnaires indicating poor sleep and lower quality of life scores. Similar to our current PSG based study, there were no significant differences reported in sleep efficiency, sleep latency, or frequency of arousals between POTS patients and control subjects. There was higher percentage of NREM stage 2 recorded in POTS patients.

Possible Mechanisms of Poor Sleep Quality in POTS

Higher Nocturnal Arousal Rates

One initial explanation for the sleep disturbances in POTS patients was a possibly higher arousal rates at night resulting in non-restorative sleep, similar to reports in patients with chronic fatigue syndrome. Sleep disruption or frequent arousals are associated with significant increases in plasma cortisol levels. In normal subjects, waking periods and stage N1 sleep accompany cortisol increases, whereas slow wave sleep is associated with declining plasma cortisol levels. For the purpose of this study, we used the AASM criteria for measuring arousals. Our PSG data, however, did not show any significant increase in arousal rates in POTS patients. It is possible that we may have noted a more significant difference using the fast Fourier transform (FFT) power spectral analysis or CAP scoring system. In future studies, we plan to take a closer look at the spectral characteristics of the sleep EEG of patients with POTS, and to determine differences from the spectral characteristics in health controls.

Underlying Psychiatric Disorders

Another possible explanation for the subjective complaints of poor sleep could relate to underlying psychiatric disorders in patients with POTS. A reduction in slow wave sleep, shortening of REM onset latency, increased REM sleep, and sleep continuity disturbances are among the symptoms found in an assessment of untreated depressed patients.17 In our study, the REM sleep latencies in POTS patients were shorter than controls, although the difference did not reach statistical significance.

Raj et al. formally assessed POTS patients for psychiatric disorders and inattention and compared them with patients with attention deficit hyperactivity disorder (ADHD) and healthy control subjects.18 POTS patients did not have an increased prevalence of major depression or anxiety disorders, including panic disorder, compared with the general population. Although they may seem anxious due to their symptoms of palpitations and tachycardia, they do not have excess cognitive anxiety. POTS patients do not have an increased lifetime prevalence of psychiatric disorders. Hence, an underlying mood disorder does not offer a clear explanation for the symptoms of poor sleep experienced by POTS patients.

NeuroCognitive Model of Insomnia

The central tenet of the “neurocognitive model of insomnia” is that insomnia is a state of cortical, cognitive, and somatic arousal.19 The cortical arousal may in turn permit cognitive processing that does not occur with normal sleep. The increased sensory and information processing during non-REM sleep, or the attenuation of the mesograde amnesia to sleep, may in turn produce a sleep state misperception. Insomnia patients have higher levels of beta and gamma power EEG activity during REM sleep as compared with subjects with normal sleep.20,21 Using functional neuroimaging, insomnia patients had elevation of global cerebral metabolism as compared with subjects with normal sleep suggestive of a state of hyperarousal during sleep.22 Spectral analysis of EEG in POTS patients may offer further insight to see if patterns similar to those seen in insomnia patients may also be seen in POTS patient.

Vgontzas et al.23 found that the 24-hour urinary levels of catecholamine metabolites, dihydroxyphenylglycol (DHPG) and 3, 4-dihydroxyphenylacetic acid (DOPAC), were positively correlated with percent of stage N1 sleep and WASO, and the 24-hour urinary free cortisol levels were positively correlated with the total wake time. These data suggest disturbances in the hypothalamic-pituitary-adrenal axis and sympathetic nervous system activity are associated with objective sleep disturbance. The subjective sleep disturbances in POTS patients may be the consequence of their state of heightened sympathetic activation.4

Polysomnogram Correlations

In this study, the PSG sleep efficiency was negatively correlated with change in HR from supine to standing. Greater increases in HR from supine to standing are driven by greater sympathetic tone and greater norepinephrine release. The hyperadrenergic state present in POTS patients may account for differences in autonomic functioning during sleep, resulting in negative correlation with sleep efficiency and consequently less restful sleep and subjective tiredness. It is possible that additional mechanisms such as hypovolemia and increased energy expenditure from a hyperadrenergic state may also contribute. Vgontzas et al.23 have shown previously that the 24-hour urinary free cortisol levels were positively correlated with the total wake time. This in turn could result in poor sleep efficiency. In a previous pilot study, we have shown that oral melatonin produces a modest decrease in standing tachycardia in POTS.24 Perhaps use of melatonin timed at night may help with changes in HR as well as improvements in sleep efficiency and sleep related symptoms. Further research is needed to determine the effects of regular nighttime use of melatonin in POTS.

POTS patients had relatively normal mean REM latency in this study, while there was a trend for prolonged REM latency in controls. The prolonged REM latency in the control patients likely represents a first night effect.25 The first night effect is an alteration of sleep structure on the first night in a sleep laboratory. In healthy subjects, REM sleep latency is increased on the first night of investigation and REM sleep percentage is slightly decreased.26 Although most healthy subjects demonstrate first night effect, it is reported only in 50% of patients suffering from major depression.27 The large standard deviation for REM latency in the POTS group in our study shows that a proportion of the POTS patients had longer REM latencies, similar to the controls. It is possible that there are subsets of POTS patients do not show the first night effect of longer REM latency similar to patients with depression, resulting in the variable findings of REM latency in POTS patients vs. controls.28

REM latency was positively correlated with the change in HR from supine to standing. REM duration was negatively correlated with change in HR from supine to standing. The excessive activation of the stress system may contribute to a hyperarousal state and possibly changes in REM sleep and nocturnal mean heart rate. This, in turn, may lead to daytime changes in HR and may be one of the contributing factors for the poor sleep, and mental and physical health reported in patients with POTS. Pharmacological measures that blunt increases in sympathetic tone and HR on standing in POTS patients may also improve symptoms of insomnia by decreasing the central nervous system hyperarousal state, although this hypothesis require further testing.

Study Limitations

The main limitation of this study is the relatively small sample size. A larger sample size might have allowed for smaller differences in other parameters to become statistically significant. We did not conduct concurrent surveys to assess sleepiness, fatigue or subjective sleep quality or activity with this study; however, we have conducted these surveys in a former study which showed that POTS patients report poor sleep quality, more daytime sleepiness, and more fatigue than healthy controls.

CONCLUSIONS

In this study, we have characterized the objective sleep patterns in subjects with POTS compared to a control group using overnight PSGs. Our results confirm that patients with POTS have no significant changes in sleep parameters as compared with healthy control subjects. The previously reported subjective diminished sleep quality reported by these patients could be due to exaggerated sympathetic nervous system activation as evidenced by elevated upright NE levels and standing HR, which may contribute to a hyperarousal state.

DISCLOSURE STATEMENT

This was not an industry supported study. The study was supported in part by NIH grants R01 HL102387 (SRR), R01 HL071784 (DR), P01 HL56693 (DR), 1 UL1 TR000445 (Clinical and Translational Science Award), and the Paden Dysautonomia Center. Dr. Shibao has received research support from Doris Duke Foundation and PHARMA Foundation and consulted for Lundbeck Pharmaceuticals. Dr. Malow has received research support from Neurim Pharmaceuticals. Dr. Raj has consulted for Medtronic, Lundbeck Pharmaceuticals, and GE Healthcare. The other authors have indicated no financial conflicts of interest.

ABBREVIATIONS

AASM

American Academy of Sleep Medicine

ADHD

attention deficit hyperactivity disorder

AHI

apnea-hypopnea index

AI

arousal index

BP

blood pressure

CRC

Clinical Research Center

DHPG

dihydroxyphenylglycol

DOPAC

3, 4-dihydroxyphenylacetic acid

EEG

electroencephalogram

EMG

electromyogram

ESS

Epworth Sleepiness Scale

FFT

Fast Fourier Transform

HR

heart rate

HRQL

health-related quality of life

NE

norepinephrine

NREM

non-rapid eye movement

PLMI

periodic leg movement index

POTS

postural tachycardia syndrome

PSG

polysomnography

PSQI

Pittsburgh Sleep Quality Index

REM

rapid eye movement

SE

sleep efficiency

SOL

sleep onset latency

SpO2

oxyhemoglobin saturation

WASO

wake after sleep onset

ACKNOWLEDGMENTS

The authors thank the patients and the staff of the Elliot V. Newman Clinical Research Center at Vanderbilt University, Nashville, TN.

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