Autonomic Neuroscience: Basic and Clinical 186 (2014) 85–90
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Autonomic Neuroscience: Basic and Clinical journal homepage: www.elsevier.com/locate/autneu
Differences in cardiac autonomic function contributes to heart rate abnormalities in POTS and IST James C. Corkal a, Iryna Palamarchuk a,b, Kurt Kimpinski a,b,⁎ a b
Department of Clinical Neurological Sciences, University Hospital, London Health Sciences Centre, London, Ontario, Canada Schulich School of Medicine & Dentistry, Western University, London, Ontario, Canada
a r t i c l e
i n f o
Article history: Received 15 May 2014 Received in revised form 10 September 2014 Accepted 11 September 2014 Keywords: Postural tachycardia syndrome Inappropriate sinus tachycardia Orthostatic intolerance Autonomic nervous system Autonomic reflex screen
a b s t r a c t Our objective was to examine the differences in cardiac autonomic function in Postural Tachycardia Syndrome (POTS) versus inappropriate sinus tachycardia (IST). Subjects (IST, n = 8; POTS, n = 12) were studied using standard measurements of the autonomic reflex screen, baroreflex function and spectral analysis. Data was compared to age/gender-matched controls (n = 20). The components of the autonomic reflex screen did not differ between groups. The exception was the significant but expected difference in postural heart rate increment on head-up tilt in POTS (47.9 ± 13.8; n = 12) compared to IST (30.9 ± 9.7; n = 8; p = 0.008). Accordingly the Orthostatic Intolerance Scale showed significantly greater orthostatic symptoms in POTS (2.6 ± 0.5; n = 12) versus IST patients (0.4 ± 0.5; n = 8; p b 0.001). Conversely, IST patients had a significantly higher resting heart rate (96 ± 12; n = 8) when compared to POTS patients (73 ± 12; n = 12; p = 0.001). There was a significant difference in vagal baroreflex sensitivity (BRSv) in POTS (8.21 ± 2.3, n = 12) compared to IST patients (5.30 ± 2.94, n = 8, p = 0.036) during the Valsalva maneuver. Only POTS subjects showed a significant increase in sympathovagal balance (LF/HF) with tilt (FFT, 8.29 ± 6.38; AR, 7.84 ± 5.24) compared to the supine position (FFT, 2.25 ± 1.75; AR, 1.99 ± 1.38; p b 0.05) for both frequency domains. Differences in cardiac autonomic function contribute to changes in positional and non-positional heart rate in postural tachycardia syndrome versus inappropriate sinus tachycardia. These findings shed further light on the autonomic dysfunction underlying POTS and IST. © 2014 Elsevier B.V. All rights reserved.
1. Introduction Postural tachycardia syndrome (POTS) is a disorder of orthostatic intolerance characterized by lightheadedness, dizziness, and palpitations associated with heart rate increments greater than 30 bpm on headup tilt (HUT) in the upright or standing position (Low et al., 1994). Inappropriate sinus tachycardia (IST) is defined as excessive sinus tachycardia greater than 90 bpm unrelated to position (Olshansky and Sullivan, 2013). Both POTS and IST can be a significant cause of morbidity particularly in younger age groups (Antiel et al., 2008; Johnson et al., 2010; Olshansky and Sullivan, 2013). There is an overlap in the clinical presentation of both disorders and can occur simultaneously in a select group Abbreviations:ARS, autonomic reflex screen; AR, autoregressive;BRSa, adrenergic baroreflex sensitivity; BRSv, vagal baroreflex sensitivity; CASS, Composite Autonomic Severity Score; DBP, diastolic blood pressure; FFT, fast Fourier transform; HR, heart rate; HRDB, heart rate deep breathing; HRV, heart rate variability; HF, high frequency; HUT, head-up tilt; IST, inappropriate sinus tachycardia; LF, low frequency; OI, orthostatic intolerance; POTS, postural tachycardia syndrome; PRT, phase recovery time; QSART, Quantitative Sudomotor Axon Reflex Test; SBP, systolic blood pressure; VM, Valsalva maneuver; VR, Valsalva ratio. ⁎ Corresponding author at: Rm. C7-131, University Hospital, London Health Sciences Centre, 339 Windermere Road, London, Ontario N6A 5A5, Canada. Tel.: + 1 519 663 3337; fax: +1 519 663 3328. E-mail address: [email protected] (K. Kimpinski).
http://dx.doi.org/10.1016/j.autneu.2014.09.016 1566-0702/© 2014 Elsevier B.V. All rights reserved.
of patients (Brady et al., 2005; Kanjwal et al., 2003). Healthy individuals that fall within younger age groups can have heart rate increments greater than 30 bpm on head-up tilt without orthostatic symptoms (Ives and Kimpinski, 2013; Singer et al., 2012). This can complicate the diagnosis of IST where individuals may have elevated heart rate increment on HUT (N30 bpm) that may not be symptomatic (or minimally symptomatic) with respect to orthostatic symptoms versus those patients expressing both IST and POTS. The inability to differentiate between POTS and IST would have implications with respect to treatment. Both conditions respond to anti-arrhythmic medications including betaadrenergic blockade, but anti-hypotensives such as midodrine and fludrocortisone are more appropriate for the treatment of POTS (Brady et al., 2005; Kanjwal et al., 2003). The pathophysiology of POTS is complicated, but several studies have shown varying autonomic abnormalities to standardized testing (Kimpinski et al., 2012; Peltier et al., 2010; Stewart, 2000). As a result, it has been proposed that POTS represents a form of limited autonomic neuropathy (Kimpinski et al., 2012; Thieben et al., 2007). The underlying mechanisms of IST are not as well-defined, but impaired baroreflex gain has been described (Leon et al., 2005; Ptaszynski et al., 2013). Additionally, treatment options such as beta-adrenergic blockers and ivabradine (a novel specific heart rate lowering agent that acts by selectively inhibiting the pacemaker If current in sinus atrial node cells) have
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been used for both POTS and IST with reasonable success in both conditions (Benezet-Mazuecos et al., 2013; Cappato et al., 2012; Khan et al., 2009; McDonald et al., 2011; Retegui et al., 2009; Weyn et al., 2011; Zellerhoff et al., 2010). To our knowledge a comparative study between IST and POTS has not been previously published. Given the clinical similarities between the two conditions and that a select group of patients express overlapping presentations of IST and POTS, we examined the differences/similarities using non-invasive measures of autonomic function to determine whether further insights into the pathophysiology of these conditions could be drawn. The specific objectives of this study were twofold. Our first objective was to compare the presence and severity of autonomic symptoms with an emphasis on orthostatic intolerance (OI) between IST and POTS using standard measures including symptom profiles and hemodynamic measurements in the supine and head-up tilt positions. Secondly, we investigated the differences in cardiac autonomic function, given the importance of heart rate as the major defining variable in both syndromes, to characterize potential differences between POTS and IST.
2. Materials and methods 2.1. Subjects Subject characteristics are presented in Table 1. Inclusion criteria for POTS patients were an orthostatic heart rate (HR) increment of 30 bpm within 5 min of HUT and associated symptoms of OI including but not limited to dizziness, lightheadedness and palpitations (Kimpinski et al., 2012). Inclusion criteria for IST comprised a resting sinus tachycardia greater than 100 bpm with a 24-hour HR average of greater than 90 bpm with symptoms of but not limited to palpitations, dyspnea, dizziness, lightheadedness, and near syncope unassociated with a change in position (Olshansky and Sullivan, 2013). Both IST and POTS patients were consecutively studied in our laboratory and further included in this study to avoid selection bias. Ethical approval to conduct this study was obtained from the University of Western Ontario's Ethics Board. Subjects were reviewed to assure they did not have a history of progressive autonomic dysfunction beyond that expected from IST or POTS. Clinical evaluations were performed by an experienced neurologist (KK) to exclude other neurological conditions. Further exclusion criteria included the following: i) pregnant or lactating females, ii) the presence of another cause of autonomic failure, iii) the presence of failure of other organ systems or systemic illness that can affect autonomic function or the subject's ability to cooperate; these included dementia, pheochromocytoma, heart failure, hypertension, renal or hepatic disease, severe anemia, alcoholism, malignant neoplasms, hypothyroidism, sympathectomy, diabetes, amyloidosis or cerebrovascular accidents, iv) concomitant therapy with anticholinergic, alpha- and beta-adrenergic antagonists or other medication which could interfere with testing of autonomic function, and v) clinically significant coronary artery disease. We did not exclude female subjects taking oral contraceptive pills.
2.2. Quantitative Sudomotor Axon Reflex Testing Standardized clinical autonomic testing was performed as previously described (Low, 2003; Low and Opfer-Gehrking, 1999) in the Autonomic Disorders Laboratory at Western University, London, Ontario. Quantitative Sudomotor Axon Reflex Testing (QSART) evaluated the integrity of the postganglionic sympathetic sudomotor axon using a Q-Sweat device (WR Medical Electronics Co., Stillwater, MN) and multi-compartmental sweat capsules. The resulting sweat response was recorded from four routine sites (forearm, proximal leg, distal leg and foot).
Table 1 Clinical characteristics.
Age (years) Sex (f:m) Disease duration (years)
Past medical history of OI Family history of OI Disease onset Acute (b1 month) Subacute (1–3 months) Gradual (N3 months) Precipitating event Viral, gastrointestinal Viral, URI Viral, unspecified Post-operative None Disease course Static Progressive Improved Relapsing–remitting Unknown Clinical symptoms Lightheadedness Weakness Presyncope/syncope Palpitations Chest pain Heat intolerance Exercise intolerance Fatigue Migraine
POTS (n = 12)
IST (n = 8)
Control (n = 20)
32 ± 10 (14–46) 11:1 5.0 ± 6.0 (1–19) (n =)a 6 5
30 ± 16 (15–56) 6:2 5.0 ± 5.0 (1–15) (n =)a 1 0
32 ± 12 (14–54) 17:3 N/A (n =)a 0 0
4 3 5
3 0 5
0 0 0
1 2 1 0 8
0 0 0 0 8
0 0 0 0 0
4 0 7 0 1
5 0 2 0 1
0 0 0 0 0
12 0 9 8 3 6 7 3 3
2 0 4 8 3 2 5 3 3
0 0 0 0 0 0 0 0 0
Values are expressed as mean ± SD. Data in parentheses indicate range. Abbreviations: f, female; IST, inappropriate sinus tachycardia; m, male; OI, orthostatic intolerance; POTS, postural orthostatic tachycardia syndrome; and URI, upper respiratory tract infection. a Denotes the number of subjects expressing a specific clinical indicator as described in the table.
2.3. Measurements of cardio-vagal function Cardio-vagal function was assessed using heart rate deep breathing (HRDB) and Valsalva ratio (VR). In brief, subjects were asked to perform deep breathing cycles using visual cues (heart rate response to deep breathing) and a Valsalva maneuver (VM) by way of forced exhalation (VR). Cardiovascular adrenergic function was evaluated by measuring blood pressure (BP) and HR responses to VM and HUT (Low, 2003; Low and Opfer-Gehrking, 1999). For the VM, subjects were instructed to inhale deeply, subsequently exhaling through a bugle with an air leak (to ensure an open glottis) (Airlife Universal Disposable Mouthpieces, WR Medical Electronics Co., Maplewood, MN) to maintain the manometer dial at an expiratory pressure of 40 mm Hg for 15 s. Each test was followed by a rest period of 2 min, with testing repeated until two responses with similar beat-to-beat BP and HR recordings were obtained. For each test, the VR was calculated as the maximum HR generated during the maneuver divided by the minimum HR occurring in the 30 s following the release of the maneuver (Low, 2003). In the current study, the testing session with the highest VR was used in our analyses.
2.4. Measurements of heart rate variability Heart rate variability (HRV) was calculated at baseline prior to tilt (supine position) and during HUT. Time domain variables included SDNN (the standard deviation of all normal RR intervals), pNN50 (proportion derived by dividing the number of interval differences of successive RR intervals greater than 50 ms by the total number of RR intervals)
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and RMSSD (square root of the mean squared differences of successive RR intervals) were calculated using Kubios HRV 2.1 software (Department of Applied Physics, University of Eastern Finland, Kuopio, Finland). Spectral analysis of the frequency domain variables was calculated to determine sympathovagal balance of both fast Fourier transform (FFT) and autoregressive (AR) spectral estimation methods (Kubios HRV 2.1 software). 2.5. Determination of baroreflex sensitivity Evaluation of baroreflex sensitivity (BRS) included calculations of BRSv (vagal component), BRSa (adrenergic component) and BRSa1 (adrenergic component, alternate calculation) from the beat-to-beat BP recordings of the VM. BRSv was determined as the slope of regression of the R-R interval (seconds) over systolic BP during early phase II. Pressure recovery time (PRT) was defined as time (seconds) from the valley of phase III (start of phase IV) to the return of phase IV to baseline. BRSa was defined as the systolic BP decrement associated with phase III divided by PRT. BRSa1 was estimated as systolic BP decrement divided by PRT, where BP decrement was a sum of the BP fall in early phase II and three-fourths of the amplitude of phase III (Huang et al., 2007; La Rovere et al., 1998, 2001). Adrenergic hemodynamic parameters: late phase II (from the valley of late phase II to the peak of phase III) and phase IV (from return to baseline to the peak) were also measured (Huang et al., 2007).
2.6. Head-up tilt Subjects were placed in the supine position for 15 min prior to HUT testing. The subject's beat-to-beat BP and HR responses were measured via a BMEYE Nexfin device (Amsterdam, The Netherlands) and an ECG device (Model 3000 Cardiac Trigger Monitor, IVY Biomedical Systems, Inc., Branford, CT) with ECG electrodes (Ambu® Blue Sensor SP, Glen Burnie, MD), respectively. All recordings were collected using WR TestWorks™ software (WR Medical Electronics Co., Stillwater, MN). Baseline recordings were obtained for a minimum of 1 min. The subject was then passively tilted to a 70° angle for a period of 5 min. Afterward, the subject was tilted back down to the supine position for a period of 5 min. The postural HR increment was calculated by subtracting the average HR in the supine position prior to tilt from the maximal HR (averaged over 30 s) between the second and fifth minute in the upright position.
2.7. Determination of the blood pressure components during head-up tilt Blood pressure components during HUT were determined from averaged beat to beat blood pressure and heart rate recordings during the immediate period after HUT and head down tilt. Values were calculated as follows: ΔDBPd, diastolic blood pressure decrement; ΔDBPr/s, diastolic blood pressure increment from minimal point to recovery/stabilization; ΔDBPov, diastolic blood pressure increment from recovery point to overshoot; DBPb, baseline diastolic blood pressure; DBPi, hypotenuse of diastolic blood pressure increment from minimal point to recovery/stabilization; ΔSBPd, systolic blood pressure decrement; ΔSBPr/s, systolic blood pressure increment from minimal point to recovery/stabilization; ΔSBPov, systolic blood pressure increment from minimal point to overshoot; SBPb, baseline systolic blood pressure; SBPi, systolic blood pressure increment calculated as a hypotenuse from the end point of SBP decrement to the start of recovery/stabilization; trec-ov, time interval between recovery of systolic blood pressure and overshoot; HRb, heart rate associated with baseline systolic blood pressure; HRmin, heart rate associated with minimal systolic blood pressure; HRr/s, heart rate associated with recovery/stabilization systolic blood pressure.
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2.8. Composite Autonomic Severity Score Composite Autonomic Severity Score (CASS) was calculated for each subject based on the autonomic reflex screen results as previously described (Low, 1993). The CASS provides a measure of the severity and distribution of autonomic failure and has been previously validated to quantify autonomic dysfunction on standard autonomic testing (Low, 1993). The 10-point CASS is divided into three sub-scores: sudomotor (0–3), cardio-vagal (0–3), and adrenergic (0–4), with total scores out of 10 presented herein. Each sub-score was calculated by comparing subject results to our previously published normative dataset (n = 121) (Ives et al., 2013), with each sub-score normalized for the confounding variable of gender. 2.9. The Orthostatic Intolerance Scale The OI Scale is a 5-point scale, with 0 being normal and 4 as the most severe. The scale was developed to describe the severity of clinical symptoms and the effect on activities of daily living related to OI. This scale has been previously described and validated (Schrezenmaier et al., 2005). 2.10. Statistical analyses Descriptive statistics are presented as mean ± standard deviation (SD). Data (nonparametric) comparing control, POTS and IST subject groups were analyzed using the Kruskal–Wallis one-way analysis of variance. Data (parametric) comparing HRV between baseline and tilt of each group (POTS, IST, and control) were analyzed using a pairedsamples t-test. All tests were 2-tailed; p b 0.05 was considered statistically significant. All statistical analyses were performed using SPSS statistical software, version 21 for Windows (SPSS Inc., Chicago, IL). 3. Results Patient characteristics are described in Table 1. POTS and IST patients had similar age and gender distributions. Additionally, POTS patients exhibited a higher frequency of orthostatic symptoms and a prior history of orthostasis (Table 1). CASS scores were low for both the POTS and IST subject groups, indicating mild autonomic dysfunction (Table 2). There was a significant difference in postural HR increment on HUT in POTS patients (47.9 ± 13.8 bpm; n = 12) compared to IST patients (31.0 ± 9.7 bpm; n = 8; p = 0.008; Table 2). Similarly, the OI scale showed significantly greater orthostatic symptoms in POTS patients (2.6 ± 0.5; n = 12) versus IST patients (0.4 ± 0.5; n = 8; p b 0.001; Table 2). Conversely, IST patients had a significantly higher resting HR (96 ± 12 bpm; n = 8) when compared to POTS patients (73 ± 12 bpm; n = 12; p = 0.001; Table 2). Measurements of cardio-vagal function (HRDB, VR) or sudomotor function (QSART) revealed no difference between all three groups (Table 3). Table 2 Autonomic and heart rate data, comparison of POTS and IST subjects.
CASS (10-point scale) OI Scale (5-point scale) Resting HR (bpm) Head-up tilt: HR increment (bpm)
POTS (n = 12)
IST (n = 8)
Control (n = 20)
0 ± 0 (0–1) 2.6 ± 0.5 73 ± 12 47.9 ± 13.8 (30.2–75.1)
0 ± 1 (0–1) 0.4 ± 0.5⁎ 96 ± 12⁎ 30.9 ± 9.7⁎
0 ± 1 (0–1) 0.0 ± 0.0⁎,⁎⁎ 62 ± 9⁎,⁎⁎ 22.5 ± 6.2⁎⁎
(17.2–44.1)
(9.8–31.2)
Values are expressed as mean ± SD. Data in parentheses indicate range. Abbreviations: bpm, beats per minute; CASS, Composite Autonomic Severity Score; IST, inappropriate sinus tachycardia; OI, orthostatic intolerance; POTS, postural orthostatic tachycardia syndrome; and HR, heart rate. ⁎ Significantly different from POTS (p b 0.05). ⁎⁎ Significantly different from IST (p b 0.05).
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There was no significant difference in the PRT components of the VM when comparing POTS and IST patients. The vagal component of the baroreflex was significantly different in POTS versus IST (POTS: 8.21 ± 2.31, n = 12; IST: 5.30 ± 2.94, n = 8, p = 0.036; Table 4). BRSv did not differ for IST/POTS when compared to controls (Table 4). With respect to the adrenergic components of the VM, there was a significant difference between control and IST, but not POTS patients for the BRSa1 (control: 14.94 ± 7.37, n = 20; IST: 34.90 ± 22.97, n = 8; POTS: 20.77 ± 11.29 p = 0.01; Table 4). Additionally, measurement of the baroreflex BRSa component was the same between all three groups. HUT systolic BP decrement and BP recovery increment were significantly reduced in POTS patients (6.77 ± 9.37 mm Hg and 9.16 ± 6.57 mm Hg respectively; n = 12) compared to IST (16.43 ± 4.67 mm Hg; p = 0.008, and 15.40 ± 4.43 mm Hg; p = 0.025 respectively; n = 7; Table 5). Diastolic BP increment in HUT was lower in POTS patients (5.30 ± 6.22 mm Hg; n = 12) compared to IST patients (11.00 ± 3.22 mm Hg; p = 0.0005; n = 7; Table 5). Diastolic BP overshoot at the end of HUT was increased in IST patients (14.78 ± 6.06 mm Hg; n = 7) compared to controls (7.86 ± 4.51; n = 19; p = 0.023). Additionally, recovery of DBP overshoot at the end of HUT was twofold faster in IST compared to controls (2.98 ± 2.21; n = 7 versus 6.28 ± 4.93; n = 19; p = 0.028; Table 5). There were no significant differences in sympathovagal balance (FFT LF/HF, AR LF/HF) or measures of HRV (SDNN, RMSDD, pNN50) at baseline (supine position) between control, POTS and IST subjects (Table 6). Both IST and POTS groups revealed a significant reduction in HRV regardless of measurement (SDNN, RMSDD, pNN50) during tilt when compared to controls (Table 6). There was a potential trend in IST, but not POTS, for a non-positional decrease HRV (Table 6). However only POTS subjects showed a significant increase in sympathovagal balance (LF/HF) for both frequency domains with tilt (FFT, 8.29 ± 6.38; AR, 7.84 ± 5.24) compared to baseline/supine position (FFT, 2.25 ± 1.75; AR, 1.99 ± 1.38; p b 0.05; Table 6). Additionally the LH and HF components showed a significant change from the supine to upright position during HUT for POTS (p = 0.01) but not IST or controls (Fig. 1). 4. Discussion To our knowledge this is the first direct comparison of autonomic symptoms and standard clinical tests of autonomic function in POTS Table 3 Autonomic reflex screen, comparison of POTS and IST subjects.
QSART sweat volume Forearm (μL)
Proximal leg (μL)
Distal leg (μL)
Foot (μL)
HRDB Avg. HR difference (bpm)
Valsalva ratio
POTS
IST
Control
0.91 ± 0.94 (0.11–3.32; n = 11) 1.54 ± 1.32 (0.43–4.83; n = 9) 0.73 ± 0.41 (0.25–1.66; n = 9) 0.61 ± 0.34 (0.29–1.34; n = 8)
0.82 ± 0.87 (0.26–2.13; n = 5) 0.97 ± 0.70 (0.54–2.20; n = 5) 0.44 ± 0.43 (0.11–1.06; n = 5) 0.38 ± 0.46 (0.07–0.91; n = 4)
0.83 ± 0.46 (0.15–1.6; n = 18) 1.31 ± 0.52 (0.46–2.67; n = 19) 1.18 ± 0.67 (0.08–3.27; n = 19) 1.01 ± 0.93 (0.04–3.72; n = 18)
22.9 ± 8.3 (7.3–33.6; n = 12) 2.17 ± 0.52 (1.49–3.22; n = 12)
20.3 ± 13.9 (7.2–41.6; n = 8) 1.99 ± 0.40 (1.14–2.42; n = 8)
19.8 ± 7.1 (10.1–38.1; n = 20) 1.91 ± 0.30 (1.53–2.64; n = 20)
Values are expressed as mean ± SD. Data in parentheses indicate range. Abbreviations: avg, average; bpm, beats per minute; HR, heart rate; HRDB, heart rate response to deep breathing; IST, inappropriate sinus tachycardia; POTS, postural orthostatic tachycardia syndrome; and QSART, Quantitative Sudomotor Axon Reflex Test.
Table 4 Components of the Valsalva maneuver in POTS and IST subjects.
PRT (s) BRSv (ms/mm Hg) BRSa (mm Hg/s) BRSa1 (mm Hg/s)
POTS (n = 12)
IST (n = 8)
Control (n = 19)
1.92 8.21 13.37 20.77
1.88 5.30 24.13 34.90
2.58 6.68 9.87 14.94
± ± ± ±
0.89 2.31 7.57 11.29
± ± ± ±
1.29 2.94⁎ 30.74 22.97
± ± ± ±
1.24 2.88 6.41 7.37⁎⁎
Values are expressed as mean ± SD. Abbreviations: BRS, baroreflex sensitivity; BRSa, standard adrenergic component of BRS; BRSa1, alternative adrenergic component of BRS; BRSv, vagal component of BRS; IST, inappropriate sinus tachycardia; POTS, postural orthostatic tachycardia syndrome; and PRT, pressure recovery time. ⁎ Significantly different from POTS (p b 0.05). ⁎⁎ Significantly different from IST (p b 0.05).
and IST patients. Our study revealed several important findings. First, non-postural (resting) HR was increased in IST patients compared to POTS patients. Second, POTS patients expressed significant orthostatic symptoms and postural tachycardia as measured by HR increment on HUT compared to IST patients. Third, increased adrenergic baroreflex sensitivity, reduced HRV, and rapid diastolic blood pressure overshoot after HUT in IST likely reflects a relative increase in sympathetic activity contributing to non-positional tachycardia. Fourth, HUT elicited a reduction in associated blood pressure changes, reduced heart rate variability and increased sympathovagal balance that argue for a predominant postural sympathetic drive that corresponds to increased heart rate increments and orthostatic symptoms associated with POTS. 4.1. Autonomic function in POTS and IST In the current study, non-postural (supine) and postural (HUT) heart rate differences were observed between POTS and IST. Specifically, POTS patients expressed reduced non-postural heart rates as well as an elevated postural tachycardia compared to IST patients. In addition to observed heart rate differences, POTS patients expressed a greater degree of OI compared to IST and controls. These results were expected due to the physiological presentations of the disorders and as a consequence of the diagnostic criteria (see Sections 2 Materials and Methods and 2.1 Subjects). Furthermore, both POTS and IST patients had a low degree of autonomic dysfunction (CASS, Table 2) that is similar to previous work (Kimpinski et al., 2012; Leon et al., 2005). The heart rate data of IST patients in the current study expressed a postural tachycardia of over 30 bpm, which falls within the heart rate criteria of POTS. However, these subjects did not complain of significant orthostasis required for the diagnosis of POTS. This elevated heart rate is most likely attributable to the young age of the IST patients (Table 1) and has been previously described in young healthy individuals (Ives and Kimpinski, 2013; Singer et al., 2012). It is interesting that an elevated standing heart rate did not appear to exacerbate postural symptoms in our IST patients. This may provide clarification in regards to the potentially divergent mechanisms that differentiate symptomatic postural tachycardia from asymptomatic tachycardia regardless of position. Moreover, it is possible that POTS and IST may “co-exist” in select patients based on predisposing baseline characteristics such as age and gender; rather than a common pathological alteration in autonomic modulation of heart rate. 4.2. Mechanisms contributing to higher non-positional heart rates in IST The current data present the first comprehensive evidence of altered cardiac autonomic function in POTS and IST patients. There was an increase in adrenergic BRS sensitivity (BRSa1) in IST patients compared to controls (Table 4). The increase in BRSa1 could contribute to the general increase in non-positional heart rate. The further trend towards reduced HRV, presumably indicating reduced vagal/parasympathetic influence on heart rate, unrelated to position (which also significantly differed from POTS and controls during HUT) may also play a role in
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Table 5 Blood pressure components of the tilt test in POTS and IST.
SBPb (mm Hg) DBPb (mm Hg) ΔSBPd (mm Hg) ΔDBPd (mm Hg) ΔSBPr/s (mm Hg) ΔDBPr/s (mm Hg) ΔSBPov (mm Hg) ΔDBPov (mm Hg) trec-ov (s) SBPi (s) DBPi (s)
POTS (n = 12)
IST (n = 7)
Control (n = 19)
112.44 69.17 −6.77 3.20 9.16 5.30 8.34 9.76 6.84 11.96 9.54
123.58 75.47 −16.43 −5.85 15.40 11.00 6.40 14.78 2.98 18.52 14.72
119.98 71.75 −11.90 −0.52 11.80 3.64 7.30 7.86 6.28 14.56 10.08
± ± ± ± ± ± ± ± ± ± ±
24.78 12.27 9.37⁎ 11.68 6.57⁎ 6.22⁎ 7.72 9.88 6.01 7.29⁎ 6.65⁎
± ± ± ± ± ± ± ± ± ± ±
15.30 6.44 4.67 7.37 4.43 3.22 4.12 6.06 2.21 3.35 3.72
± ± ± ± ± ± ± ± ± ± ±
14.92 9.68 11.92 3.75 10.22 5.30⁎ 3.23 4.51⁎ 4.93⁎ 12.15 7.93
Values expressed as mean ± SD. Abbreviations: ΔDBPd, diastolic blood pressure decrement; ΔDBPr/s, diastolic blood pressure increment from minimal point till recovery/stabilization; ΔDBPov, diastolic blood pressure increment from recovery point till overshoot; DBPb, baseline diastolic blood pressure; DBPi, hypotenuse of diastolic blood pressure increment from minimal point to recovery/stabilization; ΔSBPd, systolic blood pressure decrement; ΔSBPr/s, systolic blood pressure increment from minimal point till recovery/ stabilization; ΔSBPov, systolic blood pressure increment from minimal point till overshoot; POTS, postural orthostatic tachycardia syndrome; SBPb, baseline systolic blood pressure; SBPi, systolic blood pressure increment calculated as a hypotenuse from the end point of SBP decrement to start time of its recovery/stabilization; trec-ov, time interval between recovery of systolic blood pressure and its overshoot; and IST, inappropriate sinus tachycardia. ⁎ Significantly different than IST (p b 0.05).
contributing to the tachycardia exhibited in IST patients (Table 6). The significantly higher and more rapid diastolic BP overshoot in IST at the end of HUT may reflect this relative increase in sympathetic activity that drives non-positional heart rate (Table 5). 4.3. Mechanisms contributing to higher heart rate increments in POTS The vagal (parasympathetic) component of the VM revealed a significant difference in POTS patients compared to IST patients. Previous research has reported that impaired vagal baroreflex function in patients with cardiovascular disease leads to poorer clinical outcomes (e.g. malignant arrhythmia and death). However, impaired vagal baroreflex function in POTS patients does not result in poorer clinical outcomes (Kimpinski et al., 2012; Thieben et al., 2007). The role a modest increase in BRSv plays in the pathophysiology of POTS is speculative and it should be noted that baroreflex function has been argued to be either non-contributory or reduced in POTS (Masuki et al., 2007; Mustafa et al., 2012). Furthermore these studies compare POTS to control subjects, which in our study did not show a significant difference. The ability to differentiate between POTS and IST with respect to BRS function remains to be elucidated. This includes the interactions between vagal and adrenergic components of the baroreflex. Furthermore, positional changes may be more important and HRV and BP in the upright position are not necessarily assessed by non-invasive measures of BRS in supine position (see below). In HUT, BP changes were significantly reduced In POTS patients compared to IST patients. Thus, this likely represents diminished BP
Fig. 1. Head-up tilt dependent changes (HUT minus supine position) in LF and HF power were significantly greater in POTS (n = 12, *p = 0.01) but not in control (n = 20) and in IST patients (n = 7). ΔHF, changes of high frequency band; ΔLF, changes of low frequency band; POTS, postural orthostatic tachycardia syndrome; and IST, inappropriate sinus tachycardia.
variability in POTS patients during transient periods of reduced BP. Moreover, this reduction in BP variability may create an increased compensatory heart rate response in POTS patients in the upright position that further exacerbates postural tachycardia. These mechanisms could be sympathetically mediated and along with reduced HRV during HUT may drive postural heart rates as reflected by measures of sympathovagal balance (Table 6). 4.4. Study limitations The current manuscript has several issues complicating the analysis that need to be addressed. The first is the relatively small number of subjects included. Unfortunately, patient recruitment is limited due to the small number of IST patients available for recruitment. While our subject numbers reported in the current manuscript are small, they are consistent with subject numbers reported in other studies (Leon et al., 2005). Our study does not preclude small differences in autonomic dysfunction as measured by the autonomic reflex screen (ARS) that may be detected with larger sample sizes. However, there do not appear to be gross clinically relevant abnormalities on the ARS that differentiate POTS from IST. Secondly, several sub-types of POTS have been proposed (i.e. neuropathic and hyper-adrenergic POTS) and may be better distinguished from IST on the basis of the autonomic reflex screen (Jacob et al., 2000; Kanjwal et al., 2011). We sequentially collected our POTS patients in order to avoid bias and, based on clinical criteria, none met the diagnostic criteria for neuropathic POTS. We did not routinely collect postural catecholamine levels in this specific group of patients to further define the POTS subjects as being hyper-adrenergic. Future analysis of postural catecholamines in IST and POTS patients is a focus of ongoing studies in our laboratory. We continue to prospectively study both IST and POTS patients in our autonomic laboratory. The major focus of such studies is to determine ideal treatment of both conditions that includes patients with overlapping features of POTS and IST. While such patients were not represented in the current study, it is important to note that there were no
Table 6 Heart rate variability in study subjects. Baseline (supine)
FFT LF/HF AR LF/HF SDNN pNN50 RMSDD
Tilt
POTS (n = 12)
IST (n = 7)
Control (n = 20)
POTS (n = 12)
2.25 1.99 56.7 21.7 54.8
3.03 2.12 36.4 8.4 25.4
2.65 2.49 63.5 24.1 55.4
8.29 7.84 48.0 5.5 20.4
± ± ± ± ±
1.75 1.38 32.5 26.8 56.0
± ± ± ± ±
2.57 1.33 20.6 7.7 14.9
± ± ± ± ±
2.19 2.59 31.6 20.7 47.0
AR, autoregressive; FFT, fast Fourier transform; HF, high frequency; and LF, low frequency. ⁎ Significantly different (p b 0.05) within group (i.e. control, IST or POTS) from baseline compared to tilt. ⁎⁎ Significantly different (p b 0.05) from controls at tilt. ⁎⁎⁎ Significantly different (p b 0.05) from IST at tilt.
± ± ± ± ±
6.38⁎ 5.24⁎ 23.1⁎⁎⁎ 9.4⁎,⁎⁎ 17.9⁎,⁎⁎
IST (n = 7)
Control (n = 20)
6.77 4.49 30.1 3.0 18.6
4.41 3.65 64.6 12.9 36.4
± ± ± ± ±
6.68 4.50 18.8⁎⁎ 4.7 10.9⁎⁎
± ± ± ± ±
3.50⁎ 2.89 17.7 17.6⁎ 22.7⁎
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specific abnormalities defining each group that would alter clinical treatment or prognosis. More specific and tailored measures of autonomic function may provide greater information on the underlying pathophysiology of both conditions. This is especially important in IST and IST/POTS overlap patients where there is little published data in comparison to POTS. Additional large systematic studies are also needed to better deal with the issues of treatment and prognostication in IST and POTS and in those patients co-expressing both disorders (Kimpinski et al., 2012). 5. Conclusions Changes in cardiac autonomic function contribute to changes in positional and non-positional heart rate in postural tachycardia syndrome versus inappropriate sinus tachycardia. These findings contribute to a further understanding of the autonomic dysfunction underlying POTS and IST. Acknowledgment This work was supported by unrestricted grant funds from the Department of Clinical Neurological Sciences Internal Research Fund. References Antiel, R.M., Risma, J.M., Grothe, R.M., Brands, C.K., Fischer, P.R., 2008. Orthostatic intolerance and gastrointestinal motility in adolescents with nausea and abdominal pain. J. Pediatr. Gastroenterol. Nutr. 46, 285–288. Benezet-Mazuecos, J., Rubio, J.M., Farre, J., Quinones, M.A., Sanchez-Borque, P., Macia, E., 2013. Long-term outcomes of ivabradine in inappropriate sinus tachycardia patients: appropriate efficacy or inappropriate patients. Pacing Clin. Electrophysiol. 36, 830–836. Brady, P.A., Low, P.A., Shen, W.K., 2005. Inappropriate sinus tachycardia, postural orthostatic tachycardia syndrome, and overlapping syndromes. Pacing Clin. Electrophysiol. 28, 1112–1121. Cappato, R., Castelvecchio, S., Ricci, C., Bianco, E., Vitali-Serdoz, L., Gnecchi-Ruscone, T., Pittalis, M., De Ambroggi, L., Baruscotti, M., Gaeta, M., Furlanello, F., Di Francesco, D., Lupo, P.P., 2012. Clinical efficacy of ivabradine in patients with inappropriate sinus tachycardia: a prospective, randomized, placebo-controlled, double-blind, crossover evaluation. J. Am. Coll. Cardiol. 60, 1323–1329. Huang, C.C., Sandroni, P., Sletten, D.M., Weigand, S.D., Low, P.A., 2007. Effect of age on adrenergic and vagal baroreflex sensitivity in normal subjects. Muscle Nerve 36, 637–642. Ives, C.T., Kimpinski, K., 2013. Higher postural heart rate increments on head-up tilt correlate with younger age but not orthostatic symptoms. J. Appl. Physiol. 115, 525–528. Ives, C.T., Berger, M.J., Kimpinski, K., 2013. The autonomic reflex screen in healthy participants from Southwestern Ontario. Can. J. Neurol. Sci. 40, 848–853. Jacob, G., Costa, F., Shannon, J.R., Robertson, R.M., Wathen, M., Stein, M., Biaggioni, I., Ertl, A., Black, B., Robertson, D., 2000. The neuropathic postural tachycardia syndrome. N. Engl. J. Med. 343, 1008–1014. Johnson, J.N., Mack, K.J., Kuntz, N.L., Brands, C.K., Porter, C.J., Fischer, P.R., 2010. Postural orthostatic tachycardia syndrome: a clinical review. Pediatr. Neurol. 42, 77–85. Kanjwal, M.Y., Kosinski, D.J., Grubb, B.P., 2003. Treatment of postural orthostatic tachycardia syndrome and inappropriate sinus tachycardia. Curr. Cardiol. Rep. 5, 402–406. Kanjwal, K., Saeed, B., Karabin, B., Kanjwal, Y., Grubb, B.P., 2011. Clinical presentation and management of patients with hyperadrenergic postural orthostatic tachycardia syndrome. A single center experience. Cardiol. J. 18, 527–531.
Khan, S., Hamid, S., Rinaldi, C., 2009. Treatment of inappropriate sinus tachycardia with ivabradine in a patient with postural orthostatic tachycardia syndrome and a dual chamber pacemaker. Pacing Clin. Electrophysiol. 32, 131–133. Kimpinski, K., Figueroa, J.J., Singer, W., Sletten, D.M., Iodice, V., Sandroni, P., Fischer, P.R., Opfer-Gehrking, T.L., Gehrking, J.A., Low, P.A., 2012. A prospective, 1-year follow-up study of postural tachycardia syndrome. Mayo Clin. Proc. 87, 746–752. La Rovere, M.T., Bigger Jr., J.T., Marcus, F.I., Mortara, A., Schwartz, P.J., 1998. Baroreflex sensitivity and heart-rate variability in prediction of total cardiac mortality after myocardial infarction. ATRAMI (Autonomic Tone and Reflexes After Myocardial Infarction) Investigators. Lancet 351, 478–484. La Rovere, M.T., Pinna, G.D., Hohnloser, S.H., Marcus, F.I., Mortara, A., Nohara, R., Bigger Jr., J.T., Camm, A.J., Schwartz, P.J., 2001. Baroreflex sensitivity and heart rate variability in the identification of patients at risk for life-threatening arrhythmias: implications for clinical trials. Circulation 103, 2072–2077. Leon, H., Guzman, J.C., Kuusela, T., Dillenburg, R., Kamath, M., Morillo, C.A., 2005. Impaired baroreflex gain in patients with inappropriate sinus tachycardia. J. Cardiovasc. Electrophysiol. 16, 64–68. Low, P.A., 1993. Composite autonomic scoring scale for laboratory quantification of generalized autonomic failure. Mayo Clin. Proc. 68, 748–752. Low, P.A., 2003. Testing the autonomic nervous system. Semin. Neurol. 23, 407–421. Low, P.A., Opfer-Gehrking, T.L., 1999. The autonomic laboratory. Neurodiagn. J. 39, 65–76. Low, P.A., Opfer-Gehrking, T.L., Textor, S.C., Schondorf, R., Suarez, G.A., Fealey, R.D., Camilleri, M., 1994. Comparison of the postural tachycardia syndrome (POTS) with orthostatic hypotension due to autonomic failure. J. Auton. Nerv. Syst. 50, 181–188. Masuki, S., Eisenach, J.H., Schrage, W.G., Dietz, N.M., Johnson, C.P., Wilkins, B.W., Dierkhising, R.A., Sandroni, P., Low, P.A., Joyner, M.J., 2007. Arterial baroreflex control of heart rate during exercise in postural tachycardia syndrome. J. Appl. Physiol. 103, 1136–1142. McDonald, C., Frith, J., Newton, J.L., 2011. Single centre experience of ivabradine in postural orthostatic tachycardia syndrome. Europace 13, 427–430. Mustafa, H.I., Raj, S.R., Diedrich, A., Black, B.K., Paranjape, S.Y., Dupont, W.D., Williams, G.H., Biaggioni, I., Robertson, D., 2012. Altered systemic hemodynamic and baroreflex response to angiotensin II in postural tachycardia syndrome. Circ. Arrhythm. Electrophysiol. 5, 173–180. Olshansky, B., Sullivan, R.M., 2013. Inappropriate sinus tachycardia. J. Am. Coll. Cardiol. 61, 793–801. Peltier, A.C., Garland, E., Raj, S.R., Sato, K., Black, B., Song, Y., Wang, L., Biaggioni, I., Diedrich, A., Robertson, D., 2010. Distal sudomotor findings in postural tachycardia syndrome. Clin. Auton. Res. 20, 93–99. Ptaszynski, P., Kaczmarek, K., Klingenheben, T., Cygankiewicz, I., Ruta, J., Wranicz, J.K., 2013. Noninvasive assessment of autonomic cardiovascular activity in patients with inappropriate sinus tachycardia. Am. J. Cardiol. 14, 811–815. Retegui, G., Quintero, M., Ruiz-Borrell, M., Revello, A., 2009. Ivabradine as a treatment option for inappropriate sinus tachycardia. Rev. Esp. Cardiol. 62 (5), 577–579 (May). Schrezenmaier, C., Gehrking, J.A., Hines, S.M., Low, P.A., Benrud-Larson, L.M., Sandroni, P., 2005. Evaluation of orthostatic hypotension: relationship of a new self-report instrument to laboratory-based measures. Mayo Clin. Proc. 80, 330–334. Singer, W., Sletten, D.M., Opfer-Gehrking, T.L., Brands, C.K., Fischer, P.R., Low, P.A., 2012. Postural tachycardia in children and adolescents: what is abnormal? J. Pediatr. 160, 222–226. Stewart, J.M., 2000. Autonomic nervous system dysfunction in adolescents with postural orthostatic tachycardia syndrome and chronic fatigue syndrome is characterized by attenuated vagal baroreflex and potentiated sympathetic vasomotion. Pediatr. Res. 48, 218–226. Thieben, M.J., Sandroni, P., Sletten, D.M., Benrud-Larson, L.M., Fealey, R.D., Vernino, S., Lennon, V.A., Shen, W.K., Low, P.A., 2007. Postural orthostatic tachycardia syndrome: the Mayo clinic experience. Mayo Clin. Proc. 82, 308–313. Weyn, T., Stockman, D., Degreef, Y., 2011. The use of ivabradine for inappropriate sinus tachycardia. Acta Cardiol. 66, 259–262. Zellerhoff, S., Hinterseer, M., Felix Krull, B., Schulze-Bahr, E., Fabritz, L., Breithardt, G., Kirchhof, P., Kaab, S., 2010. Ivabradine in patients with inappropriate sinus tachycardia. Naunyn Schmiedebergs Arch. Pharmacol. 382, 483–486.
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Autonomic Neuroscience: Basic and Clinical journal homepage: www.elsevier.com/locate/autneu
Differences in cardiac autonomic function contributes to heart rate abnormalities in POTS and IST James C. Corkal a, Iryna Palamarchuk a,b, Kurt Kimpinski a,b,⁎ a b
Department of Clinical Neurological Sciences, University Hospital, London Health Sciences Centre, London, Ontario, Canada Schulich School of Medicine & Dentistry, Western University, London, Ontario, Canada
a r t i c l e
i n f o
Article history: Received 15 May 2014 Received in revised form 10 September 2014 Accepted 11 September 2014 Keywords: Postural tachycardia syndrome Inappropriate sinus tachycardia Orthostatic intolerance Autonomic nervous system Autonomic reflex screen
a b s t r a c t Our objective was to examine the differences in cardiac autonomic function in Postural Tachycardia Syndrome (POTS) versus inappropriate sinus tachycardia (IST). Subjects (IST, n = 8; POTS, n = 12) were studied using standard measurements of the autonomic reflex screen, baroreflex function and spectral analysis. Data was compared to age/gender-matched controls (n = 20). The components of the autonomic reflex screen did not differ between groups. The exception was the significant but expected difference in postural heart rate increment on head-up tilt in POTS (47.9 ± 13.8; n = 12) compared to IST (30.9 ± 9.7; n = 8; p = 0.008). Accordingly the Orthostatic Intolerance Scale showed significantly greater orthostatic symptoms in POTS (2.6 ± 0.5; n = 12) versus IST patients (0.4 ± 0.5; n = 8; p b 0.001). Conversely, IST patients had a significantly higher resting heart rate (96 ± 12; n = 8) when compared to POTS patients (73 ± 12; n = 12; p = 0.001). There was a significant difference in vagal baroreflex sensitivity (BRSv) in POTS (8.21 ± 2.3, n = 12) compared to IST patients (5.30 ± 2.94, n = 8, p = 0.036) during the Valsalva maneuver. Only POTS subjects showed a significant increase in sympathovagal balance (LF/HF) with tilt (FFT, 8.29 ± 6.38; AR, 7.84 ± 5.24) compared to the supine position (FFT, 2.25 ± 1.75; AR, 1.99 ± 1.38; p b 0.05) for both frequency domains. Differences in cardiac autonomic function contribute to changes in positional and non-positional heart rate in postural tachycardia syndrome versus inappropriate sinus tachycardia. These findings shed further light on the autonomic dysfunction underlying POTS and IST. © 2014 Elsevier B.V. All rights reserved.
1. Introduction Postural tachycardia syndrome (POTS) is a disorder of orthostatic intolerance characterized by lightheadedness, dizziness, and palpitations associated with heart rate increments greater than 30 bpm on headup tilt (HUT) in the upright or standing position (Low et al., 1994). Inappropriate sinus tachycardia (IST) is defined as excessive sinus tachycardia greater than 90 bpm unrelated to position (Olshansky and Sullivan, 2013). Both POTS and IST can be a significant cause of morbidity particularly in younger age groups (Antiel et al., 2008; Johnson et al., 2010; Olshansky and Sullivan, 2013). There is an overlap in the clinical presentation of both disorders and can occur simultaneously in a select group Abbreviations:ARS, autonomic reflex screen; AR, autoregressive;BRSa, adrenergic baroreflex sensitivity; BRSv, vagal baroreflex sensitivity; CASS, Composite Autonomic Severity Score; DBP, diastolic blood pressure; FFT, fast Fourier transform; HR, heart rate; HRDB, heart rate deep breathing; HRV, heart rate variability; HF, high frequency; HUT, head-up tilt; IST, inappropriate sinus tachycardia; LF, low frequency; OI, orthostatic intolerance; POTS, postural tachycardia syndrome; PRT, phase recovery time; QSART, Quantitative Sudomotor Axon Reflex Test; SBP, systolic blood pressure; VM, Valsalva maneuver; VR, Valsalva ratio. ⁎ Corresponding author at: Rm. C7-131, University Hospital, London Health Sciences Centre, 339 Windermere Road, London, Ontario N6A 5A5, Canada. Tel.: + 1 519 663 3337; fax: +1 519 663 3328. E-mail address: [email protected] (K. Kimpinski).
http://dx.doi.org/10.1016/j.autneu.2014.09.016 1566-0702/© 2014 Elsevier B.V. All rights reserved.
of patients (Brady et al., 2005; Kanjwal et al., 2003). Healthy individuals that fall within younger age groups can have heart rate increments greater than 30 bpm on head-up tilt without orthostatic symptoms (Ives and Kimpinski, 2013; Singer et al., 2012). This can complicate the diagnosis of IST where individuals may have elevated heart rate increment on HUT (N30 bpm) that may not be symptomatic (or minimally symptomatic) with respect to orthostatic symptoms versus those patients expressing both IST and POTS. The inability to differentiate between POTS and IST would have implications with respect to treatment. Both conditions respond to anti-arrhythmic medications including betaadrenergic blockade, but anti-hypotensives such as midodrine and fludrocortisone are more appropriate for the treatment of POTS (Brady et al., 2005; Kanjwal et al., 2003). The pathophysiology of POTS is complicated, but several studies have shown varying autonomic abnormalities to standardized testing (Kimpinski et al., 2012; Peltier et al., 2010; Stewart, 2000). As a result, it has been proposed that POTS represents a form of limited autonomic neuropathy (Kimpinski et al., 2012; Thieben et al., 2007). The underlying mechanisms of IST are not as well-defined, but impaired baroreflex gain has been described (Leon et al., 2005; Ptaszynski et al., 2013). Additionally, treatment options such as beta-adrenergic blockers and ivabradine (a novel specific heart rate lowering agent that acts by selectively inhibiting the pacemaker If current in sinus atrial node cells) have
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been used for both POTS and IST with reasonable success in both conditions (Benezet-Mazuecos et al., 2013; Cappato et al., 2012; Khan et al., 2009; McDonald et al., 2011; Retegui et al., 2009; Weyn et al., 2011; Zellerhoff et al., 2010). To our knowledge a comparative study between IST and POTS has not been previously published. Given the clinical similarities between the two conditions and that a select group of patients express overlapping presentations of IST and POTS, we examined the differences/similarities using non-invasive measures of autonomic function to determine whether further insights into the pathophysiology of these conditions could be drawn. The specific objectives of this study were twofold. Our first objective was to compare the presence and severity of autonomic symptoms with an emphasis on orthostatic intolerance (OI) between IST and POTS using standard measures including symptom profiles and hemodynamic measurements in the supine and head-up tilt positions. Secondly, we investigated the differences in cardiac autonomic function, given the importance of heart rate as the major defining variable in both syndromes, to characterize potential differences between POTS and IST.
2. Materials and methods 2.1. Subjects Subject characteristics are presented in Table 1. Inclusion criteria for POTS patients were an orthostatic heart rate (HR) increment of 30 bpm within 5 min of HUT and associated symptoms of OI including but not limited to dizziness, lightheadedness and palpitations (Kimpinski et al., 2012). Inclusion criteria for IST comprised a resting sinus tachycardia greater than 100 bpm with a 24-hour HR average of greater than 90 bpm with symptoms of but not limited to palpitations, dyspnea, dizziness, lightheadedness, and near syncope unassociated with a change in position (Olshansky and Sullivan, 2013). Both IST and POTS patients were consecutively studied in our laboratory and further included in this study to avoid selection bias. Ethical approval to conduct this study was obtained from the University of Western Ontario's Ethics Board. Subjects were reviewed to assure they did not have a history of progressive autonomic dysfunction beyond that expected from IST or POTS. Clinical evaluations were performed by an experienced neurologist (KK) to exclude other neurological conditions. Further exclusion criteria included the following: i) pregnant or lactating females, ii) the presence of another cause of autonomic failure, iii) the presence of failure of other organ systems or systemic illness that can affect autonomic function or the subject's ability to cooperate; these included dementia, pheochromocytoma, heart failure, hypertension, renal or hepatic disease, severe anemia, alcoholism, malignant neoplasms, hypothyroidism, sympathectomy, diabetes, amyloidosis or cerebrovascular accidents, iv) concomitant therapy with anticholinergic, alpha- and beta-adrenergic antagonists or other medication which could interfere with testing of autonomic function, and v) clinically significant coronary artery disease. We did not exclude female subjects taking oral contraceptive pills.
2.2. Quantitative Sudomotor Axon Reflex Testing Standardized clinical autonomic testing was performed as previously described (Low, 2003; Low and Opfer-Gehrking, 1999) in the Autonomic Disorders Laboratory at Western University, London, Ontario. Quantitative Sudomotor Axon Reflex Testing (QSART) evaluated the integrity of the postganglionic sympathetic sudomotor axon using a Q-Sweat device (WR Medical Electronics Co., Stillwater, MN) and multi-compartmental sweat capsules. The resulting sweat response was recorded from four routine sites (forearm, proximal leg, distal leg and foot).
Table 1 Clinical characteristics.
Age (years) Sex (f:m) Disease duration (years)
Past medical history of OI Family history of OI Disease onset Acute (b1 month) Subacute (1–3 months) Gradual (N3 months) Precipitating event Viral, gastrointestinal Viral, URI Viral, unspecified Post-operative None Disease course Static Progressive Improved Relapsing–remitting Unknown Clinical symptoms Lightheadedness Weakness Presyncope/syncope Palpitations Chest pain Heat intolerance Exercise intolerance Fatigue Migraine
POTS (n = 12)
IST (n = 8)
Control (n = 20)
32 ± 10 (14–46) 11:1 5.0 ± 6.0 (1–19) (n =)a 6 5
30 ± 16 (15–56) 6:2 5.0 ± 5.0 (1–15) (n =)a 1 0
32 ± 12 (14–54) 17:3 N/A (n =)a 0 0
4 3 5
3 0 5
0 0 0
1 2 1 0 8
0 0 0 0 8
0 0 0 0 0
4 0 7 0 1
5 0 2 0 1
0 0 0 0 0
12 0 9 8 3 6 7 3 3
2 0 4 8 3 2 5 3 3
0 0 0 0 0 0 0 0 0
Values are expressed as mean ± SD. Data in parentheses indicate range. Abbreviations: f, female; IST, inappropriate sinus tachycardia; m, male; OI, orthostatic intolerance; POTS, postural orthostatic tachycardia syndrome; and URI, upper respiratory tract infection. a Denotes the number of subjects expressing a specific clinical indicator as described in the table.
2.3. Measurements of cardio-vagal function Cardio-vagal function was assessed using heart rate deep breathing (HRDB) and Valsalva ratio (VR). In brief, subjects were asked to perform deep breathing cycles using visual cues (heart rate response to deep breathing) and a Valsalva maneuver (VM) by way of forced exhalation (VR). Cardiovascular adrenergic function was evaluated by measuring blood pressure (BP) and HR responses to VM and HUT (Low, 2003; Low and Opfer-Gehrking, 1999). For the VM, subjects were instructed to inhale deeply, subsequently exhaling through a bugle with an air leak (to ensure an open glottis) (Airlife Universal Disposable Mouthpieces, WR Medical Electronics Co., Maplewood, MN) to maintain the manometer dial at an expiratory pressure of 40 mm Hg for 15 s. Each test was followed by a rest period of 2 min, with testing repeated until two responses with similar beat-to-beat BP and HR recordings were obtained. For each test, the VR was calculated as the maximum HR generated during the maneuver divided by the minimum HR occurring in the 30 s following the release of the maneuver (Low, 2003). In the current study, the testing session with the highest VR was used in our analyses.
2.4. Measurements of heart rate variability Heart rate variability (HRV) was calculated at baseline prior to tilt (supine position) and during HUT. Time domain variables included SDNN (the standard deviation of all normal RR intervals), pNN50 (proportion derived by dividing the number of interval differences of successive RR intervals greater than 50 ms by the total number of RR intervals)
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and RMSSD (square root of the mean squared differences of successive RR intervals) were calculated using Kubios HRV 2.1 software (Department of Applied Physics, University of Eastern Finland, Kuopio, Finland). Spectral analysis of the frequency domain variables was calculated to determine sympathovagal balance of both fast Fourier transform (FFT) and autoregressive (AR) spectral estimation methods (Kubios HRV 2.1 software). 2.5. Determination of baroreflex sensitivity Evaluation of baroreflex sensitivity (BRS) included calculations of BRSv (vagal component), BRSa (adrenergic component) and BRSa1 (adrenergic component, alternate calculation) from the beat-to-beat BP recordings of the VM. BRSv was determined as the slope of regression of the R-R interval (seconds) over systolic BP during early phase II. Pressure recovery time (PRT) was defined as time (seconds) from the valley of phase III (start of phase IV) to the return of phase IV to baseline. BRSa was defined as the systolic BP decrement associated with phase III divided by PRT. BRSa1 was estimated as systolic BP decrement divided by PRT, where BP decrement was a sum of the BP fall in early phase II and three-fourths of the amplitude of phase III (Huang et al., 2007; La Rovere et al., 1998, 2001). Adrenergic hemodynamic parameters: late phase II (from the valley of late phase II to the peak of phase III) and phase IV (from return to baseline to the peak) were also measured (Huang et al., 2007).
2.6. Head-up tilt Subjects were placed in the supine position for 15 min prior to HUT testing. The subject's beat-to-beat BP and HR responses were measured via a BMEYE Nexfin device (Amsterdam, The Netherlands) and an ECG device (Model 3000 Cardiac Trigger Monitor, IVY Biomedical Systems, Inc., Branford, CT) with ECG electrodes (Ambu® Blue Sensor SP, Glen Burnie, MD), respectively. All recordings were collected using WR TestWorks™ software (WR Medical Electronics Co., Stillwater, MN). Baseline recordings were obtained for a minimum of 1 min. The subject was then passively tilted to a 70° angle for a period of 5 min. Afterward, the subject was tilted back down to the supine position for a period of 5 min. The postural HR increment was calculated by subtracting the average HR in the supine position prior to tilt from the maximal HR (averaged over 30 s) between the second and fifth minute in the upright position.
2.7. Determination of the blood pressure components during head-up tilt Blood pressure components during HUT were determined from averaged beat to beat blood pressure and heart rate recordings during the immediate period after HUT and head down tilt. Values were calculated as follows: ΔDBPd, diastolic blood pressure decrement; ΔDBPr/s, diastolic blood pressure increment from minimal point to recovery/stabilization; ΔDBPov, diastolic blood pressure increment from recovery point to overshoot; DBPb, baseline diastolic blood pressure; DBPi, hypotenuse of diastolic blood pressure increment from minimal point to recovery/stabilization; ΔSBPd, systolic blood pressure decrement; ΔSBPr/s, systolic blood pressure increment from minimal point to recovery/stabilization; ΔSBPov, systolic blood pressure increment from minimal point to overshoot; SBPb, baseline systolic blood pressure; SBPi, systolic blood pressure increment calculated as a hypotenuse from the end point of SBP decrement to the start of recovery/stabilization; trec-ov, time interval between recovery of systolic blood pressure and overshoot; HRb, heart rate associated with baseline systolic blood pressure; HRmin, heart rate associated with minimal systolic blood pressure; HRr/s, heart rate associated with recovery/stabilization systolic blood pressure.
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2.8. Composite Autonomic Severity Score Composite Autonomic Severity Score (CASS) was calculated for each subject based on the autonomic reflex screen results as previously described (Low, 1993). The CASS provides a measure of the severity and distribution of autonomic failure and has been previously validated to quantify autonomic dysfunction on standard autonomic testing (Low, 1993). The 10-point CASS is divided into three sub-scores: sudomotor (0–3), cardio-vagal (0–3), and adrenergic (0–4), with total scores out of 10 presented herein. Each sub-score was calculated by comparing subject results to our previously published normative dataset (n = 121) (Ives et al., 2013), with each sub-score normalized for the confounding variable of gender. 2.9. The Orthostatic Intolerance Scale The OI Scale is a 5-point scale, with 0 being normal and 4 as the most severe. The scale was developed to describe the severity of clinical symptoms and the effect on activities of daily living related to OI. This scale has been previously described and validated (Schrezenmaier et al., 2005). 2.10. Statistical analyses Descriptive statistics are presented as mean ± standard deviation (SD). Data (nonparametric) comparing control, POTS and IST subject groups were analyzed using the Kruskal–Wallis one-way analysis of variance. Data (parametric) comparing HRV between baseline and tilt of each group (POTS, IST, and control) were analyzed using a pairedsamples t-test. All tests were 2-tailed; p b 0.05 was considered statistically significant. All statistical analyses were performed using SPSS statistical software, version 21 for Windows (SPSS Inc., Chicago, IL). 3. Results Patient characteristics are described in Table 1. POTS and IST patients had similar age and gender distributions. Additionally, POTS patients exhibited a higher frequency of orthostatic symptoms and a prior history of orthostasis (Table 1). CASS scores were low for both the POTS and IST subject groups, indicating mild autonomic dysfunction (Table 2). There was a significant difference in postural HR increment on HUT in POTS patients (47.9 ± 13.8 bpm; n = 12) compared to IST patients (31.0 ± 9.7 bpm; n = 8; p = 0.008; Table 2). Similarly, the OI scale showed significantly greater orthostatic symptoms in POTS patients (2.6 ± 0.5; n = 12) versus IST patients (0.4 ± 0.5; n = 8; p b 0.001; Table 2). Conversely, IST patients had a significantly higher resting HR (96 ± 12 bpm; n = 8) when compared to POTS patients (73 ± 12 bpm; n = 12; p = 0.001; Table 2). Measurements of cardio-vagal function (HRDB, VR) or sudomotor function (QSART) revealed no difference between all three groups (Table 3). Table 2 Autonomic and heart rate data, comparison of POTS and IST subjects.
CASS (10-point scale) OI Scale (5-point scale) Resting HR (bpm) Head-up tilt: HR increment (bpm)
POTS (n = 12)
IST (n = 8)
Control (n = 20)
0 ± 0 (0–1) 2.6 ± 0.5 73 ± 12 47.9 ± 13.8 (30.2–75.1)
0 ± 1 (0–1) 0.4 ± 0.5⁎ 96 ± 12⁎ 30.9 ± 9.7⁎
0 ± 1 (0–1) 0.0 ± 0.0⁎,⁎⁎ 62 ± 9⁎,⁎⁎ 22.5 ± 6.2⁎⁎
(17.2–44.1)
(9.8–31.2)
Values are expressed as mean ± SD. Data in parentheses indicate range. Abbreviations: bpm, beats per minute; CASS, Composite Autonomic Severity Score; IST, inappropriate sinus tachycardia; OI, orthostatic intolerance; POTS, postural orthostatic tachycardia syndrome; and HR, heart rate. ⁎ Significantly different from POTS (p b 0.05). ⁎⁎ Significantly different from IST (p b 0.05).
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There was no significant difference in the PRT components of the VM when comparing POTS and IST patients. The vagal component of the baroreflex was significantly different in POTS versus IST (POTS: 8.21 ± 2.31, n = 12; IST: 5.30 ± 2.94, n = 8, p = 0.036; Table 4). BRSv did not differ for IST/POTS when compared to controls (Table 4). With respect to the adrenergic components of the VM, there was a significant difference between control and IST, but not POTS patients for the BRSa1 (control: 14.94 ± 7.37, n = 20; IST: 34.90 ± 22.97, n = 8; POTS: 20.77 ± 11.29 p = 0.01; Table 4). Additionally, measurement of the baroreflex BRSa component was the same between all three groups. HUT systolic BP decrement and BP recovery increment were significantly reduced in POTS patients (6.77 ± 9.37 mm Hg and 9.16 ± 6.57 mm Hg respectively; n = 12) compared to IST (16.43 ± 4.67 mm Hg; p = 0.008, and 15.40 ± 4.43 mm Hg; p = 0.025 respectively; n = 7; Table 5). Diastolic BP increment in HUT was lower in POTS patients (5.30 ± 6.22 mm Hg; n = 12) compared to IST patients (11.00 ± 3.22 mm Hg; p = 0.0005; n = 7; Table 5). Diastolic BP overshoot at the end of HUT was increased in IST patients (14.78 ± 6.06 mm Hg; n = 7) compared to controls (7.86 ± 4.51; n = 19; p = 0.023). Additionally, recovery of DBP overshoot at the end of HUT was twofold faster in IST compared to controls (2.98 ± 2.21; n = 7 versus 6.28 ± 4.93; n = 19; p = 0.028; Table 5). There were no significant differences in sympathovagal balance (FFT LF/HF, AR LF/HF) or measures of HRV (SDNN, RMSDD, pNN50) at baseline (supine position) between control, POTS and IST subjects (Table 6). Both IST and POTS groups revealed a significant reduction in HRV regardless of measurement (SDNN, RMSDD, pNN50) during tilt when compared to controls (Table 6). There was a potential trend in IST, but not POTS, for a non-positional decrease HRV (Table 6). However only POTS subjects showed a significant increase in sympathovagal balance (LF/HF) for both frequency domains with tilt (FFT, 8.29 ± 6.38; AR, 7.84 ± 5.24) compared to baseline/supine position (FFT, 2.25 ± 1.75; AR, 1.99 ± 1.38; p b 0.05; Table 6). Additionally the LH and HF components showed a significant change from the supine to upright position during HUT for POTS (p = 0.01) but not IST or controls (Fig. 1). 4. Discussion To our knowledge this is the first direct comparison of autonomic symptoms and standard clinical tests of autonomic function in POTS Table 3 Autonomic reflex screen, comparison of POTS and IST subjects.
QSART sweat volume Forearm (μL)
Proximal leg (μL)
Distal leg (μL)
Foot (μL)
HRDB Avg. HR difference (bpm)
Valsalva ratio
POTS
IST
Control
0.91 ± 0.94 (0.11–3.32; n = 11) 1.54 ± 1.32 (0.43–4.83; n = 9) 0.73 ± 0.41 (0.25–1.66; n = 9) 0.61 ± 0.34 (0.29–1.34; n = 8)
0.82 ± 0.87 (0.26–2.13; n = 5) 0.97 ± 0.70 (0.54–2.20; n = 5) 0.44 ± 0.43 (0.11–1.06; n = 5) 0.38 ± 0.46 (0.07–0.91; n = 4)
0.83 ± 0.46 (0.15–1.6; n = 18) 1.31 ± 0.52 (0.46–2.67; n = 19) 1.18 ± 0.67 (0.08–3.27; n = 19) 1.01 ± 0.93 (0.04–3.72; n = 18)
22.9 ± 8.3 (7.3–33.6; n = 12) 2.17 ± 0.52 (1.49–3.22; n = 12)
20.3 ± 13.9 (7.2–41.6; n = 8) 1.99 ± 0.40 (1.14–2.42; n = 8)
19.8 ± 7.1 (10.1–38.1; n = 20) 1.91 ± 0.30 (1.53–2.64; n = 20)
Values are expressed as mean ± SD. Data in parentheses indicate range. Abbreviations: avg, average; bpm, beats per minute; HR, heart rate; HRDB, heart rate response to deep breathing; IST, inappropriate sinus tachycardia; POTS, postural orthostatic tachycardia syndrome; and QSART, Quantitative Sudomotor Axon Reflex Test.
Table 4 Components of the Valsalva maneuver in POTS and IST subjects.
PRT (s) BRSv (ms/mm Hg) BRSa (mm Hg/s) BRSa1 (mm Hg/s)
POTS (n = 12)
IST (n = 8)
Control (n = 19)
1.92 8.21 13.37 20.77
1.88 5.30 24.13 34.90
2.58 6.68 9.87 14.94
± ± ± ±
0.89 2.31 7.57 11.29
± ± ± ±
1.29 2.94⁎ 30.74 22.97
± ± ± ±
1.24 2.88 6.41 7.37⁎⁎
Values are expressed as mean ± SD. Abbreviations: BRS, baroreflex sensitivity; BRSa, standard adrenergic component of BRS; BRSa1, alternative adrenergic component of BRS; BRSv, vagal component of BRS; IST, inappropriate sinus tachycardia; POTS, postural orthostatic tachycardia syndrome; and PRT, pressure recovery time. ⁎ Significantly different from POTS (p b 0.05). ⁎⁎ Significantly different from IST (p b 0.05).
and IST patients. Our study revealed several important findings. First, non-postural (resting) HR was increased in IST patients compared to POTS patients. Second, POTS patients expressed significant orthostatic symptoms and postural tachycardia as measured by HR increment on HUT compared to IST patients. Third, increased adrenergic baroreflex sensitivity, reduced HRV, and rapid diastolic blood pressure overshoot after HUT in IST likely reflects a relative increase in sympathetic activity contributing to non-positional tachycardia. Fourth, HUT elicited a reduction in associated blood pressure changes, reduced heart rate variability and increased sympathovagal balance that argue for a predominant postural sympathetic drive that corresponds to increased heart rate increments and orthostatic symptoms associated with POTS. 4.1. Autonomic function in POTS and IST In the current study, non-postural (supine) and postural (HUT) heart rate differences were observed between POTS and IST. Specifically, POTS patients expressed reduced non-postural heart rates as well as an elevated postural tachycardia compared to IST patients. In addition to observed heart rate differences, POTS patients expressed a greater degree of OI compared to IST and controls. These results were expected due to the physiological presentations of the disorders and as a consequence of the diagnostic criteria (see Sections 2 Materials and Methods and 2.1 Subjects). Furthermore, both POTS and IST patients had a low degree of autonomic dysfunction (CASS, Table 2) that is similar to previous work (Kimpinski et al., 2012; Leon et al., 2005). The heart rate data of IST patients in the current study expressed a postural tachycardia of over 30 bpm, which falls within the heart rate criteria of POTS. However, these subjects did not complain of significant orthostasis required for the diagnosis of POTS. This elevated heart rate is most likely attributable to the young age of the IST patients (Table 1) and has been previously described in young healthy individuals (Ives and Kimpinski, 2013; Singer et al., 2012). It is interesting that an elevated standing heart rate did not appear to exacerbate postural symptoms in our IST patients. This may provide clarification in regards to the potentially divergent mechanisms that differentiate symptomatic postural tachycardia from asymptomatic tachycardia regardless of position. Moreover, it is possible that POTS and IST may “co-exist” in select patients based on predisposing baseline characteristics such as age and gender; rather than a common pathological alteration in autonomic modulation of heart rate. 4.2. Mechanisms contributing to higher non-positional heart rates in IST The current data present the first comprehensive evidence of altered cardiac autonomic function in POTS and IST patients. There was an increase in adrenergic BRS sensitivity (BRSa1) in IST patients compared to controls (Table 4). The increase in BRSa1 could contribute to the general increase in non-positional heart rate. The further trend towards reduced HRV, presumably indicating reduced vagal/parasympathetic influence on heart rate, unrelated to position (which also significantly differed from POTS and controls during HUT) may also play a role in
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Table 5 Blood pressure components of the tilt test in POTS and IST.
SBPb (mm Hg) DBPb (mm Hg) ΔSBPd (mm Hg) ΔDBPd (mm Hg) ΔSBPr/s (mm Hg) ΔDBPr/s (mm Hg) ΔSBPov (mm Hg) ΔDBPov (mm Hg) trec-ov (s) SBPi (s) DBPi (s)
POTS (n = 12)
IST (n = 7)
Control (n = 19)
112.44 69.17 −6.77 3.20 9.16 5.30 8.34 9.76 6.84 11.96 9.54
123.58 75.47 −16.43 −5.85 15.40 11.00 6.40 14.78 2.98 18.52 14.72
119.98 71.75 −11.90 −0.52 11.80 3.64 7.30 7.86 6.28 14.56 10.08
± ± ± ± ± ± ± ± ± ± ±
24.78 12.27 9.37⁎ 11.68 6.57⁎ 6.22⁎ 7.72 9.88 6.01 7.29⁎ 6.65⁎
± ± ± ± ± ± ± ± ± ± ±
15.30 6.44 4.67 7.37 4.43 3.22 4.12 6.06 2.21 3.35 3.72
± ± ± ± ± ± ± ± ± ± ±
14.92 9.68 11.92 3.75 10.22 5.30⁎ 3.23 4.51⁎ 4.93⁎ 12.15 7.93
Values expressed as mean ± SD. Abbreviations: ΔDBPd, diastolic blood pressure decrement; ΔDBPr/s, diastolic blood pressure increment from minimal point till recovery/stabilization; ΔDBPov, diastolic blood pressure increment from recovery point till overshoot; DBPb, baseline diastolic blood pressure; DBPi, hypotenuse of diastolic blood pressure increment from minimal point to recovery/stabilization; ΔSBPd, systolic blood pressure decrement; ΔSBPr/s, systolic blood pressure increment from minimal point till recovery/ stabilization; ΔSBPov, systolic blood pressure increment from minimal point till overshoot; POTS, postural orthostatic tachycardia syndrome; SBPb, baseline systolic blood pressure; SBPi, systolic blood pressure increment calculated as a hypotenuse from the end point of SBP decrement to start time of its recovery/stabilization; trec-ov, time interval between recovery of systolic blood pressure and its overshoot; and IST, inappropriate sinus tachycardia. ⁎ Significantly different than IST (p b 0.05).
contributing to the tachycardia exhibited in IST patients (Table 6). The significantly higher and more rapid diastolic BP overshoot in IST at the end of HUT may reflect this relative increase in sympathetic activity that drives non-positional heart rate (Table 5). 4.3. Mechanisms contributing to higher heart rate increments in POTS The vagal (parasympathetic) component of the VM revealed a significant difference in POTS patients compared to IST patients. Previous research has reported that impaired vagal baroreflex function in patients with cardiovascular disease leads to poorer clinical outcomes (e.g. malignant arrhythmia and death). However, impaired vagal baroreflex function in POTS patients does not result in poorer clinical outcomes (Kimpinski et al., 2012; Thieben et al., 2007). The role a modest increase in BRSv plays in the pathophysiology of POTS is speculative and it should be noted that baroreflex function has been argued to be either non-contributory or reduced in POTS (Masuki et al., 2007; Mustafa et al., 2012). Furthermore these studies compare POTS to control subjects, which in our study did not show a significant difference. The ability to differentiate between POTS and IST with respect to BRS function remains to be elucidated. This includes the interactions between vagal and adrenergic components of the baroreflex. Furthermore, positional changes may be more important and HRV and BP in the upright position are not necessarily assessed by non-invasive measures of BRS in supine position (see below). In HUT, BP changes were significantly reduced In POTS patients compared to IST patients. Thus, this likely represents diminished BP
Fig. 1. Head-up tilt dependent changes (HUT minus supine position) in LF and HF power were significantly greater in POTS (n = 12, *p = 0.01) but not in control (n = 20) and in IST patients (n = 7). ΔHF, changes of high frequency band; ΔLF, changes of low frequency band; POTS, postural orthostatic tachycardia syndrome; and IST, inappropriate sinus tachycardia.
variability in POTS patients during transient periods of reduced BP. Moreover, this reduction in BP variability may create an increased compensatory heart rate response in POTS patients in the upright position that further exacerbates postural tachycardia. These mechanisms could be sympathetically mediated and along with reduced HRV during HUT may drive postural heart rates as reflected by measures of sympathovagal balance (Table 6). 4.4. Study limitations The current manuscript has several issues complicating the analysis that need to be addressed. The first is the relatively small number of subjects included. Unfortunately, patient recruitment is limited due to the small number of IST patients available for recruitment. While our subject numbers reported in the current manuscript are small, they are consistent with subject numbers reported in other studies (Leon et al., 2005). Our study does not preclude small differences in autonomic dysfunction as measured by the autonomic reflex screen (ARS) that may be detected with larger sample sizes. However, there do not appear to be gross clinically relevant abnormalities on the ARS that differentiate POTS from IST. Secondly, several sub-types of POTS have been proposed (i.e. neuropathic and hyper-adrenergic POTS) and may be better distinguished from IST on the basis of the autonomic reflex screen (Jacob et al., 2000; Kanjwal et al., 2011). We sequentially collected our POTS patients in order to avoid bias and, based on clinical criteria, none met the diagnostic criteria for neuropathic POTS. We did not routinely collect postural catecholamine levels in this specific group of patients to further define the POTS subjects as being hyper-adrenergic. Future analysis of postural catecholamines in IST and POTS patients is a focus of ongoing studies in our laboratory. We continue to prospectively study both IST and POTS patients in our autonomic laboratory. The major focus of such studies is to determine ideal treatment of both conditions that includes patients with overlapping features of POTS and IST. While such patients were not represented in the current study, it is important to note that there were no
Table 6 Heart rate variability in study subjects. Baseline (supine)
FFT LF/HF AR LF/HF SDNN pNN50 RMSDD
Tilt
POTS (n = 12)
IST (n = 7)
Control (n = 20)
POTS (n = 12)
2.25 1.99 56.7 21.7 54.8
3.03 2.12 36.4 8.4 25.4
2.65 2.49 63.5 24.1 55.4
8.29 7.84 48.0 5.5 20.4
± ± ± ± ±
1.75 1.38 32.5 26.8 56.0
± ± ± ± ±
2.57 1.33 20.6 7.7 14.9
± ± ± ± ±
2.19 2.59 31.6 20.7 47.0
AR, autoregressive; FFT, fast Fourier transform; HF, high frequency; and LF, low frequency. ⁎ Significantly different (p b 0.05) within group (i.e. control, IST or POTS) from baseline compared to tilt. ⁎⁎ Significantly different (p b 0.05) from controls at tilt. ⁎⁎⁎ Significantly different (p b 0.05) from IST at tilt.
± ± ± ± ±
6.38⁎ 5.24⁎ 23.1⁎⁎⁎ 9.4⁎,⁎⁎ 17.9⁎,⁎⁎
IST (n = 7)
Control (n = 20)
6.77 4.49 30.1 3.0 18.6
4.41 3.65 64.6 12.9 36.4
± ± ± ± ±
6.68 4.50 18.8⁎⁎ 4.7 10.9⁎⁎
± ± ± ± ±
3.50⁎ 2.89 17.7 17.6⁎ 22.7⁎
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specific abnormalities defining each group that would alter clinical treatment or prognosis. More specific and tailored measures of autonomic function may provide greater information on the underlying pathophysiology of both conditions. This is especially important in IST and IST/POTS overlap patients where there is little published data in comparison to POTS. Additional large systematic studies are also needed to better deal with the issues of treatment and prognostication in IST and POTS and in those patients co-expressing both disorders (Kimpinski et al., 2012). 5. Conclusions Changes in cardiac autonomic function contribute to changes in positional and non-positional heart rate in postural tachycardia syndrome versus inappropriate sinus tachycardia. These findings contribute to a further understanding of the autonomic dysfunction underlying POTS and IST. Acknowledgment This work was supported by unrestricted grant funds from the Department of Clinical Neurological Sciences Internal Research Fund. References Antiel, R.M., Risma, J.M., Grothe, R.M., Brands, C.K., Fischer, P.R., 2008. Orthostatic intolerance and gastrointestinal motility in adolescents with nausea and abdominal pain. J. Pediatr. Gastroenterol. Nutr. 46, 285–288. Benezet-Mazuecos, J., Rubio, J.M., Farre, J., Quinones, M.A., Sanchez-Borque, P., Macia, E., 2013. Long-term outcomes of ivabradine in inappropriate sinus tachycardia patients: appropriate efficacy or inappropriate patients. Pacing Clin. Electrophysiol. 36, 830–836. Brady, P.A., Low, P.A., Shen, W.K., 2005. Inappropriate sinus tachycardia, postural orthostatic tachycardia syndrome, and overlapping syndromes. Pacing Clin. Electrophysiol. 28, 1112–1121. Cappato, R., Castelvecchio, S., Ricci, C., Bianco, E., Vitali-Serdoz, L., Gnecchi-Ruscone, T., Pittalis, M., De Ambroggi, L., Baruscotti, M., Gaeta, M., Furlanello, F., Di Francesco, D., Lupo, P.P., 2012. Clinical efficacy of ivabradine in patients with inappropriate sinus tachycardia: a prospective, randomized, placebo-controlled, double-blind, crossover evaluation. J. Am. Coll. Cardiol. 60, 1323–1329. Huang, C.C., Sandroni, P., Sletten, D.M., Weigand, S.D., Low, P.A., 2007. Effect of age on adrenergic and vagal baroreflex sensitivity in normal subjects. Muscle Nerve 36, 637–642. Ives, C.T., Kimpinski, K., 2013. Higher postural heart rate increments on head-up tilt correlate with younger age but not orthostatic symptoms. J. Appl. Physiol. 115, 525–528. Ives, C.T., Berger, M.J., Kimpinski, K., 2013. The autonomic reflex screen in healthy participants from Southwestern Ontario. Can. J. Neurol. Sci. 40, 848–853. Jacob, G., Costa, F., Shannon, J.R., Robertson, R.M., Wathen, M., Stein, M., Biaggioni, I., Ertl, A., Black, B., Robertson, D., 2000. The neuropathic postural tachycardia syndrome. N. Engl. J. Med. 343, 1008–1014. Johnson, J.N., Mack, K.J., Kuntz, N.L., Brands, C.K., Porter, C.J., Fischer, P.R., 2010. Postural orthostatic tachycardia syndrome: a clinical review. Pediatr. Neurol. 42, 77–85. Kanjwal, M.Y., Kosinski, D.J., Grubb, B.P., 2003. Treatment of postural orthostatic tachycardia syndrome and inappropriate sinus tachycardia. Curr. Cardiol. Rep. 5, 402–406. Kanjwal, K., Saeed, B., Karabin, B., Kanjwal, Y., Grubb, B.P., 2011. Clinical presentation and management of patients with hyperadrenergic postural orthostatic tachycardia syndrome. A single center experience. Cardiol. J. 18, 527–531.
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