Download Reduced stroke volume during exercise in postural tachycardia

J Appl Physiol 103: 1128–1135, 2007.
First published July 12, 2007; doi:10.1152/japplphysiol.00175.2007.
Reduced stroke volume during exercise in postural tachycardia syndrome
Shizue Masuki,1,3 John H. Eisenach,1 William G. Schrage,1 Christopher P. Johnson,1 Niki M. Dietz,1
Brad W. Wilkins,1 Paola Sandroni,2 Phillip A. Low,2 and Michael J. Joyner1
Departments of 1Anesthesiology and 2Neurology, Mayo Clinic and Foundation, Rochester, Minnesota; and 3Department
of Sports Medical Sciences, Shinshu University Graduate School of Medicine, Matsumoto, Japan
Submitted 11 February 2007; accepted in final form 5 July 2007
cardiac output; blood pressure; deconditioning; orthostatic intolerance
of blood flow to active muscles is absent, as in autonomic
failure, arterial pressure falls with exercise due to excessive
muscle vasodilation (20, 29). Because sympathetic denervation, especially in the legs, is reported in some POTS patients
(12), this might cause exaggerated skeletal vasodilation and
make it difficult to regulate arterial pressure during exercise
and lead to exercise intolerance in POTS.
On the other hand, stroke volume (SV) is a key variable that
affects physical fitness and maximal aerobic capacity (3, 26).
Endurance exercise training increases SV, whereas detraining
or deconditioning reduces SV (5, 17, 26). Bed rest studies have
demonstrated a marked reduction in SV and a greater elevation
in HR during submaximal exercise after bed rest and that the
reduction in SV was responsible for a fall in maximal oxygen
consumption (26). Based on these results, it is possible that
reduced SV due to secondary deconditioning may play an
important role in the exercise intolerance reported by patients
with POTS.
In this study, we hypothesized that SV in the patients is
reduced during exercise compared with controls while the level
of arterial pressure is relatively well maintained by greater
increases in HR. We also tested the alternative hypothesis that
arterial pressure in the patients falls with exercise due to
excessive peripheral vasodilation. To examine these hypotheses, we directly measured arterial pressure, HR, and cardiac
output (CO) during exercise in POTS patients and healthy
control subjects, and we also determined SV and total peripheral resistance (TPR). Moreover, to assess the possibility of
exaggerated venous pooling and inadequate cardiac venous
return (31–34) during exercise, we included both upright and
supine exercise, because supine exercise provides a condition
facilitating venous return by minimizing peripheral pooling of
blood.
(POTS) is a clinical syndrome of orthostatic intolerance characterized by excessive
increases in heart rate (HR) during orthostatic stress in the
absence of orthostatic hypotension. Patients with POTS often
complain of chronic fatigue, exercise intolerance, and lightheadedness (19, 27). Mostly young, previously healthy women,
these patients are often unable to continue with their work or
education (27). Thus POTS can be quite debilitating with
significant limitations to activities of daily living and to even
low-intensity exercise (1, 18). However, to our knowledge,
there have been no studies evaluating how POTS affects
cardiovascular regulation during exercise.
During exercise, muscle blood flow increases markedly,
whereas sympathetic vasoconstriction is blunted but not eliminated, in the active muscles of healthy humans so that arterial
pressure is maintained (7, 37). When this sympathetic restraint
The studies were approved by the Institutional Review Board of the
Mayo Clinic, and each participant gave prospective written informed
consent. Thirteen POTS patients (29 ⫾ 2 yr; 11 women, 2 men;
weight, 68 ⫾ 2 kg; height, 171 ⫾ 2 cm; body mass index, 23 ⫾ 1
kg/m2) participated in this study. For comparison, we matched 10
healthy normal community-dwelling control subjects (32 ⫾ 3 yr; 8
women, 2 men: weight, 66 ⫾ 2 kg; height, 167 ⫾ 2 cm; body mass
index, 23 ⫾ 1 kg/m2). All subjects were Caucasian American, nonsmokers, and normotensive. All women had a negative serum pregnancy test the day before the study. They were also studied during
Address for reprint requests and other correspondence: M. J. Joyner, Dept.
of Anesthesiology, Mayo Clinic College of Medicine, 200 First St. SW,
Rochester, MN 55905 (e-mail: [email protected]).
The costs of publication of this article were defrayed in part by the payment
of page charges. The article must therefore be hereby marked “advertisement”
in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
POSTURAL TACHYCARDIA SYNDROME
1128
METHODS
Subjects
8750-7587/07 $8.00 Copyright © 2007 the American Physiological Society
http://www. jap.org
Downloaded from http://jap.physiology.org/ by 10.220.33.6 on May 2, 2017
Masuki S, Eisenach JH, Schrage WG, Johnson CP, Dietz
NM, Wilkins BW, Sandroni P, Low PA, Joyner MJ. Reduced
stroke volume during exercise in postural tachycardia syndrome.
J Appl Physiol 103: 1128–1135, 2007. First published July 12,
2007; doi:10.1152/japplphysiol.00175.2007.—Postural tachycardia
syndrome (POTS) is characterized by excessive tachycardia without
hypotension during orthostasis. Most POTS patients also report exercise intolerance. To assess cardiovascular regulation during exercise
in POTS, patients (n ⫽ 13) and healthy controls (n ⫽ 10) performed
graded cycle exercise at 25, 50, and 75 W in both supine and upright
positions while arterial pressure (arterial catheter), heart rate (HR;
measured by ECG), and cardiac output (open-circuit acetylene breathing) were measured. In both positions, mean arterial pressure, cardiac
output, and total peripheral resistance at rest and during exercise were
similar in patients and controls (P ⬎ 0.05). However, supine stroke
volume (SV) tended to be lower in the patients than controls at rest
(99 ⫾ 5 vs. 110 ⫾ 9 ml) and during 75-W exercise (97 ⫾ 5 vs. 111 ⫾
7 ml) (P ⫽ 0.07), and HR was higher in the patients than controls at
rest (76 ⫾ 3 vs. 62 ⫾ 4 beats/min) and during 75-W exercise (127 ⫾
3 vs. 114 ⫾ 5 beats/min) (both P ⬍ 0.01). Upright SV was significantly lower in the patients than controls at rest (57 ⫾ 3 vs. 81 ⫾ 6
ml) and during 75-W exercise (70 ⫾ 4 vs. 94 ⫾ 6 ml) (both P ⬍ 0.01),
and HR was much higher in the patients than controls at rest (103 ⫾
3 vs. 81 ⫾ 4 beats/min) and during 75-W exercise (164 ⫾ 3 vs. 131 ⫾
7 beats/min) (both P ⬍ 0.001). The change (upright ⫺ supine) in SV
was inversely correlated with the change in HR for all participants at
rest (R2 ⫽ 0.32), at 25 W (R2 ⫽ 0.49), 50 W (R2 ⫽ 0.60), and 75 W
(R2 ⫽ 0.32) (P ⬍ 0.01). These results suggest that greater elevation in
HR in POTS patients during exercise, especially while upright, was
secondary to reduced SV and associated with exercise intolerance.
REDUCED STROKE VOLUME DURING EXERCISE IN POTS
Measurements
Arterial catheterization. Under aseptic conditions, a 5-cm 20-gauge
catheter was inserted into the radial artery of the nondominant arm
under local anesthesia (1% lidocaine). Because one female control
subject and one female patient had a radial artery that was difficult to
catheterize, the catheter was inserted into the brachial artery of the
nondominant arm in these two participants. The arterial catheter was
connected to a pressure transducer for determination of arterial pressure and continuously flushed at 3 ml/h with heparinized saline (6).
While supine the arm was positioned at heart level, and while upright
the arm was also positioned at heart level using an arm holder. Arterial
blood samples were obtained at selective time points for measurement
of plasma catecholamines (norepinephrine, epinephrine, and dopamine). These samples were centrifuged and stored at ⫺70°C for later
measurement of plasma catecholamines via high-performance liquid
chromatography (29).
HR and CO. HR was monitored by using a three-lead electrocardiogram. CO (l/min) was estimated using an open-circuit acetylene
washin method (15). This method allows the noninvasive determination of CO and can be repeated every 4 – 6 min.
Forearm blood flow. To assess blood flow in a nonactive vascular
bed, brachial artery diameter and blood velocity of the nondominant
arm were measured with a 12-MHz linear-array Doppler probe (model
M12L, Vivid 7, General Electric, Milwaukee, WI) with a probe
insonation angle previously calibrated to 60°. Diameter measurements
corresponded to the QRS complex (end diastole) of the electrocardiogram. Forearm blood flow (FBF) was calculated as brachial blood
velocity multiplied by brachial artery cross-sectional area and expressed as milliliters per minute (7, 25, 30). Because one female and
one male control (but none of the POTS patients) had a brachial artery
that bifurcated into smaller arteries further upstream, we could not
determine FBF in these two controls. Therefore, the presented FBF
responses to exercise in controls represent the values in eight control
subjects.
and a forearm intravenous line was started. A standardized very light
meal was served at 10 AM, and in the afternoon the subjects participated in an orthostatic trial that has been previously published (21).
After the trial, subjects received a standardized light meal at 4 PM and
a standardized evening meal at 7 PM. After 10 PM, subjects fasted
and received overnight intravenous fluid hydration (saline, 125 ml/h
for 8 h) to ensure both adequate and comparable hydration in all the
subjects. The subjects received a standardized very light meal the next
day at 9 AM, and they were studied at 10 AM.
Venous blood samples were obtained at noon the day before the
study and at 7 AM the day of the study to determine hematocrit,
hemoglobin concentration, and plasma osmolality. The percent
change in plasma volume to overnight saline infusion was calculated
using hematocrit and hemoglobin concentration (11). Because we
were unable to obtain venous blood samples from one female POTS
patient, the data reported represent the values in 12 POTS patients.
After arterial catheterization, the subjects rested for 30 min in
supine position. A stand test was then performed to assess the severity
of orthostatic tachycardia. After a 2-min supine baseline period, the
subjects stood for 2 min while HR and arterial pressure were monitored. A 2-min standing period was chosen to minimize the duration
of any orthostatic symptoms in the patients. After resumption of the
supine position and stabilization of vital signs, the subjects performed
a bout of exercise (see protocol, Fig. 1). No participants complained
of light-headedness or other orthostatic symptoms before the bout of
exercise. The bout included a 10-min supine resting period, and
incremental supine cycling exercise at 25, 50, and 75 W (⬃60
revolutions/min) for 7 min each, while HR, arterial pressure, and FBF
were continuously measured. CO was measured at 3.5 and 9.5 min of
rest and at 3.5 min of each workload. Arterial blood samples were
obtained at 5 min of rest and at ⬃4.2 min of each workload to assess
the effect of POTS on catecholamine responses to exercise. After
supine exercise, subjects rested while sitting on a chair for 70 min, and
they had a glass of water (150 ml) at 10 –15 min of the intermission.
Although drinking much more water (480 ml) can affect HR in POTS
patients (35), the amount we provided was small, and it has been
reported that it does not change plasma volume or plasma osmolality
(16). The bicycle exercise trial was then repeated while sitting upright
on the bicycle.
The protocols were designed to increase the chances that the
patients could complete part or all of the study; thus we did not
randomize for exercise posture because of the possibility that POTS
patients would exhibit orthostatic symptoms and fatigue during upright exercise and the study would have to be terminated. Consequently, all patients and controls completed the supine and upright
exercise trials in this study. The laboratory temperature was maintained at 19 –21°C during the study.
Protocol
All studies were performed in the General Clinical Research Center
(GCRC). All participants were advised to refrain from caffeine,
alcohol, and exercise at least 24 h before GCRC admission. They
reported to the GCRC between 8 and 9 AM the day before the study,
J Appl Physiol • VOL
Fig. 1. Experimental protocol. CO, cardiac output; HR, heart rate; AP, arterial
pressure. Subjects performed bicycle exercise in both supine and upright
positions. The upright trial followed supine trial after resting for 70 min.
103 • OCTOBER 2007 •
www.jap.org
Downloaded from http://jap.physiology.org/ by 10.220.33.6 on May 2, 2017
days 15–21 of the menstrual cycle (midluteal) or during the second
week of hormone pills in a standard cycle of oral contraceptives to
minimize variability in autonomic control of cardiovascular function
due to reproductive hormone status (9, 22).
The POTS patients were selected on the basis of a preexisting
tilt-test diagnosis, including 1) a sustained increase in HR of ⱖ30
beats/min or a sustained HR of ⱖ120 beats/min within 10 min of
initiation of the tilt; 2) absence of orthostatic hypotension defined as
a sustained drop in systolic arterial pressure (SAP) of ⱖ20 mmHg
and/or in diastolic arterial pressure (DAP) of ⱖ10 mmHg; and
3) presence of orthostatic symptoms, including light-headedness,
dizziness, nausea, head pressure, and dyspnea. All POTS patients
were sufficiently bothered by their orthostatic symptoms that they
sought medical treatment, but they were free of organ system dysfunction or systemic illness that could affect the study results. Medications that could affect autonomic function were withdrawn for at
least five half-lives before the study.
Control subjects were recruited from the local community and
selected based on the following criteria: 1) no history of systemic
diseases; 2) no history of neurological disorders, including syncope or
orthostatic intolerance; and 3) no history of taking medications that
are indicated for the aforementioned disorders and not taking medications except oral contraceptives. Data were collected as part of a
large series of studies (21, 21a), and more detailed criteria for
inclusion in the subjects were described in the preceding study (21).
1129
1130
REDUCED STROKE VOLUME DURING EXERCISE IN POTS
Analyses
Data were digitized at 600 Hz, stored on a computer, and analyzed
offline with signal processing software (Windaq, Dataq Instruments,
Akron, OH). HR was determined from the electrocardiogram signal.
SAP, DAP, and mean arterial pressure (MAP) were derived from the
arterial pressure waveform. Pulse pressure (PP) was calculated as
SAP ⫺ DAP. Forearm vascular conductance (FVC) was calculated as
(FBF/MAP) ⫻ 100, and expressed as milliliters per minute per 100
millimeters of Hg. Although we did not use forearm venous pressure
to calculate FVC, it has been reported that in either supine or upright
position, forearm venous pressure was not different in POTS patients
and healthy controls (32, 33). HR, arterial pressure, FBF, and FVC
reported represent an average of minutes 2–3 during resting or during
each workload. Resting CO represents an average of two measurements at rest. SV was calculated as CO/HR, and it was expressed as
milliliters. TPR was calculated as MAP/CO, and expressed as millimeters of Hg per liter per minute.
patients (P ⫽ 0.03), but it did not increase in the controls
(1.4 ⫾ 1.9%; P ⫽ 0.47).
Table 1 shows HR and arterial pressure responses to stand
test. At baseline, HR was significantly higher in the patients
than the controls (P ⫽ 0.001), but SAP, DAP, and MAP were
not different between the groups (P ⫽ 0.53– 0.92). The HR
response to standing was greater in the patients (P ⬍ 0.001),
but the SAP and MAP responses to standing were not different
between the groups (P ⫽ 0.24 – 0.32), whereas the DAP response was significantly greater in the patients (P ⫽ 0.0099).
HR and Arterial Pressure
Patient Characteristics and Stand Test
CO, SV, and TPR
There were no differences in age, height, body weight, or
body mass index between POTS patients and controls (P ⫽
0.17– 0.70). Overnight saline infusion produced a significant
decrease in hematocrit (38.1 ⫾ 0.9 vs. 37.4 ⫾ 0.9%; pre- vs.
postinfusion), hemoglobin concentration (13.2 ⫾ 0.3 vs.
13.0 ⫾ 0.3 g/dl; pre- vs. postinfusion), and plasma osmolality
(286 ⫾ 1 vs. 284 ⫾ 1 mosmol/kgH2O; pre- vs. postinfusion) in
the patients (P ⫽ 0.02– 0.04), but it did not change hematocrit
(37.2 ⫾ 0.9 vs. 36.9 ⫾ 0.8%; pre- vs. postinfusion), hemoglobin concentration (12.6 ⫾ 0.3 vs. 12.5 ⫾ 0.3 g/dl; pre- vs.
postinfusion), and osmolality (286 ⫾ 1 vs. 287 ⫾ 1 mosmol/
kgH2O; pre- vs. postinfusion) in the controls (P ⫽ 0.33– 0.56),
and there were no differences in these parameters between the
groups (P ⫽ 0.27– 0.58). Similarly, overnight saline infusion
significantly increased plasma volume by 3.1 ⫾ 1.2% in the
As shown in Fig. 3, supine and upright cycling produced a
significant increase in CO and SV, and decrease in TPR in the
patients and controls (P ⬍ 0.02), except for supine SV in either
group (P ⫽ 0.28 – 0.84).
CO at rest and the response to exercise were not different in
the patients and controls in either position (P ⫽ 0.38 – 0.88).
Similarly, TPR at rest and the response to exercise were not
different in the patients and controls in either position (P ⫽
0.07– 0.20).
Supine SV in the patients tended to be lower than the
controls at rest (99 ⫾ 5 vs. 110 ⫾ 9 ml) and during exercise
(highest workload, 97 ⫾ 5 vs. 111 ⫾ 7 ml) (P ⫽ 0.07). Upright
posture further decreased SV in the patients, and the SV in the
patients was significantly lower than the controls at rest (57 ⫾
3 vs. 81 ⫾ 6 ml; P ⫽ 0.003) and during exercise (highest
Statistics
Values are expressed as means ⫾ SE. Group differences in subject
characteristics were tested by a one-way ANOVA. Group differences
in the HR, arterial pressure, CO, SV, TPR, FVC, and catecholamine
responses to exercise, and HR and arterial pressure responses to
standing were tested by a two-way ANOVA for repeated measures.
The effects of overnight saline infusion on hematocrit, hemoglobin,
plasma osmolality, and plasma volume were tested by a two-way
ANOVA for repeated measures. Subsequent post hoc tests to determine significant differences in the various pairwise comparisons were
performed using Fisher’s least significant difference test. All P values
⬍0.05 were considered statistically significant.
Table 1. HR and arterial pressure responses to standing
Control (n ⫽ 10)
HR, beats/min
SAP, mmHg
DAP, mmHg
MAP, mmHg
POTS (n ⫽ 13)
Baseline
Standing
⌬
Baseline
Standing
⌬
62⫾3
134⫾4
68⫾2
91⫾3
74⫾4§
137⫾4
73⫾3‡
93⫾3
12⫾2
3⫾3
5⫾1
3⫾2
78⫾2*
134⫾2
67⫾1
89⫾1
111⫾2§
134⫾3
78⫾1§
94⫾2‡
33⫾3†
⫺1⫾2
11⫾2*
6⫾2
Values are means ⫾ SE; n, no. of subjects. POTS, postural tachycardia syndrome; HR, heart rate; SAP, DAP, and MAP, systolic, diastolic, and mean arterial
pressure, respectively; ⌬, difference between baseline and standing. Significant differences from the controls: *P ⬍ 0.01 and †P ⬍ 0.001. Significant differences
from the values at baseline in each group. ‡P ⬍ 0.01 and §P ⬍ 0.001.
J Appl Physiol • VOL
103 • OCTOBER 2007 •
www.jap.org
Downloaded from http://jap.physiology.org/ by 10.220.33.6 on May 2, 2017
RESULTS
As shown in Fig. 2, supine and upright cycling produced a
significant increase in HR, MAP, and PP in the patients and
controls (P ⬍ 0.001).
While supine, HR in the patients was significantly higher
than the controls at rest (76 ⫾ 3 vs. 62 ⫾ 4 beats/min; P ⫽
0.004) and during exercise (highest workload, 127 ⫾ 3 vs.
114 ⫾ 5 beats/min; P ⫽ 0.006). Upright posture further
increased HR in the patients, and the HR in the patients was
much higher than the controls at rest (103 ⫾ 3 vs. 81 ⫾ 4
beats/min; P ⬍ 0.001) and during exercise (highest workload,
164 ⫾ 3 vs. 131 ⫾ 7 beats/min; P ⬍ 0.001), whereas the
change from rest to exercise was not different between the
groups in either position (P ⫽ 0.12– 0.99).
SAP, MAP, and DAP at rest and the responses to exercise
were not different in the patients and controls in either position
(P ⫽ 0.13– 0.86). Similarly, PP at rest and the response to
exercise were not different in the patients and controls in either
position (P ⫽ 0.19 – 0.83).
REDUCED STROKE VOLUME DURING EXERCISE IN POTS
1131
workload, 70 ⫾ 4 vs. 94 ⫾ 6 ml; P ⫽ 0.003), whereas the
change from rest to exercise was not different between the
groups in either position (P ⫽ 0.45– 0.96).
To assess whether decrease in SV with a change from supine
to upright position is associated with increase in HR, delta SV
(upright ⫺ supine) was plotted against delta HR (upright ⫺
supine) at rest and at 25-, 50-, or 75-W exercise in all the
subjects. Consequently, the delta SV was inversely and significantly correlated with the delta HR at rest (R2 ⫽ 0.32, P ⫽
0.005), 25-W (R2 ⫽ 0.49, P ⬍ 0.001), 50-W (R2 ⫽ 0.60, P ⬍
0.001), and 75-W exercise (R2 ⫽ 0.32, P ⫽ 0.005) (Fig. 4).
FVC
FVC at rest and response to exercise were similar between POTS patients and controls. While supine, FVC
(ml䡠 min⫺1 䡠100 mmHg⫺1) at rest was 67 ⫾ 5 ml䡠 min⫺1 䡠100
mmHg⫺1 in the patients and 57 ⫾ 9 ml 䡠min⫺1 䡠100 mmHg⫺1
in the controls (P ⫽ 0.42). During supine cycling at highest
workload, FVC increased to 116 ⫾ 13 ml䡠min⫺1 䡠100
mmHg⫺1 in the patients vs. 83 ⫾ 14 ml䡠 min⫺1 䡠100 mmHg⫺1
in the controls, with no significant difference in the values
J Appl Physiol • VOL
between the groups (P ⫽ 0.26). While upright, FVC at rest
was 55 ⫾ 4 ml 䡠 min⫺1 䡠 100 mmHg⫺1 in the patients and
44 ⫾ 6 ml 䡠 min⫺1 䡠 100 mmHg⫺1in the controls (P ⫽ 0.55).
During upright cycling at highest workload, FVC was 57 ⫾
5 ml 䡠 min⫺1 䡠 100 mmHg⫺1 in the patients vs. 58 ⫾ 9
ml 䡠 min⫺1 䡠 100 mmHg⫺1 in the controls, with no significant
difference in the values between the groups (P ⫽ 0.90).
Catecholamine Values
The catecholamine responses to cycling exercise are summarized in Table 2. Supine and upright cycling produced a
significant increase in norepinephrine and epinephrine in the
patients and controls (P ⬍ 0.003), whereas dopamine did not
increase (P ⫽ 0.17– 0.56) except for upright cycling for the
patients (P ⫽ 0.008). The norepinephrine was significantly
higher at higher workloads in the patients than the controls in
the upright position (P ⫽ 0.04), but it was not different in the
supine position (P ⫽ 0.33). Epinephrine and dopamine responses to exercise were similar between the groups in both
positions (P ⫽ 0.48 – 0.78).
103 • OCTOBER 2007 •
www.jap.org
Downloaded from http://jap.physiology.org/ by 10.220.33.6 on May 2, 2017
Fig. 2. HR, systolic arterial pressure (SAP), diastolic
arterial pressure (DAP), mean arterial pressure (MAP),
and pulse pressure (PP) responses to supine and upright
exercise. Mean and SE bars are presented for the 10
healthy controls (Cont) and 13 postural tachycardia
syndrome (POTS) patients. **Significant differences
between the 2 groups, P ⬍ 0.01. ***Significant differences between the 2 groups, P ⬍ 0.001.
1132
REDUCED STROKE VOLUME DURING EXERCISE IN POTS
Downloaded from http://jap.physiology.org/ by 10.220.33.6 on May 2, 2017
Fig. 3. CO, stroke volume (SV), and total peripheral
resistance (TPR) responses to supine and upright exercise. Values are means ⫾ SE for the 10 healthy controls
and 13 POTS patients. **Significant differences between the 2 groups, P ⬍ 0.01.
DISCUSSION
To our knowledge, this is the first study that has evaluated
the cardiovascular responses to exercise in POTS patients. The
major findings in the present study are as follows. 1) In either
the supine or upright position, arterial pressure, CO, TPR, and
FVC at rest and the responses to exercise were not different
in the patients and controls. 2) At rest and during exercise, SV
in the patients tended to be lower than controls in supine
position, and it was significantly lower than controls in upright
position. 3) Coincident with the smaller SV, the patients had
higher HR than controls, especially in upright position. Thus
our results suggest that greater elevation in HR during exercise
in POTS is related to a reduced SV rather than to an excessive
vasodilation in the exercising muscles.
Reduced SV in POTS
Reduced SV during exercise in POTS patients may be
caused by deconditioning. Saltin et al. (26) reported that in
J Appl Physiol • VOL
healthy young men, a 20-day period of bed rest reduced SV
during submaximal exercise by 20% in the supine position and
by 30% in the upright position and that the reduction in SV was
entirely responsible for a fall in maximal oxygen consumption.
They also mentioned that a decrease in plasma volume after
bed rest (8%) cannot fully account for the reduction in SV. In
this study, we performed overnight saline infusion (vs. overt
volume loading) to eliminate the potential effect of acute
hypovolemia, because hypovolemia and chronic “underhydration” has been reported in some POTS patients (8, 25). We
confirmed that the infusion decreased hematocrit, hemoglobin
concentration, and plasma osmolality, and increased plasma
volume, in the patients, whereas it did not change these
parameters in the controls. Nevertheless, SV in the POTS
patients tended to be lower than controls in supine position at
rest and during exercise, and it was much lower compared with
the controls in upright position. Thus, although SV can be
reduced after hypovolemia, factors other than acute hypovolemia may also contribute to the reduced SV in POTS.
103 • OCTOBER 2007 •
www.jap.org
1133
REDUCED STROKE VOLUME DURING EXERCISE IN POTS
Fig. 4. Relationship between delta SV (upright ⫺ supine) vs. delta HR
(upright ⫺ supine) at rest and at 50-W exercise in the 10 healthy controls and
13 POTS patients. Decrease in SV was correlated with increased in HR at rest
(P ⬍ 0.01) and at 50-W exercise (P ⬍ 0.001).
Recently, Fu et al. (10) reported that left ventricular mass
was much smaller in female POTS patients than in healthy
women. A smaller (and therefore, less “distensible”) heart
would result in a steeper Frank-Starling relationship, leading to
an excessive reduction in SV during orthostasis (10, 17), which
might contribute to a much lower SV during upright exercise in
the POTS patients in the present study. Along these lines,
POTS patients often become significantly disabled, during
even simple activities such as eating, showering, or lowintensity exercise (19). To cope with these symptoms, patients
often reduce their standing time and activity level (2). Perhaps
this behavioral pattern then leads to a cycle of inactivity and
secondary deconditioning that induces cardiac atrophy (23).
Taken together, these results suggest that secondary deconditioning and cardiac atrophy may be a major contributing factor to the
reduced SV in POTS patients.
Higher HR in POTS
We observed higher HR in the POTS patients during exercise, especially in the upright position, which may be a compensatory response to reduced SV to maintain CO. In the
classic study comparing nonathletes vs. athletes, CO for a
given workload is similar but HR is higher in nonathletes than
athletes due to a smaller SV (4). Similarly, after bed rest CO
for a given workload is slightly lower but relatively maintained
in most of the subjects, whereas HR is higher after bed rest
than before due to a smaller SV (26). In this study, HR was
higher and SV was lower in the POTS patients than controls
during exercise (Figs. 2 and 3). Moreover, as shown in Fig. 4,
the decrease in SV was inversely correlated with the increase
in HR, suggesting that HR is increased more when SV is
reduced. Consequently, CO in the patients was well maintained
in the same level as the control subjects (Fig. 3). On the other
hand, HR in the patients would reach a maximal level at a
lower workload. Therefore, if exercise had been maximal, we
would almost certainly have seen dramatically reduced maximal CO in the patients due to a lower SV. Thus the higher HR
in POTS patients may serve as a compensatory response to
Table 2. Catecholamine response to exercise
Control (n ⫽ 10)
Rest
25 W
50 W
POTS (n ⫽ 13)
75 W
Rest
25 W
50 W
75 W
195⫾24
44⫾13
12⫾2
286⫾43§
56⫾17†
15⫾2
292⫾40§
60⫾14‡
13⫾3
358⫾55§
66⫾17§
14⫾4
363⫾31
60⫾13
13⫾2
522⫾49
69⫾16
14⫾3
742⫾81*§
91⫾17†
21⫾7
1227⫾166*§
143⫾25§
38⫾13‡
Supine
Norepinephrine, pg/ml
Epinephrine, pg/ml
Dopamine, pg/ml
179⫾21
35⫾6
14⫾2
215⫾27
39⫾6
11⫾1
237⫾29‡
49⫾9†
17⫾6
Norepinephrine, pg/ml
Epinephrine, pg/ml
Dopamine, pg/ml
301⫾32
60⫾9
13⫾3
372⫾38
58⫾8
14⫾2
479⫾53‡
80⫾11
17⫾4
296⫾44§
58⫾8§
16⫾4
Upright
818⫾114§
141⫾21§
19⫾4
Values are means ⫾ SE; n, no. of subjects. *Significant differences from the controls, P ⬍ 0.05. Significant differences from the values at rest in each group:
†P ⬍ 0.05, ‡P ⬍ 0.01, and §P ⬍ 0.001.
J Appl Physiol • VOL
103 • OCTOBER 2007 •
www.jap.org
Downloaded from http://jap.physiology.org/ by 10.220.33.6 on May 2, 2017
Another possible factor contributing to the reduced SV in
POTS is exaggerated venous pooling. Streeten et al. (34)
reported that patients with orthostatic tachycardia had excessive venous pooling in the leg while standing. Stewart et al.
(32, 33) reported in POTS patients that calf blood volume
increased twice as much and thoracic blood volume decreased
markedly compared with controls during head-up tilt, and this
indicated that POTS is related to inadequate cardiac venous
return during orthostasis. However, to date, no studies have
evaluated venous return during exercise in POTS. In the
present study, we included supine exercise to provide a condition facilitating venous return by minimizing peripheral pooling of blood. However, we observed reduced SV in POTS
patients during supine as well as upright exercise. Thus, although increased venous pooling may partially explain the
marked reduction in SV during the upright posture, because
CO during exercise was the same in the patients and controls
in both positions, venous return during exercise was also likely
similar. Therefore, other factors such as the reduced cardiac size
reported by Fu and colleagues (10) that would lead to reduced SV
during exercise should also be considered as major explanations
for the reduced SV in the POTS patients.
1134
REDUCED STROKE VOLUME DURING EXERCISE IN POTS
Experimental Considerations
There are five main experimental considerations that deserve
additional discussion. First, we performed overnight saline
infusion, which might have altered the native physiology in
POTS patients. It has been reported that acute volume loading
greatly blunts orthostatic tachycardia in POTS (13). However,
our goal was to ensure a normovolemic state, without overt
volume loading. Indeed, the increase in plasma volume after
overnight saline infusion was only 3%, which is equivalent to
⬃70 ml based on the plasma volume reported in the previous
study of POTS (24). Also, excessive tachycardia during standing was seen in the patients after overnight saline infusion.
Thus the effect of overnight saline infusion on the response to
exercise in the POTS patients was likely minor in this study.
Second, we did not randomize the order of the supine and
upright exercise trials because of concerns about excessive
fatigue and orthostatic symptoms in the patients. However, the
results in the patients were compared with controls subjects
who underwent the same protocol. Unexpectedly, the patients
J Appl Physiol • VOL
were not exhausted by the supine exercise, likely because the
exercise workloads we used were relatively low. Therefore, we
believe it is unlikely that the order affected the main outcomes of
the study. Additionally, participating in an orthostatic trial prior to
the present investigation might have exacerbated the symptoms in
POTS (19). However, no patients complained of severe symptoms
compared with their daily lives before the present investigation.
Third, we used the term “upright” as “sitting upright on the
bicycle,” but this may be a little different from standing or
head-up tilt. For example, norepinephrine at rest in upright
position tended to be higher in our patients than controls but
this was nonsignificant, whereas high systemic norepinephrine
concentrations have been reported during standing in POTS patients (12, 14, 28). This is likely because the level of orthostatic
stress is lower during sitting upright on the bicycle (in this study)
than during standing for POTS patients. Probably for the same
reason, CO at rest in upright position was not different in our
patients and controls, whereas inadequate venous return has been
reported during head-up tilt in POTS patients (31, 32).
Fourth, we did not directly measure blood flow to the muscle
or other nonexercising organs except forearm. Because partial
sympathetic denervation in the legs (12) and splanchnic hyperemia (31, 36) are reported in some POTS patients, further
studies are needed to assess how redistribution of blood flow
occurs during exercise in these patients so that TPR and arterial
pressure are maintained similar to controls.
Fifth, we did not measure cardiac volume in this study.
However, based on the SV responses we observed, the study of
Fu et al. (10), and classic ideas about cardiac size and exercise
tolerance (4, 23, 26), it seems reasonable to suggest that
“cardiac atrophy” is a major contributing factor to exercise
intolerance in POTS.
Perspectives
How can we apply the implications of the present findings to
physiological strategies in POTS? Saltin et al. (26) reported
that physical training after bed rest dramatically increased SV,
CO, and oxygen uptake at maximal exercise compared with
those values after bed rest, whereas there was no change in
maximal HR. This suggests that graded physical training may
have beneficial effects in POTS.
In summary, the results from the present investigation demonstrate that in both supine and upright positions, arterial
pressure, CO, TPR, and FVC responses to exercise were
similar in the POTS patients and controls, and that to maintain
CO during exercise, HR in the patients was elevated with
reduced SV. Furthermore, the inverse relationship between HR
and SV suggests that greater elevation in HR may serve as a
compensatory adaptation to reduced SV in POTS.
ACKNOWLEDGMENTS
We thank Ruth Kraft, Karen Krucker, Shelly Roberts, Branton Walker,
Lynn Sokolnicki, and Jessica Abenstein for excellent technical assistance and
the subjects who participated in this study.
GRANTS
This research was supported by National Institutes of Health (NIH) Grant
NS-32352 (to M. J. Joyner), National Center for Research Resources Grant
K23-17520 (to J. H. Eisenach), NIH General Clinical Research Center Grant RR00585 (to the Mayo Clinic, Rochester, MN), and the Uehara Memorial
Foundation (to S. Masuki).
103 • OCTOBER 2007 •
www.jap.org
Downloaded from http://jap.physiology.org/ by 10.220.33.6 on May 2, 2017
reduced SV that maintains CO during submaximal exercise in
the patients. This interpretation is consistent with our laboratory’s recent observations (in the same groups of subjects) that
the exaggerated HR response to orthostatic stress is a physiological response to venous pooling in the POTS patients and
not of psychogenic origin (21).
Another possible explanation for the increased levels of HR
in the patients is a reflex response to the excessive vasodilation
in exercising muscles. When sympathetic restraint of blood
flow to active muscles is absent, in autonomic failure, blood
pressure falls by ⬃40 mmHg with exercise even in supine
position (20, 29). However, as shown in Figs. 2 and 3, the TPR
and MAP responses to exercise were not different in the POTS
patients and controls in either position, indicating that sympathetic restraint of muscle blood flow is well preserved in POTS.
In addition, FVC (in nonexercising forearm) responses to
exercise were not different in the POTS patients and controls in
either position. Taken together, these results suggest that the
increased levels of HR in the patients are not a response to
excessive vasodilation in peripheral vessels during exercise,
but may be a compensatory response to reduced SV.
Norepinephrine concentrations were higher at higher workloads in the patients than the controls in the upright position,
whereas they were similar between the groups in supine position (Table 2). Although the mechanisms responsible for the
higher norepinephrine concentrations are not clear, it might be
partially explained as a characteristic of POTS. POTS patients
frequently have high systemic plasma norepinephrine concentrations during orthostasis compared with healthy controls (12,
14, 28). Jacob et al. (14) reported that the decrease in norepinephrine clearance during standing was greater in patients than
control subjects, although the increase in norepinephrine spillover was similar in patients and control subjects, indicating
that much of the increase in plasma norepinephrine was due to
a decrease in clearance. By contrast, the higher norepinephrine
during upright exercise might be simply explained by higher
relative exercise intensity in the patients than the controls with an
associated greater level of sympathetic activation. However, we
observed the higher norepinephrine during upright but not supine
exercise, suggesting that the increase had a postural component.
REDUCED STROKE VOLUME DURING EXERCISE IN POTS
REFERENCES
J Appl Physiol • VOL
20. Marshall RJ, Schirger A, Shepherd JT. Blood pressure during supine
exercise in idiopathic orthostatic hypotension. Circulation 24: 76 – 81, 1961.
21. Masuki S, Eisenach JH, Johnson CP, Dietz NM, Benrud-Larson LM,
Schrage WG, Curry TB, Sandroni P, Low PA, Joyner MJ. Excessive
heart rate response to orthostatic stress in postural tachycardia syndrome
is not caused by anxiety. J Appl Physiol 102: 896 –903, 2007.
21a.Masuki S, Eisenach JH, Schrage WG, Dietz NM, Johnson CP, Wilkins
BW, Dierkhising RA, Sandroni P, Low PA, Joyner MJ. Arterial baroreflex
control of heart rate during exercise in postural tachycardia syndrome. J Appl
Physiol. doi: 10.1152/japplphysiol.00176.2007.
22. Minson CT, Halliwill JR, Young TM, Joyner MJ. Influence of the
menstrual cycle on sympathetic activity, baroreflex sensitivity, and vascular transduction in young women. Circulation 101: 862– 868, 2000.
23. Perhonen MA, Franco F, Lane LD, Buckey JC, Blomqvist CG,
Zerwekh JE, Peshock RM, Weatherall PT, Levine BD. Cardiac atrophy
after bed rest and spaceflight. J Appl Physiol 91: 645– 653, 2001.
24. Raj SR, Biaggioni I, Yamhure PC, Black BK, Paranjape SY, Byrne
DW, Robertson D. Renin-aldosterone paradox and perturbed blood volume regulation underlying postural tachycardia syndrome. Circulation
111: 1574 –1582, 2005.
25. Rosenmeier JB, Dinenno FA, Fritzlar SJ, Joyner MJ. Alpha1- and
alpha2-adrenergic vasoconstriction is blunted in contracting human
muscle. J Physiol 547: 971–976, 2003.
26. Saltin B, Blomqvist G, Mitchell JH, Johnson RL Jr, Wildenthal K,
Chapman CB. Response to exercise after bed rest and after training.
Circulation 38: VII1–78, 1968.
27. Sandroni P, Opfer-Gehrking TL, McPhee BR, Low PA. Postural
tachycardia syndrome: clinical features and follow-up study. Mayo Clin
Proc 74: 1106 –1110, 1999.
28. Schondorf R, Low PA. Idiopathic postural orthostatic tachycardia syndrome: an attenuated form of acute pandysautonomia? Neurology 43:
132–137, 1993.
29. Schrage WG, Eisenach JH, Dinenno FA, Roberts SK, Johnson CP,
Sandroni P, Low PA, Joyner MJ. Effects of midodrine on exerciseinduced hypotension and blood pressure recovery in autonomic failure.
J Appl Physiol 97: 1978 –1984, 2004.
30. Schrage WG, Joyner MJ, Dinenno FA. Local inhibition of nitric oxide
and prostaglandins independently reduces forearm exercise hyperaemia in
humans. J Physiol 557: 599 – 611, 2004.
31. Stewart JM, Medow MS, Glover JL, Montgomery LD. Persistent
splanchnic hyperemia during upright tilt in postural tachycardia syndrome.
Am J Physiol Heart Circ Physiol 290: H665–H673, 2006.
32. Stewart JM, Montgomery LD. Regional blood volume and peripheral
blood flow in postural tachycardia syndrome. Am J Physiol Heart Circ
Physiol 287: H1319 –H1327, 2004.
33. Stewart JM, Weldon A. Vascular perturbations in the chronic orthostatic
intolerance of the postural orthostatic tachycardia syndrome. J Appl
Physiol 89: 1505–1512, 2000.
34. Streeten DH, Anderson GH Jr, Richardson R, Thomas FD. Abnormal
orthostatic changes in blood pressure and heart rate in subjects with intact
sympathetic nervous function: evidence for excessive venous pooling.
J Lab Clin Med 111: 326 –335, 1988.
35. Taneja I, Raj SR, Harris P, Byrne D, Jordan J, Robertson D.
Autonomic effect of water ingestion in Postural Tachycardia Syndrome
(Abstract). FASEB J 21: A512, 2007.
36. Tani H, Singer W, McPhee BR, Opfer-Gehrking TL, Haruma K,
Kajiyama G, Low PA. Splanchnic-mesenteric capacitance bed in the postural tachycardia syndrome (POTS). Auton Neurosci 86: 107–113, 2000.
37. Tschakovsky ME, Sujirattanawimol K, Ruble SB, Valic Z, Joyner MJ.
Is sympathetic neural vasoconstriction blunted in the vascular bed of
exercising human muscle? J Physiol 541: 623– 635, 2002.
103 • OCTOBER 2007 •
www.jap.org
Downloaded from http://jap.physiology.org/ by 10.220.33.6 on May 2, 2017
1. Ali YS, Daamen N, Jacob G, Jordan J, Shannon JR, Biaggioni I,
Robertson D. Orthostatic intolerance: a disorder of young women. Obstet
Gynecol Surv 55: 251–259, 2000.
2. Benrud-Larson LM, Sandroni P, Haythornthwaite JA, Rummans TA,
Low PA. Correlates of functional disability in patients with postural
tachycardia syndrome: preliminary cross-sectional findings. Health
Psychol 22: 643– 648, 2003.
3. Bevegard BS, Shepherd JT. Regulation of the circulation during exercise
in man. Physiol Rev 47: 178 –213, 1967.
4. Bevegard S. Studies on the regulation of the circulation in man. With
special reference to the stroke volume and the effect of muscular work,
body position and artificially induced variations of the heart rate. Acta
Physiol Scand Suppl 57: 1–36, 1962.
5. Coyle EF, Martin WH 3rd, Sinacore DR, Joyner MJ, Hagberg JM,
Holloszy JO. Time course of loss of adaptations after stopping prolonged
intense endurance training. J Appl Physiol 57: 1857–1864, 1984.
6. Dietz NM, Rivera JM, Eggener SE, Fix RT, Warner DO, Joyner MJ.
Nitric oxide contributes to the rise in forearm blood flow during mental
stress in humans. J Physiol 480: 361–368, 1994.
7. Dinenno FA, Joyner MJ. Blunted sympathetic vasoconstriction in contracting skeletal muscle of healthy humans: is nitric oxide obligatory?
J Physiol 553: 281–292, 2003.
8. Fouad FM, Tadena-Thome L, Bravo EL, Tarazi RC. Idiopathic hypovolemia. Ann Intern Med 104: 298 –303, 1986.
9. Freedman RR, Girgis R. Effects of menstrual cycle and race on peripheral
vascular alpha-adrenergic responsiveness. Hypertension 35: 795–799, 2000.
10. Fu Q, Shook R, Shibata S, Okazaki K, Hastings J, Dorfman T, Conner
C, Palmer MD, Jacob G, Levine BD. Cardiac size: a potential mechanism for gender differences in orthostatic intolerance and POTS?
(Abstract). Clin Auton Res 16: 321, 2006.
11. Greenleaf JE, Convertino VA, Mangseth GR. Plasma volume during
stress in man: osmolality and red cell volume. J Appl Physiol 47:
1031–1038, 1979.
12. Jacob G, Costa F, Shannon JR, Robertson RM, Wathen M, Stein M,
Biaggioni I, Ertl A, Black B, Robertson D. The neuropathic postural
tachycardia syndrome. N Engl J Med 343: 1008 –1014, 2000.
13. Jacob G, Shannon JR, Black B, Biaggioni I, Mosqueda-Garcia R, Robertson RM, Robertson D. Effects of volume loading and pressor agents in
idiopathic orthostatic tachycardia. Circulation 96: 575–580, 1997.
14. Jacob G, Shannon JR, Costa F, Furlan R, Biaggioni I, MosquedaGarcia R, Robertson RM, Robertson D. Abnormal norepinephrine
clearance and adrenergic receptor sensitivity in idiopathic orthostatic
intolerance. Circulation 99: 1706 –1712, 1999.
15. Johnson BD, Beck KC, Proctor DN, Miller J, Dietz NM, Joyner MJ.
Cardiac output during exercise by the open circuit acetylene washin method:
comparison with direct Fick. J Appl Physiol 88: 1650 –1658, 2000.
16. Kamijo Y, Okumoto T, Takeno Y, Okazaki K, Inaki M, Masuki S,
Nose H. Transient cutaneous vasodilatation and hypotension after drinking in dehydrated and exercising men. J Physiol 568: 689 – 698, 2005.
17. Levine BD, Zuckerman JH, Pawelczyk JA. Cardiac atrophy after
bed-rest deconditioning: a nonneural mechanism for orthostatic intolerance. Circulation 96: 517–525, 1997.
18. Low PA, Opfer-Gehrking TL, Textor SC, Benarroch EE, Shen WK,
Schondorf R, Suarez GA, Rummans TA. Postural tachycardia syndrome
(POTS). Neurology 45: S19 –S25, 1995.
19. Low PA, Schondorf R, Novak V, Sandroni P, Opfer-Gehrking TL,
Novak P. Postural tachycardia syndrome. In: Clinical Autonomic Disorders (2nd ed.), edited by Low PA. Philadelphia, PA: Lippincott-Raven,
1997, p. 681– 697.
1135