Handbook of Clinical Neurology, Vol.

117 (3rd series)

Autonomic Nervous System
R.M. Buijs and D.F. Swaab, Editors
© 2013 Elsevier B.V. All rights reserved

Chapter 13

Exercise and the autonomic nervous system

QI FU1,2 AND BENJAMIN D. LEVINE1,2*
1
University of Texas Southwestern Medical Center, Dallas, TX, USA
2
Institute for Exercise and Environmental Medicine, Texas Health Presbyterian Hospital Dallas, TX, USA

INTRODUCTION measure of work capacity, it is usually normalized to

body mass, and in its most familiar form is expressed
Physical activity (dynamic exercise) is a key component
as milliliters per kilogram per minute (mL/kg/min).
of a healthy lifestyle. Increased physical activity or exer-
One of the most inviolate relationships in all of exercise
cise training is not only protective against cardiovascular physiology is that between oxygen uptake and cardiac
disease, hypertension, colon and breast cancer, type II
output. Regardless of age, sex, or the presence of vari-
diabetes, and obesity, but also effective in improving
ous disease states, in general, about 5–6 liters of cardiac
functional capacity in patients with these medical condi-
output are required for every liter of oxygen uptake
tions, as well as in patients with autonomic disorders.
above rest (Fig. 13.1) (Rowell, 1993b; Levine, 2001). When
Exercise training also improves mental health, helps to
this relationship is depressed, as in patients with conges-
prevent depression, and promotes or maintains positive tive heart failure (Chomsky et al., 1996), it may be a sign
self-esteem. Endurance or “dynamic” exercise, such as of severe underlying disease with impending decompen-
running, jogging, cycling, swimming, rowing, or walk- sation (Martin et al., 1989). Conversely, when it is exag-
ing, and strength training, such as weight-lifting, are gerated, as in patients with metabolic myopathies (Haller
two major forms of exercise. In this chapter, we predom- et al., 1991; Taivassalo et al., 2001, 2003), it gives strong
inately focus on dynamic exercise. clues to the processes regulating cardiac output.
There is now convincing evidence that some of the
protective and therapeutic effects of exercise training
are related, in a substantive fashion, to effects on the THE FICK PRINCIPLE
autonomic nervous system (Joyner and Green, 2009). Oxygen uptake is a function of the triple-product of
In addition, training-induced improvement in vascular heart rate and stroke volume (i.e., cardiac output) and
endothelial function, blood volume expansion, cardiac arterial-mixed venous oxygen difference or total system
remodeling, insulin resistance, and renal-adrenal func- arteriovenous oxygen difference (Rowell, 1993b) – the
tion may also contribute to the protection and treatment Fick principle:
of cardiovascular, metabolic, and autonomic disorders.
_  avO2 difference
V_ O2 ¼ Qc
¼ HR  SV  avO2 difference
ACUTE EXERCISE
where V_ O2 is oxygen uptake, Qc _ is cardiac output, HR, is
Oxygen uptake
heart rate, SV is stroke volume, and a-vO2 difference is
During dynamic exercise, the uptake and transport of total system arteriovenous oxygen difference. The
oxygen is required for oxidative phosphorylation and degree to which each of the variables can increase deter-
the efficient production of adenosine triphosphate mines the upper limit for whole-body oxygen consump-
(ATP) to support the metabolic demands of the body tion, and this limit is called the maximal oxygen uptake
(Levine, 2001). The primary unit of oxygen uptake is _ 2 max) (Levine, 2008). Maximal heart rate and max-
(VO
liters of oxygen per minute (L/min), and, in absolute imal arteriovenous difference are usually similar in ath-
terms, is a direct function of body size. However, as a letes and nonathletes alike; the factor most commonly

*Correspondence to: B.D. Levine, Institute for Exercise and Environmental Medicine, Texas Health Presbyterian Hospital Dallas,
7232 Greenville Avenue, Suite 435, Dallas, TX 75231, USA. E-mail: benjaminlevine@TexasHealth.org
148 Q. FU AND B.D. LEVINE
Metabolic myopathies 220 Sedentary men
20 Sedentary women
Male athletes
200 Female athletes

180
15
Qc (L/min)

160

HR (bpm)
5–6 liters

10 140

Congestive heart failure 120

5 100
1 liter
80
0
0 500 1000 1500 2000 2500
60
0 20 40 60 80 100 120
• •
VO2 (mL/min) Percent VO2max (%)
Fig. 13.1. Relationship between increases in oxygen uptake Fig. 13.2. Comparisons of heart rate (HR) responses during
_ 2 ) and the corresponding increases in cardiac output
(VO submaximal and maximal exercise in sedentary men and
_
(Qc) during exercise in humans, which in most cases is women and during submaximal exercise in highly trained male
5–6/1. When this relationship is depressed, as in patients with and female athletes at the same relative work rate, expressed as
congestive heart failure, it may be a sign of severe underlying the percentage of maximal oxygen uptake (VO _ 2 max), which
disease with impending decompensation. Conversely, when represents a matter of cardiovascular control during exercise
it is exaggerated, as in patients with metabolic myopathies, in normal humans. (Adapted with permission from Fu and
_ (Adapted
it gives strong clues to the processes regulating Qc. Levine, 2005.)
with permission from Levine, 2001.)
nonathletic individuals, maximal stroke volume is
accounting for the different values of VO_ 2 max in differ- achieved for the most part at relatively low levels of exer-
ent individuals of different fitness levels is stroke vol- cise intensity (approximately 50% of maximal oxygen
ume (Rowell, 1993b). uptake), as pericardial constraint serves to limit left
At low levels of exercise, heart rate increases almost ventricular end-diastolic volume. At rest, arteriovenous
exclusively via vagal withdrawal, with little evidence for oxygen difference is normally 4.5 mL/100 mL/min
systematic increases in sympathetic activity until the (approximately 23% extraction), and at VO _ 2 max this
intensity of exercise is at or above the maximal steady difference is commonly close to 16 mL/100 mL/min
state (Ray et al., 1992; Rowell, 1993b). The key determi- (about 80–85% extraction) (Rowell, 1993b).
nant of the magnitude of the heart rate response to exer-
cise is the relative intensity as well as the absolute
Neural mechanisms for the exercise response
amount of muscle mass engaged, while central com-
mand plays an essential role in the increase in heart rate The cardiovascular response during exercise is initiated
during exercise (Levine, 2001). If heart rate is normal- by a feed-forward mechanism, termed “central com-
ized or scaled by expressing it in relation to the relative mand,” which involves higher brain centers such as the
oxygen uptake, for example, percent of VO _ 2 max, then motor cortex, hypothalamic and mesencephalic loco-
diverse individuals appear to respond in virtually identi- motor regions that activate parallel circuits controlling
cal fashion (Fig. 13.2) (Rowell, 1993b; Fu and Levine, locomotor, cardiovascular, and ventilatory functions
2005), indicating that the cardiovascular response is (Krogh and Lindhard, 1913; Mitchell, 1990). As exercise
more closely related to the relative than absolute meta- continues, both mechanical and metabolic signals from
bolic demands. active skeletal muscle provide feedback to cardiovas-
Gravity plays a critical role in determining the distri- cular centers in the brain through group III and IV mus-
bution of blood within the cardiovascular system, and cle afferents, the so-called “exercise pressor reflex,” to
body posture markedly affects the relative importance precisely match systemic oxygen delivery with metabolic
of changes in stroke volume (Levine, 2001). In the demand (Alam and Smirk, 1937; Mitchell, 1990;
upright position, stroke volume is only about one-half Michelini and Stern, 2009).
its value in the supine position due to blood pooling in Contracting skeletal muscle produces vasodilatory
the legs and a reduction in left ventricular end-diastolic metabolites (i.e., adenosine, prostaglandins, nitric oxide)
volume. At the onset of exercise, the pumping action of which attenuate sympathetically mediated vasoconstric-
skeletal muscle acts to augment venous return substan- tion, and this phenomenon is known as “functional
tially, and stroke volume normally increases > 50% via sympatholysis” (Remensnyder et al., 1962; Dinenno
the Starling mechanism (Levine, 2001). At least for most and Joyner, 2003; Keller et al., 2004). However, it has
 EXERCISE AND THE AUTONOMIC NERVOUS SYSTEM 149
been found that nitric oxide is not obligatory for func- relationship between heart rate or arterial pressure and
tional sympatholysis in contracting skeletal muscles of carotid sinus pressure, as shown in Figure 13.4. Upward
healthy humans (Dinenno and Joyner, 2003). Enhanced resetting of the operating point of the arterial baroreflex
endothelium-derived hyperpolarizing factor activity in appears to be the major factor responsible for the
conditions of nitric oxide deficiency may contribute to sympathy-excitatory response and increasing blood
functional sympatholysis (Ozkor et al., 2011). Vascular pressure during exercise (DiCarlo and Bishop, 1992).
resistance in active skeletal muscle decreases to facilitate It has been proposed that central command resets the
increases in muscle perfusion, while in inactive skeletal arterial baroreflex and in turn raises cardiac output by
muscle vascular resistance increases so that systemic sudden withdrawal of tonic outflow to the heart
arterial blood pressure can be supported (Joyner and (Rowell, 1993a). Conversely, activation of the exercise
Thomas, 2003; Keller et al., 2004). If sympathetically pressor reflex may also contribute to the resetting of
medicated vasoconstriction is impaired, for instance, the arterial baroreflex (Rowell and O’Leary, 1990;
in patients with autonomic failure, hypotension will Ichinose et al., 2008).
occur during exercise, and at times this hypotension
may be profound. Additionally, cardiac output increases
Heart rate recovery from exercise
proportionate with oxygen uptake, thus allowing the
maintenance or, in most cases, an increase in mean Early recovery of the heart rate after acute bouts of exer-
arterial pressure. An overview of the neural mechanisms cise appears to be dominated by vagal reactivation with
responsible for the cardiovascular response during sympathetic withdrawal becoming more important later
exercise is shown in Figure 13.3. in recovery (Imai et al., 1994; Pierpont et al., 2000). This
There is a parallel increase in arterial pressure and notion is supported by the findings of Goldberger et al.
heart rate at the beginning and during exercise, indicat- showing that administration of atropine, a muscarinic
ing a resetting of the arterial baroreflex. Indeed, many receptor antagonist, completely abolishes heart rate
human and animal studies have shown that the barore- recovery as well as time domain measures of heart rate
flex control of heart rate and arterial pressure resets variability during recovery from exercise (Goldberger
with little change in gain or sensitivity during exercise et al., 2006). It is further supported by the results of
(Bevegard and Shepherd, 1966; Joyner, 2006; Raven, Dewland et al. showing that pyridostigmine, an acetyl-
2008). Sensitivity refers to the change in arterial pressure cholinesterase inhibitor that selectively augments the
caused by a given change in pressure at the arterial baro- parasympathetic (vagal) efferent signals, enhances heart
receptors (most commonly the isolated carotid sinus) rate recovery (Dewland et al., 2007). The rate of heart
(Rowell, 1993a). It also refers to the slope of the rate return to baseline after exercise has been proposed

Brain
Skeletal muscle
Ventrolateral Medulla ergoreceptors
(Cardiovascular Center) (mechanoreceptors
metaboreceptors)
e x
Ce

cis efle
Co

er
nt

r
m

Ex sor
ra
m

es
an

Pr
d

Arteria
l Cardiac
Barore
flexes Cardiopulmonary mechanoreceptors
Arterial reflexes
mechanoreceptors
carotid
aortic inactive
skeletal muscle

Kidney and active

splanchnic bed skeletal muscle Muscle
vasoconstriction vasoconstriction

Modulation of Heart
vasomotor tone chronotropic function
inotropic

Fig. 13.3. Autonomic neural control of the cardiovascular response during exercise. Central command initiates the exercise pres-
sor response, which is maintained and augmented via feedback from baroreceptors, as well as by stimulation of skeletal muscle
mechanically and metabolically sensitive receptors. After integration in the brain, efferent responses via the parasympathetic
(vagal) and sympathetic nervous systems result in increased heart rate and contractility, vasoconstriction in inactive muscle,
and vasodilation in active muscle beds mediated by release of local vasodilating substances (“functional sympatholysis”).
(Adapted with permission from Levine, 2001.)
150 Q. FU AND B.D. LEVINE
Central command 10
9
8
7

Relative risk
1st
6
5
Overall resetting 4
2nd
3
3rd
2
4th 5th
1
OP 0
SNA (HR or BP)

CP
0 5 10 15 20 25 30 35
Heart rate recovery (bpm)

Exercise Fig. 13.5. Estimates of the relative risk of death within 6 years
according to heart rate recovery 1 minute after cessation
Rest of exercise. Circles represent the relative risk of death for
each of the quintiles as compared with the quintile with the
greatest reduction (5th). Dashed lines represents the 95%
confidence interval. The abbreviation bpm denotes beats per
BP (CSP)
minute. (Adapted with permission from Cole et al., 1999.)

independent predictor of death (Watanabe et al., 2001).

However, the rate of heart rate recovery is substantially
Exercise pressor reflex greater between standing and supine positions, and could
Fig. 13.4. Hypothetical stimulus-response curves for arterial lead to misclassification of some patients (Levine et al.,
baroreflex at rest and during exercise, expressed as relationship unpublished results). Central command is restored more
between sympathetic nerve activity (SNA) and blood pressure quickly when supine compared with standing. Thus, for
(BP) (or often in experiments as relationship between BP or accurate measurements of heart rate recovery, values for
HR and isolated carotid sinus pressure (CSP)). Resetting of distinguishing high from low risk patients should be stan-
the baroreflex occurs from rest to exercise. Central command dardized for body position during recovery. Also,
plays a determinant role in the baroreflex resetting, while the patients who achieve a low peak heart rate will have a
exercise pressor reflex is also involved in this resetting. OP, correspondingly low heart rate recovery compared to
operating point; CP, centering point. (Adapted with permission
those who achieve a higher peak heart rate, even though
from Rowell and O’Leary, 1990; Raven et al., 2006.)
control of R-R interval is the same, based on the recip-
rocal relationship between heart rate and R-R interval.
to be associated with fitness and good health (Shetler Thus, a low heart rate recovery may reflect a low peak
et al., 2001), and is usually calculated from peak exercise heart rate rather than an intrinsic defect in autonomic
to minute 1 or 2 of recovery (Cole et al., 1999, 2000; control.
Nishime et al., 2000; Rosenwinkel et al., 2001).
A reduced rate of heart rate recovery, which may be a
Exercise response in autonomic disorders
reflection of decreased vagal activity, is a powerful pre-
dictor of overall mortality, independent of workload, the In general, patients with autonomic disorders have low
presence or absence of myocardial perfusion defects, _ 2 max, indicating reduced physical fitness
levels of VO
and changes in heart rate during exercise (Fig. 13.5) and exercise capacity. Moreover, the vast majority of
(Cole et al., 1999). the patients have blunted or abnormal cardiovascular
Cole et al. proposed that an abnormal heart rate recov- response to exercise, especially during maximal exercise.
ery was defined as a reduction of 12 beats per minute
or less from the heart rate at peak exercise to 1 minute
PARKINSON’S DISEASE
after the cessation of exercise in a cool-down period
(Cole et al., 1999). Subsequently, Watanabe et al. con- The effect of Parkinson’s disease on exercise is not well
firmed that even in the absence of a cool-down period characterized. A recent report on Parkinson’s disease
and after accounting for left ventricular systolic showed that during submaximal exercise, cardiac
function, heart rate recovery was still a powerful and contractility was the lowest in patients with reduced
 EXERCISE AND THE AUTONOMIC NERVOUS SYSTEM 151
123
I-metaiodobenzylguanidine (MIBG) uptake, an indi- plasma norepinephrine concentrations were subnormal
cation of cardiac sympathetic denervation, when com- in both forms and did not increase with exercise, while
pared with innerved patients and healthy controls; postural hypotension was enhanced after exercise to
however, arterial pressure and heart rate responses were the same extent in both forms (Smith and Mathias,
not significantly different between the three groups 1996). The greater cardiovascular abnormalities in
(Nakamura et al., 2010). Although the cardiovascular response to exercise in the cerebellar form suggest that
responses at submaximal or lower levels of exercise cerebellar or brainstem autonomic pathways are
appear to be similar between patients with Parkinson’s impaired to a larger extent in the cerebellar form than
disease and healthy individuals, it has been found that in the Parkinsonian form of multiple system atrophy
half of the patients exhibit blunted responses at peak (Smith and Mathias, 1996).
or maximal exercise (Werner et al., 2006).
PURE AUTONOMIC FAILURE
SPINAL CORD INJURY
It has been shown that patients with pure autonomic
Different injury levels in patients with spinal cord injury failure have an abnormal fall in blood pressure and an
may have different exercise responses as a result of the attenuated increase in heart rate during exercise (Smith
interruption of pathways in the spinal cord to the periph- et al., 1995, 1996a; Smith and Mathias, 1996; Humm
eral sympathetic nervous system in addition to the motor et al., 2008), which is presumably attributable to reduced
paralysis. For example, it was found that tetraplegics had sympathetic nerve activity to the heart and vasculature
low epinephrine and norepinephrine at rest and only and blunted sympathetic a-adrenergic vasoconstriction
slightly increased during exercise, while their impaired in inactive (nonexercising) skeletal muscle (Smith et al.,
cardiac sympathetic innervations caused restricted 1996b; Schrage et al., 2004). Humm et al. reported that
cardioacceleration and markedly reduced VO _ 2 max water drinking did not change the abnormal cardiovascu-
(Schmid et al., 1998). High-lesion paraplegics were found lar responses to supine cycling exercise but improved
to have comparable norepinephrine but lower epineph- orthostatic tolerance postexercise in patients with pure
rine levels as a result of partial innervation of the norad- autonomic failure (Humm et al., 2008). However, in
renergic system and denervation of the adrenal medulla autonomic failure due to familial amyloid polyneuropa-
(Schmid et al., 1998). Conversely, spinal cord injury thy and in selective sympathetic failure due to dopamine
below T5 showed an augmented basal and exercise- b-hydroxylase deficiency, blood pressure usually
induced upper spinal thoracic sympathetic activity remains unchanged with exercise (Smith et al., 1995;
compared with healthy controls (Schmid et al., 1998). Smith and Mathias, 1996).
Claydon et al. also found that abnormal cardiovascular
responses to exercise and transient postexercise hypo- BAROREFLEX FAILURE
tension were common in cervical but not thoracic spinal
cord injury, which may be partly related to loss of des- In contrast to patients with autonomic failure who usually
cending sympathetic nervous control of the heart and have severe orthostatic hypotension and reduced sympa-
vasculature following high spinal cord injury (Claydon thetic activation, patients with baroreflex failure have
et al., 2006). Additionally, it was recently reported that little orthostatic hypotension and their illness is domi-
metaboreflex-induced blood pressure rise associated nated by volatile hypertension (Robertson et al., 1993).
with arm cycling exercise was blunted in patients with It was found that baroreflex failure patients had an exces-
spinal cord injury compared with healthy controls sive increase in blood pressure during exercise (Ziegler
(Crisafulli et al., 2009). et al., 1993), which is probably due to impaired baroreflex
buffering. This notion seems to be supported by the
MULTIPLE SYSTEM ATROPHY results of previous studies showing that blood pressure
is more variable in patients who have no carotid barore-
The cardiovascular response to exercise differs between flex, either as a result of bilateral glomectomy for glomus
two clinical subgroups of multiple system atrophy (Shy– tumors or because of neck irradiation (Smit et al., 2002;
Drager syndrome), with a larger fall in arterial pressure Timmers et al., 2003a, b).
during supine leg exercise but not during standing after
exercise in the cerebellar form than in the Parkinsonian
NEUROMUSCULAR MYOPATHIES
form (Smith et al., 1995; Smith and Mathias, 1996). Heart
rate increased similarly in both groups, systemic vascu- Neuromuscular diseases (myopathies) produce two
lar resistance fell similarly, but cardiac output rose more major patterns of exercise intolerance; in muscular dys-
in patients with the Parkinsonian form compared with _ 2 max due to the loss
trophies, patients have reduced VO
the cerebellar form (Smith and Mathias, 1996). Resting of functional muscle mass; in disorders of muscle energy
152 Q. FU AND B.D. LEVINE
metabolism, an imbalance in muscle energy production when expressed at the percent of VO _ 2 max (relative
and utilization in exercise results in exertional muscle pain, workload), there is no difference in the heart rate
cramping, weakness, or fatigue (Haller and Lewis, 1984). responses between POTS patients and healthy controls
Patients with mitochondrial myopathies have significantly (Shook et al., 2007). These results may suggest that
_ 2 max, impaired muscle oxygen extraction indi-
lower VO POTS patients have no intrinsic abnormality of heart rate
cated by subnormal system arteriovenous oxygen differ- regulation during exercise. The tachycardia during exer-
ence at maximal exercise despite normal oxygen cise in POTS patients is not due to abnormal baroreflex
carrying capacity, but markedly higher cardiac output control of heart rate (Masuki et al., 2007a), but rather
when compared with sedentary healthy individuals due to a reduced stroke volume.
(Haller et al., 1991; Taivassalo et al., 2001, 2003).

CHRONIC EXERCISE TRAINING

POSTURAL ORTHOSTATIC TACHYCARDIA SYNDROME
Both central command and the exercise pressor reflex
Patients with the postural orthostatic tachycardia syn- are important in determining the cardiovascular
drome (POTS, also called chronic orthostatic intoler- response during exercise, while dynamic interactions
ance) usually have reduced exercise tolerance and low between these feed-forward and feedback circuits are
_ 2 max. Recent investigations have demonstrated that
VO associated with beneficial long-term adjustments in the
POTS patients have greater heart rate and smaller stroke sympathetic and parasympathetic nervous systems.
volume for each level of absolute workload during The beneficial effects can be observed soon after the
submaximal and maximal exercise when compared with initiation of exercise and are sustained as long as activity
healthy but sedentary individuals (Masuki et al., 2007a, is continued. Figure 13.6 depicts the major beneficial
b; Shibata et al., 2012; Shook et al., 2007). However, effects of exercise training in humans.

Sympathetic tone

Baroreflex Vagal tone Heart rate

sensitivity Cardiac size/mass

Cardiac function

Endothelial
function

Hemoglobin
mass

Insulin Blood/plasma
resistance Exercise volume

Renal-adrenal
Obesity function

Blood pressure
Fig. 13.6. Effects of exercise training on the autonomic nervous system, cardiovascular system, and renal-adrenal system in
humans.
 EXERCISE AND THE AUTONOMIC NERVOUS SYSTEM 153
Exercise training and vascular function is activated during each bout of exercise, repeated activa-
tion of this system may result in an attenuation of sympa-
Exercise training can increase the release of nitric oxide
thetic activity (Grassi et al., 2000; Fraga et al., 2007;
through shear stress during exercise, while chronic
Fu et al., 2010). Animal studies have suggested that nitric
increases in nitric oxide may lead to functional and his-
oxide decreases overall sympathetic excitability within the
tological alterations of vascular endothelium, causing
brainstem and possibly through actions in higher brain
enhanced vascular structure and function (Niebauer
regions (i.e., hypothalamus) (Goodson et al., 1994; Patel
and Cooke, 1996; Green et al., 2004). Many studies have
et al., 1996). Because of the inevitable experimental
shown that exercise training augments endothelial, nitric
restrictions, it is unclear whether the increased release of
oxide-dependent vasodilation in both large and small
nitric oxide with exercise training has a central sym-
vessels, while the extent of the improvement in humans
pathoinhibitory effect in humans. On the other hand, exer-
depends upon the muscle mass subjected to training;
cise is protective against weight gain and visceral obesity,
with forearm exercise, changes are restricted to the fore-
which may also contribute to the reduction in sympathetic
arm vessels, while lower body training can induce more
activity (Joyner and Green, 2009). Training-induced mus-
generalized benefit (Green et al., 2004). It has been
cle adaptations appear to be important in attenuating insu-
found that regular exercise or exercise training can pre-
lin mediated sympathetic activation (Julius et al., 1991;
vent the age-associated loss in endothelium-dependent
Baron et al., 1993; Kohno et al., 2000; Henriksen, 2002),
vasodilatation and restore levels in previously sedentary
and may be especially enhanced by strength training which
middle-aged and older healthy individuals, which may
increases overall muscle mass (Kraus and Levine, 2007;
contribute to the reduced risk of cardiovascular disease
Church et al., 2010).
in this population (DeSouza et al., 2000). However, the
Exercise training decreases resting heart rate as a
impact of exercise training on vascular endothelial func-
result of an increase in vagal tone and a decline in the
tion may depend on the balance between reactive oxygen
intrinsic heart rate, while a reduction in sympathetic
species, antioxidant defenses, and their impact on nitric
activity likely has, at most, minimal impact
oxide bioavailability (Green et al., 2004).
(Rosenwinkel et al., 2001). Trained individuals recover
Exercise training was reported to improve arterial com-
from an acute bout of exercise more rapidly than
pliance in healthy individuals (Tanaka et al., 2000) and
untrained individuals (Hagberg et al., 1979, 1980; Imai
induce structural enlargement of conduit vessels (Lloyd
et al., 1994; Rosenwinkel et al., 2001). The more rapid
et al., 2001; Prior et al., 2003). Vascular conductance
heart rate recovery in trained individuals seems to be
was also reported to be improved with training, which is
independent of a sympathetic response, because an
not endothelial mediated and probably reflects structural
early study showed that the clearance of plasma norepi-
adaptations required to accommodate a high muscle blood
nephrine during recovery did not change significantly
flow (Martin et al., 1987; Snell et al., 1987). We recently
after 2 months of detraining (Hagberg et al., 1979).
found that in people over the age of 65 years lifelong
Rather, a vagally mediated mechanism is more likely
daily exercise training may minimize arterial stiffening,
to be responsible for the rapid heart rate recovery in
but the training effect is limited particularly when started
trained people (Rosenwinkel et al., 2001). Numerous
later in life (Shibata et al., 2008). In contrast to its ability
studies have found that exercise training improves
to favorably modulate the stiffness of large elastic
cardiac autonomic balance (i.e., increasing parasympa-
arteries, exercise training does not consistently modulate
thetic while decreasing sympathetic regulation of the
the changes in left ventricular structure and diastolic
heart) and increases heart rate variability (Levy et al.,
function that occur with physiological aging in humans
1998; Iwasaki et al., 2003; Rennie et al., 2003;
(Gates et al., 2003; Shibata et al., 2008; Fujimoto
Okazaki et al., 2005; Galbreath et al., 2011). Additionally,
et al., 2010). It does, however, increase stroke volume
exercise training can result in cardiac remodeling,
and the Starling mechanism, presumably by improved
increase cardiac size and mass, and improve cardiac
ventricular-arterial coupling via endothelial mechanisms
function (Levine et al., 1991a, b; Levine, 1993; Fu
(Fujimoto et al., 2010).
et al., 2010).
Exercise training improves baroreflex function in
different populations (Iwasaki et al., 2003; Okazaki
Adaptation of the autonomic nervous system
et al., 2005; Galbreath et al., 2011), and is protective
Recent research has indicated that exercise training against age-related reductions in baroreflex sensitivity
remodels cardiorespiratory centers, and thereby reduces (Monahan et al., 2000; Joyner and Green, 2009). The
sympathetic and enhances parasympathetic (vagal) out- improvement in baroreflex function with exercise train-
flow (Green et al., 2004; Nelson et al., 2005; Billman and ing could be a result of both greater blood vessel disten-
Kukielka, 2007). Since the sympathetic nervous system sibility and better signal transduction in barosensitive
154 Q. FU AND B.D. LEVINE
areas of the carotid sinus and aortic arch (Monahan EXERCISE THERAPY
et al., 2000; Tanaka et al., 2000), or it could also
There is abundant evidence showing that regular exer-
represent improved or maintained central integration
cise or exercise training is not only protective against
in the brainstem cardiovascular centers (Joyner and
cardiovascular disease (Mora et al., 2007; Blair and
Green, 2009).
Numerous studies have shown that exercise training Morris, 2009), hypertension (Fu et al., 2008), type II
lowers blood pressure. Training-induced reduction in diabetes (Tuomilehto et al., 2001; Knowler et al., 2002;
blood pressure is likely to be attributable to an increase Lindstrom et al., 2006), breast and colon cancer
in nitric oxide release resulting from increased vascular (Hardman, 2001; Khan et al., 2010), and obesity (Wolf
shear stress during exercise (Kingwell, 2000). Conversely, and Woodworth, 2009; Cheriyath et al., 2010), but also
training has been found to improve aerobic capacity and effective in improving functional capacity in patients
vascular conductance, and lower body fat, each of which with heart failure, myocardial infarction, or after coro-
could also contribute to the reduction in blood pressure nary artery bypass surgery by increasing vagal modula-
(Blair et al., 1984; Duncan et al., 1985; Snell et al., 1987; tion and decreasing sympathetic tone (Routledge et al.,
Hall et al., 2001). However, many investigators believe 2010). Exercise training also seems to be effective in
that the blood pressure reduction with exercise training the prevention of sudden cardiac death by augmenting
is primarily mediated by a neural mechanism, because baroreflex sensitivity and heart rate variability (La
vasomotor sympathetic nerve activity decreases after Rovere et al., 2001).
training (Grassi et al., 1992; Brown et al., 2002; Laterza Clinical studies have proven that exercise training
et al., 2007; Fu et al., 2010). improves functional capacity in patients with autonomic
disorders, such as Parkinson’s disease (Baatile et al.,
2000; de Goede et al., 2001; Yousefi et al., 2009), stroke
(Harrington et al., 2010), multiple sclerosis (Dalgas et al.,
Improvement of renal-adrenal function 2009; Dettmers et al., 2009; Snook and Motl, 2009), spi-
Exercise training may improve renal-adrenal function nal cord injury (Hicks et al., 2003; Valent et al., 2007,
and decrease circulating levels of angiotensin II or 2009; Millar et al., 2009), Guillain–Barré syndrome
angiotensin II-induced vasoconstriction (Rush and (Pitetti et al., 1993; Garssen et al., 2004; Bussmann
Aultman, 2008). Zucker et al. observed in animals with et al., 2007), muscular dystrophy (Olsen et al., 2005;
heart failure that exercise training reduces the expres- Sveen et al., 2008; Voet et al., 2010), or metabolic
sion of the angiotensin II type I (AT1) receptors in the myopathies (Taivassalo et al., 2001; Wenz et al., 2009).
paraventricular nucleus of the hypothalamus and in Exercise training also improves mental health (Raglin,
the rostral ventrolateral medulla and nucleus tractus 1990), helps to prevent depression (Craft et al., 2008),
solitarius (Zucker et al., 2004). A previous human study and promotes or maintains positive self-esteem (Piko
showed that exercise training may suppress the renin– and Keresztes, 2006). Recent human research has dem-
angiotensin–aldosterone system (Hespel et al., 1988). onstrated that training improves older people’s cognitive
Using a radiotracer technique, Meredith et al. found in function, and is neuroprotective in many neurodegener-
initially sedentary healthy men that resting renal but ative and neuromuscular diseases.
not cardiac norepinephrine spillover decreased after Although the effects of exercise training on ortho-
1 month of exercise training (Meredith et al., 1991), indi- static tolerance in healthy individuals are controversial,
cating that the reduction in resting sympathetic activity increased orthostatic tolerance after mild to moderate
with training is largely confined to the kidney. Research training has been found in patients with unexplained
in patients with chronic heart failure showed that the syncope or orthostatic hypotension (Mtinangi and
reduction in sympathetic nerve activity and the improve- Hainsworth, 1998). Increased baroreflex sensitivity and
ment in baroreflex function after exercise training are decreased frequency of syncopal episodes after training
due to the concomitant reduction in angiotensin II, as were observed in patients with neurally mediated syn-
well as angiotensin receptors in the central nervous cope (Gardenghi et al., 2007). Additionally, it was
system (Mousa et al., 2008). A recent study from our observed that exercise training has a beneficial effect
laboratory found that exercise training improved on physiological and subjective parameters in patients
renal-adrenal function in patients with POTS (Fu et al., with chronic fatigue syndrome (Joosen et al., 2008),
2011). Additionally, exercise training can increase and also leads to an improvement of symptoms in the
total hemoglobin mass, red blood cell volume, and majority of patients with orthostatic intolerance
plasma/blood volume (Saltin et al., 1968; Harris et al., (Winker et al., 2005).
2003; El-Sayed et al., 2005; Goodman et al., 2005; We have recently found that a “personalized” short-
Fu et al., 2010). term (3 months) exercise training program improves or
 EXERCISE AND THE AUTONOMIC NERVOUS SYSTEM 155
even cures POTS in most patients; more importantly, Table 13.2
patient quality of life, as assessed by the 36-Item Calculations of heart rate zones for the exercise
Short-Form Health Survey, is significantly improved training program
after training (Fu et al., 2010, 2011). This carefully con-
trolled exercise training program was initially developed 1. Determine approximate maximal heart rate (HR): take
for spaceflight and bed rest countermeasures (Iwasaki 220 – age ¼ maximal HR
2. Determine the heart rate reserve (HRR): take maximal
et al., 2003; Shibata et al., 2010). Numerous studies have
HR  supine resting HR ¼ HRR
shown that microgravity exposure can elicit a “POTS-
3. Take HRR  0.75 ¼ 75% of HRR
like” syndrome in astronauts and fit individuals, while 4. Determine the mid maximal steady state (MSS) HR: add
“cardiovascular deconditioning” (i.e., cardiac atrophy 75% of HRR þ supine resting HR ¼ mid MSS HR
and hypovolemia) is one primary underlying mechanism. 5. Determine MSS zone: 10 beats around the mid MSS HR
Results from our laboratory and others have suggested 6. Determine base pace zone: 20 beats < lowest MSS zone HR
that POTS per se is a consequence or signature of “car- 7. Determine recovery: <lowest base pace HR
diovascular deconditioning” (Masuki et al., 2007a, b; 8. Determine race pace: 10–15 beats > highest MSS HR
Joyner and Masuki, 2008; Fu et al., 2010, 2011; 9. Determine interval training zone: >highest race pace but
Galbreath et al., 2011), and, therefore, increases in phys- not higher than maximal HR (at least 5 beats lower than
ical fitness (i.e., “reconditioning”) with exercise training maximal HR)
can improve or cure this syndrome. It has been well dem-
onstrated that exercise training expands plasma and
blood volume (Saltin et al., 1968), increases cardiac size Table 13.3
and mass (Dorfman et al., 2007), prevents cardiac atro-
A template of workouts prescribed over a 3 month
phy and increases orthostatic tolerance in healthy indi-
training program
viduals after prolonged period of bed rest (Dorfman
et al., 2007). Training
The training program implemented in our laboratory
is shown in Table 13.1 (Iwasaki et al., 2003; Okazaki et al., Max steady
2005; Dorfman et al., 2007; Fu et al., 2010; Shibata et al., Month Recovery Base pace state
2010). Table 13.2 depicts the calculations of heart rate
zones for the exercise training program. The heart rate 1 2 @ 40 minutes 10 @ 30 minutes 2 @ 20 minutes
at the “maximal steady state” is set at approximately 2 3 @ 40 minutes 10 @ 40 minutes 3 @ 25 minutes
75% of the maximal heart rate. The workout zones are 3 3 @ 40 minutes 10 @ 50 minutes 3 @ 35 minutes
structured around the maximal steady state value. A
template of workouts prescribed over 3 months of train-
ing program is displayed in Table 13.3. The majority of
the training sessions, particularly during the early once per week, and are always followed by recovery ses-
phases, are prescribed as “base pace training” with target sions. In addition to the endurance training, resistance
heart rate equivalent to 75–85% of maximal. Initially, training using weight lifting is also undertaken. Weight
patients train 3–4 times per week for 20–40 minutes per lifting starts from once a week, 15–20 minutes per ses-
session. As the patients become relatively fit, the dura- sion, and gradually increases to twice a week, 30–40
tion of the base pace training is prolonged and subse- minutes per session.
quently sessions of increased intensity (i.e., maximal Given the beneficial effects of exercise training, the
steady state) are added first once per 2 weeks and then American Heart Association, the US Surgeon General,
the Centers for Disease Control and Prevention, and
the American College of Sports Medicine recommend
Table 13.1
at least 30 minutes per day of at least moderate-intensity
Training zones exercise, including brisk walking, jogging, cycling,
swimming, or running on most, and preferably all, days
Training zone Heart rate of the week (Marcus et al., 2006). Physicians’ advice to
increase physical activity can be a strong motivator to
Intervals > Race pace patients, and advice conveyed as a written prescription
Race pace 10–15 bpm > MSS
may enhance success. Supervised exercise training is
Maximal steady state (MSS) (Take 220 – age)  5 bpm
Base pace 20 bpm < MSS preferable to maximize functional capacity. Heart rate
Recovery <Base pace can be used as an easily measured estimate of relative
exercise intensity, and the target training heart rate is
156 Q. FU AND B.D. LEVINE
usually set at approximately 75% of the maximal heart Baron AD, Brechtel-Hook G, Johnson A et al. (1993). Skeletal
rate [(take 220  age)  5 beats/min] (Table 13.2). How- muscle blood flow. A possible link between insulin resis-
ever, it is important to emphasize that these are only tance and blood pressure. Hypertension 21: 129–135.
guidelines that in some patients, such as those who are Bevegard BS, Shepherd JT (1966). Circulatory effects of
stimulating the carotid arterial stretch receptors in man at
taking b-blockers or other medications or with underly-
rest and during exercise. J Clin Invest 45: 132–142.
ing autonomic disorders, may affect the heart rate
Billman GE, Kukielka M (2007). Effect of endurance exercise
response to exercise and may not accurately reflect exer- training on heart rate onset and heart rate recovery
cise intensity. responses to submaximal exercise in animals susceptible
For patients with autonomic disorders, heat and body to ventricular fibrillation. J Appl Physiol 102: 231–240.
temperature during exercise may compromise blood Blair SN, Morris JN (2009). Healthy hearts – and the universal
pressure further (by further increases in vascular con- benefits of being physically active: physical activity and
ductance); cooling the skin or semirecumbent exercise health. Ann Epidemiol 19: 253–256.
is recommended. For patients with POTS or orthostatic Blair SN, Goodyear NN, Gibbons LW et al. (1984). Physical
intolerance, exercise training should be initiated by using fitness and incidence of hypertension in healthy normoten-
a recumbent bike, rowing, or swimming (Fu et al., 2010). sive men and women. JAMA 252: 487–490.
Brown MD, Dengel DR, Hogikyan RV et al. (2002).
The use of only semirecumbent exercise at the beginning
Sympathetic activity and the heterogenous blood pressure
is a critical strategy, allowing patients to exercise while
response to exercise training in hypertensives. J Appl
avoiding the upright posture that elicits their symptoms. Physiol 92: 1434–1442.
As the patients become relatively fit, the duration and Bussmann JB, Garssen MP, van Doorn PA et al. (2007).
intensity of exercise should be progressively increased, Analysing the favourable effects of physical exercise:
and upright exercise (e.g., upright bike, walking on the relationships between physical fitness, fatigue and function-
treadmill, or jogging) can be gradually added as toler- ing in Guillain–Barre syndrome and chronic inflammatory
ated (Fu et al., 2010). demyelinating polyneuropathy. J Rehabil Med 39: 121–125.
In summary, a sedentary lifestyle is considered to be Cheriyath P, Duan Y, Qian Z et al. (2010). Obesity, physical
one of the most important modifiable risk factors for activity and the development of metabolic syndrome: the
morbidity and mortality in humans. Physical activity or Atherosclerosis Risk in Communities Study. Eur J
Cardiovasc Prev Rehabil 17: 309–313.
exercise training is necessary to maintain overall health
Chomsky DB, Lang CC, Rayos GH et al. (1996).
and functional capacity, and it plays a crucial role
Hemodynamic exercise testing. A valuable tool in the
in the prevention of cardiovascular disease, sudden selection of cardiac transplantation candidates.
cardiac death, hypertension, type II diabetes, colon Circulation 94: 3176–3183.
cancer, breast cancer, and obesity. Exercise training Church TS, Blair SN, Cocreham S et al. (2010). Effects of aer-
improves functional capacity in patients with auto- obic and resistance training on hemoglobin A1c levels in
nomic disorders, and can be therapeutic for patients patients with type 2 diabetes: a randomized controlled trial.
with orthostatic intolerance, syncope, or POTS. In JAMA 304: 2253–2262.
addition, exercise training improves mental health, Claydon VE, Hol AT, Eng JJ et al. (2006). Cardiovascular
helps to prevent depression, and promotes or maintains responses and postexercise hypotension after arm cycling
positive self-esteem. Adaptations involving the auto- exercise in subjects with spinal cord injury. Arch Phys
Med Rehabil 87: 1106–1114.
nomic nervous system play a large role in the protec-
Cole CR, Blackstone EH, Pashkow FJ et al. (1999). Heart-rate
tive and therapeutic effects of exercise training.
recovery immediately after exercise as a predictor of mor-
Moderate-intensity exercise at least 30 minutes per tality. N Engl J Med 341: 1351–1357.
day and at least 5 days per week is recommended Cole CR, Foody JM, Blackstone EH et al. (2000). Heart rate
for the vast majority of people. Supervised exercise recovery after submaximal exercise testing as a predictor
training is preferable to maximize functional capacity, of mortality in a cardiovascularly healthy cohort. Ann
and may be particularly important for patients with Intern Med 132: 552–555.
autonomic disorders. Craft LL, Perna FA, Freund KM et al. (2008). Psychosocial
correlates of exercise in women with self-reported depres-
REFERENCES sive symptoms. J Phys Act Health 5: 469–480.
Crisafulli A, Milia R, Vitelli S et al. (2009).
Alam M, Smirk FH (1937). Observations in man upon a blood Hemodynamic responses to metaboreflex activation:
pressure raising reflex arising from the voluntary muscles. insights from spinal cord-injured humans. Eur J Appl
J Physiol 89: 372–383. Physiol 106: 525–533.
Baatile J, Langbein WE, Weaver F et al. (2000). Effect of Dalgas U, Stenager E, Jakobsen J et al. (2009). Resistance
exercise on perceived quality of life of individuals with training improves muscle strength and functional capacity
Parkinson’s disease. J Rehabil Res Dev 37: 529–534. in multiple sclerosis. Neurology 73: 1478–1484.
 EXERCISE AND THE AUTONOMIC NERVOUS SYSTEM 157
de Goede CJ, Keus SH, Kwakkel G et al. (2001). The effects of Relation to habitual exercise and arterial stiffness. Eur
physical therapy in Parkinson’s disease: a research synthe- Heart J 24: 2213–2220.
sis. Arch Phys Med Rehabil 82: 509–515. Goldberger JJ, Le FK, Lahiri M et al. (2006). Assessment of
DeSouza CA, Shapiro LF, Clevenger CM et al. (2000). parasympathetic reactivation after exercise. Am J Physiol
Regular aerobic exercise prevents and restores age-related Heart Circ Physiol 290: H2446–H2452.
declines in endothelium-dependent vasodilation in healthy Goodman JM, Liu PP, Green HJ (2005). Left ventricular adap-
men. Circulation 102: 1351–1357. tations following short-term endurance training. J Appl
Dettmers C, Sulzmann M, Ruchay-Plossl A et al. (2009). Physiol 98: 454–460.
Endurance exercise improves walking distance in MS Goodson AR, Leibold JM, Gutterman DD (1994). Inhibition of
patients with fatigue. Acta Neurol Scand 120: 251–257. nitric oxide synthesis augments centrally induced sympa-
Dewland TA, Androne AS, Lee FA et al. (2007). Effect of thetic coronary vasoconstriction in cats. Am J Physiol
acetylcholinesterase inhibition with pyridostigmine on Heart Circ Physiol 267: H1272–H1278.
cardiac parasympathetic function in sedentary adults and Grassi G, Seravalle G, Bertinieri G et al. (2000). Sympathetic
trained athletes. Am J Physiol Heart Circ Physiol 293: and reflex alterations in systo-diastolic and systolic hyper-
H86–H92. tension of the elderly. J Hypertens 18: 587–593.
DiCarlo SE, Bishop VS (1992). Onset of exercise shifts oper- Grassi G, Seravalle G, Calhoun D et al. (1992). Physical exer-
ating point of arterial baroreflex to higher pressures. Am J cise in essential hypertension. Chest 101: 312S–314S.
Physiol Heart Circ Physiol 262: H303–H307. Green DJ, Maiorana A, O’Driscoll G et al. (2004). Effect of
Dinenno FA, Joyner MJ (2003). Blunted sympathetic vasocon- exercise training on endothelium-derived nitric oxide func-
striction in contracting skeletal muscle of healthy humans: tion in humans. J Physiol 561: 1–25.
is nitric oxide obligatory? J Physiol 553: 281–292. Hagberg JM, Hickson RC, McLane JA et al. (1979).
Dorfman TA, Levine BD, Tillery T et al. (2007). Cardiac atro- Disappearance of norepinephrine from the circulation fol-
phy in women following bed rest. J Appl Physiol 103: 8–16. lowing strenuous exercise. J Appl Physiol 47: 1311–1314.
Duncan JJ, Farr JE, Upton SJ et al. (1985). The effects of aer- Hagberg JM, Hickson RC, Ehsani AA et al. (1980). Faster
obic exercise on plasma catecholamines and blood pressure adjustment to and recovery from submaximal exercise in
in patients with mild essential hypertension. JAMA 254: the trained state. J Appl Physiol 48: 218–224.
2609–2613. Hall JE, Hildebrandt DA, Kuo J (2001). Obesity hypertension:
El-Sayed MS, Ali N, El-Sayed Ali Z (2005). Haemorheology role of leptin and sympathetic nervous system. Am J
in exercise and training. Sports Med 35: 649–670. Hypertens 14: 103S–115S.
Fraga R, Franco FG, Roveda F et al. (2007). Exercise training Haller RG, Lewis SF (1984). Pathophysiology of exercise perfor-
reduces sympathetic nerve activity in heart failure patients mance in muscle disease. Med Sci Sports Exerc 16: 456–459.
treated with carvedilol. Eur J Heart Fail 9: 630–636. Haller RG, Henriksson KG, Jorfeldt L et al. (1991). Deficiency
Fu Q, Levine BD (2005). Cardiovascular response to exercise of skeletal muscle succinate dehydrogenase and aconitase.
in women. Med Sci Sports Exerc 37: 1433–1435. Pathophysiology of exercise in a novel human muscle oxi-
Fu Q, Vongpatanasin W, Levine BD (2008). Neural and non- dative defect. J Clin Invest 88: 1197–1206.
neural mechanisms for sex differences in elderly hyperten- Hardman AE (2001). Physical activity and cancer risk. Proc
sion: can exercise training help? Hypertension 52: 787–794. Nutr Soc 60: 107–113.
Fu Q, Vangundy TB, Galbreath MM et al. (2010). Cardiac ori- Harrington R, Taylor G, Hollinghurst S et al. (2010). A
gins of the postural orthostatic tachycardia syndrome. J Am community-based exercise and education scheme for
Coll Cardiol 55: 2858–2868. stroke survivors: a randomized controlled trial and eco-
Fu Q, VanGundy TB, Shibata S et al. (2011). Exercise training nomic evaluation. Clin Rehabil 24: 3–15.
versus propranolol in the treatment of the postural ortho- Harris SK, Petrella RJ, Overend TJ et al. (2003). Short-term
static tachycardia syndrome. Hypertension 58: 167–175. training effects on left ventricular diastolic function and
Fujimoto N, Prasad A, Hastings JL et al. (2010). oxygen uptake in older and younger men. Clin J Sport
Cardiovascular effects of 1 year of progressive and vigor- Med 13: 245–251.
ous exercise training in previously sedentary individuals Henriksen EJ (2002). Invited review: effects of acute exercise
older than 65 years of age. Circulation 122: 1797–1805. and exercise training on insulin resistance. J Appl Physiol
Galbreath MM, Shibata S, VanGundy TB et al. (2011). Effects 93: 788–796.
of exercise training on arterial-cardiac baroreflex function Hespel P, Lijnen P, Van Hoof R et al. (1988). Effects of phys-
in POTS. Clin Auton Res 21: 73–80. ical endurance training on the plasma renin-angiotensin-
Gardenghi G, Rondon MU, Braga AM et al. (2007). The effects aldosterone system in normal man. J Endocrinol 116:
of exercise training on arterial baroreflex sensitivity in neu- 443–449.
rally mediated syncope patients. Eur Heart J 28: 2749–2755. Hicks AL, Martin KA, Ditor DS et al. (2003). Long-term exer-
Garssen MP, Bussmann JB, Schmitz PI et al. (2004). Physical cise training in persons with spinal cord injury: effects on
training and fatigue, fitness, and quality of life in Guillain– strength, arm ergometry performance and psychological
Barre syndrome and CIDP. Neurology 63: 2393–2395. well-being. Spinal Cord 41: 34–43.
Gates PE, Tanaka H, Graves J et al. (2003). Left ventricular Humm AM, Mason LM, Mathias CJ (2008). Effects of water
structure and diastolic function with human ageing. drinking on cardiovascular responses to supine exercise
158 Q. FU AND B.D. LEVINE
and on orthostatic hypotension after exercise in pure auto- Laterza MC, de Matos LD, Trombetta IC et al. (2007).
nomic failure. J Neurol Neurosurg Psychiatry 79: Exercise training restores baroreflex sensitivity in never-
1160–1164. treated hypertensive patients. Hypertension 49: 1298–1306.
Ichinose M, Saito M, Kondo N et al. (2008). Baroreflex and Levine BD (1993). Regulation of central blood volume and
muscle metaboreflex: control of muscle sympathetic nerve cardiac filling in endurance athletes: the Frank–Starling
activity. Med Sci Sports Exerc 40: 2037–2045. mechanism as a determinant of orthostatic tolerance.
Imai K, Sato H, Hori M et al. (1994). Vagally mediated heart Med Sci Sports Exerc 25: 727–732.
rate recovery after exercise is accelerated in athletes but Levine BD (2001). Exercise physiology for the clinician. In:
blunted in patients with chronic heart failure. J Am Coll Thompson PD (Ed.), Exercise and Sports Cardiology.
Cardiol 24: 1529–1535. McGraw-Hill, Medical Publishing Division, New York,
Iwasaki K, Zhang R, Zuckerman JH et al. (2003). Dose- pp. 3–29.
response relationship of the cardiovascular adaptation to Levine BD (2008). VO2max: what do we know, and what do
endurance training in healthy adults: how much training we still need to know? J Physiol 586: 25–34.
for what benefit? J Appl Physiol 95: 1575–1583. Levine BD, Buckey JC, Fritsch JM et al. (1991a). Physical fit-
Joosen M, Sluiter J, Joling C et al. (2008). Evaluation of the ness and cardiovascular regulation: mechanisms of ortho-
effects of a training programme for patients with prolonged static intolerance. J Appl Physiol 70: 112–122.
fatigue on physiological parameters and fatigue com- Levine BD, Lane LD, Buckey JC et al. (1991b). Left ventric-
plaints. Int J Occup Med Environ Health 21: 237–246. ular pressure-volume and Frank–Starling relations in
Joyner MJ (2006). Baroreceptor function during exercise: endurance athletes. Implications for orthostatic tolerance
resetting the record. Exp Physiol 91: 27–36. and exercise performance. Circulation 84: 1016–1023.
Joyner MJ, Green DJ (2009). Exercise protects the cardiovas- Levy WC, Cerqueira MD, Harp GD et al. (1998). Effect
cular system: effects beyond traditional risk factors. J of endurance exercise training on heart rate variability at rest
Physiol 587: 5551–5558. in healthy young and older men. Am J Cardiol 82: 1236–1241.
Joyner MJ, Masuki S (2008). POTS versus deconditioning: the Lindstrom J, Ilanne-Parikka P, Peltonen M et al. (2006).
same or different? Clin Auton Res 18: 300–307. Sustained reduction in the incidence of type 2 diabetes
Joyner MJ, Thomas GD (2003). Having it both ways? by lifestyle intervention: follow-up of the Finnish
Vasoconstriction in contracting muscles. J Physiol 550: 333. Diabetes Prevention Study. Lancet 368: 1673–1679.
Julius S, Gudbrandsson T, Jamerson K et al. (1991). The hemo- Lloyd PG, Yang HT, Terjung RL (2001). Arteriogenesis and
dynamic link between insulin resistance and hypertension. angiogenesis in rat ischemic hindlimb: role of nitric oxide.
J Hypertens 9: 983–986. Am J Physiol Heart Circ Physiol 281: H2528–H2538.
Keller DM, Ogoh S, Greene S et al. (2004). Inhibition of KATP Marcus BH, Williams DM, Dubbert PM et al. (2006). Physical
channel activity augments baroreflex-mediated vasocon- activity intervention studies: what we know and what we
striction in exercising human skeletal muscle. J Physiol need to know: a scientific statement from the American
561: 273–282. Heart Association Council on Nutrition, Physical
Khan N, Afaq F, Mukhtar H (2010). Lifestyle as risk factor for Activity, and Metabolism (Subcommittee on Physical
cancer: evidence from human studies. Cancer Lett 293: Activity); Council on Cardiovascular Disease in the
133–143. Young; and the Interdisciplinary Working Group on
Kingwell BA (2000). Nitric oxide as a metabolic regulator dur- Quality of Care and Outcomes Research. Circulation 114:
ing exercise: effects of training in health and disease. Clin 2739–2752.
Exp Pharmacol Physiol 27: 239–250. Martin WH 3rd, Montgomery J, Snell PG et al. (1987).
Knowler WC, Barrett-Connor E, Fowler SE et al. (2002). Cardiovascular adaptations to intense swim training in sed-
Reduction in the incidence of type 2 diabetes with entary middle-aged men and women. Circulation 75:
lifestyle intervention or metformin. N Engl J Med 346: 323–330.
393–403. Martin WH 3rd, Berman WI, Buckey JC et al. (1989). Effects
Kohno K, Matsuoka H, Takenaka K et al. (2000). Depressor of active muscle mass size on cardiopulmonary responses
effect by exercise training is associated with amelioration to exercise in congestive heart failure. J Am Coll Cardiol 14:
of hyperinsulinemia and sympathetic overactivity. Intern 683–694.
Med 39: 1013–1019. Masuki S, Eisenach JH, Schrage WG et al. (2007a). Arterial
Kraus WE, Levine BD (2007). Exercise training for diabetes: baroreflex control of heart rate during exercise in postural
the “strength” of the evidence. Ann Intern Med 147: tachycardia syndrome. J Appl Physiol 103: 1136–1142.
423–424. Masuki S, Eisenach JH, Schrage WG et al. (2007b). Reduced
Krogh A, Lindhard J (1913). The regulation of respiration and stroke volume during exercise in postural tachycardia syn-
circulation during the initial stages of muscular work. J drome. J Appl Physiol 103: 1128–1135.
Physiol 47: 112–136. Meredith IT, Friberg P, Jennings GL et al. (1991). Exercise
La Rovere MT, Pinna GD, Hohnloser SH et al. (2001). training lowers resting renal but not cardiac sympathetic
Baroreflex sensitivity and heart rate variability in the iden- activity in humans. Hypertension 18: 575–582.
tification of patients at risk for life-threatening arrhyth- Michelini LC, Stern JE (2009). Exercise-induced neuronal
mias: implications for clinical trials. Circulation 103: plasticity in central autonomic networks: role in cardiovas-
2072–2077. cular control. Exp Physiol 94: 947–960.
 EXERCISE AND THE AUTONOMIC NERVOUS SYSTEM 159
Millar PJ, Rakobowchuk M, Adams MM et al. (2009). Prior BM, Lloyd PG, Yang HT et al. (2003). Exercise-induced
Effects of short-term training on heart rate dynamics in vascular remodeling. Exerc Sport Sci Rev 31: 26–33.
individuals with spinal cord injury. Auton Neurosci 150: Raglin JS (1990). Exercise and mental health. Beneficial and
116–121. detrimental effects. Sports Med 9: 323–329.
Mitchell JH (1990). J.B. Wolffe memorial lecture. Neural con- Raven PB (2008). Recent advances in baroreflex control of
trol of the circulation during exercise. Med Sci Sports blood pressure during exercise in humans: an overview.
Exerc 22: 141–154. Med Sci Sports Exerc 40: 2033–2036.
Monahan KD, Dinenno FA, Tanaka H et al. (2000). Regular Raven PB, Fadel PJ, Ogoh S (2006). Arterial baroreflex reset-
aerobic exercise modulates age-associated declines in car- ting during exercise: a current perspective. Exp Physiol 91
diovagal baroreflex sensitivity in healthy men. J Physiol (1): 37–49.
529: 263–271. Ray CA, Rea RF, Clary MP et al. (1992). Muscle sympathetic
Mora S, Cook N, Buring JE et al. (2007). Physical activity and nerve responses to static leg exercise. J Appl Physiol 73:
reduced risk of cardiovascular events: potential mediating 1523–1529.
mechanisms. Circulation 116: 2110–2118. Remensnyder JP, Mitchell JH, Sarnoff SJ (1962). Functional
Mousa TM, Liu D, Cornish KG et al. (2008). Exercise training sympatholysis during muscular activity. Observations on
enhances baroreflex sensitivity by an angiotensin influence of carotid sinus on oxygen uptake. Circ Res 11:
II-dependent mechanism in chronic heart failure. J Appl 370–380.
Physiol 104: 616–624. Rennie KL, Hemingway H, Kumari M et al. (2003). Effects of
Mtinangi BL, Hainsworth R (1998). Increased orthostatic moderate and vigorous physical activity on heart rate var-
tolerance following moderate exercise training in patients iability in a British study of civil servants. Am J Epidemiol
with unexplained syncope. Heart 80: 596–600. 158: 135–143.
Nakamura T, Hirayama M, Yamashita F et al. (2010). Lowered Robertson D, Hollister AS, Biaggioni I et al. (1993). The diag-
cardiac sympathetic nerve performance in response to nosis and treatment of baroreflex failure. N Engl J Med 329:
exercise in Parkinson’s disease. Mov Disord 25: 1183–1189. 1449–1455.
Nelson AJ, Juraska JM, Musch TI et al. (2005). Neuroplastic Rosenwinkel ET, Bloomfield DM, Arwady MA et al. (2001).
adaptations to exercise: neuronal remodeling in cardio- Exercise and autonomic function in health and cardiovas-
respiratory and locomotor areas. J Appl Physiol 99: cular disease. Cardiol Clin 19: 369–387.
2312–2322. Routledge FS, Campbell TS, McFetridge-Durdle JA et al.
Niebauer J, Cooke JP (1996). Cardiovascular effects of (2010). Improvements in heart rate variability with exer-
exercise: role of endothelial shear stress. J Am Coll cise therapy. Can J Cardiol 26: 303–312.
Cardiol 28: 1652–1660. Rowell LB (1993a). Arterial baroreflexes, central command,
Nishime EO, Cole CR, Blackstone EH et al. (2000). Heart rate and muscle chemoreflexes: a synthesis. In: LB Rowell
recovery and treadmill exercise score as predictors of (Ed.), Human Cardiovascular Control. Oxford University
mortality in patients referred for exercise ECG. JAMA Press, New York, pp. 441–483.
284: 1392–1398. Rowell LB (1993b). Central circulatory adjustments to dynamic
Okazaki K, Iwasaki K, Prasad A et al. (2005). Dose-response exercise. In: LB Rowell (Ed.), Human Cardiovascular
relationship of endurance training for autonomic circula- Control. Oxford University Press, New York, pp. 162–203.
tory control in healthy seniors. J Appl Physiol 99: Rowell LB, O’Leary DS (1990). Reflex control of the circula-
1041–1049. tion during exercise: chemoreflexes and mechanoreflexes.
Olsen DB, Orngreen MC, Vissing J (2005). Aerobic training J Appl Physiol 69: 407–418.
improves exercise performance in facioscapulohumeral Rush JW, Aultman CD (2008). Vascular biology of angioten-
muscular dystrophy. Neurology 64: 1064–1066. sin and the impact of physical activity. Appl Physiol Nutr
Ozkor MA, Murrow JR, Rahman AM et al. (2011). Metab 33: 162–172.
Endothelium-derived hyperpolarizing factor determines Saltin B, Blomqvist G, Mitchell JH et al. (1968). Response to
resting and stimulated forearm vasodilator tone in health exercise after bed rest and after training. Circulation 38:
and in disease. Circulation 123: 2244–2253. VII1–VII78.
Patel KP, Zhang K, Zucker IH et al. (1996). Decreased gene Schmid A, Huonker M, Barturen JM et al. (1998).
expression of neuronal nitric oxide synthase in hypothala- Catecholamines, heart rate, and oxygen uptake during exer-
mus and brainstem of rats in heart failure. Brain Res 734: cise in persons with spinal cord injury. J Appl Physiol 85:
109–115. 635–641.
Pierpont GL, Stolpman DR, Gornick CC (2000). Heart rate Schrage WG, Eisenach JH, Dinenno FA et al. (2004). Effects
recovery post-exercise as an index of parasympathetic of midodrine on exercise-induced hypotension and blood
activity. J Auton Nerv Syst 80: 169–174. pressure recovery in autonomic failure. J Appl Physiol
Piko BF, Keresztes N (2006). Physical activity, psychosocial 97: 1978–1984.
health, and life goals among youth. J Community Health Shetler K, Marcus R, Froelicher VF et al. (2001). Heart rate
31: 136–145. recovery: validation and methodologic issues. J Am Coll
Pitetti KH, Barrett PJ, Abbas D (1993). Endurance exercise Cardiol 38: 1980–1987.
training in Guillain–Barre syndrome. Arch Phys Med Shibata S, Hastings JL, Prasad A et al. (2008). “Dynamic”
Rehabil 74: 761–765. Starling mechanism: effects of ageing and physical
160 Q. FU AND B.D. LEVINE
fitness on ventricular-arterial coupling. J Physiol 586: Tanaka H, Dinenno FA, Monahan KD et al. (2000). Aging,
1951–1962. habitual exercise, and dynamic arterial compliance.
Shibata S, Perhonen M, Levine BD (2010). Supine cycling plus Circulation 102: 1270–1275.
volume loading prevent cardiovascular deconditioning Timmers HJ, Karemaker JM, Wieling W et al. (2003a).
during bed rest. J Appl Physiol 108: 1177–1186. Baroreflex and chemoreflex function after bilateral carotid
Shibata S, Fu Q, Bivens TB et al. (2012). Short-term exercise body tumor resection. J Hypertens 21: 591–599.
training improves the cardiovascular response to exercise Timmers HJ, Karemaker JM, Wieling W et al. (2003b).
in the postural orchostatic tachycardia syndrome. J Baroreflex control of muscle sympathetic nerve activity
Physiol 590: 3495–3505. after carotid body tumor resection. Hypertension 42:
Shook RP, Fu Q, Vangundy TB et al. (2007). Patients with 143–149.
postural orthostatic tachycardia syndrome (POTS) have a Tuomilehto J, Lindstrom J, Eriksson JG et al. (2001).
lower level of fitness compared to healthy but sedentary Prevention of type 2 diabetes mellitus by changes in life-
females. Med Sci Sports Exerc 39: S169. style among subjects with impaired glucose tolerance. N
Smit AA, Timmers HJ, Wieling W et al. (2002). Long-term Engl J Med 344: 1343–1350.
effects of carotid sinus denervation on arterial blood Valent L, Dallmeijer A, Houdijk H et al. (2007). The effects of
pressure in humans. Circulation 105: 1329–1335. upper body exercise on the physical capacity of people with
Smith GD, Mathias CJ (1996). Differences in cardiovascular a spinal cord injury: a systematic review. Clin Rehabil 21:
responses to supine exercise and to standing after exercise 315–330.
in two clinical subgroups of Shy–Drager syndrome (multi- Valent LJ, Dallmeijer AJ, Houdijk H et al. (2009). Effects of
ple system atrophy). J Neurol Neurosurg Psychiatry 61: hand cycle training on physical capacity in individuals with
297–303. tetraplegia: a clinical trial. Phys Ther 89: 1051–1060.
Smith GD, Watson LP, Pavitt DV et al. (1995). Abnormal Voet NB, van der Kooi EL, Riphagen II et al. (2010). Strength
cardiovascular and catecholamine responses to supine training and aerobic exercise training for muscle disease.
exercise in human subjects with sympathetic dysfunction. Cochrane Database Syst Rev CD003907.
J Physiol 484: 255–265. Watanabe J, Thamilarasan M, Blackstone EH et al. (2001).
Smith GD, Watson LP, Mathias CJ (1996a). Cardiovascular Heart rate recovery immediately after treadmill exercise
and catecholamine changes induced by supine exercise and left ventricular systolic dysfunction as predictors of
and upright posture in vasovagal syncope. Comparisons mortality: the case of stress echocardiography.
with normal subjects and subjects with sympathetic dener- Circulation 104: 1911–1916.
vation. Eur Heart J 17: 1882–1890. Wenz T, Diaz F, Hernandez D et al. (2009). Endurance exer-
Smith GD, Watson LP, Mathias CJ (1996b). Neurohumoral, cise is protective for mice with mitochondrial myopathy.
peptidergic and biochemical responses to supine exercise in J Appl Physiol 106: 1712–1719.
two groups with primary autonomic failure: Shy–Drager Werner WG, DiFrancisco-Donoghue J, Lamberg EM (2006).
syndrome/multiple system atrophy and pure autonomic Cardiovascular response to treadmill testing in Parkinson
failure. Clin Auton Res 6: 255–262. disease. J Neurol Phys Ther 30: 68–73.
Snell PG, Martin WH, Buckey JC et al. (1987). Maximal vas- Winker R, Barth A, Bidmon D et al. (2005). Endurance exer-
cular leg conductance in trained and untrained men. J Appl cise training in orthostatic intolerance: a randomized, con-
Physiol 62: 606–610. trolled trial. Hypertension 45: 391–398.
Snook EM, Motl RW (2009). Effect of exercise training on Wolf AM, Woodworth KA (2009). Obesity prevention:
walking mobility in multiple sclerosis: a meta-analysis. recommended strategies and challenges. Am J Med 122:
Neurorehabil Neural Repair 23: 108–116. S19–S23.
Sveen ML, Jeppesen TD, Hauerslev S et al. (2008). Endurance Yousefi B, Tadibi V, Khoei AF et al. (2009). Exercise therapy,
training improves fitness and strength in patients with quality of life, and activities of daily living in patients with
Becker muscular dystrophy. Brain 131: 2824–2831. Parkinson disease: a small scale quasi-randomised trial.
Taivassalo T, Shoubridge EA, Chen J et al. (2001). Aerobic Trials 10: 67.
conditioning in patients with mitochondrial myopathies: Ziegler MG, Ruiz-Ramon P, Shapiro MH (1993). Abnormal
physiological, biochemical, and genetic effects. Ann stress responses in patients with diseases affecting the
Neurol 50: 133–141. sympathetic nervous system. Psychosom Med 55: 339–346.
Taivassalo T, Jensen TD, Kennaway N et al. (2003). The spec- Zucker IH, Patel KP, Schultz HD et al. (2004). Exercise
trum of exercise tolerance in mitochondrial myopathies: a training and sympathetic regulation in experimental heart
study of 40 patients. Brain 126: 413–423. failure. Exerc Sport Sci Rev 32: 107–111.