Exercise and the Cardiovascular System
HK Hammond, University of California San Diego, San Diego, CA, USA
Ó 2014 Elsevier Inc. All rights reserved.
This article is a revision of the previous edition article by George E. Taffet, Robert W. Holtz, Charlotte A. Tate, volume 3, pp. 865–871, Ó 1997, Elsevier
Inc.
Nomenclature
AVO2D Arterial oxygen content minus pulmonary artery
oxygen content, a measure of oxygen extraction.
CO, Q Terms used to denote cardiac output (CO) or blood
flow (Q).
EDV End-diastolic volume.
ESV End-systolic volume.
Dynamic vs Static Exercise
The terms aerobic, isotonic, and dynamic are often used
interchangeably to refer to activity that is predominantly fueled
by oxidative phosphorylation (aerobic), is performed against
a constant load (isotonic), involving the rhythmic repeated
contractions of large groups (legs, arms) of skeletal muscle
(dynamic). Adenosine triphosphate (ATP) is the molecular
source for energy production in mitochondria in exercising
muscle cells. Although ATP is generated predominantly aero-
bically at low and moderate effort intensity, anaerobic
production of ATP is also recruited at higher effort intensity.
For example, anaerobic production of ATP is initiated at 70%
of maximal effort. Although the term isotonic is often used,
running involves variations in muscle load, and, hence, is not
purely isotonic. Because of these distinctions, I will use the
term dynamic in referring to exercise that is largely oxygen-
dependent – namely, running, bicycling, swimming, and
cross-country skiing.
The terms anaerobic, isometric, resistive, and static refer to
activity that is predominantly fueled by the anaerobic break-
down of glucose to lactate. This type of exercise is performed at
a relatively constant muscle length (isometric) and, in its pure
form, involves no movement (static). The current article will
treat static exercise only briefly mainly to emphasize its differ-
ences from dynamic exercise.
The effects of static and dynamic exercises are quite different,
owing to the different hemodynamic challenges imposed
by these two types of exercise (Figure 1). The nature of low
resistance, high oxygen-consuming exercise such as running
would be predicted to result in substantial increases in oxygen
delivery to exercising muscle, which in turn is directly related to
blood flow. Consequently, to fuel the 11-fold increase in
oxygen consumption in exercising leg muscle, a greater than
threefold increase in cardiac output (CO) – 90% of which goes
to exercising muscle – is observed. The high metabolic rate of
exercising muscle is naturally associated with profound release
of adenosine, a consequence of the catalysis of ATP. Adenosine,
a profoundly potent vasodilator, released in abundance in
exercising muscle beds, counterbalances vasoconstriction
Reference Module in Biomedical Research, 3rd edition http://dx.doi.org/10.1016/B978-0-12-801238-3.00023-4
LV Left ventricle, left ventricular.
VO2 Rate of oxygen extraction (oxygen used in ml kg
1
min
1).
Work rate The amount of work performed in 1 min,
reported in kilopond meters per minute (KPM min
1). The
term workload is often used instead.
associated with increased sympathetic activation, the net effect
being substantial vasodilatation in vascular beds, perfusion
of exercising skeletal muscle. Consequently, despite a greater
than threefold increase in CO at peak effort, one sees only
a 25% increase in mean arterial pressure (MAP).
In contrast, the more limited distribution of muscle mass
and the less demand for oxygen required for purely static
exercise – of single-hand grip in the data shown in Figure 1 –
would be predicted to require less augmentation in blood
flow, and produce less metabolic vasodilatation. Conse-
quently, CO increases less than is seen with dynamic exercise
and peripheral resistance does not fall.
Cardiovascular Responses during Dynamic Exercise
Circulatory responses in dynamic exercise are proportional
to aerobic requirements and to work rate (Figure 2). Oxygen
consumption (VO2) at peak dynamic exercise is the best
measure of aerobic fitness, so it is useful to examine the Fick
relationship to see what changes occur to increase maximal
oxygen consumption.
VO2 ¼ CO  AVO2D
This relationship shows that oxygen consumption (VO2) is
a product of CO and the difference in oxygen content between
arterial and mixed venous blood (AVO2D). The increase in
oxygen consumption during an acute bout of dynamic exer-
cise, therefore, results from increased oxygen delivery via
increased CO, and increased peripheral use of oxygen. They
are in balance at peak exercise so that each contributes
approximately equally to the net increase in oxygen
consumption.
Before proceeding to the specific hemodynamic effects
associated with increasing effort intensity, we will analyze
physiological adjustments in the context of the Fick equation.
As shown in Table 1, it is useful to analyze fold increases of
(vs basal measures) VO2, CO, and AVO2D during peak
dynamic exercise. The table provides measurements in an
apocryphal normal healthy but sedentary 40-year-old human
1
2 Exercise and the Cardiovascular System

Static Dynamic
Oxygen 40
consumption 25
(ml kg−1 min−1) 10

180
Heart rate
(beats min−1) 120
60

Arterial Mean
180 Systolic
blood 120
pressure 60
(mmHg) Diastolic

Cadiac 15 80 Stroke
index 10 60 volume
(l min m−2) 5 40 (ml min−1 kg−1)

Systemic 20
vascular
15
resistance
10 40% MVC Δ100 KPM min−1
(PRU)
0 0.5 1.0 1.5 2.0 0 3 6 9 12
Minutes Minutes

Figure 1 A comparison of acute effects of static (isometric) and dynamic exercises on oxygen consumption, heart rate, arterial blood pressure,
stroke volume, and systemic vascular resistance. Pure static exercise (handgrip) was performed at 40% of maximum voluntary contraction; dynamic
exercise was performed on a bicycle, increasing work rate to 100 kilopond meters per minute (KPM min
1). Static exercise tends to increase arterial
blood pressure and minimally influence cardiac output compared with dynamic exercise, which is associated with minimal increases in mean arterial
pressure, reduction in peripheral vascular resistance, and striking increases in cardiac output. PRU, peripheral resistance units. From Longhurst, J.C.,
Mitchell, J.H., 1983. Does endurance training benefit the cardiovascular system? J. Cardiovasc. Med. 8, 227–236.

Table 1 Fick equation analysis of CO and AVO2D at peak exercise

Basal Peak effort Fold increase

VO2 (l min
1) 0.25 2.8 11.2

AVO2D (ml dl
1) 4.5 16 3.6
CO (l min
1) 5.5  0.8 17.5  2.6 3.2
HR (beats min
1) 75 180 2.4
SV (ml)a 73 97 1.3

AVO2D, arterial to mixed venous oxygen content difference; VO2, oxygen

Figure 2 Linear relationship between cardiac output and oxygen
consumption. Cardiac output (CO), oxygen consumption (VO2), and
work rate (not shown) are tightly coupled during dynamic exercise.
Cardiovascular responses are matched tightly to metabolic require-
ments. For each additional liter of oxygen consumed, cardiac output
increases by 6 l min
1.
subject weighing 70 kg. Measurements are obtained during
treadmill exercise on a standard protocol where grade and
speed are sequentially increased at set intervals until the subject
is exhausted. Leads have been attached to enable electrocar-
diographic recording, catheters placed in the radial and
pulmonary arteries for blood sampling, and expired air is
collected to measure oxygen consumption.
consumption; CO, cardiac output; mean of three measurements by thermal dilution;
HR, heart rate; SV, stroke volume.
a
SV is calculated from the mean CO and heart rate (CO  HR), other values are
measured; subject is 40-year-old, 70 kg sedentary but otherwise healthy.
Observations from Table 1
l The increase in CO is achieved primarily via increased heart
rate (HR) with a relatively smaller contribution via stroke
volume (SV).
l The striking increase in VO2 (11.2-fold increase vs basal) is
attained via similar contributions of oxygen delivery (CO
increases 3.2-fold) and oxygen extraction (AVO2D increases
3.6-fold).
Using the Fick equation as a framework, we now will
examine CO (SV  HR), VO2, and AVO2D.

Stroke Volume
Although SV increases during upright dynamic exercise (it
changes minimally if at all during swimming), its contribution
to increases in CO at peak effort is relatively small. Table 1
illustrates that most of the increases in CO stems from a 2.4-
fold increase in HR, with a relatively small increase (1.3-fold)
in SV. It is difficult to measure SV directly in human subjects at
rest, and even harder during exercise, so typically this is
a calculated measure, based on CO and HR. Although HR can
be precisely measured, measures of CO typically have coeffi-
cients of variation of 15% in healthy subjects, so value shown
for basal SV in Table 1 (73 ml) translates to a range from 64 to
84 ml. Alterations in SV of 24 ml, the difference between basal
and peak exercise in Table 1, are barely outside experimental
error. To determine rigorously whether such a small change
predominantly reflects in increased left ventricular (LV) end-
diastolic volume (EDV) (Starling effect) or a reduction in LV
end-systolic volume (ESV) (an inotropic effect) is an irresolv-
able matter in humans. Although magnetic resonance imaging
and computed tomography have enabled resolution of rela-
tively small changes in LV volume in human subjects, their
application to upright dynamic exercise is limited. Suffice it to
say that during peak exercise, increased HR is the primary
means by which CO increases, and HR increases in SV are less
important.
Studies using ultrasonic micrometers to measure LV
volumes during maximal upright dynamic exercise in dogs
confirm that increases in LV EDV during dynamic exercise are a
minor contributor to increasing CO during peak effort (Vatner
et al., 1972). The difficulty in demonstrating that the Starling
effect is a dominant factor in the exercise response is also re-
ported in clinical studies (Stratton et al., 1994).
HR also rises linearly with work rate and plateaus briefly
right before exhaustion. Therefore, it can be used as an objec-
tive assessment of effort intensity. There is a decline in maximal
HR with age, i.e., it falls about 10 beats min
1 per decade.
A useful formula provides an estimate of maximal HR:
Maximal HR ¼ 220
age
For example, a 40-year-old subject would be predicted to
attain a maximal exercise HR of 180 beats min
1. Although
more complex formulas may provide somewhat better esti-
mates, the standard error of the estimate of these formulas is
15 beats min
1, providing rough but useful guidelines.
Barring primary abnormalities in cardiac conduction system
function or pharmacological agents that influence HR, the
value of HR at maximal effort should be close to the one pre-
dicted by formula. The individual also provides a subjective
assessment of whether they feel they are approaching maximal
effort.
HR alone, however, is an inadequate means to increase CO.
For example, a doubling of HR by atrial pacing in a supine
nonexercising subject results in a halving of SV and no change
in CO. A case can be made that the force–frequency effect may
provide a small increase in CO in this setting, but it would be
small, of the order of a 10% increase. While it is true that
patients with third degree AV block with extremely low HR
(<40 beats min
1) may have increased CO with increased HR,
this does not apply when basal HR is in the physiologically
normal range and is then doubled by pacing. The dependence
Exercise and the Cardiovascular System 3
Figure 3 The effect of atrial pacing in conscious resting dogs demon-
strates a progressive reduction in left ventricular (LV) diameter, and
hence LV volume, with increasing heart rate (HR). Increasing HR alone,
without a means of increasing venous return and preload, is an ineffec-
tive means of increasing cardiac output. Modified from Rushmer, R.F.,
1976. Cardiovascular Dynamics. W.B. Saunders Co., Philadelphia,
pp. 70–112.
of CO on venous return is at play here, and doubling the HR by
atrial pacing does not provide a means of increasing venous
return, hence the fall in SV (Figure 3). In contrast, having
a subject double his/her resting HR by running on a treadmill
would more than double CO – SV would be maintained and
likely increased somewhat (Table 1) due to increased inotropy
associated with increased sympathetic activation.
Oxygen consumption. Oxygen consumption (VO2) is
measured in ml kg
1 min
1. The normal basal VO2 is
3.5 ml kg
1 min
1, and is referred to as 1 MET (metabolic
equivalent of task) in many exercise laboratories. This is
a useful index that enables one to refer to multiples of basal
VO2. The VO2 at peak effort (VO2max) is a reliable and
reproducible measure of aerobic fitness.
There is a 10 ml kg
1 min
1 decay in VO2max with each
decade in life. A useful formula to predict VO2max (in METS) is
Maximal METS ¼ 15
(age/10).
For example, a sedentary but otherwise healthy 40-year-old
should be able to achieve 15
(40/10) ¼ 11 METS at peak
dynamic effort. Since 1 MET ¼ 3.5 ml kg
1 min
1, this would
be 11 (3.5) ¼ 39 ml kg
1 min
1. By comparison, a 20-year-old
sedentary subject would be anticipated to attain 2 METS more
(two decades younger) or an additional 7 ml kg
1 min
1 for
a total of 46 ml kg
1 min
1. If one would collect expired air on
such an individual, the actual measure of VO2 would be near
this value, and, for research purposes actual measurement of
VO2 is preferred. However, in clinical settings, one can calculate
METS based on treadmill grade and speed and estimate
a subject’s aerobic fitness on the basis of maximal work rate
achieved. We will later examine the effects of chronic sustained
dynamic exercise (training), where the hallmark of a training
effect is increased VO2max. A normal (not genetically gifted)
subject should be able to increase his/her VO2max by about
25% – for our 40-year-old subject with a pretraining VO2max
of 39 ml kg
1 min
1, this would mean attaining a VO2max
after training of 49 ml kg
1 min
1 – superior to a sedentary
subject who is 20 years younger.
In contrast, the typical 40-year-old 70 kg patient with well-
treated congestive heart failure, who normally would have
a VO2max of 39 ml kg
1 min
1, would likely attain less than
50% of this value – around 20 ml kg
1 min
1. The primary
4 Exercise and the Cardiovascular System
VO2 = CO x AVO2D
CO = VO2 ÷ AVO2D (10)
= (20 ml min–1 kg–1) (70 kg) ÷ 16 ml dl–1 (10)
= (1400 ml min–1) ÷ 160 ml l–1
= 8.8 l min–1
Figure 4 Use of Fick equation to calculate cardiac output (CO) from
measured oxygen consumption (VO2) and oxygen extraction (AVO2D).
Since the AVO2D at maximal effort is relatively fixed (16 ml dl
1), VO2
is a direct correlate of CO. In clinical settings, this is quite useful,
because VO2 and work rate are tightly coupled, and, therefore, maximal
treadmill performance provides information about maximal heart
function.
problem would be a marked diminution in maximal CO; HR
and AVO2D would be similar at peak effort. For example, using
the Fick equation and assuming an AVO2D of 16 ml dl
1, the
CO associated with a VO2max of 20 ml kg
1 min
1in such
a subject would be 8.8 l min
1 (Figure 4), 50% of that antic-
ipated in a normal subject of the same age and weight
(Table 1). Nowhere are the physiological principles of exercise
more relevant than in managing patients with cardiovascular
diseases.
Oxygen Extraction (AVO2D)
At peak dynamic effort, regardless of fitness, the arterial to
mixed venous oxygen content difference approaches
16 ml dl
1. To maintain the same relative oxygen extraction
(AVO2D) in the setting of higher flow rates (CO), it requires
a proportional increase in the absolute amount of oxygen
extracted – otherwise, at high CO, the AVO2D would narrow.
The relative invariance of this term enables one to calculate
either CO or VO2 using the fixed value for AVO2Dmax and
knowing one of the other two values (Figure 4).
Exercise Responses during Increasing Effort Intensity
(Table 2)
The cardiovascular system has the following missions during
dynamic exercise: (1) supply oxygen to the site of oxygen
extraction and chemical energy production (the mitochondria
of exercising muscle), (2) transport metabolic products away
from exercising muscle, and (3) dissipate heat. Basal oxygen
levels in skeletal muscle cells can support exercise only for
several seconds – blood flow and its attendant oxygen delivery
immediately are required to support aerobic metabolism. An
initial anticipatory central sympathetic outflow precedes exer-
cise, which serves to increase HR and CO and decrease venous
compliance. Central parasympathetic withdrawal also occurs
early in the exercise response, accounting for the chronotropic
response during mild intensity exercise (Table 2).
Mild-Intensity Exercise (HR < 100 beats minL1)
Shortly after the beginning of exercise, muscle blood flow
increases 15-fold predominantly through local vasodilatation
in the vascular beds perfusing exercising skeletal muscle.
Table 2 Cardiovascular physiological responses to dynamic
exercise
Low intensity (HR < 100 beats minL1)
l Increased heart rate (via vagal withdrawal)
l Increased venous return (via muscle contraction in legs)
Moderate intensity (HR 100–140 beats minL1)
l Increased sympathetic tone leads to marked increases in
l Heart rate
l Venous return
l Left ventricular contractility
High intensity (HR 140–180 beats minL1)
l Maximal increase in sympathetic activation (neural and adrenal
medulla)
l Attainment of maximal increases in
l Heart rate
l Venous return
l Left ventricular contractility
l Marked vasodilation in exercising muscle vascular beds
l Cardiac output increases greater than threefold – 18 l min
1
l Mean arterial pressure increases only 25% (due to vasodilation)
Sedentary 70 kg, 40-year-old subject.
Reduced parasympathetic tone results in an increased HR early
in exercise, but at levels of exercise beyond 50% of maximal
work capacity, sympathetic activity becomes the more impor-
tant means of further increasing HR. Reduced vascular resis-
tance increases perfusion of active muscle beds. The combined
effects of the mechanical pumping action of contracting
muscles and increased venoconstriction via sympathetic
adrenergic activation augment venous return.
Moderate-Intensity Exercise (HR 100–140 beats minL1)
Progressive increases in sympathetic activation – a consequence
of the release of norepinephrine from adrenergic nerve termi-
nals that impinge sinoatrial node, atrioventricular node, and
atrial and ventricular cardiac myocytes result in further
increases in HR and LV contractility, and in reduced venous
compliance, increasing venous return even further.
High-Intensity Exercise (HR 140–180 beats minL1)
As maximal effort intensity is attained, sympathetic activation
reaches its zenith. In addition to neural release of norepi-
nephrine, the adrenal medulla releases epinephrine. A gener-
alized arteriolar constriction would be predicted is this setting,
yet MAP increases just minimally, no more than 25%, despite
a greater than threefold increase in CO. In a brilliant
demonstration of biological economy, adenosine-release –
a metabolic consequence of ATP utilization in actively con-
tracting skeletal muscle – provides profound vasodilation.
A regional metabolic vasodilation counterbalancing other-
wise systemic vasoconstriction enables a diversion of blood
away from inactive regions and toward exercising muscle.
Although the absolute blood flow to the splanchnic bed is
maintained, the relative amount of the CO that perfuses it is
much reduced during exercise, owing to increased sympa-
thetic tone. The result of these integrated cardiovascular
responses is that maximal dynamic effort is associated with an

11-fold increase in VO2 and a greater than threefold increase
in CO compared with basal.
Throughout exercise, CO is precisely matched to metabolic
needs. The acute exercise response is one of increased sympa-
thetic tone modified by local vasodilation in exercising muscle.
Increased venous return, decreased systemic resistance, and
enhanced contractile state increase CO. The physiological
responses to dynamic exercise are exquisitely integrated among
the pulmonary and systemic circulations. The lungs, the heart,
and cellular metabolism work in exquisite harmony (Figure 5).
Fuel Utilization
Exercising muscle uses three fuel sources: free fatty acids,
glucose, and muscle glycogen. Preferential use of fats as fuel,
in the form of free fatty acids, forestalls the use of muscle
glycogen stores, which are limited, and circumvents anaerobic
metabolism. When oxygen is sufficiently abundant, glycogen
undergoes aerobic metabolism – otherwise it is anaerobically
metabolized, generating pyruvate and later, lactate. Increasing
concentrations of lactate in mixed venous blood during exer-
cise indicates that anaerobic metabolism has been activated to
supplement aerobic metabolism. Anaerobic metabolism is
triggered generally at 70% of maximal effort and higher. Lactate
is buffered by bicarbonate, the partial pressure of CO2
increases, ventilatory rate increases, and the linear relationship
between minute ventilation and oxygen uptake becomes
exponential. This point is known as the anaerobic threshold,
which indicates high effort intensity, and, if continued, immi-
nent exhaustion.
Physiological Adaptations Associated with Chronic
Dynamic Exercise (Table 3)
Anticipated changes following chronic bouts of sustained
dynamic exercise (commonly called training or conditioning)
include (1) increased VO2 at peak exercise – a sine qua non of
the trained state, (2) increased CO at peak exercise (providing
increased oxygen delivery), (3) reduced systemic vascular
resistance (SVR) at peak exercise, (4) resting and relative
Figure 5 There is exquisite integration during dynamic exercise among the pulmonary and systemic circulations, linking the lung, the heart, and
cellular metabolism. QCO2 and QO2 denote CO2 and O2 delivery via cardiac output; VCO2 and VO2 denote rates of CO2 production and O2 consump-
tion; SV, stroke volume; HR, heart rate. Modified from Wasserman, K., Whipp, B.J., 1975. Exercise physiology in health and disease. Am. Rev.
Respir. Dis. 112, 219–249.
Exercise and the Cardiovascular System 5
Table 3 Physiological adaptations associated with chronic dynamic
exercise
At maximal effort
l Increased VO2 (sine qua non)
l Increased CO
l Reduced SVR
Resting and relative bradycardia
Increased oxidative capacity (in active skeletal muscle)
Increased use of free fatty acids as fuel
Myocardial hypertrophy (occasional and nonpathological)
VO2, oxygen consumption; CO, cardiac output; SVR, systemic vascular resistance.
bradycardia (relative bradycardia is reduced HR at matched
submaximal work rates after training), (5) increased oxidative
capacity in active skeletal muscle (providing increased oxygen
extraction), (6) increased utilization of fats to fuel exercise, and
(7) myocardial hypertrophy (when present, this is a non-
pathological, mild, reversible eccentric hypertrophy (Table 3)).
In the subsequent section, each of these adaptations will be
discussed.
Skeletal Muscle
Skeletal muscle is composed of two fiber types. Slow-twitch
(ST) fibers have higher myoglobin content, more mitochon-
dria, and higher oxidative capacity than fast-twitch (FT) fibers.
FT fibers have higher glycolytic capacity and are better suited for
high-intensity, short-duration activities. ST fibers are better
suited for low-intensity prolonged efforts like distance running.
Elite sprinters have a greater proportion of FT fibers, elite
marathon runners have more ST fibers, reflecting a genetic
predisposition to excel in these events. There have been no
compelling studies in humans indicating that training can
change the proportion of ST and FT fibers. Nevertheless,
marked changes occur in skeletal muscle after training –
changes that are specific to muscle groups trained. The most
important of these changes, seen consistently and predictably,
is increased oxidative enzyme capacity, which reflects a conflu-
ence of findings including increases in mitochondrial volume,
oxidative enzymes, capillary blood volume, and myoglobin.
6 Exercise and the Cardiovascular System
Fuel Utilization in the Trained Subject
Active skeletal muscle undergoes substantial increases in
oxidative capacity after training. In dynamic exercise, exercising
muscle may represent 50% of the body mass. Major changes in
oxidative capacity in such a large mass predictably would
influence fuel utilization. Skeletal muscle glycogen stores are
a determinant of performance duration. Increased free fatty
acid metabolism enables the trained subject to delay mobili-
zation of muscle glycogen stores. When muscle glycogen is
exhausted, the so-called wall is hit, a major cause of disap-
pointment among marathon runners. Increased peripheral
extraction of oxygen enables the conditioned subject to post-
pone the deleterious effects of lactate accumulation until
higher workloads are achieved. These two adaptations result in
improved endurance and an increased maximal work capacity.
Systemic Vascular Resistance
CO at peak effort in the sedentary subject reaches nearly
18 l min
1 (Table 1), a greater than threefold increase above
basal CO. The trained 70 kg 40-year-old subject, by compar-
ison, with a maximal VO2 increasing from around 40 to
50 ml kg
1 min
1 – a 25% increase – would attain a CO of
22 l min
1. Elite athletes have attained a CO at peak effort of up
to 40 l min
1. Most of this increase in CO is distributed to
exercising muscle beds. Despite these large relative increases in
maximal CO after training, the MAP of blood during maximal
effort is unchanged. MAP is a product of CO (blood flow) and
SVR. Consequently, if maximal CO has increased with no
change in MAP, SVR has decreased. Although the precise
mechanism for this is unknown, it requires modification of
arteriolar resistance, and to some extent reflects alterations in
sympathetic tone, at least at matched submaximal work rates.
But at peak effort, reduction in resistance is independent of
sympathetic activation, and may reflect increased metabolic
vasodilation.
Training Effects on HR
Aside from increases in maximal VO2, resting bradycardia is the
best known of the modifications associated with the trained
state. Less discussed but just as anticipated is relative brady-
cardia – a reduced HR at matched work rates after training.
The precise molecular mechanisms for these alterations in
Figure 6 Heart rate (HR) response before and after training. Left: The linear relation between HR and oxygen consumption (VO2) reflects sympa-
thetic activation. A hallmark of the trained state is decreased HR response at matched rates of VO2 or work rates, indicating less stress at any
submaximal level of effort. Right: Sympathetic activity reflects relative, not absolute work. HR expressed as a percent of VO2: HR response reflects
relative, not absolute effort.
chronotropy reflect interdependence among such elements as
autonomic activation, adaptations in skeletal muscle, and
altered chronotropic responsiveness to neurogenic and
humoral influences.
The literature has an abundance of animal and clinical
studies documenting alterations in sympathetic and para-
sympathetic activation resulting from training. Basal plasma
and myocardial levels of norepinephrine are unaltered by
training, but plasma norepinephrine levels – which reflect its
release from adrenergic nerve terminals throughout the body –
are reduced at matched submaximal work rates, providing
a plausible mechanism for relative bradycardia, namely, that
there is less sympathetic activation at a given work rate after
training.
Resting Bradycardia
Basal HR and its response during exercise are mediated via
parasympathetic and sympathetic input, which determine the
slope of Phase 4 depolarization of the sinoatrial node.
Consequently, parasympathetic tone may be important in
exercise-associated bradycardia. Studies conducted in rodents
have found training-associated increases in myocardial
concentrations of acetylcholine, but submaximal doses of
atropine evoke lower HR responses in trained than in seden-
tary human subjects. These studies suggest roles for both limbs
of the autonomic nervous system in training-associated
bradycardia. Other studies indicate alterations in compo-
nents of the b-adrenergic receptor $ G-protein $ adenylyl
cyclase signaling pathway that contribute to training-associ-
ated resting bradycardia, but such speculations must accom-
modate the finding that HR at maximal effort is unchanged by
training, making alterations in receptor-mediated signaling
difficult to embrace.
Relative Bradycardia
Sympathetic activation reflects absolute and not relative work
rates. Plasma norepinephrine levels are reduced at matched
submaximal work rates after training, indicating that sympa-
thetic activation is related to exertion (stress) required to attain
a work rate rather than the amount of work performed
(Figure 6). Consequently norepinephrine levels are similar at
maximal effort, regardless of the absolute work rate attained.

Local adaptations in trained muscle may be important in
bradycardia at submaximal work rates; relative bradycardia is
observed only when exercising the trained limb (Figure 7).
Presumably, the peripheral adaptations that occur in skeletal
muscle and the peripheral circulation are important in reducing
the amount of stress resulting from any absolute work rate.
Central sympathetic drive is reduced and thus HR response is
reduced, possibly due to a peripheral signal from muscle.
In summary, following chronic dynamic exercise, there is an
enhanced parasympathetic tone at rest that may contribute to
resting bradycardia. With the onset of exercise, reduction in
sympathetic activation for any matched submaximal work
rate results in relative bradycardia. Changes in myocardial
b-adrenergic receptor affinity or numbers are variable and
difficult to interpret. Both central and peripheral factors are
important in the bradycardia that is observed.
SV in the Trained Subject
Basal CO is unchanged by training, but reduced basal HR is an
expected finding. Using data in Table 1, let us propose that the
subject undergoes rigorous training for 6 months and attains
a basal HR of 50 beats min
1. With a CO of 5.5 l min
1, the
subject’s posttraining SV would be 100 ml, a 1.5-fold increase
vs pretraining. This change would, in the basal state, reflect
predominantly increased LV EDV, and would reflect a mild
eccentric LV hypertrophy. Even a 15% increase in LV end-
diastolic dimension (a mere 7.5 mm increase in LV end-
diastolic diameter from 50 mm pretraining) would yield
a 50% increase in EDV. In our example (Table 1), a 25%
increase in maximal VO2 after training would be associated
180 Arm training
160 Arm work Leg work
140
120
Heart rate
100
Leg training
180
Leg work
Arm work
160
140
120
100
200 400 600 800 1000 1200
Work load (kpm mm−1)
Figure 7 The effects of arm or leg training on the heart rate response to subsequent arm or leg exercise demonstrate that relative bradycardia at
matched workloads (KPM min
1 ¼ kilopond meters per minute) occurs only when exercising the trained limb. Dashed lines refer to posttraining
responses. Modified from Clausen, J.P., Trap-Jensen, J., Lassen, N.A., 1970. The effects of training on the heart rate during arm and leg exercise.
Scand. J. Clin. Lab. Invest. 26, 295–301.
Exercise and the Cardiovascular System 7
with a maximal CO of 22 l min
1. Maximal HR is unchanged
by training, so SV at peak effort after training would increase
from 97 (pretraining, Table 1) to 122 ml.
SV is also higher at any matched work rate after training. The
relationship between work performed and oxygen cost is
unchanged, so SV at matched HR is greater after training. SV can
increase via increased contractility, increased EDV, decreased
ESV, or increased ejection fraction. Experimental evidence
consistently supports increased EDV as the most important
factor accounting for the increases in maximal CO associated
with training.
Intrinsic Myocardial Adaptations
Oxidative Enzyme Profile
Since the heart is a striated muscle, it is reasonable to ask
whether similar training-induced adaptations are seen in the
myocardium as in skeletal muscle. However, alterations in
mitochondrial volume and density that were seen in active
skeletal muscle are not seen in heart after chronic dynamic
exercise. The heart, one could argue, is the ultimate aerobic
muscle, beating constantly. Its oxidative enzyme profile is
already optimal, and the added work of sustaining higher HR
for an hour or more daily – a typical exercise training regimen –
does not increase its oxidative phosphorylation capacity.
LV Hypertrophy
Training-associated myocardial hypertrophy is anticipated with
strenuous training programs. Longitudinal studies in humans
Arm vs leg training
• Training-associated bradycardia
occurs only when exercising the
trained limb.
• Training adaptations that enable
exercise to be conducted with less
sympathetic tone reside in the
trained muscle.
8 Exercise and the Cardiovascular System
are limited to noninvasive techniques of assessment of LV
dimension and mass – detection of significant hypertrophy is
seen in roughly half of published studies, typically showing
small increases in LV end-diastolic dimension, as expected, with
insignificant changes in wall thickness. The LV hypertrophy
associated with chronic dynamic exercise is of the volume
overload type, with maintenance of the usual ratio of wall
thickness to internal diameter (such that wall stress remains
normal). There is no evidence that this type of hypertrophy is
harmful and it regresses if training is discontinued. In contrast,
chronic static exercise training, with its predominant pressure-
load (Figure 1), is sometimes associated with concentric left
ventricular hypertrophy – an increase in LV wall thickness.
LV Contractility
Although maximal CO predictably increases following
training, it is not clear to what degree this is the result of
reduced SVR, altered venous return, or changes in LV contractile
function. The demonstration of primary changes in LV
contractility is difficult and requires invasive studies. Few such
studies have been performed in humans. Animal studies have
been performed, but are hampered by the common use of
anesthetic agents, which themselves are commonly negative
inotropes. Detailed studies of LV function before and after
training in conscious mammals are rare, and most were per-
formed decades ago. Many studies examine the effects of
chronic exercise on isolated papillary muscle mechanics or
open-chest anesthetized animals. Extrapolating data from such
studies to normal physiological states is perilous. No compel-
ling evidence indicates that training changes the contractile
state of the normal heart.
Summary of Adaptations of Training
The physiologic results of acute dynamic exercise include
complex neurologic, hormonal, pulmonary, and cardiovas-
cular adjustments that provide an integrated response perfectly
matching oxygen supply with oxygen demands (Figure 5).
Long-term repeated bouts of dynamic exercise of sufficient
intensity and duration yield predictable changes in anatomy
and physiology.
Increased maximal VO2 is the sine qua non of the trained
state. This is accomplished via balanced increases in oxygen
delivery (due to increases in SV) and oxygen utilization (due
to increases in perfusion of and oxygen utilization in exer-
cising skeletal muscle). Changes in skeletal muscle include
increases in capillary blood volume, mitochondrial density,
and oxidative pathway enzymes, as well as more efficient
regulation of blood flow. These adaptations result in an
increased oxygen extraction and more favorable fuel utiliza-
tion. Oxygen extraction increases, accounting for 50% of
increased maximal VO2, and endurance improves. The trained
heart beats slower and has a larger SV at rest and through
a broad range of work rates. Maximal CO increases substan-
tially, through increased SV, accounting for 50% of increased
maximal VO2. The metabolic and biochemical changes found
in skeletal muscle are not found in cardiac muscle, and LV
contractility does not change.
See also: Normal Cardiac Physiology and Ventricular Function;
Pulmonary Circulation; Respiratory Physiology.
References
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Longhurst, J.C., Mitchell, J.H., 1983. Does endurance training benefit the cardio-
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Rushmer, R.F., 1976. Cardiovascular Dynamics. W.B. Saunders Co., Philadelphia,
pp. 70–112.
Stratton, J.R., Levy, W.C., Cerqueira, M.D., Schwartz, R.S., Abrass, I.B., 1994.
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Further Reading
Fadel, P.J., Raven, P.B., 2012. Human investigations into the arterial and cardiopul-
monary baroreflexes during exercise. Exp. Physiol. 97, 39–50.
Jeppesen, J., Kiens, B., 2012. Regulation and limitations to fatty acid oxidation during
exercise. J. Physiol. 590, 1059–1068.
Perrino, C., Gargiulo, G., Pironti, G., et al., 2011. Cardiovascular effects of treadmill
exercise in physiological and pathological preclinical settings. Am. J. Physiol. Heart
Circ. Physiol. 300, H1983–H1989.