Sex-Specific Ventricular and Vascular

Adaptations to Exercise 21
Jill N. Barnes and Qi Fu

Cardiovascular adaptation during exercise. Art work by Piet Michiels, Leuven, Belgium

J. N. Barnes (*) Abstract

University of Wisconsin-Madison, Madison, WI, USA Increasing data suggest that there are sex
e-mail: jnbarnes@wisc.edu
differences in ventricular and vascular
Q. Fu adaptations to aerobic (endurance) exercise,
Institute for Exercise and Environmental Medicine, Dallas,
TX, USA which may be attributed to different physical
and physiological features in men and women.
University of Texas Southwestern Medical Center, Dallas,
TX, USA Despite that cardiovascular control during
e-mail: QiFu@texashealth.org acute exercise at the same relative work rate

# Springer International Publishing AG, part of Springer Nature 2018 329

P. L. M. Kerkhof, V. M. Miller (eds.), Sex-Specific Analysis of Cardiovascular Function,
Advances in Experimental Medicine and Biology 1065, https://doi.org/10.1007/978-3-319-77932-4_21
330
(e.g., the percentage of peak oxygen uptake)
appears to be similar between the sexes,
women have blunted responses or adaptations
to prolonged (e.g.,
1 year) exercise training
compared with men. Currently, there is little
evidence to suggest that exercise-induced vas-
cular adaptations are different between men
and women. Furthermore, sex differences in
skeletal muscle adaptations to exercise, and
how this influences cardiovascular function,
remain unclear. Identifying potential differ-
ences and the mechanisms behind such
exercise-induced adaptations is important for
the optimization of exercise interventions
between men and women across the life span.
Keywords
Exercise · Cardiovascular adaptation ·
Endurance training · Aerobic fitness · Cardiac
output · Stroke volume · Heart rate · Oxygen
uptake
Introduction
The cardiovascular system has a distinctive
ability to quickly adapt to acute increases in
workload caused by muscle contraction. Addi-
tionally, regular exercise induces long-term
adaptations in the structure and function of the
cardiovascular system. The majority of the
research in this area has focused on adaptations
in men, but emerging evidence on the adaptations
in women now exists. Men and women have
different physical and physiological features
(e.g., body size, muscle mass, sex hormones,
etc.), which may impact their responses to exer-
cise. This chapter will focus on reviewing the
cardiovascular adaptations to exercise and
similarities and differences between men and
women. Understanding sex-specific differences
in exercise adaptations is important not only to
physiologists but also to clinicians, as these
differences could impact exercise rehabilitation
for patient populations.
J. N. Barnes and Q. Fu
Cardiac Contribution to Aerobic
Fitness
During aerobic (endurance) exercise, the uptake
and transport of oxygen is required for oxidative
phosphorylation and the efficient production of
adenosine triphosphate to support the metabolic
demands of the body. Oxygen uptake is a func-
tion of cardiac output (e.g., central factor) and
total system arteriovenous oxygen difference
(e.g., peripheral factor) [84]. The ability to
increase one or both of these variables determines
a person’s aerobic capacity [42], and the upper
limit for whole-body oxygen uptake is called the
peak oxygen uptake (VO2peak) [53]. VO2peak is
the best objective measure of aerobic fitness and
is a widely used index of the integrity of cardio-
vascular function [92].
Women usually have VO2peak values that are
5–15% lower than men of comparable training
status and a similar age, whereas correction of
VO2peak values for body weight or lean body
mass does not correct the discrepancy in men
and women completely [12]. It has been found
that the difference in peak arteriovenous
oxygen difference is relatively small between
the sexes, as well as between highly trained and
untrained individuals [21, 40, 68, 94], though
the mechanisms behind it may differ (e.g.,
differences in muscle blood flow, capillary den-
sity, muscle fiber characteristics, mitochondrial
function, etc.). The factor most commonly
accounting for the different values of VO2peak
in men and women is cardiac output. Indeed,
lower cardiac output was found to contribute to
the lower absolute and relative VO2peak in
women [115].
Cardiac output is the product of heart rate and
stroke volume. Previous studies have demon-
strated that peak heart rate during exercise is
similar between men and women regardless of
fitness levels [21, 30, 40, 68], while advancing
age is associated with a decrease in peak heart rate
in both sexes [68]. Indeed, the most consistent sex
difference in cardiovascular responses during
submaximal and maximal exercise is a lower
stroke volume of women and a smaller increase
21 Sex-Specific Ventricular and Vascular Adaptations to Exercise
in stroke volume from rest to exercise [21, 38, 39,
68, 69]. It has been proposed that the smaller
stroke volume and its attenuated response during
exercise in women are mainly attributed to a
smaller heart size, particularly left ventricular
volume and mass [7, 32, 41]. The difference
in heart size has also been assumed to account
for a majority of the difference in VO2peak in
both sexes [41, 61]. Additionally, sex-related
differences in myocardial remodeling could influ-
ence left ventricular contractility, which may also
account for the smaller stroke volume and its
attenuated response during exercise in women
[76, 111]. Indeed, Aksut et al. found that during
submaximal exercise, the decrease in left ventric-
ular end-systolic volume was less in young
women than in young men [1]. However, left
ventricular contractility was reported to be greater
in women than men after the age of 65 years
[19]. Thus, older women have a greater ability
to eject stroke volume (i.e., hypercontractile),
and left ventricular end-systolic volume could
be lower in older women than in older men
[26]. Conversely, women, especially older
women, have reduced blood volume compared
with age-matched men, which also contributes
Fig. 21.1 Left ventricular (LV) volume indexes across
relative work rates from rest to peak effort in young (aged
<40 years; a) and older (aged >60 years; b) males (solid
lines) and females (dashed lines). (a) Analysis of covari-
ance shows no significant interaction or overall difference
331
to the smaller stroke volume and cardiac output
at rest and during exercise [7, 61, 115]. These
results suggest that sex may be an important
factor determining the central hemodynamic
response to exercise in humans.
In contrast, some investigators reported no
differences in stroke volume index, cardiac
index, left ventricular end-diastolic and
end-systolic volume indexes in the time course,
or magnitude of changes with respect to oxygen
uptake, expressed as the percentage of VO2peak
in men and women aged <40 years (Fig. 21.1a)
[26, 101]. Whereas in people over the age of
60 years, all cardiac volume indexes are consis-
tently larger in men across relative work rates,
indicating greater reliance on the Frank-Starling
mechanism to augment cardiac index
(Fig. 21.1b) [26].
A potential important aspect when comparing
people of different body sizes is the methods for
scaling or normalization. Ratiometrically it can be
used when there is a linear relationship between
body size and cardiovascular parameters. But
often this is not the case and allometric scaling
is needed. Indeed, when stroke volume is scaled
to lean body mass, sex differences become less
in cardiac volumes between young men and women. (b) In
older group, all cardiac volume indexes are consistently
larger in men across relative work rates compared with
women. (Adapted with permission from Fleg et al. [26])
332
noticeable [12]. Lean body mass has been
suggested as a possible factor causing differences
in exercise cardiac output [89]. An earlier study
by Freedson et al. [29] showed that in young men
and young women matched on VO2peak (L/min
and mL/kg.min), men had a lower cardiac output
and stroke volume and a higher arteriovenous
oxygen difference during submaximal exercise
(bicycle ergometer test at 35% of VO2peak).
When these variables were expressed indepen-
dent of lean body mass, the above differences
became nonsignificant [29]. These results support
the notion that cardiac output differences between
the sexes during submaximal exercise are due, in
part, to differences in lean body mass. On the
other hand, blood volume and hemoglobin mass
remain lower in women compared with men even
when scaled for body mass [7, 12, 61]. Blood
volume, hemoglobin, and hematocrit values are
15–20% lower in women, including elite athletes;
these factors probably contribute to the lower
VO2peak in women and lower average values
for endurance exercise performance [12, 42].
Previous studies have demonstrated that there
are rather substantial physiological and morpho-
logical sex differences between untrained or sed-
entary men and women, but these differences
become less noticeable in highly trained male
and female athletes who are competing in the
same event or sport [116, 77, 119, 112]. For
Fig. 21.2 Comparisons of 220
heart rate (HR) responses
during submaximal and 200
maximal exercise in
sedentary men and women 180
and during submaximal
HR (bpm)
exercise in highly trained 160
male and female athletes at
the same relative work rate, 140
expressed as the percentage
of maximal oxygen uptake 120
(VO2max), which
represents a matter of 100
cardiovascular control
during exercise in healthy 80
humans. (Adapted with
permission from Fu and 60
Levine [30])
J. N. Barnes and Q. Fu
example, Zwiren et al. found that in men and
women with similar training backgrounds and
nonsignificantly different mean VO2peak in
mL/kg in fat-free mass.min, the differences in
cardiovascular responses between the sexes at
various percentages of VO2peak were smaller
than previously thought [119]. It seems that the
sex difference in certain cardiovascular responses
during exercise is a consequence of different
levels of physical condition of the men and
women. In accordance with this assumption, it
was found that the increase in heart rate during
submaximal and maximal exercise was greatest in
untrained women and smallest in highly trained
men at the same absolute work rate, which was
expressed as VO2 (mL/kg.min); however, when
the heart rate responses at the same relative work
rate, namely, the percentage of VO2peak were
compared, there were no differences among
groups (Fig. 21.2) [30]. These results suggest
that cardiovascular control during acute exercise
is similar in men and women no matter whether
they are trained or untrained. Although there are
some physiological differences that may affect
the mechanism of the changes, the overall
response of the cardiovascular system to acute
exercise is similar in men and women [61, 67].
One of the key principles in exercise physiol-
ogy in humans is the remarkably constant rela-
tionship between the increase in oxygen uptake
Sedentary Men
Sedentary Women
Male Athletes
Female Athletes
0 20 40 60 80 100 120
Percent VO2 max (%)
21 Sex-Specific Ventricular and Vascular Adaptations to Exercise
Metabolic Myopathies
20
15
Qc (l/min) 5-6 liters
10
5
1 liter
0
0 500
Fig. 21.3 Relationship between increases in oxygen
uptake (VO2) and the corresponding increases in cardiac
output (Qc) during exercise in humans, which in most
cases is 5–6/1. When this relationship is depressed, like
in patients with congestive heart failure, it may be a sign of
(work rate) and the corresponding increase in
cardiac output. Regardless of sex, age, or aerobic
fitness, in general, about 5–6 liters of cardiac
output are required for every liter of oxygen
uptake above rest (Fig. 21.3) [30, 31, 33, 52, 79,
84]. When this relationship is depressed, it may
be a sign of severe underlying disease with
impending decompensation. Conversely, when it
is exaggerated, like in patients with metabolic
myopathies, it gives strong clues to the processes
regulating cardiac output.
VO2peak decreases with advancing age, and a
lower stroke volume, heart rate, and arteriove-
nous oxygen difference at maximal exercise all
contribute to the age-related decline in VO2peak
in both untrained and highly trained individuals
[68, 92]. Nearly half of the age-related difference
in VO2peak is explained by a smaller stroke vol-
ume, and the remainder by a lower heart rate and
arteriovenous oxygen difference at maximal exer-
cise. It was found that age and sex each had a
significant impact on aerobic fitness; VO2peak
declined with age approximately 40% from 20s
to 80s years old in both sexes, but at any age it
was greater in men than in women even after
normalization for body weight [26]. Longitudinal
333
Congestive Heart Failure
1000 1500 2000 2500
.VO2 (ml/min)
severe underlying disease with impending decompensa-
tion. Conversely, when it is exaggerated, like in patients
with metabolic myopathies, it gives strong clues to the
processes regulating Qc. (Adapted with permission from
Fu and Levine [31])
studies showed that the rate of decline in
VO2peak in healthy adults was not constant
across the age span, as assumed by cross-
sectional studies, but accelerated markedly with
each successive age decade, especially in men,
regardless of physical activity habits [26].
Hossack and Bruce also found that the normal
range of peak values for VO2, heart rate, cardiac
index, and stroke index during treadmill exercise
testing decreased with age in both sexes, but men
had a significantly greater reduction than women
[38]. Fitzgerald et al. reported that the absolute
(mL/kg.min per year) rate of decline in VO2peak
with age was greatest in highly trained women,
next greatest in active women, and lowest in
sedentary women; however, when expressed as
percentage or relative decrease from mean levels
at approximately 25 years of age, the rate of
decline in VO2peak was similar in the three
groups [24]. Ogawa et al. also reported similar
rates of decline in VO2peak with age in untrained
and highly trained men and women [68]. Similar
to the previous findings in untrained women
[15, 48, 49], it was found that menopausal status
did not affect cardiovascular fitness in masters
women runners [112].
334
Collectively, it seems that sex does not signifi-
cantly affect cardiovascular control during endur-
ance exercise in both untrained and highly trained
individuals. For any task requiring a given abso-
lute oxygen uptake, women are working at a
higher percentage of their exercise capacity than
men. This would result in a higher heart rate,
greater stress, and a quicker onset of fatigue
during exercise. If allowed to work at a similar
percentage of their peak exercise capacity, men
and women would have similar cardiovascular
responses. Lastly, aerobic fitness declines with
advancing age but accelerates markedly with
each successive age decade, especially in men.
Left Ventricular and Myocardial
Adaptations to Exercise Training
Regular exercise or exercise training promotes
beneficial adaptations in the cardiovascular
system which have cardioprotective effects
[78]. Moderate to vigorous endurance training
increases VO2peak and exercise capacity through
an increase in stroke volume or an increase in
arteriovenous oxygen difference or both in
humans. Depending on age and training duration,
men and women could have different cardiovas-
cular adaptations to exercise training even if they
achieve similar increases in VO2peak.
Previous studies have demonstrated that in
young women, increases in stroke volume, arte-
riovenous oxygen difference, and VO2peak with
endurance training are similar to those in young
men [12, 58, 59, 85, 95]. The increase in stroke
volume after endurance training could be the
result of left ventricular volume-overload hyper-
trophy leading to enhanced cardiac filling,
increased myocardial contractile function (e.g.,
enhanced contractile response to β-adrenergic
stimulation), reduced afterload, increased blood
volume, or a combination of these factors [37, 40,
44, 81, 82]. Although the absolute increase in
blood volume after exercise training was reported
to be greater in young men compared with young
women, the relative (percent) change did not dif-
fer between the sexes [58]. In addition, the
increase in stroke volume in young men and
J. N. Barnes and Q. Fu
young women appears to be independent of
afterload because it was found that diastolic
blood pressure remained unchanged in men but
increased in women after training [58]. Recent
research has shown that endurance training up to
3 months elicits similar increases in left ventricu-
lar mass and end-diastolic volume in initially
sedentary young men and young women [40].
Despite similar adaptations in young men
and young women reported in previous
investigations, cross-sectional studies in athletes
suggest that endurance training augments cardio-
vascular structure and function with apparently
different phenotypes in males and females. Spe-
cifically, female athletes have smaller left ventric-
ular dimensions and wall thickness compared
with male athletes [17, 102, 114]. One possible
explanation for this discrepancy may be the dura-
tion of training. In almost all previous training
studies comparing young men versus young
women, the intervention period is relatively
short (e.g., 3 months) which could have missed
or underestimated sex differences in cardiovascu-
lar adaptations. To support this notion, it was
found that 3 months of intense training in male
and female rowers caused similar cardiovascular
adaptations between the sexes [4]. In addition, the
alterations in cardiovascular function resulting
from 20 weeks of endurance training were very
similar across sex, age, and race with few
exceptions [117]. However after prolonged (e.g.,
1 year) intensive endurance training, initially sed-
entary young women were found to have a
blunted cardiovascular response compared with
young men [40].
Howden et al. [40] observed that previously
sedentary young men progressively increased
VO2peak, left ventricular mass, and mean wall
thickness before reaching a plateau from month
9 to 12 of training. In contrast, despite exactly the
same training, the response in young women was
markedly blunted, with VO2peak, left ventricular
mass, and mean wall thickness plateauing
after only 3 months of training (Fig. 21.4)
[40]. These results suggest that the development
of left ventricular hypertrophy, which is in paral-
lel with the increase in VO2peak, is significantly
blunted in young women. Interestingly, the
21 Sex-Specific Ventricular and Vascular Adaptations to Exercise
Fig. 21.4 Sex differences in cardiovascular adaptations
to prolonged endurance training in initially sedentary
young individuals. A and B: effect of 1 year of endurance
training on maximal oxygen uptake (VO2max) indexed to
baseline body mass in males and females (left), significant
sex  time interaction P ¼ 0.084 and changes in left
ventricular (LV) mass measured by magnetic resonance
response of left ventricular end-diastolic volume
was not influenced by sex (e.g., increased by 20%
in young men and 18% in young women after
1 year of training). However, young men had
greater augmentation of the Frank-Starling
mechanisms (the relationship between left ven-
tricular filling pressure and stroke volume) after
1 year of training compared with young women,
indicating a greater diastolic reserve in men
[40]. This adaptation to training is extremely ben-
eficial for performing exercise, allowing
individuals to generate a higher stroke volume
and cardiac output in response to an increase in
left ventricular filling pressure. Indeed, an
enhanced Frank-Starling mechanism has been
shown to be a hallmark characteristic of endur-
ance athletes [54].
The mechanisms underlying sex differences in
left ventricular hypertrophy following prolonged
endurance training in young individuals are
unclear, but endogenous sex hormones (e.g.,
androgen and estrogen) may be involved. Regular
exercise can increase circulating levels of testos-
terone, which promotes muscle growth through
335
imaging (MRI) scaled to baseline fat-free mass, significant
sex  time interaction P ¼ 0.031 (right). Both measured
every 3 months during the training program. FFM, fat-free
mass. Post hoc comparison with baseline (*), with month
3 (Ɨ), and with month 6 (ǂ) for P < 0.05 from liner mixed
model. (Adapted with permission from Howden et al. [40])
protein synthesis and inhibits protein degradation
[108]. On the other hand, estrogen may attenuate
or prevent the development of left ventricular
hypertrophy with exercise training in premeno-
pausal women via estrogen receptor β [27, 35, 74,
91]. In addition, estrogen-mediated atrial natri-
uretic factor (ANF) may also prevent left ventric-
ular hypertrophy in young women [76]. Animal
studies showed that estrogen exerted profound
antihypertrophic effects on ventricular myocytes,
by transactivation of the ANF gene and activation
of the ANF receptor in an autocrine/paracrine
manner, which in turn evokes cytoplasmic cyclic
guanosine monophosphate signaling downstream
of the guanylyl cyclase-A receptor [3]. On the
other hand, male rats were found to exhibit higher
cardiac angiotensin I-converting enzyme (ACE)
and angiotensin-converting enzyme 2 (ACE2)
activity, as well as left ventricular hypertrophy
compared with female rats, while orchiectomy
decreased the activity of these enzymes and
hypertrophy, and ovariectomy increased hyper-
trophy and ACE2 but did not change ACE activ-
ity [18]. These results suggest that the interaction
336
between sex hormones and the cardiac renin-
angiotensin system components is also essential
for left ventricular remodeling.
Healthy older individuals can respond to
prolonged endurance exercise training with
adaptations similar to those of younger indivi-
duals [34, 87]. However, older men and older
women have different cardiovascular adaptations
to training. For instance, Spina et al. found that in
older women, stroke volume during maximal
exercise did not increase after 9–12 months of
endurance training even though increases in
VO2peak were similar between the sexes
(increased by 22% in older women and 19% in
older men) [94]. The entire increase in VO2peak
after training in older women was accounted for
by a greater arteriovenous oxygen difference
during maximal exercise [94]. Conversely, older
men were found to increase stroke volume during
maximal exercise and improve left ventricular
systolic function with training [20, 88]. These
results indicate a difference in the mechanisms
for cardiovascular adaptations to endurance train-
ing in older men and older women.
A possible explanation for the lack of a
training-induced increase in stroke volume
during acute exercise in older women is that
they do not develop left ventricular hypertrophy,
and moreover, their myocardial function remains
unchanged. Using radionuclide ventriculography,
Spina et al. were unable to detect any left ventric-
ular enlargement or changes in left ventricular
ejection fraction in older women after training
[96]. It was also found that endurance training
had no effect on left ventricular function
(β-adrenergic-mediated contractile function), left
ventricular end-diastolic dimension, wall thick-
ness, or mass in older women [97]. In addition,
older women do not have any improvement in
left ventricular filling dynamics after training,
whereas older men do [93]. Furthermore, previ-
ous studies showed that older women were unable
to expand blood volume with endurance training
[98]. Estrogen deficiency might also explain
why stroke volume does not increase in older
women with exercise training [94]. In contrast,
J. N. Barnes and Q. Fu
it was found that in older men, left ventricular
end-diastolic dimension increased by 13% and
wall thickness increased by 14%, while the
thickness-to-radius ratio remained unchanged
after training, indicating physiological eccentric
hypertrophy [20]. Different from older women,
blood volume increased after training in older
men [69].
Collectively, there are sex differences in the
cardiovascular adaptations to endurance exercise
training. For young women, increases in stroke
volume, arteriovenous oxygen difference,
VO2peak, and left ventricular remodeling with
short-term (e.g., 3 months) endurance training
are similar to those in young men. However,
young women have blunted increases in VO2peak
and left ventricular hypertrophy after prolonged
(e.g.,
1 year) training. For older women, stroke
volume during acute exercise does not increase
after endurance training even though increases in
VO2peak are similar between the sexes. Lack of
left ventricular remodeling and blood volume
expansion may be responsible for a blunted car-
diovascular response to exercise training in older
women.
Ventricular-Vascular Coupling
and the Role of Exercise
Structural and functional adaptations to exercise
training involve the left ventricle, as discussed
above, and the vasculature. With each myocardial
contraction and subsequent ejection of blood
from the ventricle, blood enters into the large
central arteries in a pulsatile (noncontinuous)
manner. Due to this high pulsatile flow, blood
pressure in the large central arteries fluctuates
with each myocardial contraction, with a typical
systolic blood pressure of 120 mmHg and dia-
stolic blood pressure of 80 mmHg in healthy
humans. Blood pressure falls dramatically
between the large central arteries and smaller
arterioles where blood flow becomes more con-
tinuous. As the left ventricle undergoes
21 Sex-Specific Ventricular and Vascular Adaptations to Exercise
remodeling to adapt to the stress of exercise train-
ing, so do the large central arteries.
The large central arteries must accommodate
the pulsatile nature of blood flow from the left
ventricle and the variable stroke volume when
transitioning from rest to exercise. The large cen-
tral arteries (including the aorta and carotid
arteries) are distensible and compliant, and as
the arteries narrow throughout the arterial tree,
there are a gradual decrease in elastic compliance
and increase in stiffness of these blood vessels.
The compliance of the large proximal arteries
is reduced with advancing age, and similarly, arte-
rial stiffness increases with age [60]. Women have
a greater age-related decline in arterial compliance
and distensibility compared with men [14, 110]
and lower arterial compliance during the middle-
aged and older years compared with men
[107]. Importantly, the sex-specific differences
appear to be dependent on the method of measure-
ment and the sample size population [73, 107].
Large-scale studies like Framingham Heart Study
indicate a statistically significant effect of sex on
the age-related increase in aortic pulse wave
velocity (PWV), a measure of arterial stiffness,
in healthy adults although not all studies show
sex differences in aortic PWV [107]. The reported
sex differences in arterial compliance or
distensibility may be due to the issue of scaling
between men and women. Because men have a
larger stature and greater diameters of the large
central arteries, for a given change in pressure,
there is a greater volume of flow through the
vessel. Therefore, although there are sex differ-
ences in compliance or distensibility measure-
ments, it is unclear if these differences have
physiological or clinical implications.
Other factors may also influence sex
differences in central arterial structure and func-
tion. Differences in sex hormones, primarily
estrogen, may affect arterial structure and func-
tion, as menopause is associated with higher
arterial stiffness (measured by PWV) [99].
Along these lines, PWV was reduced following
12 months of menopausal hormone therapy in
postmenopausal women, suggesting a protective
effect of estrogen [46]. Testosterone has sex-
specific effects on PWV, with higher circulating
337
androgen levels associated with greater PWV in
postmenopausal women [16], yet higher total tes-
tosterone is correlated with lower PWV in men
[109]. Another factor that may affect men and
women differently is distribution of adipose tis-
sue. More abdominal adiposity is associated with
greater arterial stiffness, but this relationship is
steeper in women, such that small increases in
abdominal adiposity have more unfavorable
effects in women compared to men [86]. Abdomi-
nal adiposity often increases during the postmen-
opausal years and is associated with greater
cardiometabolic risk [71].
Regular aerobic (endurance) exercise is a com-
mon lifestyle intervention to prevent or reverse
obesity and affects central arterial structure and
function. In men, endurance training improved
carotid arterial compliance, and endurance-
trained men demonstrate more compliant arteries
compared with their sedentary middle-aged and
older counterparts [105]. Similarly, physically
active women did not experience the age-related
increases in aortic PWV when compared with
sedentary women [104]. Thus, these studies
suggest that habitual physical activity and/or
endurance training may prevent or slow the
age-associated increase in arterial stiffness.
Although there may be sex differences in
baseline arterial stiffness measurements, currently
there is little evidence to suggest that exercise-
induced arterial adaptations are different between
men and women. It should be noted that differ-
ences between men and women in response to
exercise training have not been systematically
tested or evaluated with different modes of
exercise.
Any increases in the rigidity or stiffness of the
central arteries will affect the central blood pres-
sure. The idea that elevated arterial stiffness
affects central and peripheral blood pressure has
been reviewed extensively elsewhere [64, 65].
Briefly, an increase in arterial stiffness results in
a faster velocity of wave travel (PWV) and an
earlier return of the reflected pulse wave. If the
reflected wave appears during the systolic phase
of myocardial contraction, it distorts the aortic
pressure waveform, which results in augmented
aortic systolic pressure. Thus, higher arterial
338
stiffness is associated with shorter wave reflection
time and augmented aortic blood pressure.
Throughout the life span, there are sex
differences in central hemodynamics such that
women have shorter wave reflection time and
greater wave augmentation [14, 57, 90]. The aug-
mented pressure elevates aortic blood pressures to
a greater extent than brachial blood pressures and
can affect ventricular-vascular coupling [60,
106]. Often the sex differences in central hemo-
dynamics are attributed to the shorter height in
women (which means a shorter distance between
the ventricle and the reflection sites in the periph-
ery). However, even after correction for height,
sex differences in central hemodynamic variables
remain [57], suggesting that in women the central
arteries may be more susceptible to age-related
changes in arterial structure compared with men.
Importantly, the amount of pressure that the
left ventricle needs to produce is dependent on the
pressure in the proximal aorta. Ventricular pres-
sure needs to increase sufficiently to open aortic
valves allowing ejection of blood into the sys-
temic circulation. Thus, aortic stiffness and ele-
vated aortic blood pressure can limit left
ventricular ejection of blood or places additional
work on the left ventricle [65].
Throughout the systolic period of the cardiac
cycle, ventricular pressure and aortic pressure
values are similar. Yaginuma et al. [118] noted
that aortic pressure is augmented in late systole
due to wave reflection [118], which would require
a similar augmentation in ventricular pressure.
Aortic systolic pressure is related to left ventricu-
lar myocardial wall stress [55]. Indeed, there is an
association between augmented systolic pressure
due to wave reflection and impaired ventricular
diastolic relaxation. There is also a relationship
between the increase in aortic systolic pressure
and myocardial ischemia [47]. Thus, ventricular-
vascular coupling is a normal phenomenon where
the structure and the function of the arteries deter-
mine arterial load, and the overall arterial load, in
turn, affects the structure and function of the left
ventricle. Ventricular-vascular coupling is a
determinant of cardiac energetics, and pathophys-
iological changes in the left ventricular workload
J. N. Barnes and Q. Fu
contribute to some cardiovascular disease states
[9, 100].
The association between central hemodynamic
variables and left ventricular function appears to
be sex-dependent. Women with higher wave
reflection have worsening left ventricular dia-
stolic function, whereas, in men, there is no such
association [90]. Similarly, there are distinct
differences between ventricular-vascular cou-
pling characteristics in men and women and
how it changes with aging. Left ventricular per-
formance (ELV, left ventricular end-systolic
elastance) is higher in men than women, and the
increase with aging is more dramatic in women
when compared with men (Fig. 21.5)
[80]. The ratio of arterial load (EA) compared
with ELV (EA/ELV) indicates ventricular-vascular
coupling, which also shows differences between
men and women. Across the life span, EA/ELV
ratio is constant in men but reduced in women
[11, 80]. This difference is primarily driven by the
increases in ELV compared with EA with advanc-
ing age. Collectively, sex differences in the inter-
action between the left ventricle and the systemic
arteries may explain the elevated risk for heart
failure with preserved ejection fraction in women
[11, 13, 45, 90].
The majority of studies investigating the ven-
tricular or vascular response to exercise have been
conducted in young healthy men. As more studies
included women, it became apparent that sex
differences exist during exercise [22, 63]. At max-
imal exercise, young men had higher ELV and EA
values compared with young women [63]. These
sex differences may be amplified by age and/or
the presence of cardiovascular risk factors. For
example, older women who were hypertensive
have greater increase in EA during exercise com-
pared with older men with hypertension [72].
Interestingly, cardiorespiratory fitness
(VO2peak) is associated with ventricular-vascular
coupling such that those with higher VO2peak
have lower EA/ELV ratio [22, 28]. The slope
of the relationship between VO2peak and
ventricular-vascular coupling is different between
men and women, with women have a greater/
steeper slope compared with men. This suggests
21 Sex-Specific Ventricular and Vascular Adaptations to Exercise 339

Fig. 21.5 Sex differences

in the association between
age and ventricular-
vascular coupling variables.
Arterial load (EA) was
indexed to body surface
area (EaI) in panel A. Left
ventricular performance or
elastance (ELV) was
indexed to body surface
area (shown as Ees) in
panel B. Women (dashed
line) had higher indexed
arterial load and indexed
left ventricular performance
compared with men (solid
line) at all ages.
Additionally, the increase
in left ventricular
performance was
significantly greater in
women. Data is adapted
from Redfield et al. [80],
and figure is used with
permission from Chantler
et al. [10]

that higher cardiorespiratory fitness may have a

disproportionate effect on EA compared with ELV
[22]. This is consistent with the idea that endur-
ance training reduces central arterial stiffness and
wave reflection, which will lower the arterial load
that the ventricle is pumping against. It is unclear
what effect exercise training has on ventricular-
vascular coupling during exercise, although a
recent pilot study suggests that short-term exer-
cise training can improve EA/ELV ratio in patients
with metabolic syndrome [28]. Whether there are
additional sex differences in such training effects
during exercise is unknown [9].
Cardiorespiratory Fitness As
a Vital Sign
Regular physical activity has been recommended
as a primary means to improve overall health. In
the landmark study by Blair et al., the association
between VO2peak and all-cause mortality was
established [8]. Although physical activity is
important in determining cardiorespiratory fit-
ness, it is VO2peak that is preferred over leisure-
time physical activity for its ability to predict
cardiovascular events [103]. High VO2peak is
340
Fig. 21.6 Metabolic
equivalent task (MET)
thresholds achieved during
Mortality rate (per 1000 person-years)
maximal exercise test is
associated with mortality
rate (expressed as per 1000
person years). Women
(shown in blue) achieved
significantly lower MET
thresholds compared with
men (shown in orange).
Shading represents 95%
confidence interval. Used
with permission from
Al-Mallah et al. [2]
associated with reduced risk of cardiovascular
events and all-cause mortality [5, 50].
The American Heart Association 2016 Scien-
tific Statement suggests that cardiorespiratory fit-
ness should be considered a vital sign [83]. The
majority of studies investigating VO2peak and
mortality have focused on men, but a few studies
have included women [36]. Sex-specific analysis
suggests that the relationship between higher car-
diorespiratory fitness and lower mortality is simi-
lar between men and women [50]. A recent meta-
analysis quantitatively determined that increasing
cardiorespiratory fitness by 1 MET translated to a
13% decline in all-cause mortality and 15%
reduction in cardiovascular disease. When men
and women were independently examined, the
minimum METs associated with a reduction in
risk at age 60 was 7 METs in men and 5 METs in
women [50]. In one study, women who achieved
2.6 METs less than men during a stress test had a
comparable prognosis of all-cause mortality
(Fig. 21.6) [2]. Therefore in these few studies,
cardiorespiratory fitness appears equally protec-
tive for men and women, but the threshold values
for risk are different. Future studies should further
evaluate cardiorespiratory fitness in both men and
women to provide normative data to guide clini-
cal diagnosis and treatment.
J. N. Barnes and Q. Fu
10.0 Men
Women
8.0
6.0
4.0
2.0
0.0
<2 <4 <6 <8 <10 <12 <14 <16 <18
MET thresholds
Exercise Is Medicine
Despite the benefits of exercise, over the last
century, our technological improvements have
greatly reduced the required physical activity
in all facets of daily life. The World Health
Organization estimates that globally, 25% of
adults are not meeting the minimum physical
activity recommendations (http://www.who.int/
mediacentre/factsheets/fs385/en/). Thus, physical
inactivity has emerged as a significant risk factor
for chronic disease and morbidity.
In medicine and health care, exercise is an
important tool in the prevention and treatment of
many diseases, specifically cardiovascular
diseases. Engaging in habitual exercise, particu-
larly regular aerobic exercise, is associated with
many favorable physiological adaptations. Habit-
ual exercise is associated with lower risk of car-
diovascular disease, hypertension, stroke, and
reduced all-cause mortality [51]. In effort to
increase physical activity, interventions have
been designed for children, adults, and patient
populations. The efficacy of the exercise inter-
vention is somewhat dependent on sex differ-
ences in cardiovascular adaptations. For
example, Martinez-Vizcaino et al. reported that
school-based physical activity intervention
21 Sex-Specific Ventricular and Vascular Adaptations to Exercise
Fig. 21.7 Summary of the primary myokines, the signal-
ing pathways involved, and the assumed physiological
effects. AMPK, AMP-activated protein kinase; BDNF,
brain-derived neurotrophic factor; CREB, cAMP
response-element-binding protein; C-X-C R2, C-X-C
receptor 2; FFA, free-fatty acid; FGF21, fibroblast growth
factor 21; Fndc5, fibronectin type III domain-containing
5 protein; Fstl1, follistatin-like 1; IGF, insulin-like growth
factor; IL-1ra, IL-1 receptor antagonist; Insl6, insulin-like
reduced cardiometabolic risk factors in boys and
girls, but the magnitude of improvement was
greater in girls [56]. In adults over 60, an exercise
intervention lowered cardiovascular risk factors
(i.e., blood pressure) to a greater extent in women
compared with men [62]. In contrast, a multicom-
ponent intervention that included exercise train-
ing in patients after open-heart surgery reported a
lower risk of future cardiovascular event in men,
but this protection was not seen in women [43].
In addition, there may be sex differences in the
response to an acute bout of exercise. During
exercise, skeletal muscle manufactures numerous
products, and these biologically active factors are
secreted into the bloodstream during muscle
341
6; LIF, leukemia inhibitory factor; NO, nitric oxide; NOS,
nitric oxide synthase; PGC-1α, peroxisome proliferator-
activated receptor-γ coactivator 1α; PI3K, phosphatidy-
linositol 3-kinase; SIRT1, sirtuin 1; SPARC, secreted pro-
tein acidic and rich in cysteine; sTNF-R, soluble TNF
receptors; trkB, tropomyosin receptor kinase; UCP1,
uncoupling protein 1. Used with permission from Fiuza-
Luces et al. [25]
contraction. Specifically, a myokine is defined
as “a cytokine or peptide which is produced in
the skeletal muscle cells and subsequently
released into the circulation to exert endocrine
or paracrine effects in other cells, tissues, or
organs” [23]. These myokines are likely the
underlying mechanisms behind the widespread,
systemic effects of regular exercise (Fig. 21.7)
[25, 113]. Interleukin-6 (IL-6), a prototypical
myokine, is released during exercise, but the
response is sex-specific [70, 75]. Treadmill run-
ning induces inflammatory cytokines (i.e., IL-6),
and the cytokine expression was dependent on
sex and the phase of the menstrual cycle in
women. [66]. In another example, men
342
demonstrated an increase in IL-6 after acute resis-
tance exercise; however there was no change in
IL-6 in women [6].
While IL-6 and other myokines are important
in the systemic benefits of exercise, they are
numerous. It takes decades of research to identify
all of the myokines and factors released by
contracting skeletal muscle. This is further com-
plicated by the technical difficulty in tracing the
physiological effects and determining the mecha-
nism of action of such myokines [113]. The
knowledge of these factors may have important
therapeutic implications, but it will likely be
impossible to synthesize a “polypill” product
that could replicate the multitude of physiological
effects of repeated muscle contraction.
The discovery of myokines has led to the pur-
suit of possible therapeutic implications of these
myokines for disease and obesity prevention. Still
others have suggested combining pharmacological
approaches, creating a polypill in attempt to mimic
the physiological effects of exercise. Fiuza-Luces
et al. [25] compared this polypill approach with
different modes of acute exercise on traditional
cardiovascular risk factors [25]. While a combina-
tion of antihypertensive and statin medications did
result in modest reductions in cardiovascular dis-
ease risk factors, this polypill combination was not
superior to an endurance exercise intervention.
Furthermore, there were no other beneficial
changes that are typically seen with exercise
interventions such as increases in cardiorespiratory
fitness and decreases in adiposity.
A limited number of the beneficial effects of
regular exercise can be replicated by acute phar-
macological manipulation; yet, there is not yet a
single low-cost regimen that mimics all of the
physiological effects of repeated skeletal muscle
contraction. Further, these pharmacological
approaches are unable to mimic the favorable
effects on psychological function, neuromuscular
coordination, and well-being [25].
Summary
The cardiovascular response and adaptation to
endurance exercise is well-characterized; how-
ever, much of this work has been conducted on
J. N. Barnes and Q. Fu
only male subjects or a small sample of men and
women combined. Thus, the sex differences dur-
ing exercise, after exercise, and in response to
exercise training are not completely known.
Furthermore, sex differences in skeletal muscle
adaptations to exercise and how these differences
influence cardiovascular function are less known.
Identifying potential differences and the mecha-
nisms behind such exercise-induced adaptations
is important for the optimization of exercise
interventions between men and women across
the life span.
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