Download Stroke Volume Dynamics During Progressive Exercise in Healthy

Pediatric Exercise Science, 2013, 25, 173-185
© 2013 Human Kinetics, Inc.
Official Journal of NASPEM and the
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REVIEW ARTICLE
Stroke Volume Dynamics
During Progressive Exercise
in Healthy Adolescents
Thomas Rowland
Baystate Medical Center
Viswanath Unnithan
Staffordshire University
Understanding cardiac responses to exercise in healthy subjects is important in the
evaluation of youth with heart disease. This review article incorporates previously
published original research from the authors’ laboratory to examine changes in stroke
volume during progressive exercise which are consistent with a model in which circulatory responses are controlled by alterations in the systemic vascular resistance.
Stroke volume dynamics and cardiovascular responses to a progressive upright cycle
test were examined in three groups of healthy, untrained adolescent subjects. These
indicated a) a progressive decease in systemic vascular resistance, b) little change in
stroke volume after an initial rise related to orthostatic changes in ventricular refilling,
c) evidence of a constant or slightly declining left ventricular end diastolic filling
pressure, d) and increases in markers of ventricular contractility. These observations
are consistent with peripheral (vascular resistance) rather than central (cardiac) control
of circulation with exercise. Changes in stroke volume during exercise need to be
interpreted in respect to alterations in heart rate and myocardial functional capacity.
From a mathematical perspective, stroke volume is a primary contributor to
cardiac output. When multiplied by the heart rate, the volume of blood expelled
by the left ventricle per beat defines the circulatory flow (cardiac output) over time
expelled by the left ventricle. Enhancement or decrement of stroke volume can
therefore be expected to serve as key markers of alterations in cardiac function
and circulatory flow (36). For this reason, attention traditionally has been focused
on factors responsible for variations of stroke volume as an indicator of cardiac
functional capacity in both health and disease.
The set of loading conditions and sympathetic neurologic influences which define
the quantity of cardiac stroke volume are well-recognized (13). Stroke volume is augmented by increases in preload (enhanced end-diastolic ventricular volume) via the
Frank-Starling mechanism as well as cardiac sympathetic stimulation but is diminished
in the face of a rise in after load (increased wall stress, greater peripheral vascular resisRowland is with the Dept. of Pediatrics, Baystate Medical Center, Springfield, MA. Unnithan is with
the Centre for Sport, Health and Exercise, Staffordshire University, Stoke-on-Trent, UK.
173
174 Rowland and Unnithan
tance). Changes in stroke volume thus reflect the combined influences of these factors
while serving as a prime indicator of the overall effectiveness of the cardiac pump.
This traditional model of the role of stroke volume in reflecting the role of
the heart as the primary controller of circulatory flow is not, however, consistent
with the cardiovascular responses observed during endurance exercise (37). Data
initially obtained from studies in animals and humans in the 1950s indicated that
facilitation and control of blood flow during such exercise is related to the role of
peripheral rather than central (i.e., cardiac) factors, most specifically the decline
in peripheral vascular resistance occurring within the exercising muscle (17,47).
By this concept, too, local vasodilatory factors within muscle conveniently link
circulatory flow rate to its augmented metabolic demands during exercise (9).
This model of circulatory control during exercise is an expression of Poisueille’s
Law, Q~P/R, whereby the circulatory flow rate (Q) is inversely related to peripheral
resistance (R) but directly to arterial pressure (P), which is maintained by heart
function. As Guyton concluded, “The heart has relatively little effect on the normal
regulation of cardiac output….The primary cause of augmented cardiac output is
believed to be the local vasodilatation in the skeletal muscle” (17).
The dynamics of heart rate and stroke volume during exercise-induced increases
in circulatory flow in this scenario are defined by the volume of systemic venous return.
By this model the stroke volume remains constant during increased exercise intensity
as blood return to the heart increases, a reflection of increased heart rate that matches
the venous return and maintains a constant left ventricular filling volume (preload).
An increase in ventricular contractility during exercise from sympathetic stimulation
and fall in peripheral vascular resistance increase myocardial contractile function,
which serves to maintain a constant stroke volume as the ejection time shortens.
In this scenario outlined above, stroke volume during exercise remains defined
by the same traditional loading and stimulant factors as in the resting state. However, in the peripheral model of circulatory responses to exercise the “meaning”
of the stroke volume changes, for the volume expelled per beat is not a functional
determinant of circulatory flow but rather a reflection of changes in heart rate and
myocardial contractility as cardiac output rises as a consequence of the fall in
peripheral vascular resistance.
Contemporary studies have supported this concept, as reviewed by Rowland
in 2008 (38). More recently we have examined changes in stroke volume during
progressive cycle exercise in young people in a series of three studies using Doppler
echocardiographic techniques. In this report we use the findings in these reports
to examine new evidence in respect to the peripheral model. These previouslypublished investigations provide additional information to support this concept,
specifically with data indicating a) the stability of left ventricular filling pressure
and b) augmented inotropic function (as indicated by tissue Doppler imaging) with
increasing exercise intensities. According to the peripheral model, a fall in systemic
vascular resistance with progressive exercise in these studies should be expected
to be accompanied by steady increases heart rate, cardiac output, and inotropic
function with little change in stroke volume or left ventricular preload.
It is important to recognize that this report describes findings during exercise
conducted in normothermic ambient conditions in healthy adolescent subjects who
were nonobese and physically active but athletically untrained. In other groups
(particularly the elderly, highly-trained athletes, and patients with heart disease)
stroke volume responses to exercise may differ (16,35).
Cardiac Responses to Exercise 175
Methods
The three studies included in this report were all conducted in the Pediatric Exercise Laboratory at Liverpool Hope University from 2008 to 2010, using similar
testing protocols. Study A involved 10 young adolescent males (mean age 15.3 ±
0.5 years), Study B 9 young adolescent females (mean age 15.0 ± 0.6 years), and
Study C 14 older adolescent males (mean age 17.9 ± 0.7 years). Findings in these
studies have been previously published in investigations of the effect of aerobic
fitness on myocardial performance (41), sex differences in myocardial functional
response to exercise (46), as well as time-of-day effects on cardiac variables (45).
For the purposes of this review, only data on athletically untrained participants in
the three studies are presented. These studies were approved by the ethics committee
of Liverpool Hope University. Informed consent and assent for participation were
obtained from parents and subjects, respectively.
All participants were in good health and taking no medications that would
affect cardiovascular function. By self-assessment of level of sexual maturation,
participants in studies A and B were in middle stages of puberty, while those in
study C were in late puberty or fully mature.
Body composition was assessed by air displacement plethysmography
(Bodpod, Life Measurement Incorporated, Concord CA). Before testing a screening echocardiogram was performed to rule out cardiac anatomic or functional
abnormalities.
Participants cycled in the upright position with a progressive protocol of 3-min
work stages on an electronically braked cycle ergometer (Excalibur Sport 925900;
Lode, Groningen, the Netherlands). Initial and incremental loads were 35 Watts for
studies A and B and 40 Watts for study C. Pedaling rate was 60 rpm. Participants
cycled to the point of exhaustion, with verbal support, defined as the point when
the specified cadence could not be maintained.
Gas exchange values were obtained using standard open circuit techniques.
Maximal oxygen uptake was defined as the mean of the two highest 20-s average values recorded during the final minute of exercise. A true exhaustive effort
was considered to have been achieved if respiratory exchange ratio over 1.00
and/or peak heart rate exceeding 180 bpm (study A and B) or 175 bpm (study
C) in conjunction with subjective evidence of fatigue (hyperpnea, sweating,
discomfort).
Heart rate was measured electrocardiographically. Stroke volume was estimated
by standard Doppler echocardiographic techniques (44). Velocity of blood flow in
the ascending aorta was recorded by a 1.9 MHz transducer directed inferiorly from
the suprasternal notch with a sweep speed of 100 mm per second. The integral of
the resultant velocity-time curves (VTI) was measured off-line. The VTI values
of the 3–5 curves with consistent highest values were averaged and multiplied by
the cross-sectional area at the level of the aortic valve leaflets to obtain estimated
stroke volume. This area was calculated from the diameter measured between the
hinge points of the fully-open aortic valve via 2-dimensional echocardiography
(parasternal long axis view) with the subject at rest sitting on the cycle ergometer.
The aortic valve ring was considered to be circular in this position, and changes
in diameter during the ejection period with exercise were assumed to be minimal.
Acceptable test-retest reproducibility and validity of this technique for assessing
stroke volume during maximal exercise have been described (44).
176 Rowland and Unnithan
Blood pressure was measured in the left arm by the auscultatory technique.
Diastolic pressure was defined as the point of muffling sounds. Mean arterial
pressure (MAP) was calculated as 1/3 (systolic-diastolic) + diastolic pressure.
Cardiac output (Q) was calculated as the product of stroke volume and heart rate,
and systemic vascular resistance was computed as MAP/Q. Cardiac output and
stroke volume were related to body surface area as the cardiac index and stroke
index, respectively.
Flow velocity across the mitral valve in early diastole (E wave) was estimated
by pulse wave Doppler interrogation at the tips of the open valve leaflets in the
apical four-chamber view. Peak values were calculated as the mean of the 3–5
consistently highest velocities. Late inflow velocity (mitral A wave) was not considered in these studies, since this wave merged with the E wave at low exercise
intensities. Values of mitral E were interpreted as reflecting the pressure gradient
between “upstream” factors (left atrial volume, pressure) and those “downstream”
(left ventricular relaxation properties) during diastole (43,57).
Left ventricular longitudinal velocities were recorded by pulse wave tissue
Doppler imaging (TDI) at the lateral aspect of the mitral valve annulus in the
apical four-chamber view. Peak TDI-S and TDI-E’ velocities were determined
as the mean of the 3–5 consistently highest values and interpreted as longitudinal
velocities in systole and early diastole, respectively. (TDI-S was not recorded in
study A.) These measurements were made while attempting to maintain alignment
between the transducer beam and the vertical axis of the heart. All determinations
were made during spontaneous respirations. TDI-S and TDI-E’ were considered
as markers of systolic (inotropic) and diastolic (myocardial relaxation) function,
respectively (34,49). Values of E/E’ were considered indicative of left ventricular
filling pressure (28).
The series of measurements of blood pressure, heart rate, VTI, mitral E, and
TDI was performed at rest, starting at 1:30 in each work stage, and during the final
minute of exercise. During the latter determination participants were requested to
maintain an upright posture and avoid exaggerated body movements but were not
otherwise constrained.
Systolic ejection time was obtained from the VTI curve. Systolic function was
estimated by the systolic ejection rate (calculated as the stroke volume divided by
ejection time), peak aortic velocity, and peak value of tissue Doppler-S (6,27).
Values are expressed as mean± SD. Unless otherwise noted, increases with
respect to exercise intensity were statistically significant for all measures.
Results and Discussion
Percent body fat for participants in studies A, B, and C were 16.0 ± 5.4%, 20.1±
5.8%, and 15.3 ± 3.4%, respectively. Screening echocardiograms were normal
in every subject. All subjects satisfied criteria for an exhaustive exercise effort.
Physiological variables measured preexercise and at maximal exercise in the three
studies are outlined in Table 1. Cardiac output rose by factors of 2.6, 3.1, and 3.4.
Calculated total peripheral vascular resistance between rest and maximal exercise
fell by -51% in study A and by -68% in study B. (Because of technical difficulties
blood pressure was not recorded in study C).
Table 1 Cardiovascular Variables With Exercise in the Three Study
Groups. Values Are Mean (Standard Deviation)
VO2max (ml kg-1 min-1)
Heart rate max (bpm)
Study A
Study B
Study C
44.4(6.6)
36.0(5.1)
44.0(5.0)
195(11)
191(9)
190(11)
1.12(0.05)
1.07(0.07)
1.26(0.07)
Preexercise
16.6(6.1)
23.0(6.9)
Max
8.1(0.2)
7.4(1.5)
Preexercise
3.52(1.08)
2.55(0.72)
2.96(0.53)
Max
9.02(2.05)
7.80(1.03)
10.13(1.18)
Preexercise
42(10)
33(6)
42(7)
Max
46(10)
41(4)
54(6)
Preexercise
266(37)
251(17)
243(18)
Max
198(10)
170(7)
158(13)
Preexercise
0.158(0.034)
0.204(0.042)
0.326(0.053)
Max
0.234(0.051)
0.368(0.060)
0.654(0.086)
Preexercise
136(23)
108(16)
118(17)
Max
208(45)
196(12)
232(27)
72(9)
75(17)
64(16)
149(23)
155(18)
149(14)
Respiratory exchange ratio max
Systemic vascular resistance (units)
Cardiac index (L min-1 m-2)
Stroke index (ml m-2)
Systolic ejection time (s)
Systolic ejection rate (ml s-1)
Peak aortic velocity (ml
Mitral E (cm
s-1)
s-1)
Preexercise
Max
Tissue Doppler S (cm s-1)
Preexercise
7.5(1.6)
8.4(2.3)
Max
18.6(2.6)
18.3(1.9)
Tissue Doppler E’ (cm s-1)
Preexercise
12.0(2.0)
11.8(2.0)
9.1(2.9)
Max
28.0(5.0)
26.8(2.7)
24.9(2.4)
E/E’
Preexercise
6.11(1.5)
6.55(2.1)
7.63(1.3)
Max
5.39(0.93)
5.81(0.62)
6.08(0.97)
177
178 Rowland and Unnithan
Pattern of Changes in Stroke Volume
Figure 1 indicates the pattern of stroke index with increasing cycle work to exhaustion in the three studies. All show the same configuration, with an initial rise (of
approximately 25%), followed by little change above a low-moderate work load.
This pattern of stroke volume response to upright exercise is consistent with
previous reports. In fact, an initial rise with subsequent little change at higher work
intensities (a so-called “plateau”) is one of the most consistently observed findings
in cardiac exercise physiology. Supporting its validity, this pattern of stroke volume
response to upright exercise has been described utilizing multiple techniques in a
wide age range of subjects from prepubertal to middle-age. These have included
indirect Fick (CO2 rebreathing; 2), direct Fick (53), thermodilution (20), thoracic
bioimpedance (5), dye dilution [10,11,19), radionuclide angiography (32), and
Doppler echocardiography (26,56).
It has been considered that this initial rise in stroke volume observed during
the initial phases of upright exercise reflects the mobilization of blood sequestered
in the lower extremities by gravity when assuming the upright or seated position
(3,48). Blood volume in the legs increases by 500–1,000 ml when an adult becomes
upright, a response which reduces central volume and consequently left ventricular
preload. As a result, cardiac output and stroke volume fall by 20–40%. At the start
of upright exercise, the pumping action of the contracting skeletal muscles in the
leg reverse this effect. Blood is returned to the central volume, which augments
left ventricular preload, and via a Frank-Starling mechanism effects a rise in stroke
volume (55).
Early studies provided an experimental underpinning for this mechanism.
Pollack and Wood reported that during the first steps of walking, venous pressure
at the ankle fell from 100 to approximately 40 mm Hg (33). Similar declines were
documented by Stick et al. (52) and Stegall (50) during treadmill walking.
Figure 1 — Stroke index responses during upright progressive cycle exercise in the three
study groups. Dashed lines connect to average maximal values.
Cardiac Responses to Exercise 179
Figure 2 — Stroke index at rest supine (S) followed by values when assuming the upright
sitting position (U), then with progressive cycle exercise in study C.
Evidence supporting this concept is provided by stroke volume values at
supine rest followed by upright exercise demonstrated in Study C. As indicated in
Figure 2, average stroke volume fell by 25% when moving to the sitting position
(with dependent legs) on the cycle ergometer from supine rest. With the onset of
exercise, stroke volume rose to approximate that recorded in the supine position,
with little further change as work intensity rose.
As expected, then, most studies have revealed no initial rise in stroke volume
when progressive cycle exercise is performed in the supine position (3,22,42,51).
However, some have reported initial increases during both supine and upright
exercise, although with a greater magnitude of rise in the latter (32,54).
A similar “flat” stroke volume response to progressive exercise is observed in
other conditions in which the influence of gravity is eliminated. No inital rise in
stroke volume has been reported with prone simulated swimming (40), astronauts
exercising in the microgravity of outer space (1), arm exercise (24), and upright
exercise while submerged in a pool, where the hydrostatic pressure gradient of the
surrounding water displaces blood cephalad away from the lower extremities (7).
These data provide compelling evidence that the early rise of stroke volume
during upright exercise reflects simply a “refilling” phenomenon, a manifestation
of increased left ventricular diastolic filling (Frank-Starling mechanism). Beyond
this response, which is related to orthostatic alterations in central blood volume,
stroke volume changes little with progressive exercise.
Alterations in Ventricular Filling (Preload)
In the three present studies, values of mitral E peak velocity rose 2.1-, 2.1-, and 2.3fold with increasing work intensity, indicating a rise in the left atrial-left ventricular
pressure gradient in the early portion of ventricular diastole which drives ventricular filling. Concomitantly, TDI-E’ rose by factors of 2.3, 2.3, and 2.7, indicative
180 Rowland and Unnithan
of augmented diastolic function (relaxation properties, elastic recoil) of the left
ventricle. The ratio of E/E’, however, did not change significantly and in all cases
demonstrated a slight gradual decline (Figure 3). E/E’ is considered as an indicator of “upstream” left atrial pressure and reflects left ventricular filling pressure.
This pattern of E/E’, then, is consistent with a stable (or slightly decreasing) left
ventricular end diastolic volume, or preload, in the course of progressive exercise.
These findings are consistent with reports by two-dimensional echocardiography [15,31,39) and radionuclide ventriculography (20,21,29,58) that left ventricular
end diastolic dimension remains unchanged or gradually declines with increasing
exercise intensity. In these studies of responses to upright exercise, this pattern was
often preceded by a slight rise at onset of exercise, consistent with the process of
orthostatic-related ventricular refilling noted above.
This stable filling volume occurs concomitantly with a 3-fourfold rise in systemic venous return to the heart. To maintain a constant left ventricular filling volume
per beat, this influx of blood flow must be de facto tightly coupled to a corresponding
rise in heart rate. The Bainbridge reflex, by which a rise in atrial pressure or volume
triggers a sympathetic reflex that increases sinus node firing rate, offers a means by
which this might be accomplished. The true existence of this reflex, first proposed
over a century ago, has been surrounded by controversy, but its function has been
clearly demonstrated in both humans and subhuman primates (4,18,30). It can be
considered the best mechanistic explanation for the close match between heart rate
and systemic venous return by which the per-beat ventricular filling volume remains
constant during progressive exercise. Alternatively, however, Clausen suggested that
the close link of heart rate to systemic venous return to the heart might be explained
by sympathetic reflexes originating in the contracting skeletal muscle (8).
This information provides evidence that progressive exercise in the upright
position is initiated by an early increase in ventricular filling from mobilization
of dependant blood in the lower extremities. Following this, ventricular preload
remains constant or declines slightly, the consequence of a rise in heart rate to match
Figure 3 — Values for E/E’ in the three study groups with progressive upright cycle exercise.
Cardiac Responses to Exercise 181
increases in systemic venous return. It appears, then, that this mechanism “defends”
left ventricular end diastolic size as exercise intensity increases, for failure of heart
rate to increase appropriately would result in progressive left ventricular dilatation.
This would result in a disadvantageous increase in left ventricular wall tension and
diminished mechanical efficiency as predicted by the law of Laplace (23).
Myocardial Inotropic Responses
As exercise intensity increases, myocardial systolic function is enhanced, expressed
as a greater force and velocity of contraction. This results in a progressive shortening
of the systolic ejection time, as well as an increased ventricular shortening fraction
or ejection fraction as end systolic dimension decreases.
This enhanced myocardial contractility is documented in our three studies by
parallel increases in markers of systolic function with increasing work. Systolic
ejection rate, TDI-S, and peak aortic velocity all rose approximately twofold. At the
same time, consistent with the research literature (e.g., Higgenbotham et al. (20)),
systolic ejection time per beat decreased by 25%, 32%, and 35% in the three studies .
Previous studies have indicated that while progressive exercise is accompanied by a relatively stable left ventricular end diastolic dimension, the end systolic
dimension progressively decreases (31,39). This results in an increase in shortening
fraction (the difference between left ventricular end diastolic dimension and systolic
dimension divided by diastolic dimension, multiplied by 100), typically from 30%
at rest to 50% at maximal exercise (17,31,39). The ventricular ejection fraction,
the three-dimensional counterpart of the shortening fraction estimated by nuclear
angiography, generally rises by 10–15% during a progressive exercise test (12,58).
Several factors may potentially contribute to this rise in inotropic function
with progressive exercise: a) decrease in afterload (with stable left ventricular size,
indicated by the fall in systemic vascular resistance), b) direct sympathetic nervous
myocardial stimulation, and c) the increasing heart rate (the force-frequency phenomenon). Each of these influences can act independently to augment myocardial
contractility and shorten ejection time; thus, identifying their relative contributions to
alterations in myocardial contractile function with exercise is problematic (6,14,25).
These observations serve to create an apparent paradox. It is clearly documented
that the ventricles empty more completely (as a consequence of enhanced myocardial contractility) as work load increases, yet the volume expelled per beat (stroke
volume) remains stable (after an initial refilling phase). This quandary is resolved
by recognizing that the enhanced contractility serves to eject the same volume of
blood during a progressively shortening ejection time. The effect of augmented myocardial contractility with progressive exercise, therefore, is to maintain, rather than
increase, stroke volume in the face of an increasingly abbreviated ejection period.
Summary
The response of the cardiovascular system in providing circulatory support for
endurance exercise involves a remarkably fine-tuned synchrony of interrelating
variables. The exercise studies described in this report, combined with information
from previous investigations, indicate that, after early postural-related ventricular
refilling, upright progressive cycle exercise performed by healthy, young, untrained
182 Rowland and Unnithan
individuals is accompanied by a) a steady fall in systemic vascular resistance, b)
little change in stroke volume, c) stable or slightly decreasing ventricular preload,
and d) progressive increases in markers of myocardial systolic function. This constellation of findings is consistent with a peripheral model of circulatory control
during exercise, modulated by alterations in systemic arteriolar conductance, in
which cardiac dynamics are dictated by the volume of systemic venous return.
In this model, as Clausen emphasized, “the vasodilation in muscle that is locally
adjusted to the work load may be considered the fundamental determinant of cardiac
output during exercise” (8).
The extraordinary complexity of the cardiovascular responses to endurance
exercise precludes an over-simplistic reductionist approach. The myriad components
of this response must all function in harmony, and in accordance with the dictates
of “symmorphosis,” the capacity of no single component should exceed that of the
entire system. Still, the experimental data obtained from the studies presented in
this report support the concept that peripheral control (i.e., alterations in muscular
arteriolar conductance) serves as the primary factor for instigating and regulating
level of circulatory blood flow during exercise in healthy individuals. Whether this
factor, or others, are responsible for defining the limits of circulatory responses to
exercise remains a critical but unanswered question.
This information does indicate that during endurance exercise, stroke volume
should be considered as a secondary, resultant variable influenced by a) the relationship between systemic venous return to the heart and the heart rate, and b)
increases in systolic and diastolic myocardial function. Any changes in stroke
volume observed during exercise therefore need to be interpreted in the context of
these modifying variables.
Acknowledgments
The authors are indebted to those individuals who contributed to the organization and performance of the three exercise studies: Piers Barker, Max Garrard, Miriam Guerra, Kathyryn
Holloway, Martin Lindley, Simon Marwood, and Denise Roche.
Study C was supported by a grant from The Children’s Miracle Network, Duke University
(CMN 3911749)
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