Adv Physiol Educ 44: 414–422, 2020;
doi:10.1152/advan.00043.2020.
A PERSONAL VIEW
Understanding preload and preload reserve within the conceptual framework
of a limited range of possible left ventricular end-diastolic volumes
X Roger E. Peverill
Monash Cardiovascular Research Centre, MonashHeart, Monash Health, Clayton, Victoria, Australia; and Department of
Medicine, School of Clinical Sciences at Monash Medical Centre, Monash University, Clayton, Victoria, Australia
Submitted 9 March 2020; accepted in final form 3 June 2020
Peverill RE. Understanding preload and preload reserve within the
conceptual framework of a limited range of possible left ventricular
end-diastolic volumes. Adv Physiol Educ 44: 414 – 422, 2020; doi:
10.1152/advan.00043.2020.—Preload has been variously defined, but
if there is to be a direct relationship with activity of the Frank-Starling
mechanism in its action to increase the force and extent of contraction,
preload must directly reflect myocardial stretch. The Frank-Starling
mechanism is activated during any stretch of a cardiac chamber
beyond its resting size, which is present immediately before contrac-
tion. Every left ventricle has an intrinsic and limited range of possible
volumes at end diastole. There is a curvilinear relationship between
left ventricular (LV) end-diastolic pressure (LVEDP) and LV end-
diastolic volume (LVEDV), and, at maximal or near maximal
LVEDV, there will be a high LVEDP. Within the possible range,
the LVEDV will be determined by the extent of filling, any change in
LVEDV will result in changed activity of the Frank-Starling mecha-
nism, and change in LVEDV might, therefore, be considered to
represent change in preload. On the other hand, it is the difference
between the current and the maximal possible LVEDV (or the preload
reserve) that may be of the most clinical relevance. There is a
reciprocal relationship between preload and preload reserve, with
minor or absent LV preload reserve indicating that there will be either
minimal or no increase in stroke volume following intravenous fluid
administration. As left atrial pressure can remain within the normal
range when the LVEDP is elevated, it is LVEDP, and not left atrial
pressure, that provides the most reliable guide to preload reserve in an
individual at a specific period in time.
Frank-Starling mechanism; left ventricle; preload; preload reserve
INTRODUCTION
Preload refers to a concept that is not only central to the
understanding of cardiac and circulation physiology, but that is
also a vital, practical consideration in clinical practice when
intravenous fluid resuscitation is being considered. However,
despite this fundamental importance, and the common use of
the term, there has been no consistent definition of preload
used in either the teaching, clinical, or research settings. Thus,
in the physiology, cardiology, and critical care literature, car-
diac preload has been variably defined as a pressure, a volume,
or, less commonly, as end-diastolic wall stress, a divergence in
definitions that has been the subject of previous discussion (38,
41, 50). In four well-known physiology textbooks, preload was
considered to be left ventricular (LV) end-diastolic volume
(LVEDV) in one (43), the LV end-diastolic pressure (LVEDP)
Correspondence: R. E. Peverill (roger.peverill@monash.edu).
414 1043-4046/20 Copyright © 2020 The American Physiological Society
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in two (27, 45), and there was no clear differentiation between
LVEDV and LVEDP in another (34). The definitions or inter-
pretations of preload in cardiology textbooks have generally
emphasized the importance of LVEDV, but isolated statements
from these books may still be considered confusing about
whether preload should be thought of as a volume or a
pressure, e.g., “The preload reflects the venous filling pressure
that fills the left atrium, which in turn fills the left ventricle
during diastole” (44). There is also confusion about which
pressure, e.g., “In the clinical setting, end-diastolic pressure
and pulmonary capillary wedge pressure are used frequently as
measures of preload” (30). Preload has often not been specif-
ically defined when the term is used in the critical care
literature, but, when defined, definitions have also been vari-
able: for example, “Preload is defined as the myocardial fiber
length at end diastole” and then in the next sentence of the
same article, “At the organ level, preload may theoretically be
assessed by measuring LV end-diastolic volume” (62). A
single measure of LVEDV has also been used as to represent
preload in scientific studies (14). The notion of preload as
end-diastolic wall stress has received consideration in both the
physiological and critical care literature, but there has also
been disagreement regarding the appropriateness of a wall
stress definition of preload (13, 41, 50).
It will be argued in this review that a direct linear relation-
ship between preload and activity of the Frank-Starling mech-
anism underlies the importance of the concept of preload, and
that definitions of preload based on a single measure of any of
LV volume, pressure, or wall stress preclude such a direct
relationship. The main themes of this review are as follows. 1)
There is an intrinsic (and limited) range of possible LVEDVs
for any ventricle, and the extent of LV chamber stretch within
this range is the only variable that provides a direct linear
relationship with the Frank-Starling mechanism. 2) LVEDP
and left atrial (LA) pressure, or its practical alternative of
pulmonary arterial wedge pressure (PAWP), can only be pre-
sumed to be equivalent in young, healthy hearts and should not
be used interchangeably in other settings, and none of these
pressures are linearly related to LV stretch. 3) Preload reserve
is the maximal increase in LVEDV that is possible during an
attempt to increase cardiac filling, its absence is best predicted
by a high LVEDP (and even more specifically by a high
transmural LVEDP), and estimation of whether there is preload
reserve is the most vital consideration when fluid administra-
tion is being considered. The above concepts are of fundamen-
tal importance for a practical understanding of preload, preload
 A CONCEPTUAL FRAMEWORK FOR PRELOAD AND PRELOAD RESERVE
reserve, and the Frank-Starling mechanism by students of
physiology, cardiologists, emergency physicians, and intensiv-
ists and also provide a foundation for decision making regard-
ing fluid resuscitation in all clinical disciplines.
An understanding of the concepts that relate to preload and
its importance for understanding heart function benefits from a
historical perspective, and such a perspective can be found in
complementary reviews that describe the early contributions to
the formulation and understanding of what has become com-
monly known as the Frank-Starling mechanism (26, 33, 42,
64). It was experiments in the early 19th century in skeletal
muscle that first showed that progressive stretching of a resting
muscle before contraction results in not only an increase in
resting tension, but also greater tension development and
energy production during contraction (33). That this principle
also applied to cardiac muscle was demonstrated in the late
19th century by a number of investigators who showed that the
force of contraction, stroke volume (SV), and stroke work
(SW) all increase as a result of a larger ventricular size just
before contraction (33, 64). In his Linacre Lecture in 1915,
Starling stated, “The law of the heart is thus the same as the
law of muscular tissue generally, that the energy of contraction,
however measured, is a function of the length of the muscle
fiber” (58). Our understanding of the Frank-Starling mecha-
nism has been further refined by numerous experiments over
the last 100 yr, encompassing studies using isolated cardiac
myocytes, strips of cardiac muscle, isolated heart preparations,
intact animals, and also studies in anesthetized and conscious
humans.
Stretch in Cardiac Muscle Experiments
The properties of myocardial contraction can be studied in
vitro by mounting a mammalian papillary muscle, trabeculae,
or strip of atrial myocardium in an oxygenated, physiological
salt solution (19, 56). The cardiac muscle is attached at each of
its ends using equipment that enables the measurement of
muscle tension at rest and during contraction. When the cardiac
muscle is stimulated while held at a fixed length, the resulting
contraction is termed isometric, and evaluation of contraction
relies on both the timing and magnitude of the active tension.
When the stimulated cardiac muscle is allowed to shorten, the
resultant contraction is termed isotonic, and evaluation of
contraction in shortening cardiac muscle can also include
measurement of the amplitude of motion and the minimum
muscle length (at the end of contraction), as well as of the
developed tension.
Preload was the term originally used for a weight attached to
one end of the muscle preparation that was used to stretch the
muscle before contraction (57). To normalize for the variation
in thickness of the muscle preparation, the force generated by
the weight was divided by the cross-sectional area of the
muscle to give a resting muscle tension (g/cm2). While it was
the muscle tension just before contraction that was considered
to be preload in the classical experiments, the vital importance
of muscle length was also recognized. Any cardiac muscle
preparation (down to the level of the cardiomyocyte) will
have a resting or slack length (Lrest), this being the length of
the unstretched preparation when it is fully relaxed (32).
Passive stretch of the cardiac muscle before contraction
results in increased force of the subsequent contraction, and
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415
the precontraction muscle length at which the subsequent
isometric force is maximal has been termed Lmax (32). Thus
there is an intrinsic range of possible muscle lengths for a
particular muscle ranging from that at Lrest to that at Lmax. At
muscle lengths less than Lmax, both the resting tension and
the subsequent active tension are less than maximal. The
relation between muscle length and active tension is not
linear, and small decreases in length below Lmax can result
in a substantial decline in both passive and actively devel-
oped tension. On the other hand, experiments done at Lmax
need to be differentiated from the situation in the normal
heart, which in most cases is not functioning at its maximum
volume.
In isotonic muscle experiments, increased preload (and thus
a longer precontraction muscle length) leads to increases in the
rate of tension development and the velocity of shortening, and
also to a larger amplitude of contraction (57). It is important to
emphasize (as in my teaching experience it is commonly
misunderstood) that, in these experiments, the minimum mus-
cle length (i.e., the muscle length at the end of contraction)
does not decrease as a result of an isolated change in preload
(8, 57, 59, 63). In other words, the increase in contraction
amplitude following an increase in preload is entirely due to
the contribution of the increased stretch, and thus increased
myocardial length, before the contraction.
A full understanding of myocardial contraction also requires
consideration of the load on the myocardium during contrac-
tion, most commonly known as the afterload. In papillary
muscle experiments, the afterload (sometimes known as the
total load, as it also included the preload) was a weight that was
lifted by the muscle during isotonic contraction, and similar to
preload, this weight was normalized to the cross-sectional
diameter of the muscle preparation and expressed as muscle
tension (57). The higher the afterload, the longer the time
interval between the electrical stimulus and the beginning of
muscle shortening, the smaller the amplitude of contraction,
and the longer the minimum muscle length at the end of
contraction (63). Similar to afterload, changes in contractility
lead to changes in both the amplitude of contraction and
minimum muscle length, with increased contractility resulting
in both a lower minimum muscle length and a larger amplitude
of contraction, and decreased contractility having the opposite
effects. Thus preload, afterload, and contractility all have
independent effects on the amplitude of contraction, and each
of these modifiers of contraction can be defined in part by the
aspect of the muscle preparation that they do not affect. Thus
neither afterload nor contractility have a direct effect on the
resting or stretched muscle length before contraction, whereas
preload has no direct effect on the minimum muscle length
after contraction.
The Functions of the Frank-Starling Mechanism
When the cardiac muscle becomes stretched an extra
amount, as it does when extra amounts of blood enter the heart
chambers, the stretched muscle contracts with a greatly in-
creased force, thereby automatically pumping the extra blood
into the arteries [Arthur C. Guyton (25)].
The Frank-Starling mechanism modifies the output of each
of the four cardiac chambers on a beat-to-beat basis. Each of
the cardiac chambers can increase its output following in-
416 A CONCEPTUAL FRAMEWORK FOR PRELOAD AND PRELOAD RESERVE
creased filling, but it is change in LVEDV that is the final and
essential part of the pathway that allows the Frank-Starling
mechanism to convert an increase in systemic venous return to
an increase in the SV ejected into the systemic circulation. The
Frank-Starling mechanism is also a vital component of the
regulation of the heart and circulatory system because it en-
sures that the amount of blood pumped out of the left and right
ventricles is equal (7). This means that blood does not have the
opportunity to accumulate in either the systemic or pulmonary
circulations, and, given that there is restriction of total cardiac
volume by the pericardium, it acts to prevent progressive
volume overload of one ventricle, resulting in compression of
the other ventricle. It is important to appreciate that the Frank-
Starling mechanism is acting during every cardiac cycle in the
normal human heart, as there is always a degree of myocardial
stretch before contraction. Thus reductions in intravascular
volume, and therefore LV filling and LVEDV, lead to a lower
SV and are a reflection of the same mechanism by which
increases in LV filling lead to increases in SV (12, 40).
Possibly less well recognized is that an increase in LVEDV
with resulting activation of the Frank-Starling mechanism can
provide an acute compensation for reduction in SV due to
diminished contractility or increased afterload. An increase in
LVEDV can also provide compensation for a chronic decrease
in contraction, but in this case a larger LVEDV may also reflect
a positive remodeling process that is independent of the degree
of chamber stretch.
Stretch and the Frank-Starling Mechanism in the Intact
Heart
Specific issues related to the relationships between cardiac
pressures, cardiac volumes, myocardial stretch, and cardiac per-
formance have been evaluated in a number of important studies in
the intact animal and human, beginning in the 1940s (5, 24, 28,
40, 54, 55). That SW, rather than either SV or cardiac output
(CO), was the most appropriate measure of the energy of LV
contraction when investigating the “Law of the Heart” was sug-
gested by Sarnoff and Berglund in 1954 (54). In a study per-
formed in anesthetized dogs, a family of LV and right ventricular
(RV) function curves was described in which there was a consis-
tent but nonlinear relationship between ventricular SW and mean
atrial pressure (54). SW was calculated as the product of SV and
the difference between mean arterial and mean atrial pressures.
The ventricular function curve (of SW) showed an initial steep
rise, but at high atrial pressures the curve flattened off to a plateau.
That mean right atrial (RA) or LA pressures may not be identical
to RV end-diastolic pressure (RVEDP) or LVEDP, respectively,
was considered by the authors, but it was observed that there was
a close linear relationship between atrial and end-diastolic pres-
sures on either side of the heart in normal dogs when these
pressures were in the low-to-medium range. On the other hand,
while a close relationship was found between atrial pressure and
the SW of the ventricle on the same side of the heart, such a
relationship was not found 1) between RA pressure and LV SW,
or between LA pressure and RV SW, 2) between either LA or RA
pressure and SV, or 3) between either atrial pressure and CO (54).
In their important 1954 study, Sarnoff and Berglund (54)
referred specifically to previous disagreement about whether it is
the volume of the ventricle or the pressure in the ventricle that is
most closely associated with the extent of the subsequent ventric-
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ular contraction. When the pressure around the ventricles was
increased by the production of cardiac tamponade, the ventricular
SW of both ventricles fell, despite increased atrial pressures, and
thus the ventricular function curves during tamponade showed an
apparent suppression. If, however, the effective filling or trans-
mural pressure (pericardial pressure minus atrial pressure) was
plotted against SW, no suppression of the ventricular function
curves was observed. This observation was also in accord with the
view that the work of the ventricle is a function of diastolic fiber
length, and that this length is related to the effective end-diastolic
pressure. As nonlinear curves have the disadvantage of being
difficult to quantify, and the use of pressure as the index of preload
introduced susceptibility to such extraneous influences as pericar-
dial pressure and septal shifting, Sarnoff and Berglund speculated
that a plot of ventricular SW against ventricular volume (or fiber
length) would be closer to a straight line. In a review from the
following year, Rushmer (51) also emphasized the importance of
cardiac fiber length and thus chamber size, rather than LVEDP, in
any investigation of the Frank-Starling mechanism.
Some 30 yr later, Glower et al. (24) investigated the relation-
ship between preload and SW in chronically instrumented dogs,
with preload assessed as either end-diastolic segment length or
chamber volume. The relationship of SW with varying end-
diastolic segment lengths or chamber volumes within individual
animals, termed the preload recruitable SW (PRSW) relationship,
was highly linear in every study (mean r ⫽ 0.97). Previous non-
linear relationships between SW and pressures could thus be
explained as being due to the exponential relation between end-
diastolic pressure and volume. Glower et al. concluded that
avoiding pressure as the measure of preload should minimize the
problematic influences of pericardial pressure, septal shifting, or
respiratory variations in intrapleural pressure. Linearity of the
PRSW relationship also provided a quantification of cardiac
performance by a simple slope and x-intercept. It is important to
emphasize that the linear relationship between LVEDV and SW
that was demonstrated in this study was based on multiple values
from individual animals during vena cava occlusion induced
reductions in venous return (and thus reductions in LVEDV), and
not on single values of LVEDV from individual members of the
group. The findings are, therefore, consistent with the notion that
change in LVEDV is directly related to change in SW, but does
not imply that a single measure of LVEDV can predict SW (24).
It is also important that it is change in SW, rather than SV, which
has the closest relationship with a change in LVEDV, and that SW
is dependent on the induced change in pressure from diastole to
systole as well as on the SV. It is clear from a reorganization of the
formula for ejection fraction (EF) (SV/LVEDV) to focus on SV
(EF ⫻ LVEDV) that a single measure of LVEDV can only
predict SV if the EF is also known. To complicate this issue
further, an increase in afterload can lead to a decrease in EF.
Further discussion of the effects of afterload on SV and SW are
beyond the scope of this review.
Stretch and the Sarcomere
The Frank-Starling mechanism is manifest at the cellular
level, within the sarcomere, where active force generation is a
function of sarcomere length (22). The mechanisms responsi-
ble for length-dependent activation within the sarcomere are
still not fully understood, but increased responsiveness to
calcium is a likely contributor, and a reduction in interfilament
 A CONCEPTUAL FRAMEWORK FOR PRELOAD AND PRELOAD RESERVE 417

lattice spacing has also been considered as a possible mecha-
nism (22). It is now believed that the giant protein titin, which
is located in the sarcomere between the Z and M lines,
functions as a bidirectional spring and can store energy during
stretch of the sarcomere, also plays an important role in
length-dependent activation (22).
The percentage of the extent by which a strip of myocardium
can be stretched from Lrest is substantially, although not
wholly, dependent on the sarcomeres in the individual cardio-
myocytes. The resting or slack length of a sarcomere is ~1.8
␮m, and the maximum possible length of a stretched sarcomere
is ~2.3 ␮m, reflecting the physiological range for resting
sarcomere length and the potential of an ~28% increase in
length from the resting state (21). It is important that sarco-
meres of 2.3 ␮m (and also myocytes and muscle strips that
have been stretched so that their sarcomeres are 2.3 ␮m) will
have minimal scope for further stretching without this resulting
in permanent muscle damage. In other words, there is a length
at which the reserve of the sarcomere for further stretching
without damage is exhausted. However, the extent by which a
cardiac chamber can be stretched from its resting size is not
just related to the sarcomeres and the myocardium, but is also
limited by the pericardium (23).
A Limited Range of Possible Ventricular Volumes and the
Limitations of a Single LVEDV Measurement as a Surrogate
for LV Stretch
Using the concept of muscle stretch described in muscle
strip experiments, stretch from Lrest to the precontraction mus-
cle length for a strip of myocardium is equivalent to the
difference between the resting LV volume (i.e., the volume of
the fully relaxed left ventricle with a transmural pressure of
zero) and the current LVEDV (see Fig. 1). This is an important
concept because LV wall stretch cannot be represented by an
absolute LV volume. This also introduces the concept that each
left ventricle must have a possible range of volumes, ranging
from a LVEDV at zero transmural LVEDP to that at which
there is a high LVEDP (25 mmHg or thereabouts). There is a
curvilinear relationship between LVEDV and LVEDP, with
the curve getting steeper at higher volumes (Fig. 1). A normal
left ventricle during rest and with moderate exercise is oper-
ating in a volume range well within these limits, but in the
presence of cardiac pathology, a ventricle could be operating
near its maximal LVEDV (associated with a high LVEDP) at
rest.
For a single measurement of LVEDV to be able to reflect
stretch of that ventricle, it would have to be apparent where the
measured volume was within the ventricle’s possible range of
volumes. However, information about the possible range of
volumes cannot be easily measured or accurately predicted.
Thus there are significant differences in the resting LVEDV
between healthy individuals of different sexes and body sizes
(e.g., different LVEDVs at a LVEDP of 8 mmHg of two
healthy young adults shown in Figs. 1 and 2), but there also can
be substantial differences in LVEDV between individuals,
even when sex and body size are both taken into consideration
(12). Moreover, there are a number of circumstances that can
lead to LV remodeling and thus change in LVEDV indepen-

30 A B C
Left ventricular end-diastolic pressure (mmHg)

20

10

0
40 60 80 100 120 140 160
Left ventricular end-diastolic volume (mL)
Fig. 1. Representation of the relationship between left ventricular (LV) end-diastolic volume (LVEDV) and LV end-diastolic pressure (LVEDP) showing the
range of possible LV volumes at end diastole for a young, healthy adult male of 1.8-m2 body surface area during variations in the amount of LV filling. The
data points are partly based on published data but also include some assumptions. The closed circles () have taken into consideration previously published data
in which pulmonary artery wedge pressure (PAWP) was altered by changes in the intravascular volume state (12), with the assumption that PAWP is similar
to LVEDP in healthy young adults, at least when pressures are within the normal range (3). The data points at higher values of LVEDP are based on extensive
evidence that there is a rapid increase in LVEDP as the ventricle gets close to its maximal LVEDV (6, 46). The points with open circles (Œ) are not based on
published data but are an extrapolation on the basis that there must be a lower limit of LVEDV as the transmural LVEDP approaches zero. The vertical dashed
lines highlight the LVEDV at a normal LVEDP (8 mmHg, A), an elevated LVEDP (15 mmHg, B), and at a LVEDP where the LVEDV is near maximal (C).
The shorter of the horizontal dotted lines demonstrates the extent of LV chamber stretch (preload) at 8-mmHg LVEDP, and the longer of the horizontal dotted
lines demonstrates the larger extent of LV chamber stretch at 15-mmHg LVEDP. The longer horizontal solid line represents the large extent of preload reserve
when the LVEDP is 8 mmHg, and the shorter horizontal solid line represents the smaller preload reserve when the LVEDP is 15 mmHg. The range of LVEDV
in this individual over the normal range of LVEDP (4 –12 mmHg) can be seen to be ~96 –142 mL. Near maximal LVEDV is assumed in this case to be when
the LVEDP is ~20 mmHg (vertical line C). Preload reserve can be defined as maximum LVEDV ⫺ current LVEDV.

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418 A CONCEPTUAL FRAMEWORK FOR PRELOAD AND PRELOAD RESERVE

30

Left ventricular end-diastolic pressure (mmHg)

Healthy senior adult female
Healthy young adult female
Young endurance female athlete

20

10

0
40 60 80 100 120 140 160
Left ventricular end-diastolic volume (mL)
Fig. 2. Representations of different relationships between left ventricular (LV) end-diastolic volume (LVEDV) and LV end-diastolic pressure (LVEDP), which
occur due to ventricular remodeling and with variations in the extent of LV filling in a healthy adult female individual of 1.5-m2 body surface area, shown at
different ages and after endurance training (young, sedentary adult, senior sedentary adult, and young, endurance-trained athlete). Horizontal dotted lines at 4,
8, and 12 mmHg LVEDP represent the lower, middle, and upper limit, respectively, of the normal range for LVEDP and demonstrate the different LVEDVs for
each remodeling scenario, with the lowest volumes in the senior sedentary adult and the highest volumes in the endurance-trained athlete. The horizontal dotted
line at 20-mmHg LVEDP reflects a LVEDP above the normal range, which also demonstrates differences in LVEDVs between the 3 remodeling scenarios. The
vertical dotted line at 100-mL LVEDV demonstrates that this volume corresponds to different LVEDPs in the 3 scenarios, and also that at this volume there would
be considerable preload reserve for the endurance-trained athlete, minimal preload reserve for the senior sedentary adult, and an intermediate amount of preload
reserve for the young, sedentary adult. The range of LVEDV for a normal range of LVEDP (4 –12 mmHg) in the young, sedentary individual is ~73–110 mL,
and comparison of this range with the young, healthy adult male shown in Fig. 1, representing a subject of similar age and training but different sex and body
size, demonstrates why a single measurement of LVEDV cannot provide information about LV chamber stretch (preload).

dent of sex and body size, including athletic training and aging PAWP can still be within the normal range while the LVEDP
(Fig. 2), and also the development of cardiac disease. The LV is considerably elevated. Human studies have shown that
remodeling effects of these processes are not accurately pre- neither central venous pressure (CVP) nor PAWP correlate
dictable and are likely to be both condition specific and with LVEDV or SV (or indeed with indexed LVEDV or SV),
individual specific. A single measurement of LVEDV will, and neither do changes in CVP or PAWP correlate with
therefore, lie within the possible range of volumes for that changes in LVEDV or SV (9 –11, 16 –18, 20, 29, 31, 36, 37,
individual, but extra information will be required for it to be 39, 53, 60).
able to reflect the extent of LV stretch. It is the transmural LVEDP (pressure difference between the
left ventricle and the pericardium at end diastole), rather than
The Limitations of LVEDP and LA Pressure as Surrogates the standard comparison of LVEDP luminal pressure with
for LVEDV and LV Stretch atmospheric pressure at a zero-reference level that will be most
closely related to the LVEDV (61). Transmural LVEDP can
That there are limitations of LVEDP as a predictor of vary independently of the LVEDP during alterations in peri-
LVEDV has been recognized for some time. The curvilinear cardial pressure, with the most common cause for an increase
relationship between LVEDP and LVEDV means that, at in pericardial pressure outside of the intensive care unit likely
higher pressures, the LVEDV increases to a lesser extent with to be an increase in RVEDP (61). In heart failure with reduced
the same absolute increase in LVEDP, and the LVEDP versus EF, the LVEDV can fall in association with a high RVEDP,
LVEDV relationship eventually reaches a degree of extreme due to ventricular interaction mediated by the pericardium (2).
steepness, at which point further changes in LVEDP are no
longer reflected in changes in LVEDV (Fig. 1) (6, 52). Nev- The Limitation of End-Diastolic Wall Stress as a Surrogate
ertheless, LVEDP does increase with increases in LV filling of LV Stretch
and LVEDV. While the PAWP, as a surrogate of LA pressure,
has been used to estimate LVEDP, there is a major limitation Preload has been defined by some investigators as end-
in using LA pressure as a predictor of LVEDP, given that, in diastolic LV wall stress (tension), which can be calculated (at
any LV pathology, a substantial LA contribution to LV filling least for the LV short axis) using the Laplace equation, with
can occur, and this can result in a LVEDP that is considerably variables comprising LVEDP and end-diastolic LV short-axis
higher than the mean LA pressure (4, 48, 49). In one compar- radius and wall thickness1 (41). One advantage of this ap-
ison of LVEDP and mean LA pressure in patients with LV proach is that it provides consistency with the definition of
disease, the LVEDP exceeded the mean LA pressure in all
patients, with the pressure difference averaging 9 mmHg and
ranging from as low as 1 to as high as 18 mmHg (4). Thus the 1
LV wall stress ⫽ (LV pressure ⫻ radius)/2 ⫻ LV wall thickness.

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 A CONCEPTUAL FRAMEWORK FOR PRELOAD AND PRELOAD RESERVE
afterload as being the LV wall stress at end systole. Thus
systolic wall stress is the load experienced by the LV wall
during ejection, also calculated using the Laplace equation,
and, as a measure of afterload, systolic wall stress has the
advantages of being directly related to LV end-systolic vol-
ume, SV, and oxygen consumption (41). On the other hand,
end-diastolic LV wall stress can be said to have a limitation as
a definition of LV stretch because calculated wall stress is not
linearly related to wall stretch and, therefore, cannot be linearly
related to the Frank-Starling mechanism.
Preload Reserve
Volume administration into the venous circulation can only
directly lead to an increase in LV output via an increase in RV
end-diastolic volume and then, in turn, via an increase in
LVEDV. However, as discussed above, there are finite limits to
the volume of any cardiac chamber (as there are for the length
of a sarcomere and the length of a strip of myocardium). The
limits of LVEDV are dependent on LV structure, the pericar-
dium and, at higher than normal intravascular volumes and
right heart pressures, can also be dependent on RVEDP due to
ventricular interaction in the setting of an intact pericardium (1,
15). Within these limits there will be an achievable maximal
limit of LVEDV (LVEDVmax), where attempts to increase
chamber filling result in a large increase in chamber pressure
but only a minor increase in volume (Fig. 1), fluid starts to
move out of the circulation into the tissues, or both processes
could occur at the same time. The difference between the
effective LVEDVmax and the current LVEDV can be thought
of as the preload reserve, and the preload reserve of an
individual at a specific time will be dependent on the intrinsic
LVEDVmax and the extent of LV filling at that time. LV filling
will be affected by the metabolic requirements of the individual
and the effect of this on venous return, the intravascular
volume and its location within the circulation, the heart rate,
and the atrial contribution to filling. The presence of preload
reserve indicates that there is potential for fluid administra-
tion to increase the LVEDV and lead to increases in SV and,
more specifically, to increases in SW. When attempts to
increase LVEDV lead to minor or absent increases in
LVEDV and large increases in LVEDP, then preload reserve
can be said to be exhausted, this being a more physiologi-
cally accurate description for what has also been previously
described as “failure of the Frank-Starling mechanism” (35).
Preload reserve also cannot be predicted by a single mea-
surement of LVEDV, given that it is the difference between
the current LVEDV and LVEDVmax and thus requires prior
information about the LVEDVmax.
A Definition of Preload That Is Not an Absolute Volume, a
Pressure, or Wall Stress
When used in the clinical setting, the term preload is gen-
erally considered to be the stimulus that directly activates the
Frank-Starling mechanism, and, therefore, having a definition
of preload that encompasses this relationship would seem to be
a justifiable aim. There can be no change in the force or extent
of LV contraction via the Frank-Starling mechanism, and thus
no change in SV or SW, without a preceding change of
LVEDV in the same direction. Any increase in stretch of
myocardial fibers of the LV chamber is expected to be accom-
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419
panied by increased stretch at the cardiomyocyte level, and
also increased stretch of the sarcomeres within the cardiomy-
ocytes, with stretch at all these levels considered to be essential
for an increase in the force of contraction of the left ventricle.
This fundamental link of stretch (at all levels of cardiac
structure) with the Frank-Starling mechanism provides a strong
rationale for including the notion of chamber stretch in a
clinical definition of preload, and limitations of a single mea-
sure of LVEDV, a left heart pressure, or end-diastolic wall
stress for the purpose of measuring chamber stretch have
already been discussed.
An important limitation of using LV stretch as a definition of
preload for clinical purposes is that there is then no practical
means of directly measuring preload in a living individual,
given that the transmural pressure of the relaxed ventricle is
always greater than zero, and, therefore, a resting LV volume
does not occur naturally in the intact organism. On the other
hand, while an absolute single value of LVEDV cannot reflect
LV stretch, change in LVEDV will always reflect change in
stretch. Moreover, it is estimation of the presence of preload
reserve (representing the potential for wall stretch) rather than
preload that could be considered to be the most important aim
in clinical circumstances where volume infusion is being con-
sidered.
If LV preload is defined as stretch of the LV cavity, then
preload is not linearly related to the LVEDP. Nevertheless, in
the absence of an increase in pericardial pressure or the
presence of acute ischemia or infarction, LVEDP (either mea-
sured or estimated) provides useful information about where a
current LVEDV lies within the range of possible LVEDVs for
a given ventricle and also allows prediction of whether there is
preload reserve, arguably the most important information for
clinical purposes. Thus there is guidance available regarding
the presence of preload reserve and the potential for volume
responsiveness when the LVEDP is either low, normal, or
high. A low LVEDP, or a LVEDP in the normal range (4 –12
mmHg), suggests the presence of preload reserve and, there-
fore, the likelihood of responsiveness to intravascular volume
infusion, whereas a LVEDP ⬎20 mmHg, and possibly ⬎15
mmHg, indicates minimal preload reserve and, therefore, min-
imal volume responsiveness (Fig. 1). While LVEDP and mean
LA pressure are often both grouped together under the term
“filling pressures” (47), it has been mentioned previously in
this review that the magnitude of LVEDP and mean LA
pressure are often not the same. In the absence of mitral valve
disease, a high PAWP predicts a high LVEDP and the absence
of preload reserve; however, a normal PAWP is not a reliable
predictor that the LVEDP is not elevated, and thus a PAWP at
the upper limit of the normal range does not indicate the
presence of preload reserve.
There are important implications arising from this perspec-
tive of preload and the accompanying concept of preload
reserve. Given that preload reserve is the most important
determinant of the potential of fluid infusion to increase SV,
and the LVEDP is the most reliable indicator of the presence or
absence of preload reserve, finding an accurate and reliable
noninvasive estimation of LVEDP may be an appropriate aim
for future investigations. A second implication is that there
may be a case for the reinterpretation of previous experimental
and clinical studies in which preload has been considered to be
either a pressure or a chamber volume. In particular, a lack of
420 A CONCEPTUAL FRAMEWORK FOR PRELOAD AND PRELOAD RESERVE
LV SW response to volume infusion implies that LVEDV has
not increased, but there are two possible explanations for this,
and these may have different clinical significance: 1) LVEDV
could not increase because it was already maximal (i.e., no
preload reserve); or 2) preload reserve was present and thus an
increase in LVEDV was possible, but the volume infusion did
not result in such an increase. With respect to teaching of these
concepts, my experience is that the diagram in Fig. 1 provides
invaluable assistance when explaining both the nature and
importance of the concepts of preload and preload reserve and
also why it is that LVEDP provides vital information about the
latter.
Conclusions
There has not been a consistent definition of cardiac preload
in the domains of either physiology or clinical medicine, and it
can be considered to be a limitation of previous definitions that
they do not provide a direct link with the Frank-Starling
mechanism. Definitions of preload for clinical purposes that
are based on pressures have been shown to have limitations,
given that LVEDP is not linearly related to LVEDV, and
changes in LVEDP are not linearly related to changes in
LVEDV, SV, or SW. PAWP has the additional limitation that
it can underestimate LVEDP. A left ventricle can be consid-
ered to have an intrinsic limited possible range of end-diastolic
volumes, with the lower end of the range at a LVEDP of 0
mmHg and the upper end of the normal range at a LVEDP of
25 mmHg or thereabouts. The LVEDV of a specific left
ventricle at a particular time is dependent on both its possible
range of volumes and the degree of filling. A definition of
preload based on a single measurement of LVEDV (or even an
indexed LVEDV) has the limitation of giving little indication
of where that volume fits within the range of possible LVEDVs
for an individual, and thus no useful information about how
much stretch of the ventricle is present. In this review, I have
argued for an alternative definition of LV preload, this being
the extent of stretch of the relaxed left ventricle at end-diastole.
In this definition, preload is directly related to the ultrastruc-
tural stimulus that underlies the Frank-Starling mechanism.
Furthermore, by this definition it would not be expected that
any of PAWP, CVP, or LVEDV could accurately describe LV
preload, as no measurement of pressures, or a single volume
measurement, can directly reflect stretch of the LV myocar-
dium. While assessing stretch of the ventricle has the important
practical limitation that it is not directly measurable, acute
change in LVEDV does reflect change in preload. The differ-
ence between the current and the maximal LVEDV (preload
reserve) changes in a reciprocal fashion with preload and is the
variable of most importance in the clinical setting when fluid
infusion is being considered. A high transmural LVEDP is a
reliable indicator of absence of preload reserve, and thus a
prediction of absence of volume responsiveness, although
LVEDP has the practical limitation that a directly measured
LVEDP is not generally available. The more commonly avail-
able pressure of PAWP is predictive of a high LVEDP when
PAWP is high (in the absence of mitral valve disease), but
cannot be used as a reliable predictor of lack of elevation of
LVEDP because it can substantially underestimate LVEDP
when there is LV disease. A high CVP can also predict lack of
fluid responsiveness and has extra significance in some circum-
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stances, because a reduction in CVP can lead to a reduction in
pericardial pressure and an increase in LV transmural pressure
and, in turn, can lead to an increase in LVEDV and SV (2).
DISCLOSURES
No conflicts of interest, financial or otherwise, are declared by the author.
AUTHOR CONTRIBUTIONS
R.E.P. prepared figures; R.E.P. drafted manuscript; R.E.P. edited and
revised manuscript; R.E.P. approved final version of manuscript.
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