Cardiac Preload
Physiology and Clinical Implications
N. Bari Olivier, DVM, Mark D. Kittleson, DVM, PhD,
and Grant G. Knowlen, DVM, PhD
PRELOAD is traditionally considered to be a significant
influence on the beat to beat performance of cardiac
muscle. Although the term and concept of preload were
introduced by physiologists, they are frequently used in
clinical settings to describe a variety of diastolic cardiac
characteristics that affect systolic performance. Unfortu-
nately, the extrapolation of the preload concept to de-
scribe the state of the intact heart in diastole has been
accompanied by inconsistencies and inaccuracies, par-
ticularly when considering the chronically diseased
heart.
The idea that the resting (diastolic) state of the heart
could influence the subsequent contractile (systolic)
state was initially presented by Frank, Starling, and their
associates more than 70 years ago.’-3 The famous
Frank-Starling law of the heart stated that “the mechan-
ical energy set free on passage from the resting to the
contracted state depends on the length of the muscle
fibers.”’ Based on studies of isolated skeletal muscles, an
ultrastructural basis for this length dependency of mus-
cular contraction was suggested which involved the spa-
tial arrangement of myofilaments in the muscle con-
tractile unit, the sarcomere. Short sarcomere lengths
were associated with overlap of the actin myofilaments
and a reduction in available cross-bridge sites and the
resulting force of contraction (Fig. 1). Increasing the
sarcomere lengths resulted in more optimal myofila-
ment and cross-bridge arrangements and increasing
contractile force. Eventually, a length was reached that
resulted in a peak value of actively generated force. This
length was called Lmax, and Lmax, corresponding to
whole muscle (m) length and sarcomere (s) length, re-
spectively. Increases in length beyond Lmax were asso-
ciated with a decline in active force generation, which,
according to the cross-bridge theory, was due to disloca-
From the Department of Physiology, College of Veterinary Medicine,
Michigan State University, East Lansing, Michigan (Olivier), the De-
partment of Medicine, School of Veterinary Medicine, University of
California-Davis, Davis, California (Kittleson), and the Department
of Veterinary Clinical Medicine and Surgery, College of Veterinary
Medicine, Washington State University, Pullman, Washington
(Knowlen).
Reprint requests: Dr. N. B. Olivier, Department of Physiology,
Michigan State University, East Lansing, MI 48824.
(Journal of Veterinary Internal Medicine 1987; 1.8 1-85)
81
tion of actin and myosin myofilaments and a reduction
in available cross-bridge sites. This cross-bridgeexplana-
tion for the length-force relationship of skeletal muscle
was assumed to hold for isolated cardiac muscle which
also exhibited a similar length-force relationship in
vitro.
Although cardiac muscle length is related to con-
tractile performance, factors other than just the cross-
bridge availability appear to be involved. Length-depen-
dent changes in intracellular calcium kinetics and the
sensitivity of contractile proteins to calcium are addi-
tional factors likely to be important. Increasing the rest-
ing length of isolated cat papillary muscle strips, for ex-
ample, results in an increase in the action potential du-
ration4 and possibly the trans-sarcolemmal influx of
calcium. Increasing muscle lengths also results in an
increase in the peak intracellular calcium concentration
([Ca++])following cell activation and a more rapid de-
cline in [Ca”] during rela~ation.~ Interestingly, the ab-
breviated calcium transient of activation at longer mus-
cle lengths is associated with prolongation of active ten-
sion development. Results from studies using isolated
intact heart preparations are consistent with these ob-
servations of papillary muscle strips.6 The reasons for
these length-dependent changes in internal [Ca”] have
not yet been fully determined, although an increase in
the rate of calcium flux across the sarcolemma and/or
release from the sarcoplasmic reticulum and an increase
in the affinity of the myofibrils for calcium’ at longer
lengths have been suggested.
The concept of cardiac preload originated from in
vitro studies of cardiac papillary muscles. These studies,
conducted in the 1950s and 1960s used a preparation
similar to that shown in Figure 2. Relaxed papillary
muscles were stretched to different lengths prior to con-
traction by suspending different masses on the opposite
arm of the lever. The weight (force) of these masses was
called the preload. From a mechanical perspective, a
load is a force and preload is the stretching force to
which a muscle fiber is subjected in the relaxed state or,
conversely, the muscle force that resists this stretch
(since at steady state no net force exists). Within limits,
increasing the preload (and resting muscle length) re-
sulted in an increase in the force of “isometric” contrac-

82 OLIVIER, KITTLESON, AND KNOWLEN
A B
FIG. 1 . A schematic of sarcomere myofilament overlap at different
sarcomere lengths. Short sarcomere lengths (A) are associated with
overlap of the thin myofilaments and reduction in effective cross-
bridges. At an optimal sarcomere length (B), the utilization of cross-
bridges between the thin and thick filaments are maximized, which
results in maximal active force generation. (Reproduced, with permis-
sion, from Janz RF. Estimation of local myocardial stress. Am J Phy-
siol 1982; 242:H876.)
tion and the shortening velocity of an “isotonic” con-
traction. As with skeletal muscle, an optimal muscle
length (Lmax,) was identified with resting lengths
greater than Lmax, associated with a decline in active
force generation. From these studies, contractile perfor-
mance of the papillary muscle and presumably the in-
tact ventricular myocardium was inferred to be preload
dependent, an unfortunate use of the term since it was
the resting muscle length, specifically the sarcomere
length, that was responsible for most of the observed
changes in contractile performance. The preload pro-
vided the force that determined this resting length. Al-
though preload and resting muscle or sarcomere length
are closely related, they are actually distinct entities and
can change independent of each other. The passive me-
chanical characteristics of the ventricular myocardium
illustrate this important distinction since cardiac sarco-
meres resist stretching beyond their optimal length
(Lmax,) of about 2.2 fim. Thus preload, i.e., the stretch-
-0, I..
M
f. t.
FIG. 2. A schematic of the isolated papillary muscle preparation illus-
trating the use of suspended loads to alter resting muscle lengths.
Increasing the preload (P)results is an increased resting length of the
papillary muscle (M), which is controlled by a stop above the fever.
Increasing resting muscle length (up to Lmax) results in an increase in
the “isometric” force of contraction, which is sensed by a force trans-
ducer (Et.) connected to the fixed end of the papillary muscle.
Journal of Veterinary
Internal Medicine
ing force, can be increased beyond that associated with
Lmax, without an appreciable change in sarcomere
length.
The effect of a change in preload in the intact heart is
not as well documented as that for isolated papillary
muscles. The ventricular myocardium is far more com-
plex than the papillary muscle, experiences continually
changing loading conditions throughout the cardiac
cycle, and is required to eject a viscous fluid into a vis-
coelastic arterial system rather than lift a mass. It is
unrealistic to expect the intact heart to behave in exactly
the same manner as an isolated papillary muscle sub-
jected to static loading conditions. Additional confusion
exists because of the inconsistent use of the term preload
in the context of the whole organ. Hemodynamic vari-
ables often cited as indices of preload include myocar-
diaI segment length, end-diastolic volume within the
ventricle, and end-diastolic pressure within the ventri-
cle. While each of these variables is a valuable descrip-
tor of diastolic properties of the ventricle, individually
they are neither measures of preload nor universally reli-
able predictors of changes in preload.
Myocardial segment length is a distance measure be-
tween ultrasonic markers embedded in a region of ven-
tricular myocardium. Pairs of ultrasonic crystals are
used to detect dynamic changes in distance between the
crystals. Acute changes in the distance between crystals
at end-diastole represent a change in regional muscle
length and presumably sarcomere length. Thus, end-dia-
stolic myocardial segment length acts as a valuable
index of muscle length rather than a measure of the
stretching force inducing that length (the preload). A
change in myocardial segment length as an indicator of
relative sarcomere length is reliable only for acute
change^.^ Chronically, the number of sarcomeres in
series between the segment markers can change and
thereby alter the transfer function between segment
length and sarcomere length. Even acute changes in seg-
ment length may be unreliable under some circum-
stances since muscle length and sarcomere length are
not directly related throughout the range of muscle
End-diastolic volume as an index of preload is similar
to that of myocardial segment length with the distinc-
tion that it represents the entire ventricle rather than a
single region. The assumption is that determinations of
diastolic ventricular volume also reflect changes in the
stretch of the ventricular wall and indirectly that of the
sarcomere. Still, volume, like segment length, is not a
measure of the stretching force or preload. Whereas an
acute change in ventricular volume is usually accompa-
nied by an increase in sarcomere length, the same rela-
tionship is not necessarily true for chronic diseases
where sarcomere numbers associated with hypertrophy
or atrophy of the ventricular myocardium change the
relationship between volume and Sarcomere length. As
 Vol. 1 . NO.2 CARDIAC PRELOAD
an example, in eccentric hypertrophy it is thought that
sarcomeres are added in series. This completely changes
the relationship between end-diastolic volume and sar-
comere length. Despite the limitations of end-diastolic
volume as a predictor of relative muscle or sarcomere
length, it is an important hemodynamic variable. In
acute situations, it does provide an index of a change in
muscle length. In chronic situations, it provides an
index of eccentric hypertrophy as long as wall thickness
is normal. It should be noted that eccentric hypertrophy,
i.e., a dilated chamber with normal wall thickness, is
more important than increased preload as a means of
compensation for chronic left ventricular diseases in
which total left ventricular stroke volume must be in-
creased to compensate for left-to-right shunts or valvu-
lar regurgitation or for myocardial failure.
Although intraventricular pressure is a measure of
force normalized for cross-sectional area, it is not a di-
rect measure of the stretching force imposed on the rest-
ing muscle fibers of the ventricular myocardium. Intra-
ventricular pressure is directed perpendicular to the en-
docardial surface rather than in the direction of the
myocardial fibers that are to be stretched (roughly paral-
lel to the endocardia1 surface). In relation to preload,
end-diastolic pressure is frequently used as an indirect
indicator of end-diastolic volume. This association is
based on the diastolic pressure-volume relationship of
the ventricle. The reciprocal of the slope of this curve
represents the compliance or elasticity ofthe ventricle. If
this diastolic pressure-volume relationship does not
change, an increase in pressure is generally associated
with an increase in volume, although the correlation
between pressure and volume is often poor." Unfortu-
nately, the ventricular diastolic pressure-volume rela-
tionship is very labile and can change even acutely in
response to a variety of stimuli. Drugs, myocardial hyp-
oxia, and tachycardia, for example, can all acutely
change the diastolic pressure-volume relationship and
invalidate end-diastolic pressure as an indicator of end-
diastolic volume unless the new pressure-volume rela-
tionship is known.12-'sAlthough inadequate as an index
of preload, end-diastolic ventricular pressure remains a
very important hemodynamic parameter. It is the major
factor influencing the development of venous conges-
tion and edema in heart failure.
The current best estimate of the diastolic stretching
force of the myocardium (preload) is diastolic wall
stress. Wall stress is the force per cross-sectional area
acting within the ventricular wall (Fig. 3) and is a func-
tion of intraventricular pressure, the geometry and in-
ternal dimension of the ventricle, and the reciprocal of
ventricular wall thi~kness.'~.''Wall stress is a calculated
value either using directly measured myocardial forces
and area or using directly measured ventricular pressure
and wall thickness and a calculated ventricular volume
according to variants of the Laplace equation, where
83
I
A B
FIG.3. A, Diastolic circumferentialwall stress is related to the product
of diastolic ventricular pressure and internal radius (r) divided by the
wall thickness (wt) of the ventricle. B, The force of internal ventricular
pressure is directed perpendicular to the myocardium while wall
stresses are oriented parallel to the muscle. (Reproduced,with permis-
sion, from Sandler H, Dodge HT. Left ventricular tension and stress in
man. Circ Res 1963; 13:91-105).
wall stress = pressure X radius/wall thickness. In either
case, the resulting value is only an approximation of the
actual stretching force since corrections are usually not
made for differences in the direction of the calculated
stress and the inhomogeneous orientation of the myo-
fibers. Wall stress calculated from intraventricular pres-
sure, ventricular radius, and wall thickness also relies on
equations whose geometric and structural assumptions
are not strictly fulfilled. The use of other parameters
such as end-diastolic pressure or volume as convenient
but incorrect measures of preload is no doubt partially
due to these difficulties in wall stress determination.
Normal values for end-diastolic circumferential wall
stress in dogs are variable and range from 10,000-
30,000 d y n e ~ / c m ~ . ~ ~A' cute
* - * ~and chronic interven-
tions such a's volume or pressure loading of the ventricle
can result in significant changes in preload. Volume
overloads routinely increase end-diastolic stress by in-
creasing chamber radius and end-diastolic pressure. The
increase in chamber radius causes the myocardium to
become thinner since it is stretched around a greater
volume. The myocardium hypertrophies to offset the
resultant increase in wall stress, which brings the wall
thickness back to or toward normal. Despite this restora-
tion of wall thickness, end-diastolic wall stress tends to
remain chronically elevated. Moderate acute volume
loads increase end-diastolic stress by about 33%. More
severe volume loading, maintained chronically in dogs
with aortocaval fistulas, results in an average end-dia-
stolic stress over 65,000 dyne~/crn'.~
Reported preload responses to experimental systolic

84 OLIVIER, KITTLESON, AND KNOWLEN
pressure loading appear to depend on the model used
and the duration of the study. When chronic aortic con-
striction is imposed abruptly in adult dogs, end-diastolic
stress at 18 days is increased by 44%.20In contrast, when
a similar degree of obstruction is imposed gradually on
young dogs, the diastolic stress 4 months later is not
significantly different from control value^.'^ The initial
increase in preload that occurs in response to acute sys-
tolic pressure loading appears to resolve with time as
compensatory myocardial concentric hypertrophy
(thicker walls, normal chamber diameter) develops.2'
The capacity for increases in preload to mediate an
increase in sarcomere length and/or systolic perfor-
mance (preload reserve) in the intact heart remains
somewhat controversial. Sarcomeres in the intact heart
strongly resist stretching beyond their optimal length of
about 2.2 pm.22,23 The observation that average end-dia-
stolic midwall sarcomere length in normal rapid-fixed
heart specimens is approximately 2.1 pm24had led some
to speculate that the reserve capacity for sarcomere
stretch is very limited. More recent reports, however,
have documented that a significant heterogeneity of sar-
comere lengths can exist across the entire width of the
ventricular wall.25Average diastolic sarcomere lengths
are shortest in the subendocardial region, intermittent in
the subepicardial region, and longest in the midwall re-
gion. Changes in preload could exploit this disparity in
Sarcomere length25and represent a potential preload re-
serve up to the limits of sarcomere stretch. In support of
this potential reserve is the observation that increases in
the diastolic stress of isolated hearts in anesthetized dogs
are associated with an increase in peak isovolumic left
ventricular pressure and myocardial fiber shorten-
ing.25,26However, baseline ventricular volume (and per-
haps sarcomere length) is less in anesthetized dogs than
it is in conscious dogs. This could lead to an enhance-
ment of the apparent reserve capacity. Results from
studies of conscious dogs are conflicting. End-diastolic
volume in conscious dogs was reported to increase only
3% in response to rapid volume loading despite large
increases in end-diastolic stress. This was interpreted as
evidence that a dog's heart normally operates near the
limit of wall fiber stretch and thus has little preload
reserve. Other investigators have concluded that a signif-
icant preload reserve does exist in dogs after showing
that an acute increase in end-diastolic stress ( 5 1%) re-
sulted in a 9% increase in end-diastolic volume and a
14% increase in stroke volume.'8 The discrepancies be-
tween these results may be due to differences in the
method of calculating ventricular volume. Another
problem in interpreting the role of preload and preload
reserve is the difficulty in isolating preload as the only
changing variable. Changes in the preload of the intact
ventricle, particularly those involving a change in end-
diastolic volume, also tend to change afterload. The re-
Journal of Veterinary
Internal Medicine
sulting cardiac function is thus influenced by at least two
changing variables. Moreover, it is at least conceivable
that some of the effects of preload on systolic perfor-
mance may not depend on an increase in sarcomere or
even muscle length.
An additional important consideration of preload re-
serve includes the potential for changes in the properties
of the myocardium to alter the transfer function be-
tween preload and muscle or sarcomere length. An in-
crease in myocardial stiffness, for example, can result in
a reduction in the degree of muscle stretch for a given
magnitude of preload. The possibility of independent
changes in muscle and sarcomere lengths in response to
a chronic change in preload further complicates the in-
terpretation of preload reserve.
The reserve in sarcomere stretch in the normal heart
apparently represents a relatively minor form of com-
pensation when considering overall cardiac responses to
disease. The sarcomere stretch reserve also tends to be
maximally utilized early in the course of volume over-
l o a d ~Thus,
. ~ even though end-diastolic wall stress may
be markedly elevated in chronic left ventricular volume
overload, it probably augments ventricular performance
no more than a small to moderate increase in wall stress,
which fully exploits the reserve for sarcomere stretch.
The primary importance of an increase in preload in
response to disease may actually be indirect, acting as a
stimulus for compensatory myocardial hypertrophy
(particularly eccentric hypertrophy),16which exerts a
much greater effect on systolic ventricular performance
than that associated with preload and sarcomere stretch
reserve.
The apparent minor role of preload reserve in overall
cardiac compensation to disease does not necessarily
diminish the importance of preload on ventricular per-
formance in acute situations. An acute reduction in pre-
load, as in hypovolemic shock, is an important negative
influence on ventricular function. Reductions in sarco-
mere stretch due to low diastolic wall stress have even
been suggested as-a partial explanation for the reduced
ventricular performance occasionally associated with in-
appropriate hypertrophy of the ventricles (hypertrophic
cardiomyopathy).28
Because of the invasive instrumentation required for
wall stress determinations, the load placed on the myo-
cardium at end-diastole is only of conceptual value for
individual clinical cases. Current evidence would also
suggest that the importance of preload reserve as a
mechanism for cardiac compensation has been overem-
phasized, particularly for chronically dilated hearts.
Rather, cardiac hypertrophy, inotropic state of the
myocardium, ventricular afterload, and heart rate are
probably more important determinants of cardiac per-
formance in chronic left ventricular disease. Preload and
its effects on systolic performance play a more impor-
Vol. 1 . NO. 2 CARDIAC PRELOAD
tant role in the normal heart, helping to adjust for such
, hings as beat-to-beat alterations in venous return and
the cardiovascular response to exercise.
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