Download Brief Review Determinants of Left Ventricular Filling and of the

827
Brief Review
Determinants of Left Ventricular Filling and
of the Diastolic Pressure-Volume Relation
John C. Gilbert and Stanton A. Glantz
U
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ntil the 1970s, the left ventricle was considered an isolated shell in which the left
ventricular diastolic pressure-volume relation depended on the myocardium's material properties and the left ventricle's wall thickness and
geometry. According to this view, the relation
between diastolic pressure and volume could change
only in response to chronic changes in the cardiac
muscle's material properties, such as scarring due
to infarction,1 or changes in cardiac geometry due
to hypertrophy. As a consequence, the diastolic
pressure-volume relation was considered unique
over the short term. A practical application of this
assumed uniqueness was that left ventricular diastolic pressure was used as a surrogate for volume
in evaluating systolic function.
However, in the early 1970s, studies of patients
with coronary artery disease contradicted this simplistic view of the diastolic pressure-volume
relation.2-6 In these patients, the left ventricular
diastolic pressure-volume curve shifted upward temporarily immediately after cardiac pacing-induced
angina and then returned to prepacing values. Later,
other investigators7-8 observed that vasodilator and
vasoconstrictor drugs, which change the vascular
loading conditions of the left ventricle, also produced
acute reversible shifts in the left ventricular diastolic
pressure-volume curve. In the process of explaining
these clinical observations, we have learned that
many factors can affect left ventricular filling and the
diastolic pressure-volume relation acutely.
The original concept that the pressure within the
left ventricle is determined by the balance between
the forces due to pressures within the ventricular
cavity that expand the ventricle and forces due to
elasticity of the myocardium that resist this expanFrom the Cardiovascular Research Institute and Department
of Medicine, University of California, San Francisco, California.
Supported by National Heart, Lung, and Blood Grant HL25869 and by National Institutes of Health Training Grant
HL-07192 (J.C.G.).
Address for correspondence: John C. Gilbert, PhD, Research
Medicine and Radiation Biophysics Division, Mail Stop 55121,
I Cyclotron Road, Lawrence Berkeley Laboratory, University
of California, Berkeley, CA 94720.
Address for reprints: Stanton A. Glantz, PhD, Professor of
Medicine, Cardiology Division, Box 0124, University of California, San Francisco, CA 94143.
Received May 17, 1988; accepted October 28, 1988.
sion remains the centerpiece of our understanding
of the diastolic pressure-volume relation. However,
it is now clear that changes in active relaxation of the
myocardium, mechanical interaction between the
ventricles, the pericardium, so-called diastolic suction, pulmonary-cardiac contact pressure, myocardial viscoelasticity, and engorgement of the coronary
vasculature all play some role in determining the left
ventricular pressure-volume relation during diastole
(Figure 1). The questions are, how large an effect
does each of these factors have on the left ventricular
diastolic pressure-volume relation, and when during
diastole do each of them act? The answers are that
during early diastole the rate of relaxation and diastolic suction are important. During late diastole (and
at end-diastole) the extent of relaxation and ventricular interaction modulated by the pericardium are
important. The other factors—pulmonary-cardiac contact pressure, viscoelasticity of the myocardium, and
engorgement of the coronary vasculature—are less
important in determining the left ventricular diastolic
pressure-volume relation.
We will first review the pressure-volume relation
itself and show how it depends on the relation
between left ventricular wall stress, pressure, and
geometry. We will then review the evidence for the
roles that the various factors play in shifting the left
ventricular diastolic pressure-volume relation, consider problems in measuring some of these factors,
explore the mechanisms of some factors, and assess
the implication of each factor for systolic function.
Geometry, Muscle Elasticity, and the Basic
Pressure-Volume Relation
The diastolic pressure-volume relation results from
forces acting both on and within the myocardium.
The forces acting on the myocardium, in turn, result
from the pressure within the left ventricle and the
other cardiac chambers and from the constraining
forces exerted on the epicardium by the pericardium and the lungs. The forces acting within the
myocardium result from the fact that the myocardium is an elastic material so that the muscle itself
develops a resisting force as it extends. The physical relations that govern these forces provide the
framework in which we will discuss the factors that
affect the diastolic pressure-volume relation.
828
Circulation Research Vol 64, No 5, May 1989
Table of Abbreviations
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h, wall thickness
1, muscle length
lo, muscle equilibrium length
p, pressure
p., pressure asymptote
r, radius
r0, initial radius
t, time
T, time constant
Vgj, end-diastolic volume
VES, end-systolic volume
Vo, equilibrium volume
a, elastic parameter
p, elastic parameter
•y, viscoelastic parameter
e, Lagrangian strain
e, strain rate (de/dt)
T), h/r (wall thickness/radius ratio)
ao Volume (ml)
-20
Elastic properties, geometry
Rate of relaxation
Extent ol relaxation
Diastolic suction
VtscoelasUdty
Vtscoelastidty
Coronary vascular engorgement
o-, stress
To understand many of the factors that affect the
left ventricular diastolic pressure-volume relation,
the left ventricle can be modeled as a simple,
pressurized, spherical shell.9 Three simplifying
assumptions permit us to derive an equation, the
Laplace Law, which relates wall stress to pressure
and geometry (i.e., radius and wall thickness).
(Stress, a, is the force per cross-sectional area of a
material such as the muscle.) The assumptions are
that 1) the left ventricle is a sphere with uniform
wall thickness, h, and inside radius, r; 2) the left
ventricle is in static equilibrium (i.e., nothing is
moving); and 3) the wall is thin, so that the stress
may be considered constant through the wall.
To begin, the sphere is cut through its center to
expose the internal forces (Figure 2A). The total
force tending to push the lower hemisphere away
from the upper hemisphere is equal to the pressure
within the sphere, p, times the internal crosssectional area, TIT2. The total force in the wall
holding the two halves together equals the wall
stress, cr, times the cross-sectional area of the wall.
These two forces must balance
0)
which simplifies to
pr=ah(2+h/r)
Pericardium
Ventricular interaction
(2)
Since we assumed a thin wall, the ratio of the
thickness to the internal radius is much smaller than
2, so we can neglect h/r. Solving Equation 2 for the
stress yields
cr=pr/2h
(3)
Equation 3, the Laplace Law for a thin-walled
sphere, relates the pressure in the left ventricle and
its geometry (i.e., radius and wall thickness) to the
FIGURE I. Several different factors affect the diastolic
pressure during diastole, with different factors being
important at different times. The myocardium's elasticity
and geometry (size and wall thickness) are important
throughout diastole; the other effects are superimposed
on the pressure due to the myocardial elasticity. During
early diastole, active relaxation and the recoil effect of
elastic energy stored in the myocardium from the previous systole (so-called "diastolic suction") determine the
atrioventricular pressure gradient and ventricular filling
rate. The dashed line shows the purely elastic pressurevolume curve of the myocardial shell in the absence of the
component due to active relaxation from the previous
beat; the negative pressures here reflect the elastic energy
stored in the myocardium from the previous systole,
which combines with the relaxation component to determine the observed pressure. Late in diastole, ventricular
interaction and the pericardium become important. Viscoelastic properties of the myocardium play a small role
during rapid filling and during atrial contraction, and
coronary vascular engorgement has a small effect late in
diastole. The different factors are listed below the curve,
with an indication of when they are important in determining the diastolic pressure. Wavey lines indicate the
approximate boundary when each factor is important.
Vgj, end-systolic volume; Vu,, end-diastolic volume; Vo,
equilibrium volume.
wall stress. According to the Laplace Law, the wall
stress in a sphere increases in direct proportion to
the internal pressure and radius and decreases in
inverse proportion to the wall thickness.
Equation 3 provides a good approximation of the
mean left ventricular stress for a given diastolic
pressure despite the fact that the left ventricle is not
"thin." "Thin" in an engineering sense usually
means that h/r <0.l. Although h/r is in the range
0.3-0.5 at end-diastole,10 Equation 3 still provides
accurate estimates of relative changes in wall stress11
and can be used to gain semiquantitative insight into
physiological processes.
The Laplace Law and the elastic properties of the
myocardium can be used to derive the ventricular
pressure-volume relation. The Laplace Law shows
Gilbert and Glantz
Determinants of Diastole
829
tion of a solid such as the myocardium. The most
common way of defining strain is Lagrangian strain,
which is defined as extension from equilibrium
length divided by the equilibrium length, e=(l-lo)/
jo. The equilibrium length is the length that a specimen of material exhibits when subjected to no
external forces. This equilibrium length is usually
used as the reference length for computing strains.
The elastic properties of the myocardium have
been described by an exponential relation between
stress (e) and strain (a)12:
r=o(e*-l)
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Strain
FIGURE 2. The elastic component of the diastolic
pressure-volume curve is determined by the balance of
the force (pressure) in the ventricular chamber tending to
push the chamber apart and force (stress) in the wall
holding it together (A), combined with the relation between
stress and strain (distension) of the myocardium (B).
These elements are combined to derive the pressurevolume relation for the left ventricle shown by the solid
line in panel C (Equation 5 in the text).13 The relation
expressed in panel C (and Equation 4) provides a good
description of the left ventricle's pressure-volume characteristics above the equilibrium volume, Vo, but not
below Vo, when the myocardial wall is in compression
and storing elastic energy (dashed line). The ability of the
myocardium to store elastic energy in compression when
the end-systolic volume is below the equilibrium volume
gives rise to the phenomenon of so-called diastolic suction, a, stress; p, pressure; r, radius of curvature (to the
endocardium); h, wall thickness; a and )9, elasticity
parameters; e, Lagrangian strain.
that as the ventricular pressure increases, the wall
stress increases, extending the muscle and thus
increasing the ventricle's radius. In our assumed
spherical ventricle, the radius is related directly to
ventricular volume (V=4 7rrV3). The next step is to
relate the waJI stress to ventricular volume.
The relation between wall stress and ventricular
volume depends on the elastic properties of the
myocardium. As in most biological materials, muscle becomes stiffer as it is extended; that is, it
requires greater increments of force to produce
each additional increment of length. The elastic
properties of the total myocardium are very difficult
to measure, but the elastic properties of a onedimensional strip of muscle is much easier. Using
one-dimensional strips of papillary muscle, the elasticity of the myocardium can be represented as a
one-dimensional stress-strain relation. Strain, e, is a
normalized, dimensionless measure of the deforma-
(4)
In a purely elastic material, the stresses depend
only on the strain (deformation), e. The parameters
a and 0 in Equation 4 are constants and determine
the precise nature of this relation, which is shown
by the curve in Figure 2B and described by Equation 4; thus, a and /3 are called elastic constants.
This one-dimensional stress-strain relation can
now be extended to a pressure-volume relation by
using the spherical ventricular geometry and the
Laplace Law for a sphere. In addition, the concept
of an equilibrium length, described above, can be
generalized to an equilibrium volume, Vo, the volume that a shell (such as the left ventricle) exhibits
when subjected to no transmural pressure. Glantz
and Kernoff13 combined the Laplace Law with
Equation 4 for the elastic properties of the myocardium to obtain an equation for the pressure-volume
relation of the left ventricle:
(5)
where
r,=h/r=l
Equation 5 reveals that the pressure-volume relation depends on three things: the elastic properties
of the myocardium (a and /3), the wall thickness (h),
and the left ventricle's equilibrium volume (Vo).
Glantz and Kernoff13 validated Equation 5 by comparing the muscle stiffness estimated from pressurevolume data obtained by inflating dog left ventricles
with the stiffness measured directly from muscle
strips removed from those hearts.
Equation 5, however, is not a good description of
the pressure-volume characteristics of the left ventricle below its equilibrium volume, Vo. As the
dashed curve in Figure 2C shows, the actual ventricular pressure drops rapidly as chamber volume
falls below Vo, whereas Equation 5 predicts little
change in pressure (dark curve in Figure 2C). This
difference is probably due to two factors: First, the
assumption of a "thin" wall is drastically violated
at small volumes. Second, Equation 4 is probably
not a good description of the elastic properties of
the myocardium in compression. The mechanics of
the heart at volumes below Vo is just beginning to be
studied.14 The rapid drop in pressure that occurs for
ventricular volumes below Vo (Figure 2C) is important for understanding so-called diastolic suction.
830
Circulation Research
Vol 64, No 5, May 1989
Effects of Hypertrophy
When the left ventricle is subjected to a chronic
volume or pressure overload, it grows. The Laplace
Law provides the theoretical framework for understanding the mechanical stimulus for the changes
that take place. 1516 In addition, while the changes
that accompany hypertrophy often have beneficial
effects in terms of helping the left ventricle maintain
systolic function in the face of increased loading,
this is often accomplished at the expense of increases
in diastolic pressure that can eventually lead to
circulatory congestion and congestive heart failure
because of increases in end-diastolic pressure necessary to maintain a given end-diastolic volume.17
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When the left ventricle is first subjected to a
volume overload, the myocardium is strained more
than usual during diastole because the difference
between the volume and equilibrium volume, Vo, is
increased. As a result of this increased strain,
diastolic wall stress and end-diastolic pressure
increase. Over time, cardiac myocytes respond by
elongating and thickening in a way that effectively
increases Vo with little or no increase in wall thickness. This increase in Vo means that the larger
volume now corresponds to a lower strain, and so
leads to correspondingly lower wall stress and diastolic pressure. The left ventricle appears to stop
growing when it has increased Vo to the point that
end-diastolic wall stress has returned to values
present before imposition of the volume overload."
This so-called eccentric hypertrophy also occurs in
response to physical training1819 and in people with
aortic or mitral insufficiency.20 The changes that
accompany volume overload seem to be primarily
those associated with changing size of the heart
(and the related changes in equilibrium volume)
rather than intrinsic changes in the elastic properties of the myocardium. "8.21.22
This situation contrasts with that observed during
pressure overload.23 In pressure overloads, the stress
that the myocardium must develop during systole is
increased because of the increased afterload. The
left ventricle responds by developing so-called concentric hypertrophy in which there is an increase in
wall thickness with little or no change in chamber
radius, presumably because of the addition of new
sarcomeres in parallel with existing ones.13 This
increase in wall thickness allows the left ventricle to
generate increased systolic pressure at a lower level
of average wall stress (i.e., force development in
individual sarcomeres) than would occur in the
absence of hypertrophy. In addition to these purely
geometric effects, the structure of the cardiac interstitium changes to increase the amount of collagen
present and thus increase the elastic stiffness.2224-26
The net effect of these changes is to lead to higher
diastolic pressure at any given volume. This upward
shift in the diastolic pressure-volume relation
accounts in part for the increase in diastolic pressure that accompanies pressure overload and the
potential for patients with pressure overload to
develop congestive heart failure.
The analysis thus far has presumed that stress in
the wall is determined principally by ventricular
geometry and myocardial elasticity. Although this
is true late in diastole when the heart is fully
relaxed, it is not true during early diastole, while
the muscle is relaxing from the previous beat and
is rapidly expanding, or during atrial systole.
During early diastole, wall stress is composed of
components due to the relaxation from the previous systole as well as the muscle's passive elastic
properties. Fortunately, the Laplace Law can still
be used to understand the effects of these stresses
because it simply relates ventricular pressure,
radius, and wall stress and thus intrinsically incorporates the state of the myocardium. Moreover,
the relation between left ventricular size, left
ventricular wall thickness, and the elasticity of the
myocardium is the single most important determinant of the diastolic pressure-volume relation.
Relaxation
The rate and extent of relaxation are two different
quantities, each of which influences the left ventricular diastolic pressure-volume relation. The extent
of relaxation is the end state of the muscle after
relaxation has completed and is the more important
of the two because it determines the myocardium's
equilibrium length, which, in turn, determines the
left ventricle's equilibrium volume. Impaired extent
of relaxation means smaller than normal equilibrium volumes, which lead to larger strains and
higher diastolic pressures at a given end-diastolic
volume. Higher pressures at the same volume result
in an upward shift in the diastolic pressure-volume
relation. Thus, the extent of relaxation is important
at the end of diastole. The rate of relaxation affects
the diastolic pressure-volume relation early in diastole because it affects the atrioventricular pressure
gradient and therefore affects filling rate during the
rapid filling phase of diastole. The rate of relaxation
generally does not influence end-diastole directly
because the relaxation process is over by the time
diastole ends.
Estimating Relaxation Rate
One must be able to quantify changes in left
ventricular relaxation to study how it affects diastolic pressure. The rate of relaxation can be quantified using the exponential relation Weiss et al27
proposed. They quantified left ventricular relaxation rate by fitting the time course of the isovolumic pressure fall beginning at the time of dP/dt^
and lasting through the mitral valve opening with
the exponential function of time:
p(t)=po e - "
(6)
where p,, is pressure at time of dP/dt^, t is time
after dP/dt^n, and T is time constant of isovolumic
pressure fall. Ventricular relaxation rate is thus
Gilbert and Glantz
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quantified by a single number, T, the relaxation
time constant. (The time constant equals the time
required for the pressure to decay to e~'=0.37 of its
original value.) This formulation also has the benefit
of being easy to compute; taking the natural logarithm of both sides of Equation 6 yields a linear
relation between ln(p) and t, with a slope of 1/T.
The major problem with Equation 6 is the implicit
assumption that if the left ventricle were allowed to
relax fully without filling (as t-><»), the pressure
would fall asymptotically to zero. Zero pressure
asymptote means that the isovolumic ventricle would
have zero wall stress when it is fully relaxed (Equation 3). However, as shown in Figure 2C, the total
ventricular wall stress is zero only if the left ventricle is at its equilibrium volume, Vo, and the endsystolic and equilibrium volumes are not necessarily the same.28-31
Equation 6 can be modified to take into account
the effect of unequal end-systolic and equilibrium
volumes by incorporating the term, p», which is the
pressure to which ventricle would relax if the ventricle were held at its end-systolic volume and
allowed to relax completely:
(7)
P(t)=(p o -P.)
One cannot observe p» directly in situ because the
mitral valve opens and the left ventricle begins
filling before the muscle fully relaxes from the
previous systole. However, Yellin et al31 observed
pressures as low as -13 mm Hg in dog left ventricles by preventing filling and allowing the ventricles
to relax completely while being held at their endsystolic volumes. This observation of negative pressures validated the hypothesis that the left ventricular end-systolic volume was smaller than the
equilibrium volume in these dogs.
Although incorporation of p . in Equation 7
improves the accuracy with which it describes
relaxation, the presence of p . in Equation 7 complicates calculation of T from data collected during
isovolumic relaxation because the natural logarithm
of both sides of Equation 7 no longer yields a linear
relation between pressure and time as it did for
Equation 6. Other methods for determination of T
have been proposed such as those using the time
derivative of both sides of Equation 7,32 solving
Equation 7 without assuming anything about p . and
without using the time derivative,33 or using a
polynomial fit to the isovolumic pressure fall,3433
but none of these methods has proven completely
satisfactory.
The problem of assuming a zero pressure asymptote (p»=0) when calculating the relaxation time
constant, T, has been put in perspective by comparing three different ways of calculating T (Figure
3). Yellin et al31 computed T: 1) by using the true p .
which they obtained experimentally by occluding
the mitral valve during systole to prevent filling
during subsequent beats (Figure 3); 2) by letting the
pressure asymptote float and determining it, together
Determinants of Diastole
831
IOOT
1) Pco = - 9 . 2 , T«, =34
2)Poo = - » . 7 , T b , =55
3)Pa> =
-201
0 . To = 3 3
'
2
time (msec)
FIGURE 3. Curve 1 shows the time course of isovolumic
relaxation when the mitral valve was occluded to prevent
filling in a dog heart. Note that the fully relaxed pressure
is -9.2 mm Hg, indicating that the end-systolic volume is
below the left ventricle's equilibrium volume. The time
constant of isovolumic relaxation derived from fitting
these data to Equation 7 is 34 msec. Under normal
conditions, however, one can only observe the isovolumic
pressure fall before the mitral valve opens and the heart
begins to fill. Curve 2 shows the resulting exponential
curve obtained by fitting Equation 8 to this limited data
set during isovolumic relaxation. Note that there are
large errors in both the value of the time constant (55
msec isovolumic data versus the true value of 34 msec) as
well as the estimated value of the pressure asymptote
(—19.7 mm Hg isovolumic data versus the true value of
—9.2 mm Hg). This problem arises because the short
isovolumic period does not contain enough information
to accurately extrapolate the full relaxation curve. Surprisingly, the value of the time constant obtained by
assuming (incorrectly) that the heart always relaxes to
zero pressure, curve 3 fitted to Equation 6, is close to the
true value (34 msec, px=0, vs. true value of 33 msec).
(From Yellin et al,3' with permission.)
with T, from the best fit analysis to the data from a
normal isovolumic relaxation period; and 3) by
assuming p«,=0, as originally proposed by Weiss et
al.27 Figure 3 shows pressure versus time curves as
a result by computing T using each of these three
approaches. Curve 1 shows the actual time course
of the relaxation in a left ventricle after occluding
the mitral valve to prevent filling. In this case, the
end-systolic volume was less than the left ventricle's equilibrium volume, and the ventricle relaxed
to a pressure of -9.2 mm Hg. Using this value for
p» in Equation 7 yields a value for the relaxation
time constant, T, of 34 msec. This is the true value.
Curve 2 shows the result obtained by using data
from the normal period of isovolumic relaxation
(from time 0 to time t,) and using a best-fit analysis
to estimate both p , and T in Equation 7. This
procedure yielded an unrealistically low value of p»
of -19.7 mm Hg and an unrealistically high value of
832
Circulation Research
Vol 64, No 5, May 1989
T of 55 msec. Curve 3 shows the result obtained by
assuming p«=0 in Equation 7 (i.e., using Equation
6) and estimating T using the data from the normal
period of isovolumic relaxation. The resulting estimate of T is 33 msec, which is surprisingly close to
the true value of 34 msec. Indeed, an important
result of the Yellin et al31 study was that although
the value of T calculated by assuming p»=0, systematically underestimates the true value of T, that
is, calculated using the true pressure asymptote
measured experimentally, it underestimates the true
value by only about 10%. Therefore, although using
Weiss et al's 27 original monoexponential formulation to determine T (Equation 6) systematically
underestimates the true time constant, T determined in this manner can still be used as a reasonable measure of how quickly the ventricle relaxes.
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Effects of Ischemia on the Extent of Relaxation
As noted in the introduction, slowed calcium
uptake by the sarcoplasmic reticulum in response to
ischemia has been proposed to explain the shifts in
the diastolic pressure-volume curve after cardiac
pacing-induced angina in patients with ischemic heart
disease. This hypothesis led several investigators to
measure the rate of relaxation in patients following
production of ischemia.4-36-42 Unfortunately, although
people routinely observed slowed relaxation (i.e., a
larger value of T), the reduction in relaxation rate
secondary to ischemia was not large enough to
produce the shifts in the diastolic pressure-volume
curve that had been observed at end-diastole. Moreover, animal studies of the effects of global ischemia
and hypoxia on myocardial stiffness43-44 failed to
demonstrate that ischemia can cause changes in
myocardial stiffness.
However, a new experimental preparation that
more closely modeled the situation that existed in
the clinical studies, clarified the link between ischemia and shifts in the diastolic pressure-volume
curve.43-47 In this preparation, occluders were placed
on the circumflex and left anterior descending coronary arteries of open-chest, open-pericardium dogs
and then tightened until flow in these two arteries
was reduced by approximately 50%. The left ventricular diastolic pressure-volume curve was not
affected by this decrease in flow. The hearts were
then paced at approximately twice the resting heart
rate. Immediately after pacing was stopped, the
pressure-volume curve shifted upward but returned
to normal within 1 minute. Thus, in contrast to
previous animal studies, reversible shifts in the
diastolic pressure-volume relation were produced
that mimicked the shifts observed in patients with
coronary artery disease.
These reversible shifts in the left ventricular
diastolic pressure-volume relation do appear to be
associated with the myocyte's ability to move calcium in and out of the cytosol, but the principal effect
of impaired calcium handling ability should be on the
extent of relaxation rather than on the rate. Although
there is some slowing of relaxation (reflected by an
increase in T) due to a reduction in the ability of the
sarcoplasmic reticulum to sequester cytosolic calcium, the primary effect seems to be accumulation of
calcium within the cytosol which, in turn, leads to an
increase in the number of active cross bridges during
diastole. The increased number of cross-bridges
remaining at the end of diastole alters the extent of
relaxation by causing the myofilaments (and therefore the equilibrium length) to be shorter than during
normal cardiac function (or during demand-induced
ischemia). The shorter equilibrium length is manifested globally as a smaller equilibrium volume (Vo).
The smaller equilibrium volume means that the strain,
wall stress, and chamber pressure increase at any
given volume even if the stress-strain characteristics
of the muscle (a and /3 in Equations 4 and 5) do not
change.
Differences from previous experimental studies
led Serizawa et al45-4* to propose that there are
actually two types of ischemia in the intact heart:
"supply-induced" and "demand-induced." During
supply-induced ischemia the normally beating heart
is underperfused (or perfused with a deoxygenated
perfusate), which reduces systolic work, oxygen
demand, and the amount of metabolic waste products produced. This is the situation that prevailed
during the earlier animal studies. Under these conditions, a low coronary flow is sufficient both to
supply oxygen and to remove metabolites, and,
consequently, there are little or no changes in the
diastolic properties of the myocardium. In contrast,
during "demand-induced" ischemia, such as that
during pacing after coronary artery occlusion, myocardial metabolic demands increase while the supply of oxygen and the capacity to remove waste
products are limited by the occlusion. As a result,
the sarcoplasmic reticulum takes up calcium more
slowly, and more actin-myosin cross bridges remain
intact at the end of relaxation.4-40-48-50 When an
excess of Ca2+ remains in the cytosol after a contraction, an excess of cross-bridges remains attached
and the equilibrium length of the muscle is shorter
than normal. Thus, inadequate supply of ATP, Ca2+
overload, leakage of Ca2+ from the sarcoplasmic
reticulum, or perhaps even the failure of the cell to
return Ca2+ to the extracellular space are all possible mechanisms that could cause the upward shift in
the diastolic pressure-volume relation that accompanies ischemia.
Although the distinction between supply-induced
and demand-induced ischemia provides an appealing explanation for the differences observed in
different experimental models of cardiac ischemia,
it does not completely explain the mechanism for
upward shifts in the diastolic pressure-volume curve
in people with coronary artery disease. The hypothesized mechanism of the shifts observed during
pacing in these patients is that the tachycardia
increases the demand for oxygen without permitting
a concomitant increase in supply. Conversely, dur-
Gilbert and Glantz Determinants of Diastole
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ing coronary artery occlusion, the reduced blood
flow supposedly results in reduced oxygen demand
because systolic function is depressed. Although
the evidence for this hypothesis is quite consistent
and convincing in otherwise healthy experimental
animals, this situation does not hold in humans with
coronary artery disease. The situation with pacinginduced angina is a clear example of demandinduced ischemia. With the advent of percutaneous
transluminal coronary angioplasty, the clinical analogue of experiments in which a coronary artery
was transiently occluded became possible. Serruys
et al51 performed a detailed study of systolic and
diastolic function in patients with coronary artery
disease during angioplasty. Heart rate and systolic
pressure remained essentially constant during the
period of balloon occlusion, but the left ventricular
diastolic pressure-volume curve shifted upward during the occlusion, then moved back toward preocclusion values after the occlusion ended. The precise mechanisms for these shifts remain to be
denned, but these results do indicate that the situation in sick people is more complex than that
which is achieved in acute animal models of transient ischemia.
The clearest evidence that impaired Ca2+ uptake by
the sarcoplasmic reticulum in the presence of hypoxia
impairs myocardial relaxation is provided by studies
of the load-dependence of relaxation in isolated
muscle taken from different animal species.52-33 In
these studies, cat, rat, and frog papillary muscles
were investigated because each species has a different amount of sarcoplasmic reticulum and therefore relaxes differently in response to changing
mechanical loading conditions. Cat myocytes are
rich in sarcoplasmic reticulum and are thus sensitive to ischemia, which alters calcium energetics
within the cell, whereas frog myocytes have relatively little sarcoplasmic reticulum. Rat myocytes
have an intermediate amount. At various times during isotonic contraction, the afterloads were increased
incrementally. In the cat papillary muscle, the time
course of relaxation changed when the load increased,
implying that relaxation was sensitive to loading
conditions. In contrast, frog heart muscle relaxation
was largely independent of load. Rat heart muscle
was in between. Thus, cardiac muscle relaxation
appears to depend on load and the ability of the
sarcoplasmic reticulum to sequester Ca2+ and hence
release actin-myosin cross-bridges.
Chuck et al54 demonstrated that hypoxia made cat
papillary muscle less sensitive to load. Hypoxia
suppresses the re-uptake of calcium by the sarcoplasmic reticulum,55-56 and this action would prolong activation because it would prolong the period
during which calcium remains in the vicinity of the
actomyosin cross-bridges. This could explain the
observed diminution of load sensitivity. Hypoxia
plus caffeine (which tends to make the sarcoplasmic
reticulum permeable to calcium) made cat papillary
muscle completely insensitive to load, and the force-
833
deflection traces for the cat muscle were similar to
those for frog papillary muscle. Thus, by making
the cat papillary muscle hypoxic and adding caffeine, the cat muscle was effectively converted to
frog heart muscle, which has little sarcoplasmic
reticulum. This means that the ability of the sarcoplasmic reticulum to sequester cytosolic Ca2+ is
probably the rate-limiting step of load-dependent
relaxation. Moreover, since hypoxia (or ischemia)
results in more calcium remaining in the cytosol at
end-diastole, the equilibrium length would also
decrease because a greater number of intact cross
bridges would result in shorter muscle fibers at
end-diastole due to the lack of complete relaxation.
Thus, hypoxia or ischemia would cause a lessening
of the extent of relaxation.
Factors That Affect the Relaxation Rate
A number of factors affect the relaxation rate but
do not shift the entire diastolic pressure-volume
relation because none of the changes in relaxation
rate is large enough to affect the ventricular pressure at end diastole. Changes in relaxation rate do,
however, affect the atrioventricular pressure gradient and thus affect the left ventricular filling rate
during early diastole.
Several factors do not affect the time constant of
isovolumic relaxation, T. For instance, T is independent of changes in ventricular volume, enddiastolic pressure, peak left ventricular pressure,
stroke volume, end-systolic fiber length, and heart
rate in isolated, isovolumically contracting dog
hearts2757 and in isolated ejecting left ventricles
with the heart on right heart bypass.58
On the other hand, several factors do affect
relaxation rate, as quantified by T. The extent of
systolic shortening and interventions thought to
influence calcium dynamics at a cellular level, such
as ischemia, exogenous calcium, and norepinephrine, affect T. 2758 The time required for pressure to
fall to 50% of its peak value (which equals 0.692T)
increased by about 20% during reperfusion after
regional ischemia but was unaffected by nitroprusside or by the ischemia itself.59 T changed by 12% to
18% while rapidly increasing or decreasing left
ventricular afterload in open-chest anesthetized dog
hearts.60 T also decreased after administration of
isoproterenol and increased after administration of
propranolol, suggesting that contractility affects T.
T increased by 58% as both end-diastolic pressure
and mean aortic systolic pressure increased during
volume loading of intact hearts in anesthetized
dogs.32 Finally, T increased by 45% after administration of phenylephrine to increase afterload in
anesthetized dogs.61 The duration of relaxation is
also increased (i.e., relaxation is slowed) in filling
versus nonfilling left ventricles.14
Although in all of the cases just listed the changes
in relaxation rate were large, they were not large
enough to change end-diastolic pressure, because
relaxation was always complete before end diastole
834
Circulation Research
Vol 64, No 5, May 1989
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Time
FIGURE 4. 7/ie rate, but not extent, of left ventricular
relaxation is slowed during reoxygenation after fifteen
minutes of hypoxia. Ischemia caused the pressure curve
to be delayed and the relaxation time constant to be
prolonged. The minimum diastolic pressure was also
higherfor the ischemic ventricle. Nevertheless, the effects
of ischemia on left ventricular relaxation rate die out
before the end of diastole and do not affect subsequent
beats. (Modified from Blaustein et al,62 with permission
of the American Heart Association.)
at normal heart rates (Figure 4).62 Ventricular relaxation is considered complete approximately 3.5T
after dP/dt^n because the ventricular pressure falls
to 3% of its value at dP/dtmm after 3.5 time
constants.63 Since T is typically about 40 msec in
dogs and humans, the effect of relaxation is essentially over 140 msec after the time of dP/dt^. This
means that relaxation from the previous systole will
not have any effect on end-diastolic pressure at
heart rates below approximately 150 to 160 beats/
min (assuming that diastole occupies 40% of the
R-R interval).6* [Weisfeldt, 1980]. At very high
heart rates, it is possible that relaxation may not be
complete before the next systole begins.
Hypertrophy and Relaxation
Whereas so-called physiological hypertrophy,
which accompanies increased physical activity, and
volume-overload hypertrophy do not appear to affect
left ventricular relaxation,19-65 pressure-overload
hypertrophy66-67 and hypertrophic cardiomyopathy68-70
reduce the rate and extent of relaxation. The reduced
rate and extent of relaxation combine to reduce
significantly the rate of left ventricular filling during
early diastole. These changes in relaxation appear
to be due to changes in the way the sarcoplasmic
reticulum handles calcium; the whole process slows
in the presence of pressure-overload hypertrophy71
or hypertrophic cardiomyopathy.72-73
Myocardial ischemia also plays a role in modulating left ventricular relaxation in the presence of
pressure-overload hypertrophy, even in the absence
of coronary artery disease. Pressure-overload hypertrophy is associated with a substantial decrease in
capillary density22 and coronary vasodilator reserve.74-75 Thus, in dogs with pressure-overload
hypertrophy, pacing tachycardia (which increases
myocardial oxygen demand) can reduce subendocardial perfusion and produce metabolic evidence of
ischemia.76 Studies of patients with aortic stenosis
also reveal hemodynamic and metabolic evidence
of ischemia in response to increased demands on
the heart,77-78 as well as histological evidence of
interstitial fibrosis compatible with ischemic injury.79
The mechanics of pressure-overload hypertrophy
also aggravate the problems associated with ensuring adequate perfusion of the subendocardium. In
thick walled shells, the stress is highest on the
inside wall, and the gradient of stresses across the
wall increases as the wall thickens. Thus, as the
myocardium thickens to reduce the average stress
in the wall, the stress near the endocardium may
increase, putting additional demands on the cells
located near the endocardium. The reduction of
capillary density and coronary reserve in this region
that accompanies pressure-overload hypertrophy
further reduces the capacity to deliver oxygen and
remove waste products in this region, particularly
when wall stresses increase in response to increased
demands put on the heart as a whole.
In sum, it appears that pressure-overload hypertrophy and hypertrophic cardiomyopathy affect
relaxation in two ways. First, the function of the
sarcoplasmic reticulum itself is depressed, slowing
the uptake (and possibly the release) of calcium.
This slowing of calcium uptake results in a slower
relaxation and may allow changes in the resting
level of calcium within the sarcomeres and so affect
the extent of relaxation as well. Second, these
forms of hypertrophy appear to be associated with
at least transient subendocardial ischemia, and the
ischemia itself affects rate and extent of relaxation.
Implications for Systolic Function
The original clinical studies of pacing-induced
angina documented the effects on the diastolic
pressure-volume relation of the entire left ventricle
and led to the search for relaxation abnormalities
the cause of these effects. However, coronary artery
disease is a regional disease, in which the regions of
the heart that are served by obstructed vessels are
affected while the regions served by unobstructed
vessels are not affected. Thus, if the mechanism for
shifts in the left ventricular diastolic pressurevolume curve during ischemia is a reduction in the
equilibrium length of the ischemic muscle because
of changes in the extent of relaxation, it should be
Gilbert and Glantz
NORMAL SEGMENT
ISCHEMIC SEGMENT
Cat* 1
to
pott pacng
LENGTH
LENGTH
5. Angiographic studies of regional wall motion
demonstrate the regional effects of ischemia after pacinginduced angina in patients with coronary artery disease.
The ischemic segment stiffened, resulting in a higher left
ventricular pressure for any given segment length (right
panel). In the normal segments, this increased pressure
caused the muscle to be stretched to longer lengths along
a single pressure-length curve (left panel). Because of the
Frank-Starling mechanism, this increased end-diastolic
stretch will make the normal muscle develop more force,
partially compensating for the stiffer muscle in the ischemic region. (From Sasayama et al30 with permission.)
FIGURE
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possible to show stiffening of the muscle in regions
served by obstructed arteries and normal diastolic
properties in the regions perfused by patent arteries. Angiographic studies of regional wall motion in
patients who had coronary artery disease have
demonstrated this point.80-81 In regions served by an
obstructed coronary artery, the diastolic pressuresegment length curve shifted upward after pacinginduced angina. In parts of the heart perfused by
normal coronary arteries, the resulting increase in
diastolic pressure led to higher stresses and therefore greater strain (extension) of the normal myocardium, which moved up a single diastolic pressuresegment length curve (Figure 5). This observation
confirmed that there are regional changes in muscle
stiffness during ischemia in patients who experienced pacing-induced angina.
Sasayama et al's 80 results also have important
implications for how the heart maintains overall
systolic function in the face of the reduced systolic
function of the ischemic myocardium. As shown in
Figure 5, the muscle outside the ischemic region is
stretched longer than normal in response to the
increase in diastolic pressure due to the stiffening of
the ischemic myocardium. Because muscle develops
more systolic force when it is stretched (according to
the Frank-Starling mechanism), the surrounding normal muscle will increase systolic performance and
help compensate for the loss of systolic function in
the ischemic region.
This work is the clinical analogue of experimental
studies conducted by Theroux et al,82 who permanently occluded the circumflex coronary artery in
dogs and then studied them in the conscious state
after they had recovered from the surgery. As
expected, in the region served by an occluded
Determinants of Diastole
835
coronary artery, both the end-diastolic segment
length (measured with implanted ultrasonic crystals) and systolic shortening decreased. The enddiastolic segment length decreased by 30% below
preocclusion lengths, with a concomitant reduction
in systolic function. Systolic function was also
reduced near the ischemic region, as demonstrated
by a 12% decrease in segment shortening. In contrast, segment lengths increased in the normal myocardium far from the ischemic region of the left
ventricle, resulting in an 8% increase in systolic
function after 4 weeks. These results can be
explained using basic mechanics and the FrankStarling mechanism without resorting to a "zone of
injury" near the ischemic area or compensatory
hyperfunction remove from the injured area. Because
all the myocardium must remain connected, the
normal myocardium near the ischemic region is
mechanically constrained by its attachments to the
(stiffer) ischemic myocardium.83 Thus, the stiffer
myocardium cannot be stretched to normal enddiastolic lengths, the sarcomeres cannot move up as
far on their individual Frank-Starling curves, and
the muscle near the ischemic region develops less
systolic force. However, for the left ventricle to fill
to its normal end-diastolic volume, muscle farther
from the stiff region must stretch more than normal
and will therefore develop greater force during
systole. Thus, compensatory lengthening in the
normal muscle due to the mechanical forces acting
in the myocardial shell tends to reduce the global
severity of regional ischemia on systolic function.
Both the extent and rate of relaxation are important determinants of the atrioventricular pressure
gradient. The extent of relaxation determines the
equilibrium length of the muscle fibers and thus the
equilibrium volume of the left ventricle. The relation between the equilibrium and end-systolic volumes determines the initial atrioventricular pressure gradient just before the ventricle begins to fill.
The rate of relaxation determines how quickly the
pressure gradient decays. Thus, both rate and extent
of relaxation affect filling rate during early diastole.
Ventricular Diastolic Suction
Normally at end-systole the muscle fibers are
compressed to lengths shorter than their equilibrium length, resulting in a left ventricular endsystolic volume smaller than the equilibrium volume. This condition stores elastic energy in the
muscle, which is released during relaxation, resulting in an elastic recoil of the ventricle. Under some
experimental conditions, negative ventricular pressures can be observed as evidence for this elastic
recoil, and, because a negative ventricular pressure
during diastole would tend to suck blood into the
ventricle from the atrium, the condition is often
called ventricular diastolic suction.
When left ventricular end-systolic volume is
smaller than equilibrium volume, the muscle fibers
are compressed to lengths shorter than their equi-
836
Circulation Research Vol 64, No 5, May 1989
200 r
ECC
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FIGURE 6. To observe the fully relaxed pressure of beating hearts directly, the mitral valve was occluded at end-systole
to prevent filling (arrow), thus allowing the left ventricle to relax completely while being held at its end-systolic volume.
The observation of negative pressures validated the hypothesis that the left ventricular end-systolic volume was smaller
than the equilibrium volume in these dogs. AoF, aortic flow; PAF, pulmonary artery flow; RVP, right ventricular
pressure; LVP, left ventricular pressure; and ECG, lead II electrocardiogram. F and NF, filling and nonfilling beats,
respectively; ES, PES, extrasystolic and postextrasystolic beats, respectively; 0,1 time of start and end, respectively, of
isovolumic relaxation in a filling beat; °°, asymptotic value of diastolic pressure in NF and PES beats. During inflow
occlusion, only the postextrasystolic beat ejected (shaded aortic flow); thus, the systolic volume of the postextrasystolic
beat was less than that of the nonfilling beat. (From Yellin et al,31 with permission.)
librium lengths, resulting in the phenomenon of
ventricular diastolic suction. The term "ventricular
diastolic suction" is unfortunate because it implies
that a distinct property of the left ventricle generates negative pressures and "sucks" blood in from
the atrium. Actually, so-called diastolic suction is
merely a manifestation of the ventricle's elastic
properties when the end-systolic volume is less than
the equilibrium volume. The forces generated during systole compress the muscle fibers to a length
shorter than their equilibrium length and in so doing
store energy in the muscle fibers and the surrounding collagen matrix as in a compressed spring. As in
a spring, the more the muscle is compressed (i.e.,
the smaller the end-systolic volume), the more
potential energy is stored in the muscle and the
larger the recoil forces.84 The muscle does not need
to be compressed very much to generate large recoil
forces because the pressure-volume curve for the
left ventricle bends down sharply at negative strains
during compression (Figure 2C). These forces
decrease the pressure in the left ventricle during
early diastole and therefore increase the atrioventricular pressure gradient, which in turn increases
left ventricular filling rate. 143185
Therefore, experimental studies have provided
the best evidence that negative pressures occur in
relaxed left ventricles when end-systolic volume is
less than equilibrium volume.86-89 Brecher et al88
observed negative left ventricular pressures after
squeezing arrested dog hearts to a small volume and
then releasing them. Tyberg et al89 used isolated dog
hearts to show that ventricular pressures as low as
-10 mm Hg could be measured by rapidly occluding
the ventricular inflow tract during ventricular systole
in a manner that did not displace any volume or
otherwise disturb the system. Suga et al90 observed
diastolic suction by removing the left atrium and
mitral valve from the heart and allowed it to beat in
a pool of blood; blood filled the ventricle even though
there was no atrial pressure driving it. Yellin and
colleagues3185-91 conducted the most elegant experiments demonstrating diastolic suction. They
implanted a modified Star-Edwards prosthetic valve
in the mitral orifice of dogs, which allowed them to
prevent left ventricular filling by rapidly occluding
the mitral orifice during systole. They recorded pressures as low as -13 mm Hg in the first beat after
occlusion and -28 mm Hg during subsequent beats
(Figure 6).
Clinical studies seldom directly demonstrate diastolic suction by revealing negative diastolic pressures because when the left ventricular pressure
falls below the left atrial pressure, the mitral valve
opens and blood flows into the ventricle. This filling
causes the left ventricular volume to increase above
Vo, so the condition that allows negative pressures
to be observed is eliminated. However, the manifestations of a smaller end-systolic than equilibrium
volume are observed occasionally in humans,92
particularly when partial occlusion of the mitral
orifice impairs normal filling. Such partial occlusion
occurs in patients with mitral stenosis, and negative
diastolic pressures as low as - 7 mm Hg have been
observed in these patients.9394 If mitral flow had
been prevented altogether (as it can be in experimental animals), even more-negative pressures could
probably be observed. Thus, partial mitral occlusion is an intermediate condition between the two
experimental cases explained above and provides
indirect evidence of diastolic suction.
Diastolic suction helps the heart respond to increased demands when contractility increases.
Increasing contractility leads to smaller end-systolic
Gilbert and Glantz Determinants of Diastole
volumes, stronger recoil forces, and thus, a larger
atrioventricular pressure gradient84-85 and more rapid
early diastolic filling.30 This increase in filling rate
maintains or even increases90 end-diastolic volume
and so maintains end-diastolic sarcomere stretch
and, therefore, systolic function.
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Ventricular Interaction
The chambers of the heart interact mechanically
with each other, particularly during diastole, when
the pressures (and, hence, wall stresses) are low.93-96
Acute increases in right ventricular volume cause
increases in left ventricular diastolic pressure. Similarly, increases in left ventricular volume increase
right ventricular diastolic pressure. Thus, in addition to ischemia, which alters relaxation, ventricular interaction also shifts the left ventricular diastolic pressure-volume curve in response to changes
in the vascular loading conditions the left ventricle
faces. The degree of direct ventricular interaction
and its importance to the left ventricular diastolic
pressure-volume relation and the overall function of
the heart depend on the mechanical forces (stresses)
to which the muscle is subject and on the elasticity
of the myocardium. The pericardium, which encloses
the entire heart, strengthens mechanical ventricular
interaction. (Pericardial effects will be discussed in
detail in the next section.)
The stresses in the intraventricular septum are
particularly important in ventricular interaction,
since the position of the septum depends on the
transseptal pressure gradient and its material properties. Shifting of the septum is an important element in mediating ventricular interaction. When the
left ventricular diastolic volume is held constant
and right ventricular volume is increased, the left
ventricular anterior-posterior dimension increases
and the septum becomes flatter and moves toward
the left ventricle.97-103
Ventricular interaction has been observed in
patients given drugs that alter ventricular loading
conditions and shift the diastolic pressure-volume
relation upward or downward. For example, ventricular interaction can explain the acute shifts
upward or downward in the pressure-volume relation in patients given the vasoconstrictor angiotensin or the vasodilator nitroprusside.7 This observation, confirmed by others,104-107 was particularly
important because it was the first evidence that
hemodynamic changes other than ischemia alter the
diastolic pressure-volume relation.
Evidence for the hypothesis that ventricular interaction was responsible for the shifts in the diastolic
pressure-volume relation after giving vasodilating
or vasoconstricting drugs to was provided by a
study in which patients were given nitroglycerine or
amyl nitrate.8 The left ventricular pressure-volume
curve shifted downward in the patients given nitroglycerine but did not shift in those patients given
amyl nitrate. Both drugs lower systemic arterial
pressure, but nitroglycerine also reduces right ven-
837
tricular filling and volume by lowering venous return.
Since nitroglycerine reduced right ventricular size
as well as lowering arterial pressure, left ventricular
pressure also fell. Therefore, ventricular interaction
appeared responsible for the downward shift of the
left ventricular pressure-volume curve.
Direct experimental evidence to support the hypothesis that ventricular interaction, modulated by the
pericardium, was the mechanism for the shifts in the
diastolic pressure-volume curve in response to vasodilation or vasoconstriction has been provided by
animal studies.108 In this study, nitroprusside was
administered to conscious dogs instrumented with
ultrasonic crystals to determine ventricular dimensions. After giving nitroprusside, the left ventricular
pressure-dimension curve shifted downward. These
shifts disappeared when the pericardium was
removed. Thus, the pericardium plays an important
role in modulating the upward and downward shifts
in the diastolic pressure-volume relation after acute
administration of vasodilators or vasoconstrictors.109
Direct Versus Series Interaction
So far we have been discussing so-called direct
ventricular interaction, which is a manifestation of
the forces transmitted through the septum (and, to a
lesser extent, via the pericardium) between the two
cardiac ventricles. However, there are two types of
ventricular interaction: direct interaction, via
mechanical forces across the septum, and series
interaction, because right ventricular output becomes
left ventricular input after passing through the pulmonary circulation.
The degree of direct ventricular interaction can
be determined from isolated heart preparations in
which the volume in one ventricle is held constant
while the pressure-volume relation of the other
ventricle is determined.110-"6 These experiments,
while easy to interpret, require severe disruption of
the normal anatomical situation in which right ventricular output becomes left ventricular input and,
thus, are of limited value in understanding the
normally functioning heart.
Determining the degree of ventricular interaction
using intact heart reflects normal physiology and
anatomy but the results are difficult to interpret.
Studies of ventricular interaction using intact hearts
have reported various degrees of direct interaction. 97100101103117 -' 21 This variability is due in
large part to the difficulty of determining the relative
roles of direct and series ventricular interaction in
the intact circulatory system. Using the traditional
approach of collecting data in physiological steady
state, it is virtually impossible to separate direct
from series ventricular interaction in the intact
circulatory system.
The problem of determining the relative roles of
direct versus series ventricular interaction in the
intact circulatory system is underscored by two
recent independent studies.119120 Using nearly identical preparations and protocols, both studies dem-
838
Circulation Research
Vol 64, No 5, May 1989
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onstrated significant changes in left ventricular shape
(particularly in the septal-free wall dimension) when
right ventricular volume increased after a pulmonary artery constriction. However, whereas Olsen
et al119 interpreted these data to indicate that direct
interaction was the less important effect, Visner et
al120 reached the opposite conclusion. To resolve
this conflict, Slinker and Glantz121 used a new
approach that took advantage of the time lag between
a change in right ventricular output and left ventricular input122-124 to separate, empirically, the series
(delayed) from the direct (immediate) ventricular
interaction. After transiently constricting the pulmonary artery or venae cavae, they measured left
and right ventricular volumes and pressures over
several seconds and found that direct interaction
was about one half as important as series interaction in determining left ventricular end-diastolic
size with the pericardium on. Removing the pericardium decreased direct interaction to about one
fifth as important as the series effect, supporting the
view that the pericardium modulates ventricular
interaction.
The relation of direct to series interaction also
depends on the stiffness of the ventricular walls. In
hypertrophied hearts with thickened ventricular walls
(resulting from three months of renal hypertension),
direct interaction at end-diastole was only about one
tenth as important as series interaction in determining left ventricular size with the pericardium on.125
Removing the pericardium had very little effect on
the relative importance of direct versus series interaction in these hypertrophied hearts because the
thicker myocardium (and particularly the intraventricular septum) carried a relatively greater proportion of the wall stress than the normal hearts.
Implications for Systolic Function
Diastolic ventricular interaction is important for
maintaining systolic function in response to changes
in loading conditions, such as those associated with
vasodilation. For instance, the downward shift in
the left ventricular diastolic pressure-volume curve,
such as that which occurs after acute administration
of the vasodilator nitroprusside, is a critical factor
in maintaining stroke volume.126 Specifically, Figure 7 shows data from a patient before and after
nitroprusside administration.7 During the control
condition, the end-diastolic pressure was 16 mm Hg,
and the end-diastolic volume was 194 ml, with a
stroke volume of 118 ml. After administering nitroprusside, the diastolic pressure-volume curve shifted
downward, so that the end-diastolic pressure fell to
9 mm Hg, but, because the curve shifted, enddiastolic volume fell only slightly, to 176 mi, and
stroke volume remained essentially constant at 114
mm Hg. Now, suppose that no ventricular interaction and no pericardium existed, so that the left
ventricular diastolic pressure volume curve moved
down a unique pressure-volume curve and the enddiastolic volume fell as end-diastolic pressure fell. If
60
Control
(HR'64)
.
40-
| (HR'7
0
80
160
Volume (ml)
7. Data from one patient showing that shifts in
the left ventricular diastolic pressure-volume curve help
maintain stroke volume (SV) in response to changes in
loading conditions after administration of the vasodilator
sodium nitroprusside (NP). Because of the shift in the
curve, stroke volume was maintained despite large reductions in end-diastolic pressure. Had the left ventricle
moved down the control pressure-volume curve, the
end-diastolic volume would have been less than the
stroke volume before administering the drug, yielding a
negative end-systolic volume (dashed line), which is
impossible. By shifting downward, the left ventricle could
exhibit a lower end-diastolic pressure with little change in
end-diastolic volume, thereby making it possible to maintain stroke volume near the control level (solid line).
(From Tyberg et al117 with permission.)
FIGURE
this had happened, then the end-diastolic volume
would have dropped to about 94 ml, making it impossible to maintain stroke volume near its original value
of 118 ml. But because the entire pressure-volume
curve shifted downward, stroke volume was maintained in the presence of a lowered end-diastolic
pressure. Thus, ventricular interaction is important
for maintaining systolic function.
The Pericardium
The pericardium surrounds the heart, reducing
friction between the heart and the surrounding
tissues and providing a barrier against infection. Its
attachments to the mediastinum help restrain the
heart from excessive motion within the chest when
body position changes. When the heart's volume
increases, the heart presses on the pericardium, which,
in turn, presses back on the epicardium and constrains the heart's expansion.128 Because it constrains
the whole heart and is stiffer than the myocardium,
the pericardium increases the mechanical interaction
between the four cardiac chambers. Thus, an increase
in the size of one ventricle causes the pressurevolume relation of the other ventricle to shift upward
due to the constraint of the pericardium.
How the Pericardium Affects the Left Ventricular
Diastolic Pressure-Volume Relation
The pericardium modulates the pressure-volume
relation both because it exerts normal stresses
50
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Heart & pericardium
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FIGURE 8. Pressure-volume relations of the heart and
pericardium, together and alone. The heart without the
pericardium has a pressure-volume relation that is far to
the right (less stiff) of the curve of the heart with
pericardium. The combined heart plus pericardium is
virtually the same as the pericardium alone, indicating
that the stiffness of the pericardium dominates the curve
for the ventricle alone particularly along the steeper
portion of the pericardium's stress-strain curve. (From
Hort129 with permission.)
perpendicular to the epicardium and because it has
a steeper stress-strain relation than the myocardium. The effect of the pericardium on the diastolic
pressure-volume relation depends on the magnitude
of the normal stress exerted by the pericardium on
the epicardium, which, in turn, depends on the
elastic properties of the pericardium (i.e., its stressstrain relation). At small pericardial volumes, pericardial stress is low and the pericardial stress-strain
curve is fairly flat, so that large changes in strain
(volume) result in only small changes in stress
(pressure). Thus, at small pericardial volumes, the
pericardium exerts only small normal stresses on
the epicardium and the effect of the pericardium on
ventricular diastolic pressure is small. However,
when heart volume increases acutely above normal
end-diastolic volumes, the pericardium is stretched
and is moved up its increasingly steeper stressstrain curve (Figure 8). At steeper portions of the
curve, small increases in strain (volume) result in
large increases in stress (pressure). Thus, the normal stress exerted on the epicardium is large, and
the pericardium contributes substantially to ventricular diastolic pressure. This increased stress means
that a higher absolute left ventricular pressure is
required to achieve a given left ventricular volume.
The key to assessing how much the pericardium
influences the left ventricular diastolic pressurevolume relation under physiological conditions is
determining where the pericardium normally operates on its pressure-volume curve. Answering this
question is difficult, and it has been the subject of
considerable debate. Several investigators have
assessed the effect of the pericardium by comparing
the left ventricular diastolic pressure-volume relations before and after removing the pericardium.97.ioi.io3.io8.i2i.i3o-i32
At high left ventricular filling
pressures (above about 10 mm Hg) pericardial stiff-
Gilbert and Glantz Determinants of Diastole
839
ness clearly increases left ventricular diastolic
pressures. 57 " 6131133 - 136 This effect becomes more
pronounced as left ventricular filling pressure and
end-diastolic volume increase. In contrast, Stokland
et al132 reported only a slight (4%) increase in left
ventricular myocardial chord lengths after they
increased blood volume and opened the pericardium
of open-chest dogs, and Tyson et al137 reported little
effect of the pericardium in conscious, chronically
instrumented dogs with low diastolic pressures. Therefore, although the constraining effect of the pericardium contributes significantly to the upward shift of
the left ventricular pressure-volume curve under the
conditions of acute cardiac dilatation, there is at
most a minimal effect at normal diastolic pressures.
The Atria
The pericardium increases mechanical coupling
not only between the two cardiac ventricles but also
between the ventricles and the atria. In a study
using postmortem dog hearts in which the mitral
and tricuspid valves were removed and the orifices
plugged with disks, Maruyama et al130 found the
effect of left atrial pressure was about one fourth
that of right ventricular pressure in determining left
ventricular pressure with the pericardium around
the heart. When the pericardium was removed,
neither the right nor the left ventricular diastolic
pressure-volume relation was affected by a 22
mm Hg increase in right or left atrial pressure alone
(Figure 9). The pericardium's role in strengthening
the interaction between the atria and ventricles is
not surprising because the atria have thinner walls,
are more easily distended, and therefore are more
tightly coupled with the pericardium than either of
the ventricles. Although the left atrium and ventricle were isolated from one another in the Maruyama
et al130 study, their results can still indicate a tighter
coupling between the pericardium and the cardiac
chambers even when the atrioventricular valves are
open. For example, during diastole, while the mitral
valve is open, the left atrium and left ventricle form
in essence a single chamber that is influenced by the
presence of pericardium. The pericardium surrounding the atria is essential for modulating the mechanical coupling between them and the ventricles.
Measuring Pericardial Pressures
Much of the controversy regarding the role of the
pericardium centers on the magnitude of the constraining forces the pericardium exerts on the epicardium. Because these forces are difficult to measure, much of the debate about the importance (or
lack of importance) of pericardial constraint revolves
around methodological issues relating to the measurement of pericardial pressure.
The most direct way to assess pericardia] constraint is to measure the normal stress exerted by
the pericardium, the so-called "pericardial pressure" between the pericardium and the epicardium.
Under normal conditions, the stresses in the peri-
840
Circulation Research
Vol 64, No 5, May 1989
Right Ventricular Pressure- Votume Relationship
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FIGURE 9.
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on chamber
pressure-volume relations. The ventricular pressurevolume relation of one ventricle is shifted upward when
the pressure in one or more of the other chambers b
increased. The pericardium causes this interaction to be
more forceful. In addition, the direct interaction effect of
the right ventricle on the left is greater than the left is on
the right, particularly with the pericardium on. The
representative right (A) and left (B) ventricular pressurevolume curves from isolated, perfused dog hearts were
obtained while holding the other three chambers at
various pressures from 5-30 cm H2O (4-22 mm Hg) with
and without the pericardium. Curves I, 2, and 3 in each
situation were with the pericardium on [pericard (+)/.
Curves 4, 5, and 6 were without the pericardium [pericard
(-)]• PRV, right ventricular pressure; PLV, left ventricular
pressure; VRV, right ventricular volume; VLV, left ventricular volume. (From Maruyama et al130 with permission of
the American Heart Association.)
cardium, which cause the ventricles to interact
more forcefully, are transmitted directly to the
epicardium as normal stresses with the small amount
of fluid in the pericardial sac serving as a lubricant.
During tamponade, when there is a significant
amount of fluid in the pericardial sac, the normal
stresses exerted by the pericardium are transmitted
to the epicardium as a fluid pressure. There is no
physical difference between these two conditions
from the point of view of the epicardium because a
normal stress and a hydrostatic pressure generate
equivalent normal stresses on the epicardium.
The two basic methods for measuring pericardial
pressure have been controversial since the 1960s,
when Holt et al138 used a thin-walled balloon to
measure pericardial pressures and reported pericardial restriction of atrial and ventricular distension,
and Wood et al139140 used open-ended catheters to
measure pericardial pressure and reported no such
restriction. Although ventricular pressures can be
measured accurately and easily with open-ended
or manometer-tipped catheters, these instruments
yield accurate measurements of pericardial pressure only in very limited situations, namely when
there is substantial fluid in the pericardium. When
there is a minimal amount of fluid in the pericardial
space, the normal stress of the pericardium acts
directly on the epicardium, and open-ended or
manometer-tipped catheters greatly underestimate
the "pressure" (normal stress) the pericardium
exerts on the epicardium.
The balloon versus catheter controversy was
resolved by comparing pericardial pressure measured in open-chest dogs with flat fluid-filled balloons and open-ended catheters while infusing saline
into the pericardium.135136141 Above pericardial fluid
volumes of 30 ml, the two methods yielded similar
results. However, below 30 ml, the open-ended
catheter substantially underestimated the pericardial pressure because there was insufficient pericardial fluid to transmit the normal stress (generated by
the pericardium) to the pressure transducer (Figure
10). In a different study, Mann et al142 used air-filled
balloons to measure pericardial pressure and also
concluded that a balloon is the appropriate way to
measure pericardial pressure.
Flat balloons always measure the normal stresses
the pericardium exerts on the epicardium because
the balloon creates a confined region for the fluid to
transduce the normal stress into a hydrostatic pressure that can be measured with a pressure transducer inside the balloon. Smiseth et al136 demonstrated this point unequivocally when they used
such a balloon to measure pericardial constraint
after cutting small slits in the pericardium. Because
the slits allowed the pericardial fluid to drain, an
open-ended catheter inserted in the pericardium
measured no pressure. Even so, the pericardium,
now similar to a stiff net, still exerted a normal
stress on the heart, which a flat balloon transducer
accurately measured. During tamponade, when the
pericardial space is filled with fluid, the balloon
floats in the pericardial fluid and senses its pressure.
Thus, the balloon measures the normal stress the
pericardium exerts on the epicardium whether or
not there is fluid in the pericardial space. Using flat
balloons is essential for accurate measurement of
pericardial pressure, unless one can ensure that
sufficient fluid exists in the pericardial space to
Gilbert and Glantz
Determinants of Diastole
841
Calculated pressure
FIGURE 10. The difference between the measured
and calculated pericardial pressures as a function
of pericardial fluid volume. The pericardial pressure measured using a flat balloon containing a
pressure transducer is compared with the pressure
measured using an open-ended catheter inserted in
the pericardial space. The pericardial pressure was
computed as the difference in measured intraventricular pressure with and without the pericardium
around the heart at various left ventricular volumes. The open-ended catheter significantly underestimates pericardial pressure unless there is at
least 30 ml liquid within the pericardium. Dark,
shaded area shows the pericardial fluid volumes at
which both methods of measurement fall within the
95% confidence interval of the calculated pressure.
The flat balloon, however, approximates the calculated pressure regardless of the volume of fluid in
the pericardium. Lightened lines indicate the 95%
confidence intervals of the pressure curves. (Modified from Smiseth et al'3S with permission of the
American Heart Association.)
en
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Open ended catheter
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95 % confidence interval
0
10
20
30
40
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PERICARDIAL FLUID VOLUME (ml)
transmit the stresses between the epicardium and
pericardium via the fluid pressure.
Measurement Artifacts Resulting From
Instrumenting the Pericardium
The experimental manipulation necessary to
instrument the pericardium can affect the observed
left ventricular diastolic pressure-volume relation.
Opening the pericardium to instrument the pericardial space invariably leads to artifacts in measuring
pericardial pressures and could account for divergent results among various experimental studies.
Gibbon and Churchill,143 Stokland et al,132 Spadaro
et al,131 and Tyson et al137 have all demonstrated
that reapposing the pericardium with sutures or glue
can magnify the pericardial constraint, particularly
if long pericardial incisions from base to apex are
used.132 To reduce the possible measurement artifacts due to opening and closing the pericardium,
Tyson et al137 suggest opening the pericardium with
an incision across the base of the heart instead of
cutting the pericardium along the long axis. They
then constrict the venae cavae to reduce heart size,
and pop the heart out of the pericardium. This
procedure leaves the pericardial sac relatively intact.
In addition, the pericardium can be left under and
covered by the heart to keep it moist while the heart
is instrumented thereby avoiding shrinkage, which
has been observed during cardiac surgery.144 After
instrumenting the heart, the process is reversed: the
venae cavae are again constricted to reduce heart
size and the heart is replaced in the pericardial sac
with a minimum of trauma to the pericardium.
When the heart is prepared in this way, the effect of
pericardia! constraint is less than is observed using
the older technique with an incision along the long
axis of the heart. This procedure has become widely
accepted for instrumenting the heart in a way that
will minimally disturb the pericardium.
Assessing Pericardial Constraint in Patients
Although knowing pericardial pressure is important in assessing pericardial constraint and hence
ventricular function during diastole, it is seldom
possible to measure pericardial pressure in patients
directly. Obviously, measuring pericardial pressures with balloons is too invasive for patients.
However, because the right ventricle and atria have
thinner walls than the left ventricle and, hence, are
more closely coupled with the pericardium, right
ventricular or atrial pressure has been proposed as
a substitute for direct measurement of pericardial
pressure. 136145146
In a comparative study between patients with
tamponade who underwent pericardiocentesis and
open-chest dogs with large pericardial effusions,
Smiseth et al141 concluded that right ventricular
pressure was a useful approximation of pericardial
842
Circulation Research
Vol 64, No 5, May 1989
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pressure. Likewise, Tyberg et al127 found that the
pericardial pressure was similar in magnitude to the
mean right atrial pressure in patients over a wide
range of these pressures (-4 to 20 mm Hg). These
investigators concluded that in normal hearts during
diastole when the right atrioventricular valve is
open, right atrial and ventricular pressures can be
used to approximate pericardial pressure.
There are clearly limits to approximating pericardial pressure with right atrial or ventricular
diastolic pressure. 125147 One example is when the
right ventricle stiffens as a result of right ventricular hypertrophy. l01 Another example is in patients
with cor pulmonale or pulmonary hypertension.148
In both cases, right atrial pressures may be much
higher than pericardial pressures. During pericardial drainage to treat cardiac tamponade, pericardial pressure falls considerably below right atrial
pressure. 124149 These low pericardial pressures
most likely occur because in patients with large
chronic pericardial effusions, the pericardium is
stretched well above its normal capacity. Thus,
removal of the pericardial fluid would result in a
very loosely fitting (or even collapsed) pericardium and no pericardial constraint. Under normal
conditions, however, the right atrial pressure can
probably be used as a reasonable approximation
for pericardial pressure during diastole.
Pericardial Adaptation to Ventricular
Hypertrophy
The pericardium adapts to chronic increases in
heart size by increasing its mass (size)150 and as the
pericardium expands over time, its effect on the left
ventricular diastolic pressure-volume relation
decreases. This changing role of the pericardium
was demonstrated by Lewinter and Pavelec151 who
compared left ventricular diastolic pressuresegment relations before and after removing the
pericardium in dogs during the early (7-9 days) and
late (34-50 days) stages of hypertrophy after imposing a chronic left ventricular overload. Removal of
the pericardium early after the volume overload
was created reduced the right and left ventricular
end-diastolic pressures and increased dimensions at
matched levels of left ventricular end-diastolic pressure greater than 10 mm Hg. Hence, shortly after
creating the volume overload, the heart had
expanded against the pericardium, which led to an
increase in diastolic left ventricular pressure. In
contrast, after left ventricular mass increased, neither left ventricular end-diastolic dimension nor
right ventricular end-diastolic pressure changed when
the pericardium was removed, indicating that the
pericardium had expanded and was exerting less of
a constraining force on the heart. Thus, when the
pericardium hypertrophies along with the heart, the
pericardium plays a smaller role in determining the
left ventricular diastolic pressure-volume relation
than in normal hearts.103131-153 The influence of the
pericardium changes because as the heart increases
in size the pericardium is stressed chronically. The
pericardium responds to this increased stress by
increasing its size. When this happens the enlarged
pericardium would operate on a flatter portion of its
stress-strain curve; the constraining forces are smaller
and the influence of the pericardium on the heart is
less than its influence before the hypertrophy.
Another effect of myocardial hypertrophy is that
the relative importance of the pericardium and of
direct ventricular interaction is less when the ventricular wall thickens. For example, in normal dog
hearts, Slinker and Glantz121 found that removing
the pericardium decreased the relative importance
of direct versus series ventricular interaction in
dogs from about one half to one fifth. In hearts that
had hypertrophied in response to three months of
renal hypertension, the importance of direct interaction was less, becoming only about one tenth as
important as series interaction with the pericardium
on and essentially zero without the pericardium.103
As the ventricular walls thicken in response to the
pressure overload, the thicker walls become less
distensible, and more of the ventricular pressure is
balanced by the elasticity of the myocardium as
opposed to the pericardium.
Implications for Systolic Function
By restricting the expansion of the heart, and
thus restricting extension of the sarcomeres that
make up the myocardium, the pericardium can
affect left ventricular systolic function via the FrankStarling mechanism under certain pathological conditions. For example, right ventricular infarction
can precipitate a low cardiac output syndrome.
Although a reduction in right ventricular systolic
function plays a role by reducing right ventricular
output and left ventricular input, ventricular interaction, mediated by the pericardium, is also important. Goldstein et al 154153 produced right ventricular
infarction in dogs by infusing mercury into the
coronary circulation. Immediately after the infarct,
the right ventricle attempted to dilate within the
pericardium, increasing pericardial pressure, increasing left ventricular diastolic pressure, and inhibiting
filling. The associated lower left ventricular enddiastolic volumes impaired systolic function because
of the Frank-Starling mechanism. When the pericardium was opened and the right ventricle was free
to dilate without competing with the left ventricle
within the pericardium, the left ventricle could
expand and increase end-diastolic volume, stroke
volume, and cardiac output.
Pulmonary-Cardiac Contact Pressure
The observation that blood pressure and cardiac
output fell in patients ventilated with positive endexpiratory pressure (PEEP) stimulated interest in
the effect of the lungs on cardiac function.136-159
Just as the ventricles and the pericardium interact
with each other because they are in physical contact, so the heart and lungs interact mechanically
Gilbert and Glantz Determinants of Diastole
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because they are in physical contact. Like the
pericardium, the lungs affect the left ventricle's
diastolic pressure-volume curve by exerting a normal stress on the heart. The contact pressure, which
is on the order of a few millimeters of mercury, has
little direct mechanical effect during systole. However, during diastole, when pressures are low,
inflating the lungs can increase pressure outside the
heart and lower the left ventricular transmural pressure at any given absolute left ventricular pressure.
This lower transmural pressure can reduce enddiastolic volume and reduce cardiac output because
of the Frank-Starling mechanism. This mechanical
interaction between the heart and lungs explains the
reduction in cardiac output that occurs during PEEP.
Lung hyperinflation or positive pressure ventilation with more than 10 cm H2O (8 mm Hg) PEEP
reduces both ventricles' diastolic size because of
the direct compressive force the lungs apply to the
heart."7122133134138160-173 Fewell et al164 directly
observed the effect of mechanical compression of
the heart by hyperinflated lungs by attaching flat
balloon pressure transducers to the epicardium of
both left and right ventricles of dog hearts. Cardiac
transmural pressures were calculated as the difference between ventricular and balloon pressures.
They determined transmural pressures during 0 and
12 cm H2O PEEP with the chest open, the chest
closed and evacuated, and with the pericardium
intact and removed. With the chest closed and the
pericardium intact, absolute left and right ventricular end-diastolic pressures increased from 4 to
FIGURE 11.
843
Hemodynamic response to
the application (upper panel) and
removal (lower panel) of 12 cm H2O
positive end-expiratory pressure. The
left ventricular end-diastolic pressure
measured with respect to atmospheric
increased by 2 mm Hg while transmural
left ventricular pressure did not change
when computed by subtracting the pressure between the lungs and the heart.
End-diastolic volume decreased by 17
ml. Heart rate increased by only 7%.
Thus, a 26% fall in cardiac output
resulted from the\ larger lung volume
(due to 12 cm H20 positive endexpiratory pressure) constricting the
heart at end-diastole. All variables
returned to normal after positive endexpiratory pressure was removed. QAo,
aorticflow;QpA, pulmonary artery flow;
PAo, aortic pressure; PLV, left ventricular pressure; PFA, pulmonary artery pressure; PRV, right ventricular pressure;
P,F, intrapleuralpressure. (From Fewell
et al' with permission.)
7 mm Hg and from 3 to 6 mm Hg respectively, when
PEEP was increased from zero to 12 cm H2O (Figure
11). In contrast, left and right ventricular enddiastolic transmural pressure and volumes both fell.
This difference between absolute and transmural
end-diastolic pressure was not due to the pericardia]
constraint because the pericardium simply transmits
the pressure exerted by the lungs and removing it
does not alter the effect of pulmonary-cardiac contact pressure. This fact was demonstrated in the
open-chest dogs in which the lungs were held away
from the heart to prevent the lungs from pressing on
the heart. Although end-diastolic volume increased
about 11% when the lungs were held away from the
heart, there was no change in either cardiac output or
ventricular end-diastolic pressure during PEEP. Lung
hyperinflation or positive pressure ventilation with
more than 10 cm H2O PEEP decreases right and left
end-diastolic volumes due to mechanical compression of the heart by the hyperinflated lungs. Heart
rate does not change; therefore, cardiac output drops
because of the Frank-Starling mechanism.173-'73 The
reduction in cardiac output appears to be primarily a
mechanical effect of the lungs pressing on the heart,
which occurs independently of changes in myocardial contractility, or neural and humoral effects.
Viscoelastic Properties of the Myocardium
So far we have seen that the primary determinants of left ventricular filling and of the diastolic
pressure-volume relation are the myocardium's
intrinsic mechanical characteristics—the geometry
844
Circulation Research Vol 64, No 5, May 1989
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of the ventricular cavity (particularly wall thickness),
the elasticity of the myocardium, and extent and rate
of relaxation—and the external forces acting on the
left ventricle through ventricular interaction, the
pericardium, and pulmonary-cardiac contact pressure. In addition to these major factors, there are two
additional factors that make a small contribution to
the diastolic pressure: viscoelasticity of the myocardium and coronary vascular engorgement.
Like most biological materials, the myocardium
is viscoelastic176177 so that stresses in the heart wall
depend on the rate at which it deforms (strain rate,
e) as well as on the magnitude of the deformation
(strain, e). This dependence means that the diastolic
pressure depends on the filling rate as well as on the
ventricular volume and that the diastolic pressure at
a given volume increases as filling rate increases.
Although there is no doubt that viscous forces
contribute to diastolic pressure, particularly during
rapid filling and atrial systole, this contribution is
probably small.
Because viscous forces increase with filling rate,
these forces are greatest during the rapid filling
phase in early diastole and atrial systole. However,
elastic recoil or restoring forces are also most
significant during rapid filling. Therefore, it is difficult to separate changes in the diastolic pressurevolume relation during early diastole due to myocardial viscoelasticity from the changes due to
active relaxation.
To demonstrate the effect of myocardial viscoelasticity on the left ventricular diastolic pressurevolume relation, several investigators have shown
that during rapid diastolic filling left ventricular
pressure exceeds that predicted by a simple elastic
model. '78-188 The most elegant analysis of viscoelastic effects in the intact heart during diastole was
done by Rankin et al,184 who represented myocardial viscoelasticity analytically. They modified the
equation for purely elastic myocardium given by
(Equation 4) to incorporate a viscous effect by
adding the term -yi.
(8)
*- \)+ye
where y is a viscosity parameter and e is de/dt, and
combined this equation with an elliptical model of
the left ventricle to compute wall stress from pressure, volume, and wall thickness. They then alternately occluded and released both venae cavae and
the aorta of dogs to obtain a variety of left ventricular sizes and filling rates. This experiment allowed
them to relate strains (e) and strain rates (e) from
measurements of left ventricular diameters obtained
from ultrasonic crystals sewn on the epicardium
with the computed wall stress. Although computation of strain rates based on ultrasonic crystal
dimension measurements of the heart may be
problematic,189 the experimental stress-strain data
fell very close to that predicted by Rankin et al's185
viscoelastic model (Figure 12). These data suggested that viscoelastic effects play a substantial
2500-
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1500
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02?
STRAIN
FIGURE 12. Close agreement between measured dynamic
diastolic stress-strain data for two beats (circles) and the
results predicted by including viscoelastic effects in the
two-element model given by Equation 8 (solid lines). The
lower solid line is the purely elastic curve (given by
Equation 5) predicted from the dynamic data when the
strain rate is near zero. Myocardial viscoelasticity causes
higher ventricular pressures to be observed than predicted by a purely elastic model during rapid filling and
atrial contraction. (From Rankin et al,185 with permission
of the American Heart Association.)
role during early diastole and atrial systole, when
filling rates are high.
The conclusions that of viscoelastic effects in the
whole heart cause increased diastolic pressures
when filling rates are high are consistent with the
observation that viscoelastic behavior can be elicited by suddenly stretching a strip of isolated
muscle177190191 and monitoring the resisting force
over time in a so-called "stress relaxation experiment." If the muscle was purely elastic, the force
would change instantaneously with the length, and
then remain constant at the value appropriate for
the new length. A three-element model, consisting
of two elastic elements (springs) and one viscous
element (dashpot) (Figure 13A), best represents the
stress relaxation response of isolated muscle.177
When length is suddenly increased, strain rate is
theoretically infinite, so the spring-dashpot combination in parallel cannot extend (because the force
in the dashpot becomes infinite) and the series
spring model extends. But this extension of the
single spring creates a force imbalance between it
and the spring-dashpot combination. These forces
redistribute themselves over time until the forces in
the two springs are equal and the material reaches a
new equilibrium at the increased length (Figure
13B). Thus, in response to a suddenly imposed
change in length, the force in the three-element
model increases asymmetrically and then falls off as
the dashpot begins to extend, reducing the total
Gilbert and Glantz Determinants of Diastole
2-efemem Vagi Model
VISCOELASTIC MODEL
EXCITATION
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STRESSRELAXATION
RESPONSE 8
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Time
Time
STRESS-RELAXATION EXPERIMENT
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EXCITATION
CREEP
RESPONSE
£
Time
CREEP EXPERIMENT
13. Two viscoelastic models used to describe
muscle, the three-element model and the two-element (or
Voigt) model (Panel A). Panel B shows the stressrelaxation response of these two models, elicited by an
imposed sudden, constant change in length (stressrelaxation experiment). For the three-element model, the
force in the series spring increases as it instantaneously
extends in response to the imposed length change; since
the strain rate is theoretically infinite at the instant of the
step change in length, the spring!dashpot combination on
the left side of the model does not move. After the series
spring extends, there is a force imbalance across the
springldashpot combination, which causes the parallel
springldashpot combination to extend, shortening the series
spring and lowering the externally measured force. This
process continues until the two springs reach equilibrium.
The two-element model responds quite differently; there is
an infinite force at the instant of the step change in length
produced as the dashpot is extended instantaneously, and
then the force immediately takes on its steady-state value.
Isolated muscle behaves like a three-element model. Panel
C shows the corresponding results for creep experiments,
when the change in length is measured in response to a
sudden, constant change in externally imposed force.
FIGURE
force in the three-element model and reaching a
new equilibrium length (Figure I3B).
Another way to elicit the muscle's viscoelastic
property would be to impose a sudden change in
845
force on the strip of muscle and observe the change
in length over time in a so-called creep experiment
(Figure 13C). (These two terms, which are very
often misused in the cardiovascular literature,
describe the response [behavior] of a particular
viscoelastic material to a specified input, that is, a
step increase in length or in force. Stress-relaxation
and creep are not mechanisms or material properties.)
In contrast to the model just discussed, Equation
8 represents a two-element viscoelastic model in
which a single elastic and viscoelastic element are
in parallel (Figure 13A). The stress-relaxation
response for this two-element model is different
from that previously described for the threeelement model; the two-element model predicts that
the material will exhibit a theoretically infinite force
for the instant immediately after the muscle is
stretched, and thereafter assume the constant value
appropriate for the new length (Figure 13B). This
response is not observed in isolated muscle. Thus,
although the fit of data observed by Rankin et al185
is compelling (Figure 12), a theoretical difficulty
remains. The two-element model defined by Equation 8 does not exhibit the stress-relaxation and
creep behavior that has been observed in isolated
cardiac muscle. This contradiction has not yet been
resolved.
The fact that viscous forces are greatest at the
same time that filling is greatest during active relaxation (or atrial systole) makes separating viscoelastic from relaxation effects difficult. Pasipoularides
et al188 proposed a mathematical method to separate
viscoelastic from relaxation effects. They subtracted a component of pressure assumed to be due
to relaxation calculated based on the monoexponential model of isovolumic pressure fall (Equation 6)
and then examined the residual pressure for evidence of viscoelastic (i.e., rate-dependent) effects.
In so doing, they assumed that the isovolumic
ventricle would relax to a zero pressure asymptote
(p»=0). Although Pasipoularides et al188 admitted
that a nonzero pressure asymptote could alter their
results by shifting the passive pressure-volume curve
up or down, they argued that this would have a
negligible effect on the passive stiffness-stress relation in their model. Using this method to evaluate
patients with normal hearts who had undergone
cardiac catheterization, they concluded that in hearts
in the "basal" state, the strain rate-dependent (viscoelastic) effects were minimal. This conclusion is
supported by Fioretti et al,192 who reasoned that
viscous effects in early diastole are overshadowed
by relaxation effects. The confounding effects of
relaxation are not present late in diastole during
atrial systole, when the ventricle is fully relaxed.
Thus viscoelastic effects probably do play a role in
increasing left ventricular pressure during atrial
systole (Figure 12).
In summary, whether or not they are measurable,
viscous forces increase continuously as a function
of filling rate. The difficulty in interpreting these
846
Circulation Research
Vol 64, No 5, May 1989
strain rate-dependent effects is that the strain rates
are highest in early diastole, when filling is fastest
and when active relaxation from the previous beat
is taking place. It is probable that most of the effects
that have been attributed to viscoelasticity during
rapid filling are due to active relaxation. However,
viscous forces make an identifiable contribution to
left ventricular pressure during atrial systole.
Coronary Vascular Engorgement
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Increasing coronary artery pressure has been
hypothesized to stiffen the network of coronary
arteries that permeate the myocardium and so stiffen
the left ventricular wall, analogous to the way
erectile tissue stiffens when it is engorged with
blood. This resultant stiffening of the left ventricular wall would be reflected in the diastolic pressurevolume relation just as if the muscle itself became
stiffer. The effect of coronary vascular engorgement
on ventricular stiffness would be most evident late
in diastole, when the coronary arteries are maximally perfused. Although myocardial stiffening as a
result of vascular engorgement has been demonstrated in isolated heart preparations, the effect is
small, so it does not contribute appreciably to the
diastolic pressure-volume relation.
The first reported evidence for a myocardial
erectile effect was the finding that the end-diastolic
pressure in isovolumically contracting dog left ventricles increased when coronary arterial perfusion
pressure increased.193 Although Salisbury et al193
did not measure chamber stiffness directly in this
study, they nevertheless showed that the left ventricular diastolic pressure increased by as much as
18 mm Hg (to 22 mm Hg) when coronary arterial
pressure increased from 35 to 125 mm Hg. They
proposed that the mechanism responsible for this
behavior was engorgement and stiffening of the
matrix of blood vessels in the myocardium. Later,
Olsen et al194 found that the left ventricular pressureminor axis strain curve shifted upward (indicating
increased ventricular stiffness) when they increased
coronary perfusion pressure from 40 to 120 mm Hg
in potassium-arrested dog hearts. To demonstrate
that coronary arterial perfusion pressure alone
caused the ventricular stiffening and not coronary
blood flow, they performed similar experiments
after administering the vasodilator adenosine to
increase coronary blood flow. The pressure-minor
axis strain relation as a function of coronary arterial
perfusion pressure were the same with or without
adenosine. Therefore, the left ventricular stiffness
depended on coronary arterial perfusion pressure
below the autoregulatory range of 80 mm Hg. The
effect, however, was small.
If increasing coronary arterial perfusion pressure
causes the myocardium to stiffen, then reducing
perfusion pressure should have the opposite effect.
By reducing coronary arterial perfusion pressure to
zero in isovolumic dog hearts, Gaasch et al 195196
observed that diastolic wall thickness decreased by
7% and diastolic pressure decreased by 23%. In
addition, Gaasch and Bernard195 found that during
reactive hyperemia (after coronary artery ligation
and reperfusion), wall thickness was 10% greater
than the control (before ligation), indicating a stiffened myocardium.
Other similar studies have not demonstrated
changes in chamber stiffness as a function of coronary perfusion pressure.43197-200 The lack of observed
changes in chamber stiffness in these studies may
have resulted from either measuring diastolic pressures and flows at a single left ventricular volume or
too small a change in the coronary perfusion pressure to obtain much effect.
The main problem encountered in studies designed
to determine whether the myocardium stiffens due
to coronary vascular engorgement is to decouple
metabolic effects (changes in the myocardium due
to changes in coronary blood flow or perfusate)
from hydraulic (erectile) effects. Many studies have
compared how myocardial stiffness changes when
coronary flow is stopped (ischemia) with how stiffness changes when the coronary arteries are perfused with a hypoxic perfusate (hypoxia). In both
cases, oxygen supply to the heart is reduced, which
affects cell metabolism, calcium flux, active relaxation, and, perhaps, myocardial stiffness. Therefore,
hypoxia or ischemia would tend to mask a possible
erectile effect by the effects of the ischemia or
hypoxia. This masking is further complicated by the
small nature of the erectile effect itself. For example,
Vogel et al201 perfused isolated rabbit hearts with a
variety of normoxic and hypoxic media and found
that changes in the diastolic pressure-volume curve
were directly related to changes in wall thickness
associated with the different perfusates, independent
of the effects of ischemia per se.
The problem of decoupling erectile (hydraulic)
from metabolic effects was directly addressed by
Watters et al202 and Bouchard et al203 who used a
rapid freeze-clamp method to stop metabolism ten
seconds after stopping coronary arterial perfusion
and measured left ventricular equatorial crosssectional area, diastolic wall thickness, developed
pressure, and high energy phosphate metabolism in
isovolumic rat and hamster hearts. Ten seconds of
ischemia was not sufficient to cause measurable
changes in metabolism but did reduce left ventricular
diastolic wall thickness by 4% and left ventricular
epicardial cross-sectional area by 8%. Thus, they
demonstrated an erectile effect independent of metabolic effects within the first 10 seconds of ischemia.
Theoretical work has also demonstrated that coronary vascular engorgement has a small effect on left
ventricular stiffness. Huyghe204 did a theoretical analysis of the beating left ventricle and intramyocardial
coronary circulation using a nonlinear, finite element
analysis which showed that diastolic ventricular stiffness increased slightly, by 10%, when coronary
perfusion pressure was increased from 45 to 120
mm Hg. Thus, both experimental and theoretical
Gilbert and Glantz Determinants of Diastole
investigation has shown that increasing coronary
perfusion pressure increases the apparent stifiFness of
the diastolic left ventricle, but the effect is small.
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Conclusion
Studies of diastolic function have been a fruitful
area of investigation for the last 10 years and our
understanding of diastolic function has changed
significantly since the last Brief Review on the
subject published in Circulation Research.51 It is
now well established that the traditional view of the
diastolic left ventricle as an isolated shell in which
filling pressure and volume are uniquely related is
incorrect: The diastolic pressure-volume relation
changes in response to changes in the heart's operating environment. The diastolic pressure-volume
relation depends on the balance between the pressure in the left ventricle and the stresses in the
myocardium. These stresses, in turn, depend on the
size and thickness of the ventricle and the elasticity
of the myocardium. Thus, when the left ventricle
contracts to a volume smaller than its equilibrium
volume, elastic energy is actually stored in the
myocardium. This stored energy is manifested as
so-called diastolic suction, which increases the atrioventricular pressure gradient and speeds filling during early diastole. In addition to these factors, there
are two major categories of factors that can acutely
change the diastolic pressure-volume curve.
The first category of factors includes those that
alter the extent of relaxation from the previous
systole, such as demand-induced ischemia. This
type of ischemia impairs active uptake of calcium
from the cytosol which yields a higher resting
concentration of calcium in the sarcomeres during
diastole and a smaller apparent equilibrium volume
for the ventricle. This smaller equilibrium volume
means that the strains (and, hence, stresses) within
the wall of the heart will be higher for any given
volume of the left ventricle than before ischemia, so
there will be a higher pressure at any given volume.
The second category of factors that alter the
diastolic pressure-volume curve includes those that
alter the external mechanical environment in which
the left ventricle resides, in particular, the other
cardiac chambers, the pericardium, and contact
pressure with the lungs. Interventions such as vasodilation and vasoconstriction alter the forces that
these other components exert on the left ventricle.
Since the pressure within the left ventricular cavity
represents the net effect of the forces within the
myocardium and those outside it, changes in these
external forces are reflected in pressure changes
within the left ventricle at any given volume, and
therefore shift the diastolic pressure-volume curve.
These changes in the diastolic pressure-volume
curve have several important implications for systolic function. First, when the end-systolic volume
is below the left ventricle's equilibrium volume, the
myocardial wall is put into compression and stores
elastic energy during systole (just as compressing a
847
spring stores energy). This energy is released when
the myocardium relaxes and acts to reduce the
ventricular pressure, thus, increasing the atrioventricular pressure gradient during early diastole.
Increasing the atrioventricular pressure gradient
causes the ventricle to fill more rapidly which helps
maintain end-diastolic volume and, via the FrankStarling mechanism, systolic function. Second, shifts
in the diastolic pressure-volume relation in response
to vascular loading changes are essential in helping
the left ventricle maintain stroke volume during
vasodilation because these shifts maintain enddiastolic volume even though left ventricular enddiastolic pressure falls during vasodilation. Finally,
the fact that filling pressure and volume are not
uniquely related means that end-diastolic pressure
cannot be used as a surrogate for end-diastolic
volume when assessing systolic function.
Acknowledgments
We thank William Parmley, Julien Hoffman, David
Teitel, Bryan Slinker, Chester Boltwood, Robert
Appleyard, Mimi Zeiger, and the referees for their
helpful criticisms of this manuscript.
References
1. Hood WB Jr, Bianco JA, Kumar K, Whiting RB: Experimental myocardial infarction IV. Reduction of left ventricular compliance in the healing phase. J Clin Invest 1970;
49:1316-1323
2. Bristow JD, van Zee BE, Judkins MP: Systolic and diastolic abnormalities of the left ventricle in coronary artery
disease: Studies in patients with little or no enlargement of
ventricular volume. Circulation 1970;17:219-229
3. Dwyer EM Jr: Left ventricular pressure-volume alterations
and regional disorders of contraction during myocardial
ischemia induced by atrial pacing. Circulation 1970;
42:1111-1122
4. McLaurin LP, Rolett EL, Grossman W: Impaired left
ventricular relaxation during pacing-induced ischemia. Am
JCardiol 1973^2:751-757
5. McCann LL, Parker JO, Butler J: Left ventricular pressurevolume relationship during myocardial ischemia in man.
Circulation 1973 ;48:775-785
6. Barry WH, Booker JZ, Alderman EL, Harrison DC:
Changes in diastolic stiffness and tone of the left ventricle
during angina pectoris. Circulation 1974;49:255-265
7. Alderman EL, Glantz SA: Acute hemodynamic interventions shift the diastolic pressure-volume curve in man.
Circulation 1976;54:662-671
8. Ludbrook PA, Byrne JD, McKnight RC: Influence of right
ventricular hemodynamics on left ventricular diastolic
pressure-volume relations in man. Circulation 1979^59:21—31
9. Stillwell GK: The law of Laplace: Some clinical applications. Mayo Clin Proc 1973;48:863
10. Sandier H, Dodge HT: Left ventricular tension and stress
in man. Circ Res 1963;13:91-104
11. Florenzano F, Glantz SA: Left-ventricular mechanical adaptations to chronic aortic regurgitation in intact dogs. Am J
Physiol 1987;252:H969-H984
12. Glantz SA: A three-element model describes excised cat
papillary muscle elasticity. Am J Physiol 1975 ;228:284-294
13. Glantz SA, Kernoff RS: Muscle stiffness determined from
canine left ventricular pressure-volume curves. Circ Res
1975;37:787-794
14. Nikolic' S, Yellin EL, Tamura K, Vetter H, Tamura T,
Meisner JS, Frater RWM: Passive properties of canine left
848
Circulation Research
Vol 64, No 5, May 1989
Downloaded from http://circres.ahajournals.org/ by guest on May 8, 2017
ventricle: Diastolic stiffness and resting forces. Circ Res
1988;62:12IO-1222
15. Grossman W, Jones D, McLaurin LP: Wall stress and
patterns of hypertrophy in the human left ventricle. J Clin
Invest 1975^6:56-64
16. Grossman W: Cardiac hypertrophy: Useful adaptation or
pathologic process? Am J Med 1980,69:576-584
17. Lorell B: Cardiac hypertrophy: The consequences for
diastole. J Am Coll Cardiol 1987;9:1189-1193
18. Rippe JM, Pape LA, Alpert JA, Ockene IS, Paraskos JA,
Kolilainen P, Anas J, Webster W: Studies of systolic
mechanics and diastolic behavior on the left ventricle in the
trained racing greyhound. Basic Res Cardiol l982;77:619-644
19. Fagard R, van den Broekle C, Bielen E, Vabhees L, Amery
A: Assessment of stiffness of the hypertrophied left ventricle of bicyclists using left ventricular inflow doppler velocimetry. J Am Coll Cardiol 1987;9:1250-1254
20. Grossman W, McLaurin LP, Stefadouros MA: Left ventricular stiffness associated with chronic pressure and volume overloads in man. Circ Res 1974;35:793-800
21. Nomura S: Diastolic property of left ventricle under experimental volume overload. Jpn Circ J 1986^0:426-432
22. Michel JB, Salzmann JL, Ossondo Nlom M, Bruneval P,
Barres D, Camilleri JP: Morphometric analysis of collagen
network and plasma perfused capillary bed in the myocardium of rats during evolution of cardiac hypertrophy. Basic
Res Cardiol 1986;81:142-154
23. Peterson KL, Tsuji J, Johnson A, DiDonna J, LeWinter M:
Diastolic left ventricular pressure-volume and stress-strain
relations in patients with valvular aortic stenosis and left
ventricular hypertrophy. Circulation 1978^8:77-89
24. Hess OM, Schneider J, Koch R, Bamert C, Grimm J,
Krayenbuehl HP: Diastolic function and myocardial structure in patients with myocardial hypertrophy: Special reference to normalized viscoelastic data. Circulation 1981;
63:360-371
25. Thiedemann KU, Holubarsch C, Medugorac I, Jacob R:
Connective tissue content and myocardial stiffness in pressure overload hypertrophy: A combined study of morphologic, morphometric, biochemical, and mechanical parameters. Basic Res Cardiol 1983 ;78:140-155
26. Weber KT, Janicki JS, Shroff SG, Pick R, Chen RM,
Bashey RI: Collagen remodeling of pressure-overload, hypertrophied nonhuman primate myocardium. Circ Res 1988;
62:757-765
27. Weiss JL, Frederiksen JW, Weisfeldt ML: Hemodynamic
determinants of the time-course of fall in canine left ventricular pressure. J Clin Invest 1976^8:751-760
28. Rushmer RF, Crystal DF, Wagner C: The functional anatomy of ventricular contraction. Circ Res 1953;3:633
29. Rushmer RF: Cardiac Diagnosis. Philadelphia/London,
WB Saunders Co, 1956
30. Sonnenblick EH: The structural basis and importance of
restoring forces and elastic recoil for the filling of the heart.
Eur Heart J l980;l(suppl A): 107-110
31. Yellin EL, Hori M, Yoran C, Sonnenblick EH, Gabbay S,
Frater RWM: Left ventricular relaxation in the filling and
nonfilling intact canine heart. Am J Physiol 1986;
25O:H62O-H629
32. Raff GL, Glantz SA: Volume loading slows left ventricular
isovolumic relaxation rate: Evidence of load-dependent
relaxation in the intact dog heart. Circ Res June 1981;
48:813-824
33. Thompson DS, Waldron CB, Coltart DJ, Jenkins BS,
Webb-Peploe MM: Estimation of time constant of left
ventricular relaxation. Br Heart J 1985;49:1426-1434
34. Paulus WJ, Lorell BH, Craig WE, Wynne J, Murgo JP,
Grossman W: Comparison of the effects of nitroprusside
and nifedipine on diastolic properties in patients with
hypertrophic cardiomyopathy: Altered left ventricular loading or improved muscle inactivation? J Am Coll Cardiol
1983^:879-886
35. Mirsky I: Assessment of diastolic function: Suggested methods and future considerations. Circulation 1984;69:836-841
36. Mann T, Brodie BR, Grossman W, McLaurin LT: Effect of
angina on the left ventricular diastolic pressure-volume
relationship. Circulation 1977 ;55:761-766
37. Mann T, Goldberg S, Mudge GH, Grossman W: Factors
contributing to altered left ventricular diastolic properties
during angina pectoris. Circulation 1979^9:14-20
38. Grossman W, Mann JT: Evidence for impaired left ventricular relaxation during acute ischemia in man. Eur J Cardiol
1978;7(suppl):239-249
39. Stein PD, Sabbah HN, Mazilli M, Anbe DT: Effect of
chronic pressure overload on the maximal rate of pressure
fall of the right ventricle. Chest 1980;78:10-15
40. Bourdillon PD, Paulus WJ, Serizawa T, Grossman W:
Effects of verapamil on regional myocardial diastolic function in pacing-induced ischemia in dogs. Am J Physiol 1986;
251:H834-H84O
41. Sasayama S, Nonogi H, Fujita M, Sakurai T, Wakabayashi
A, Kawai C, Eiho S, Kuwahara M: Analysis of asynchronous wall motion by regional pressure-length loops in
patients with coronary artery disease. J Am Coll Cardiol
1984;4:259-267
42. Carroll JD, Lang RM, Neumann AL, Borow KM, Rajfer
SI: The differential effects of positive inotropic and vasodilator therapy on diastolic properties in patients with
congestive cardiomyopathy. Circulation 1986;74:815-825
43. Palacios 1, Johnson RA, Newell JB, Powell WJ Jr: Left
ventricular end-diastolic pressure-volume relationship with
experimental acute global ischemia. Circulation 1976;
53:428-436
44. Smiseth OA, Refsum H, Junemann M, Sievers RE, Lipton
MJ, Carlsson E, Tyberg JV: Ventricular diastolic pressurevolume shifts during acute ischemic left ventricular failure
in dogs. J Am Coll Cardiol 1984^:966-977
45. Serizawa T, Carabello BA, Grossman W: Effect of pacinginduced ischemia on left ventricular diastolic pressurevolume relations in dogs with coronary stenoses. Circ Res
1980;46:430-439
46. Serizawa T, Vogel WM, Apstein CS, Grossman W: Comparison of acute alterations in left ventricular relaxation and
diastolic chamber stiffness induced by hypoxia and ischemia. J Clin Invest 198l;68:91-102
47. Paulus WJ, Serizawa T, Grossman W: Altered left ventricular diastolic properties during pacing-induced ischemia in
dogs with coronary stenosis potentiation by caffeine. Circ
Res 1982^0:218-227
48. Nayler WG, Williams A: Relaxation in heart muscle: Some
morphological and biochemical considerations. Eur J Cardiol 1978;7(suppl):35-5O
49. Nayler WG, Poole-Wilson PA, Williams A: Hypoxia and
calcium. J Mol Cell Cardiol 1979;11:683-706
50. Carroll JD, Hess OM, Hirzel HO, Krayenbuehl HP: Exerciseinduced ischemia: The influence of altered relaxation on early
diastolic pressures. Circulation l983;67:521-528
51. Serruys PW, Wyns W, Piscione F, de Feyter P, Hugenholtz
PG: Ejection, filling, and diastasis during transluminal
occlusion in man: Consideration on global and regional left
ventricular function, in Grossman W, Lorell BH (eds):
Diastolic Relaxation of the Heart. Boston, Martinus Nijhoff
Publishing, 1988, pp 255-280
52. Brutsaert DL, De Clerck NM, Goethals MA, Housmans
PR: Relaxation of ventricular cardiac muscle. J Physiol
1978 ;283:469-480
53. Chuck LHS, Goethals MA, Parmley WW, Brutsaert DL:
Load-insensitive relaxation caused by hypoxia in mammalian cardiac muscle. Circ Res 1981 ;48:797-803
54. Chuck LHS, Parmley WW: Caffeine reversal of lengthdependent changes in myocardial contractile state in the
cat. Circ Res l980;47:592-598
55. Schwartz A, Sordahl LA, Entman ML, Allen JC, Reddy
YS, Goldsetin MA, Luchi RJ, Wyborny LE: Abnormal
biochemistry in myocardial failure^ Am J Cardiol 1973;
32:407-422
56. Brodie BR, Chuck L, Klausner S, Grossman W, Parmley
WW: Effects of sodium nitroprusside and nitroglycerin on
Gilbert and Glantz Determinants of Diastole
57.
58.
59.
60.
61.
62.
Downloaded from http://circres.ahajournals.org/ by guest on May 8, 2017
63.
64.
65.
66.
67.
68.
69.
70.
71.
72.
73.
74.
75.
76.
tension prolongation of cat papillary muscle during recovery from hypoxia. Circ Res 1976^9:596-601
Glantz SA, Parmley WW: Factors which affect the diastolic
pressure-volume curve. Circ Res 1978;42:171—180
Frederiksen JW, Weiss JL, Weisfeldt ML: Time constant
of isovolumic pressure fall: Determinants in the working
left ventricle. Am J Physiol 1978;235:H701-H706
Gaasch WH, Bing OHL: Myocardial relaxation. I. Effect of
nitroprusside on the tension prolongation phenomenon. Am
J Physiol 1979;237:HI85-H190
Gaasch WH, Blaustein AS, Andrias CW, Donahue RP,
Avitall B: Myocardial relaxation. 11. Hemodynamic determinants of rate of left ventricular isovolumic pressure
decline. Am J Physiol 1980;239:Hl-H6
Karliner JS, LeWinter MM, Engler R, O'Rourke RA:
Pharmacologic and hemodynamic influences on the rate of
isovolumic left ventricular relaxation in the normal conscious dog. J Clin Invest 1977;60:511-521
Blaustein AS, Gaasch WH: Myocardial relaxation. HI.
Reoxygenation mechanics in the intact dog heart. Circ Res
1981;49:633-639
Weisfeldt ML, Frederiksen JW, Yin FCP, Weiss JL: Evidence of incomplete left ventricular relaxation in the dog. J
Clin Invest 1978;62:1296-1302
Weisfeldt ML, Weiss JL, Frederiksen JT, Yin FCP: Quantification of incomplete left ventricular relaxation: Relationship to the time constant for isovolumic pressure fall. Eur
Heart J 1980;l(suppl A):119-129
Granger CB, Karimeddini MK, Smith VE, Shapiro HR,
Katz AM, Riba AL: Rapid ventricular filling in left ventricular hypertrophy. I. Physiologic hypertrophy. J Am Coll
Cardiol 1985;5:862-868
Hanrath P, Mathey DG, Siegert R, Bleifeld W: Left ventricular relaxation and filling pattern in different forms of
left ventricular hypertrophy: An echocardiographic study.
Am J Cardiol 1980;45:15-23
Smith VE, Schulman P, Karimeddini MK, White WB,
Merran MK, Katz AM: Rapid ventricular filling in left
ventricular hypertrophy. II. Pathologic hypertrophy. J Am
Coll Cardiol 1985 ;5:869-874
Lorell BH, Paulus WJ, Grossman W, Wynne J, Cohen PF:
Modification of abnormal left ventricular diastolic properties by nifedipine in patients with hypertropnic cardiomyopathy. Circulation 1982;65:499-507
Alvares RF, Shaver JA, Gamble WH, Goodwin JF: Isovolumic relaxation period in hypertrophic cardiomyopathy.
J Am Coll Cardiol 1984^:71-81
Betocchi S, Bonow RO, Bacharach SL, Rosing DR, Maron
BJ, Green MV: Isovolumic relaxation period in hypertrophic cardiomyopathy: Assessment by radionuclide angiography. J Am Coll Cardiol 1986,7:74-81
Gwathmey JK, Morgan JP: Altered calcium handling in
experimental pressure-overload hypertrophy in the ferret.
Circ Res 1985^7:836-843
Morgan JP, Morgan KG: Calcium and cardiovascular function: Intracellular calcium levels during contraction and
relaxation of mammalian cardiac and vascular smooth
muscle as detected with aequorin. Am J Med 1984;
77(suppl 5A):33-46
Gwathmey JK, Copelas L, MacKinnon R, Schoen FJ,
Feldman MD, Grossman W, Morgan JP: Abnormal intracellular calcium handling in myocardium from patients with
end-stage heart failure. Circ Res 1987;61:70-76
Alyono D, Anderson RW, Parrish DG, Dai X, Bache RJ:
Alterations of myocardial blood flow associated with experimental canine left ventricular hypertrophy secondary to
valvular aortic stenosis. Circ Res 1986^8:47-57
Tomanek RJ, Palmer PJ, Peiffer GL, Schreiber KL, Eastham CL, Marcus ML: Morphometry of canine coronary
arteries, arterioles, and capillaries during hypertension and
left ventricular hypertrophy. Circ Res 1986,58:38-46
Bache RJ, Arentzen CE, Simon AB, Vrobel TR: Abnormalities in myocardial perfusion during tachycardia in dogs
849
with left ventricular hypertrophy: Metabolic evidence for
myocardial ischemia. Circulation 1984;69:409-417
77. Fifer MA, Bourdillon PD, Lorell BH: Altered left ventricular diastolic properties during pacing-induced angina in
patients with aortic stenosis. Circulation 1986;74:675-683
78. Diver DJ, Royal HD, Aroesty JM, McKay RG, Ferguson
JJ, Warren SE, Lorell BH: Diastolic function in patients
with aortic stenosis: Influence of left ventricular load reduction. J Am Coll Cardiol 1988;12:642-648
79. Hess OM, Ritter M, Schneider J, Grimm J, Turina M,
Krayenbuehl HP: Diastolic stiffness and myocardial structure in aortic valve disease before and after valve replacement. Circulation 1984;69:855-865
80. Sasayama S, Nonogi H, Miyazaki S, Sakurai T, Kawai C,
Eiho S, Kuwahara M: Changes in diastolic properties of the
regional myocardium during pacing-induced ischemia in
human subjects. J Am Coll Cardiol 1985^:599-606
81. Grossman W: Why is left ventricular diastolic pressure
increased during angina pectoris? J Am Coll Cardiol 1985;
5:607-608
82. Theroux P, Ross J Jr, Franklin D, Covell JW, Bloor CM,
Sasayama S: Regional myocardial function and dimensions
early and late after myocardial infarction in the unanesthetized dog. Circ Res 1977;40:158-165
83. Janz RF, Waldron RJ: Predicted effect of chronic apical
aneurysms on the passive stiffness of the human left ventricle. Circ Res 1978;42(2):255-263
84. Zile MR, Blaustein AS, Gaasch WH: In the normal left
ventricle catecholamine induced changes in filling rate are
mediated through changes in end systolic size (abstract).
Circulation 1985;72(suppl III):III-88
85. Hori M, Yellin EL, Sonnenblick EH: Left ventricular
diastolic suction as a mechanism of ventricular filling. Jpn
Circ] 1982;46:124-129
86. Bloom WL: Demonstration of diastolic filling of the beating
excised heart (motion picture) (abstract). Am J Physiol
1955,183:597
87. Bloom WL: Diastolic filling of the beating excised heart.
Am J Physiol 1956;187:143-144
88. Brecher GA: Critical review of recent work on ventricular
diastolic suction. Circ Res 1958;6:554-566
89. Tyberg JV, Keon WJ, Sonnenblick EH, Urschel CW:
Mechanics of ventricular diastole. Cardiovasc Res 1970;
4:423-428
90. SugaH, GotoY, Igarashi Y, YamadaO, NozawaT, Yasumura
Y: Ventricular suction under zero source pressure for filling.
Am J Physiol 1986;251:H47-H55
91. Hori M, Inoue M, Kitakaze M, Tsujioka K, Ishida Y, Jukunami M, Nakajima S, Kitabatake A, Abe H: Loading sequence
is a major determinant of afterioad-dependent relaxation in
intact canine heart. Am J Physiol 1985;249:H747-H754
92. Roberts WC, Brownlee WJ, Jones AA, Luke JL: Sucking
action of the left ventricle: Demonstration of a physiologic
principle by a gunshot wound penetrating only the right side
of the heart. Am J Cardiol 1979;43:1234-1237
93. Sabbah HN, Anbe DT, Stein PD: Negative intraventricular
diastolic pressure in patients with mitral stenosis: Evidence
of left ventricular diastolic suction. Am J Cardiol 1980;
45:562-566
94. Sabbah HN, Anbe ST, Stein PD: Can the human right
ventricle create a negative diastolic pressure suggestive of
suction? Cathet Cardiovasc Diagn 1981 ;7:259-267
95. Janicki JS, Weber KT: Factors influencing the diastolic
pressure volume relation of the cardiac ventricles. Fed
Proc 1980;39:133-140
96. Bove AA, Santamore WP: Ventricular interdependence.
Prog Cardiovasc Dis 1981 ;23:365-388
97. Glantz SA, Misbach GA, Moores WY, Mathey DG, Lekven
J, Stowe DF, Parmley WW, Tyberg JV: The pericardium
substantially affects the left ventricular diastolic pressurevolume relationship in the dog. Circ Res 1978;42:433-441
98. Lorell BH, Palacios I, Daggett WM, Jacobs ML, Fowler
BN, Newell JB: Right ventricular distension and left ventricular compliance. Am J Physiol 1981;240:H87-H98
850
Circulation Research
Vol 64, No 5, May 1989
Downloaded from http://circres.ahajournals.org/ by guest on May 8, 2017
99. Weber KT, Janicki JS, Shroff S, Fishman AP: Contractile
mechanics and interaction of the right and left ventricles.
Am J Cardiol 1981;47:686-695
100. Kingma I, Tyberg JV, Smith ER: Effects of diastolic
transseptal pressure gradient on ventricular septal position
and motion. Circulation 1983;68:1304-1314
101. Little WC, Badke FR, O'Rourke RA: Effect of right ventricular pressure on the end-diastolic left ventricular pressurevolume relationship before and after chronic right ventricular pressure overload in dogs without pericardia. Circ Res
1984^4:719-730
102. Sunagawa K, Maughan WL, Burkhoff D, Sagawa K: Left
ventricular interaction with arterial load studied in isolated
canine ventricle. Am J Physiol 1983,245:H773-H780
103. Slinker BK, Chagas ACP, Glantz SA: The importance of
direct ventricular interaction decreases in chronic pressure
overload hypertrophy in the dog. Am J Physiol 1987;
253:H347-H357
104. Parmley WW, Chuck L, Chatterjee K, Klausner SC, Glantz
SA, Ratshin RA: Acute changes in the diastolic pressurevolume relationship of the left ventricle. Eur J Cardiol
1976;4(suppl): 105-120
105. Brodie BR, Grossman W, Mann T, McLaurin LP: Effects
of sodium nitroprusside on left ventricular diastolic pressurevolume relations. J Clin Invest 1977^9:59-68
106. Ludbrook PA, Byrne JD, Kumik PB, McKnight RC: Influence of reduction of preload and afterload by nitroglycerin
on left ventricular diastolic pressure-volume relations and
relaxation in man. Circulation 1977^6:937-943
107. Ludbrook PA, Byrne JD, Reed FR, McKnight RC: Modification of left ventricular diastolic behavior by isometric
handgrip exercise. Circulation 1980;62:357-370
108. Shirato K, Shabetai R, Bhargava V, Franklin D, Ross J Jr:
Alteration of the left ventricular diastolic pressure-segment
length relation produced by the pericardium: Effects of
cardiac distension and afterload reduction in conscious
dogs. Circulation 1978,57:1191-1198
109. Ross J: Acute displacement of the diastolic pressurevolume curve of the left ventricle: Role of the pericardium
and the right ventricle (editorial). Circulation 1979^9:32-37
110. Ullrich KJ, Riecker G, Kramer K: Das Druckvolumdiagramm des Warmblueterherzens Isometrische Gleichgewichtskurven. Pflugers Arch l954;259:481-498
111. Taylor RR, Covell JW, Sonnenblick EH, Ross J JR: Dependence of ventricular distensibility in filling of the opposite
ventricle. Am J Physiol 1967;213:711-718
112. Bemis CE, Serur JR, Borkenhagen D, Sonnenblick EH,
Urschel CW: Influence of right ventricular filling pressure
on left ventricular pressure and dimension. Circ Res 1974;
34:498-504
113. Elzinga G, van Grondelle R, Westerhof N, van den Bos
GC: Ventricular interference. Ami Physiol 1974^26:941-947
114. Santamore WP, Lynch PR, Meier G, Heckman J, Bove
AA: Myocardial interaction between the ventricles. J Appl
Physiol l976;41:362-368
115. Santamore WP, Shaffer TH, Hughes D: A theoretical and
experimental model of ventricular interdependence. Basic
Res Cardiol 1986;81:529-538
116. Janicki JS, Weber KT: The pericardium and ventricular
interaction, distensibility, and function. Am J Physiol 1980;
238:H494-H503
117. Stool EW, Mulloins CB, Leshin SJ, Mitchell JH: Dimensional changes of the left ventricle during acute pulmonary
arterial hypertension in dogs. Am J Cardiol 197433:868-875
118. Molaug M, Geiran O, Kiil F: Dynamics of the interventricular septum and free ventricular walls during selective left
ventricular volume loading in dogs. Ada Physiol Scand
1983;119:81-89
119. Olsen CO, Tyson GS, Maier GW, Spratt JA, Davis JW,
Rankin JS: Dynamic ventricular interaction in the conscious dog. Circ Res 1983^2:85-104
120. Visner MS, Arentzen CE, O'Connor MJ, Larson EV,
Anderson RW: Alterations in left ventricular threedimensional dynamic geometry and systolic function during
acute right ventricular hypertension in the conscious dog.
Circulation 1983;67:353-365
121. Slinker BK, Glantz SA: End-systolic and end-diastolic
ventricular interaction. Am J Physiol 1986;251 :H 1062-H1075
122. Ruskin J, Bache RJ, Rembert JC, Greenfield JC Jr: Pressureflow studies in man: Effect of respiration on left ventricular
stroke volume. Circulation 1973;48:79-85
123. Elzinga G, Piene H, De Jong JP: Left and right ventricular
pump function and consequences of having two pumps in
one heart. Circ Res 1980;46:564-574
124. Boltwood CM Jr: Ventricular performance related to transmural filling pressure in clinical cardiac tamponade. Circulation 1987;75:941-955
125. Slinker BK, Ditchey RV, Bell SP, LeWinter MM: Right
heart pressure does not equal pericardial pressure in the
potassium chloride-arrested canine heart in situ. Circulation l987;76:357-362
126. Tyberg JV, Misbach GA, Parmley WW, Glantz SA: Effects
of the pericardium on left ventricular performance, in Baan
J, Amtzenius AC, Yellin EL (eds): Cardiac Dynamics. The
Hague/Boston/London, Martinus Njjhoff Publishing, 1987,
pp 159-168
127. Tyberg JV, Taichman GC, Smith ER, Douglas MWS,
Smiseth OA, Keon WJ: The relationship between pericardial pressure and right atrial pressure: An intraoperative
study. Circulation 1986,73:428-432
128. Mirsky I, Rankin JS: The effects of geometry, elasticity,
and external pressures on the diastolic pressure-volume
and stiffness-stress relations: How important is the pericardium? Circ Res 1979;44:601-611
129. Hort W: Herzbeutel und Herzgroesse. Arch Kreislaufforsch 1964;44:21-35
130. Maruyama Y, Ashikawa K, Isoyama S, Kanatsuka H,
Ino-Oka E, Takishima T: Mechanical interactions between
four heart chambers with and without the pericardium in
canine hearts. Circ Res 1982;50:86-100
131. Spadaro J, Bing OHL, Gaasch WH, Weintraub RM: Pericardia! modulation of right and left ventricular diastolic
interaction. Circ Res 1981 ;48:233-238
132. Stokland O, Miller MM, Lekven J, Ilebekk A: The significance of the intact pericardium for cardiac performance in
the dog. Circ Res 1980;47:27-32
133. Robotham JL, Mitzner W: A model of the effects of
respiration on left ventricular performance. J Appl Physiol
1979;46:411-418
134. Robotham JL, Rabson J, Permutt S, Bromberger-Bamea B:
Left ventricular hemodynamics during respiration. J Appl
Physiol W9;47:1295-1303
135. Smiseth OA, Kingma I, Refsum H, Smith ER, Tyberg JV:
The pericardial hypothesis: A mechanism of acute shifts of
the left ventricular diastolic pressure-volume relation. Clin
Physiol 1985^:403-415
136. Smiseth OA, Frais MA, Kingma I, Smith ER, Tyberg JV:
Assessment of pericardial constraint in dogs. Circulation
1985;71:158-164
137. Tyson GS Jr, Maier GW, Olsen CO, Davis JW, Rankin JS:
Pericardial influences on ventricular filling in the conscious
dog: An analysis based on pericardial pressure. Circ Res
1984^4:173-184
138. Holt JP, Rhode EA, Kines H: Pericardial and ventricular
pressure. Circ Res 1960,8:1171-1181
139. Wood EH, Nolan AC, Donald DE: Technics for Measurement of Intrapleural and Pericardial Pressures in Dogs
Studied Without Thoracotomy and Methods for Their Applications to Study of Intrathoracic Pressure Relationships
During Exposure to Forward Acceleration (+Gx). Technical Document Rep AMRL-TDR-63-107. Wright-Patterson
Air Force Base, Ohio, US Air Force 6570 Aerospace
Medical Research Laboratory, 1963, pp 1-12
140. Kenner HM, Wood EH: Intrapericardial, intrapleural, and
intracardiac pressures during acute heart failure in dogs
studied without thoracotomy. Circ Res 1966;19:1071-1079
141. Smiseth OA, Frais MA, Kingma I, White AVM, Knudtson
ML, Cohen JA, Manyari DE, Smith ER, Tyberg JV:
Gilbert and Glantz
Downloaded from http://circres.ahajournals.org/ by guest on May 8, 2017
Assessment of pericardial constraint: The relation between
right ventricular filling pressure and pericardia) pressure
measured after pericardiocentesis. J Am Coll Cardiol 1986;
7:307-314
142. Mann D, Lew W, Ban-Hayashi E, Shabetai R, Waldman L,
LeWinter MM: In vivo mechanical behavior of canine
pericardium. Am J Physiol 1986;251(pt 2):H349-H356
143. Gibbon JH Jr, Churchill ED: The mechanical influence of
the pericardium upon cardiac function. J Clin Invest 1931;
10:405-422
144. Cunningham JN Jr, Spencer FC, Zeff R, Williams CD,
Cukingham R, Mullin M: Influence of primary closure of
the pericardium after open-heart surgery on the frequency
of tamponade, postcardiotomy syndrome, and pulmonary
complications. J Thorac Cardiovasc Surg 1975;70:119-125
145. Boltwood CM Jr, Shah PM: The pericardium in health and
disease. Curr Probl Cardiol 1984;9:1-70
146. Smiseth OS, Refsum H, Tyberg JV: Pericardial pressure
assessed by right atrial pressure: A basis for calculation of
left ventricular transmural pressure. Am Heart J 1984;
IO8(pt l):603-605
147. Santamore WP, Constantinescu M, Little WC: Direct assessment of right ventricular transmural pressure. Circulation
1987;75:744-747
148. Boltwood CM Jr, Slutsky A, Drinkwater DC Jr, Lang S,
Mulder DG, Shah PM: Intraoperative measurement of
pericardial constraint: Role in ventricular diastolic mechanics. J Am Coll Cardiol 1986;8:1289-1297
149. Reddy PS, Curtiss EJ, O'Toole JD, Shaver JA: Cardiac
tamponade: Hemodynamic observations in man. Circulation 1978^8:265-272
150. Freeman GL, LeWinter MM; Pericardial adaptations during chronic cardiac dilation in dogs. Circ Res 1984;
54:294-300
151. LeWinter MM, Pavelec R: Influence of the pericardium on
left ventricular end-diastolic pressure-segment relations
during early and later stages of experimental chronic volume overload in dogs. Circ Ress 1982^0:501-509
152. Lee JM, Boughner DR: Tissue mechanics of canine pericardium in different test environments. Circ Res 1981;
49:533-544
153. Lee MC, LeWinter MM, Freeman GL, Shabetai R, Fung
YC: Biaxial mechanical properties of the pericardium in
normal and volume overload dogs. Am J Physiol 1985;
249(pt 2):H222-H230
154. Goldstein JA, Vlahakes GJ, Verrier ED, Shiller NB, Tyberg
JV, Ports TA, Parmley WW, Chatterjee K: The role of right
ventricular systolic dysfunction and elevated intrapericardial pressure in the genesis of low output in experimental
right ventricular infarction. Circulation 1982;65:5l3-522
155. Goldstein JA, Vlahakes GJ, Verrier ED, Shiller NB, Botvinick E, Tyberg JV, Parmley WW, Chatterjee K: Volume
loading improves low cardiac output in experimental right
ventricular infarction. J Am Coll Cardiol 1983;2:270-277
156. Cournand A, Motley HL, Werko L, Richards DW Jr:
Physiological studies of the effects of intermittent positive
pressure breathing on cardiac output in man. Am J Physiol
I948;I52:I62-I74
157. Powers SR, Manna! R, Neclerio M, English M, Marr C,
Leather R, Ueda H, Williams G, Custead W, Dutton R:
Physiologic consequences of positive end-expiratory pressure (PEEP) ventilation. Ann Surg 1973,178:265-272
158. Smith PK, Tyson GS Jr, Hammon JW Jr, Olsen CO,
Hopkins RA, Maier GW, Sabiston DC Jr, Rankin JS:
Cardiovascular effects of ventilation with positive expiratory airway pressure. Ann Surg I982;195:121—130
159. Dorinsky PM, Whitcomb ME: The effect of PEEP on
cardiac output. Chest 1983;84:2I0-216
160. Robotham JL, Lixfeld W, Holland L, MacGregor J, Bryan
AC, Rabson J: Effects of respiration on cardiac performance. J Appl Physiol 1978;44:703-709
161. Robotham JL, Wise RA, Bromberger-Barnea B: Effects of
changes in abdominal pressure on left ventricular perfor-
162.
163.
164.
165.
166.
167.
168.
169.
170.
171.
172.
173.
174.
175.
176.
177.
178.
179.
180.
181.
182.
183.
184.
185.
Determinants of Diastole
851
mance and regional blood flow. Crit Care Med 1985;
13:803-809
Scharf SM, Brown R, Tow DE, Parisi AF: Cardiac effects
of increased lung volume and decreased pleura] pressure in
man. J Appl Physiol 1979;47:257-262
Scharf SM, Bianco JA, Tow DE, Brown R: The effects of
large negative intrathoracic pressure on left ventricular
function in patients with coronary artery disease. Circulation 1981;63:871-875
Fewell JE, Abendschein DR, Murray JF, Rapaport E:
Continuous positive-pressure ventilation decreases right
and left ventricular end-diastolic volumes in the dog. Circ
Res 1980;46:125-132
Fewell JE, Abendschein DR, Carlson CJ, Rapaport E,
Murray JF: Mechanism of decreased right and left ventricular end-diastolic volumes during continuous positivepressure ventilation in dogs. Circ Res 1980;47:467-472
Fewell JE, Abendschein DR, Carlson CJ, Rapaport E,
Murray JF: Am J Physiol 1981;240:H821-H826
Santamore WP, Heckman JL, Bove AA: Cardiovascular
changes from expiration to inspiration during IPPV. Am J
Physiol 1983;245:H307-H312
Santamore WP, Bove AA, Heckman JL: Right and left
ventricular pressure-volume response to positive endexpiratory pressure. Am J Physiol 1984;246:H114-H119
Santamore WP, Heckman JL, Bove AA: Right and left
ventricular pressure-volume response to respiratory maneuvers. J Appl Physiol 1984^7:1520-1527
Wallis TW, Robotham JL, Compean R, Kindred MK:
Mechanical heart-lung interaction with positive endexpiratory pressure. J Appl Physiol 1983^4:1039-1047
Cassidy SS, Ramanathan M: Dimensional analysis of the
left ventricle during PEEP: Relative septal and lateral wall
displacements. Am J Physiol 1984;246:H792-H805
Olsen CO, Tyson GS, Maier GW, Davis JW, Rankin JS:
Diminished stroke volume during inspiration: A reverse
thoracic pump. Circulation l985;72:668-679
Calvin JW, Baer RW, Glantz SA: Pulmonary injury
depresses cardiac systolic function through starling mechanism. Am J Physiol 1986^51 :H722-H733
Krayenbuehl HP, Rurina J, Hess O: Left ventricular function in chronic pulmonary hypertension. Am J Cardiol
1978;41:l 150-1158
Marini JJ, Culver BH, Butler J: Effect of positive endexpiratory pressure on canine ventricular function curves.
J Appl Physiol 1981 ^ 1:1367-1374
Pinto JG, Fung YC: Mechanical properties of the heart
muscle in the passive state. J Biomech I973;6:597-616
Glantz SA: A constitutive equation for the passive properties of muscle. J Biomech I974;7:137-145
Noble M1M, Milne ENC, Goerke RJ, Carlsson E, Domenech
RJ, Saunders KB, Hoffman JIE: Left ventricular filling and
diastolic pressure-volume relations in the conscious dog.
Circ Res l%9;24:269-283
Templeton GH, Ecker RR, Mitchell JH: Left ventricular
stiffness during diastole and systole: The influence of changes
in volume and inotropic state. Cardiovasc Res 1972;6:95-100
Templeton GH, Donald TC HI, Mitchell JH, Hefner LL:
Dynamic stiffness of papillary muscle during contraction
and relaxation. Am J Physiol 1973^24:692-698
Templeton GH, Nardizzi LR: Elastic and viscous stiffness
of the canine left ventricle. J Appl Physiol 1974;36:123-127
Templeton GH, Wildenthal K, Willerson JT, Mitchell JH:
Influence of acute myocardial depression on left ventricular
stiffness and its elastic and viscous components. J Clin
Invest 1975^6:278-285
Gaasch WH, Cole JS, Quinones MA, Alexander JK:
Dynamic determinants of left ventricular diastolic pressurevolume relationship in man. Circulation 1975^1:317-323
Kennish A, Yellin E, Frater RW: Dynamic stiffness profiles
in the left ventricle. Am J Physiol 1975,39:665-671
Rankin JS, Arentzen CE, McHale PA, Ling D, Anderson
RW: Viscoelastic properties of the diastolic left ventricle in
the conscious dog. Circ Res 1977;4l:37-45
852
Circulation Research
Vol 64, No 5, May 1989
Downloaded from http://circres.ahajournals.org/ by guest on May 8, 2017
186. Hess OM, Grimm J, Krayenbuehl HP: Diastolic simple
elastic and viscoelastic properties of the left ventricle in
man. Circulation 1979;59:1178-1187
187. Pouleur H, Karliner JS, LeWinter MM, Covell JW: Diastolic viscous properties of the intact canine left ventricle.
Circ Res 1979,45:410-419
188. Pasipoularides A, Mirsky I, Hess OM, Grimm J, Krayenbuehl HP: Myocardial relaxation and passive diastolic
properties in man. Circulation 1986;74:991-1001
189. Slinker BK, Glantz SA: The accuracy of inferring left
ventricular volume from dimension depends on the frequency of information needed to answer a given question.
Circ Res 1985^6:161-174
190. Hoffman BF, Bassett AL, Bartelstone HJ: Some mechanical properties of isolated mammalian cardiac muscle. Circ
Res 1968;23:291-312
191. Noble MIM: The diastolic viscous properties of cat papillary muscle. Circ Res 1977;40:288-292
192. Fioretti P, Broer RW, Meester GT, Serruys PW: Interaction of left ventricular relaxation and filling during early
diastole in human subjects. Am J Cardiol 1980;46:197-203
193. Salisbury PF, Cross CE, Rieben PA: Influence of coronary
artery pressure upon myocardial elasticity. Circ Res 1960;
8:794-800
194. Olsen CO, Rankin JS, Arentzen CE, Ring WS, McHale PA,
Anderson RW: The deformational characteristics of the left
ventricle in the conscious dog. Circ Res 1981;49:843-855
195. Gaasch WH, Bernard SA: The effect of acute changes in
coronary blood flow on left ventricular end-diastolic wall
thickness: An echocardiographic study. Circulation 1977;
56:593-597
1%. Gaasch WH, Bing OHL, Franklin A, Rhodes D, Bernard
SA, Weintraub RM: The influence of acute alterations in
coronary blood flow on left ventricular diastolic compliance
and wall thickness. Euro J Cardiol I978;7(suppl): 147-161
197. Abel RM, Reis RL: Effects of coronary blood flow and
perfusion pressure on left ventricular contractility in dogs.
Circ Res I97O;27:%1-971
198. Arnold G, Kosche K, Meissner E, Netzert A, Lochner W:
The importance of the perfusion pressure in the coronary
arteries for the contractility and the oxygen consumption of
the heart. Pflugers Arch 1968;299:339-356
199. Templeton GH, Wildenthal K, Mitchell JH: Influence of
coronary blood flow on left ventricular contractility and
stiffness. Am J Physiol 1972;223:1216-1220
200. Spadaro J, Bing OHL, Gaasch WH, Laraia P, Franklin A,
Weintraub RM: Effects of perfusion pressure on myocardial performance, metabolism wall thickness, and compliance: Comparison of the beating and fibrillating heart. J
Thorac Cardiovasc Surg 1982,84:398-405
201. Vogel WM, Apstein CS, Briggs LL, Gaasch WH, Ahn J:
Acute alterations in left ventricular diastolic chamber stiffness role of the "Erectile" effect of coronary arterial
pressure and flow in normal and damaged hearts. Circ Res
1982^1:465-478
202. Watters TA, Bouchard A, Wu ST, Parmley WW, WickmanCoffelt J: Hydrodynamics in the heart modulates work.
Heart Vessels (in press)
203. Bouchard A, Watters TA, Wu S, Parmley WW, Stone RD,
Botvinick E, Sievers R, Jasmin G, Wickman-Coffelt J:
Effects of altered coronary perfusion pressure on function
and metabolism of normal and cardiomyopathic hamster
hearts. J Mol Cell Cardiol 1987;19 (in press)
204. Huyghe JMRJ: Non-linear finite element models of the
beating left ventricle and the intramyocardial coronary
circulation (PhD dissertation). Technical University, Eindhoven, The Netherlands, 1986
KEY WORDS • cardiac mechanics • relaxation • ischemia •
diastolic suction • viscoelasticity • ventricular interaction •
pericardium • cardiopulmonary interaction • left ventricle •
cardiac filling • coronary vascular engorgement
Determinants of left ventricular filling and of the diastolic pressure-volume relation.
J C Gilbert and S A Glantz
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Circ Res. 1989;64:827-852
doi: 10.1161/01.RES.64.5.827
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